Journal - Dolutegravir - Protocol

Protocol
Protocol for: Turkova A, White E, Mujuru HA, et al. Dolutegravir as first- or second-line treatment for HIV-1
infection in children. N Engl J Med 2021;385:2531-43. DOI: 10.1056/NEJMoa2108793
This trial protocol has been provided by the authors to give readers additional information about the work.
ODYSSEY
SUPPLEMENT
This supplement contains the following items:
1. Final protocol (version 6.0) with summary of protocol amendments (section 17, pages 80-91)
2. Original protocol (version 2.0)
3. Final statistical analysis plan (version 5.0) with summary of changes (pages 1-2)
4. Original statistical analysis plan (version 1.0)

ODYSSEY (PENTA 20):
A randomised trial of dolutegravir
(DTG)-based antiretroviral therapy vs.
standard of care (SOC) in children with
HIV infection starting first-line or
switching to second-line ART.
Version: 6.0
Date: 8th November 2019
ISRCTN #: ISRCTN91737921
EUDRACT #: 2014-002632-14
NCT #: NCT02259127
Authorised by:
Name: Professor Ian Weller

Role: Chair ODYSSEY Trial Steering Committee
Signature:
Name: Professor Carlo Giaquinto

Role: Chair, PENTA Foundation
Signature:

ODYSSEY Protocol
Version 6.0 8th November 2019
GENERAL INFORMATION
The trial will be co-ordinated and monitored by the UK Medical Research Council (MRC) Clinical Trials
Unit at University College London (UCL), (hereafter referred to as MRC CTU) in collaboration with
INSERM-ANRS SC10-US019, France (INSERM-ANRS) and the Program for HIV Prevention and
Treatment, Thailand (PHPT). Liaison between these Clinical Trials Units (CTUs) and clinical centres in
each country will be similar to that organised for other trials conducted by the Paediatric European
Network for the treatment of AIDS (PENTA), with a combination of direct liaison with a CTU (see
Section 2.3) and liaison via a local co-ordinating centre. Clinical centres in South Africa, Uganda and
Zimbabwe will be coordinated by MRC CTU; clinical centres in US, Uganda and South Africa joining the
trial from the International Maternal Pediatric Adolescent AIDS Clinical Trials Network (IMPAACT, US)
will also be coordinated through MRC CTU. The trial will be supervised by the ODYSSEY Trial
Management Group (TMG) who will report to the ODYSSEY Trial Steering Committee (TSC) (see
Appendix XVII for the committee structure within PENTA). The TSC may decide to terminate the trial
for any reason including the recommendation of the Independent Data Monitoring Committee
(IDMC).
This document was constructed using the MRC CTU Protocol Template Version 7.0. The CTU
endorses the Standard Protocol Items: Recommendations For Interventional Trials (SPIRIT) initiative.
It describes the
ODYSSEY (PENTA 20): trial, coordinated by the MRC CTU, INSERM-ANRS and PHPT, and provides
information about procedures for entering participants into it. The protocol should not be used as
an aide-memoire or guide for the treatment of other children or young people with HIV infection.
Every care was taken in drafting this protocol, but corrections or amendments may be necessary.
These will be circulated to the registered investigators in the trial, but centres entering participants
for the first time are advised to contact one of the co-ordinating CTUs to confirm they have the most
up-to-date version. Clinical problems relating to this trial should be addressed with the relevant CTU.
COMPLIANCE
The trial will be conducted in compliance with the approved protocol, the Declaration of Helsinki
2013, the principles of Good Clinical Practice (GCP) as laid down by the ICH topic E6 (R2),
Commission Clinical Trials Directive 2005/28/EC* with the implementation in national legislation in
the UK by Statutory Instrument 2004/1031 and subsequent amendments, General Data Protection
Regulation and the UK Data Protection Act 2018 (DPA number: Z6364106), and the UK Policy
Framework for Health and Social Care Research.
*Until the Clinical Trials Regulation EU No 536/2014 becomes applicable, the trial will be conducted
in accordance with the Clinical Trials Directive as implemented in the UK statutory instrument. When
the directive is repealed on the day of entry into application of the Clinical Trial Regulation the trial
will work towards implementation of the Regulation (536/2014) following any transition period.
SPONSOR
Paediatric European Network for Treatment of AIDS (PENTA) Foundation is the trial Sponsor and has
delegated responsibility for the overall management of the
ODYSSEY (PENTA 20): trial to the MRC CTU at UCL, INSERM-ANRS and PHPT. Queries relating to
Penta sponsorship of this trial should be addressed to Carlo Giaquinto, Chair of Penta
Foundation, Torre di Ricerca Pediatrica, Corso Stati Uniti 4, Padova, 35127, Italy.
CHIEF INVESTIGATORS
Dr Pablo Rojo, Hospital 12 de Octubre, Madrid, Spain
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ODYSSEY Protocol
Professor Diana M Gibb, MRC CTU at UCL, London, UK
FUNDING
This study is funded by ViiV Healthcare. MRC CTU at UCL and INSERM SC10 are supported by the MRC
(UK) and INSERM-ANRS (France) respectively. INSERM-ANRS supports the trial in France. PENTA
Foundation and EuroCoord provide support to sites in Europe.
AUTHORISATIONS AND APPROVALS

This trial will be submitted for approval by Research Ethics Committees/Institutional Review Boards
and by all required regulatory authorities in each of the participating countries.
TRIAL REGISTRATION
This trial has been registered with EudraCT, ISRCTN and Clinicaltrials.gov.
RANDOMISATIONS
For those sites randomising directly, training will be provided for DIRECT
RANDOMISATION ONLINE as part of the site initiation and database training. Individual
passwords will be provided.
Alternatively, sites can fax or send by password protected email the Randomisation CRF to
the relevant CTU:
MRC CTU, Monday to Friday 09:00 to 17:00
Tel: +44 (0) 20 7670 4786
Fax: +44 (0) 20 7670 4814
Email: mrcctu.trial-odyssey@ucl.ac.uk
Inserm-ANRS, Monday to Friday 09:00 to 17:00

Tel: + 33 1 45 59 50 83 / 52 55
Fax: + 33 1 46 58 72 93
Email: penta.sc10@inserm.fr
PHPT, Monday to Friday 09:00 to 18:00

Tel: +66 (0) 53 814 633 240 910-12 ext. 710316
Fax: +66 53 240 913814 269
Email: suwalai.chalermpantmetagul@phpt.org
SAE REPORTING
Within 24 hours of becoming aware of an SAE, please fax or email a
completed Event form to the relevant CTU. Please ensure that an acknowledgment of
receipt by the CTU is received.
MRC CTU: fax: +44 (0) 20 7670 4814 or email: mrcctu.trial-odyssey@ucl.ac.uk
Inserm-ANRS: fax: + 33 1 46 58 72 93 or email: penta.sc10@inserm.fr
PHPT: fax: +66 53 240 913 or email: suwalai.chalermpantmetagul@phpt.org
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ODYSSEY Protocol
SPONSOR
PENTA FOUNDATION, ITALY: PENTA Foundation

Torre della Ricerca Pediatrica Corso Stati Uniti 4
Padova, 35127, Italy
Tel: +39 049 821 5447
STAFF:
Chair: Carlo Giaquinto
Project Tiziana Grossele
Managers: Giulio Vecchia
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ODYSSEY Protocol
TRIAL ADMINISTRATION AND MAIN CONTACTS

Please direct all queries to the relevant CTU (see contacts below) in the first instance; clinical queries
will be passed to the Medical Experts via the MRC CTU Trial Manager.
MRC CTU, UK: MRC CTU at UCL

Institute of Clinical Trials & Methodology
90 High Holborn, 2nd Floor
London, WC1V 6LJ, UK
Tel: +44 (0) 207 670 4700
STAFF:
Programme Lead: Diana M Gibb, MD, MSc
Clinical Project Manager: Clare Shakeshaft, BA, MSc
Trial Managers: Tatiana Sarfati, BSc, MSc
Shabinah Ali, BSc, MSc
Data Managers: Anne Marie Borges Da Silva, BSc
Rachel Oguntimehin, BSc
Trial Statistician: Debbie Ford, PhD
Statisticians: Ben Wynne, BSc, Msc
Ellen White, BSc, MSc
Trial Physician: Anna Turkova, MRCPCH
SITES:
Participating PENTA Centres in:
Germany, UK, (as listed on www.penta-id.org)
Collaborating Centres
Thanyawee Puthanakit, MD The HIV Netherlands Australia Thailand Research
Collaboration (HIV-NAT), 104 Ratchadamri Road,
Pathumwan, Bangkok 10330, Thailand
James Gita Hakim, FRCP University of Zimbabwe Clinical Research Centre
Kusum Nathoo, MBChB, MRCP, MSc (UZCRC),
Hilda Angela Mujuru, MBChB, MMed, Box A1578 Avondale, Harare, Zimbabwe
MSc
Mutsa Bwakura-Dangarembizi, MBChB,
MMed, MSc
Cissy Kityo Mutuluuza, MSc, MBChB Joint Clinical Research Centre (JCRC),Plot 101
Victor Musiime, MBChB, MMED, PhD Lubowa Estates, off Entebbe road, Kampala,
Elizabeth Kaudha, MBChB, MMED Uganda
Abbas Lugemwa MBChB Joint Clinical Research Centre (JCRC), Mbarara, P.O
Box 40, Mbarara Regional referral Hospital,
Mbarara, Uganda
Adeodata Kekitiinwa MBChB MMED Baylor College of Medicine Bristol Myers Squibb
Children’s Clinical Centre of Excellence, Block 5,
Mulago Hospital, P.O. Box 72052, Kampala, Uganda
Mark F. Cotton, FCPaed (SA), M.Med Family Clinical Research Unit (FAM-CRU),
(Paed), PhD, DCH (SA), DTM&H University of Stellenbosch, Tygerberg Children’s
Hospital, Ward J8, Francie van Zijl Avenue, Parow,
7505, Cape Town, South Africa
Avy Violari, MD, FCPaed (SA) Chris Hani Baragwanath Hospital: Perinatal HIV
Research Unit, Chris Hani Baragwanath Hospital,
ODYSSEY (PENTA 20) Page v

ODYSSEY Protocol
P.O. Box 114, Diepkloof, 1864, Soweto, South

Africa
Perinatal HIV Research Unit, Klerksdorp/Tsepong

Hospital Complex
Matlosana, South Africa
Moherndran Archary MBChB. DCH(SA). Durban International Clinical Research Site,
FCPaeds(SA). Paeds ID (SA) Parkhome, Gate 1-King Edward VIII Hospital,
Umbilo Road, Congella, Durban, KwaZulu-Natal,
4013, South Africa
Ward D1, Wentworth Hospital, Sidmouth Avenue

Wentworth, Durban, 4052, South Africa
Nigel Klein, BSc, MBBS, MRCP, PhD, Africa Health Research Institute (AHRI),
FRCPCH Hlabisa Hospital, 60 Saunders Street,
Hlabisa 3937, South Africa
INSERM-ANRS, FRANCE: 16 Avenue Paul Vaillant Couturier

Villejuif Cedex, 94807, France
Tel: +33 1 4559 5290
STAFF:
Project leader: Alexandra Compagnucci, MD
Trial Managers: Yoann Riault, MSc
Alexandra Coelho, PhD
Christelle Koukam
Senior Trial Yacine Saidi, PhD
Manager:
SITES:
Portugal, and Spain (as listed on www.penta-id.org)
PHPT, THAILAND: PHPT/IRD

195 (3rd-4th Floor), Kaew Nawarat Rd.,
Muang, 50000 Chiang Mai, Thailand
Tel: + 66 (0) 5324 0910-12
Email: tim.cressey@phpt.org
STAFF:
Project leader: Tim Cressey, PhD
Trial Manager: Suwalai Chalermpantmetagul, RN, MPH
Trial Physician Gonzague Jourdain, MD, PhD
Specialist:
Thai Site Leader: Chaiwat Ngampiyasakul, MD
Trial virologist Woottichai Khamduang, PhD
Trial pharmacist Asst. Prof. Dujrudee Chinwong, M.Pharm, PhD
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ODYSSEY Protocol
SITES:
Participating PHPT Centres in:
Thailand:
Chaiwat Ngampiyaskul, MD Prapokklao Hospital, Chantaburi;
Pornchai Techakunakorn, MD Phayao Hospital, Phayao
Pradthana Ounchanum, MD Chiangrai Prachanukroh Hospital, Chiang Rai
Suparat Kanjanavanit, MD Nakornping Hospital, Chiang Mai
Ussanee Srirompotong, MD Khon Kaen Hospital, Khon Kaen;
Sathaporn Na-Rajsima, MD Mahasarakam Hospital, Mahasarakam
Woottichai Khamduang, PhD Faculty of Associated Medical Sciences, Chiang
Mai University
IMPAACT, US: IMPAACT Operations Center

FHI 360
359 Blackwell Street, Ste 200
Durham, NC27701, US
Email: IMPAACT.OperationsCenter@fstrf.org
STAFF:
Co-ordinator: Elaine Abrams, MD
Clinical Trials Katie McCarthy, MPH
Specialist:
SITES:
Collaborating Centres in:
Uganda
Linda N. Barlow-Mosha, MD, MPH, FAAP Makerere University – John Hopkins University
Philippa Musoke, MD Research Collaboration, Upper Mulago Hill Road,
MU-JHU Research House, Old Mulago Hill, P.O. Box
23491, Kampala, Uganda
Protocol expert: Pharmacology

864 Department of Clinical Pharmacy and Nijmegen Institute for Infection, Inflammation and
Immunity (N4i),
Radboud Univ, Nijmegen Med. Ctr. Nijmegen Geert Grooteplein 10, 6525 GA Nijmegen,
The Netherlands.
David Burger, PhD Email: david.burger@radboudumc.nl
Immunology/Virology Committee
Nigel Klein, BSc, MBBS, UCL Institute of Child Health, Email: n.klein@ucl.ac.uk
MRCP, PhD, FRCPCH London, UK
Anita De Rossi, PhD University of Padova, Italy Email: anita.derossi@unipd.it
Eleni Nastouli, FRCPCH, UCL Division of Infection & Immunity Email: e.nastouli@ucl.ac.uk
FRCPath
Maria Angeles Munoz Hospital General Gregorio Marañón, Email:
Fernandez, PhD Madrid, Spain mmunoz.hgugm@gmail.com
Other members to be confirmed
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SUMMARY OF TRIAL
SUMMARY INFORMATION TYPE SUMMARY DETAILS

ACRONYM ODYSSEY (Once daily dolutegravir based ART in young people vs.
standard therapy)
Long Title of Trial A randomised trial of dolutegravir (DTG)-based antiretroviral therapy
vs. standard of care (SOC) in children with HIV infection starting first-
line or switching to second-line ART (PENTA 20)
Version 5.0
Date 1st March 2019
ISRCTN # ISRCTN91737921
EudraCT # 2014-002632-14
NCT # NCT02259127
Study Design An open-label, multi-centre, randomised (1:1), non-inferiority, Phase
II/III, 96-week, 2-arm clinical trial to compare the efficacy and toxicity
of DTG plus 2 NRTI vs. standard of care (SOC) in HIV-infected children
aged less than 18 years who are starting first-line ART (ODYSSEY A) or
switching to second-line ART (ODYSSEY B).
Type of Participants to HIV-1 infected children younger than 18 years planning to start first-
be Studied line or second-line antiretroviral therapy
Setting International
Interventions to be DTG + 2 NRTI (DTG arm) vs. SOC (SOC arm) in first-line and second-line
Compared antiretroviral regimens
Study Hypothesis DTG + 2 NRTIs is non-inferior to SOC (NNRTI or bPI or INSTI + 2 or 3
NRTIs) in terms of efficacy and superior in terms of toxicity profile
Primary Outcome Difference in proportion with failure (clinical or virological) by 96
Measure(s) for the weeks, estimated using time to the first occurrence of any of the
Randomised Phase following components:
Insufficient virological response defined as <1 log10 drop at week
24 and switch to second/third line ART for treatment failure
Viral load (VL)≥400 c/ml at or after 36 weeks confirmed by next
visit
Death due to any cause
Any new or recurrent AIDS defining event (WHO 4) or severe WHO
3 event, adjudicated by the Endpoint Review Committee
Secondary Outcome Secondary efficacy outcomes:
Measure(s) for the Difference in proportion with clinical or virological failure (as
Randomised Phase defined above) by 48 weeks
Time to any new or recurrent AIDS defining event (WHO 4) or
severe WHO 3 event, confirmed by the Endpoint Review
Committee
Proportion of children with VL <50 c/ml at 48 and 96 weeks
Rate of clinical events over 96 weeks: WHO 4, severe WHO 3
events and death
Change in CD4 count, CD4 percentage and CD4 / CD8 ratio from
baseline to weeks 48 and 96
Proportion developing new resistance mutations
Secondary safety outcomes:
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ODYSSEY Protocol
Change in total cholesterol, triglycerides and lipid fractions (LDL,

HDL) from baseline to weeks 48 and 96. Change in total
cholesterol from baseline to week 96 will be used to formally
assess superiority of DTG arm vs SOC arm
Incidence of serious adverse events
Incidence of new clinical and laboratory grade 3 and 4 adverse
events
Incidence of adverse events (of any grade) leading to treatment
modification
Other secondary outcomes:
Quality of life
Adherence and acceptability
Randomisation Children starting first- and second-line ART will be randomised
separately (both in 1:1 ratio) :
ODYSSEY A (first-line ART):
DTG + 2 NRTIs
SOC (defined as NNRTI or bPI or INSTI + 2 or 3 NRTIs)
ODYSSEY B (second-line ART):
DTG + 2 NRTI
SOC (defined as NNRTI or bPI or INSTI+ 2 NRTIs)
Number of Participants 700 HIV-1 infected children, including 310 children starting first-line
to be Studied (ODYSSEY A) and 390 starting second-line ART (ODYSSEY B). At least
60 additional children weighing 3-<14kg will be enrolled in separate
strata.
Duration Participants will be enrolled in the main trial over 96-120 weeks; with
up to 78 weeks (July 2018 to end of 2019) to recruit participants
weighing 3-<14kg. Participants recruited in the main trial (≥14kg) will
be followed until the last recruited participant reaches week 96;
participants recruited weighing 3-<14kg will each be followed for a
minimum of 96 weeks.
Ancillary The following sub-studies will be performed in selected sites (see
Studies/Substudies Section 10 for participating countries):
TB-PK substudy will evaluate the pharmacokinetics of dolutegravir co-
administered with rifampicin in HIV/TB co-infected children.
Weight band PK substudies WB-PK1 and WB-PK2 will be undertaken
in children 3 to < 40 kg with the aims of simplifying doses and
formulations of DTG using WHO weight bands.
Immunology/virology substudy will explore mechanisms of CD4
reconstitution, immune activation, HIV reservoir and replication in
DTG and SOC arms.
Qualitative substudy will investigate how best to support children and
young people to maintain optimal adherence to second-line
treatment.
The Youth Trial Board will develop a model of meaningful engagement
and participation of adolescent patient representatives in paediatric
clinical trials.
Folate substudy will look at possible differences in folate and vitamin
B12 levels between the DTG and SOC arms
Sponsor PENTA Foundation
Funder Funded by ViiV Healthcare and the PENTA Foundation. MRC CTU at
UCL and INSERM SC10 are supported by the MRC (UK) and INSERM-
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ODYSSEY Protocol
ANRS (France) respectively; INSERM-ANRS supports the trial in France;

Eurocoord provide support for the sites in Europe
Partners MRC CTU at UCL, INSERM-ANRS, PHPT, IMPAACT, Eurocoord, PENTA
Chief Investigator Pablo Rojo and Diana M Gibb
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ODYSSEY Protocol
TRIAL SCHEMA
Note:
At least 60 additional children weighing 3-<14kg will be enrolled and followed up for 96 weeks
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ODYSSEY Protocol
TRIAL ASSESSMENT SCHEDULE FOR RANDOMISED PHASE OF THE TRIAL
Study visit at
end of
WEEK Screening Randomisation (2) 4 12 24 36 48 60 72 84 96 Further follow-up
randomised
0a
phase*
Patient information sheet and
X
consent for screening
Informed consent for trial
X
enrolment
History and clinical assessment b X X (X)t X X X X X X X X X Every 12 weeks X
Tanner scale c X X X X X Every 24 weeks X
Lipodystrophy assessment p X X X Every 48 weeks X
Drug supply to next visit X (X) X X X X X X X X X Every 12 weeks
HIV-1 RNA viral load d Xd (X) (X) (X) (X) (X) (X) (X) (X) (X) (X) (X) As per local practice Xd
T cell lymphocyte subsets e X X X X X (X) X (X) X (X) X As per local practice X
Biochemistry f X (X) (X)t X (X) X (X) X (X) X (X) X As per local practice X
Haematology g X X (X)t X (X) X (X) X (X) X (X) X As per local practice X
Lipids/glucose h Xo (X) X X Every 48 weeks X
Bone profile i (X) (X) (X) (Every 48 weeks) (X)
Urine dipstick j X X X Every 48 weeks X
Quality of Life questionnaire c X X X X X Every 48 weeks X
Pregnancy test k X Xk X X X X X X X X X X Every 12 weeks X
Plasma storage l, q X X (X) X X X X X X X X X Every 12 weeks X
(At next clinic visit if
Red blood cell folate (RBC)/RBC
X the 96 week sample
storage and B12/serum storage u
is not collected)
PBMC (Cell) storage m Xm Xm Xm Xm
Adherence questionnaire, q, r Xn X X X X X X X X X Every 12 weeks X
Acceptability, sleep & mood
Xs X X X X X X Every 24 weeks X
questionnaire q, r, v
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ODYSSEY Protocol
Notes:
( ) Optional, not mandatory.
* For participants recruited weighing ≥14kg this will be after the last participant reaches 96 weeks follow-up; for participants recruited weighing <14kg this
will be their 96 week visit which should be at or after 96 weeks. Participants receiving DTG 5mg in sites in sub-Saharan Africa (South Africa, Uganda and
Zimbabwe) and DTG 50mg or Triumeq in Thailand (at PHPT sites and HIV-NAT) at their study visit at the end of the randomised phase will be asked to
consent to extended follow-up in order to collect safety data so that DTG can continue to be provided to these participants. Other participants will also be
asked to consent to extended follow-up. Please see Appendix XX for more details.
Darker shaded boxes indicate visits where overnight fasting is required for blood lipids/glucose.
Up to 12 mls of blood may be collected at each visit for routine assays and tests plus an additional 8-18 mls blood may be collected for storage (plasma and
when requested, PBMCs). Total amounts drawn will depend upon the size of the child and their health, please refer to Appendix XI for the maximum
allowable blood-draw volumes for children.
a. Randomisation visit should take place within 4 weeks after the screening visit, ideally within 2 weeks
b. Clinical assessment: including height, weight (and adjustment of drug doses accordingly) and mid upper arm circumference (MUAC), change in HIV
disease stage, clinical events and presence of adverse events
c. In children aged 8 or over
d. Real-time viral loads will be measured on all children in ODYSSEY B at the screening visit, unless a viral load result of ≥500 c/ml dated within four weeks
of the screening visit is available. If such a result is not available it is mandatory that this test is done in ODYSSEY B participants. Please always ensure
that there is enough blood taken for this assay as it is a priority test at screening for ODYSSEY B. For children recruited in ODYSSEY A, this is not
mandatory. Thereafter in both ODYSSEY A and B, viral loads should be measured locally at sites according to the routine frequency, where viral loads
are not measured in real time, they will be run retrospectively in batches on stored plasma
e. CD4 and CD8 percentage and absolute, total lymphocyte count. In addition, immunophenotyping (IPT) on the same blood draw will be done at the sites
participating in the immunology/virology substudy, and where IPT tests are available. At the other sites IPT will be done on the cell storage samples.
f. Biochemistry: mandatory: creatinine, bilirubin, ALT; optional (if results are available or routinely done): AST
g. Haematology: Hb, MCV, WBC, lymphocytes, neutrophils, platelets
h. Lipids/Glucose: triglycerides, cholesterol (total, HDL, LDL), glucose (overnight fasting required at randomisation and weeks 24 and 48, and then every
48 weeks, and at the study visit at the end of the randomised phase)
i. Bone profile (optional): calcium, phosphate, alkaline phosphatase
j. Urine dipstick: for protein and glucose, performed at randomisation and then every 48 weeks and at end of study visit
k. Pregnancy test: urine sample; the test should be performed for all females of childbearing potential at screening, randomisation and all trial follow-up
visits and at other time-points if required.
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ODYSSEY Protocol
l. Plasma storage: for retrospective HIV-1 RNA viral load, resistance testing where not routinely available locally, sparse PK sampling, folate substudy and
immunology/virology substudy. See Appendix XII, Appendix XIII, Manual of Operations (MOP) and Lab MOP for more details. Samples may be assayed
locally, or moved to another country.
m. Peripheral blood mononuclear cells (PBMCs) will be stored at selected sites only, for use in the immunology/virology substudy. Please see Appendix XII,
MOP and Lab MOP for more details.
n. Baseline adherence questionnaire for patients screened for ODYSSEY B and currently taking their first-line treatment
o. The glucose test at the randomisation visit may be omitted if there is a medical justification (e.g. anaemia) to limit the total volume of blood drawn.
p. At selected sites bioelectrical impedance analysis (BIA) measurements will be done.
q. In case of attendance at an unscheduled visit at the point of treatment failure, plasma storage and adherence and acceptability questionnaires should
be done. (The acceptability questionnaire should also be done if treatment failure occurs at a scheduled visit where it is not normally done, e.g. week
36).
r. Adherence and acceptability questionnaires should also be completed if ART regimen is changed.
s. The mood and sleep section of the acceptability questionnaire should be completed at the enrolment visit.
t. Clinical assessment, haematology and biochemistry tests at week 2 are required for all children 3-<14kg and optional for children ≥14kg.
u. RBC storage for RBC folate levels and serum / serum storage for B12 levels for Folate/B12 substudy at selected sites only (see section 10.5). The bloods
will be taken from the same blood draw as used for plasma isolation and storage.
v. The sleep and mood section of the acceptability questionnaire should only be completed for participants aged 6 years and over.
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ODYSSEY Protocol
CONTENTS
GENERAL INFORMATION .............................................................................................................. II
SUMMARY OF TRIAL ................................................................................................................. VIII
TRIAL SCHEMA ........................................................................................................................... 11
TRIAL ASSESSMENT SCHEDULE FOR RANDOMISED PHASE OF THE TRIAL ...................................... 12
CONTENTS ................................................................................................................................. 15
ABBREVIATIONS......................................................................................................................... 20
1 BACKGROUND ............................................................................................................... 23
1.1 DTG ADULT TRIALS ............................................................................................................ 23
1.2 DTG IN CHILDREN .............................................................................................................. 24
1.3 FIRST- AND SECOND-LINE ART OPTIONS FOR CHILDREN: THE PLACE OF DTG .................................... 25
1.4 DTG WITH ANTI-TUBERCULOSIS (TB) THERAPY ......................................................................... 26
1.5 DTG AND PREGNANCY ......................................................................................................... 26
1.6 DTG FORMULATIONS AND MARKETING AUTHORISATION ............................................................. 26
1.7 RATIONALE AND OBJECTIVES ................................................................................................ 27
2 SELECTION OF SITES/CLINICIANS..................................................................................... 28
2.1 SITE/INVESTIGATOR INCLUSION CRITERIA ................................................................................. 28
2.2 APPROVAL AND ACTIVATION ................................................................................................. 28
2.3 SITE MANAGEMENT ............................................................................................................ 29
3 SELECTION OF PATIENTS ................................................................................................. 30

3.1 PATIENT INCLUSION CRITERIA ................................................................................................ 30
3.1.1 All patients: .............................................................................................................................. 30
3.1.2 Additional criteria for ODYSSEY A: ........................................................................................... 30
3.1.3 Additional criteria for ODYSSEY B: ........................................................................................... 30
3.2 PATIENT EXCLUSION CRITERIA ............................................................................................... 31
3.3 CONSIDERATIONS FOR USE OF DIFFERENT NRTI ......................................................................... 31
3.3.1 ABC-containing products.......................................................................................................... 31
3.4 NUMBER OF PATIENTS ......................................................................................................... 32
3.5 CO-ENROLMENT GUIDELINES................................................................................................. 32
3.6 SCREENING PROCEDURES & PRE-RANDOMISATION INVESTIGATIONS .............................................. 33
3.6.1 Screening visit .......................................................................................................................... 33
4 REGISTRATION & RANDOMISATION ............................................................................... 34

4.1 RANDOMISATION PRACTICALITIES .......................................................................................... 34
4.2 CO-ENROLMENT GUIDELINES................................................................................................. 35
5 TREATMENT OF PATIENTS .............................................................................................. 36

5.1 GENERAL INFORMATION ...................................................................................................... 36
5.1.1 NRTI BACKBONE CHANGE DURING FOLLOW UP...................................................................... 37
5.2 SOC ARM ........................................................................................................................ 37
5.2.1 SOC ODYSSEY A ........................................................................................................................ 37
5.2.2 SOC ODYSSEY B ........................................................................................................................ 38
5.3 DTG ARM ........................................................................................................................ 39
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5.3.1 DTG ........................................................................................................................................... 40

5.3.2 Fixed dose combination of DTG, ABC and 3TC......................................................................... 42
5.4 DISPENSING ...................................................................................................................... 42
5.5 ART MODIFICATIONS, INTERRUPTIONS & DISCONTINUATIONS ...................................................... 42
5.5.1 General considerations on changes of arvs during the trial .................................................... 42
5.5.2 Adverse reactions & Discontinuations of DTG ......................................................................... 43
5.6 ACCOUNTABILITY & UNUSED DRUGS/DEVICES .......................................................................... 45
5.7 ADHERENCE & ACCEPTABILITY ............................................................................................... 45
5.8 OVERDOSE OF TRIAL MEDICATION .......................................................................................... 45
5.9 PROTOCOL TREATMENT DISCONTINUATION .............................................................................. 45
5.10 NON-TRIAL TREATMENT AND SIGNIFICANT DRUG INTERACTIONS ........................................... 46
6 ASSESSMENTS & FOLLOW-UP ......................................................................................... 47

6.1 TRIAL ASSESSMENT SCHEDULE ............................................................................................... 47
6.1.1 Randomised Phase ................................................................................................................... 47
6.1.2 Extended Follow-up of ODYSSEY Participants.......................................................................... 48
6.2 PROCEDURES FOR ASSESSING EFFICACY ................................................................................... 48
6.2.1 Clinical: ..................................................................................................................................... 48
6.2.2 Immunology: ............................................................................................................................ 49
6.2.3 Viral load testing: ..................................................................................................................... 49
6.2.4 Resistance testing .................................................................................................................... 49
6.3 PROCEDURES FOR ASSESSING SAFETY ...................................................................................... 50
6.4 PROCEDURES FOR ASSESSING QUALITY OF LIFE .......................................................................... 50
6.5 ADHERENCE ASSESSMENTS ................................................................................................... 50
6.6 MANAGEMENT OF PARTICIPANTS WITH TREATMENT FAILURE ...................................................... 50
6.7 MANAGEMENT OF CHILDREN DIAGNOSED WITH TUBERCULOSIS (TB) ............................................... 51
6.7.1 Management of children with tuberculosis infection in the DTG arm .................................... 51
6.7.2 Management of children with tuberculosis in the SOC arm .................................................... 51
6.8 MANAGEMENT OF PREGNANCY .............................................................................................. 51
6.9 EARLY STOPPING OF FOLLOW-UP ............................................................................................ 53
6.10 PARTICIPANT TRANSFERS ..................................................................................................... 53
6.11 END OF TRIAL .................................................................................................................... 54
7 SAFETY REPORTING ........................................................................................................ 56

7.1 DEFINITIONS ..................................................................................................................... 56
7.1.1 Medicinal Products .................................................................................................................. 57
7.1.2 Adverse Events ......................................................................................................................... 57
7.1.3 Disease-related Events ............................................................................................................. 57
7.1.4 Other Notable Events ............................................................................................................... 57
7.2 INVESTIGATOR RESPONSIBILITIES ............................................................................................ 58
7.2.1 Investigator Assessment .......................................................................................................... 59
7.2.2 Notification Procedure ............................................................................................................. 60
7.3 CTU RESPONSIBILITIES ........................................................................................................ 62
8 QUALITY ASSURANCE & CONTROL .................................................................................. 63

8.1 RISK ASSESSMENT .............................................................................................................. 63
8.2 CENTRAL MONITORING AT CTU ............................................................................................. 63
8.3 ON-SITE MONITORING ........................................................................................................ 63
8.3.1 Direct Access to Participant Records ....................................................................................... 64
8.3.2 Confidentiality .......................................................................................................................... 64
9 STATISTICAL CONSIDERATIONS ....................................................................................... 65

9.1 METHOD OF RANDOMISATION .............................................................................................. 65

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9.2 OUTCOME MEASURES ......................................................................................................... 65

9.2.1 Primary efficacy outcome (over 96 weeks).............................................................................. 65
9.2.2 Secondary efficacy outcomes .................................................................................................. 65
9.2.3 Secondary safety outcomes ..................................................................................................... 66
9.2.4 Other secondary outcomes ...................................................................................................... 66
9.3 SAMPLE SIZE ..................................................................................................................... 66
9.4 INTERIM MONITORING & ANALYSES ....................................................................................... 66
9.5 ANALYSIS PLAN (BRIEF) ....................................................................................................... 66
10 ANCILLARY STUDIES ....................................................................................................... 68

10.1 PHARMACOKINETIC SUBSTUDIES ............................................................................................ 68
10.1.1 WB-PK1..................................................................................................................................... 68
10.1.2 WB-PK2..................................................................................................................................... 68
10.1.3 TB-PK SUBSTUDY ...................................................................................................................... 68
10.2 IMMUNOLOGY/VIROLOGY SUBSTUDY ...................................................................................... 69
10.3 QUALITATIVE SUBSTUDY: OPTIMISING ADHERENCE TO SECOND-LINE TREATMENT. .............................. 69
10.4 YOUTH TRIAL BOARD PROJECT .............................................................................................. 69
10.5 FOLATE AND VITAMIN B12 SUBSTUDY ..................................................................................... 70
11 REGULATORY & ETHICAL ISSUES ..................................................................................... 71

11.1 COMPLIANCE..................................................................................................................... 71
11.1.1 Regulatory Compliance ............................................................................................................ 71
11.1.2 Site Compliance........................................................................................................................ 71
11.1.3 Data Collection & Retention .................................................................................................... 71
11.2 ETHICAL CONDUCT OF THE STUDY ........................................................................................... 72
11.2.1 Ethical Considerations .............................................................................................................. 72
11.2.2 Ethical Approvals ...................................................................................................................... 73
11.3 COMPETENT AUTHORITY APPROVALS ...................................................................................... 73
11.4 OTHER APPROVALS ............................................................................................................. 74
12 INDEMNITY .................................................................................................................... 75
13 FINANCE ........................................................................................................................ 76
14 OVERSIGHT & TRIAL COMMITTEES.................................................................................. 77

14.1 TRIAL MANAGEMENT GROUP (TMG) ..................................................................................... 77
14.2 TRIAL STEERING COMMITTEE (TSC) ........................................................................................ 77
14.3 INDEPENDENT DATA MONITORING COMMITTEE (IDMC] ............................................................. 77
14.4 ENDPOINT REVIEW COMMITTEE ............................................................................................. 77
14.5 ROLE OF STUDY SPONSOR .................................................................................................... 77
15 PUBLICATION ................................................................................................................. 78
15.1 PUBLICATION .................................................................................................................... 78
15.2 FEEDBACK TO PARTICIPANTS.................................................................................................. 78
16 DATA AND/OR SAMPLE SHARING ................................................................................... 79
17 PROTOCOL AMENDMENTS ............................................................................................. 80
18 REFERENCES................................................................................................................... 92
19 APPENDIX I TEMPLATE PATIENT INFORMATION SHEETS ................................................. 96

PARENT/CARER INFORMATION SHEET - MAIN STUDY ONLY ......................................................... 96

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PARTICIPANT INFORMATION SHEET - MAIN STUDY ONLY .......................................................... 103

CHILDREN’S INFORMATION SHEET - MAIN STUDY ONLY ............................................................. 109
PARENT/CARER INFORMATION SHEET – EXTENDED FOLLOW-UP ............................................... 110
PARTICIPANT INFORMATION SHEET – EXTENDED FOLLOW-UP ................................................... 114
CHILDREN’S INFORMATION SHEET – EXTENDED FOLLOW-UP ........................................................ 118
PARENT/CARER INFORMATION SHEET – MAIN STUDY & WEIGHT BAND PK 1 (3 TO <14KG).......... 119
CHILDREN’S INFORMATION SHEET – MAIN STUDY & WEIGHT BAND PK 1 (3 TO <14KG) ............... 126
PARENT/CARER INFORMATION SHEET –WEIGHT BAND PK 1 (3KG TO <25KG) ............................. 127
CHILDREN’S INFORMATION SHEET – WEIGHT BAND PK 1 (3 TO <25KG) ....................................... 130
PARENT/CARER INFORMATION SHEET – WEIGHT BAND PK 2 (25KG TO <40KG) ........................... 131
PARTICIPANT INFORMATION SHEET –WEIGHT BAND PK 2 (25KG TO <40KG) ............................... 134
PARENT/CARER INFORMATION SHEET FOR TB PHARMACOKINETIC (PK) SUBSTUDY .................... 136
PARTICIPANT INFORMATION SHEET FOR TB PHARMACOKINETIC (PK) SUBSTUDY ....................... 139
PARTICIPANT INFORMATION SHEET FOR IN-DEPTH INTERVIEWS 15-18 YEAR OLDS ..................... 143
PARTICIPANT INFORMATION SHEET FOR IN-DEPTH INTERVIEWS 10-14 YEAR OLDS ..................... 146
PARENT/CARER INFORMATION SHEET FOR IN-DEPTH INTERVIEWS ............................................ 149
PARTICIPANT INFORMATION SHEET FOR IN-DEPTH INTERVIEWS - CAREGIVERS ............................. 152
PARTICIPANT INFORMATION SHEET FOR IN-DEPTH INTERVIEW 15-19 YEAR OLDS (DTG ALERT) ..... 155
PARTICIPANT INFORMATION SHEET FOR IN-DEPTH INTERVIEW 10-14 YEAR OLDS (DTG ALERT) ..... 158
PARENT/CARER INFORMATION SHEET FOR IN-DEPTH INTERVIEW (DTG ALERT) ............................ 161
PARTICIPANT INFORMATION SHEET FOR FOCUS GROUPS 15-19 YEAR OLDS................................ 164
PARTICIPANT INFORMATION SHEET FOR FOCUS GROUPS 10-14 YEAR OLDS................................ 167
PARENT/CARER INFORMATION SHEET FOR FOCUS GROUPS....................................................... 170
PARTICIPANT INFORMATION SHEET FOR YOUNG PEOPLE .......................................................... 174
PARENT/CARER INFORMATION SHEET ...................................................................................... 177
YTB FACILITATOR INFORMATION SHEET .................................................................................... 180
20 APPENDIX II TEMPLATE CONSENT AND ASSENT FORMS................................................. 182

PARENT/CARER – MAIN STUDY CONSENT TO SCREENING .......................................................... 182
PARENT/CARER – MAIN STUDY CONSENT TO RANDOMISATION ................................................ 183
PARTICIPANT –MAIN STUDY ASSENT TO SCREENING.................................................................. 185
PARTICIPANT- MAIN STUDY ASSENT TO RANDOMISATION ........................................................ 186
PARTICIPANT – MAIN STUDY CONSENT TO CONTINUED PARTICIPATION FOR YOUNG PEOPLE WHO REACH THE
AGE OF CONSENT WHILST IN THE TRIAL .......................................................................... 188
PARENT/CARER – CONSENT TO EXTENDED FOLLOW-UP ............................................................. 196
PARTICIPANT – CONSENT TO EXTENDED FOLLOW-UP ................................................................ 198
PARTICIPANT – ASSENT TO EXTENDED FOLLOW-UP ................................................................... 200
PARTICIPANT - CONSENT TO STORAGE OF BLOOD SAMPLES FOR FUTURE TESTING ..................... 203
PARTICIPANT – ASSENT TO STORAGE OF BLOOD SAMPLES FOR FUTURE TESTING........................ 204
PARENT/CARER – MAIN STUDY & WB PK 1 CONSENT TO SCREENING (3 TO <14KG) ...................... 205
PARENT/CARER – MAIN STUDY & WB PK 1 CONSENT TO RANDOMISATION (3 TO <14KG)............ 206
PARTICIPANT – MAIN STUDY & WB PK 1 ASSENT TO SCREENING (3 TO <14KG) ........................... 208
PARTICIPANT- MAIN STUDY & WB PK 1 ASSENT TO RANDOMISATION (3 TO <14KG) ................... 209
PARENT/CARER - CONSENT TO PHARMACOKINETIC (WB PK 1) STUDY (3 TO <25KG) .................... 211
PARTICIPANT - ASSENT TO PHARMACOKINETIC (WB PK 1) SUBSTUDY (3 TO <25KG) .................... 213
PARENT/CARER - CONSENT TO PHARMACOKINETIC (WB PK 2) STUDY (≥25KG) ........................... 215
PARTICIPANT - ASSENT TO PHARMACOKINETIC (WB PK 2) STUDY (≥25KG) .................................. 216
PARENT/CARER - CONSENT TO PHARMACOKINETIC (TB PK) STUDY ............................................ 218
PARTICIPANT - ASSENT TO PHARMACOKINETIC (TB PK) STUDY ................................................... 219
ASSENT FORM FOR IN-DEPTH INTERVIEWS 10-17 YEAR OLDS ..................................................... 222
CONSENT FORM FOR IN-DEPTH INTERVIEWS YOUNG PEOPLE (18 YEARS OLD) ............................ 223
CONSENT FORM FOR IN-DEPTH INTERVIEWS PARENT/CARERS................................................... 225

ODYSSEY Protocol
CONSENT FORM FOR IN-DEPTH INTERVIEWS WITH CAREGIVERS ..................................................... 227

ASSENT FORM FOR IN-DEPTH INTERVIEWS 10-17 YEAR OLDS (DTG)............................................ 229
CONSENT FORM FOR IN-DEPTH INTERVIEWS YOUNG PEOPLE (18-19 YEARS OLD) (DTG) .............. 230
CONSENT FORM FOR IN-DEPTH INTERVIEWS PARENT/CARERS (DTG) ......................................... 232
ASSENT FORM FOR FOCUS GROUP DISCUSSIONS (10-17 YEAR OLDS) .......................................... 234
CONSENT FORM FOR FOCUS GROUP DISCUSSIONS (YOUNG PEOPLE OVER 18-19 YEARS.............. 236
CONSENT FORM FOR FOCUS GROUP DISCUSSIONS (PARENT/CARERS) ....................................... 238
ASSENT FORM FOR YOUTH TRIAL BOARD PROJECT FOR YOUNG PEOPLE ..................................... 241
CONSENT FORM FOR YOUTH TRIAL BOARD PROJECT FOR YOUNG ADULT PARTICIPANTS ................ 243
CONSENT FORM FOR YOUTH TRIAL BOARD PROJECT FOR PARENTS/ GUARDIANS ....................... 245
21 APPENDIX III TEMPLATE GP LETTER .............................................................................. 249
22 APPENDIX IV TEMPLATE ADHERENCE QUESTIONNAIRES ............................................... 250
23 APPENDIX V TEMPLATE ACCEPTABILITY QUESTIONNAIRES ........................................... 252
24 APPENDIX VI ADAPTED WHO CLINICAL STAGING OF HIV/AIDS FOR PATIENTS WITH

CONFIRMED HIV INFECTION ..................................................................................................... 257
25 APPENDIX VII ADAPTED DIAGNOSTIC CRITERIA FOR WHO CLINICAL STAGING EVENTS IN
CHILDREN YOUNGER THAN 15 YEARS ....................................................................................... 260
26 APPENDIX VIII CRITERIA FOR WHO CLINICAL STAGING EVENTS FOR YOUNG PEOPLE 15
YEARS AND OLDER ................................................................................................................... 266
27 APPENDIX IX ADAPTED DAIDS TOXICITY GRADINGS...................................................... 272
28 APPENDIX X TANNER SCALES ....................................................................................... 288
29 APPENDIX XI SAFE LIMITS OF BLOOD SAMPLE VOLUMES IN CHILDREN.......................... 290
30 APPENDIX XII IMMUNOLOGY/VIROLOGY SUBSTUDY ..................................................... 291
31 APPENDIX XIII WEIGHT BAND PHARMACOKINETIC SUBSTUDIES (WB-PK) 1 & 2 ............. 297
32 APPENDIX XIV PHARMACOKINETIC SUBSTUDY IN PARTICIPANTS RECEIVING RIFAMPICIN

AS PART OF ANTI-TB TREATMENT OR TB PREVENTION THERAPY WHILE ON DTG: ...................... 305
33 APPENDIX XV QUALITATIVE SUBSTUDY ........................................................................ 308
34 APPENDIX XVI YOUTH TRIAL BOARD PROJECT ............................................................. 313
35 APPENDIX XVII ODYSSEY STRUCTURE ........................................................................... 316
36 APPENDIX XVIII FOLATE AND VITAMIN B12 SUBSTUDY ................................................. 317
37 APPENDIX XIX DOLUTEGRAVIR DOSING IN THE ODYSSEY TRIAL ACROSS DIFFERENT

PROTOCOL VERSIONS............................................................................................................... 321
38 APPENDIX XX ARRANGEMENTS FOR THE EXTENDED FOLLOW-UP OF ODYSSEY

PARTICIPANTS ......................................................................................................................... 322

ODYSSEY Protocol
ABBREVIATIONS
Abbreviation Expansion
ABC Abacavir
AE Adverse Event
ANRS National Agency for Research (France)
AR Adverse Reaction
ART Antiretroviral Therapy
ARV Antiretrovirals
ATV Atazanavir
AUC Area Under Curve
BIA Bioelectrial impedance analysis
BID Twice Daily
bPI Boosted Protease Inhibitor
c/ml Copies per ml
CDC Centres for Disease Control
COBI or c Cobicistat
CI Confidence Interval
CI Chief Investigator
CRF Case Report Form
CTA Clinical Trials Authorisation (Europe)
CTU Clinical Trials Unit (MRC, INSERM-ANRS, PHPT - as appropriate for the country)
d4T Stavudine
ddI Didanosine
DRV/r Darunavir/ritonavir
DSMS Drug Supply Management System
DSUR Development Safety Update Report
DT Dispersible tablet
DTG Dolutegravir
EFV Efavirenz
EMA European Medicines Agency

ERC Endpoint Review Committee
EU European Union
EUDRACT European Union Drug Regulatory Agency Clinical Trial
EVG Elvitegravir

ODYSSEY Protocol
EVI Eviplera
FCT Film-coated tablet
FDA Food and Drug Administration
FDC Fixed Dose Combination
FTC Emtricitabine
HAART Highly Active Antiretroviral Therapy
HBV Hepatitis B Virus
HDL High-Density Lipoproteins
HIV Human Immunodeficiency Virus
HIV NAT HIV Netherlands Australia Thailand Research Collaboration
HSR Hypersensitive Reaction
IB Investigator’s Brochure
ICH GCP International Conference on Harmonisation (of Technical Requirements for
Registration of Pharmaceuticals for Human Use) Good Clinical Practice
IDMC Independent Data Monitoring Committee
IMP Investigational Medical Product
IMPAACT International Maternal Paediatric Adolescents AIDS Clinical Trials
INSTI Integrase Strand Transfer Inhibitor
INSERM-ANRS Institut National de la Santé et de la Recherche Médicale
INSERM-ANRS Institut National de la Santé et de la Recherche Médicale Service Commun 10 –
SC10-US019 Unité de Services 019
ISF Investigator Site File
ISRCTN International Standard Randomised Controlled Trial Number
LDL Low-Density Lipoproteins
LPV/r Lopinavir/ritonavir
MOP Manual of Operations
MRC CTU Medical Research Council Clinical Trials Unit at UCL (UK)
MUAC Mid Upper Arm Circumference
NHS National Health Service (UK)
NNRTI Non-nucleoside Reverse Transcriptase Inhibitor
NRTI Nucleoside Reverse Transcriptase Inhibitor
QD Once daily
QoL Quality of Life Questionnaire
PENTA Paediatric European Network for Treatment of AIDS
PHPT Program for HIV Prevention and Treatment (Thailand)

ODYSSEY Protocol
PI Protease Inhibitor
PIS Patient information Sheet
PK Pharmacokinetics
pMTCT Prevention of Mother to Child Transmission
QA Quality Assurance
QC Quality Control
R&D Research & Development
RAL Raltegravir
RBC Red blood cell
RPV Rilpivirine
RTV or r Ritonavir
SAE Serious Adverse Event
SAP Statistical Analysis Plan
SAR Serious Adverse Reaction
SOC Standard Of Care (defined as the antiretroviral regimen routinely prescribed at a
particular site for an ART-naïve or for an ART-experienced patient)
SPF Summary of Product Characteristics
SSA Sub-Saharan Africa
SUSAR Suspected Unexpected Serious Adverse Reaction
TAF Tenofovir alafenamide
TAM Thymidine Analogue resistance Mutation
TB Tuberculosis
TDF Tenofovir
TDM Therapeutic Drug Monitoring
TMF Trial Master File
TMG Trial Management Group
TMT Trial Management Team
TSC Trial Steering Committee
UAR Unexpected Adverse Reaction
ULN Upper Limit of Normality
VL Viral Load
YTB Youth Trial Board
ZDV Zidovudine
3TC Lamivudine

ODYSSEY Protocol
1 BACKGROUND
With the development of new antiretroviral drugs (ARVs), including new drug classes, which offer
simplified, more potent options for first- and second-line therapy with fewer adverse effects in adults,
there is a need to evaluate their place in paediatric HIV treatment.
Unique issues for HIV-infected children include: potential for perinatal transmission of viruses
resistant to antiretroviral therapy (ART) regimens taken by mothers during pregnancy and
breastfeeding; special consideration of adverse events as children take drugs during growth and
development and will be on them for much longer than adults; and the need for age appropriate once
daily formulations, preferably fixed dose scored dispersible combinations which may require different
ratios of drugs from those used in adults.
Globally, more than 80% of HIV-infected children live in Sub Saharan Africa (SSA). Although there has
been substantial improvement in ART coverage over the last few years, only half of children in need
of treatment have access to ART [1, 2]. Rapid disease progression and high early mortality require that
ART is started early in life and many children still die before they are diagnosed. Children <3 years in
low/middle income countries are taking either non-nucleoside reverse transcriptase inhibitors
(NNRTI)-based ART (e.g. most African countries, India, Eastern Europe) or ritonavir boosted protease
inhibitor (bPI) lopinavir/ritonavir (LPV/r)-based ART (South Africa; some centres of excellence in SSA).
Children >3 years in SSA, including South Africa, start NNRTI-based ART. In both well-resourced and
resource-limited settings, there is a need for alternative first- and second-line regimens which can be
given in the face of possible transmitted resistance (from prevention of mother to child transmission
pMTCT) or resistance arising from first-line ART, whether PI or NNRTI based. New regimens need to
be potent, durable, non-toxic and available in acceptable once daily formulations with correct drug
ratios. Ideally regimens should be robust with a high barrier to resistance, have minimal cross-
resistance and minimal interactions with anti-tuberculosis drugs.
Dolutegravir (DTG) is a second-generation integrase inhibitor (INSTI) with the advantage of once daily
dosing, a good short-term safety profile, low pharmacokinetic variability, few drug-to-drug
interactions, rapid and robust virological response with an optimised background treatment, a distinct
resistance profile from raltegravir, a high genetic barrier to resistance and high potency at a low
milligram dose. Combination regimens with DTG will therefore be attractive for children starting first-
line ART and for those switching to second-line for reasons of toxicity or failure.
1.1 DTG ADULT TRIALS
There are encouraging efficacy and safety data from Phase II and III studies of DTG in adults [3-6] with
reassuring safety data reported at 96 week endpoints [3, 4]. SPRING-2, SINGLE and FLAMINGO Phase
III studies were conducted on treatment-naïve adults. SPRING-2 showed that DTG once daily (QD) is
non-inferior to twice daily (BID) raltegravir in combination with ABC+3TC or TDF+FTC at 96 weeks, and
superior in patients with VL >100,000 c/ml [4]. SINGLE compared DTG in combination with ABC+3TC
to efavirenz (EFV) in combination with TDF+FTC. Results showed that the DTG combination is superior
in efficacy and safety at 48 weeks and are consistent for patients with VL </>100,000 c/ml and CD4
count </>200 cells/mm3 [6]. A subsequent analysis of bone marker changes at 48 weeks demonstrated
that DTG+ABC+3TC was associated with significantly smaller changes compared to Atripla
(EFV/TDF/FTC) indicating more active bone turnover in patients on Atripla, which may correlate with
the known TDF-associated effect on bone mineral density over time [7, 8].
FLAMINGO, an open-label, non-inferiority trial compared DTG with darunavir (DRV) boosted with
ritonavir (/r) plus investigator-selected TDF+FTC or ABC+3TC in previously untreated adults. The trial
showed that DTG was superior to DRV/r at 48 and 96 weeks [9]. The difference was most pronounced

ODYSSEY Protocol
in participants with baseline viral load ≥100,000 c/ml. There was no treatment-emergent resistance
to study drugs [9]. Patients randomised to DTG had better lipid profiles with significantly less grade 2
or above low-density lipoprotein cholesterol results (2% versus 7%, p<0.001).
A recently published systematic reviews and meta-analyses of ART regimens in adults compared
virological efficacy (HIV-1 RNA <50 c/ml) at 48 and 96 weeks and CD4 change at 48 weeks of DTG-
based ART and other recommended third agents for the first-line treatment . Results showed that
DTG has a higher probability of virological suppression and better CD4 cell responses than most
guideline recommended third agents (standard-dose EFV, atazanavir (ATV)/r, DRV/r and LPV/r) [10,
11] .
The studies in treatment-experienced adult patients also showed encouraging results. SAILING, a
Phase III trial in treatment-experienced, INSTI-naïve patients, with at least two-class drug resistance,
compared QD DTG- versus raltegravir-based ART combined with no more than 2 other agents, one of
which was fully active: by 48 weeks, 71% vs. 64% patients reached undetectable viral load [12].
VIKING-3, a Phase II study of safety and efficacy of BID DTG in highly treatment-experienced patients
with previous resistance to INSTI and 2 other classes (70% patients had mutations to PIs), showed that
69% reached undetectable viral load at 24 weeks and 56% at 48 weeks of treatment. Only 3% of
patients discontinued treatment due to adverse events [13].
A single tablet of DTG + 3TC + ABC has been developed, providing an attractive option of a one-pill
once daily regimen for older children >12 years. A PK study in healthy volunteers demonstrated that
FDC DTG 50mg/ABC 600mg/3TC 300mg is bioequivalent to DTG alone in combination with ABC/3TC
[14].
In order to inform the ODYSSEY design, an exploratory analysis of subjects receiving DTG plus 1-2 NRTIs
in SAILING was conducted. None of the 32 subjects in the DTG arm, who received an NRTI-based
background regimen, experienced protocol defined virological failure by week 48, including no cases
of virological failure in 13 subjects receiving less than 2 fully active NRTIs by phenotype (12 received
one fully active NRTI and 1 received two inactive NRTIs)[15]. Based on this exploratory analysis, DTG
+ 2 NRTIs appears to have good activity through 48 weeks in treatment-experienced patients when at
least one of the NRTIs was fully active by phenotype. However, because of the small sample size, an
increased risk of virological failure in subjects receiving DTG with less than 2 fully active NRTIs cannot
be ruled out based on these data alone.
1.2 DTG IN CHILDREN
A paediatric dose-finding Phase I/II study IMPAACT P1093 is ongoing. The results are available for
children 6 to 18 years of age. The study enrolled treatment-experienced children failing their regimen
who were started on DTG with an optimized background regimen containing at least one fully active
antiretroviral drug [16, 17] . In 23 children aged 12-18 years who received DTG 50 mg PK results were
comparable to adults [17]. 48-week data showed that DTG was well tolerated with two patients
experiencing grade 3 laboratory adverse events, which were evaluated as not related to DTG; 74%
children (95% CI 52% to 90%) achieved viral load of <400 c/ml. There were no drug-related clinical
adverse events, no grade 3 or 4 clinical events, and no serious adverse events. 48-week results of the
PK, safety and virological efficacy study in 23 children 6 to 12 years of age were recently reported and
showed adequate AUC24 and C24 with the dose of ~1 mg/kg [18]. Three subjects experienced grade 3
laboratory events all of which were unrelated to DTG. There were no grade 4 AEs, SAEs or study
discontinuations secondary to AEs. The study in children less than 6 years of age down to 4 weeks of
age is ongoing.

ODYSSEY Protocol
1.3 FIRST- AND SECOND-LINE ART OPTIONS FOR CHILDREN: THE PLACE OF DTG
DTG-based treatment with two NRTIs offers a potent regimen, with advantages of low toxicity, and
the potential for once daily dosing. The rapid virological response observed following initiation of ART
with DTG-based ART will be highly relevant for children with very high viral loads, which is commonly
observed in younger children. DTG has high potency at a low milligram dose, and therefore it could
be particularly attractive for young children in both well-resourced and resource-limited settings, who
have limited options and may be more likely to be infected with resistant viruses through mother-to-
child transmission (MTCT). A DTG-based first-line regimen is likely to be better tolerated and
logistically advantageous for ART programmes currently using liquid LPV/r, as well as needing to be
dosed once rather than twice daily.
The choice of NRTI backbone depends on the child’s age, history of previous NRTI exposure (for ART
experienced children) and drug availability in a country. The combination of abacavir (ABC) +
lamivudine (3TC) is already frequently used as a preferred first-line nucleoside reverse transcriptase
inhibitors (NRTI) ‘backbone’ and tenofovir disoproxil fumarate (TDF) + emtricitabine (FTC) or TDF +
3TC are increasingly being used in older children (TDF recently received regulatory approval by both
Food and Drug Administration (FDA) and European Medicines Agency (EMA) for children >2 years of
age). Furthermore, there are reasons to use ABC or TDF as part of a first-line regimen as resistance to
both these drugs follows the same ‘resistance pathway’ and does not affect potency to zidovudine
(ZDV) for second-line (and in fact may result in hyper-susceptibility to ZDV), whereas using ZDV in first-
line typically results in accumulation of thymidine analogue resistance mutations (TAMs) which may
limit second-line NRTI options. The WHO 2016 guidelines recommend ABC as part of preferred first-
line ART in children 3 to <10 years and ABC or ZDV in children <3 years; if ZDV is used in first-line, then
ABC + 3TC are recommended in second-line [19]. PK data from PENTA trials [20, 21] and most recently,
96-week viral load and clinical efficacy data as well as safety data from the paediatric ARROW trial,
have shown that once daily dosing with ABC + 3TC is non-inferior to twice daily in terms of viral load
suppression, safety and clinical efficacy [22] . Thus, with ABC + 3TC, DTG has the potential to be part
of a potent, safe and simple fixed dose combination (FDC) for both first- and second-line ART in
children.
DTG can be used as part of a second-line regimen in children failing first-line PI-based therapy; despite
the presence of viral rebound for long periods, the NRTI backbone remains relatively protected in the
presence of a boosted PI (bPI). No TAMs developed in children failing LPV/r-based first line ART in a
large paediatric study (CHER) [23] and only 3/22 (14%) developed ≤2 TAMs and none developed >2
TAMs in the PENPACT1 trial [24] when switch was delayed until children had viral load (VL) >30,000
c/ml. Children failing NNRTI-based regimens developed TAMs more frequently. The PENPACT1 study
showed that 3/20 (15%) children who were randomised to switch their first-line ART at VL of 1000
c/ml developed one TAM, whereas children randomised to switch at VL of 30,000 c/ml developed
TAMs at higher rates: 9/22 (41%) developed ≥1 TAM, 5/22 (23%) ≥2 TAMs and 4/22 (18%) had 3 TAMs
[24]. In small studies in Uganda nearly 10% of children developed a first TAM by 6 months of early
virological failure on NNRTI-based regimen [25, 26] and 9% developed 2 TAMs by 12 months of
virological failure [26]. ABC is expected to retain its potency in the presence of no more than two
TAMs. Therefore, for children in resource-limited countries in whom ZDV has been used first-line and
VL and resistance testing are not available, it might still be expected that ABC potency might not be
unduly compromised when used with DTG (which itself has a high barrier to resistance) and that this
regimen might have similar potency and greater acceptability compared with a bPI-based second-line
regimen. Patients who are failing ABC + 3TC or stavudine (d4T) + 3TC containing first-line ART are at
risk of accumulating the K65R mutation and thus susceptibility to ABC or TDF containing second-line
ART may be reduced. Variable rates of acquiring the K65R mutation are reported in paediatric trials.
In the PENPACT1 trial 1/14 children on ABC + 3TC developed the K65R mutation [24, 27]. A multi-
centre study in sub-Saharan Africa found that K65R occurred in 3/20 (15%) and 13/47 (28%) adults

ODYSSEY Protocol
failing on d4T-or TDF-containing ART respectively, after 12 months of virological failure [27]. However,
the majority of patients switching empirically to ZDV, ABC or TDF-containing ART would be expected
to have at least 2 active drugs with a DTG-based regimen, and therefore to have an effective ART
regimen. Supporting this, adult studies from Africa showed high rates of virological re-suppression
with empirically prescribed and re-cycled second-line ART even when switching ART very late [27-30].
Of note, DTG can be used in liver and renal impairment without dose modification [14, 31].
1.4 DTG WITH ANTI-TUBERCULOSIS (TB) THERAPY
A PK study of co-administration of DTG with rifampicin in healthy adult volunteers showed that BID
DTG overcomes the induction effect of rifampicin [32] and therefore can be used in HIV/TB co-
infection. A recently reported study in HIV-infected adults with TB treated confirmed that increasing
DTG dose to 50mg BID co-administered with rifampicin results in a similar DTG exposure to DTG 50mg
QD without rifampicin [33]. The study showed DTG was effective and well-tolerated in HIV/TB co-
infected adults receiving rifampicin-based TB treatment. It will be important to study the DTG PK in
children on ART who require anti-TB treatment with rifampicin, as in many settings TB is common in
HIV-infected children, even when on ART.
1.5 DTG AND PREGNANCY
Reproductive toxicology animal studies, including embryofetal development studies in rats and
rabbits, showed no evidence of adverse developmental outcomes [34]
In May 2018, a National Institutes of Health (NIH)-funded observational surveillance study in Botswana
(TSEPAMO) evaluating the safety of ART regimens in pregnancy identified an increased risk of neural
tube defects (NTD) amongst infants of women who initiated DTG-based regimens prior to pregnancy.
The study reported 4 cases of NTD out of 426 infants in women who conceived on DTG (risk 0.9%),
this compares to 14 out of 11,173 infants born to women receiving non-DTG-based regimens (risk
0.13%)[35]. In a further report including all data through to March 2019 there were 5 cases of NTD in
1683 deliveries where their mother was taking DTG at conception (0.3% of deliveries) (36), suggesting
the increased risk is ~3-fold, lower than the 10-fold risk initially estimated.
There were no reported NTDs in infants of 1729 women in the TSEPAMO study who started DTG during
pregnancy, including 280 women who initiated ART during the first trimester of pregnancy [37].
This study and other surveilance studies are ongoing and other reproductive studies on DTG safety
have been initiated. More data on safety of DTG for women of childbearing age and their infants are
expected in the next year.
Following the alert, it was communicated to the ODYSSEY sites that all female participants who are
sexually active must use highly effective contraception (section 6.8; [38])).
1.6 DTG FORMULATIONS AND MARKETING AUTHORISATION
DTG is available as film-coated 10mg, 25mg and 50mg tablets and dispersible 5mg tablets and all
formulations are provided by ViiV for the ODYSSEY trial. The dispersible tablets are approximately 1.6
times more bioavailable than the film-coated tablets and are currently being studied in DTG paediatric
trials (ODYSSEY and IMPAACT P1093[38, 39]).

ODYSSEY Protocol
FDA and EMA have approved DTG 50mg QD for adolescents ≥40kg and DTG 35mg QD for children
weighing 30 to <40kg, and EMA has approved DTG 25mg QD for children 20-<25kg and DTG 20mg QD
for children ≥6 years weighing 15-<20kg. FDC (DTG+3TC+ABC) is approved in paediatric patients
weighing ≥40kg by EMA and FDA. The dose finding and safety assessment study IMPAACT P1093 in
younger children is ongoing.
1.7 RATIONALE AND OBJECTIVES
DTG is a new drug which offers the potential to be highly effective, safe and simple when used as part
of first- or second-line ART regimens. Following adult Phase II/III trials, DTG needs evaluation to
determine its place as first-line and second-line therapy in adolescent and paediatric HIV treatment.
Standard ART for children is a NNRTI or bPI, plus 2 NRTI and where possible fixed drug combinations
(FDC) are preferred to support adherence. Concerns have been raised about the potency of NVP-
based ART in infants [40], and EFV is not readily available for children <3 years. Neither EFV nor NVP
are available in a 3-drug once-daily FDC for children <12 years of age. The most frequently used FDC
in adolescents is EFV+TDF+FTC (or 3TC). With currently used doses, EFV may cause significant
neuropsychological side effects [42]. The commonly available bPI for young children is LPV/r, an
unpleasant tasting liquid requiring a cold chain. LPV/r tablets for children are relatively large and need
to be swallowed whole or they lose bioavailability. Two other PIs, ATV and DRV, are available for older
children in high-income countries but need to be boosted with ritonavir tablets. Adult US and
European guidelines now recommend integrase inhibitors as part of first-line regimens. In contrast,
INSTI are used infrequently in children: raltegravir-based ART is used in some clinics, generally for
second-line, following treatment failure on LPV/r-based regimens and elvitegravir-based FDC has been
recently introduced for adolescents in high-income countries, mostly for simplification. Finally, TDF,
a preferred NRTI in adults and adolescents [19], has long-term renal and bone toxicity, and therefore
concerns remain for its use in growing children.
DTG with two NRTIs will potentially offer a potent and safe regimen for both ART-naïve and ART-
experienced children and is available as a FDC with ABC and 3TC for children >12 years.
No randomised trial has been undertaken comparing this new regimen with standard of care in
children, who potentially have more to gain in terms of minimising long term HIV and ART
complications, improving long-term adherence to medication and gaining better quality of life than
adults.
ODYSSEY will be a pragmatic strategy trial evaluating the efficacy and safety of once daily DTG-based
ART compared with standard of care in children and adolescents starting first- or second-line ART in
resource-limited and well-resourced settings.

ODYSSEY Protocol
2 SELECTION OF SITES/CLINICIANS
The trial sponsor has overall responsibility for site and investigator selection.
2.1 SITE/INVESTIGATOR INCLUSION CRITERIA
Clinical sites invited to enrol children and young people in ODYSSEY will usually have previously
collaborated in trials with the MRC CTU, INSERM-ANRS, PHPT or IMPAACT. In the case of a new site
wishing to participate, the site will need to demonstrate sufficient resources to conduct clinical trial
research with children and young people.
The principal investigator will sign an Investigator’s Agreement for that institution on behalf of all staff
at that site who will be working on the ODYSSEY trial. The principal investigator will sign to confirm
that:
The institution has an adequate number of qualified staff and adequate facilities for the
foreseen duration of the trial to conduct the trial properly and safely.
All staff assisting with the trial are adequately informed about the protocol, the investigational
products and their trial-related duties.
The trial will be conducted in accordance with the current protocol and changes will only be
made when necessary to protect the safety, rights or welfare of participants.
The trial will be conducted in compliance with the principles of ICH GCP and applicable
regulatory requirements.
The institution will permit monitoring and auditing by the relevant CTU and inspection by the
appropriate regulatory authorities. Direct access will be made available to all trial-related
sites, data/documents and reports.
The institution will maintain an Investigator Site File (ISF), which will contain essential
documents for the conduct of the trial.
All trial data will be submitted in a timely manner and as described in the protocol.
All Serious Adverse Events (SAEs) will be reported to the relevant CTU within 24 hours of the
investigator becoming aware of the event. The initial SAE report shall be promptly followed
by detailed follow up reports.
All employees, students or agents engaged in the research shall maintain the confidentiality
of information.
No data on trial participants will be disclosed without the approval of the Trial Steering
Committee (TSC).
All trial-related documents will be retained for at least 15 years after the completion of the
trial.
In addition to the points above and in compliance with the principles of ICH GCP, all institutions
participating in the trial will complete a delegation log and forward this to the CTU. Each person
working on the ODYSSEY trial must complete a section of this log and indicate their responsibilities as
agreed with the principal investigator. The CTU must be immediately notified of any changes to trial
personnel and/or their responsibilities. An up-to-date copy of this log must be stored in the ISF at the
institution and also in the Trial Master File (TMF) at the CTU.
2.2 APPROVAL AND ACTIVATION
MRC CTU, INSERM-ANRS or PHPT staff will visit new sites prior to the trial commencing at that site in
order to carry out a site and lab risk assessment and set-up visit. This visit should be attended by the

ODYSSEY Protocol
principal investigator at that site (the clinician), the clinic nurse(s), and representatives from the
laboratory and pharmacy and any other staff who will be involved in the ODYSSEY trial. At the trial
set-up visit the trial management staff should ensure that the following minimum criteria are met
before the site enrols participants into the trial:
The clinician should be experienced in the management of children/young people with HIV or
work in close contact with a specialist HIV unit/site.
Staff involved in the trial must have training in Good Clinical Practice (GCP).
Pharmacy staff are able to keep detailed records of the trial medications prescribed.
There exists good communication between all of the above departments.
Laboratories have quality certification procedures, are enrolled with an EQA program and
have the capacity to run the trial scheduled assays/store trial samples.
Training will be provided for all sites participating in ODYSSEY. Where sites have participated in
previous PENTA trials, site initiation training may be conducted via web conferencing or similar.
Training in the use of ABC will be included in the site initiation.
2.3 SITE MANAGEMENT
Sites in the United Kingdom are managed by the MRC CTU. Sites in Germany, South Africa, Thailand
(HIV-NAT), Uganda, US and Zimbabwe are managed by the MRC CTU together with national co-
ordinators and local monitors. This includes those sites in Uganda that are supported by IMPAACT.
Sites in France are managed by INSERM-ANRS; sites in Argentina, Portugal and Spain are managed by
INSERM-ANRS together with national co-ordinators and local monitors. PHPT sites in Thailand are
managed directly by PHPT.

ODYSSEY Protocol
3 SELECTION OF PATIENTS
Participants will be selected by medical investigators at the participating sites, who should be aware
of eligibility criteria in advance of screening participants for the trial.
Eligible participants (or carers, as appropriate) must:
Be able to understand and comply with protocol requirements, instructions, and restrictions
Be likely to complete the study as planned
Be considered appropriate candidates for participation in an investigative clinical trial with
oral medication
The eligibility criteria are the standards used to ensure that only medically appropriate participants
are considered for this study. Participants not meeting the criteria should not join the study. For the
safety of the participants, as well as to ensure that the results of this study can be useful for making
treatment decisions regarding other children and adolescents with HIV, it is important that no
exceptions be made to these criteria for admission to the study.
Participants will be considered eligible for enrolment in this trial only if they fulfil all the inclusion
criteria and none of the exclusion criteria as defined below.
3.1 PATIENT INCLUSION CRITERIA
3.1.1 ALL PATIENTS:

Children ≥28 days and <18 years weighing ≥3kg with confirmed HIV-1 infection*
Parents/carers and children, where applicable, give informed written consent
Girls who have reached menses must have a negative pregnancy test at screening and
randomisation and be willing to adhere to effective methods of contraception if sexually
active
Children with co-infections who need to start ART according to local/national guidelines
Parents/carers and children, where applicable, willing to adhere to a minimum of 96 weeks'
follow-up
*Children weighing 3 to <14kg must be eligible and willing to participate in the Weight band (WB)-
PK1 substudy unless direct enrolment for the child’s weight band has opened following the WB-PK1
substudy (see Section 5.3.1 and Appendix XIII) and/or dosing information has become available from
the IMPAACT P1093 DTG dose-finding study.
3.1.2 ADDITIONAL CRITERIA FOR ODYSSEY A:

Planning to start first-line ART
3.1.3 ADDITIONAL CRITERIA FOR ODYSSEY B:

Planning to start second-line ART defined as either: (i) switch of at least 2 ART drugs due to
treatment failure; or (ii) switch of only the third agent due to treatment failure where drug
sensitivity tests show no mutations conferring NRTI resistance (see Section 5.2.2)
Treated with only one previous ART regimen. Single drug substitutions for toxicity,
simplification, changes in national guidelines or drug availability are allowed
At least one NRTI with predicted preserved activity available for a background regimen

ODYSSEY Protocol
In settings where resistance tests are routinely available, at least one active NRTI from
TDF/TAF, ABC or ZDV should have preserved activity based on cumulative results of resistance
tests (see Section 5.2.2)
In settings where resistance tests are not routinely available, children who are due to switch
according to national guidelines should have at least one new NRTI predicted to be available
from TDF/TAF, ABC or ZDV (see Section 5.2.2)
Viral load ≥500 c/ml at screening visit or within 4 weeks prior to screening
See Section 3.3 for additional considerations for inclusion in the study depending on NRTI
backbone.
3.2 PATIENT EXCLUSION CRITERIA
History or presence of known allergy or contraindications to DTG

History or presence of known allergy or contraindications to proposed available NRTI
backbone or proposed available SOC third agent.
Alanine aminotransferase (ALT) ≥5 times the upper limit of normal (ULN), OR ALT ≥3xULN and
bilirubin ≥2xULN
Patients with severe hepatic impairment or unstable liver disease (as defined by the presence
of ascites, encephalopathy, coagulopathy, hypoalbuminaemia, oesophageal or gastric varices,
or persistent jaundice), known biliary abnormalities (with the exception of Gilbert's syndrome
or asymptomatic gallstones)
Anticipated need for Hepatitis C virus (HCV) therapy during the study
Pregnancy or breastfeeding
Evidence of lack of susceptibility to integrase inhibitors or more than a 2-week exposure to
antiretrovirals of this class
3.3 CONSIDERATIONS FOR USE OF DIFFERENT NRTI
3.3.1 ABC-CONTAINING PRODUCTS
HLA-B*5701 testing
In countries where HLA-B*5701 screening is considered standard of care and HLA-B*5701 status is
unknown (even if the subject has previously tolerated ABC), investigators must test for HLA-B*5701
and the results of the test must be received prior to starting ABC. Children who are HLA-B*5701
positive must not be given ABC.
In countries where HLA-B*5701 screening is not considered standard of care, investigators must
obtain a complete history of previous exposure to ABC-containing products. In cases requiring
discontinuation of abacavir, they should evaluate for the possibility of a clinically suspected
hypersensitivity reaction (HSR). If the possibility of a HSR cannot be ruled out then treatment with
any ABC-containing product should not be started, due to the risk for a potential life-threatening and
sometimes fatal re-challenge reaction. Where participants have previously tolerated treatment with
ABC, restarting ABC treatment as part of this study must be done in a setting where medical assistance
is readily available.
The use of ABC-containing products in participants should be in accordance with the corresponding
local product information.
3TC-, FTC- and TDF/TAF-containing products

ODYSSEY Protocol
HBV-co-infected patients
Patients known to have chronic HBV infection (HBsAg positive OR anti-HBc positive with HBV DNA
present) should be treated with TDF ideally in combination with either 3TC or FTC. Monotherapy with
either 3TC or FTC for treatment of HBV is not recommended, and 3TC should not be used in
combination with FTC. In young patients for whom TDF is not available, consideration should be given
to use of 3TC- or FTC-sparing regimens to avoid development of 3TC or FTC resistance in HBV.
Some participants with chronic HBV disease may experience clinical or laboratory evidence of
recurrent hepatitis upon discontinuation of 3TC, FTC or TDF/TAF. If 3TC, FTC or TDF/TAF is
discontinued in participants co-infected with HBV, periodic monitoring of liver chemistry tests should
be considered.
Renal impairment
The use of TDF is not recommended in children with renal impairment. TDF should be discontinued
in children who develop renal impairment on TDF therapy.
In patients with moderate-severe renal impairment and creatinine clearance <50 ml/min, the dose of
3TC or FTC should be adjusted in accordance with the local product information.
ZDV-containing products
Patients with either of the following haematology results at screening should not receive ZDV-
containing products:
Haemoglobin (Hb) concentration <7.5 g/dL or 4.65 mmol/L
Absolute neutrophil count <500/mm3 or 0.5 x 109/L
Alternative causes for anaemia and/or neutropenia, such as concurrent bacterial, mycobacterial or
fungal infection, malaria, helminthiasis, malignancy and/or malnutrition should be investigated. ZDV
should be substituted with an alternative NRTI if alternative causes for anaemia and/or neutropenia
cannot be identified.
3.4 NUMBER OF PATIENTS
A minimum of 700 children will be enrolled into the main trial over 96-120 weeks. This will include
≥310 children starting first-line (ODYSSEY A) and ≥390 children starting second-line ART (ODYSSEY B).
Children will be recruited from clinical centres in Africa, Europe, Asia, North and South America.
All children randomised into ODYSSEY weighing ≥14kg will contribute to the target numbers of 310 in
ODYSSEY A and 390 in ODYSSEY B.
In addition, over a period of up to 78 weeks (July 2018 to end of 2019) we will recruit a minimum of
20 children in each of the 3 lower weight bands (3-6kg, 6-10kg, 10-14kg; total ≥60 children).
3.5 CO-ENROLMENT GUIDELINES
Co-enrolment in previous or future trials is considered in Section 4.2.

ODYSSEY Protocol
3.6 SCREENING PROCEDURES & PRE-RANDOMISATION INVESTIGATIONS
3.6.1 SCREENING VISIT

At screening, parents/carers of HIV-infected children and adolescents will be given an information
sheet about the ODYSSEY trial and asked to give written consent before any trial-specific procedures
are performed or any blood is taken for the trial (see Appendices I - II).
Signed consent forms must be kept by the investigator in the ISF, a copy in the child's clinical records
and a copy given to the participant or family.
At this visit the patient will be allocated a Trial Number and an anonymous code taken from a
sequential list included in the ISF.
Screening procedures will include a clinical assessment, T cell lymphocyte subsets (including total
lymphocytes, CD4, CD8), haematology, biochemistry (see Trial Assessment Schedule, page x) and
plasma/cell storage. Stored samples will be discarded if the patient is not randomised into the study;
HIV-1 RNA viral load is required for ODYSSEY B at screening or within 4 weeks prior to screening. Girls
who have started menses will be given information about the risks of pregnancy in the trial and
advised on how to avoid pregnancy. A pregnancy test will be performed at screening in girls who have
started menses. Any female participant found to be pregnant will not be eligible for the trial.
For children being screened for ODYSSEY B, i.e. children requiring a switch to second-line ART, the
parent/carer, or any young person who administers their own medication, should complete an
adherence questionnaire (See Appendix IV).
As soon as the results are received and eligibility has been confirmed, the Screening Form with
confirmation of eligibility and receipt of informed consent, clinical history and assessment,
haematology, biochemistry, previous immunology and virology should be entered on the trial
database or sent to the appropriate CTU. Eligibility for the study will be confirmed and the
randomisation visit should be scheduled within 4 weeks after the screening visit.

ODYSSEY Protocol
4 REGISTRATION & RANDOMISATION
Randomisation should take place within 4 weeks after the screening visit, ideally within 2 weeks.
The participant’s eligibility for enrolment will be confirmed, including the results of screening
laboratory tests. Participants or carers must confirm that they have read the relevant patient
information sheets (see Appendix I). Continued agreement to enter in the trial must be confirmed
from parents/carers after explanation of the aims, methods, benefits and potential hazards (see
Appendix II). Older children should give assent to trial participation if they know their HIV status.
Signed consent forms must be kept by the investigator and documented in the CRF, a copy stored in
the clinical records and a copy given to the participant or family. It must be made completely and
unambiguously clear that the participant (or parent/carer of a child) is free to refuse to participate in
all or any aspect of the trial, at any time and for any reason, without compromising the care of the
child.
The randomisation process will be securely embedded within the database, a web-based system
controlled through an authorised user name and password. Selected sites will be able to randomise
patients directly. An option to fax the Randomisation Form to the appropriate CTU, who will perform
the randomisation, will also be available. Patients will be randomised to DTG or SOC arms in a 1:1
ratio (see Section 4.1 below).
Enrolment assessments will be performed as summarised in the Trial Assessment Schedule. Blood
should be taken for plasma storage. Cells will be stored in selected sites with this capacity. A repeat
pregnancy test should be performed in girls who have started menses. Any female participant found
to be pregnant will not be eligible for the trial. The questions relating to sleep and mood on the
Acceptability, Sleep and Mood Questionnaire should be completed at the enrolment visit.
The clinician should complete the Enrolment Form and send to the appropriate CTU once all the
laboratory results are available, or enter the CRF data directly onto the secure web-based trial
database.
A clinic visit should be scheduled for 4 weeks after the week 0 visit (week 4 visit). At the sites where
children are routinely seen at 2 weeks after the start of new ART, this can be included as an additional
visit and procedures undertaken as per the Trial Assessment Schedule.
4.1 RANDOMISATION PRACTICALITIES
The participant (child) and carer should be physically present together with a study clinician at the
time of randomisation.
To randomise a participant, the information contained on a completed Randomisation Form will be

entered into the online trial database accessible from the CTU (or the clinical site if appropriate) to
automatically check for eligibility. Only those with completed and verified screening forms on the
database will be able to be randomised. The details of the participant’s treatment allocation and trial
number will be notified to clinical staff.
If a centre’s internet connection to the database is unavailable at the time of randomisation, the
participant’s details can be provided to staff at the relevant CTU by fax or by telephone. At the CTU,
staff will verify eligibility and perform the randomisation using the online system. The details of the

ODYSSEY Protocol
participant’s treatment allocation and trial number will be notified to the trial team at the site by fax
or phone, with follow-up confirmation.
The clinician should complete a prescription with the participant's details and ART regimen as
allocated. The pharmacist or pharmacy technician should ensure that the participant and/or carers
know how to take/administer the different drugs before they leave the clinic.
RANDOMISATIONS THROUGH A CTU

To randomise fax or send by password protected email the Randomisation CRF to the
relevant CTU:
MRC CTU, UK, Monday to Friday 9:00 AM to 17:00
Tel: +44 (0) 20 7670 4786
Fax: +44 (0) 20 7670 4814
Inserm-ANRS, France, Monday to Friday 9:00 AM to 17:00

Tel: + 33 1 45 59 50 83 / 52 55
Fax: + 33 1 46 58 72 93
PHPT, Thailand, Monday to Friday 9:00 AM to 18:00

Tel: +66 (0) 53 814 633 ext 710
Fax: +66 53 814 269
Email: kanchana.than-in-at@phpt.org
For those sites randomising directly, training will be provided as part of the site initiation and database
training. Individual passwords will be provided.
ENROLMENT OF MULTIPLE PARTICIPANTS FROM THE SAME FAMILY/HOUSEHOLD INTO THE TRIAL
If more than one child from a family/household is to be enrolled at the same time and in the same
stratum (ODYSSEY A or ODYSSEY B) they will be allocated to the same arm to facilitate their care
(please refer to Manual of Operations).
Co-enrolment in compatible studies is allowed by the protocol but must first be approved by the CTU
with previous discussion within the TMG. Centres should also adhere to local guidelines concerning
co-enrolment in other trials.

ODYSSEY Protocol
5 TREATMENT OF PATIENTS
5.1 GENERAL INFORMATION
Participants will be enrolled in two different strata depending on their previous ART experience:
ODYSSEY A: children starting first-line ART
ODYSSEY B: children starting second-line ART.
Within each stratum, children will be randomised 1:1 to either DTG-based ART (DTG arm) or standard
of care (bPI-, or NNRTI- or INSTI-based ART; SOC arm).
DTG (including Triumeq, as appropriate) will be provided by ViiV for the duration of the randomised
phase of the ODYSSEY trial. Triumeq will only be supplied in countries where it is licensed. At sites
where generic DTG-containing FDCs are available through the national programme it may be preferred
for participants in the DTG arm to be on a once-daily, one-pill regimen, rather than taking DTG supplied
by ViiV as a separate tablet, in order to aid adherence, but this must not lead to a change to the NRTI
backbone. If the DTG-containing FDC is to be dispensed from a general clinic/Department of Health
pharmacy rather than the clinical trial pharmacy it must be ensured that all necessary local
requirements are met and approvals are in place for the pharmacy to do so. All cases where this may
apply should be discussed with MRC CTU at UCL prior to switching the participant.
For sites outside Europe, the following NRTIs will also be provided by ViiV where required for the
duration of the ODYSSEY trial: ABC, 3TC, Kivexa and Combivir. After the end of the randomised phase
of the trial, DTG will be provided by ViiV for those children randomised to the DTG arm at the
discretion of their clinician until it is available and recommended for children in their country of
residence. For sites in sub-Saharan Africa the Mylan formulation of ABC/3TC 120/60mg will be
provided for the duration of the randomised phase, if required.
All carers of children starting ABC will receive warning cards and additional information about this
drug. In the countries where HLA-B*5701 testing is routinely performed, the test results should be
received prior to starting ABC. Children who are HLA-B*5701 positive should not be given ABC.
The NRTI choice in children who are starting second-line ART will depend on the history of previously
used NRTIs and the resistance profile, if performed. The decision will be made by the treating clinician
The following should be considered:
1. In countries, where resistance tests are routinely performed, at least one active NRTI from
TDF/TAF, ABC or ZDV should be chosen based on all resistance test results in the child (historic
and recent). The interpretation of the mutations should be based on the up-to-date version
of the Stanford HIV Drug Resistance Database (http://hivdb.stanford.edu/). If the child has
been on ZDV or D4T first-line, and ABC or TDF/TAF are in the planned SOC for second-line,
then no more than two TAMs or one TAM + M184V are allowed. If the chosen regimen
contains ABC or TDF/TAF, no presence (historic or recent) of K65R mutation is allowed.
2. In countries where resistance tests are not routinely performed, clinicians should follow
national/WHO Guidelines. At least one new NRTI with presumed preserved activity (from ABC,
TDF or ZDV) should be chosen.
The planned SOC regimen to be used if randomised to SOC should be recorded on the screening and
randomisation CRFs. Treatment should start on the day of randomisation or the following morning.

ODYSSEY Protocol
Treatment will be open-label and will be dispensed at randomisation for 4 weeks and then at
maximum 12 weekly intervals. Where drug has been supplied for the trial, it will be stored separately
from routine clinic drug supplies in a designated section at the study site.
5.1.1 NRTI BACKBONE CHANGE DURING FOLLOW UP
The proposed NRTI backbone for all participants should be chosen following the considerations in
sections 3.1 to 3.3 and 5.2 to 5.3. Participants must be prescribed the NRTI backbone that was chosen
prior to randomisation irrespective of the randomised allocation as randomisation is stratified by NRTI
backbone.
Additionally participants should remain on the same backbone throughout the duration of the trial
unless substituting for toxicity, intolerance or switching for treatment failure. Change of NRTI
backbone for simplification while in the trial should be avoided, if possible. In cases where the clinician
thinks that this should be done in the patient’s best interest, this should be discussed with the relevant
CTU and/or TMG.
Upon completion of the randomised phase of the trial clinicians are free to change NRTI backbone as
per international/national treatment guidelines.
5.2 SOC ARM
All participants in the SOC arm will receive ART including either an NNRTI (e.g. NVP, EFV or RPV), a bPI
(e.g. LPV/r, ATV/r, ATV/c, DRV/r, DRV/c) or an INSTI other than DTG (e.g. RAL, EVG/c), plus 2 (or 3
(ODYSSEY A only)) NRTIs following international (WHO, PENTA, US), national or local
recommendations for first- or second-line therapy. See Tables 1 and 2 below for commonly used first-
and second-line options for standard of care. The exact choice of antiretrovirals will be made by the
treating clinician, but should take into account what is being used in national programmes, as this will
ensure that participants can stay on the same regimens long-term. Inclusion of different regimens in
the trial increases generalisability, and will form a pre-planned subgroup analysis population.
Participants randomised to SOC must be prescribed the class of non-NRTI drug that was chosen prior
to randomisation as randomisation is stratified by bPI vs. non-bPI. The doses of antiretrovirals should
be in accordance to those recommended in the product information or according to international
(WHO, PENTA, US)/national guidelines as appropriate for the country. Doses should be recalculated
at every visit (until the adult dose is reached).
See Section 3.3 for additional considerations that investigators should take into account before
selecting and initiating the NRTI backbone.
5.2.1 SOC ODYSSEY A

SOC first-line ART varies across the sites and countries in ODYSSEY. See Table 1 for commonly used
first-line ART options. D4T or ddI may still be an option for young children in whom ZDV and ABC are
contraindicated and if these NRTIs are included in the national guidelines.

ODYSSEY Protocol
Table 1. ART in ODYSSEY A (First-line treatment)

Examples of first-line ART regimens for SOC
Population
NNRTI + 2or3 NRTI bPI + 2NRTI INSTI +2NRTI
WHO 2016§ LPV/r + ABC(or ZDV) +
preferred first-line 3TC
Children <3
years NVP + ABC(or ZDV) + 3TC RAL+ ABC(or ZDV) + 3TC
Other first line
options
NVP + ZDV + ABC + 3TC*
WHO 2016§
EFV + ABC + 3TC
preferred first-line
Children 3 to NVP + ABC + 3TC LPV/r + ABC+ 3TC RAL + ABC +3TC
<10 years Other first line EFV(or NVP) + ZDV +3TC ATV/r + ABC + 3TC RAL + ZDV +3TC
options
EFV(or NVP) + TDF + LPV/r (or ATV/r) + ZDV
3TC(or FTC) + 3TC
WHO 2016§
EFV + TDF + 3TC(or FTC)
preferred first-line
ATV/r (ATV/c or DRV/r
EFV + ABC + 3TC(or FTC) or DRV/c) + TDF(TAF or EVG/c+TDF (or TAF)+FTC
ABC) + 3TC(or FTC)
Adolescents ATV/r(ATV/c or DRV/r
Other first-line EFV(or NVP) + ZDV + 3TC RAL + ABC +3TC
or DRV/c) + ZDV + 3TC
options
NVP + TDF(TAF or ABC) + LPV/r + TDF(TAF or
RAL + ZDV +3TC
3TC(or FTC) ABC) + 3TC(or FTC)
RPV + TDF(TAFor ABC) +
LPV/r + ZDV +3TC
3TC(or FTC)
§ World Health Organization. Consolidated guidelines on the use of antiretroviral drugs for treating and preventing HIV
infection: recommendations for a public health approach – 2nd ed. June 2016. Available:
http://apps.who.int/iris/bitstream/10665/208825/1/9789241549684_eng.pdf?ua=1
*For infants and children aged less than 3 years, at the sites where this regimen is routinely used
5.2.2 SOC ODYSSEY B

For all children failing their first-line regimen, adherence issues should be addressed prior to switching
to second-line as per standard practice in the clinic. Children and adolescents are eligible for
enrolment once their clinician decides to switch them to second-line. Once daily regimens should be
considered where possible to sustain adherence.
The choice of second-line ART will be based on international (WHO, PENTA, US) or national guidelines.
See Table 2 for possible second-line ART options.

ODYSSEY Protocol
Table 2. ART in ODYSSEY B (Second-line treatment)

Examples of sequencing of ART regimens following treatment failure on first-line for
SOC
Population
WHO 2016§ preferred
Failed first-line Other second-line options
second-line
NVP + 2NRTI LPV/r + 2NRTI* RAL + 2NRTI*
Children <3 years
LPV/r + 2NRTI RAL + 2NRTI* NVP + 2NRTI*
EFV(or NVP) + 2NRTI LPV/r + 2NRTI* DRV/r(or ATV/r) + 2NRTI*
Children 3 to <10 years RAL + 2NRTI* or
LPV/r + 2NRTI EFV + 2NRTI*
DRV/r(or ATV/r) + 2NRTI*
DRV/r (or DRV/c) + 2NRTI*

Adolescents EFV(or NVP) + 2NRTI ATV/r (or LPV/r) + 2NRTI* or
EVG/c +TAF + FTC
RAL + 2NRTI* or
DRV/r(or DRV/c) + 2NRTI*
or
ATV/r(or ATV/c)+2NRTI*
LPV/r + 2NRTI -
or
EFV (orNVP or RPV) +
2NRTI* or
EVG/c +TDF(or TAF) + FTC
§ World Health Organization. Consolidated guidelines on the use of antiretroviral drugs for treating and preventing
HIV infection: recommendations for a public health approach – 2nd ed. June 2016. Available:
*NRTI for second-line - at least one NRTI with preserved activity (measured by resistance tests or presumed from the
history of previous ART) from ABC, TDF/TAF or ZDV. Didanosine or d4T may be used in second-line where no other
drugs are available.
In countries, where resistance tests are routinely performed, the cumulative results of all resistance
tests should be taken into account. Resistance tests give the most reliable results when collected while
the patient is still taking the failing regimen or within 4 weeks of stopping the drugs. If the tests are
taken without drug pressure, they may give false negative results (show no resistance mutations) and
should not be relied on when choosing the second-line ART.
In general, children with treatment failure on an NNRTI-based regimen are switched to a bPI-based
regimen. Children experiencing treatment failure on bPI-based ART may be switched to a more potent
bPI (for example change of LPV/r to DRV/r in children >3 years) or to an NNRTI-based or INSTI-based
regimen if adherence can be assured.
5.3 DTG ARM
Children randomised to the DTG-containing regimen (DTG-arm) will receive DTG plus 2 NRTIs, with at
least one NRTI having preserved activity. The choice of NRTI will be at the clinician’s discretion and
depend on guidelines and drug availability (See Section 5.2 above on choice of NRTI backbone for the
first and second-line ART in the participating sites).

ODYSSEY Protocol
For children starting second-line ART, the same considerations should be given to addressing
adherence, as outlined in the previous section (Section 5.2.2).
Options for drug regimens for ODYSSEY A:
DTG + ABC + 3TC

DTG + ZDV + 3TC
DTG + TDF + 3TC (or FTC)
DTG + TAF +3TC (or FTC)
Options for drug regimens for ODYSSEY B:
DTG + 2 NRTI
At least one of the NRTIs from ZDV, ABC, TDF (or TAF) should have preserved activity (measured by
resistance tests or presumed from the history of previous ART). D4T or ddi may be used where the
listed NRTIs are contraindicated or not available.
5.3.1 DTG
Dosing will be once daily according to weight bands (Table 3). The dose should be adjusted
accordingly for a child who moves weight band. Children 3 - <14kg are enrolled via the Lower Weight
Band PK (WB-PK) substudy (Appendix XIII) until the doses are confirmed acceptable and safe.
On the basis of WB-PK1 part I [43] and WB-PK1 part II [44] results (see Appendix XIII), reviewed by
the IDMC, TMT, TMG and TSC, the TSC made a recommendation that all children ≥20kg should be
changed to DTG 50mg FCT. Patients 14-<20kg who participated in PK substudies on 25mg DT should
continue on the same dose. Participants on 30mg DT who remain in the same weight band should
complete 24-weeks follow-up before moving to DTG 50mg FCT.
Following the review of the results of the ongoing PK substudies, other DTG doses and formulations
may be studied with accompanying PK as appropriate.
Based on ODYSSEY WB-PK2 results [45] (see Appendix XIII), reviewed by IDMC, TMT<TMG and TSC,
the TSC recommended that children in the weight bands 25 - <40kg previously receiving DTG 25mg
(<30kg) or 35mg (30 - <40kg) should be changed to DTG 50mg QD (film-coated tablet).
Table 3: Dolutegravir dosing in ODYSSEY

Once daily DTG dose and formulations in ODYSSEY
WHO
Wt bands, kg 5mg, 50mg,
Dispersible tablet Film-coated tablet
3-<6 1 (5mg) / 2 (10mg)*
6-<10 3 (15mg)*
10-<14 4 (20mg)*
14-<20 5 (25mg)§
20-<25 - 1 (50mg)¥
25-<35 - 1 (50mg)
≥35 - 1 (50mg)
Infants <6 months of age should receive DTG 5mg QD while infants ≥6 months of age should receive DTG 10mg QD, both as dispersible
tablets.

ODYSSEY Protocol
* Children 3-<14kg will be recruited at WB-PK sites and must be willing to go into the PK substudy if randomised to DTG (Lower WB-PK1
substudy); first children 6-<14kg will be recruited aged ≥6 months (Appendix XIII). The dose may be modified based on data from the ongoing
P1093 study and the data from this study.
§ Children 14-<20kg previously receiving either DTG 20mg QD as two 10mg film-coated tablets or DTG 25mg QD as one film-coated tablet
will be changed to DTG 25mg QD given as five 5mg dispersible tablets.
¥ Children 20-<25kg previously receiving DTG 25mg QD as one 25mg film-coated tablet were initially changed to either DTG 30mg QD (six
5mg dispersible tablets) or DTG 50mg QD (one 50mg film-coated tablet) depending on site. From protocol v5.0, all children 20-<25kg should
receive DTG 50mg QD as one film-coated tablet. Those who prefer to remain on DTG 30mg DT will be able to do so until they move weight
band.
Children weighing 3 to <14kg

Children 3-<14kg will be recruited at PK sites and must be willing to go into the initial PK substudy if
randomised to DTG (Appendix XIII).
Children weighing 3-<6kg randomised to the DTG arm will receive DTG 5mg or 10mg depending on
age (<6 months and ≥6 months of age, respectively) as dispersible tablets QD. Children 6-<10kg and
10-<14kg receive 15mg and 20mg QD as dispersible tablets respectively (Table 3). The dose rationale
for dosing in these weight bands is provided in Appendix XIII. These doses (with the exception of the
5mg DT dose for children <6 months of age and between 3-<6kg) are better aligned to the planned
paediatric Triumeq dispersible tablet (DTG/ABC/3TC 5/60/30) which is under development as one of
the future mid-priority paediatric formulations recommended by WHO-led Paediatric Antiretroviral
Drug Optimization (PADO) group [46].
Based on available PK and safety data from ODYSSEY and/or P1093 (36), doses in ODYSSEY in the 3
lowest weight bands will be reviewed and may be modified (with further PK and safety data if
required) leading to a decision on the appropriate DTG dose for children in these weight bands.
(Appendix XIII).

Children in the 14 - <20kg weight band previously receiving either DTG 20mg QD (two 10mg film-
coated tablets) or DTG 25mg QD (one 25mg film-coated tablet) will be changed to DTG 25mg QD (five
5mg dispersible tablets; see rationale in Appendix XIII).

Children weighing 20 to <25kg previously receiving DTG 25mg QD as one 25mg film-coated tablet
were initially changed to either DTG 30mg QD (six 5mg dispersible tablets) or DTG 50mg QD (one 50mg
film-coated tablet) depending on site (Appendix XIII). Following the review of PK and safety data from
WB-PK1 part II, all children 20-<25kg will now receive DTG 50mg QD as one film-coated tablet. Those
who prefer to remain on DTG 30mg DT will be able to do so until they move weight band.

Following the review of PK and safety data from WB-PK2 (Appendix XIII), all children 25-<40kg will
now receive DTG 50mg QD as one film-coated tablet or as part of a fixed dose combination.
Children weighing ≥40 kg

Children in this weight band receive DTG 50mg film-coated tablet QD.
In countries where a paediatric licensed DTG dose for a particular weight band differs from the doses
to be used in ODYSSEY, the DTG dosing to be used at the site should be discussed with the lead CTU.

ODYSSEY Protocol
5.3.2 FIXED DOSE COMBINATION OF DTG, ABC AND 3TC

For all children above 12 years (≥40 kg), whether ART-naïve or ART-experienced (with chosen NRTI
backbone ABC + 3TC), a three drug fixed dose combination (FDC) tablet containing DTG 50 mg + ABC
600 mg + 3TC 300 mg (Triumeq) can be provided.
Following the analysis of WB-PK2 results for children weighing 25-<40kg which were reviewed by
ODYSSEY and ViiV experts and the IDMC, and considered acceptable, children ≥25kg on DTG and
ABC+3TC in the main trial are able to move to FDC (DTG 50mg + ABC 600 mg + 3TC 300mg) QD provided
they are able to swallow the large tablet.
5.4 DISPENSING
For all trial drugs, the designated trial pharmacist or nurse will confirm receipt of supplies prior to the
commencement of the trial. Inventories will be conducted regularly, and logs returned to the
appropriate CTU.
All drugs dispensed to participants will be recorded on a dispensing log or logged online. At each site,
a named person (trial pharmacist or research nurse) must maintain complete records of all medication
dispensed and returned.
Throughout the treatment period, carers will be provided with a supply of drugs sufficient to last until
the next clinic visit and will be requested to return all empty container packs and to bring any container
packs in use or unused to the follow-up clinic.
On no account should any drug assigned to a participant be used by anyone else. Unused trial drug
must be returned to the site if a participant withdraws from treatment.
5.5 ART MODIFICATIONS, INTERRUPTIONS & DISCONTINUATIONS
5.5.1 GENERAL CONSIDERATIONS ON CHANGES OF ARVs DURING THE TRIAL
For both arms, should the study clinician believe ART should be interrupted, discontinued, or that a
change in treatment is necessary, then the relevant CTU should be notified.
Switching of the current ART regimen in the randomised phase should only occur if there is
immunological, virological or clinical treatment failure (according to local clinical practice), at which
point a new regimen should be chosen. Resistance tests or Therapeutic Drug Monitoring (TDM) may
be used to inform change of regimen, according to local clinical practice. In exceptional circumstances
where standard-of-care third-line is not available at site, and with prior agreement from the relevant
CTU and the Trial Management Group, study drug may be used as third-line for children in the SOC
arm who have failed second-line treatment. If simplification of the ART regimen in the randomised
phase is deemed necessary for clinical reasons during follow-up, this may be allowed, but must first
be discussed with the appropriate CTU. In the extended follow-up phase simplification is allowed and
could be done as per routine practice.
If a female participant on DTG-based regimen is identified as pregnant within the first 8 weeks after
their last menstrual period, the site clinician should discuss the risks and benefits of their current
regimen. If there are other good options to replace DTG, then switching to a non-DTG ART regimen is
recommended.

ODYSSEY Protocol
Toxicity will be managed according to standard clinical practice. Blood tests additional to those
described in the trial schedule may be requested for clinical management of the participant.
Wherever possible and appropriate, side effects will initially be managed by symptomatic measures
and administration of appropriate (non-contraindicated) medication. Interruption or substitution of
drugs should be avoided except in the event of grade 3 or 4 toxicity that is considered at least possibly
related to one or more of the ARVs. Wherever possible, an alternative ARV should be substituted
from the same class in order to maintain the participant’s randomised treatment strategy.
Management of adverse events/toxicity should generally follow the criteria below, but clinicians
should use their clinical judgment as to the best management for an individual participant. If in doubt,
contact the relevant CTU to obtain advice.
NOTE: In the event of a discontinuation of an ABC-containing product for any reason (aside from
possible hypersensitivity), re-initiation of this drug should be undertaken with caution. The
investigator must obtain a complete history of the events surrounding the discontinuation of the ABC-
containing product and evaluate for the possibility of a clinically suspected hypersensitivity reaction
(HSR) to ABC. Regardless of a subject’s HLA-B*5701 status, if a hypersensitivity reaction cannot be
excluded, then ABC must not be restarted.
Grade 1 and 2
Continue ARVs
Manage using symptomatic measures and other concomitant medication, if appropriate
Raised serum aminotransferase ≥3xULN and total serum bilirubin level ≥2xULN (or coagulopathy (INR
>1.5) without hyperbilirubinemia) may indicate idiosyncratic drug induced liver injury [47] and
recommendations for Grade 3 or 4 toxicity events as outlined below should be followed.
Grade 3 or 4:
Request laboratory results and repeat confirmatory laboratory results within 72 hours if
relevant
Continue study drugs pending receipt of the confirmatory laboratory tests/repeat
observations, unless there is an immediate need to substitute ART
Continue to work-up to exclude other causes
Following confirmation of toxicity, and lack of other cause data:
if the child is not too sick, substitute ART immediately
otherwise, stop all drugs and restart with substituted drugs when the child has
improved
stagger stop NNRTI wherever possible to avoid functional monotherapy and risk of
resistance (as per PENTA/national guidelines)
5.5.2 ADVERSE REACTIONS & DISCONTINUATIONS OF DTG

5.5.2.A Liver toxicity
Stopping criteria based on liver function test thresholds have been designed to assure participant
safety during administration of the medication and the follow-up period. It may be necessary to
substitute DTG should any of the following criteria be met:
ALT ≥3xULN and bilirubin ≥2xULN
ALT ≥5xULN and symptoms of acute hepatitis or hypersensitivity (fatigue, nausea, vomiting,
right upper quadrant pain, fever, rash or eosinophilia)

ODYSSEY Protocol
ALT ≥ 5xULN for more than 2 weeks with bilirubin <2xULN and no symptoms of acute hepatitis
or hypersensitivity
ALT ≥8xULN
Participants who develop ALT ≥5xULN should be followed weekly until resolution or stabilization (ALT
<5xULN on 2 consecutive evaluations).
When liver chemistry stopping criteria are met, investigator must:

Notify the relevant CTU of the event by e-mail within 24 hours of its occurrence and report
the event on the Event form (see 7.1.5.A). Additional information will then be requested from
the sites.
Discontinue DTG and substitute for an appropriate alternative (the child will continue follow
up in the study). If an alternative cause of the raised liver enzymes is more likely (e.g. Hepatitis
A, anti-TB treatment) then the investigator must contact the MRC CTU.
If DTG is discontinued for liver toxicity, participants should not restart DTG due to the risk of a
recurrent reaction. If an alternative cause of the raised liver enzymes is more likely, restarting of DTG
may be permitted but the investigator must have discussed and agreed this with the MRC CTU.
5.5.2.B Allergic reaction or rash
Participants may continue DTG for grade 1 or 2 allergic reactions or rash at the discretion of the
investigator. Consideration should be made as to whether another ARV or another drug maybe
causing the reaction. The carer/participant should be advised to contact the investigator immediately
if there is any worsening of symptoms if mucosal involvement develops or if further systemic signs or
symptoms develop. Antihistamines, topical corticosteroids, or antipruritic agents may be prescribed.
Participants with grade ≥2 rash that is associated with an increase in ALT OR grade ≥3 allergic reactions
or rash that are considered to be possibly or probably related to DTG should permanently discontinue
DTG and substitute with an appropriate alternative; the participant will remain in the study.
Investigators should contact the CTU to discuss cases if there is any uncertainty about the course of
action. Participants should be treated as clinically appropriate and follow-up of the AE should be
reported on CRFs as appropriate.
Participants receiving an ABC-containing product should be evaluated for the possibility of a clinically
suspected HSR and managed appropriately as outlined in the local product information, regardless of
a subject’s HLA-B*5701 status.
5.5.2.C Suicidal Ideation Behaviours and Sleep Disorders
Participants with HIV infection may occasionally present with symptoms of depression and/or
suicidality (suicidal ideation or behaviour). In addition, insomnia and depression have been
infrequently reported with the use of several antiretroviral drugs, including efavirenz, darunavir,
atazanavir and integrase inhibitors. Suicidal ideation has also been associated with efavirenz and
integrase inhibitors, primarily in patients with pre-existing depression or psychiatric conditions.
Therefore, participants in both arms in ODYSSEY should be monitored appropriately for suicidal
ideation and behaviour or any other unusual changes in behaviour. It is recommended that the
subjects who experience signs of suicidal ideation or behaviour have prompt clinical evaluation and
the investigator considers mental health consultation or referral and discontinuation of the
corresponding drugs. See section 7.1.5 C for reporting of these events.

ODYSSEY Protocol
5.6 ACCOUNTABILITY & UNUSED DRUGS/DEVICES
Procedures for drug shipping, labelling, resupply, accountability and destruction will be detailed in the
ODYSSEY Pharmacy MOP. Drug accountability will be regularly monitored and the remaining stocks
checked against the amounts dispensed.
5.7 ADHERENCE & ACCEPTABILITY
Adherence to ART will be assessed by pill counts and short adherence questions at study visits (see
Appendix IV). The importance of adherence should be reinforced at each visit. Non-adherence should
prompt the study clinician to identify and address the cause(s) (e.g. side effects, social challenges).
An acceptability, sleep and mood questionnaire at enrolment and at weeks 4, 12, 24, 48, 72, 96 and
then 24 weekly until the end of study, will elicit participant opinions about the different regimens,
particularly with regard to pill burden; complexity and stigma (see Appendices V-VI). At enrolment,
only the questions about sleep and mood should be answered.
5.8 OVERDOSE OF TRIAL MEDICATION
All participants/carers should be counselled about the importance of taking/administering the

medications as prescribed. It is particularly important that participants and carers understand the
quantity of medicines they should be given. Participants must be told to contact the clinic immediately
if they take too much medication. If the overdose fits the criteria of an SAE (see Section 7.1) it should
be reported appropriately.
5.9 PROTOCOL TREATMENT DISCONTINUATION
In consenting to the trial, participants and carers are consenting to trial treatment, trial follow-up and
data collection. However, an individual participant may stop treatment early for any of the following
reasons:
(i) Unacceptable toxicity (clinical or laboratory) or adverse event

(ii) Disease progression necessitating change of regimen
(iii) Virological failure
(iv) Withdrawal of consent for treatment by the participant or carer
As the child’s participation in the trial is entirely voluntary, they or their carer may choose to
discontinue the trial treatment at any time without penalty or loss of benefits to which they are
otherwise entitled.
Although the participant and/or carer are not required to give a reason for discontinuing their trial
treatment, reasonable effort should be made to establish this reason while fully respecting the
participant’s rights.
Participants should remain in the trial for the purpose of follow-up and data analysis (unless the
participant or carer withdraws their consent from all stages of the trial). If a patient is withdrawn
from follow-up, refer to Section 6.9.
Data will be kept and included for participants who stop follow-up early, up to the point of exit.

ODYSSEY Protocol
5.10 NON-TRIAL TREATMENT AND SIGNIFICANT DRUG INTERACTIONS
Families and participants should be advised to notify their clinician of any current or proposed
concomitant medication, whether prescribed or over-the-counter. All necessary concomitant
medications will be recorded in the study CRFs.
Dofetilide, a class III antiarrhythmic agent, not licensed in children <18 years, is the only drug that is
contraindicated for co-administration with DTG.
A few drugs have important drug interactions with DTG and require dose adjustment of DTG or their
intake should be separated in time. Table 4 shows some of the interacting drugs that may be relevant
for the patients in ODYSSEY. For full information see dolutegravir SPC.
Table 4. Significant drug interactions with DTG and recommended actions
Anticonvulsants
Oxcarbazepine Weight-appropriate dose of DTG should be doubled (given twice
Phenytoin daily).
Phenobarbital
Sodium valproate Careful clinical and adherence monitoring are advised and a
repeat VL can be considered.
Herbal products
St. John's wort Weight-appropriate dose of DTG should be doubled (given twice
daily).
Antacids and supplements
Magnesium/ aluminium- Calcium supplements, iron supplements or multivitamins should
containing antacid be taken well separated in time from the administration of DTG
Calcium supplements (minimum 2 hours after or 6 hours before DTG). Alternatively DTG
Iron supplements can be taken with food.
Multivitamin
Antimycobacterials
Rifampicin Weight-appropriate dose of DTG should be doubled (given twice
daily).
Please refer to DTG SmPC (https://www.medicines.org.uk/emc/product/5248/smpc ) and

the University of Liverpool HIV Drug Interactions site (https://www.hiv-
druginteractions.org/drug_queries/new) for the full list of the possible drug interactions.

ODYSSEY Protocol
6 ASSESSMENTS & FOLLOW-UP
Trial visit schedules will be prepared for each participant at randomisation, and participants should be
followed on the same schedule even if their trial medication is discontinued. The target dates for trial
visits are determined by the date of randomisation and are not affected by subsequent events. The
schedule sent or generated after randomisation defines visit dates (with windows) necessary for data
collection, but the participant may be seen more frequently for clinical care as needed.
Participants should attend on the scheduled day whenever possible, unless agreed in advance with
the clinic. Clinics may choose to re-schedule visits to allow for public holidays or other unavoidable
circumstances that affect the scheduled visit date. During the treatment period, if participants are
unable to attend on the day, every effort should be made to complete the visit as soon as possible and
within 14 days of the scheduled date. If a scheduled visit is missed without notice then the research
team should endeavour to contact the participant by phone or by home visit.
If a participant is more than 14 days late for a scheduled study visit (during the treatment period), an
additional visit will be performed as soon as possible, including the appropriate assessments that were
specified in the trial schedule for the visit week that was missed.
6.1 TRIAL ASSESSMENT SCHEDULE
6.1.1 RANDOMISED PHASE

All participants will be seen at screening, enrolment (randomisation, week 0) and then at weeks 2 (for
children 3-<14kg), 4, 12, 24, 36, 48, 60, 72, 84 and at week 96 (see Trial Assessment Schedule). All
participants should then be followed-up in clinic every 12 weeks until the last participant enrolled up
to the end of recruitment for the main trial (see 3.4) reaches week 96 or for a minimum of 96 weeks,
whichever is greater. Clinical assessment at week 2 is required for children 3-<14kg and optional for
children ≥14kg at sites with the standard practice to review participants at 2 weeks after starting new
antiretrovirals.
A full clinical assessment and the following will be undertaken as specified in the Trial Assessment
Schedule:
Medical history since last visit including intercurrent illnesses, all AEs, signs and symptoms of
HIV disease with WHO stage on every visit
Weight, height and mid-upper arm circumference (MUAC) on every visit
Viral load as per local practice (in ODYSSEY B viral load must be measured at screening unless
the viral load has been done within 4 weeks prior to screening)
Haematology at screening, weeks 0, 2 (for children 3-<14kg), 4, 24, 48, 72, 96 and at the study
visit at the end of the randomised phase, and at other time points as per local practice.
T cell lymphocyte subsets at screening, weeks 0, 4, 12, 24, 48, 72, 96 and at the study visit at
the end of the randomised phase, and at other time points as per local practice.
Plasma storage at screening, week 0, 4, 12 and then 12 weekly and at the study visit at the
end of the randomised phase.
RBC folate/RBC storage and B12/serum storage at week 96 or later
Cell storage (at the selected sites) at week 0, 12, 48, and 96
Biochemistry at screening, 2 (for children 3-<14kg), week 4, 24, 48, 72 and 96 and at the study
visit at the end of the randomised phase, and if indicated or if required by local practice.
Participants should be fasting at week 0, 48 and 96, every 48 weeks and at the study visit at
the end of the randomised phase in order to obtain fasting lipids and glucose values
Bone profile (optional) at randomisation, week 48, 96 and then 48 weekly, and at the study
visit at the end of the randomised phase at the sites where these tests are done routinely

ODYSSEY Protocol
Urine dipstick at randomisation, week 48, 96 and then 48 weekly, and at the study visit at the
end of the randomised phase.
Tanner scales (see Appendix X) should be completed at week 0 and repeated every 24 weeks
(unless previous scores of 5) until the study visit at the end of the randomised phase in
children aged 8 or over.
Lipodystrophy clinical assessment should be performed at week 0 and repeated at weeks 48
and 96 then 48 weekly and at the study visit at the end of the randomised phase.
Pregnancy tests should be performed for all females of childbearing potential at screening,
randomisation and all trial follow-up visits (including unscheduled visits), regardless of
whether the participant has recently had her period. All boys and girls of reproductive age
will be given continuing advice about avoiding pregnancy; information about contraception
use will be recorded. If a pregnancy test performed during the trial is positive, please notify
the appropriate CTU, following procedures detailed in Sections 6.8 and 7.2.1.
In addition at each visit the following should be recorded:

Assessment of adherence to ART by adherence questionnaire while the participant is on
treatment
Changes in ART and other concomitant medication
All adverse events since the last protocol visit, including haematological abnormalities,
pancreatitis, diarrhoea, clinical lipodystrophy, acute illnesses
Change in HIV disease stage since last protocol visit
Inpatient and outpatient attendances with any documented test results
The next supply of drugs to last until the next clinic visit will be dispensed. Prescriptions of ART and
any alterations to prescribed doses should be recorded on the CRF. Doses should be checked at every
visit and adjusted for body surface area, or weight as appropriate.
Additional study visits, for example if the child develops drug toxicity or other clinical events should
be recorded using appropriate forms. At such visits, laboratory tests should be performed as clinically
indicated. Participants will also be given a patient card with the contact details for the trial research
team at their site and information on ABC hypersensitivity if receiving ABC.
For the frequency of the assessments after week 96, see the Trial Assessment Schedule.
6.1.2 EXTENDED FOLLOW-UP OF ODYSSEY PARTICIPANTS

When participants attend for their study visit at the end of the randomised phase (after the last patient
reaches 96 weeks for children recruited weighing ≥14kg or the 96 week visit for children <14kg),
consent/assent will be requested in order for them to enter into a period of extended follow-up. The
purpose of this extended follow-up is to collect further safety data for participants who will continue
to receive ViiV Healthcare supplied dolutegravir (where the formulation that they are taking is not
available through the country’s national HIV treatment programme) and also to monitor long-term
safety and effectiveness of dolutegravir versus standard of care (at selected sites, subject to sufficient
funding). The child’s visit schedule and care will be as per local clinic guidelines with a small amount
of data to be collected in addition to this. Please see Appendix XX for further details on the
arrangements for extended follow-up.
6.2 PROCEDURES FOR ASSESSING EFFICACY
6.2.1 CLINICAL:
A symptom checklist and targeted physical examination (to evaluate any reported symptoms) will be
performed at each visit during the randomised phase. Hospital admissions will be solicited at all visits,

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regardless of the trial phase. Where there is any clinical suspicion of a WHO Stage 3 or 4 disease event,
centres will endeavour to investigate to the full extent possible given local availability of imaging and
laboratory investigations (particularly microbiology) in order to establish a clear diagnosis of the event.
The lists of WHO stages and diagnostic criteria are provided (see Appendices VII-IX). The site will
report the event and the clinical investigations that support the diagnosis on the Event form in order
to enable an independent evaluation of the event. An endpoint review committee will review all
clinical endpoints occurring during the randomised phase to ensure that they satisfy the diagnostic
criteria.
6.2.2 IMMUNOLOGY:
Blood will be collected according to the appropriate trial assessment schedule, depending on whether
the participant is in the randomised phase or extended follow-up period of the trial, for the
determination of total and percentage CD4 and CD8 T cell counts. The T cell subsets will be measured
using the standard assay in the laboratory operating at each site according to quality-assured
procedures.
6.2.3 VIRAL LOAD TESTING:

At sites where plasma HIV viral load (VL) is routinely measured every 12-16 weeks, VL should be
measured at screening, week 4, 12, 24 and then every 12 weeks until the study visit at the end of the
randomised phase.
At the sites where VLs are not routinely measured every 12-16 weeks, real-time viral load should be
measured at the screening visit for participants in ODYSSEY B, unless one has been done within 4
weeks prior to screening. Viral loads should then be done according to local routine practice. Viral
loads will be measured retrospectively on EDTA-plasma samples stored at screening, enrolment
(ODYSSEY A), week 4, 12, 24, and then every 12 weeks until the end of the randomised phase.
Retrospective VL measurements will be done in batches using the same assay (lower limit of detection
of no greater than 50 c/ml) in one or more designated PENTA laboratories. The Independent Data
Monitoring Committee (IDMC) (Section 14.3) will review VL results on all patients during the
randomised phase.
If the participant meets the definition of treatment failure during the trial (WHO 2016 guidelines), and
the treating physician wishes to modify treatment, they may perform a VL test at their site, to confirm
treatment failure prior to switch. In this situation the management of the participant will be discussed
with the relevant CTU and the trial Clinical Advice Group.
6.2.4 RESISTANCE TESTING

At sites where genotypic resistance testing is part of routine care, for children experiencing virological
failure tests should be run on the latest sample while the child is still on the same treatment. At sites
where genotypic resistance testing is not a part of routine care baseline samples will be tested
retrospectively using stored EDTA-plasma to assess background regimen activity at baseline and
batched genotypic resistance testing will be performed on the samples with viral load reaching
current threshold for resistance assays. Additional resistance tests will be performed on stored
plasma samples in selected participants at the end of the randomised phase of the trial to define in
more detail the pattern of resistance development. Samples may be assayed locally where possible,
or moved to another country.
Drug resistance mutations will be classified using the Stanford database algorithm. The results of all
resistance tests performed in individual participants will be given to the treating physician after the
last participant has completed 96 weeks follow-up, or as soon thereafter as results become available.

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6.3 PROCEDURES FOR ASSESSING SAFETY
The clinical examination at each visit will explicitly prompt for symptoms relating to possible drug
toxicities. Blood will be drawn at trial visits to assess laboratory safety parameters as per the
appropriate Trial Assessment Schedule depending on whether the participant is in the randomised
phase or extended follow-up period of the trial. Additional safety blood tests or investigations may
be performed to investigate symptoms or monitor emergent laboratory test abnormalities as clinically
indicated.
Adverse events will be reported on the case report form. Adverse events (clinical and laboratory) will
be graded using the 2014 Division of AIDS toxicity grading scale (see Appendix IX). Grade 1 and 2
clinical events do not need to be reported unless resulting in a change of ART regimen. Serious adverse
events will be defined according to ICH GCP, and should be reported to the CTU within 24 hours of the
site being aware (see Section 7 - Safety Reporting). All adverse events meeting the definitions above
should be reported on study CRFs, regardless of their relationship to HIV.
6.4 PROCEDURES FOR ASSESSING QUALITY OF LIFE
Quality of life questionnaire adapted from EQ-5D questionnaires [48] should be completed by all
children aged 8 or over, regardless of which arm they are in, at randomisation (week 0), 12, 24, 48
weeks and then every 48 weeks and at the study visit at the end of the randomised phase.
6.5 ADHERENCE ASSESSMENTS
Adherence issues should be addressed with potential participants in ODYSSEY B before screening for
the trial and an adherence questionnaire should be completed at the screening visit. At 4 and 12
weeks and thereafter every 12 weeks until the end of the randomised phase, carers and children,
where appropriate, will be asked to complete an adherence questionnaire. This will include questions
about adherence to all the antiretrovirals.
6.6 MANAGEMENT OF PARTICIPANTS WITH TREATMENT FAILURE
In settings where viral load measurement is part of routine care, viral loads will be measured
locally. Participants experiencing virological failure should have reasons for virological failure
investigated as per local practice (addressing problems with adherence, adequate dosing,
drug interactions, and if available, drug levels, resistance mutations) prior to decisions being
made about switching ART. ART management decisions (discontinuation of the previous
regimen, change to the new regimen) should also be made by the treating clinician as per
accepted local practice. Advice from the Clinical Advice Group should be sought during the
randomised phase of the trial and the CTU also contacted. The participant should continue to
be seen 12 weekly until the end of the randomised phase (see Trial Assessment Schedule for
randomised phase of the trial). Participants should follow local practice at subsequent visits.
CRFs should be completed at each follow up visit.
In settings where viral load measurement is not routine care, the efficacy of treatment will be
monitored using clinical assessment and local CD4 cell counts/percentage. During the
randomised phase, therapy will be maintained according to the randomised strategy until
there is clinical or immunological failure, defined for the protocol as after at least 36 weeks
on the allocated regimen. Where available, a targeted viral load should be done to confirm
treatment failure prior to switch. If the treating clinician decides to switch therapy, then the

ODYSSEY Protocol
next regimen should be given according to guidelines and paediatrician choice and based on
the local availability of antiretrovirals; advice can also be obtained from the Clinical Advice
Group. The clinician can at any stage give alternative treatment to that specified in the
protocol if it is considered to be in the participant’s best interest. However this should be
discussed first with the CTU if the participant is in the randomised phase of the trial.
6.7 MANAGEMENT OF CHILDREN DIAGNOSED WITH TUBERCULOSIS (TB)
Participants with TB at enrolment or who develop TB during the trial should receive TB treatment
following national guidelines (usually rifampicin, isoniazid, pyrazinamide, and ethambutol). Where
available, cultures should be tested for sensitivity to first-line anti-TB drugs and regimens modified on
the basis of these results.
Participants may need to be referred to the national TB treatment programme in order to access anti-
tuberculosis medication, and close liaison between the trial team and the TB treatment providers will
be required.
6.7.1 MANAGEMENT OF CHILDREN WITH TUBERCULOSIS INFECTION IN THE DTG ARM

DTG pharmacokinetics are influenced by concomitant treatment with rifampicin. This interaction can
be overcome by giving the weight-appropriate dose of DTG twice daily, i.e. the protocol daily dose is
doubled.
Therefore, in a child on rifampicin, the DTG dose needs to be increased from QD to BID and remain
BID until 2 weeks after the last dose of rifampicin has been given (the enzyme inducing effect of
rifampicin slowly fades away after discontinuing the drug).
Although not compulsory, at least 12 children in the DTG arm receiving rifampicin as part of anti-TB
treatment or TB prevention therapy will be invited to participate in the TB substudy for children on
DTG and rifampicin (see Section 10.1.3 and Appendix XIV).
6.7.2 MANAGEMENT OF CHILDREN WITH TUBERCULOSIS IN THE SOC ARM

As rifampicin interacts with some ARVs, including PIs and NNRTIs, change of regimen may be needed
for co-infected children in SOC arm. Guidance on the choice of ART for children with TB can be found
in the WHO 2016 guidelines and in national guidelines and may differ between countries. Children
who are on EFV-based ART can continue on the same regimen while those (>3 years) receiving NVP
should be switched to EFV. Children receiving LPV/r-based ART can continue on their regimen if they
receive super-boosted ritonavir (increasing ritonavir to achieve a LPV/r ratio of 1:1), or they can be
switched to EFV (if >3 years). As an alternative, children receiving NVP or LPV/r with rifampicin may
change to triple NRTI (ZDV + 3TC + ABC) [49] or the NVP dose should be increased to the maximum
recommended, i.e. 200 mg/m2 BID. In order to obtain better exposure in younger children, the
maintenance dose can be further increased by 20-30% after two weeks of starting (H Lyall, S Welch,
unpublished data). CTUs should be notified and advice sought from the Clinical Advice Group.
6.8 MANAGEMENT OF PREGNANCY
Reproductive toxicology animal studies, including embryofoetal development studies in rats and
rabbits, showed no evidence of adverse developmental outcomes [34].
A National Institutes of Health (NIH)-funded observational surveillance study in Botswana (TSEPAMO)

evaluating the safety of ART regimens in pregnancy has recently identified an increased risk of neural

ODYSSEY Protocol
tube defects (NTD) amongst infants of women who initiated DTG-based regimens prior to pregnancy
(see Background). This study and other surveillance studies are ongoing and other reproductive
studies on DTG safety have been initiated. More data on safety of DTG for women of childbearing age
and their infants are expected in the next year.
All eligible girls with childbearing potential will be counselled about the potential risks associated with
pregnancy during the trial and the potential risks of antiretroviral therapy on the infant. If the girl
then chooses to enter the trial, she will be advised to use highly effective contraception and to report
to the study site staff as soon as possible if there is a possibility of pregnancy.
Following the safety alert, ODYSSEY sites were advised that all female participants who are sexually
active must use highly effective contraception [38]. This includes:
1. Combined (estrogen and progestogen containing) hormonal contraception associated with
inhibition of ovulation
a. oral
b. intravaginal
c. transdermal
2. Progestogen-only hormonal contraception associated with inhibition of ovulation
a. oral (eg. containing 75 micrograms desogestrel)
b. injectable
c. implantable
3. Intrauterine device (IUD)
4. Intrauterine hormone-releasing system ( IUS)
DTG has no interaction with hormonal contraceptives, and therefore any hormonal contraceptives
inhibiting ovulation can be used in female participants in the DTG arm. For participants in the SOC
arm, the site clinician should consider drug interactions between some third agents (nevirapine and
protease inhibitors) and a number of hormonal contraceptives. Please refer to the table
‘Recommendations for co-administration of different types of contraception with antiretrovirals in the
MOP for guidance on prescribing hormonal contraceptives for participants.
Pregnancy testing will be undertaken at screening and randomisation in girls who have reached
menses. If pregnant, she will be ineligible for the trial. For randomised females who have reached
menses, pregnancy tests will be repeated at all trial follow-up visit and at other time-points as
required. Females will be encouraged to disclose missed menses as soon as possible; if this happens,
a pregnancy test should be done.
Female participants taking DTG who are intending to become pregnant or are identified to be
pregnant, need to discuss the risks and benefits of their current regimens with their health care
providers. The neural tube closes within 4 weeks of conception and therefore switching off DTG is
particularly relevant for women diagnosed with pregnancy early. If women are in very early
pregnancy (within 8 weeks from last menstrual period) and there are other good options to replace
DTG, then switching to a non-DTG ART regimen is strongly recommended as per DHHS guidance [50].
Those who are pregnant and are 8 weeks or greater from last menstrual period may continue DTG-
based regimens. Discontinuing DTG-based regimens is unlikely to confer any benefits after the
neural tube has formed, and medication changes during pregnancy could increase the risk of viremia
and transmission of HIV to the infant.
There is also a risk that a young person may become non-adherent if their DTG-based ART regimen is
well tolerated but this is then changed. The clinician should therefore use his/her judgement about
whether benefits of continuing a pregnant woman on DTG-containing products are deemed to
outweigh the risks (e.g., individual cases from study populations with limited treatment options, or

ODYSSEY Protocol
risk of poor adherence on alternative ART regimen, especially if pregnancy comes to light late and
near to the time of delivery). Where local regulatory regulations allow, the woman may continue
DTG and the case should be discussed with MRC CTU. Pregnant participants should be encouraged
to remain in the study whether or not their ART regimen is changed at this time.
Pregnant participants should receive counselling about their options and receive support to make
decisions about continuing pregnancy. Folic acid should be provided to be taken throughout the first
trimester. For females on DTG who become pregnant, advice on breast-feeding will be given according
to local or national lactation and treatment guidelines and standard of care. All infants will receive
infant prophylaxis according to the current local standard of care.
Reporting of pregnancy and pregnancy-related events are outlined in section 7.1.5.D.
6.9 EARLY STOPPING OF FOLLOW-UP
If a participant or their carer chooses to discontinue the trial treatment, the participant should
continue to be followed until the end of the trial providing the participant and their carer are willing;
that is, they should be encouraged not to leave the trial. However, if the participant and/or carer do
not wish to remain on trial follow-up, they should be offered the option of continuing with routine
follow up and permission to collect minimal routine outcomes from the patient’s notes should be
requested. If they do not wish to provide information about routine follow up, their decision must be
respected and the patient will be withdrawn from the trial completely. The CTU should be informed
of this in writing using the appropriate documentation. Participants stopping early have a negative
impact on a trial's data.
If the medical data collected during the participant's time in the trial are kept for research and analysis
purposes, they can be further anonymised if necessary. Consent for future (but not past) use of stored
samples already collected can be refused when leaving the trial early (but this should be discouraged
and should follow a discussion with the patient/carer).
Participants and carers may change their minds about stopping trial follow-up at any time and re-
consent to re-enter participation in the trial.
Participants who stop trial follow-up early will not be replaced, as the total sample size includes an
adjustment for losses to follow-up.
6.10 PARTICIPANT TRANSFERS
If a participant moves from the area, reasonable efforts should be made to continue their follow-up,
e.g. by them continuing to come for visits providing the site has sufficient resources, or by conducting
nurse only visits over the telephone and providing drugs and clinical care at a local clinic. If a local site
is conducting the trial, the participant can be transferred there; a copy of the participant’s CRFs should
be provided to the new site and the parent/carer will need to sign a new consent form. Once this has
been done, the new site will take over responsibility for the participant; until this has been done,
responsibility for the participant lies with the original site.
If none of the above options are possible, then the participant should be considered as lost to follow-
up. The participant and/or carer may or may not choose to formally register this as a withdrawal of
consent.

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6.11 END OF TRIAL
After target accrual is reached (see Section 3.4 and Analysis Plan Section 9.5) the end of main trial
recruitment date will be defined. Recruitment will then stop for children ≥14kg. Recruitment will
continue in the 3 lower weight bands (3-<6kg, 6-<10kg and 10-<14kg) until at least 20 children are
recruited in each weight band. Follow-up for children recruited up to the end of main trial recruitment
date will continue during the randomised phase until the last child recruited has completed 96 weeks
follow-up; all such participants will attend a study visit for the end of the randomised phase after the
last child reaches 96 weeks.
Analysis of the main trial will be conducted at this time. Results will not be available until
approximately 6 months after children in the main trial have attended their final study visit (in the
randomised phase), retrospective viral load testing is complete and the database has been locked.
Each of the children recruited in the lower weight bands after the end of main trial recruitment date
will continue to be followed up for 96 weeks. Children in the lower weight bands should attend for
their study visit for the end of the randomised phase at or after 96 weeks; they should not attend for
this visit prior to the ‘diary date’ given in the participant’s visit schedule.
After the end of the randomised phase DTG will be provided by ViiV for those children randomised to
the DTG arm until it is available and recommended for children in their country of residence. Where
DTG is available locally, a short supply of trial stock will be provided to enable participants to transition
smoothly onto the national antiretroviral treatment programme. Participants receiving Triumeq
should be switched to DTG 50mg plus a separate fixed dose combination of ABC/3TC 600/300mg
(Kivexa or generic equivalent) on the national programme if Triumeq is not available locally.
Children weighing <20kg at sites in South Africa, Uganda and Zimbabwe still receiving DTG 5mg at the
end of the randomised phase will continue into extended follow-up until they reach 20kg (and can
switch to DTG 50mg, available locally) or generic dispersible DTG becomes available locally. Children
weighing ≥20kg randomised to the DTG arm at these sites are expected to have access to DTG 50mg
through their country’s national antiretroviral treatment programme by the end of the randomised
phase of the trial.
Children in Thailand randomised to the DTG arm will continue into extended follow-up so that DTG
50mg can continue to be provided. Participants receiving Triumeq will be switched to (DTG 50mg
provided by ViiV) plus a separate fixed dose combination of ABC/3TC 600/300mg (Kivexa or generic
equivalent available through the national antiretroviral treatment programme) for this period.
All children in DTG and SOC arms at sites in Africa and Thailand may continue into extended follow-
up, subject to sufficient funding. Children in extended follow-up will attend clinic visits as per local
practice (see Appendix XX for more details). SAEs will continue to be reported as per trial requirements
(Section 7).
The ODYSSEY trial comprises a randomised phase and an extended follow-up phase. The end of the
trial will be when all children have attended their final study visit (in randomised or extended follow-
up phase, any retrospective viral load testing is complete and the database has been locked for the
end of trial. The date of the expected end of the trial will be communicated to the participating centres
approximately 3-6 months before the trial ends. The sponsor, or the sponsor’s representative in each
country, will notify the national regulatory body and ethics committee of the end of the trial. The

ODYSSEY Protocol
Principal Investigator at each site will be responsible for notifying local ethics boards and any other
local bodies, such as R&D departments.

ODYSSEY Protocol
7 SAFETY REPORTING
The principles of GCP require that both investigators and Sponsors follow specific procedures when
notifying and reporting adverse events or reactions in clinical trials. These procedures are described
in this section of the protocol. Section 7.1 lists definitions, Section 7.2 gives details of the investigator
responsibilities and Section 7.3 provides information on MRC CTU responsibilities.
7.1 DEFINITIONS
The definitions of the EU Directive 2001/20/EC Article 2 based on the principles of GCP apply to this
trial protocol. These definitions are given in Table 5.
Table 5: Definitions
TERM DEFINITION
Adverse Event (AE) Any untoward medical occurrence in a patient or clinical trial
subject to whom a medicinal product has been administered
including occurrences that are not necessarily caused by or
related to that product.
Adverse Reaction (AR) Any untoward and unintended response to an investigational
medicinal product related to any dose administered.
Unexpected Adverse Reaction (UAR) An adverse reaction, the nature or severity of which is not
consistent with the information about the medicinal product in
question set out in the Summary of Product Characteristics (SPC)
or Investigator Brochure (IB) for that product.
Serious Adverse Event (SAE) or Serious Respectively any adverse event, adverse reaction or unexpected
Adverse Reaction (SAR) or Suspected adverse reaction that:
Unexpected Serious Adverse Reaction Results in death
(SUSAR) Is life-threatening*
Requires hospitalisation or prolongation of existing
hospitalisation**
Results in persistent or significant disability or
incapacity
Consists of a congenital anomaly or birth defect
Is another important medical condition***
*The term life-threatening in the definition of a serious event refers to an event in which the patient
is at risk of death at the time of the event; it does not refer to an event that hypothetically might
cause death if it were more severe, for example, a silent myocardial infarction.
**Hospitalisation is defined as an inpatient admission, regardless of length of stay, even if the

hospitalisation is a precautionary measure for continued observation. Hospitalisations for a
pre-existing condition, that has not worsened or for an elective procedure do not constitute an
SAE.
*** Medical judgement should be exercised in deciding whether an AE or AR is serious in other

situations. The following should also be considered serious: important AEs or ARs that are not
immediately life-threatening or do not result in death or hospitalisation but may jeopardise the
subject or may require intervention to prevent one of the other outcomes listed in the definition
above; for example, a secondary malignancy, an allergic bronchospasm requiring intensive

ODYSSEY Protocol
emergency treatment, seizures or blood dyscrasias that do not result in hospitalisation or

development of drug dependency.
7.1.1 MEDICINAL PRODUCTS

An investigational medicinal product (IMP) is defined as the tested investigational medicinal product
and the comparators used in the study (EU guidance ENTR/CT 3, April 2006 revision). In ODYSSEY DTG,
Triumeq and 3rd agent comparators prescribed in the SOC arm are the IMP.
Adverse reactions include any untoward or unintended response to drugs. Reactions to the IMP or
the other antiretrovirals should be reported appropriately.
7.1.2 ADVERSE EVENTS

Adverse Events include:
An exacerbation of a pre-existing illness
An increase in frequency or intensity of a pre-existing episodic event or condition
A condition (even though it may have been present prior to the start of the trial) detected
after trial drug administration
Continuous persistent disease or a symptom present at baseline that worsens following
administration of the study treatment
Adverse events which do not require reporting in this trial:

Overdose of medication without signs or symptoms
Grade 1 or 2 events which do not result in any changes to ART
Adverse Events do not include:

Medical or surgical procedures; the condition that leads to the procedure is the adverse event
Pre-existing disease or a condition present before treatment that does not worsen
Hospitalisations where no untoward or unintended response has occurred, e.g., elective
cosmetic surgery, social admissions
7.1.3 DISEASE-RELATED EVENTS

All adverse events meeting the definitions above should be reported on study CRFs, regardless of their
relationship to HIV and should be graded. In particular, all deaths should be reported as fatal SAEs.
7.1.4 OTHER NOTABLE EVENTS

7.1.4.A Liver events
All suspected cases of drug induced liver injury in both arms should be reported as a notable event
and AE or SAE as appropriate on an Event form and, during the randomised phase, should be sent to
the relevant CTU within 24 hours of the site becoming aware. Reporting timelines during extended
follow-up for notable events which don’t constitute a SAE are outlined in Appendix XX. Additional
information will be then requested from the sites. Any results of liver investigations, including liver
biopsy and/or imaging should be reported.
7.1.4.B ABC Hypersensitivity reaction (HSR)

Clinically suspected ABC HSR should be reported as a notable event and AE or SAE as appropriate on
an Event form and, during the randomised phase, should be sent to the relevant CTU within 24 hours
of the site becoming aware. Reporting timelines during extended follow-up for notable events which
don’t constitute a SAE are outline in Appendix XX. Additional information will be requested from the
sites and should be completed within one week of the onset of the hypersensitivity reaction.

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7.1.4.C Suicidal Ideation or Behaviours

A possible suicidality-related adverse event (PSRAE) should be reported as a notable event and AE or
SAE as appropriate on an Event form and, during the randomised phase, should be sent to the relevant
CTU within 24 hours of the site becoming aware. Reporting timelines during extended follow-up for
notable events which don’t constitute a SAE are outline in Appendix XX. A PSRAE may include, but is
not limited to, an event that involves suicidal ideation, a preparatory act toward imminent suicidal
behaviour, a suicide attempt, or a completed suicide. The investigator will exercise his or her medical
and scientific judgment in deciding whether an event is possibly suicide-related. Following receipt of
the report, the Investigator will be requested to collect additional information which should be
reported to the relevant CTU within one week of the investigator diagnosing a possible suicidality-
related adverse event.
7.1.4.D Pregnancy
Pregnancy occurring during participation in ODYSSEY should be reported as a notable event on an
Event form and sent to the relevant CTU (see Section 6.8). All pregnancies will be reported to ViiV and
registered with the Antiretroviral Pregnancy Register.
Any pregnancy that occurs in a trial participant will be followed up to determine outcome (including
premature termination) and status of mother and child, which must also be reported to the CTU on a
Pregnancy Outcome form. The clinical team responsible will be informed of the mother’s participation
in the trial and will be asked to inform the relevant CTU if there is any suspicion of any adverse effect
of the trial medication.
Spontaneous abortions, pregnancy complications and elective terminations for medical reasons must
be reported on an Event form if the event meets the criteria of a reportable AE or SAE.
Any adverse event occurring in an infant born to a female trial participant within 30 days of delivery
should be reported in order to evaluate any possible adverse reaction related to in utero exposure to
the study drugs [51].
Any SAE occurring in association with a pregnancy brought to the investigator´s attention after the
participant has completed the study and considered by the investigator as possibly related to the
investigational product, should also be reported as an SAE. Any event fulfilling the criteria of an SAE
(e.g. congenital abnormality or birth defect) should be reported within 24 hours of the Investigator
becoming aware of the event.
Follow-up of a child born to the partner of a male participant (who was taking trial treatment at the
time of conception) will be according to local practice.
At the end of pregnancy, the investigator will complete an Outcome of Pregnancy CRF.
Reporting timelines during extended follow-up for notable events which don’t constitute a SAE are
outline in Appendix XX.
7.2 INVESTIGATOR RESPONSIBILITIES
All grade 3 and above clinical and laboratory AEs should be reported in the relevant section of the
Event Form. Grade 1 and 2 clinical and laboratory AEs should be reported only if they result in change
of ART. All ARs, whether expected or not, should be recorded in the participant’s medical notes and
reported on the Follow-up Form. SAEs and SARs and notable events should be reported to the
relevant CTU within 24 hours of the site becoming aware of the event. Reporting timelines during
extended follow-up for reportable events which don’t constitute a SAE are outline in Appendix XX.

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7.2.1 INVESTIGATOR ASSESSMENT
7.2.1.A Seriousness
When an AE or AR occurs, the investigator responsible for the care of the patient must first assess
whether or not the event is serious using the definition given in Table 5. If the event is serious, then
an Event Form must be completed and the CTU notified within 24 hours.
7.2.1.B Severity or Grading of Adverse Events

The severity of all AEs and/or ARs (serious and non-serious) in this trial should be graded using the
toxicity grading in Appendix IX.
7.2.1.C Causality
The investigator must assess the causality of all serious events or reactions in relation to the trial
therapy using the definitions in Table 6. There are five categories: unrelated, unlikely, possible,
probable, and definitely related. If the causality assessment is unrelated or unlikely to be related, the
event is classified as an SAE. If the causality is assessed as possible, probable or definitely related,
then the event is classified as an SAR.
Table 6: Assigning Type of SAE through Causality
RELATIONSHIP DESCRIPTION SAE TYPE

Definitely There is clear evidence to suggest a causal relationship and SAR
other possible contributing factors can be ruled out.
Probable There is evidence to suggest a causal relationship and the SAR

influence of other factors is unlikely.
Possible There is some evidence to suggest a causal relationship (for SAR

example, because the event occurs within a reasonable time
after administration of the trial medication). However, the
influence of other factors may have contributed to the event
(for example, the patient’s clinical condition, other
concomitant treatments).
Unlikely There is little evidence to suggest that there is a causal Unrelated SAE
relationship (for example, the event did not occur within a
reasonable time after administration of the trial medication).
There is another reasonable explanation for the event (for
example, the patient’s clinical condition, other concomitant
treatment).
Unrelated There is no evidence of any causal relationship Unrelated SAE
If an SAE is considered to be related to an antiretroviral and drug is stopped or the dose modified,
refer to Section 5.5.
7.2.1.D Expectedness
If there is at least a possible involvement of the trial treatment (or comparator), the investigator may
make an initial assessment of the expectedness of the event, however the Sponsor has the overall
responsibility for determination of expectedness. An unexpected adverse reaction is one not
previously reported in the current Reference Safety Information (i.e. the Investigator’s Brochure (for

ODYSSEY Protocol
DTG and DTG-containing products), or Summary of Product Characteristics (SPC; for all other ARVs)),
that should be accessed through the ODYSSEY reserved area on the Penta website (https://penta-
id.org/reserved-area/#odyssey), or one that is more frequent or more severe than previously
reported. The definition of an unexpected adverse reaction (UAR) is given in Table 5. If a SAR is
assessed as being unexpected, it becomes a SUSAR. If there is at least a possible involvement of the
trial treatment, the Investigator should make an initial assessment of the expectedness of the event.
The Sponsor will have the final responsibility for determination of expectedness (for reporting
purposes), and this decision will be made on the basis of the above definition and the information
provided by the Investigator. Please see the Manual of Operations for a summary of expected
toxicities for ARVs.
7.2.1.E Notification
The relevant CTU should be notified of all SAEs and notable events within 24 hours of the investigator
becoming aware of the event. Reporting timelines during extended follow-up for notable events which
don’t constitute a SAE are outlined in Appendix XX.
Investigators should notify the relevant CTU of all reportable AEs (section 7.2), SAEs and notable
events occurring from the time of randomisation until the end of the trial or end of extended follow
up, whichever is later. Any subsequent events that may be attributed to treatment should also be
reported to national reporting schemes where relevant.
7.2.2 NOTIFICATION PROCEDURE

1. The Event Form must be completed by an investigator (a clinician named on the Signature List
and Delegation of Responsibilities Log who is responsible for the participant’s care; this will
be either the Principal Investigator or another medically qualified person with delegated
authority for Event reporting). Due care should be paid to the grading, causality and
expectedness of the event as outlined above. In the absence of the responsible investigator,
the form should be completed and signed by a member of the site trial team and faxed or
emailed as appropriate. The responsible investigator should subsequently check the Event
Form, make changes as appropriate, sign and then re-fax to the CTU as soon as possible. The
initial report must be followed by detailed, written reports as appropriate.
2. The minimum information required for reporting an AE, SAE or notable event are the trial
number and partial date of birth, name of investigator reporting, the event and why the event
is considered serious or meets the criteria of a reportable event.
3. Follow-up: participants must be followed up until clinical recovery is complete and laboratory
results have returned to normal or baseline, or until the event has stabilised. A further Event
Form, indicated as ‘Follow-up’ should be completed and faxed to the relevant CTU as
information becomes available. Extra, annotated information and/or copies of test results
may be provided separately. The participant must be identified by trial number, anonymous
code, and date of birth only. The participant’s name should not be used on any
correspondence and should be deleted from any test results.
4. Staff should follow their institution’s procedure for local notification requirements.

ODYSSEY Protocol
SAE REPORTING
Within 24 hours of becoming aware of an SAE or notable event, please fax or email a
completed Event form to the relevant CTU. Please ensure that an acknowledgment of
MRC CTU: fax: +44 (0) 20 7670 4814 or email: mrcctu.trial-odyssey@ucl.ac.uk
PHPT: fax: +66 53 240 913 or email: suwalai.chalermpantmetagul@phpt.org

ODYSSEY Protocol
7.3 CTU RESPONSIBILITIES
Medically-qualified staff at the CTUs and/or the Chief Investigator (or a medically-qualified delegate)
will review all event reports received. The causality assessment given by the local investigator at the
hospital cannot be overruled; in the case of disagreement, both opinions will be provided in any
subsequent reports.
The CTUs are undertaking the duties of trial sponsor and are responsible for the reporting of SAEs to
the relevant regulatory authorities (MHRA and competent authorities of other European member
states and any other countries in which the trial is taking place) and research ethics committees of any
countries in which the trial is taking place, as appropriate. This responsibility may be delegated to
country principal investigators for relevant reporting requirements in individual countries. Fatal and
life-threatening SUSARs must be reported to the competent authorities within 7 days of the relevant
CTU becoming aware of the event; other SUSARs must be reported within 15 days.
The relevant CTU will also keep all investigators informed of any safety issues that arise during the
course of the trial.
MRC CTU will prepare annual Development Safety Update Reports (DSURs) on behalf of the sponsor
which will be submitted to the Competent Authorities and Ethics Committees in each country
participating in the trial.
Any drug companies involved will also be notified of reportable (serious and unexpected and drug-
related/unknown relationship) events as per the requirements outlined in the individual contract.

ODYSSEY Protocol
8 QUALITY ASSURANCE & CONTROL
8.1 RISK ASSESSMENT
The Quality Assurance (QA) and Quality Control (QC) considerations have been based on a formal Risk
Assessment, which acknowledges the risks associated with the conduct of the trial and how to address
them with QA and QC processes. QA includes all the planned and systematic actions established to
ensure the trial is performed and data generated, documented and/or recorded and reported in
compliance with the principles of ICH GCP and applicable regulatory requirements. QC includes the
operational techniques and activities done within the QA system to verify that the requirements for
quality of the trial-related activities are fulfilled. This Risk Assessment has been reviewed by the MRC
CTU Research Governance Committee (RGC) and has led to the development of a Data Management
Plan (DMP), Safety Reporting Plan and Monitoring Plan which will be separately reviewed by the
Quality Management Advisory Group (QMAG).
8.2 CENTRAL MONITORING AT CTU
Where local staff have successfully completed training on the trial database, data will be entered into
the trial database directly at the clinical site. The site will retain the original CRF. Data stored on the
central database will be checked at the CTU for missing or unusual values (range checks) and checked
for consistency within participants over time. If any such problems are identified, the site will be
contacted and asked to verify or correct the entry. Changes will be made on the original CRF and
entered into the database at the site. The CTU will also send reminders for any overdue and/or missing
data with the regular inconsistency reports of errors.
Alternatively sites can send completed CRFs to the CTU for data entry. Data received at CTUs will be
checked and if problems are identified, a missing data report of the problematic data will be sent to
the local site by secure e-mail for checking and confirmation or correction, as appropriate – any data
which are changed should be crossed through with a single line, dated and initialled. The amended
data should be returned to the appropriate CTU and the amended data should also be filed in the
notes at site. The CTUs will send reminders for any overdue and missing data.
Other essential trial issues, events and outputs will be detailed in the Monitoring Plan that is based on
the trial-specific Risk Assessment.
8.3 ON-SITE MONITORING
Staff from the CTUs or local monitors will visit clinical sites to validate and monitor data. The
frequency, type and intensity for routine monitoring and the requirements for triggered monitoring
will be detailed in the Monitoring Plan. This plan will also detail the procedures for review and sign-
off. All monitoring will adhere to the principles of ICH GCP.
Monitors will:
verify completeness of the Investigator Site File

confirm adherence to protocol
review procedures and resources
o in the trial clinic
o in the trial pharmacy

ODYSSEY Protocol
o in the trial laboratories
advise on additional training as needed
The investigator (or delegated deputy) should work with the monitor to ensure that any problems
detected are resolved.
8.3.1 DIRECT ACCESS TO PARTICIPANT RECORDS

Participating investigators will allow trial-related monitoring, including audits, ethics committee
review and regulatory inspections by providing direct access to source data and documents as
required. If required locally, consent for this should be obtained from parents/carers and children, if
appropriate. Such information will be treated as strictly confidential and will in no circumstances be
made publicly available.
The following data should be verifiable from source documents:

all signed consent forms
all Eligibility and clinical and laboratory data at enrolment
all clinical endpoints and all SAEs
routine patient clinical and laboratory data
trial drug accountability
8.3.2 CONFIDENTIALITY
We plan to follow the principles of the UK DPA regardless of the countries where the trial is being
conducted.
The investigator must assure that the participants’ anonymity will be maintained i.e. their identities
are protected from unauthorised parties. Participants will be assigned a trial identification number to
be used on all CRFs and no names will be used beyond the clinical care of the participant, in order to
maintain confidentiality. All trial records, including a participant trial register linking identification
numbers and names, will be kept in secure locations at each site.

ODYSSEY Protocol
9 STATISTICAL CONSIDERATIONS
9.1 METHOD OF RANDOMISATION
Randomisation of children weighing ≥14kg will be stratified by:

antiretroviral treatment: naïve or experienced (ODYSSEY A or ODYSSEY B)
routine availability at site of resistance tests vs. non availability of resistance tests, for children
failing treatment
bPI vs. non-bPI ART offered as SOC
NRTI backbone : ABC/3TC or ABC/3TC/ZDV vs. TDF/3TC or TDF/FTC or TAF/3TC or TAF/FTC
vs. Other
Randomisation of children weighing 3-<14kg will be performed separately stratified by

weight band at randomisation: 3-<6kg vs. 6-<10kg vs. 10-<14kg
The randomisation lists will be prepared by staff at the MRC CTU under the direction of the trial
statistician. The randomisation lists will be generated by random permuted blocks and will be securely
incorporated within the web-enabled trial database. Randomisation will not take place until after
informed consent has been confirmed and the participant is ready to receive therapy.
9.2 OUTCOME MEASURES
The primary comparison for the study is to compare DTG-based regimen versus SOC for the primary
efficacy outcome in the combined population (naïve and experienced); subpopulation analyses
(ODYSSEY A and ODYSSEY B) are key secondary comparisons. Outcomes are described below for the
randomised phase.
9.2.1 PRIMARY EFFICACY OUTCOME (OVER 96 WEEKS)

Difference in the probability of virological or clinical failure by 96 weeks, estimated by Kaplan-Meier
methods using time to the first occurrence of any of the following components (note, this does not
mean VL must be performed in real time):
Insufficient virological response defined as <1 log10 drop at week 24 (or VL≥50c/mL at week
24 in a participant with VL<500c/mL at baseline) and switch to second/third line ART for
treatment failure
VL ≥400 c/ml at or after 36 weeks confirmed by next visit
Any new or recurrent AIDS defining event (WHO 4) or severe WHO 3 events, confirmed by the
Endpoint Review Committee
9.2.2 SECONDARY EFFICACY OUTCOMES

Difference in proportion with clinical or virological failure (as defined above) by 48 weeks
Time to any new or recurrent AIDS defining event (WHO 4) or severe WHO 3 events, confirmed
by the Endpoint Review Committee
Rate of clinical events over 96 weeks: WHO 4, severe WHO 3 events and death
Change in CD4 count and percentage and CD4/CD8 ratio from baseline to weeks 48 and 96

ODYSSEY Protocol
9.2.3 SECONDARY SAFETY OUTCOMES

Change in total cholesterol, triglycerides and lipid fractions (LDL, HDL) from baseline to weeks
48 and 96 (change in total cholesterol from baseline to week 96 will be used to formally assess
superiority of DTG based regimen vs. SOC)
Incidence of new clinical and laboratory grade 3 and 4 adverse events
Incidence of adverse events (of any grade) leading to treatment modification
9.2.4 OTHER SECONDARY OUTCOMES

Quality of life
Outcomes in extended follow-up will focus on safety and possible long-term toxicities. See Appendix
XX for further details.
9.3 SAMPLE SIZE
Based on previous HIV studies a non-inferiority margin (delta) of 10-12% is considered acceptable.
Assuming a failure rate of 18% overall (both first-line and second-line children combined) in the DTG
arm and SOC arm by 96 weeks and allowing for 10% loss to follow up, 700 children will provide 90%
power to exclude (at two-sided 5% significance level) a difference of more than 10% between the two
arms. If the upper bound of the two-sided 95% confidence limit for the difference in the proportion
failing (DTG – SOC) is less than 10% (the margin of non-inferiority) the DTG-regimen will be considered
to be non-inferior to the SOC.
Enrolling 310 first-line ART and 390 second-line ART children will provide 80% power to exclude a
difference of more than 12% between the DTG and SOC arms in both subgroups, assuming a failure
rate of 15% in ART-naïve (based on previous trials, including the recent ARROW trial [49] in Africa),
and 20% in ART-experienced with loss to follow up of 10%.
9.4 INTERIM MONITORING & ANALYSES
An IDMC Charter will be drawn up that describes the membership of the IDMC, relationships with
other committees, terms of reference, decision-making processes, and the timing and frequency of
interim analyses (with a description of stopping rules and/or guidelines). The IDMC will meet within
6 months after the trial opens; although the IDMC will in general meet annually, the frequency of
subsequent meetings will be determined by the IDMC and could be more frequent if they deem
necessary. The IDMC can recommend premature closure or reporting of the trial, or that recruitment
be discontinued or modified. Such recommendations would be made if, in the view of the IDMC, there
is proof beyond reasonable doubt that one of the allocated strategies is better than its comparator in
terms of a difference of clinically significant magnitude in a primary outcome. The guiding statistical
criteria for “proof beyond reasonable doubt” is a Haybittle-Peto type rule based on the 99.9%
confidence interval of the relative hazard of death in each interim analysis.
9.5 ANALYSIS PLAN (BRIEF)
For the primary analysis of main trial participants, the two treatment groups (DTG and SOC) will be
compared in terms of the cumulative probability of clinical or virological failure by week 96 (CPF96)
(as defined above) as estimated by the Kaplan-Meier method, adjusting for stratification factors. DTG

ODYSSEY Protocol
will be considered non-inferior to SOC if the upper limit of the 95% confidence interval of the
difference in CPF96 (DTG-SOC) is less than the non-inferiority margin of 10%. The number and
percentage of participants with at least one component of the primary endpoint and the number and
percentage for each component will be summarised.
Secondary analyses will summarise the rate of the composite primary endpoint per 100 person years
by treatment group, and a treatment hazard ratio (HR: DTG to SOC) plus two-sided 95% confidence
interval estimated by a Cox proportional hazards model. The primary analysis is by intention to treat
and includes all randomised participants. A sensitivity analysis will be done with the per protocol
population, censoring events after a participant stops the initial randomised trial treatment.
Participants with VL<50 (or <400) c/ml at 48 and 96 weeks will be compared between arms based on
(i) crude proportions and (ii) using the FDA snapshot algorithm to determine the proportion of
participants with VL<50 (or <400) c/ml.
The secondary endpoints of change in total cholesterol, triglycerides and lipid fractions (LDL, HDL)
from baseline to weeks 48 and 96 will be analysed using analysis of covariance to compare the change
in mean level between the two arms, adjusting for baseline value and stratification factors. These
analyses will be carried out on all randomised participants (intention to treat) and change in total
cholesterol from baseline to week 96 will assess the superiority of DTG compared to SOC for this
parameter.
There will be a secondary analysis of primary and secondary endpoints in all children recruited
weighing<14kg (where DTG dose is determined) when this group has completed 96 weeks follow-up.
The primary endpoint will be re-evaluated in all children including those in the main trial and
children recruited <14kg (where DTG dose is determined) when follow-up to a minimum of 96 weeks
is complete.
Intention to treat analyses including all randomised participants will be performed for all other
endpoints using the following statistical methods:
Descriptive statistics for the summary of baseline characteristics
Fishers Exact test and logistic regression for the analysis of binary variables
Analysis of variance and linear regression models for the analysis of continuous variables,
adjusting for baseline
Poisson regression for the analysis of incidence of clinical/adverse events
Log-rank test and Cox proportional hazard model for the analysis of time to event variables
Clinical and adverse events will be summarised using an in-house coding system.
Full details of all analyses will be provided in the Statistical Analysis Plan (SAP). This will include any
additional pre-planned subgroup analyses.
A second SAP will be written for the extended follow-up phase.

ODYSSEY Protocol
10 ANCILLARY STUDIES
10.1 PHARMACOKINETIC SUBSTUDIES
10.1.1 WB-PK1
PHARMACOKINETICS OF DOLUTEGRAVIR IN WHO WEIGHT BANDS 3 TO <6KG, 6 TO <10KG, 10 TO
<14KG, 14 TO <20KG AND 20 TO <25KG
Children weighing 3 to <25kg randomised to DTG will be recruited to the substudy until at least 8
children per weight band have evaluable PK curves on the investigated dose/formulation. Children will
have a single 24h PK curve at least 1 week after starting DTG-based ART or changing to a new
dose/formulation. Additional children may be recruited if a large interpatient variability in the PK
parameters (i.e. >50% in AUC0-24, Ctrough or Cmax) within the weight band is seen. PK, safety and
tolerability will be assessed.
The substudy will be undertaken at clinical sites in Uganda, South Africa and Zimbabwe. For further
information see Appendix XIII.
10.1.2 WB-PK2
A CROSSOVER PHARMACOKINETICS SUBSTUDY OF DOLUTEGRAVIR IN CHILDREN WEIGHING 25 TO
<40KG WITH DOSE CHANGE TO DTG 50MG QD (the substudy is completed)
Children weighing 25 to <40kg taking DTG according to the previous version of the protocol (25mg for
25-<30kg weight band and 35mg for 30-<40kg weight band) were enrolled in the substudy until at
least 8 children per weight band had evaluable PK curves. Participants had two 24h PK curves
performed: the first curve on dosing they received prior to the dose change for at least 1 week and
the second curve at least 1 week after changing to a 50mg tablet. Following the review of the PK
results, clinical and laboratory adverse events and treatment discontinuations, children 25-<40kg in
the main trial were switched to DTG 50mg film-coated tablet QD (Section 5.3).
The substudy was undertaken at clinical sites in Uganda and Zimbabwe. For further information see
Appendix XIII.
10.1.3 TB-PK SUBSTUDY

PHARMACOKINETICS OF DOLUTEGRAVIR CO-ADMINISTERED WITH RIFAMPICIN IN HIV/TB CO-
INFECTED CHILDREN
The substudy will evaluate the pharmacokinetics of DTG co-administered with rifampicin in HIV/TB co-
infected children and estimate the impact of rifampicin on DTG plasma concentrations. Children aged
6 to <18 years treated for TB with rifampicin-containing regimen are enrolled. At least six children per
age band 6 to <12 years and 12 to <18 years will be enrolled; the number may be increased if
intersubject variability of DTG PK parameters in children appears much larger than that reported in
non HIV-infected adults or if less than 2 children per WHO weight band have complete PK data. We
anticipate few children <6 years being treated for TB with a rifampicin-containing regimen during
ODYSSEY; however any who receive rifampicin treatment for TB or TB infection will be approached for
recruitment. Participants will have two PK curves performed: the first curve (12h) during the last

ODYSSEY Protocol
month of rifampicin-containing TB treatment and the second curve (24h) four weeks after
discontinuation of rifampicin (two weeks after changing DTG from BID to QD). Pharmacokinetics of
BID DTG and QD DTG within participants will be compared and evaluated against the available data in
children and adults.
The substudy will be undertaken at clinical sites in Uganda, South Africa and Zimbabwe. For further
information see Appendix XIV.
10.2 IMMUNOLOGY/VIROLOGY SUBSTUDY
The substudy will assess the impact of DTG on the mechanisms of CD4 reconstitution, immune
activation and HIV reservoir and replication. The study aims to collect samples from at least 350
children (as many as possible from ODYSSEY A). Blood samples for plasma will be collected at each
study visit according to the trial assessment schedule for the randomised phase of the ODYSSEY trial,
PBMCs will be collected at enrolment, and at 12, 48 and 96 weeks for sites participating in the
substudy. Samples will be stored locally and later transferred to the Institute of Child Health, UCL or
the African Health Research Institute (AHRI) Laboratories for analyses. Changes in thymic output,
immune activation biomarkers and viral reservoirs and replication will be compared between DTG and
SOC arms.
The substudy will be undertaken at clinical sites in Uganda, South Africa and Zimbabwe and Europe.
For further information see Appendix XII.
10.3 QUALITATIVE SUBSTUDY: OPTIMISING ADHERENCE TO SECOND-LINE TREATMENT.
The qualitative substudy will explore how moving onto second-line treatment affects young people’s
treatment engagement and identify how best to support them to maintain optimal treatment
adherence. Participants enrolled in ODYSSEY B aged 10-18 years who have known about their HIV
status for a minimum of six months will be recruited. Two ODYSSEY trial sites, JCRC in Uganda and the
University of Zimbabwe, Harare in Zimbabwe, will be involved; each site will recruit 20 participants
(40 in total). Two in-depth individual interviews and a series of focus group discussions with trial
participants at different stages of the trial will be conducted. Consultations with a Youth Trial Board
(see below) to assist with the dissemination materials will be arranged.
The substudy will be undertaken at clinical sites in Uganda and Zimbabwe. For further information see
Appendix XV.
10.4 YOUTH TRIAL BOARD PROJECT
A MULTI-COUNTRY MODEL OF USER INVOLVEMENT TO ENGAGE ADOLESCENTS LIVING

WITH HIV IN THE DEVELOPMENT AND DELIVERY OF PAEDIATRIC CLINICAL TRIALS
The project will develop a model of meaningful engagement and participation of adolescent patient
representatives in paediatric clinical trials and research studies. It will take place in 4 countries
participating in ODYSSEY: the UK, South Africa, Uganda and Zimbabwe. Children living with HIV, aged
15-≤19 years will be included. At least half of the children involved will be ODYSSEY trial participants.
Youth Trial boards (YTB), groups of at least 6 young people in each of the four sites, will be established.
Each YTB will receive training to ensure understanding of clinical trials and their role. Once trained,

ODYSSEY Protocol
they will provide feedback to the ODYSSEY trial investigators on different aspects of the trial, including
provision of the trial information, consent process, engagement with children and adolescents and
retention of the participants during the trial. The YTB will be involved in dissemination of the ODYSSEY
trial materials and the results. They will also participate at the development stage of new clinical trials
as opportunities arise. At the end of the project the model will be adopted for a wider use in paediatric
HIV trials and studies.
The substudy will be undertaken at clinical sites in South Africa, Uganda, Zimbabwe and the UK. For
further information see Appendix XVI.
10.5 FOLATE AND VITAMIN B12 SUBSTUDY
DOLUTEGRAVIR AND FOLATE AND B12 LEVELS AMONG CHILDREN AND ADOLESCENTS IN
THE ODYSSEY TRIAL
Recent concerns have been raised about the use of dolutegravir (DTG) in pregnant women. In a
preliminary unscheduled analysis of an ongoing NIH-funded birth surveillance study in Botswana, an
increased risk of neural tube defects (NTDs) among infants of women who became pregnant while
taking DTG-based regimens has been reported. It is well known that maternal folate deficiency
increases the risk of NTDs, however it is unknown whether DTG may affect folate levels.
The substudy will compare the folate levels among children and adolescents randomized to DTG
versus those on a SOC ART regimen. The study aims to collect samples from children enrolled in
ODYSSEY in sub Saharan sites and to determine whether there is a potential association between DTG
and folate status.
Folate plasma levels will be assayed at baseline and 4 weeks after commencing trial treatment using
plasma that is routinely stored as part of the main ODYSSEY protocol (see Trial Assessment Schedule).
In addition, red cell folate and vitamin B12 levels will be assayed using the same blood draw as for
plasma isolation at week 96 (or the next clinic visit after this timepoint if collection at week 96 is not
possible). Where assays cannot be done in real time, the blood samples or lysates will be stored for
subsequent testing.
The substudy will be undertaken at selected sites in Uganda. For further information see Appendix
XVIII.

ODYSSEY Protocol
11 REGULATORY & ETHICAL ISSUES
11.1 COMPLIANCE
11.1.1 REGULATORY COMPLIANCE

The trial complies with the principles of the Declaration of Helsinki of 2013.
It will also be conducted in compliance with the approved protocol, the principles of Good Clinical
Practice (GCP) as laid down by the European Commission Directive 2005/28/EC* with the
implementation in national legislation in countries in the EU and subsequent amendments and
appropriate data protection and regulatory legislation in participating countries, the UK Data
Protection Act (DPA UCL’s number Z6364106), and the National Health Service (NHS) Research
Governance Framework for Health and Social Care (RGF).
*Until the Clinical Trials Regulation EU No 536/2014 becomes applicable, the trial will be conducted
in accordance with the Clinical Trials Directive as implemented in the UK statutory instrument. When
the directive is repealed on the day of entry into application of the Clinical Trial Regulation the trial
will work towards implementation of the Regulation (536/2014) following any transition period.
11.1.2 SITE COMPLIANCE

The site will comply with the above and with the principles of GCP as laid down by the ICH topic E6
(Note for Guidance on GCP), Commission Directive 2005/28/EC (the European Directive 2001/20/EC
[where applicable]) and applicable national regulations. An agreement will be in place between the
site, PENTA and the appropriate CTU, setting out respective roles and responsibilities (see Section 13
- Finance).
The site will inform the relevant CTU as soon as they are aware of a possible serious breach of
compliance, so that the CTU can report this breach if necessary within 7 days as per the UK regulatory
requirements. For the purposes of this regulation, a 'serious breach' is one that is likely to affect to a
significant degree:
• The safety or physical or mental integrity of the participants in the trial, or
• The scientific value of the trial
11.1.3 DATA COLLECTION & RETENTION

CRFs, clinical notes and administrative documentation should be kept in a secure location (for
example, locked filing cabinets in a room with restricted access) and held for a minimum period as
determined by the current clinical trial legislation in effect. Currently this will be for a minimum of 15
years after the end of the trial. The EU Clinical Trial Regulation 536/2014 is due to come in to
application in 2020 and, if still applicable to ODYSSEY following the transition period, the sponsor and
the investigator shall archive the content of the clinical trial master file for at least 25 years after the
end of the clinical trial, unless other Union law requires archiving for a longer period. However, the
medical files of subjects shall be archived in accordance with national law. During this period, all data
should be accessible, with suitable notice, to the competent or equivalent authorities, the Sponsor,
and other relevant parties in accordance with the applicable regulations. The data may be subject to
an audit by the competent authorities. Medical files of trial participants should be retained in
accordance with the maximum period of time permitted by the hospital, institution or private practice.

ODYSSEY Protocol
11.2 ETHICAL CONDUCT OF THE STUDY
11.2.1 ETHICAL CONSIDERATIONS

Participation in a randomised controlled trial means that the participant and/or their carer as
appropriate, agree to randomisation but neither the participant, carer nor clinician are able to choose
all aspects of the participant's treatment. Participants will receive different treatments and toxicities
are different by arm; this will be explained to children/families. The risks of HIV-1 viral load rebound
due to a possibly less potent regimen and the use of a novel agent will be explained to
children/families. Consent will be sought from parents/carers and from participants where allowed
by national regulations. Participants not able to consent for themselves, but deemed able to
understand about the trial, will be asked to assent.
As described above, the main risks to the participants are from the potential toxicity from integrase
inhibitors. However, this possibility needs to be balanced against the risks from SOC ART. In addition,
the trial will evaluate the net clinical/virological risk-benefit comparing DTG with SOC.
11.2.1.A Safety Profile of DTG

DTG has been taken by large numbers of adults in Phase III trials, and is licensed for the treatment of
HIV infection in adults and children aged 6 and above weighing at least 15 kg.
The most common side effects of DTG in adults are headache, diarrhoea, abdominal pain, feeling sick,
light headed or weak, worrying often and having sleep problems. Some adults taking dolutegravir have
reported feeling depressed or having suicidal thoughts; these may not be related to this medicine in
all cases. There is a small chance that dolutegravir may cause a rash, itching, vomiting, stomach pain,
sleep problems, lack of energy, an increase in weight, feeling light headed, sad or worried or may
cause serious liver problems (with signs of vomiting, jaundice or stomach pain).
In May 2018, an observational surveillance study in Botswana (TSEPAMO) evaluating the safety of ART
regimens in pregnancy identified an increased risk of neural tube defects (NTD) amongst infants of
women who initiated DTG-based regimens prior to pregnancy (0.9%, which compares to a risk of
~0.1% in infants born to women on non-DTG based regimens; see Background). In a further report
including all data through to March 2019 there were 5 cases of NTD in 1683 deliveries where their
mother was taking DTG at conception (0.3% of deliveries) (36), suggesting the increased risk is ~3-fold,
lower than the 10-fold risk initially estimated. To protect female participants and their unborn infants
from this potential risk, all female participants who are sexually active must use highly effective
contraception (see section 6.8). Females on DTG identified to be pregnant within 8 weeks after LMP
should be changed to an alternative non-DTG ART regimen provided optimal options to replace DTG
are available for them.
At the present time there is limited experience with the use of this drug in the paediatric population.
Standard procedures are in place to record Serious Adverse Events arising from the use of DTG (or any
study drug) in the trial, and such events will be evaluated and reported to ethics committees and
regulatory agencies within specified timelines. The IDMC will closely monitor Serious Adverse Events
and grade 3 and 4 events occurring during the randomised phase of the trial in all treatment groups
and will be able to advise appropriate action if there is a pattern of serious toxicity emerging from one
or more of the drugs.
11.2.1.B Burden of investigations

The follow-up study visits coincide with the usual frequency of visits for routine clinical care. Two
extra visits are scheduled at the start of the trial to monitor participant’s safety and adherence to
medication. Additional tests (over and above routine care) may be required.

ODYSSEY Protocol
11.2.1.C Post-trial treatment

Provision of DTG will continue after the randomised phase of the trial, for participants randomised to
receive DTG who are still receiving it, until it is locally approved and available for the child’s age and
weight band. Safety follow-up of those participants receiving DTG after the randomised phase will
be performed.
11.2.1.D Informing potential trial participants of possible benefits and known risks
Participants and carers will be informed fully of known risks and possible benefits by means of a
patient information sheet and this will be reinforced by discussions with the trial research teams at
the individual sites prior to enrolment.
11.2.1.E Confidentiality
Participants’ confidentiality will be maintained throughout the trial. Patient data will be identified by
the trial number and a 3 letter computer generated anonymous code, date of birth and sex; samples
sent to central testing facilities will be identified only by the trial number and a 3 letter computer
generated anonymous code, date of collection, type of sample and visit number.
11.2.2 ETHICAL APPROVALS

Before initiation of the trial at each clinical site, the protocol, all informed consent forms, and
information materials to be given to the prospective participant and carer will be submitted to
national/local ethics committees for approval as required. Any further amendments will be submitted
and approved by each ethics committee.
The rights of the participant and carer to refuse to participate in the trial without giving a reason must
be respected. After the participant has entered into the trial, the clinician must remain free to give
alternative treatment to that specified in the protocol, at any stage, if he/she feels it to be in the best
interest of the participant. The reason for doing so, however, should be recorded; the participant will
remain within the trial for the purpose of follow-up and for data analysis by the treatment option to
which they have been allocated. Similarly, the carer/participant must remain free to change their
mind at any time about the protocol treatment and trial follow-up without giving a reason and without
prejudicing his/her further treatment.
11.3 COMPETENT AUTHORITY APPROVALS
This protocol will be submitted to the national competent or equivalent authority in each country
where the trial will be conducted.
This is a Clinical Trial of an Investigational Medicinal Product (IMP) as defined by the EU Directive
2001/20/EC. Therefore, a CTA is required in the EU. In countries outside of the EU, local and national
regulatory requirements will be followed.
The EudraCT number for the trial is 2014-002632-14.
The progress of the trial and safety issues will be reported to the competent authority, regulatory
agency or equivalent in accordance with local requirements and practices in a timely manner.
Safety reports, including expedited reporting and SUSARs will be submitted to the competent
authorities in accordance with each authority’s requirements in a timely manner.

ODYSSEY Protocol
11.4 OTHER APPROVALS
The protocol will be submitted by those delegated to do so to the relevant R&D department of each
participating site or to other local departments for approval as required in each country. A copy of
the local R&D approval (or other relevant approval as above) and of the PIS and Consent Form (CF) on
local headed paper should be forwarded to the relevant CTU before any participants are screened for
eligibility.

ODYSSEY Protocol
12 INDEMNITY
In consideration of the agreement by the Principal Investigator at each centre to supervise the trial,
the PENTA Foundation undertakes to indemnify the Principal Investigator at each centre and the
institutions which participate in the trial and their employees and agents in respect of any claims made
against them by any third party which arises out of or as a result of the supervision or conduct of the
trial (including any claim arising in respect of the technical procedures described in the protocol which
participants would not have been exposed but for their participation in the trial). Full details of the
Indemnity agreement are given in a separate document. Cover against claims arising from medical
negligence is not included.

ODYSSEY Protocol
13 FINANCE
Research support will be provided to the clinical centres for additional visits. In some specific cases
and agreed by national ethics bodies, transport facilities, payments or vouchers will be given to
participants or their families in compensation for the time spent in clinic particularly during substudies.
In some countries and as required by national legislation the health service cost of all protocol visits
will be covered by the sponsor or sponsor’s representative.
DTG (including Triumeq, as appropriate) will be provided by ViiV for the duration of the randomised
phase of the ODYSSEY trial. DTG 5mg dispersible tablets will only be provided to sites in South Africa,
Uganda and Zimbabwe, and Triumeq will only be supplied in countries where it is licensed. For sites
outside Europe, the following NRTIs will also be provided by ViiV where required for the duration of
the ODYSSEY trial: ABC, 3TC, Kivexa and Combivir. After the end of the randomised phase, DTG will
be provided by ViiV for those children randomised to the DTG arm until it is available and
recommended for children in their country of residence. For sites in sub-Saharan Africa the Mylan
formulation of ABC/3TC 120/60mg will be provided for the duration of the randomised phase, if
required.

ODYSSEY Protocol
14 OVERSIGHT & TRIAL COMMITTEES
There are a number of committees involved with the oversight of the trial. These committees are
detailed below, and the relationship between them is shown (see Appendix XVII).
14.1 TRIAL MANAGEMENT GROUP (TMG)
A Trial Management Group (TMG) will be formed comprising Chief Investigator(s), other lead
investigators (clinical and non-clinical) and members of the CTUs: MRC CTU, INSERM-ANRS and PHPT.
The TMG will be responsible for the day-to-day running and management of the trial. It will meet
monthly during the recruitment phase and thereafter at least every other month. Part of this trial
includes a Youth Trial Board (YTB) substudy (see Appendix XVI) and the YTB work with the TMG.
14.2 TRIAL STEERING COMMITTEE (TSC)
The trial will be supervised by the ODYSSEY TMG who will report to the ODYSSEY Trial Steering
Committee (TSC). The TSC has membership from the TMG plus independent members, including a PPI
representative and the Chair. The role of the TSC is to provide overall supervision for the trial and
provide advice through its independent Chair. The ultimate decision for the continuation of the trial
lies with the TSC. Further details of TSC functioning are presented in the TSC Charter. The ODYSSEY
TSC may decide to terminate the trial for any reason including the recommendation of the
Independent Data Monitoring Committee (IDMC).
14.3 INDEPENDENT DATA MONITORING COMMITTEE (IDMC]
The Independent Data Monitoring Committee (IDMC) which oversees all PENTA trials will be the only
group who sees the confidential, accumulating data for the trial. Reports to the IDMC will be produced
by the CTU statisticians. The IDMC will meet within 6 months of the trial opening; the frequency of
meetings will be dictated in the IDMC charter. The IDMC will consider data using the statistical analysis
plan (see Section 9.5) and will advise the TSC. The IDMC can recommend premature closure or
reporting of the trial, or that recruitment to any research arm is discontinued.
Further details of IDMC functioning and the procedures for interim analysis and monitoring are
provided in the IDMC Charter.
14.4 ENDPOINT REVIEW COMMITTEE
An Endpoint Review Committee will be appointed whose remit will be to determine the validity of
potential clinical endpoints in terms of meeting the standard criteria, as defined by the protocol. It
will have an independent Chair. No member will review endpoints from their own site. Terms of
reference for the Endpoint Review Committee will be drawn up.
14.5 ROLE OF STUDY SPONSOR
The sponsor of the trial is the PENTA Foundation. The management of the trial is delegated by the
sponsor to the CTUs: MRC CTU, INSERM-ANRS and PHPT.

ODYSSEY Protocol
15 PUBLICATION
15.1 PUBLICATION
The ODYSSEY TMG will be responsible for preparing the manuscript for rapid publication. High priority
will be given to this and it would be anticipated that a report would be completed within six months
of the latter of database lock or receipt of retrospective viral loads for participants recruited weighing
≥14kg into the main trial. The final publication will require the approval of the ODYSSEY TMG and TSC.
No other publications, including all or any part of the results, either written or verbal, will be made
before the definitive manuscript has been agreed and accepted for publication without the prior
approval of the ODYSSEY TMG and TSC. Individual clinicians must not publish data concerning their
participants that are directly relevant to questions posed by the trial until the TMG has published its
report. Responsibility for data analysis and publication for ODYSSEY will reside within the PENTA
network and be governed by PENTA policies.
The trial will be registered with the internationally accepted clinical trials register, clinicaltrials.gov.
The ISRCTN number will be attached to all publications resulting from this trial. The ODYSSEY TSC is
the custodian of the data and specimens generated from the ODYSSEY trial; ODYSSEY trial data are
not the property of individual participating investigators or health care facilities where the data were
generated.
The data derived from this clinical trial are considered the property of the ODYSSEY TSC. The
presentation or publication of any data collected by the participating investigators on
participants entered into this trial is under the direct control of the TMG and TSC (and the
IDMC before the end of the trial). This is true whether the publication or presentation is
concerned directly with the results of the trial or is associated with the trial in some other
way.
Outcome data by randomised group will not be revealed to the participating investigators
until the data collection phase and primary full analysis of the trial has been completed. This
policy safeguards against possible bias affecting the data collection. The IDMC will be
monitoring the outcome results and may recommend that the trial be stopped for safety
reasons or if a definitive answer is reached earlier than the scheduled end of the trial.
15.2 FEEDBACK TO PARTICIPANTS
At the end of the study, letters will be sent by trial sites to participants and families to inform them
when the trial will be closing.
When the trial results are available, an information sheet in lay terms will be provided for every trial
participant and carers to explain the results of the trial. This will be distributed to the Principal
Investigators at each site so that the paediatrician can discuss it with the child and/or parent/carer to
explain the outcome of the trial.

ODYSSEY Protocol
16 DATA AND/OR SAMPLE SHARING
Data will be shared according to the MRC CTU’s controlled access approach, based on the following
principles:
No data should be released that would compromise an ongoing trial or study.
There must be a strong scientific or other legitimate rationale for the data to be used for
the requested purpose.
Investigators who have invested time and effort into developing a trial or study should
have a period of exclusivity in which to pursue their aims with the data, before key trial
data are made available to other researchers.
The resources required to process requests should not be under-estimated, particularly
successful requests which lead to preparing data for release. Therefore adequate
resources must be available in order to comply in a timely manner or at all, and the
scientific aims of the study must justify the use of such resources.
Data exchange complies with Information Governance and Data Security Policies in all of
the relevant countries.
Researchers wishing to access ODYSSEY data should contact the Trial Management Group in the first
instance.

ODYSSEY Protocol
17 PROTOCOL AMENDMENTS
Changes to protocol version 5.0 creating protocol version 6.0 8th November 2019
Major changes
1. The following sections have been amended to include information on extended follow-up
and to clarify the differing requirements between the randomised phase and the extended
follow-up phase:
Trial Summary: Clarified that trial outcomes are for randomised phase.
Trial Assessment Schedule for Randomised Phase of the Trial: Renamed to clarified
that it is to be used for the randomised phase of the trial; End of Study visit
renamed for clarity; footnote added to explain when participants should have their
study visit for the end of the randomised phase and continue in extended follow-up.
Treatment of patients (including sub-sections 5.1, 5.1.1, 5.5.1): Clarified drug supply
arrangements for the randomised phase and extended follow-up; clarified that a
participant’s NRTI backbone may be changed after completion of the randomised
phase; differences in approach to ART modifications, interruptions and
discontinuations between the randomised phase and extended follow-up described.
Assessments & Follow-Up (including sub-sections 6.1, 6.2, 6.3, 6.4, 6.5, 6.6, 6.11):
Described assessments required during randomised phase and directed to Appendix
XX for those required during extended follow-up.
Safety reporting (including subsections 7.1.4.A, 7.1.4.B, 7.1.4.C, 7.1.4.D, 7.2,
7.2.1.E): Clarified that reporting timeframes outlined for events that are not SAEs
are for those occurring during the randomised phase; reporting timeframes for non-
SAEs occurring during extended follow-up are outlined in Appendix XX.
Statistical considerations (including subsections 9.2, 9.5): Updated to clarify that
trial outcomes documented are for the randomised phase; outcomes in extended
follow-up will focus on safety and possible long-term toxicities; a second SAP will be
written for the extended follow-up phase.
Ancillary studies (subsection 10.2): Clarified that time-points for collection of PBMCs
for immunology virology substudy can be found in the Trial Assessment Schedule
for the Randomised Phase of the Trial.
Regulatory & Ethical Issues (including subsections 11.2.1.A, 11.2.1.C): Clarified that
the IDMC will only review events occurring during the randomised phase; clarified
drug supply arrangements for the randomised phase and extended follow-up.
Finance: Clarified drug supply arrangements for the randomised phase and
extended follow-up.
Appendix I: Added parent/carer PIS, participant PIS and simplified PIS for younger
children for extended follow-up.
Appendix II: Added parent/carer ICF, participant ICF and participant assent forms
for extended follow-up.
Appendix XIII: Clarified that the IDMC will review PK and safety data from the
randomised phase of the trial.
Appendix XX: New appendix added to describe the arrangements for the extended
follow-up of ODYSSEY participants
2. The following section has been amended to describe an update to the end of trial definition:
Assessments & Follow-Up (subsection 6.11): End of Trial definition updated.
3. Safety Reporting (Section 7.1.1): Correction of trial IMP definition

ODYSSEY Protocol
Minor changes
1. Front page: Logos updated

2. General Information: Compliance and safety information updated to comply with newly
released MRC CTU protocol template; Penta, MRC CTU and PHPT details updated, including
contact details for SAE reporting for PHPT sites.
3. Trial Assessment Schedule: Clarified that Sleep and Mood section of the Acceptability, Sleep
and Mood questionnaire should only be completed for children aged 6 years and over, and
that lipids/glucose tests after week 96 should also be should be performed under fasted
conditions.
4. Introduction: Updated information on DTG and pregnancy based on more recent data from
the TSEPAMO study.
5. Section 5.3.1: Clarified that DTG dose should be adjusted if a child moves weight band
(removed reference to moving up a weight band); removed reference to WB-PK1 part III;
removed that DTG dosing would initially be dependent on age for participants weighing 3-
<6kg; removed that recruitment to lower weight bands may be opened at all sites; removed
that DTG doses may change again based on PK data.
6. Section 5.9: Added reference to Section 6.9 for further information if a patient is withdrawn
from follow-up.
7. Section 6.1.1: Minor updates to ensure consistency with Trial Assessment Schedule for
Randomised Phase of the Trial
8. Section 6.9: Added statement on impact on trial data if participants stop trial follow-up
early .
9. Section 7: Minor corrections throughout.
10. Section 7.1.2: Clarification of adverse event definition and those that require reporting.
11. Section 7.1.4.D – The timeframe for AEs in infants born to female participants to be
collected increased to 30 days after delivery.
12. Section 7.2.1.C: Table 6 reordered to align with that in recently updated MRC CTU protocol
template.
13. Section 7.2.1.D: Updated to clarify that the site investigator should make an initial
assessment of expectedness but that Sponsor has overall responsibility; location of current
RSI documentation added.
14. Section 7.2.2: Clarified that the “investigator” reporting events does not need to be the PI, it
can be another medically qualified person with delegated responsibility for event reporting;
contact details for event reporting added to this section
15. Section 7.3: Clarified that medically-qualified staff at the CTUs and/or the Chief Investigator
(or a medically-qualified delegate) will review all event reports received, clarified to whom
SAEs may be reported (regulatory authorities) and applicable timelines; MRC CTU produce
the annual DSUR, clarified events will be reported to drug companies involved as per the
individual contract requirements
16. Section 8: Minor updates throughout as per recently released MRC CTU protocol template.
17. Section 10.5: Minor correction to folate substudy appendix number
18. Section 11.1: Updated throughout to reference Clinical Trials Regulation EU No 536/2014
19. Section 11.2.1.A: Updated information on DTG and pregnancy following recent release of
results from TSEPAMO study.
20. Section 14: Minor updates to include information on Patient and Pubic Involvement, as per
MRC CTU protocol template.
21. Section 15: Updated to include timeline for reporting trial results.
22. Section 16: Added as per MRC CTU protocol template.
23. Appendix II: Corrections made to Participant Re-Consent to ODYSSEY trial.

ODYSSEY Protocol
24. Appendix XIII: WB-PK1 part III removed; removed that DTG dosing would initially be
dependent on age for participants weighing 3-<6kg.
25. Appendix XIX: Removed DTG dosing for WB-PK participants relating to WB-PK1 part III;
removed that DTG dosing would initially be dependent on age for participants weighing 3-
<6kg.
Changes to protocol version 4.0 creating protocol version 5.0 1st March 2019
Major changes
1. Summary: Virological response component of primary outcome measure updated so that
children who do not respond virologically will not be included as failures unless their
clinician switches them from first to second-line treatment (ODYSSEY A) or second to third-
line treatment (ODYSSEY B) or they have confirmed viral load ≥400 c/ml at or after 36
weeks; addition of folate substudy.
2. Trial assessment schedule and section 6.1: RBC folate/RBC storage and B12/serum storage
for folate substudy added and footnotes updated accordingly.
3. Section 5.3.1: Updated to describe changes to DTG dosing within the main trial, based on
latest PK and safety data, and also ongoing WB-PK doses. Detailed WB-PK substudy
information removed to avoid duplication as included in Appendix XIII.
4. Section 5.5.1: Recommended switching female participants on DTG-based regimen
identified to be pregnant within the first 8 weeks after the last menstrual period to a non-
DTG ART regimen if there are other good options available to replace DTG.
5. Section 9.2.1: Virological response component of primary outcome measure updated so
that children who do not respond virologically will not be included as failures unless their
clinician switches them from first to second-line treatment (ODYSSEY A) or second to third-
line treatment (ODYSSEY B) or they have confirmed viral load ≥400 c/ml at or after 36
weeks.
6. Section 10: Addition of folate substudy; minor updates to other substudies.
7. Appendix I: Updates to main trial PISs to include updated safety information, collection of
information on babies born to female participants, information on data collection and
storage; additional Qualitative substudy PISs to include in-depth interviews with caregivers,
and in-depth interviews with participants on DTG following the safety alert; added PIS for
YTB facilitators.
8. Appendix II: Addition of parent/carer and participant re-consent to the ODYSSEY trial and
participant re-assent to the ODYSSEY trial; additional Qualitative substudy consent forms to
include in-depth interviews with caregivers and consent/assent forms for in-depth
interviews with participants on DTG following the safety alert; added consent form for YTB
facilitators.
9. Appendix XV: Updated following DTG safety alert and to include caregiver interviews.
10. Appendix XVIII: Added for folate substudy.
11. Appendix XIX: Added for tabulation of dolutegravir dosing in the ODYSSEY trial across
different protocol versions.
Minor changes
1. General information: Updated email address for contacting MRC CTU regarding
randomisations & SAE reporting; staff details; collaborating centre details
2. Summary: Removed that participants 3-<14kg may contribute to the 700 children in the
main trial as main trial finished recruitment before lower weight bands opened and
therefore at least 60 additional children will be recruited; clarification of recruitment period
for children 3-<14kg.

ODYSSEY Protocol
3. Trial schema: Added footnote to briefly describe enrolment and follow up of children 3-
<14kg;
4. Trial assessment schedule: Pregnancy tests to be performed at all trial visits, and other
time-points if required, for all females of childbearing potential.
5. Abbreviations: Updated
6. Section 1.3: Minor update (WHO 2016 no longer most recent guidelines)
7. Section 1.4: Updated to reference recent study.
8. Section 1.5: Section added to include information on TSEPAMO study and dolutegravir
safety alert. Subsequent sections renumbered accordingly.
9. Section 1.6: Added information on DTG formulations available.
10. Section 3.1.1: Footnote amended for clarification.
11. Section 3.4: Clarification and update of recruitment period for children 3-<14kg.
12. Section 4.1: Updated email address for contacting MRC CTU regarding randomisations.
13. Section 5.1: Removed US as no longer participating; updated that DTG-containing FDCs may
be sourced through national programmes where available.
14. Section 5.3.2: Updated to clarify that participants 25-<40kg whose DTG dose is increased to
50mg following the results of WB-PK2 and are already receiving ABC 600mg + 3TC 300mg
may switch to Triumeq.
15. Section 5.5.2.A: Updated to enable possiblity of restarting DTG if alternative cause for
explanation of raised liver enzymes is more likely.
16. Section 5.5.2.C: Updated for clarification.
17. Section 5.10: Sodium valproate added to list of drugs with significant interactions; update to
information regarding concomitant calcium/iron/vitamin supplements; added reference to
link to University of Liverpool HIV Drug Interactions website added.
18. Section 6.1: Pregnancy tests to be performed at all trial visits, and other time-points if
required, for all females of childbearing potential; information about contraception use to
be recorded; RBC folate/RBC storage and B12/serum storage for folate substudy added.
19. Section 6.7.1: Children in the DTG arm receiving rifampicin as part of TB prevention therapy
may also participate in the TB-PK substudy.
20. Section 6.8: Updated to include information on TSEPAMO study; list of highly effective
contraception that must be used if female participants are sexually active; updated
guidance to sites if female participants taking DTG are intending to/become pregnant
during the trial.
21. Section 7.1.5.D: Reporting of events in infants born to female trial participants added; other
minor update for clarification.
22. Section 7.2.1.D: Updated to clarify that the most recently approved IB should be used for
assessing expectedness for DTG and DTG-containing products but that SPC should be used
for all other ARVs.
23. Section 9.5: Clarified primary analysis refers to main trial participants; clinical and adverse
events will be summarised using an in-house coding system
24. Section 11.2.1.A: Updated with information on common side effects and dolutegravir in
pregnancy safety alert.
25. Section 13: Clarification of the drugs provided for the trial and to which sites/countries.
26. Appendix I: Updates to WB-PK1 PISs to include children 3-<14kg; updates to Qualitative
substudy focus group PISs; updates to YTB PIS.
27. Appendix II: Updates to parent/carer main study consent to randomisation, participant
main study consent to continued participation for young people who reach the age of
consent whilst in the trial; updates to WB-PK1 consent/assent forms to include children 3-
<14kg; update to title of consent form for Qualitative focus group discussions (young people
18-19 years); updated YTB consent/assent forms.

ODYSSEY Protocol
28. Appendix XIII: Updated to include results and outcomes of the WB-PK substudies to date
and to fully describe updates to the WB-PK1 substudy (parts II & III). Rearrangement of
some sections and other minor amendments for clarification purposes; Table 10 moved to
appendix XIX.
29. Appendix XIV: Children in the DTG arm receiving rifampicin as part of TB prevention therapy
may also participate in the TB-PK substudy; clarified that children <6 years may be
recruited.
30. Appendix XVI: Updated to include interviews and to clarify that ≥32 young people will take
part.
31. Appendix XVII: Odyssey structure updated with sites added/deleted as appropriate.
Changes to protocol 3.0 creating version 4.0 22nd December 2017
Major changes
1. Summary: In the number of patients, added that 60 additional children 3-<14kg will be
enrolled, some of whom may contribute to the 700 children in the main trial (see below
changes in sections 9.1 and 9.5).
2. Section 6.1 and Trial assessment schedule footnote t: Clinical assessment, haematology and
biochemistry tests at week 2 are required for all children 3-<14kg.
3. Section 3.1.1: Inclusion criteria expanded to include children aged ≥28 days and weighing 3-
<14kg.
4. Section 3.4: Explanation that 60 additional children 3-<14kg will be enrolled as a separate
group, some of whom may contribute to the 700 children in the main trial. Recruitment
period increased to 96-120 weeks, to allow recruitment of younger/lighter children.
5. Section 5.3.1: Table 3 and the text are updated to include formulations and dosing
information on children 3-<14kg recruited via an updated WB-PK1 substudy. Added
information about the lead-in PK substudy for the weight band 3 to <14kg. Children 14-
<20kg will receive DTG 25mg to simplify the dosing to one DTG 25mg tablet QD instead of
two DTG 10mg tablets QD and to avoid confusion with two different dosing for this weight
band in the trial. Added that ViiV Healthcare is confirming the suggested dose for children 3-
<6kg. Also added that children 14-<25kg who are able to swallow tablets will be taking DTG
25mg tablets and those who cannot swallow will take dispersible tablets. Information on
WB-PK1 is removed as repeated in Appendix XIII.
6. Section 6.11: The end of the main trial recruitment is defined. Explained that recruitment of
children 3-<14kg may be continued after the end of the main trial recruitment reached and
that all children will be followed up for a minimum of 96 weeks.
7. Section 9.1: Added that children 3-<14kg will be recruited and randomised as a separate
group stratified by A/B and the 3 weight bands. Randomisation of children ≥14kg continues
as previously.
8. Section 9.5: Added that children recruited in the 3 lower weight bands before recruitment
targets have been achieved will contribute to the total accrual numbers for the main trial if
their doses are confirmed to be optimal doses. Added that there will be a separate
secondary analysis of all children <14kg when this group has completed 96 weeks follow-up.
9. Appendix XIII: WB-PK1 substudy is updated to include children 3-<14kg. Table 9 updated.
References updated.
Minor changes
1. General information: Updated staff details; CTU address; added address of new
collaborating centre.
2. Summary: Recruitment period increased to 96-120 weeks.

ODYSSEY Protocol
3. Trial assessment schedule footnote d: For clarity and consistency added that the screening
viral load test for ODYSSEY B participants may be omitted if a result of ≥500 copies is
available up to 4 weeks prior to the screening visit. (This change was included as part of the
previous protocol version 3.0 and the details can be found elsewhere in sections 3.1.3 and
3.6.1. and for completeness and consistency is now added to the assessment schedule
footnotes).
4. List of abbreviations: DT (dispersible tablet) added
5. Section 1.5: Information on marketing authorisation is updated.
6. Section 2.3: Deleted sites no longer participating, including Brazil and an IMPAACT-
supported site in South Africa.
7. Section 3.1.3: TAF added to the list of drugs in the additional inclusion criteria for ODYSSEY
B.
8. Section 3.3.1: TAF added to section on considerations of use of different NRTI.
9. Section 4 and Section 5.7 and Trial assessment Schedule: Updated that the Sleep and mood
section of Acceptability, Sleep and Mood Questionnaire is to be completed at enrolment.
10. Section 5.1: Added TAF to list of NRTIs.
11. Section 5.2: – Added ATV/c to list of bPIs and added “e.g.” in order to clarify other less
common drugs not listed may also be included.
12. Section 5.2.1 Table 1 and Section 5.2.2 Table 2: ATV/c, DRV/c and TDF or TAF are added in
the examples of ART regimens for the SOC arm.
13. Section 5.3: TAF is added in the examples of NRTI backbone for the DTG arm.
14. Section 5.3.1: For children 20-<25kg added that doses in this weight band will be reviewed
and, if necessary, modified based on PK and safety data from ODYSSEY and/or P1093.
Clarified information on all weight bands in the WBPK substudies. Information on WB-PK1 is
removed as repeated in Appendix XIII.
15. Section 5.5.1: Added that in exceptional circumstances study drug may be provided as third-
line treatment for children in the SOC arm who have failed second-line treatment.
16. Section 5.5.2.C: Added that prompt clinical evaluation should be done (instead of
considered) for participants who experience signs of suicidal ideation or behaviour.
17. Section 6.3: – Corrected typo - version of DAIDS from 2010 to 2014
18. Section 6.8: Information on reporting of pregnancy moved to the relevant section on safety
reporting 7.1.5.
19. Section 7.1.5: Reporting of notable events is clarified. Added that the suspected cases of
drug induced liver injury should be reported in both arms.
20. Section 7.2: clarified reporting of laboratory AEs, SAEs, SARs and notable events.
21. Sections 7.2.1 and 7.2.2: Clarified that notable events should be reported within 24 hours of
the investigator becoming aware of the event.
22. Section 7.3: Clarified that the CTUs will review all reported notable events.
23. Section 8.3: Updated to clarify monitoring processes. Removed repetition on permission
and consent to access patient data.
24. Section 8.3.2: Confidentiality section clarified.
25. Section 10.1: Updated information on PK substudies.
26. Section 17: References updated.
27. Appendix I: Titles of Patient Information Sheets are updated to include children weighing
≥3kg.
28. Appendix II: Titles of Template Consent and Assent Forms are updated to include children
weighing ≥3kg. Main study consent to continued participation for young people who reach
the age of consent whilst in the trial added.
29. Appendix XIII: Updated list of sites participating in WB-PK substudies.
30. Appendix XIV: Clarified that younger children <6 years may be recruited once the
appropriate DTG doses are confirmed for them in WB-PK1 substudy. Updated information

ODYSSEY Protocol
in study design paragraph and Figure 1 that the 1st PK day (TB-PK1, 12h curve) may be
performed within the last month of co-administration. Removed details of specific sites as
the TB-PK will take place at all sites in Uganda, South Africa and Zimbabwe.
31. Appendix XVII: Odyssey structure updated with sites added/deleted as appropriate.
Minor corrections
Changes to protocol version 2.0 creating version 3.0 18th January 2017
Major changes
10. Summary of Trial and section 5.2: Added that INSTIs (other than DTG) can be included as a
SOC third agent option. Clarified that PI means a boosted PI.
11. Summary of Trial secondary outcomes: Changed from ≥50 and ≥400 copies to <50 and <400
copies.
12. Summary of Trial and section 10 Ancillary substudies: Added WB-PK1 and WB-PK2
substudies. Renamed TB-PK substudy to differentiate from new PK substudies. Added
Qualitative and Youth Trial Board substudies.
13. Updated Trial Schema to include INSTI in SOC Arm for ODYSSEY A and replace RAL with
INSTI in SOC for ODYSSEY B.
14. Trial Assessment Schedule and accompanying notes: Added that the glucose test can be
optional at the randomisation visit if there is a medical justification to limit the amount of
blood drawn. Renamed EQ-5D questionnaire as Quality of Life questionnaire (as using an
adapted version of the EQ-5D). Changed frequency of plasma storage after 96 weeks from
every 24 weeks to every 12 weeks. Removed PBMC storage at screening, week 2 and the
end of study visit. Changed acceptability questionnaire to acceptability, sleep and mood
questionnaire and added that this will be done at week 12. Revised volumes for blood
collection, differentiating for blood to be used for tests and for storage. Added that
lipodystrophy and bone profile (optional) to be done at the end of study visit. Added
clarifications regarding mandatory and optional tests. Clarified that adherence
questionnaire for ODYSSEY B at screening visit only to be done if participant is currently on
treatment. Added that BIA measurements will be done at selected sites. Added that, if not
already scheduled, plasma storage, adherence and acceptability questionnaires should be
done at point of treatment failure, and adherence and acceptability questionnaires if ART
regimen changes.
15. Background: Updates and clarifications made.
16. Section 3.1.1 Patient inclusion criteria all patients: Replaced DTG dose known for
age/weight band with “weighing ≥14 kg and DTG dose known for the child’s weight-band”,
and added details regarding the inclusion criteria for children weighing 14 to <20kg.
17. Section 3.1.3 Additional criteria for ODYSSEY B: Additional definition of starting second-line
ART as switch of only the third agent due to treatment failure where resistance tests show
no NRTI mutations. Clarification that reasons for substitutions could also include changes in
national guidelines or drug availability. Removed time period for cumulative results of
resistance testing. Replaced viral load of >1000 copies with >500 copies at screening visit,
and added that can also be within 4 weeks prior to screening.
18. Section 3.6.1: Removed words “for screening” and “screening” in order to comply with local
requirements for consent procedures.
19. Section 3.6.1: Added viral load for ODYSSEY B may be done at screening or within 4 weeks
prior to screening.
20. Section 4: Amended wording “written informed consent… must then be obtained” with
“Continued agreement… must be confirmed” in order to comply with local requirements for
consent procedures.

ODYSSEY Protocol
21. Section 5: Major reorganisation to this section: Added a general information section to
clarify information relevant to all participants, regardless of treatment allocation. Moved
text previously in either ODYSSEY A or B sections to this section as applicable to all
participants (e.g. ABC warning cards).
22. Section 5.1.1: Added section 5.1.1 to clarify that participants must be prescribed the NRTI
backbone selected prior to randomisation and added further guidance regarding changes to
the NRTI backbone during the trial.
23. Section 5.1 and 5.2: Updated SOC drug options to include RPV and INSTIs. Tables 1 and 2
updated and moved to sections 5.2.1 and 5.2.2. Added for clarification that participants
randomised to SOC must be prescribed the class of non-NRTI drug that was chosen prior to
randomisation.
24. Section 5.2.2: Added further guidance regarding addressing adherence issues.
25. Section 5.2.2: Further guidance on interpretation of resistance test results added. Added
that ddi or d4T may be used in second-line where no other drugs are available.
26. Section 5.3.1: Added information about DTG dosing according to the following weight
bands: 14 to <20kg, 20 to <25kg, 25 to <40kg, and >40kg. Added information about the lead-
in PK substudy (WB-PK1) for the weight bands 14 to <20kg and 20 to <25kg; and about the
cross-over PK substudy (WB-PK2) for the weight band 25 to <40kg. Added table 3
summarising DTG dosing and formulations to be used in ODYSSEY.
27. Section 5.3.2: Added that (subject to satisfactory PK results) children ≥25kg in the main trial
on DTG+ABC+3TC would be able to move to an FDC.
28. Added Section 5.5.2.C Suicidal Ideation Behaviours and Sleep Disorders.
29. Section 5.7: Acceptability questionnaire now incorporates questions on sleep and mood and
week 12 now added (which was previously missing in error).
30. Section 5.10: Added information and table 4 on significant drug interactions with DTG.
31. Section 6.1 and 6.2.3: Added that for ODYSSEY B the viral load can be done at screening or 4
weeks prior.
32. Section 6.1: Removed PBMC storage at screening.
33. Section 6.2.4: Clarification that for children experiencing virological failure. Replaced >1000
c/ml with current threshold for resistance assays.
34. Section 6.4: Renamed EQ-5D questionnaire as Quality of Life questionnaire (as using an
adapted version of the EQ-5D).
35. Section 6.7.1: Changed from at least ‘10’ children to ‘12’.
36. Section 7.2: Added that Grade 1 clinical AEs should be reported only if they result in change
of ART, (as well as Grade 2).
37. Section 9.1: Clarification that availability of resistance tests is for each particular site and is
with respect to children who are failing treatment.
38. Section 9.1: Added TAF/3TC and TAF/FTC to TDF stratification group.
39. Section 9.1: Added that randomisation will be stratified by NRTI backbone.
40. Section 9.2.2: Changed, (<50 and <400 copies rather than ≥). Deleted “with a subgroup
analyses according to the activity of the background regimen”.
41. Appendix I Template information sheets Main study: Reworded explanation of second-line
treatment. Updated volumes of blood collection from 2 to 3 teaspoons to 3 to 6 teaspoons.
Deleted the visit schedule. Added sentence regarding depression or having suicidal thoughts
in possible disadvantages of taking part. Added more detail on section “what will happen to
information about me/my child collected during the study”.
42. Appendix I: Added information sheet for the WB-PK 1 substudy (also incorporating the main
trial).
43. Appendix I: Added information sheet for the WB-PK 2 substudy (also incorporating the main
trial).

ODYSSEY Protocol
44. Appendix I: Renamed information sheet for TB PK substudy. Added further details to “what
will happen to information about me/my child collected during this substudy”. Reduced
number of samples collected from 10 to 7. Changed wording from hospital to clinic.
45. Appendix I: Added information sheets for Qualitative substudy.
46. Appendix I: Added information sheets for Youth Trial Board substudy.
47. Appendix II: Added consent and assent forms for WB-PK 1 and WB-PK 2 substudies.
48. Appendix II: Added consent and assent forms for Qualitative substudy.
49. Appendix II: Added consent and assent forms for Youth Trial Board substudy.
50. Appendix IV: Updated adherence questionnaires.
51. Appendices V and VI: Updated acceptability questionnaires and also incorporated additional
questions on sleep and mood. No longer different questionnaires for ODYSSEY A and B
therefore Appendix VI deleted.
52. Added Appendix XI and Table 7 on safe limits of blood sample volumes in children.
53. Updated Appendix XII on the Immunology/virology substudy.
54. Added Appendix XIII on the Weight band pharmacokinetics substudies WB-PK 1 & 2.
55. Updated Appendix XIV on the TB PK substudy.
56. Added Appendix XV on the Qualitative Substudy.
57. Added Appendix XVI on the Youth Trials Board project.
Minor changes
1. Cover page: Mylan logo added.

2. General information: Updated phone number and e-mail address for MRC CTU
randomisations.
3. General information: Updated e-mail address for SAE reporting for MRC CTU coordinated
sites.
4. General information: Updated staff details at PENTA foundation, MRC CTU, INSERM-ANRS
and PHPT.
5. General information: Updated details of staff at collaborating centres and removed
countries and centres no longer participating. Updated and added new collaborating
centres.
6. General information: Added e-mail addresses for David Burger, Nigel Klein and Maria
Munoz Ferndandez.
7. Summary of Trial: Clarified that PI means a boosted PI.
8. Summary of Trial and sections 9.2.1 to 9.2.3; Primary and secondary outcomes:
clarifications made to how endpoints will be assessed.
9. Summary of Trial: Secondary outcome measures, deleted word “suppression”.
10. Summary of Trial and sections 9.2.3 and 9.5 Added that change in total cholesterol from
baseline to week 96 will be used to assess superiority of DTG arm vs SOC arm.
11. Summary of Trial and section 10, ancillary substudies: Added “see section 10 for
participating countries”. Reworded summary Immunology/virology substudy for clarity and
consistency.
12. Abbreviations: List updated. Removed EQ-5D and replaced with QoL.
13. Section 2.3 Site Management: Removed countries no longer participating.
14. Section 3.2 Patient exclusion criteria. Minor rewording for clarification regarding history of
presence of known allergy or contraindications to DTG, proposed available SOC third agent
or NRTI backbone.
15. Section 4 Registration & Randomisation: Minor rewording for clarity. Updated the MRC CTU
contact details for randomisations. Clarified that family also can mean household for
enrolment of multiple participants.

ODYSSEY Protocol
16. Section 5.1: Clarifications regarding drug supply added, and that that the Mylan formulation
of ABC/3TC 120/60mg will be provided in sub-Saharan Africa if required.
17. Section 5.4: Clarification that refers to trial drugs.
18. Section 5.5: Renamed section title for clarity (deleted word “dose”).
19. Section 5.5.1: Renamed section title for clarity. Moved sentence on “if simplification…is
deemed necessary” to the end of the section. Added word “treatment”. Minor clarification
regarding recommendations if possible drug induced liver injury.
20. Section 5.5.2: Renamed section title for clarity. Added word “appropriate” before CTU.
21. Section 5.7 Heading reworded for clarity from Compliance and adherence to adherence and
acceptability. Deleted words “participant-reported” in first sentence for clarity.
22. Section 5.8: Reworded “pills” as may include liquid formulations.
23. Section 6.1: Clarification that if previous Tanner scores of 5, no need to continue doing
Tanner scores at subsequent visits. Added “and then 48 weekly” and “and at end of study”
to those measurements where this was missing, in order to match the Trial Assessment
Schedule.
24. Section 6.2.4: Added that samples may be assayed locally where possible, or moved to
another country.
25. Section 6.4 Added “and at end of study” for the quality of life questionnaire”.
26. Sections 6.7 to 6.7.2. Clarification that participants may either have TB at enrolment or
develop TB during the trial. Clarification that not compulsory to enter the substudy if
participant has TB. Other minor rewording for clarification.
27. Section 6.11: Clarification that the trial will be considered closed when the last patient to be
enrolled reaches 96 weeks.
28. Sections 7.1, 7.1.5 and 7.2.1: Table 4 renumbered as Table 5.
29. Section 7.2.1: Table 5 renumbered as Table 6.
30. Section 7.1.5: Renamed section title as other notable events, renumbered some section
titles from 7.3.x to 7.2.x
31. Section 7.3: Corrected spelling error.
32. Section 8.2: Deleted MRC as relevant to all CTUs.
33. Section 9.1: Clarification that availability of resistance testing is relevant to “before switch
to second line”.
34. Section 9.2.3: Added “change in total cholesterol from baseline to week 96”.
35. Section 9.2.4: Removed “as assessed by patient completed questionnaires”.
36. Section 9.5: Added paragraph on how the proportion of participants with VL <50 or <400
will be determined.
37. Section 10: Added a short summary of the ancillary studies details of which countries are
participating.
38. Section 11.2.1.E: Corrected that computer generated anonymous codes will be three letters
not four. Corrected that full date of birth, not just month and year of birth will be used.
Added further details on identifiers for stored samples.
39. Section 13: Clarification regarding arrangements for drug supply.
40. Appendix I: Grammar correction in patient/carer information sheet “what happens at the
end of the study” section.
41. TB-PK information sheet – changed wording from “Rifampicin” to “anti-TB medicine” to
make easier to understand. Changed blood sample amount from “less than” half a teaspoon
to “about” half a teaspoon.
42. Appendix II: Parent/carer – main trial consent to screening, corrected typo on last
statement.
43. Appendix II: Added screening assent form.
44. Appendix II: Added participant consent to storage of blood samples for future testing form.
45. Appendix II: Renamed consent form for TB PK substudy (added “TB”).

ODYSSEY Protocol
46. Renumbering of Appendices throughout document following deletion of appendix VI.

47. Appendix IX: Updated DAIDS Tables to 2014 version.
48. Appendix XVII updated ODYSSEY structure to remove countries and collaborating sites no
longer participating and to include new collaborating sites.
Changes to protocol version 1.1 creating version 2.0 6th March 2015
Cover page: IMPAACT logo updated.
General Information: Details for collaborating centres in Klerksdorp, South Africa (PHRU) and
Memphis, US (St Jude Children’s Research Hospital) added
General Information & Section 2.3 Site Management: US removed in relation to IMPAACT and
added as a MRC collaborator.
General Information: MRC CTU at UCL staff details updated.
Trial Assessment Schedule: Timing of urine dipstick tests corrected – tests at end of study visit
added.
Trial Assessment Schedule & Section 6.4 Procedures for Assessing Quality of Life: Removal of
reference to EQ-5D-Y questionnaire, replaced with EQ-5D. EuroQol website link added to section
6.4.
Trial Assessment Schedule: Total blood volume to be collected clarified.
Abbreviations: List updated to include EQ-5D.
Section 6.8 Management of Pregnancy: Clarified that pregnant participants should be encouraged
to remain in the study even if ART regimen is changed.
Section 7.3.1.D Expectedness: Updated information on responsibilities for determination of
expectedness of serious adverse events.
Changes to protocol version 1.0 creating version 1.1 11 December 2014 (the protocol was still a
draft document at this stage but a “final” version was required for review by Viiv resulting in version
numbers taking this format. Neither protocol version 1.0 nor version 1.1 have been reviewed by an
ethics committee or competent authority).
General Information, Summary of Trial, Section 2 Selection of Sites/Clinicians & Section 14 Oversight
& Trial Committees: Details of IMPAACT involvement added.
General Information: Funding information corrected to reflect current status.
General Information: Sponsor details added.
General Information: Immunology/Virology Committee member details updated.
Summary of Trial: Updated for consistency and minor amendments for clarification.
Trial Schema, Section 5.1 Introduction & Section 5.2 SOC Arm: Addition of raltegravir to SOC arm of
ODYSSEY B.
Trial Assessment Schedule & Section 6.1 Trial Assessment Schedule: Addition of urine dipstick tests.
Trial Assessment Schedule, Section 3.1.1 Patient Inclusion Criteria, Section 6.1 Trial Assessment
Schedule & Section 6.8 Management of Pregnancy: Pregnancy test requirements clarified.
Trial Assessment Schedule: Timing of Tanner scale measurements, lipodystrophy assessments and
study drug supply clarified.
Trial Assessment Schedule: Timing of screening and randomisation visits clarified.
Abbreviations: List updated accordingly.
Section 1 Background: Updated
Section 2 Selection of Sites: General wording updated and update to laboratory requirements.
Clarified that a site and lab risk assessment will be carried out prior to site activation.
Section 3.2 Patient Exclusion Criteria: Bilirubin must be ≥2xULN.
Section 5 Treatment of Patients & Section 13 Finance: Triumeq can be provided by Viiv Healthcare
as appropriate.

ODYSSEY Protocol
Section 5.5.2.A Liver Toxicity: Stopping criteria updated to include that DTG should be substituted if
ALT ≥3xULN and bilirubin ≥2xULN, or that ALT ≥5xULN for more than 2 weeks with bilirubin <2xULN
and no symptoms of acute hepatitis or hypersensitivity.
Section 6.2.2 Immunology, Section 8.3.1 Direct Access to Participant Records & Section 9.2.2
Secondary Efficacy Outcomes: Clarification that total and percentage CD8 T cell counts should also
be measured and access will be required to a random sample of this data. This data will be used to
provide CD4/CD8 ratios required as a secondary efficacy outcome.
Section 6.2.4 Resistance Testing: At sites where genotypic resistance testing is not performed as
standard of care baseline samples will be tested retrospectively and batched genotypic resistance
testing will be performed on samples with viral load >1000 c/ml.
Section 6.7.1 Management of Children with Tuberculosis in the DTG Arm & Section 10.2
Pharmacokinetic Substudy in Participants Developing TB while on DTG: At least 10 children with TB
receiving DTG and rifampicin will be invited to participate in the PK substudy.
Section 6.8 Management of Pregnancy: Clarification that all infants born to female participants will
receive infant prophylaxis according to current local standard of care.
Section 6.8 Management of Pregnancy: Clarification that any pregnancy that occurs during study
participation must be reported as a notable event.
Section 6.10 Participant Transfers: Patients can continue to attend visits at original site if sufficient
resources are available, or nurse only telephone visits can be conducted with drugs and clinical care
provided at a local clinic. Participant should be considered lost to follow-up if none of the options
are possible.
Section 7.4 CTU Responsibilities: Modified for general applicability. CTUS are responsible for
reporting of SAEs to relevant regulatory authorities and research ethics committees. This
responsibility may be delegated to country principal investigators.
Section 8.3 On-Site Monitoring: Monitors will evaluate laboratory procedures and sample storage.
Section 9 Statistical Considerations: Randomisation will be stratified by bPI/non-bPI-base ART
offered as SOC (to include RAL).
Section 13 Finance: Drugs provided by Viiv Healthcare corrected.
Minor corrections

ODYSSEY Protocol
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Treatment Regimens in Botswana. The New England journal of medicine. 2019(381):827-40.
37. Zash R, Jacobson DL, Diseko M, Mayondi G, Mmalane M, Essex M, et al. Comparative safety
of dolutegravir-based or efavirenz-based antiretroviral treatment started during pregnancy in
Botswana: an observational study. The Lancet Global health. 2018;6(7):e804-e810.
38. Heads of Medicines Agencies, C.T.F.G. Recommendations related to contraception and
pregnancy testing in clinical trials. 15 Sep 2014; Available from:
http://www.hma.eu/fileadmin/dateien/Human_Medicines/01-
About_HMA/Working_Groups/CTFG/2014_09_HMA_CTFG_Contraception.pdf.
39. Patel P, Song I, Borland J, Chen S, Peppercorn A, Wajima T, et al. Relative bioavailability of a
paediatric granule formulation of the HIV integrase inhibitor dolutegravir in healthy adult subjects.
Antivir Ther. 2014;19(3):229-33.
40. Buchanan AM HM, Conn I, Davies M, Choukour M, Wynne BR. . Relative Bioavailability of a
Dolutegravir Dispersible Tablet and the Effects of Low- and High-Mineral-Content Water on the
Tablet in Healthy Adults. Clin Pharmacol Drug Dev. 2017;6(6):577-583.
41. Penazzato M, Prendergast A, Tierney J, Cotton M, Gibb D. Effectiveness of antiretroviral
therapy in HIV-infected children under 2 years of age. Cochrane Database Syst Rev, 2012. 7: p.
CD004772.
42. Abers MS, Shandera WX, Kass JS. Neurological and psychiatric adverse effects of
antiretroviral drugs. CNS Drugs, 2014. 28(2): p. 131-45.
43. Bollen P, Turkova A, Mujuru H, Musiime V, Amuge P, Lugemwa A, et al., editors. Steady-
state pharmacokinetics and early safety data in HIV-infected African children weighing 14 to <25kg
on film-coated dolutegravir 25mg tablets in the ODYSSEY trial. 10th International Workshop on HIV
Pediatrics. 2018. Amsterdam, the Netherlands.
44. Bollen P, Turkova A, Mujuru H, Kaudha E, Lugemwa A, Amuge P, Colbers A, Moore C,Parker
A, Musiime V, Hakim JG, Ford D, Gibb D, Burger D, and the ODYSSEY trial team, Adult dolutegravir
50mg film-coated tablets in children living with HIV weighing 20 to <25kg, in Conference of
Retroviruses and Opportunistic Infections (CROI). 2019: Seattle, WA.
45. Turkova A, Bollen P, Kaudha E, Chidziva E, Lugemwa A, Kekitiinwa A, Parker A, Shakeshaft C,
Montero S, Colbers A, Nanduudu A, Mujuru H, Makumbi S, Amuge P, Rojo P, Ford D, Burger DM,
Gibb DM, and the ODYSSEY trial team. Steady-state pharmacokinetics and early safety data in HIV-
infected African children weighing ≥25kg after switching to 50mg film-coated dolutegravir tablets in
the ODYSSEY trial, in 10th International Workshop on HIV Pediatrics. 2018: Amsterdam, The
Netherlands.
46. WHO, Paediatric Antiretroviral Drug Optimization (PADO) Meeting 3. WHO.
47. Fontana RJ, Watkins PB, Bonkovsky HL, Chalasani N, Davern T, Serrano J, et al. Drug-Induced
Liver Injury Network (DILIN) prospective study: rationale, design and conduct. Drug Saf, 2009. 32(1):
p. 55-68.
48. Wille N, Badia X, Bonsel G, Burstrom K, Cavrini G, Devlin N, et al. Development of the EQ-
5D-Y: a child-friendly version of the EQ-5D. Qual Life Res, 2010. 19(6): p. 875-86.

ODYSSEY Protocol
49. Kekitiinwa A, Cook A, Nathoo K, Mugyenyi P, Nahirya-Ntege P, Bakeera-Kitaka S, et al.

Routine versus clinically driven laboratory monitoring and first-line antiretroviral therapy strategies
in African children with HIV (ARROW): a 5-year open-label randomised factorial trial. Lancet.
2013;381(9875):1391-403.
50. AIDSinfo. Recommendations Regarding the Use of Dolutegravir in Adults and Adolescents
with HIV who are Pregnant or of Child-Bearing Potential. 2018 May 30, 2018; Available from:
https://aidsinfo.nih.gov/news/2109/recommendations-regarding-the-use-of-dolutegravir-in-adults-
and-adolescents-with-hiv-who-are-pregnant-or-of-child-bearing-potential.
51. EMA. Guideline on good pharmacovigilance practices (GVP) Module VI – Collection,
management and submission of reports of suspected adverse reactions to medicinal products (Rev
2), in Guideline on good pharmacovigilance practices (GVP). 2017: EMA.

ODYSSEY Protocol
19 APPENDIX I TEMPLATE PATIENT INFORMATION SHEETS
PARENT/CARER INFORMATION SHEET - MAIN STUDY ONLY
ODYSSEY STUDY
We are inviting you and your child to take part in a research study
Before you decide whether to take part, it is important for you and your child to understand why we
want to carry out this study and what it will mean for you both.
Please take time to read the following information and to discuss it with friends, family and with your
doctor or clinic nurse if you wish.
You are free to decide if you want your child to take part in this research study. If you choose not to
take part, this will not affect the care your child gets from your doctor or nurse.
If you decide to take part in the study you can stop taking part at any time without giving a reason.
Ask your study doctor or nurse if anything is not clear or if you would like more information.
Thank you for reading this information.
Important to know
If you decide to take part your child will have some extra visits to the clinic at the beginning of the
study.
A computer program will choose which treatment your child will take. Neither you nor your doctor
will be able to choose which group your child is in.
Contents
1. Why are we doing this study?

2. Why has my child been asked to take part?
3. What will happen if we decide not to take part?
4. What will happen if my child takes part?
5. What medicines will my child be given if we take part?
6. What are the possible benefits and disadvantages of taking part?
7. Study questionnaires
8. More information about taking part

ODYSSEY Protocol
1 Why are we doing this study?
Dolutegravir is a new medicine being used to treat adults with HIV.

In adults it has been shown to be effective and safe, with few side effects, and it only needs to be
taken once a day.
Sometimes a medicine works differently in growing children than in adults, so we need to check how
it works in children as well. Dolutegravir could be an excellent option for children if the study finds it
works as well as it does in adults.
ODYSSEY will see how children and adolescents taking dolutegravir as part of their anti-HIV medicines
compare to others taking different anti-HIV medicines.
2 Why has my child been asked to take part?
We are aiming to ask 700 children and young people from many countries to take part.
Your child has been asked to participate because:
A. He/She is about to start taking anti-HIV medicine for the first time.
Or
B. He/She is already taking one set of anti-HIV medicine that is no longer working well and your
doctor has decided it is time your child changes to a new combination. This is known as “second-
line” treatment.
3 What will happen if we decide not to take part?
It is totally up to you and your child whether or not he/she takes part in this study.
It is your right to decide not to take part if you wish.
This will not affect your child’s care now or in the future in any way.
4 What will happen if my child takes part?

If you decide to take part, we will go through this information sheet together. We will give a copy to
you to keep. You will be asked to sign a consent form to show you have understood the information
and have agreed for your child to have some blood tests and a check-up to see whether they can go
into the study.
If the results show that your child can participate, we will invite him/her to enter the study. We need
to know that you have fully understood the study and then we will ask you to sign a second consent
form for your child to join.
Your child’s health will be watched closely during the study.

ODYSSEY Protocol
In the first 2 months you will need to come for 3 appointments. Once your doctor is happy that your
child has no side effects from the medicines and is doing well, they will change to having 3-monthly
appointments.
These visits are to make sure your child is continuing to do well. If for any reason your doctor has any
concerns, they will change your child’s treatment in the normal way.
In addition to blood tests to check for any side effects, a small amount of extra blood will be collected
at each visit. The total amount of blood taken will never exceed a safe limit and will be between 3 and
6 teaspoons depending upon the age of your child. Part of this sample will be stored to be used to
check the amount of virus in the blood and to look at how the body fights HIV. We would like your
agreement that we can store these samples anonymously (without your child’s name or exact date
of birth) for up to 15 years.
Your child will be in the study for at least 2 years. When the study ends, if your child is doing well they
may be able to remain on the same anti-HIV medicines they have been taking during the study, but
you will need to discuss this with your doctor.
It is important that you know that this is a voluntary study so if at any time you decide that your
child does not want to be involved anymore, you can stop and it will not affect the care that your
child receives in the future.
5 What medicines will my child be given if we take part?
If your child joins the study, a computer will choose which group he/she will be in so it is fair and we
can truly compare the treatments.
There will be two groups in the study:
Standard of care group: meaning your child will receive the usual, nationally approved anti-HIV
medicine.
Dolutegravir group: meaning your child will take a combination of anti-HIV medicines that
includes the new medicine, dolutegravir.
6 What are the possible benefits and disadvantages of taking part?
What are the possible benefits of taking part in this study?

We cannot promise that participating in the study will directly help your child. Compared to other
anti-HIV medicines dolutegravir may have fewer side effects and needs to be taken only once a day
which may make it easier to take medicines long-term.
However, if your child is in the ‘standard of care’ group they will receive the same anti-HIV medicines
as children not taking part in ODYSSEY, although your child will be watched very carefully for any side
effects and responses to the treatment. All the information we get will help children and young people
across the world with HIV and in the future it may mean your child has the chance to change to
medicines that are easier to take.
What are the possible disadvantages and risks of taking part in this study?
Whichever group they are in your child will have 3 extra visits to the clinic.

ODYSSEY Protocol
Anti-HIV medicines, like all medicines, can have side effects; most common are nausea, vomiting,
abdominal discomfort, diarrhoea, rash or may affect the liver. If your child feels unwell, you should
contact the clinic as soon as possible.
The new medicine, dolutegravir, has been shown to be effective, with few side effects in adults, but
we don’t know if this will be the same in children (which is why we need to do this study). The most
common side effects in adults are headache, diarrhoea, abdominal pain feeling sick, light headed or
weak, worrying often and having sleep problems. Some adults taking dolutegravir have reported
feeling depressed or having suicidal thoughts, these may not be related to this medicine in all cases.
There is a small chance that dolutegravir may cause a rash, itching, vomiting, stomach pain, sleep
problems, lack of energy, an increase in weight, feeling light headed, sad or worried or may cause
serious liver problems (with signs of vomiting, jaundice or stomach pain), which is why the doctor
needs to follow your child closely. If your child has these signs for more than a day you should inform
your doctor straight away.
Risks in Pregnancy and anti-HIV medicines

There is very little information about the effect of dolutegravir in unborn babies. In a recent study
from Botswana, approximately 1 in 100 women who were taking dolutegravir when they became
pregnant had babies with serious brain and/or spine problems. In the same study, approximately 1 in
1000 women who were taking other antiretrovirals had babies with brain and/or spine problems,
which is similar to what is seen in women without HIV. These problems happen very early in
pregnancy, before many women even know that they are pregnant. We do not know for sure if these
problems are because of dolutegravir. The study in Botswana and other similar studies are ongoing.
We expect more information about this in the near future. In the meantime, we would like to tell you
about this possible risk.
If your child could become pregnant, she will need a pregnancy test before entering the study. She
will not be able to join the study if the test shows she is pregnant. She should avoid getting pregnant
while in the study, and use effective contraceptives if she is having sex. While in the study, please let
us know if she is thinking about having a baby before she starts trying, or if she thinks she is pregnant.
Pregnancy tests will be done regularly during the study to find out early if she is pregnant or not and
to give her the appropriate medical care. If she does get pregnant, she will be able to stay in the study
and her doctor will talk to you both about whether she needs to change her medicine. Once she
delivers, her baby will be assessed by a doctor for any problems and the baby will be followed for
approximately 4 weeks to monitor their health. Health information, including HIV status, will be
collected about the baby. If she has already had a baby whilst being on the study, health information
captured by the hospital during this time period will be collected for the study.
7 Study questionnaires
We are very interested in finding out what children, young people and families feel about the study
and how it is affecting their wellbeing. Over the course of the study we will ask you and your child to
complete questionnaires asking how your child takes their medicines, what it’s like taking medicine
and how they feel in general.

ODYSSEY Protocol
8 More information about taking part
Additional studies
There are some additional studies that are part of ODYSSEY. If they are run at your clinic your doctor
may talk to you and your child about taking part.
Who is organising the study?

ODYSSEY is organised by the PENTA Foundation, an independent organisation that concentrates
specifically on treatment issues for children and young people infected with HIV.
Who has checked this study is safe?

The information about this study has been checked by an independent group of people (a Research
Ethics Committee) to make sure that, as far as possible, the safety and wellbeing of anyone taking
part in the study is protected.
A second group (the Independent Data Monitoring Committee) will meet regularly during the study
to review the results as they come out and will recommend if the study is safe to continue. This is
standard for all studies looking at medicines for adults or children.
What if something goes wrong?

The PENTA Foundation has made arrangements for compensation should your child come to any
harm from participating in this study. If your child is harmed due to someone’s negligence then you
may have reasons for legal action for compensation against the clinic where this occurred.
With your permission your child’s GP will be informed of his/her participation in the study. Your
hospital doctor is not receiving any personal payment for carrying out this research. [Country specific,
delete if not applicable]
What will happen to information about my child collected during the study?
The Fondazione PENTA Onlus, based in Italy and Sponsor for this study, is the owner of data and acts
as Joint Data Controller. University College London (UCL) through the MRC Clinical Trial Unit at UCL,
will be using information from your child and your child’s medical records in order to undertake this
study and will act, along with the Sponsor, as Joint Data Controller for this study and Data Processor.
This means that PENTA and UCL are responsible for looking after your child’s information and using
it properly. UCL and the sponsor designated trial co-ordinating units will keep information about your
child for a minimum of 15 years after the study has finished.
Your and your child’s rights to access, change, move or erase their information are limited, as we need
to manage information in specific ways in order for the research to be reliable and accurate. If your
child withdraws from the study, we will keep the information about your child that we have already
obtained. To safeguard your child’s rights, we will use the minimum personally identifiable
information possible.
All ODYSSEY study information received by the above organisations and other authorised
independent individuals will be kept completely confidential and names will not be used. Your child
will only be identified using a study number, an anonymous code and their date of birth.
Your child’s clinic notes may be looked at by the above organisations and authorised independent
individuals to make sure that the ODYSSEY study is being properly carried out. They may also be seen
by the companies who are supplying medicine for the study or relevant international regulatory
authorities. Confidentiality will be maintained at all times.

ODYSSEY Protocol
If the results of this study are reported or published your child’s name will not be used nor any
information that could be used to identify your child. The study will be conducted in agreement with
the country specific data protection regulations.
You can find out more about how we use your child’s information at
www.ctu.mrc.ac.uk/general/privacy-policy and www.penta-id.org/study-participants-privacy.
How your child’s data will be stored and collected

Your child’s clinic will collect information from your child and your child’s medical records for this
research study in accordance with our instructions.
Your child’s clinic will keep your child’s name, NHS Number and contact details confidential and will
not pass this information to anyone outside of the clinic. Your child’s clinic will use this information
as needed, to contact your child about the research study, and make sure that relevant information
about the study is recorded for your child’s care, and to oversee the quality of the study. Certain
individuals from UCL, authorised regulatory organisations and authorised independent individuals
may look at your child’s medical and research records to check the accuracy of the research study.
They may also be seen by the companies who are supplying medicines for the study or relevant
international regulatory authorities. The people who analyse the information will not be able to
identify your child and will not be able to find out your child’s name, NHS number or contact details.
UCL will collect information about your child for this research study from your child’s clinic. This
information will include health information. This data may be used by UCL and other authorised
research collaborators to conduct the trial and associated sub-studies.
How your data will be used in future & other research

When your child agrees to take part in a research study, the information about your child’s health
and care may be provided to researchers running other research studies in this organisation and in
other organisations. These organisations may be universities, NHS organisations or companies
involved in health and care research in this country or abroad. Your child’s information will only be
used by organisations and researchers to conduct research in accordance with the relevant
legislation, ethics and NHS research policy requirements.
We won't share information with others that can identify your child. The information will only be used
for the purpose of health and care research, and cannot be used to contact you or to affect your
child’s care. It will not be used to make decisions about future services available to your child, such
as insurance.
What happens at the end of the study?

You and your child and their doctor will continue to make decisions about your child’s medicines once
the study has finished. If your child is in the dolutegravir group and treatment with dolutegravir
appears to be a safe and effective way of treating children and young people with HIV then they may
be able to stay on these medicines. We would also like to continue to collect routine information
about your child after the study has ended so we can look at the long term effects of the new
medicines.
What if new information about dolutegravir becomes available during the

study?
Sometimes during a study, new information becomes available about the medicines that are being
studied. An independent committee will look at any new information and will also look at the

ODYSSEY Protocol
information collected so far in the study and decide if any changes are needed. If this happens, your
doctor will tell you about it and discuss whether you want your child to continue in the study. If you
decide to stop taking part in the study, your doctor will continue your child’s regular care.
How can my child join the study?

If your child would like to join the ODYSSEY study please speak to the staff at your nearest clinic where
the study is run during your next appointment.
How to contact us?

Contact: ____________________________
Tel: ____________________________

ODYSSEY Protocol
PARTICIPANT INFORMATION SHEET - MAIN STUDY ONLY
ODYSSEY STUDY
We are inviting you to take part in a research study
Before you decide whether to take part, it is important for you to understand why we want to carry
out this study and what it will mean for you.
Please take time to read the following information and to discuss it with friends, family and with your
doctor or clinic nurse if you wish.
You are free to decide if you want to take part in this research study. If you choose not to take part,
this will not affect the care you get from your doctor or nurse.
Important to know
If you decide to take part you will have some extra visits to the clinic at the beginning of the
study.
A computer program will choose which treatment you will take. Neither you nor your doctor
will be able to choose which group you are in.
Contents
2. Why have I been asked to take part?
3. What will happen if I decide not to take part?
4. What will happen if I take part?
5. What medicines will I be given?

ODYSSEY Protocol

In adults it has been shown to be effective and safe, with few side effects and it only needs to be
taken once a day.
2 Why have I been asked to take part?
We are aiming to ask 700 young people like yourself, from many countries to take part.
You have been asked to participate because:
A: You are about to start taking anti-HIV medicine for the first time
or
B: You are already taking one set of anti-HIV medicine that is no longer working well and your doctor
has decided it is time you change to a new combination. This is known as “second-line” treatment.
3 What will happen if I decide not to take part?
It is totally up to you whether or not you take part in this study.

This will not affect your care now or in the future in any way.
4 What will happen if I take part?

If you decide to take part we will go through this information sheet together. We will give a copy to
you to keep. Your parent/carer will be asked to sign a consent form to show you have both
understood the information and agreed to have some blood tests and a check-up to see whether you
can go into the study.
If the results show that you can participate we will invite you to enter the study. We need to know
that you have fully understood the study and then we will ask your parent/carer to sign a second
consent form for you to join. We will also ask you to sign a form giving your assent to join the study.
Your health will be watched closely during the study. In the first 2 months you will need to come for
3 appointments. Once your doctor is happy that you have no side effects from the medicines and you
are doing well, you will change to having 3-monthly appointments.
These visits are to make sure you are continuing to do well. If for any reason your doctor has any

ODYSSEY Protocol
concerns, they will change your treatment in the normal way.

6 teaspoons depending on your age. Part of this sample will be stored to be used to check the amount
of virus in the blood and to look at how the body fights HIV. We would like your agreement that we
can store these samples anonymously (without your name or exact date of birth) for up to 15 years.
You will be on the study for at least 2 years. When the study ends, if you are doing well, you may be
able to remain on the treatment you have been taking during the study, but you will need to discuss
this with your doctor.
It is important that you know that this is a voluntary study so if at any time you decide that you do
not want to be involved anymore, you can stop and it will not affect the care that you receive in the
future.
5 What medicines will I be given?
If you join the study, a computer will choose which group you will be in so it is fair and we can truly
compare the treatments.
Standard of Care group: meaning you will receive the usual, nationally approved anti-HIV medicine.
Dolutegravir group: meaning you will take a combination of anti-HIV medicines that includes the new
medicine, dolutegravir.

We cannot promise that participating in the study will directly help you. Compared to other anti-HIV
medicines, dolutegravir may have fewer side effects and needs to be taken only once a day which
may make it easier to take medicines long-term.
If you are in the ‘standard of care’ group you will receive the same anti-HIV medicines as children not
taking part in ODYSSEY although you will still be watched very carefully for any side effects and
responses to the treatment. All the information we get will help children and young people across the
world with HIV, and in the future it may mean you have the chance to change to medicines that are
easier to take.
Whichever group you are in you will have 3 extra visits to the clinic.
abdominal discomfort, diarrhoea, rash or may affect the liver. If you feel unwell, you should contact
the clinic as soon as possible.
The new medicine, dolutegravir, has been shown to be effective with few side effects in adults, but
There is a small chance that dolutegravir may cause a rash, itching, vomiting, stomach pain, sleep

ODYSSEY Protocol
problems, lack of energy, an increase in weight, feeling light headed, sad or worried or may cause
serious liver problems (with signs of vomiting, jaundice or stomach pain), which is why the doctor
needs to follow you closely. If you have these signs for more than a day you should inform your doctor
straight away.

There is very little information about the effect of dolutegravir in unborn babies. In a recent study
from Botswana, approximately 1 in 100 women who were taking dolutegravir when they became
pregnant had babies with serious brain and/or spine problems. In the same study, approximately 1 in
1000 women who were taking other antiretrovirals had babies with brain and/or spine problems,
which is similar to what is seen in women without HIV. These problems happen very early in
pregnancy, before many women even know that they are pregnant. We do not know for sure if these
problems are because of dolutegravir. The study in Botswana and other similar studies are ongoing.
We expect more information about this in the near future. In the meantime, we would like to tell you
about this possible risk.
If you are a girl who has started your period you will need a pregnancy test before entering the study.
You will not be able to join the study if the test shows you are pregnant. You should avoid getting
pregnant while in the study, and use effective if you are having sex. While in the study, please let us
know if you are thinking about having a baby before you start trying, or if you think you are pregnant.
Pregnancy tests will be done regularly during the study to find out early if you are pregnant or not
and to give you the appropriate medical care. If you do get pregnant, you will be able to stay in the
study and your doctor will talk to you about whether you need to change your medicine. Once you
deliver, your baby will be assessed by a doctor for any problems and the baby will be followed for
approximately 4 weeks to monitor their health. Health information, including HIV status, will be
collected about the baby. If you have already had a baby whilst being on the study, health information
captured by the hospital during this time period will be collected for the study.
and how it is affecting their wellbeing. Over the course of the study we will ask you to complete
questionnaires asking how you take your medicines, what it’s like taking medicine and how you feel
in general.
Additional studies
may talk to you about taking part.


The information about this study has been checked by an independent group of people (a
Research Ethics Committee) to make sure that as far as possible, the safety and wellbeing of
anyone taking part in the study is protected.

ODYSSEY Protocol
to review the results as they come out and will recommend if the trial is safe to continue. This is

The PENTA Foundation has made arrangements for compensation should you come to any harm from
participating in this study. If you are harmed due to someone’s negligence then you may have
reasons for legal action for compensation against the clinic where this occurred.
With your permission your GP will be informed of your participation in the study. Your hospital doctor
is not receiving any personal payment for carrying out this research. [Country specific, delete if not
applicable]
What will happen to information about me collected during the study?

will be using information from you and your medical records in order to undertake this study and will
act, along with the Sponsor, as Joint Data Controller for this study and Data Processor. This means
that PENTA and UCL are responsible for looking after your information and using it properly. UCL and
the sponsor designated trial co-ordinating units will keep information about you for a minimum of 15
years after the study has finished.
You and your parent/carer’s rights to access, change, move or erase your information are limited, as
we need to manage information in specific ways in order for the research to be reliable and accurate.
If you withdraw from the study, we will keep the information about your child that we have already
obtained. To safeguard your rights, we will use the minimum personally identifiable information
possible.
All ODYSSEY study information received by the above organisations and other authorised
independent individuals will be kept completely confidential and names will not be used. You will only
be identified using a study number, an anonymous code and your date of birth.
Your clinic notes may be looked at by the above organisations and authorised independent individuals
to make sure that the ODYSSEY study is being properly carried out. They may also be seen by the
companies who are supplying medicine for the study or relevant international regulatory authorities.
Confidentiality will be maintained at all times.
If the results of this study are reported or published your name will not be used nor any information
that could be used to identify you. The study will be conducted in agreement with the country specific
data protection regulations.
You can find out more about how we use your information at www.ctu.mrc.ac.uk/general/privacy-
policy and www.penta-id.org/study-participants-privacy.
How your data will be stored and collected

Your clinic will collect information from you and your medical records for this research study in
accordance with our instructions.
Your clinic will keep your name, NHS Number and contact details confidential and will not pass this
information to anyone outside of the clinic. Your clinic will use this information as needed, to contact
you or your parent/carer about the research study, and make sure that relevant information about

ODYSSEY Protocol
the study is recorded for your care, and to oversee the quality of the study. Certain individuals from
UCL, authorised regulatory organisations and authorised independent individuals may look at your
medical and research records to check the accuracy of the research study. They may also be seen by
the companies who are supplying medicines for the study or relevant international regulatory
authorities. The people who analyse the information will not be able to identify you and will not be
able to find out your name, NHS number or contact details.
UCL will collect information about you for this research study from your clinic. This information will
include health information, This data may be used by UCL and other authorised research collaborators
to conduct the trial and associated sub-studies.

When you agree to take part in a research study, the information about your health and care may be
provided to researchers running other research studies in this organisation and in other organisations.
These organisations may be universities, NHS organisations or companies involved in health and care
research in this country or abroad. Your information will only be used by organisations and
researchers to conduct research in accordance with the relevant legislation, ethics and NHS research
policy requirements.
We won't share information with others that can identify you. The information will only be used for
the purpose of health and care research, and cannot be used to contact you or to affect your care. It
will not be used to make decisions about future services available to you, such as insurance.

You, your parent/carer and your doctor will continue to make decisions about your medicines once
the study has finished.
If you are in the dolutegravir group and treatment with dolutegravir appears to be a safe and effective
way of treating children and young people with HIV then you may stay on these medicines.
We would also like to continue to collect your routine information after the study has ended so we
can look at the long term effects of the new medications.

course of the study?
studied. An independent committee will look at any new information and will also look at the data
collected so far in the study and decide if any changes are needed. If this happens, your doctor will
tell you about it and discuss whether you want to continue in the study. If you decide to stop taking
part in the study, your doctor will continue your regular care.
How can I join the study?

If you would like to join the ODYSSEY study please speak to the staff at your nearest clinic where the
study is run during your next appointment.
How to contact us?

Contact:_________________________
Tel:_____________________________

ODYSSEY Protocol
CHILDREN’S INFORMATION SHEET - MAIN STUDY ONLY

ODYSSEY Protocol
PARENT/CARER INFORMATION SHEET – EXTENDED FOLLOW-UP
ODYSSEY STUDY
Contents
1. Why are we requesting extended follow-up?

1 Why are we requesting extended follow-up?
We are requesting extended follow-up so that we can continue to collect safety information from children
and adolescents enrolled in ODYSSEY. This information is important as it will enable the long term safety
and effectiveness of dolutegravir in children and adolescents to be assessed.
If your child is currently taking dolutegravir in a form that is not currently available through your country’s
national treatment programme, we are also required to collect further safety information.
Your child has been asked to take part in extended follow-up because he/she is enrolled in the ODYSSEY
trial and we would like to collect further information on the treatment that they receive in order to assess
the safety of dolutegravir over a longer period of time.
It is totally up to you and your child whether or not he/she takes part in extended follow-up.
If you choose that your child will not take part, but your child is currently taking a form of dolutegravir that
is not available through your country’s national treatment programme, then it may be necessary for your
doctor to change your child’s anti-HIV medicine so that they will take another appropriate drug in place of
dolutegravir. If your child is taking anti-HIV medicines that are available through your country’s national
treatment programme then their treatment may not need to be changed if you choose not to take part.

ODYSSEY Protocol

If you decide to take part, we will go through this information sheet together. We will give you a copy to
keep. You will be asked to sign a consent form to show you have understood the information and have agreed
for your child to continue in extended follow-up.
Once your child is in the extended follow-up period they will attend for regular clinic visits which will be
similar to routine care in your country. Blood tests will be performed as per local practice and, if your child
could become pregnant, a pregnancy test will be performed at every visit. Sleep and Mood Questionnaire
data will be collected annually. Your child will remain in extended follow-up for a period of up to 3 years (until
May 2023)
It is important that you know that this is a voluntary study so if at any time you decide that you do not want
to be involved anymore, you can stop and it will not affect the care that you receive in the future.
What are the possible benefits of taking part in extended follow-up?

Although there may not be any direct benefits to you or your child of taking part, the information collected
will help us to improve the treatment of other children and adolescents who are living with HIV.
If your child is taking a form of dolutegravir that is not available through your country’s national HIV
treatment programme then taking part will enable them to continue taking the same treatment. In these
circumstances the medicine will continue to be provided to your clinic, by a drug company working with the
study team, free of charge to your child.
Anti-HIV medicines, like all medicines, can have side effects; most common are nausea, vomiting, abdominal
discomfort, diarrhoea, rash or may affect the liver. If your child feels unwell, you should contact the clinic as
soon as possible.
Dolutegravir has been shown to be effective, with few side effects in adults, but we don’t know if this will be
the same in children (which is why we need to do this study). The most common side effects in adults are
headache, diarrhoea, abdominal pain, feeling sick, light headed or weak, worrying often and having sleep
problems. Some adults taking dolutegravir have reported feeling depressed or having suicidal thoughts, these
may not be related to this medicine in all cases. There is a small chance that dolutegravir may cause a rash,
itching, vomiting, stomach pain, sleep problems, lack of energy, an increase in weight, feeling light headed,
sad or worried or may cause serious liver problems (with signs of vomiting, jaundice or stomach pain), which
is why the doctor needs to follow your child closely. If your child has these signs for more than a day you
should inform your doctor straight away.

There is very little information about the effect of dolutegravir in unborn babies. In a recent study from
Botswana, approximately 3 in 1000 women who were taking dolutegravir when they became pregnant had
babies with serious brain and/or spine problems. In the same study, approximately 1 in 1000 women who
were taking other antiretrovirals had babies with brain and/or spine problems, which is similar to what is
seen in women without HIV. These problems happen very early in pregnancy, before many women even
know that they are pregnant. We do not know for sure if these problems are because of dolutegravir. The
study in Botswana and other similar studies are ongoing. We expect more information about this in the near
future. In the meantime, we would like to tell you about this possible risk.

ODYSSEY Protocol
If your child could become pregnant, she should avoid getting pregnant while in extended trial follow-up, and
use effective contraceptives if she is having sex. While in extended follow-up, please let us know if she is
thinking about having a baby before she starts trying, or if she thinks she is pregnant. Pregnancy tests will
continue to be done regularly during extended follow-up to find out early if she is pregnant or not and to give
her the appropriate medical care. If she does get pregnant, she will be able to stay in extended follow-up and
her doctor will talk to you both about whether she needs to change her medicine. Once she delivers, her
baby will be assessed by a doctor for any problems and the baby will be followed for approximately 4 weeks
to monitor their health. Health information, including HIV status, will be collected about the baby. If she has
already had a baby whilst being on the study, health information captured by the hospital during this time
period will be collected for the study.

The PENTA Foundation has made arrangements for compensation should your child come to any harm from
participating in this study. If your child is harmed due to someone’s negligence then you may have reasons
for legal action for compensation against the clinic where this occurred.
What will happen to information about my child collected during follow-up?

The Fondazione PENTA Onlus, based in Italy and Sponsor for this study, is the owner of data and acts as Joint
Data Controller. University College London (UCL) through the MRC Clinical Trial Unit at UCL, will be using
information from your child and your child’s medical records in order to undertake this study and will act,
along with the Sponsor, as Joint Data Controller for this study and Data Processor. This means that PENTA
and UCL are responsible for looking after your child’s information and using it properly. UCL and the sponsor
designated trial co-ordinating units will keep information about your child for a minimum of 15 years after
the study has finished.
Your and your child’s rights to access, change, move or erase their information are limited, as we need to
manage information in specific ways in order for the research to be reliable and accurate. If your child
withdraws from the study, we will keep the information about your child that we have already obtained. To
safeguard your child’s rights, we will use the minimum personally identifiable information possible.
All ODYSSEY study information received by the above organisations and other authorised independent
individuals will be kept completely confidential and names will not be used. Your child will only be identified
using a study number, an anonymous code and their date of birth.
Your child’s clinic notes may be looked at by the above organisations and authorised independent individuals
to make sure that the ODYSSEY study is being properly carried out. They may also be seen by the companies
who are supplying medicine for the study or relevant international regulatory authorities. Confidentiality will
be maintained at all times.
If the results of this study are reported or published your child’s name will not be used nor any information
that could be used to identify your child. The study will be conducted in agreement with the country specific
You can find out more about how we use your child’s information at www.ctu.mrc.ac.uk/general/privacy-
policy and www.penta-id.org/study-participants-privacy.

Your child’s clinic will collect information from your child and your child’s medical records for this research
study in accordance with our instructions.

ODYSSEY Protocol
Your child’s clinic will keep your child’s name and contact details confidential and will not pass this
information to anyone outside of the clinic. Your child’s clinic will use this information as needed, to contact
your child about the research study, and make sure that relevant information about the study is recorded for
your child’s care, and to oversee the quality of the study. Certain individuals from UCL, authorised regulatory
organisations and authorised independent individuals may look at your child’s medical and research records
to check the accuracy of the research study. They may also be seen by the companies who are supplying
medicines for the study or relevant international regulatory authorities. The people who analyse the
information will not be able to identify your child and will not be able to find out your child’s name or contact
details.
UCL will collect information about your child for this research study from your child’s clinic. This information
will include health information. This data may be used by UCL and other authorised research collaborators
to conduct the trial and associated sub-studies.

When your child agrees to take part in a research study, the information about your child’s health and care
may be provided to researchers running other research studies in this organisation and in other
organisations. These organisations may be universities, hospitals or companies involved in health and care
research in this country or abroad. Your child’s information will only be used by organisations and researchers
to conduct research in accordance with the relevant legislation and ethics requirements.
We won't share information with others that can identify your child. The information will only be used for
the purpose of health and care research, and cannot be used to contact you or to affect your child’s care. It
will not be used to make decisions about future services available to your child, such as insurance.
What happens at the end of extended follow-up?

You, your child and their doctor will continue to make decisions about your child’s medicines once extended
follow-up has finished. If, at the end of this follow-up period, dolutegravir is still not available through your
country’s national treatment programme, your child may have to change to different anti-HIV medicines.
How to contact us?

Contact: ____________________________
Tel: ____________________________

ODYSSEY Protocol
PARTICIPANT INFORMATION SHEET – EXTENDED FOLLOW-UP
ODYSSEY STUDY
Contents
1. Why are we requesting extended follow-up?

1 Why are we requesting extended follow-up?
We are requesting extended follow-up so that we can continue to collect safety information from children
and young people taking part in ODYSSEY. This information is important as it will enable the long term
safety and effectiveness of dolutegravir in children and adolescents to be assessed.
If you are currently taking dolutegravir in a form that is not currently available through your country’s
national treatment programme, we are also required to collect further safety information.
You have been asked to take part in extended follow-up because you are taking part in the ODYSSEY trial
and we would like to collect further information on the treatment that you receive in order to assess the
safety of dolutegravir over a longer period of time.
It is totally up to you whether or not you take part in extended follow-up.

If you choose not to take part, but you are currently taking a form of dolutegravir that is not available through
your country’s national treatment programme, then it may be necessary for your doctor to change your anti-
HIV medicine so that you will take another appropriate drug in place of dolutegravir. If you are taking anti-
HIV medicines that are available through your country’s national treatment programme then your treatment
may not need to be changed if you choose not to take part.

If you decide to take part, we will go through this information sheet together. We will give you a copy to
keep. If you are not old enough to give consent yourself, your parent/carer will be asked to sign a consent

ODYSSEY Protocol
form to show you have both understood the information and have agreed to continue in extended follow-
up.
Once you are in the extended follow-up period you will attend for regular clinic visits which will be similar to
routine care in your country. Blood tests will be performed as per local practice and, if you could become
pregnant, a pregnancy test will be performed at every visit. Sleep and Mood Questionnaire data will be
collected annually. You will remain in extended follow-up for a period of up to 3 years (until May 2023)
It is important that you know that this is a voluntary study so if at any time you decide that you do not want
to be involved anymore, you can stop and it will not affect the care that you receive in the future.
What are the possible benefits of taking part in extended follow-up?

Although there may not be any direct benefits to you of taking part, the information collected will help us to
improve the treatment of other children and adolescents who are living with HIV.
If you are taking a form of dolutegravir that is not available through your country’s national HIV treatment
programme then taking part will enable you to continue taking the same treatment. If this is the case, the
medicine will continue to be provided to your clinic, by a drug company working with the study team, free of
charge.
Anti-HIV medicines, like all medicines, can have side effects; most common are nausea, vomiting, abdominal
discomfort, diarrhoea, rash or may affect the liver. If you feel unwell, you should contact the clinic as soon
as possible.
Dolutegravir has been shown to be effective with few side effects in adults, but we don’t know if this will be
the same in children (which is why we need to do this study). The most common side effects in adults are
headache, diarrhoea, abdominal pain, feeling sick, light headed or weak, worrying often and having sleep
problems. Some adults taking dolutegravir have reported feeling depressed or having suicidal thoughts, these
may not be related to this medicine in all cases. There is a small chance that dolutegravir may cause a rash,
itching, vomiting, stomach pain, sleep problems, lack of energy, an increase in weight, feeling light headed,
sad or worried or may cause serious liver problems (with signs of vomiting, jaundice or stomach pain), which
is why the doctor needs to follow you closely. If you have these signs for more than a day you should inform
your doctor straight away.

There is very little information about the effect of dolutegravir in unborn babies. In a recent study from
Botswana, approximately 3 in 1000 women who were taking dolutegravir when they became pregnant had
babies with serious brain and/or spine problems. In the same study, approximately 1 in 1000 women who
were taking other antiretrovirals had babies with brain and/or spine problems, which is similar to what is
seen in women without HIV. These problems happen very early in pregnancy, before many women even
know that they are pregnant. We do not know for sure if these problems are because of dolutegravir. The
study in Botswana and other similar studies are ongoing. We expect more information about this in the near
future. In the meantime, we would like to tell you about this possible risk.
If you are a girl who has started your period you should avoid getting pregnant while in extended trial follow-
up, and use effective contraceptives if you are having sex. While in extended follow-up, please let us know if
you are thinking about having a baby before you start trying, or if you think you are pregnant. Pregnancy
tests will continue to be done regularly during extended follow-up to find out early if you are pregnant or not

ODYSSEY Protocol
and to give you the appropriate medical care. If you do get pregnant, you will be able to stay in extended
follow-up and your doctor will talk to you about whether you need to change your medicine. Once you
deliver, your baby will be assessed by a doctor for any problems and the baby will be followed for
approximately 4 weeks to monitor their health. Health information, including HIV status, will be collected
about the baby. If you have already had a baby whilst being on the study, health information captured by the
hospital during this time period will be collected for the study.

participating in this study. If you are harmed due to someone’s negligence then you may have reasons for
legal action for compensation against the clinic where this occurred.

The Fondazione PENTA Onlus, based in Italy and Sponsor for this study, is the owner of data and acts as Joint
Data Controller. University College London (UCL) through the MRC Clinical Trial Unit at UCL, will be using
information from you and your medical records in order to undertake this study and will act, along with the
Sponsor, as Joint Data Controller for this study and Data Processor. This means that PENTA and UCL are
responsible for looking after your information and using it properly. UCL and the sponsor designated trial co-
ordinating units will keep information about you for a minimum of 15 years after the study has finished.
You and your parent/carer’s rights to access, change, move or erase your information are limited, as we need
to manage information in specific ways in order for the research to be reliable and accurate. If you withdraw
from the study, we will keep the information about your child that we have already obtained. To safeguard
your rights, we will use the minimum personally identifiable information possible.
individuals will be kept completely confidential and names will not be used. You will only be identified using
a study number, an anonymous code and your date of birth.
Your clinic notes may be looked at by the above organisations and authorised independent individuals to
make sure that the ODYSSEY study is being properly carried out. They may also be seen by the companies
who are supplying medicine for the study or relevant international regulatory authorities. Confidentiality will
If the results of this study are reported or published your name will not be used nor any information that
could be used to identify you. The study will be conducted in agreement with the country specific data
protection regulations.
You can find out more about how we use your information at www.ctu.mrc.ac.uk/general/privacy-policy and
www.penta-id.org/study-participants-privacy.
How your data will be stored and collected

Your clinic will collect information from you and your medical records for this research study in accordance
with our instructions.
Your clinic will keep your name and contact details confidential and will not pass this information to anyone
outside of the clinic. Your clinic will use this information as needed, to contact you or your parent/carer about
the research study, and make sure that relevant information about the study is recorded for your care, and

ODYSSEY Protocol
to oversee the quality of the study. Certain individuals from UCL, authorised regulatory organisations and
authorised independent individuals may look at your medical and research records to check the accuracy of
the research study. They may also be seen by the companies who are supplying medicines for the study or
relevant international regulatory authorities. The people who analyse the information will not be able to
identify you and will not be able to find out your name or contact details.
UCL will collect information about you for this research study from your clinic. This information will include
health information, This data may be used by UCL and other authorised research collaborators to conduct
the trial and associated sub-studies.

When you agree to take part in a research study, the information about your health and care may be provided
to researchers running other research studies in this organisation and in other organisations. These
organisations may be universities, NHS organisations or companies involved in health and care research in
this country or abroad. Your information will only be used by organisations and researchers to conduct
research in accordance with the relevant legislation, ethics and NHS research policy requirements.
We won't share information with others that can identify you. The information will only be used for the
purpose of health and care research, and cannot be used to contact you or to affect your care. It will not be
used to make decisions about future services available to you, such as insurance.
What happens at the end of extended follow-up?

You, your parent/carer and your doctor will continue to make decisions about your medicines once extended
follow-up has finished. If, at the end of this follow-up period, dolutegravir is still not available through your
country’s national treatment programme, you may have to change to different anti-HIV medicines.
How to contact us?

Contact:_________________________
Tel:_____________________________

ODYSSEY Protocol
CHILDREN’S INFORMATION SHEET – EXTENDED FOLLOW-UP
ODYSSEY STUDY
(PENTA 20)
You are taking part in a study called ODYSSEY. In ODYSSEY we have been looking at
a new medicine for children called dolutegravir.
We would like to collect more information on dolutegravir and the other medicines
that children in ODYSSEY are taking. To do this we would like you to stay in the
ODYSSEY study until May 2023 (up to an extra 3 years after you would have finished
taking part).
The information that we collect will help us find out if dolutegravir is still safe and
working well even after children have been taking it for a long time.
The doctors will still watch you closely but now you will only need to attend for
visits at the same times that you would if you were not taking part in the study.
Most of the tests that you will have are the same as those you would have outside
of the study but you or your carer will sometimes also be asked to answer some
questions on how easy you find it to take your medicine.
It is still up to you whether you take part in the study. If you say yes now you can
change your mind at any time and stop being part of the study. It is up to you.

ODYSSEY Protocol
PARENT/CARER INFORMATION SHEET – MAIN STUDY & WEIGHT BAND PK 1 (3 TO <14KG)
ODYSSEY STUDY
Before you decide whether to take part, it is important for you and your child to understand why we want to
carry out this study and what it will mean for you both.
Please take time to read the following information and to discuss it with friends, family and with your doctor
or clinic nurse if you wish.
You are free to decide if you want your child to take part in this research study. If you choose not to take
part, this will not affect the care your child gets from your doctor or nurse.
Important to know
If you decide to take part your child will have some extra visits to the clinic at the beginning of the study.
A computer program will choose which treatment your child will take. Neither you nor your doctor will be
able to choose which group your child is in
If your child is in the dolutegravir group they will be asked to come into the clinic and stay for a whole day at
least 1 week after starting the new medicine. He/she will have up to 7 blood samples taken during the day
(over a 24 hour period) to test the level of medicine in their blood. We will also need to take a blood sample
the next morning. Your child can stay overnight or we will provide transport for you to come back the next
day.
Contents

ODYSSEY Protocol

taken once a day.
Weight band Pharmacokinetic (PK) Study (checking the level of medicine in the blood):
We need to check that the dose of the new medicine is correct for younger children. If your child joins
the study and is put in the dolutegravir group he/she will come into the clinic for a PK blood sampling
day.
Or
B. He/She is already taking one set of anti-HIV medicine that is no longer working well and your doctor
has decided it is time your child changes to a new combination. This is known as “second-line”
treatment.

into the study.
If the results show that your child can participate, we will invite him/her to enter the study. We need
to know that you have fully understood the study and then we will ask you to sign a second consent
form for your child to join.

ODYSSEY Protocol
In the first 2 months you will need to come for 3 or 4 appointments. Once your doctor is happy that
your child has no side effects from the medicines and is doing well, they will change to having 3-
monthly appointments.
These visits are to make sure your child is continuing to do well. If for any reason your doctor has any
concerns, they will change your child’s treatment in the normal way.
6 teaspoons depending upon the age of your child. Part of this sample will be stored to be used to
check the amount of virus in the blood and to look at how the body fights HIV. We would like your
agreement that we can store these samples anonymously (without your child’s name or exact date of
birth) for up to 15 years.
Your child will be in the study for at least 2 years. When the study ends, if your child is doing well they
may be able to remain on the same anti-HIV medicines they have been taking during the study, but
you will need to discuss this with your doctor.
PK (blood levels) Study (only to be done in children allocated to the dolutegravir group)
If your child is in the dolutegravir group they will be asked to come into the clinic and stay for a whole
day at least 1 week after starting the new medicine. He/she will have up to 7 blood samples taken
during the day (over a 24 hour period) to test the level of medicine in their blood. A local anaesthetic
cream will be used to make the skin numb and a thin tube (called a cannula) will be inserted into a
vein for the day to enable the blood samples to be taken. All blood samples will be taken from the
cannula, so only one needle prick is required. Each blood sample will be small (less than half a
teaspoon) and is an amount which is safe for your child’s age and weight.
We will also need to take a blood sample the next morning. Your child can stay overnight or we will
provide transport for you to come back the next day.
The laboratory needs to know exactly when your child took their medicine so you will be asked to
record the time of giving the medicine the day before. Immediately after the first blood sample is
taken your child will be given breakfast (we will provide all their meals during the day) with their usual
dose of medicine.
medicine.
Dolutegravir group: meaning your child will take a combination of anti-HIV medicines that includes
the new medicine, dolutegravir. Children in this group will also take part in PK (blood levels) study.

ODYSSEY Protocol
We cannot promise that participating in the study will directly help your child. Compared to other anti-
HIV medicines dolutegravir may have fewer side effects and needs to be taken only once a day which
as children not taking part in ODYSSEY, although your child will be watched very carefully for any side
effects and responses to the treatment. All the information we get will help children and young people
across the world with HIV and in the future it may mean your child has the chance to change to
medicines that are easier to take.
Whichever group they are in your child will have 3 or 4 extra visits to the clinic and if they are in the
dolutegravir group, they will come in for a full day (and possibly an overnight stay) at clinic for the
blood sampling day.
In most of these cases the person had a history of similar problems before starting dolutegravir. There
is a small chance that dolutegravir may cause a rash, itching, vomiting, stomach pain, sleep problems,
lack of energy, an increase in weight, feeling light headed, sad or worried or may cause serious liver
problems (with signs of vomiting, jaundice or stomach pain), which is why the doctor needs to follow
your child closely. If your child has these signs for more than a day you should inform your doctor
straight away.
Pregnancy and anti-HIV medicines

There is very little information about the effect of dolutegravir in unborn babies. If your child could
become pregnant, she will need a pregnancy test before entering the study. She will not be able to
join the study if the test shows she is pregnant. We encourage her to use effective contraceptives and
for her to let us know straightaway if at any time she thinks she may have become pregnant. If this is
confirmed with a pregnancy test her treatment will be reviewed by the doctor. She will be able to stay
in the study if she becomes pregnant.
Additional studies

ODYSSEY Protocol


Ethics Committee) to make sure that, as far as possible, the safety and wellbeing of anyone taking part
in the study is protected.

The PENTA Foundation has made arrangements for compensation should your child come to any harm
from participating in this study. If your child is harmed due to someone’s negligence then you may
have reasons for legal action for compensation against the clinic where this occurred.
will be using information from your child and your child’s medical records in order to undertake this
study and will act, along with the Sponsor, as Joint Data Controller for this study and Data Processor.
This means that PENTA and UCL are responsible for looking after your child’s information and using it
properly. UCL and the sponsor designated trial co-ordinating units will keep information about your
child for a minimum of 15 years after the study has finished.
Your and your child’s rights to access, change, move or erase their information are limited, as we need
to manage information in specific ways in order for the research to be reliable and accurate. If your
child withdraws from the study, we will keep the information about your child that we have already
obtained. To safeguard your child’s rights, we will use the minimum personally identifiable
information possible.
individuals will be kept completely confidential and names will not be used. Your child will only be
identified using a study number, an anonymous code and their date of birth.
Your child’s clinic notes may be looked at by the above organisations and authorised independent
individuals to make sure that the ODYSSEY study is being properly carried out. They may also be seen
by the companies who are supplying medicine for the study or relevant international regulatory
authorities. Confidentiality will be maintained at all times.
You can find out more about how we use your child’s information at
www.ctu.mrc.ac.uk/general/privacy-policy and www.penta-id.org/study-participants-privacy.

ODYSSEY Protocol

Your child’s clinic will collect information from your child and your child’s medical records for this
research study in accordance with our instructions.
Your child’s clinic will keep your child’s name, NHS Number and contact details confidential and will
not pass this information to anyone outside of the clinic. Your child’s clinic will use this information as
needed, to contact your child about the research study, and make sure that relevant information
about the study is recorded for your child’s care, and to oversee the quality of the study. Certain
individuals from UCL, authorised regulatory organisations and authorised independent individuals
may look at your child’s medical and research records to check the accuracy of the research study.
They may also be seen by the companies who are supplying medicines for the study or relevant
international regulatory authorities. The people who analyse the information will not be able to
identify your child and will not be able to find out your child’s name, NHS number or contact details.
UCL will collect information about your child for this research study from your child’s clinic. This
information will include health information. This data may be used by UCL and other authorised
research collaborators to conduct the trial and associated sub-studies.

When your child agrees to take part in a research study, the information about your child’s health and
care may be provided to researchers running other research studies in this organisation and in other
organisations. These organisations may be universities, NHS organisations or companies involved in
health and care research in this country or abroad. Your child’s information will only be used by
organisations and researchers to conduct research in accordance with the relevant legislation, ethics
and NHS research policy requirements.
We won't share information with others that can identify your child. The information will only be used
for the purpose of health and care research, and cannot be used to contact you or to affect your child’s
care. It will not be used to make decisions about future services available to your child, such as
insurance.

You and your child and their doctor will continue to make decisions about your child’s medicines once
the study has finished. If your child is in the dolutegravir group and treatment with dolutegravir
appears to be a safe and effective way of treating children and young people with HIV then they may
be able to stay on these medicines. We would also like to continue to collect routine information about
your child after the study has ended so we can look at the long term effects of the new medicines.

study?

If your child would like to join the ODYSSEY study please speak to the staff at your nearest clinic where
the study is run during your next appointment.

ODYSSEY Protocol
How to contact us?
Contact: _________________________
Tel: _________________________

ODYSSEY Protocol
CHILDREN’S INFORMATION SHEET – MAIN STUDY & WEIGHT BAND PK 1 (3 TO <14KG)
ODYSSEY STUDY
Odyssey is a study. Studies take groups of people and ask them to do something and
then see if there are any changes. This study is looking at some new medicine for
children
Dolutegravir is the name of the new medicine, we know it works very well with adults
but we don’t know how it works with children
You have been asked to take part because you need to start taking medicine or you
need to change the medicine you are on.
So why be involved? Well, this new medicine is exciting as it will mean a big difference
for lots of children around the world, so you can be part of something that makes a
big difference.
Studies run in different ways. This one has two groups: one will take the new medicine
and the other will take the medicine your doctor has given to lots of children like you.
This is so both groups can be watched to see any differences. This is decided randomly
– like pulling names out of a hat – so you can’t choose which one you are in.
Everyone taking part will be closely watched by doctors, so you will need to come to
some extra clinic visits in the first two months and after that it’ll be every three
months.
You can say yes now, but if you change your mind at any point, you can stop being part
of the study, it’s up to you.
BLOOD LEVELS STUDY

If you are in the group taking the new medicine, after at least one week of taking this
new medicine you will be asked to spend a whole day at the clinic so we can check how
much of the medicine is in your blood. We will take up to 7 small blood samples during
the day (over a 24 hour period). Each blood sample will be small (less than half a
teaspoon) and the amount of blood taken will be safe for your age and weight.
After the first blood sample is taken you will be given breakfast (we will provide all
your meals during this day) with your usual dose of medicine.
We also need a sample the next morning. Your clinic team will let you know whether
you need to stay overnight or come back the next day to have this sample taken .

ODYSSEY Protocol
PARENT/CARER INFORMATION SHEET –WEIGHT BAND PK 1 (3KG TO <25KG)
ODYSSEY WEIGHT BAND PK 1 –

BLOOD LEVELS STUDY
We need to confirm that the dose of the new medicine is suitable for children who weigh 3kg
to 25kg. If your child joins this study he/she will need to come into the clinic for a whole day
(over a 24 hour period) when samples will be taken to check the pharmacokinetics (PK) which
means the levels of medicine in their blood.
Children being asked to take part in this study are taking part in ODYSSEY, weigh between 3kg
to 25kg and are taking dolutegravir. We are aiming to ask a small group of children to take
part.
Your child has been asked to take part either because:
A. he/she is already taking part in ODYSSEY
OR
B. you and your child may be thinking about taking part in ODYSSEY; in this case your
child may only take part in this additional study if they join the ODYSSEY trial and they
are allocated dolutegravir.
If you or your child decides not to take part in the PK (blood levels) study this will not stop
your child from taking part in ODYSSEY or affect your child’s care now or in the future in any
way.

If you decide to take part, we will go through this information sheet together. We will give
you a copy to keep. You will be asked to sign a consent form to show you understand the
information and agree to take part.
If your child does take part, blood samples will be taken from your child and stored so
researchers can learn more about anti-HIV medicines. If at any point your child wants to stop

ODYSSEY Protocol
being in the study we hope that you will still allow us to use these samples. If, however, you
do not give your permission then we will destroy them.
Your child’s wellbeing will be monitored closely during the study. If for any reason his/her
medicine needs to be changed this will be done by their doctor.
Important to know
If your child is eligible and does take part they will need to spend one whole day in
the clinic after at least 1 week of taking dolutegravir.
On the day booked for the blood sampling visit your child will be asked to come to the clinic
for a whole day. He/she will have up to 7 blood samples taken during the day (over a 24 hour
period) to test the level of medicine in their blood. A cream with local pain-killing effect will
be used to make the skin numb and a thin flexible tube (called a cannula) will be inserted into
a vein for the day to enable the blood samples to be taken more easily. All blood samples will
be taken from the cannula so only one needle prick is required. Each blood sample will be
small (less than half a teaspoon), and the amount will be is safe for your child’s age and
weight.
We will also need to take a blood sample the next morning. Your child can stay overnight or
we will provide transport for you to come back the next day.
At this point the PK (Blood Levels) study will end. However, usual clinic ODYSSEY visits will
continue for routine monitoring of your child’s health.

We cannot promise that participating in the study will directly help your child but the results
of this study will give us more information about the dosing of dolutegravir for children and
young people. It is very important that we have this information so we can make sure that
children are given the correct amount of medicine.
This information will help children and young people across the world with HIV and in the
future it may mean your child has the chance to get the most appropriate amount of
medicine.
It’s important to think about these before deciding to take part.
This study will not result in any risk to your child’s health. However, your child will have to
spend one day at the clinic and may need to stay overnight on this day.
On the PK day, up to 7 small blood samples will be taken but only one needle prick will be
needed.

ODYSSEY Protocol

This study has been looked at by an independent group of people (a Research Ethics
Committee) to make sure that, as far as possible, the safety and wellbeing of anyone taking
A second group (the Independent Data Monitoring Committee) will review the results as they
come out and will recommend if the study is safe to continue. This is standard for all studies
looking at medicines for adults or children.

The PENTA Foundation has made arrangements for compensation should your child come to
any harm from participating in this study. However, if your child is harmed due to someone’s
negligence then you may have reasons for legal action for compensation against the hospital
where the negligence occurred.
With your permission your child’s GP will be informed of his/her participation in the study.
Your hospital doctor is not receiving any personal payment for carrying out this research.
[Country specific, delete if not applicable]
What will happen to information about my child collected during this study?
All information collected during the ODYSSEY study will be kept completely confidential and
names will not be used. Your child will only be identified using a study number, an
anonymous code and their date of birth. Your child’s clinic notes may be looked at by study
staff from the PENTA Foundation, the trials units co-ordinating the study or other
independent people authorised to make sure that the ODYSSEY study is being properly carried
out. They may also be seen by the companies who are supplying medicine for the study or
relevant international regulatory authorities. Confidentiality will be maintained at all times.
If the results of this study are reported or published no information will be included that could
identify your child (no name or date of birth). The study will be conducted in agreement with
7 Contacts for more information
If you would like more information about the study please ask the doctor or nurse at your
clinic. If you still need more information please call:
Contact: _________________________
Tel: _____________________________

ODYSSEY Protocol
CHILDREN’S INFORMATION SHEET – WEIGHT BAND PK 1 (3 TO <25KG)
ODYSSEY PK (BLOOD LEVELS) STUDY

We need to confirm that the dose of the new medicine is suitable for children who are
about the same weight as you. If you join this study you will need to come into the
clinic for a whole day when samples will be taken to check the levels of medicine in
the blood.
You have been asked to take part because either

A. you are part of the ODYSSEY study and are taking the new medicine
OR
B. you may be taking part in ODYSSEY and could be starting to take the new
medicine if and when you start the study.
You can say yes now, but if you change your mind at any point, you can stop being
part of the study, it’s up to you.
After at least one week in the study and taking the new medicine you will be asked to
spend a whole day at the clinic so we can check how much of the medicine is in your
blood. We will take up to 7 small blood samples during the day (over a 24 hour period).
Each blood sample will be small (less than half a teaspoon), and the amount will be is
safe for your age and weight.
After the first blood sample is taken you will be given breakfast (we will provide all your
meals during this day) with your usual dose of medicine.
We also need a sample the next morning. Your clinic team will let you know whether
you need to stay overnight or come back the next day to have this sample taken .

ODYSSEY Protocol
PARENT/CARER INFORMATION SHEET – WEIGHT BAND PK 2 (25KG TO <40KG)
ODYSSEY WEIGHT BAND PK 2 –

BLOOD LEVELS STUDY
We need to check that a different dose of dolutegravir is suitable for children who weigh 25kg to 40kg.

Children being asked to take part in this study are taking part in ODYSSEY, weigh between 25kg and
40kg and are taking dolutegravir. We are aiming to ask a small group of children to take part.
Your child has been asked to take part either because:
A. he/she is already taking part in ODYSSEY
OR
B. you and your child may be thinking about taking part in ODYSSEY; in this case your child may
only take part in this additional study if they join the ODYSSEY trial and they are allocated
dolutegravir.
If you or your child decides not to take part this will not stop your child from taking part in ODYSSEY
or affect your child’s care now or in the future in any way.

If you decide to take part, we will go through this information sheet together. We will give you a copy
to keep. You will be asked to sign a consent form to show you understand the information and agree
to take part.
If your child does take part, blood samples will be taken from your child and stored so researchers can
learn more about anti-HIV medicines. If at any point your child wants to stop being in the study we
hope that you will still allow us to use these samples. If, however, you do not give your permission
then we will destroy them.
Your child’s wellbeing will be monitored closely during the study. If for any reason his/her medicine
needs to be changed this will be done by their doctor.
Important to know

ODYSSEY Protocol
If your child is eligible and does take part in the blood levels study they will need to spend
one whole day at the clinic after at least 1 week of taking dolutegravir.
Your child’s dose will be changed after the first PK (blood sampling) day.
At least 1 week after your child has been changed to the new dose of dolutegravir, he/she
will spend a second day at the clinic.
Your child will also have to come in for a clinic visit at 2, 4 and 12 weeks after starting the
new dose of dolutegravir. Where possible these visits will be timed to coincide with
scheduled ODYSSEY study visits to minimise additional clinic visits.
On the day booked for the first blood sampling visit your child will be asked to come to the clinic for a
whole day. He/she will have up to 7 blood samples taken during the day (over a 24 hour period) to
test the level of medicine in their blood. A cream with local pain-killing effect will be used to make the
skin numb and a thin flexible tube (called a cannula) will be inserted into a vein for the day to enable
the blood samples to be taken more easily. All blood samples will be taken from the cannula so only
one needle prick is required. Each blood sample will be small (less than half a teaspoon), and the
amount will be is safe for your child’s age and weight.
We will also need to take a blood sample the next morning. Your child may stay overnight or we will
provide transport for you to come back the next day.
At least one week after your child has switched to the new dose of dolutegravir he/she will be asked
to spend a second day at the clinic and another set of blood samples will be taken. Like for the first PK
day this may also require an overnight stay in hospital.
2, 4 and 12 weeks after starting the new dose of dolutegravir your child will be asked to come to clinic
for clinical assessment, some blood tests and we will ask you and your child to complete a short
questionnaire. These visits are to make sure that your child is doing well and is healthy whilst taking
the new dose.
At this point the PK (Blood Levels) study will end. However, usual clinic ODYSSEY visits will continue
for routine monitoring of your child’s health.

We cannot promise that participating in the study will directly help your child but the results of this
study will give us more information about which dose of dolutegravir works better for children and
young people. It is very important that we have this information so we can make sure that children
are given the correct amount of medicine.
This information will help children and young people across the world with HIV and in the future it
may mean your child has the chance to get the most appropriate amount of medicine.
This study will not result in any risk to your child’s health. However, your child will have to spend two
days at the clinic and may need to stay overnight on these days.

ODYSSEY Protocol
On each PK day, up to 7 small blood samples will be taken but only one needle prick will be needed.
Your child will have to attend at least 1 or 2 additional visits after starting the new dose in order to
check they are doing well.

This study has been looked at by an independent group of people (a Research Ethics Committee) to
make sure that, as far as possible, the safety and wellbeing of anyone taking part in the study is
protected.
A second group (the Independent Data Monitoring Committee) will review the results as they come
out and will recommend if the study is safe to continue. This is standard for all studies looking at
medicines for adults or children.

The PENTA Foundation has made arrangements for compensation should your child come to any harm
from participating in this study. However, if your child is harmed due to someone’s negligence then
you may have reasons for legal action for compensation against the hospital where the negligence
occurred.
All information collected during the ODYSSEY study will be kept completely confidential and names
will not be used. Your child will only be identified using a study number an anonymous code and
their date of birth. Your child’s clinic notes may be looked at by study staff from the PENTA Foundation,
the trials units co-ordinating the study or other independent people authorised to make sure that the
ODYSSEY study is being properly carried out. They may also be seen by the companies who are
supplying medicine for the study or relevant international regulatory authorities. Confidentiality will
If the results of this study are reported or published no information will be included that could identify
your child (no name or date of birth). The study will be conducted in agreement with the country
specific data protection regulations.
If you would like more information about the study please ask the doctor or nurse at your clinic. If you
still need more information please call:
Contact: _________________________
Tel: _____________________________

ODYSSEY Protocol
PARTICIPANT INFORMATION SHEET –WEIGHT BAND PK 2 (25KG TO <40KG)
ODYSSEY WEIGHT BAND PK 2 -

BLOOD LEVELS STUDY
We need to check that a different dose of the new medicine is suitable for children who weigh about
the same as you.
You have been asked to take part because either
A. you are part of the ODYSSEY study and are taking the new medicine
OR
B. you may be taking part in ODYSSEY and could be starting to take the new medicine if and
when you start the study.
It is totally up to you whether or not to take part in this study.
If you decide not to take part this will not stop you from taking part in ODYSSEY or affect your care
now or in the future in any way.

If you decide you would like to take part, we will go through this information sheet together. We will
give you a copy to keep. You will be asked to sign an assent form to show you understand the
Important to know
If you do take part you will need to spend one whole day in the clinic after at least 1 week
of taking the new medicine.
Your dose will be changed after the first blood sampling day.
After at least 1 week of being on the new dose of your medicine you will spend a second day
at the clinic.
You will also have to come in for a clinic visit at 2, 4 and 12 weeks after starting the new
dose of medicine.

ODYSSEY Protocol
On the day booked for the first blood sampling visit you will be asked to come to the clinic for a whole
day.
You will have up to 7 blood samples taken during the day (over a 24 hour period) to test the level of
medicine in your blood. A cream will be used to make the skin numb and a thin flexible tube (called a
cannula) will be inserted into a vein for the day to enable the blood samples to be taken more easily.
All blood samples will be taken from the cannula so only one needle prick is required.
Each blood sample will be small (less than half a teaspoon), and the amount will be is safe for your age
and weight.
We will also need to take a blood sample the next morning. You can stay overnight or we will provide
transport for you to come back the next day.
At least one week after you have switched to the new dose of medicine you will be asked to spend a
second day at the clinic and another set of blood samples will be taken. Like the first blood sampling
day, this may also require an overnight stay in the clinic.
2, 4 and 12 weeks after starting the new dose you will be asked to come to clinic to make sure that
you are doing well and are healthy whilst taking the new dose.
At this point the blood levels study will end. However, usual clinic ODYSSEY visits will continue for
routine monitoring of your health.

ODYSSEY Protocol
PARENT/CARER INFORMATION SHEET FOR TB PHARMACOKINETIC (PK) SUBSTUDY
ODYSSEY TB PK STUDY:
DOLUTEGRAVIR + anti-TB medicines
Many people taking dolutegravir also need to take anti-TB medicines.
Studies looking at this in adults have shown the amount of dolutegravir needs to be doubled
if anti-TB medicines are taken at the same time.
In children there isn't enough information about how much we need to increase the amount
of dolutegravir if anti-TB medicines are taken.
We hope this study will help us to find the best treatment for children like yours.
Your child has been asked to participate because he/she is part of the ODYSSEY study and is
taking dolutegravir and anti-TB medicines.
We are asking at least 12 children and young people to take part.
It is totally up to you and your child whether or not he/she takes part in this study. It is your
right to decide not to take part if you wish.
If you or your child decides not to take part this will not stop your child from taking part in
ODYSSEY or affect your child’s care now or in the future in any way.
If you do decide to take part, blood samples will be taken and stored from your child so
researchers can learn more about anti-HIV medicines. If at any point your child wants to stop
being in the study we hope that you will still allow us to use these samples. If, however, you
do not give your permission then we will destroy them.

ODYSSEY Protocol
If you do decide to take part, we will go through this information sheet together. We will give
you a copy to keep. You will be asked to sign a consent form to show you understand the
Your child’s wellbeing will be monitored closely during the study. If for any reason his/her
medicine needs to be changed this will be done by their doctor in the usual way.
Important to know
If you decide to take part your child will need to spend one day in clinic while
taking anti-TB medicines.
At least a month after your child stops taking anti-TB medicines, he/she will spend
a second day at the clinic and may need to stay overnight.
At the start of the study your child will be taking dolutegravir and anti-TB medicines. At this
point we will take some blood samples to measure the level of dolutegravir in the blood.
Your child will be asked to come into clinic for a whole day. He/she will have up to 7 blood
samples taken during the day (over a 12 hour period) to test the level of dolutegravir and anti-
TB medicine in their blood. A cream with local pain-killing effect will be used to make the skin
numb and a thin flexible tube (called a cannula) will be inserted into a vein for the day to
enable the blood samples to be taken. All blood samples will be taken from the cannula so
only one needle prick is required. Each blood sample will be small (about half a teaspoon),
and the amount will be is safe for your child’s age and weight.
At least a month after your child has completed his/her anti-TB treatment he/she will be
asked to spend a second day at the clinic and another 7 blood samples will be taken (over 24
hours). This may require an overnight stay in hospital.
At this point the dolutegravir-anti-TB medicines study will end. However, usual clinic ODYSSEY
visits will continue for routine monitoring of your child’s health.

of this study will give us more information about how dolutegravir and anti-TB medicines
work together in children. It is very important that we have this information so we can make
sure that children are given the correct amount of medicine.
This information will help children and young people across the world with HIV and TB and in
the future it may mean your child has the chance to get the most appropriate amount of
medicines.
This study will not result in any risk to your child’s health. However, your child will have to
spend separate two days at the clinic and may need to stay overnight on the second day.
Each day, up to 7 small blood samples will be taken but only one needle prick will be needed
each day.

ODYSSEY Protocol

A second group (the Independent Data Monitoring Committee) will meet regularly during the
study to review the results as they come out and will recommend if the study is safe to
continue. This is standard for all studies looking at medicines for adults or children.

any harm from participating in this study. However, if your child is harmed due to someone’s
negligence then you may have reasons for legal action for compensation against the hospital
where the negligence occurred.
names will not be used. Your child will only be identified using a study number, an
anonymous code and their date of birth. Your child’s clinic notes may be looked at by study
staff from the PENTA Foundation, the trials units co-ordinating the study or other
independent people authorised to ensure that the ODYSSEY study is being properly carried
out. They may also be seen by the companies who are supplying medicine for the study or
relevant international regulatory authorities. Confidentiality will be maintained at all times.
If the results of this study are reported or published no information will be included that could
identify your child (no name or date of birth). The study will be conducted in agreement with
Contact: _________________________
Tel: _____________________________

ODYSSEY Protocol
PARTICIPANT INFORMATION SHEET FOR TB PHARMACOKINETIC (PK) SUBSTUDY
ODYSSEY TB PK STUDY:
Studies looking at this in adults have shown the amount of dolutegravir needs to be doubled if anti-
TB medicines are taken at the same time.
In children there isn't enough information about how much we need to increase the amount of
dolutegravir if anti-TB medicines are taken.
We hope this study will help us to find the best treatment for young people like you.

You have been asked to participate because you are part of the ODYSSEY study and are taking
dolutegravir and anti-TB medicines.
We are asking at least 12 young people to take part.
It is totally up to you whether or not you take part in this study. It is your right to decide not to take
part if you wish.
If you decide not to take part this will not stop you from taking part in ODYSSEY or affect your care
now or in the future in any way.
If you do decide to take part, blood samples will be taken and stored from you so researchers can
learn more about anti-HIV medicines. If at any point you want to stop being in the study we hope that
you will still allow us to use these samples. If, however, you do not give your permission then we will
destroy them.
If you do decide to take part, we will go through this information sheet together. We will give a copy
to you to keep. Your parent/carer will then be asked to sign a consent form to show you both
understand the information and agree to take part. We will also ask you to sign a form giving your
assent to join the study.

ODYSSEY Protocol
Your wellbeing will be monitored closely during the study. If for any reason your medicine needs to
be changed this will be done by your doctor in the usual way.
Important to know
If you decide to take part you will need to spend one day in clinic while taking anti-TB
medicines.
At least a month after you stop taking anti-TB medicines, you will spend a second day at the
clinic and may need to stay overnight.
At the start of the study you will be taking dolutegravir and anti-TB medicines. At this point we will
take some blood samples to measure the level of dolutegravir in the blood.
You will be asked to come into hospital for a whole day. You will have up to 7 blood samples taken
during the day (over a 12 hour period) to test the level of dolutegravir and anti-TB medicine in your
blood. A cream with local pain-killing effect will be used to make the skin numb and a thin flexible tube
(called a cannula) will be inserted into a vein for the day to enable the blood samples to be taken. All
blood samples will be taken from the cannula, so only one needle prick is required. Each blood sample
will be small (about half a teaspoon), and the amount will be is safe for your age and weight.
At least a month after you have completed your anti-TB treatment you will be asked to spend a second
day at the clinic and another 7 blood samples will be taken (over a 24 hour period). This may require
an overnight stay in hospital.
At this point the dolutegravir-anti-TB medicines study will end. However, usual clinic ODYSSEY visits
will continue for routine monitoring of your health.

We cannot promise that participating in the study will directly help you but the results of this study
will give us more information about how dolutegravir and anti-TB medicines work together in children
and young people. It is very important that we have this information so we can make sure that children
and young people are given the correct amount of medicine.
This information will help children and young people across the world with HIV and TB and in the
future it may mean you have the chance to get the most appropriate amount of medicines.
This study will not result in any risk to your health. However, you will have to spend two days in the
clinic and may need to stay overnight on the second day.
Each day, up to 7 small blood samples will be taken but only one needle prick will be needed each day.

This study has been looked at by an independent group of people (a Research Ethics Committee) to
make sure that, as far as possible, the safety and wellbeing of anyone taking part in the study is

ODYSSEY Protocol
protected.

participating in this study. However, if you are harmed due to someone’s negligence then you may
have reasons for legal action for compensation against the hospital where the negligence occurred.
With your permission your GP will be informed of your participation in the study. Your hospital doctor
is not receiving any personal payment for carrying out this research. [Country specific, delete if not
applicable]
What will happen to my information collected during this study?

will not be used. You will only be identified using a study number, an anonymous code and their date
of birth. Your clinic notes may be looked at by study staff from the PENTA Foundation, the trials units
co-ordinating the study or other independent people authorised to ensure that the ODYSSEY study is
being properly carried out. They may also be seen by the companies who are supplying medicine for
the study or relevant international regulatory authorities. Confidentiality will be maintained at all
times.
If the results of this study are reported or published no information will be included that could identify
you (no name or date of birth). The study will be conducted in agreement with the country specific
If you would like more information about the study please ask the doctor or nurse at your clinic. If you
still need more information please call:
Contact: _________________________
Tel: _____________________________

ODYSSEY Protocol
INFORMATION SHEETS FOR QUALITATIVE SUBSTUDY
Information sheets for in-depth interviews (IDIs)- 10-18 year olds

Information sheets – IDIs- young people (15- 18 year olds)
Information sheets- IDIs – young people (10-14 year olds)
Information sheets- IDIs- parents/ guardians
Information sheets – IDIs- caregivers
Information sheets – IDIs- young people (15- 19 year olds) - DTG alert
Information sheets- IDIs – young people (10-14 year olds) - DTG alert
Information sheets- IDIs- parents/ guardians - DTG alert
Information sheets for focus group discussions (FGDs) 10-18 year olds
Information sheets- FGDs- young people (15-18 year olds)
Information sheets- FGDs- young people (10-14 year olds)
Information sheets- FGDs- parents/ guardians

ODYSSEY Protocol
ODYSSEY QUALITATIVE STUDY:

PARTICIPANT INFORMATION SHEET FOR IN-DEPTH INTERVIEWS 15-18 YEAR OLDS
(Insert version no and date)
We are doing a study to hear from young people (aged 10-18 years) about their experiences
of growing up with HIV. We would like you to join our study.
Before you decide if you want to take part please read this information sheet carefully and
ask any questions you may have.
What is the purpose of the study?

This is a study to find out about what it is like for young people growing up with HIV and taking
HIV treatment. In particular, we are looking to better understand what it is like to take second-
line HIV treatment. Second-line means that you were already taking one set of anti-HIV
medicine that were no longer working well and your doctor decided it was time for you
change to a new combination. We are interested in learning from young people what can
make it difficult to take their treatment and what might help make it easier. We will do this
by talking with young people, like you, about their experiences. This is because we think that
the best way to learn about the experiences of young people is to listen carefully to what they
have to say. This type of research is called a qualitative study.
Why is the study being done?

Until now there hasn’t been much research done which asks young people themselves about
their experiences of being on second-line treatment. This is why we are doing the study. By
listening to what young people tell us we hope to make some suggestions about how to
improve support for young people to take their treatment.
Who is doing the study?

This study is being run in two of the sites, one in Uganda and one in Zimbabwe, where the
ODYSSEY trial is being conducted. This qualitative study is being done by a small team of
researchers from Uganda, Zimbabwe and the United Kingdom. We have done similar research
before in these sites and are experienced in talking with young people.
Why are we asking you?

We are asking whether you would like to take part in this study because you are participating
in the ODYSSEY trial and are aged between 10-18 years old.
What would I be asked to do?

We would like you to meet a researcher for two interviews. The first interview will be close
to when you begin the ODYSSEY trial and the second interview would take place later on in
the trial. Each interview will be like a conversation and will last for about an hour. There are
no wrong or right answers. You do not have to talk about any topics that you do not want to.
You can stop the interview at any time, without having to explain why.
We would like to audio record these interviews, if this is OK with you. The interview will take
place somewhere that you feel comfortable, probably a private place at the clinic.

ODYSSEY Protocol
What will happen to any information collected about me during this study?
Any information that you share with us will only be seen by members of the research team.
This means that whenever we write or talk about anything you have told us we never use
your real name. All information about you will be stored securely.
The only exception to this is if you tell us something that makes us worried about you or
another young person’s safety, such as physical harm or neglect. If we think that we should
tell someone else, we will talk to you about it first and ask if you would like us to do that.
How will the research be used?

The findings of this study will be reported to a wide range of people who are involved in
providing treatment, care and support for children and young people living with HIV. The
findings will be used to guide the way young people on second-line HIV treatment are
supported in the future.
What are the benefits and risks of taking part?

You will be part of a study that aims to help young people live well with HIV and to support
those taking second-line treatment. Some young people may find the opportunity to talk
about their experiences of growing up with HIV and taking treatment to be a really good thing.
Some young people though might find it a difficult subject to talk about. The researcher will
take care to ask questions sensitively. It is up to you what you want to tell us. Also if you want
there can be someone available from your clinic to talk to if you feel that you want to at any
point during the study, including after the interview.
Do I have to take part?

No, you do not have to take part in the study. Your access to the clinic will not be affected in
anyway if you decide not to take part. It will not affect any of the services that you currently
receive. If you do decide to take part but later change your mind this is OK too.
Will I receive anything for taking part?

Yes, your travel expenses will be covered for the interviews. If you are accompanied to the
interview then your escort’s travel expenses will be covered too. You will also receive 10,000
Ugandan shillings or local equivalent. [Uganda- delete as appropriate]
Yes, your travel expenses will be covered for the interviews. You will receive US$7 per
interview or local equivalent. If you are accompanied to the interview then your escort’s
travel expenses will be covered too. [Zimbabwe- delete as appropriate]
Can I have some more information before I decide?

If you would like to find out more before deciding the staff at your clinic can arrange for you
to speak to one of the researchers more about it.
I’m happy to take part. Now what?

Once you have signed the assent or consent form and, if you are under 18 years old your carer
has given their consent, the researcher will contact you and your carer, if necessary, to
arrange the first interview.

ODYSSEY Protocol
What happens if you have questions?

If you or the person who takes care of you have any questions, you can contact: xxxxxxxx
If you cannot access a telephone to call, you can ask xxxxxxxx (a person from your
clinic/village) to telephone for you so you can ask your question.
Thank you for reading this!

ODYSSEY Protocol

PARTICIPANT INFORMATION SHEET FOR IN-DEPTH INTERVIEWS 10-14 YEAR OLDS
We are doing a study with young people (aged 10-18 years) about their experiences of
growing up with HIV. We would like you to join our study.
Before you decide if you want to take part we would like you to read the information below
carefully. Someone can help you read it if that is easier. It is important that you understand
what we are asking you to do and you should feel comfortable to ask any questions, however
big or small.

This is a study to find out about what it is like for young people when they are growing up
with HIV. We are really interested to understand more about what it is like for you and other
young people to take your HIV treatment every day. We especially want to understand what
it is like when your treatment has been changed to what is called second-line. Second-line
means that you were already taking one set of anti-HIV medicine that were no longer working
well and your doctor decided it was time for you change to a new combination. We want to
know what can make it difficult to take treatment and what might help make it easier. We
will do this by talking with young people, like you, about what it is like. This is because we
think that the best way to learn about this is to listen carefully to what young people have to
say.

We don’t at the moment know very much about what it is like for young people to take
second-line treatment. So we are doing this study so that we can learn more about it. This will
help us to make suggestions about how to help young people with taking their treatment.

This study is being run in Uganda and Zimbabwe. The researchers working on this study are
from Uganda, Zimbabwe as well as the United Kingdom. We have done lots of work like this
before.

We are asking whether you would like to take part in this study because you are already
talking part in the ODYSSEY trial and are aged between 10-18 years old.

We would like you to meet a researcher for two interviews. The first interview will happen
after you have started the ODYSSEY trial and the second interview will take place later on in
the trial. The interviews will be like a conversation. They will last for about an hour. There are
no wrong or right answers. You do not have to talk about anything that you don’t want to and
you will not need to say why.
As we want to listen very carefully to everything that you tell us we would like to audio record
the interviews. We will only record them if you are OK with this.

ODYSSEY Protocol
The interview will take place somewhere that you feel comfortable. This will probably be at
the clinic, somewhere private so that no one can overhear what we will be talking about.
Anything that you tell us will only be listened to by the research team. This means that
whenever we write or talk about anything you have told us we never use your real name. We
will be very careful to keep all the information about you locked away so that no one else can
see it.
another young person’s safety. If we are concerned and think that we should tell someone
else, we will talk to you about it first and ask if you would like us to do that.

We will tell lots of people who look after children and young people living with HIV what we
have learnt from our study. What we learn will be used to guide the way young people on
second-line HIV treatment are supported in the future

You will be part of a study that aims to help young people live well with HIV and to support
those taking second-line treatment. Some young people may find the opportunity to talk
about their experiences of growing up with HIV and taking treatment to be a really good thing.
Some young people though might find it a difficult subject to talk about. The researcher will
take care to ask questions thoughtfully. It is up to you what you want to tell us. Also if you
want there can be someone available from your clinic to talk to if you feel that you want to at
any point during the study, including after the interview.

No, you do not have to take part in the study. If you say no, everything that you receive at the
clinic will be just the same as before. If you do decide to take part but later change your mind
this is OK too.

Yes, your travel expenses will be covered for the interviews. If you are accompanied to the
interview then the expenses of the person who comes with you will also be covered. You will
also receive 10,000 Ugandan shillings or local equivalent. [Uganda- delete as appropriate]
Yes, your travel expenses will be covered for the interviews. You will receive US$7 per
interview or local equivalent. If you are accompanied to the interview then the person who
comes with you will be covered too. [Zimbabwe- delete as appropriate]

ODYSSEY Protocol
to speak to one of the researchers more about it. We will be very happy to answer any of
your questions.

Once you and your carer have signed the assent or consent form the researcher will contact
you and your carer to arrange the first interview.

If you or the person who takes care of you have any questions you can contact: xxxxxxxx

ODYSSEY Protocol

PARENT/CARER INFORMATION SHEET FOR IN-DEPTH INTERVIEWS
of growing up with HIV. We would like your child to join our study.
Before you decide if you want your child to take part please read this information sheet
carefully and ask any questions you may have.

HIV treatment. In particular, we are looking to better understand what it is like to be on
second-line HIV treatment. Second-line means that someone was already taking one set of
anti-HIV medicine that were no longer working well and their doctor decided it was time for
them change to a new combination. We are interested in learning from young people what
can make it difficult to take treatment and what might help make it easier. This will be done
by talking with young people, like your child, about their experiences. This is because we think
that the best way to learn about the experiences of young people is to listen carefully to what
they have to say. This type of research is called a qualitative study.

Up until now there hasn’t been much research done which asks young people themselves
about their experiences of being on second-line treatment. This is why we are doing the study.
By listening to what young people tell us we hope to make some suggestions about how to
improve support for young people to take their treatment.

This study is being run in two sites where the ODYSSEY trial is being conducted. One is at JCRC
in Uganda and one is at the University of Zimbabwe in Harare, Zimbabwe. This qualitative
study is being done by a small team of researchers from Uganda, Zimbabwe and the United
Kingdom. We have done similar research before in these sites and are experienced in talking
with young people about similar topics.
Why are we asking your child?

We are asking whether you are happy for your child to take part in this study because your
child is already participating in the ODYSSEY trial and is aged between 10-18 years old.
What would my child be asked to do?

We would like your child to meet with a researcher for two interviews. The first interview will
be close to when they begin the ODYSSEY trial and the second interview would take place
later on in the trial. Each interview will be like a conversation and will last for about an hour.
There are no wrong or right answers. Your child does not have to talk about anything that
they do not want to. Your child can stop the interview at any time, without having to explain
why.

ODYSSEY Protocol
We would like to audio record these interviews, if this is OK with you and your child. The
interview will take place somewhere that your child feels comfortable, probably at the clinic
where a private place will be found for them to meet the researcher.
What will happen to any information collected about my child during this study?
Any information that your child shares with us will only be seen by members of the research
team. This means that whenever we write or talk about anything your child has told us we
would never use their real name. All information about your child will be stored securely.
The only exception to this is if your child tells us something that makes us worried about your
child or another young person’s safety, such as physical harm or neglect. If we think that we
should tell someone else, we will talk to them about it first and ask if they would like us to do
that.

findings will be used to guide the way young people on second-line HIV treatment are
supported in the future

Your child will be part of a study that aims to help young people live well with HIV and to
support those taking second-line treatment. Some young people may find the opportunity to
talk about their experiences of growing up with HIV and taking treatment to be a really good
thing. Some young people though might find it a difficult subject to talk about. The researcher
will take care to ask questions sensitively. It is up to your child what they want to tell us. Also
if your child wants there can be someone available from their clinic to talk to if they feel that
they want to at any point during the study, including after the interview.
Does my child have to take part?

No, they do not have to take part in the study. Their access to the clinic will not be affected
in anyway if you or your child decides that you do not want them to take part. It will not affect
any of the services that they currently receive. If your child does decide to take part but later
changes their mind this is OK too.
Will my child receive anything for taking part?

Yes, their travel expenses will be covered for the interviews. If they are accompanied to the
interview then their escort’s travel expenses will be covered too. They will also receive 10,000
Yes, their travel expenses will be covered for the interviews. They will receive US$7 per
interview or local equivalent. If they are accompanied to the interview then their escort’s

If you would like to find out more before you decide the staff at your clinic can arrange for
you to speak to one of the researchers more about it.

ODYSSEY Protocol
I’m happy for my child to take part. Now what?

Once you have signed the consent form and, if your child has given their assent, the
researcher will contact you and your child to arrange the first interview.

If you or your child have any questions you can contact: xxxxxxxxx

ODYSSEY Protocol

PARTICIPANT INFORMATION SHEET FOR IN-DEPTH INTERVIEWS - CAREGIVERS
As part of the Odyssey trial we are doing a study to hear from young people (aged 10-19 years)
about their experiences of growing up with HIV and their caregivers. We would like you to
join our study.

HIV treatment. In particular, we are looking to better understand what it is like for young
people to grow up well with HIV, including being able to take their treatment well and access
the information that they need. We are interested in learning from young people and their
caregivers what can make it difficult for young people to grow up well with HIV and what
might help make it easier. We will do this by talking with young people and their caregivers,
like you, about their experiences. This is because we think that the best way to learn about
the experiences of young people is to listen carefully to what they have to say. This type of
research is called a qualitative study.

their experiences of growing up with HIV and also what it is like for their caregivers. This is
why we are doing the study. By listening to what young people and their caregivers tell us we
hope to make some suggestions about how to improve support for young people.

before in these sites and are experienced in talking with caregivers and young people.

We are asking whether you would like to take part in this study because a young person that
you care for is participating in the ODYSSEY trial. They have agreed that it is okay if we ask
you if you would like to be involved in the caregiver part of our study.

We would like you to meet a researcher for an interview. The interview will be like a
conversation and will last for about an hour. There are no wrong or right answers. You do not
have to talk about any topics that you do not want to. You can stop the interview at any time,
without having to explain why.

ODYSSEY Protocol
your real name. We will not reveal any information that you tell us that can be personally
linked to you to anyone else, including the young person you care for. Nor shall we share
anything with you that they have told us. All information about you will be stored securely.
The only exception to this is if you tell us something that makes us worried about a young
person’s safety, such as physical harm or neglect. If we think that we should tell someone

findings will be used to guide the way young people on HIV treatment are supported in the
future.

You will be part of a study that aims to help young people live well with HIV as they grow up.
Some people may find the opportunity to talk about what it is like to care for someone who
is growing up with HIV to be a really good thing. Some though might find it a difficult subject
to talk about. The researcher will take care to ask questions sensitively. It is up to you what
you want to tell us. Also if you want there can be someone available from your clinic to talk
to if you feel that you want to at any point during the study, including after the interview.

No, you do not have to take part in the study. Your own or the young person’s access to the
clinic will not be affected in anyway if you decide not to take part. It will not affect any of the
services that you or they currently receive. If you do decide to take part but later change
your mind this is OK too.

Yes, your travel expenses will be covered for the interview. You will also receive 10,000
Yes, your travel expenses will be covered for the interview. You will receive US$7 per
interview or local equivalent. [Zimbabwe- delete as appropriate]


Once you have signed the consent form the researcher will contact you to arrange the
interview.

ODYSSEY Protocol


ODYSSEY Protocol

PARTICIPANT INFORMATION SHEET FOR IN-DEPTH INTERVIEW 15-19 YEAR OLDS (DTG alert)
of growing up with HIV and the discussions they have within the HIV clinic. We would like to
invite you to take part.

This is a study to find out about what it is like for young people growing up with HIV, taking
HIV treatment and being part of ODYSSEY. In particular, we are looking to better understand
what you discuss about growing up with HIV with healthcare staff and others and what sorts
of information you would like to have about growing up with HIV. We will do this by talking
with young people, like you, about their experiences. This is because we think that the best
way to learn about the experiences and attitudes of young people is to listen carefully to what
they have to say. This type of research is called a qualitative study.

their experiences of being in trials and on HIV treatment. This is why we are doing the study.
By listening to what young people tell us we hope to make some suggestions about how to
improve support for young people to take their treatment and provide them with information
that they would find helpful.

before in these sites and are experienced in talking with young people.


We would like you to meet a researcher for an interview. The interview will be like a
conversation and will last for about an hour. There are no wrong or right answers. You do not
have to talk about any topics that you do not want to. You can stop the interview at any time,
without having to explain why.
We would like to audio record this interview, if this is OK with you. The interview will take

ODYSSEY Protocol
another young person’s safety, such as physical harm or neglect. If we think that we should
tell someone else, we will talk to you about it first and ask if you would like us to do that.

future.

You will be part of a study that aims to help young people live well with HIV and to provide
them with the information that they need and can understand. Some young people may find
the opportunity to talk about their experiences of growing up with HIV to be a really good
will take care to ask questions sensitively. It is up to you what you want to tell us. Also if you

No, you do not have to take part in the study. Your access to the clinic will not be affected in
anyway if you decide not to take part. It will not affect any of the services that you currently

Yes, your travel expenses will be covered for the interview. If you are accompanied to the
interview then your escort’s travel expenses will be covered too. You will also receive 10,000
interview or local equivalent. If you are accompanied to the interview then your escort’s


has given their consent, the researcher will contact you and your carer, if necessary, to
arrange the first interview.

ODYSSEY Protocol


ODYSSEY Protocol

PARTICIPANT INFORMATION SHEET FOR IN-DEPTH INTERVIEW 10-14 YEAR OLDS (DTG alert)
We are doing a study with young people (aged 10-19 years) about their experiences of
growing up with HIV. We would like you to join our study.
Before you decide if you want to take part we would like you to read the information below
carefully. Someone can help you read it if that is easier. It is important that you understand
what we are asking you to do and you should feel comfortable to ask any questions, however
big or small.

it is like to talk about growing up with HIV and being part of ODYSSEY trial, as well as what
sorts of information you would like to have about growing up with HIV. We will do this by
talking with young people. This is because we think that the best way to learn about this is to
listen carefully to what young people have to say.

We don’t at the moment know very much about what it is like for young people who are on
HIV treatment and in a clinical trial. So we are doing this study so that we can learn more
about it. This will help us to make suggestions about how to help young people with taking
their treatment and to have the information that they want to grow up well with HIV.

before.


We would like you to meet a researcher for an interview. This will be like a conversation and
will last for about an hour. There are no wrong or right answers. You do not have to talk about
anything that you don’t want to and you will not need to say why.
As we want to listen very carefully to everything that you tell us we would like to audio record
the interview. We will only record them if you are OK with this.
The interview will take place somewhere that you feel comfortable. This will probably be at
the clinic, somewhere private so that no one can overhear what we will be talking about.

ODYSSEY Protocol
Anything that you tell us will only be listened to by the research team. This means that
whenever we write or talk about anything you have told us we never use your real name. We
will be very careful to keep all the information about you locked away so that no one else can
see it.

We will tell lots of people who look after children and young people living with HIV what we
have learnt from our study. What we learn will be used to guide the way young people on
HIV treatment are supported in the future

You will be part of a study that aims to help young people live well with HIV and to provide
them with the information that they need and can understand. Some young people may find
the opportunity to talk about their experiences of growing up with HIV to be a really good
will take care to ask questions thoughtfully. It is up to you what you want to tell us. Also if you

this is OK too.

Yes, your travel expenses will be covered for the interview. If you are accompanied to the
interview then the expenses of the person who comes with you will also be covered. You will
also receive 10,000 Ugandan shillings or local equivalent. [Uganda- delete as appropriate]
interview or local equivalent. If you are accompanied to the interview then the person who

your questions.

Once you and your carer have signed the assent or consent form the researcher will contact
you and your carer to arrange the first interview.

ODYSSEY Protocol

If you or the person who takes care of you have any questions you can contact: xxxxxxxx

ODYSSEY Protocol

PARENT/CARER INFORMATION SHEET FOR IN-DEPTH INTERVIEW (DTG alert)
of growing up with HIV and being part of a clinical trial. We would like your child to join our
study.

This is a study to find out about what it is like for young people growing up with HIV, taking
HIV treatment and being part of ODYSSEY. In particular, we are looking to better understand
what information they receive about growing up with HIV, whether they understand the
information that they are given and their ideas about what forms of information would be
helpful to them. . This will be done by talking with young people, like your child, about their
experiences. This is because we think that the best way to learn about the experiences of
young people is to listen carefully to what they have to say. This type of research is called a
qualitative study.

about their experiences of being in a trial, on HIV treatment and what information they want
about growing up with HIV. This is why we are doing the study. By listening to what young
people tell us we hope to make some suggestions about how to improve support for young
people to take their treatment and to have the information that they want to grow up well
with HIV.

in Uganda and one is at the University of Zimbabwe in Harare, Zimbabwe. This qualitative
study is being done by a small team of researchers from Uganda, Zimbabwe and the United
with young people about similar topics.

We are asking whether you are happy for your child to take part in this study because your
child is already participating in the ODYSSEY trial and is aged between 10-19 years old.

We would like your child to meet with a researcher for an interview. This interview will be like
a conversation and will last for about an hour. There are no wrong or right answers. Your child
does not have to talk about anything that they do not want to. Your child can stop the
interview at any time, without having to explain why.

ODYSSEY Protocol
We would like to audio record this interview, if this is OK with you and your child. The
interview will take place somewhere that your child feels comfortable, probably at the clinic
where a private place will be found for them to meet the researcher.
would never use their real name. All information about your child will be stored securely.
The only exception to this is if your child tells us something that makes us worried about your
child or another young person’s safety, such as physical harm or neglect. If we think that we
should tell someone else, we will talk to them about it first and ask if they would like us to do
that.

future

Your child will be part of a study that aims to help young people live well with HIV and to
provide them with the information that they need and can understand. . Some young people
may find the opportunity to talk about their experiences of growing up with HIV to be a really
good thing. Some young people though might find it a difficult subject to talk about. The
researcher will take care to ask questions sensitively. It is up to your child what they want to
tell us. Also if your child wants there can be someone available from their clinic to talk to if
they feel that they want to at any point during the study, including after the interview.

No, they do not have to take part in the study. Their access to the clinic will not be affected
in anyway if you or your child decides that you do not want them to take part. It will not affect
any of the services that they currently receive. If your child does decide to take part but later
changes their mind this is OK too.

Yes, their travel expenses will be covered for the interview. If they are accompanied to the
interview then their escort’s travel expenses will be covered too. They will also receive 10,000
Yes, their travel expenses will be covered for the interview. They will receive US$7 per
interview or local equivalent. If they are accompanied to the interview then their escort’s

If you would like to find out more before you decide the staff at your clinic can arrange for
you to speak to one of the researchers more about it.

ODYSSEY Protocol

Once you have signed the consent form and, if your child has given their assent, the
researcher will contact you and your child to arrange the first interview.

If you or your child have any questions you can contact: xxxxxxxxx

ODYSSEY Protocol

PARTICIPANT INFORMATION SHEET FOR FOCUS GROUPS 15-19 YEAR OLDS
ask any questions that you may have.

HIV treatment. In particular, we are looking to better understand what it is like to be on HIV
treatment, what you discuss within the HIV clinic with healthcare staff and others and what
sorts of information you would like to have about growing up with HIV. This will be done by
talking with young people, like you, about their experiences. This is because we think that the
best way to learn about the experiences of young people is to listen carefully to what they
have to say. This type of research is called a qualitative study.

about their experiences of being in trials and on HIV treatment. This is why we are doing the
study. By listening to what young people tell us we hope to make some suggestions about
how to improve support for young people to take their treatment and in the information that
they receive.

This study is being run in two sites in Uganda and Zimbabwe, where the ODYSSEY trial is being
conducted. This qualitative study is being done by a small team of researchers from Uganda,
Zimbabwe and the United Kingdom. We have done similar research before in these sites and
are experienced in talking with young people.


We would like to talk to you in a group with other young people who are also on HIV
treatment and taking part in the ODYSSEY trial. This is called a focus group. We would like you
to take part in two focus groups.
In each focus group there will be a maximum of 7 other young people present and the
researcher/s. All the young people will be from the same clinic as you. It will last about an
hour. We would like to audio record what you say unless you do not want this. You do not

ODYSSEY Protocol
have to talk about things that you do not want to talk about, and you can leave the focus
group at any time and without explaining why.
In the first focus group we will talk as a group about young people’s experience of taking HIV
treatment, being part of the trial and what it is like to complete some of the trial.
In the second focus group we will talk as a group about what we have learnt so far from our
research. We are really interested to know what you think about what we have found. We’d
also like to talk about whether you think that we have correctly understood your situation
and those of other young people like you. Together we will talk about how we should tell
other people, such as doctors, the trial teams, and families about what we have learnt and
the most effective ways to do this.
Everyone in the group will be asked to not say anything about what they hear in the focus
group, except to the researchers or the study counsellors. All the participants are involved in
the trial and attend the same clinic as you.
another young person’s safety, such as physical harm or neglect. If we have to tell someone
else, we will talk to you about it first.

future. It will also be used to help people who are conducting other HIV treatment trials with
young people.

You will be part of a study that aims to help young people to live well with HIV, maintain long
term adherence and to be given the information that they need and can understand to be
able to do so. Some young people may find the opportunity to talk about their HIV treatment
to be a really good thing. Some young people though might find it difficult to talk about. The
researchers have done research with young people and will take care to ask questions
sensitively. It is up to you what you want to tell the group. Also if you want, there can be
someone available from your clinic to talk to if you feel that you want to at any point during
the study, including after the focus group.

No, you do not have to take part in the study. It will not affect any of the services you currently

ODYSSEY Protocol
Yes, your travel expenses will be covered for the focus groups. If you are accompanied to the
focus groups then your escort’s travel expenses will be covered too. You will also receive
10,000 Ugandan shillings or local equivalent. [Uganda- delete as appropriate]
Yes, your travel expenses will be covered for the focus groups. You will receive US$7 per focus
group or local equivalent. If you are accompanied to the focus group then your escort’s travel
expenses will be covered too. [Zimbabwe- delete as appropriate]

your questions.

has given their consent, the researcher will contact you and your carer to arrange the focus
group.

If you or the person who takes care of you have any questions you can contact: xxxxxxx
Thank you for reading this! If you do decide to take part your help will be very valuable.

ODYSSEY Protocol

PARTICIPANT INFORMATION SHEET FOR FOCUS GROUPS 10-14 YEAR OLDS
Before you decide if you want to take part please read this information sheet carefully.
Someone can read it to you if that is easier. It is important that you understand what we are
asking you to do and you should feel comfortable to ask any questions that you have, however
big or small.

you discuss within the HIV clinic with healthcare staff and others and what sorts of
information you would like to have about growing up with HIV. We will do this by talking with
young people, like you, about what it is like. This is because we think that the best way to
learn about this is to listen carefully to what young people have to say.

We don’t at the moment know very much about what it is like for young people to take HIV
treatment well and what kind of information you think that you need to help you. So we are
doing this study so that we can know more about it. This will help us to make suggestions
about how to help young people with taking their treatment.

before.


We would like to talk to you in a group with other young people who are also on HIV
treatment and taking part in the ODYSSEY trial. This is called a focus group. We would like you
to take part in two focus groups.
researcher/s. All the young people will be from the same clinic as you. It will last about an
hour. We would like to audio record what you say unless you do not want this. You do not
have to talk about things that you do not want to talk about, and you can leave the focus
group at any time and without explaining why.

ODYSSEY Protocol
In the first focus group we will talk as a group about what it is like to take HIV treatment. We
will also talk about how everyone in the group has found being part of the ODYSSEY trial,
including filling in some of the trial’s questionnaires.
research. We are really interested to know what you think about what we have found.
Together we will talk about how we should tell other people, such as doctors, about what we
have learnt from our study.
Everyone in the group will be asked to not say anything about what they hear in the focus
the trial and attend the same clinic as you.
your real name. We will be very careful to keep all the information about you locked away so
that no one else can see it.

We will tell lots of people who look after children and young people living with HIV about
what we have learnt from our study. This will be used to guide the way young people on
second-line HIV treatment are supported in the future.

You will be part of a study that aims to help young people live well with HIV and to be given
the information that they need and can understand to be able to do so . Some young people
may find the opportunity to talk about their experiences of growing up with HIV to be a really
good thing. Some young people though might find it a difficult subject to talk about. The
researcher will take care to ask questions thoughtfully. It is up to you what you want to tell
the group. Also if you want there can be someone available from your clinic to talk to if you
feel that you want to at any point during the study, including after the interview.

this is OK too.

Yes, your travel expenses will be covered for the focus groups. If you are accompanied to the
focus groups then the expenses of the person who comes with you will also be covered. You
will also receive 10,000 Ugandan shillings or local equivalent. [Uganda- delete as appropriate]

ODYSSEY Protocol
Yes, your travel expenses will be covered for the focus groups. You will receive US$7 per focus
group or local equivalent. If you are accompanied to the focus group then the person who

your questions.

group.

If you or the person who takes care of you have any questions you can contact: xxxxxx

ODYSSEY Protocol

PARENT/CARER INFORMATION SHEET FOR FOCUS GROUPS
of growing up with HIV. We would like your child to join our study.

HIV treatment. In particular, we are looking to better understand what they discuss within
the HIV clinic with healthcare staff and others and what sorts of information they would like
to have about growing up with HIV. This will be done by talking with young people, like your
child, about their experiences. This is because we think that the best way to learn about the
experiences of young people is to listen carefully to what they have to say. This type of
research is called a qualitative study.

about their experiences of growing up with HIV and the information that they think might
help them. This is why we are doing the study. By listening to what young people tell us we
hope to make some suggestions about how to improve support for young people.

in Uganda and one is at University of Zimbabwe in Harare, Zimbabwe. This qualitative study
is being done by a small team of researchers from Uganda, Zimbabwe and the United
with young people.
Why are we asking your child to take part?

We are asking whether you would like your child to take part in this study because your child
is participating in the ODYSSEY trial and are aged between 10-19 years old.

We would like to talk to your child in a group with other young people who are also on HIV
treatment and taking part in the ODYSSEY trial. This is called a focus group. We would like
your child to take part in two focus groups.
researcher/s. All the young people will be from the same clinic as your child. It will last about
an hour. We would like to audio record what your child and the other young people say unless
you or your child do not want this. Your child does not have to talk about things that they do
not want to talk about, and your child can leave the focus group at any time and without
explaining why.

ODYSSEY Protocol
In the first focus group we will talk as a group about young people’s experience of taking HIV
treatment, being part of the trial and what it is like to complete the some of the trial
questionnaires.
research. We are really interested to know what your child thinks about what we have found.
Together we will talk about how we should tell other people, such as doctors, the trial teams,
and families about what we have learnt and the most effective ways to do this.
Everyone in the group will be asked not to say anything about what they hear in the focus
the trial and attend the same clinic as your child.
will never use their real name. All information about your child will be stored securely.
The only exception to this is if your child tells us something that makes us worried about them
or another young person’s safety, such as physical harm or neglect. If we have to tell someone
else, we will talk to your child about it first.

future. It will also be used to help people who are conducting other HIV treatment trials with
young people.

Your child will be part of a study that aims to help young people maintain long term adherence
to second-line treatment. Some young people may find the opportunity to talk about their
HIV treatment to be a really good thing. Some young people though might find it difficult to
talk about. The researchers have done research with young people and will take care to ask
questions sensitively. It is up to your child what they want to tell us. Also if your child wants,
there can be someone available from their clinic to talk to if they feel that they want to at any
point during the study, including after the focus group.

No, your child does not have to take part in the study. It will not affect any of the services that
they currently receive. If your child does decide to take part but later changes their mind this
is OK too.

Yes, your child’s travel expenses will be covered for the focus groups. If they are accompanied
to the focus groups then the expenses of the person who comes with your child will also be
covered. They will also receive 10,000 Ugandan shillings or local equivalent. [Uganda- delete
as appropriate]

ODYSSEY Protocol
Yes, their travel expenses will be covered for the focus groups. They will receive US$7 per
focus group or local equivalent. If your child is accompanied to the focus group then the
person who comes with them will be covered too. [Zimbabwe- delete as appropriate]

your questions.

group.

If you or your child have any questions you can contact: xxxxxxxx
Thank you for reading this! If you do decide to take part your help will be very valuable.

ODYSSEY Protocol
INFORMATION SHEETS FOR YOUTH TRIAL BOARD SUBSTUDY
Information sheets - young people

Information sheets - parents/ guardian
Information sheets – YTB facilitators

ODYSSEY Protocol
YOUTH TRIAL BOARD

PARTICIPANT INFORMATION SHEET FOR YOUNG PEOPLE
What is a clinical trial?

Clinical trials see how well new medication works or whether medication can be given in
different ways. They last for a few years and 100s of patients are involved with scientists
watching them closely to look at what happens. The aim of most clinical trials is that the
findings (‘findings’ are all the things the scientists see) may lead to better health care.
Lots of children and young people living with HIV are part of clinical trials but, until now, they
have had very few opportunities to say how they think a clinical trial is run, explain its findings
to other children and young people and how the findings are shown publicly.
What is a Youth Trial Board (YTB)?
We are running a project in partnership with ODYSSEY - a new clinical trial - to set up four
YTBs. A YTB will be a group of up to 8 young people living with HIV who come together 3-4
times a year and learn about clinical trials, have a say on how they are run and help produce
information for children, young people and the public about what the trial findings are.
The aim of each YTB is:
1) to give a voice to the children and young people involved in the trial,
2) to improve the experience for those children and young people taking part, so they
understand what they are taking part in and what the trial finds out.
This is a pilot project, which means no one has tried to do this before. It means that although
there will be certain things a YTB must do, we will be working out how they run as we go along
and you will have a say in this. We have different countries involved in this pilot, so we can
see how YTBs work in different settings.
Helping design YTBs
If you become a member of a YTB, we will keep asking you about what it’s like and how you
think it could be made better. We will do this at each meeting and at the end of the whole
project. We would also like to have an interview with you to chat about what it is like being a
YTB member, what works well and what could be done better. We will use the things all the
YTB members tell us and what we learn from running YTBs for two years to make a toolkit.
This toolkit will tell others about what we have learnt and how to set up their own YTBs.
Before you decide whether you want to be involved, it is important that you understand what
we are doing and what being involved will mean. Please read this information sheet carefully
and ask any questions you may have.
Thank you!

ODYSSEY Protocol
What are we asking you to do?

Being a YTB member means you need to come to YTB meetings. These meetings will be with
up to 7 other young people living with HIV from your country aged 15-19 years old and up to
3 adult facilitators.
We would like to have an interview with you about what it is like being part of a YTB. This
interview will be like a conversation and will last for about an hour. It will be a conversation
between you and the researcher. There are no wrong or right answers. You do not have to
talk about any topics that you do not want to. You can stop the interview at any time, without
having to explain why.
place somewhere that you feel comfortable
What will happen at YTB meetings?

At a YTB meeting you and the other YTB members will:
Learn about trials and how they work

Work out ways to ask other children and young people who are on the trial about their
experiences
Learn about how to be an advocate (an advocate is someone that speaks for other
people) and then do this at meetings with people who run clinical trials
Be creative and involved in designing ways to get messages about the trial to the
children and young people who are part of it
Decide what is important and how you are going to tell this to either the people
running the trial or to children on the trial
Help to design how YTBs can work well in the future

We are asking you to think about whether you would like to be involved because you are aged
between 15-19 years of age.
Learning from you

If you decide that you would like to take part in a YTB, it is very important that we learn from
you and the other YTB members. We will have activities, games and also time to talk in an
individual interview, where you will be asked about the best and the worst things about being
a member of a YTB. We want to know your ideas and opinions. We call these ‘reflections’
because you will be telling us about what you feel and think.

ODYSSEY Protocol
Examples of what we would be writing down include what YTB members think works or
doesn’t work in a YTB and in a clinical trial and what you would like the people running the
trial to understand about what it’s like to be a young person living with HIV who is taking part
in a clinical trial.
You will be asked at the start of being a YTB member to agree for us to use your reflections,
we call this ‘giving consent’. If you change your mind, you can take your consent away. We
will not be angry with you and want to support you to feel happy and comfortable. You are
able to stop taking part in the study at any time. You have control over all of this and it’s fully
your decision.
What will we do with all the information from the YTB meetings and interviews?
We would like to use this information to help us design the YTB model. What all YTB members
say in their reflections and interviews will be written down and what you say will help us build
a YTB model which can be used in other clinical trials so that young people feel really listened
to and are able to change things. These reflections will also be used as part of the guidance
we will write on how to set up YTBs in all countries.
Will what I say be confidential?
None of what we see, hear and write down will be linked back to you. Everything will be
anonymised, which means it won’t have your name so that someone could link it back to you.
Anything that does have information that we can link back to you will just be seen by members
of the project team. This means that whenever we write or talk about anything you have told
us, we never use your real name. All information about you will be stored securely.
What are the benefits and risks of being involved?
You will be part of a project that aims to develop a way to meaningfully involve young people
in how trials are run. The overall goal of YTBs is to improve the experiences of children and
young people participating in trials and this project is an early step in achieving this goal. There
are no risks to you in being involved.
NO, you do not have to take part. If you prefer to not take part, that is absolutely OK. Saying
no will also not affect any of the services that you receive. If you decide to take part but later
change your mind this is OK too.

ODYSSEY Protocol
YOUTH TRIAL BOARD

PARENT/CARER INFORMATION SHEET

What is a clinical trial?
Clinical trials see how well new medication works or whether medication can be given in
different ways. They can last for a few years and often 100s of patients are involved with
scientists watching them closely to look at what happens. The aim of most clinical trials is that
the findings (‘findings’ is all the things the scientists see) may lead to better health care.
Lots of children and young people living with HIV are part of clinical trials but, until now, they
have had very few opportunities to say how they think a clinical trial is run, explain its findings
to other children and young people and how the findings are shown publicly.
and you will have a say in this. We have different countries involved in this pilot, so we can
see how this works in different settings.
Helping design YTBs
If your child becomes a member of a YTB, we will be asking them about what it’s like and how
they think it could be made better throughout the project. We will do this at each meeting
and at the end of the project. We would also like to have an interview with your child to speak
with them about what it is like being a YTB member, what works well and what could be
improved. We will use the things all the YTB members tell us and what we learn from running
YTBs for two years to make a toolkit. This toolkit will tell others about what we have learnt
and how to set up their own YTBs.
Before you decide whether you want your child to be involved, it is important that you
understand what we are doing and what being involved will mean. Please read this
information sheet carefully and ask any questions you may have.

ODYSSEY Protocol
Thank you!
What are we asking your child to do?
Being a YTB member means your child needs to come to YTB meetings. These meetings will
be with up to 7 other young people aged 15-19 years old from your country living with HIV
and up to 3 adult facilitators.
We would like to have an interview with your child about what it is like for them being part
of a YTB. This interview will be like a conversation and will last for about an hour. It will be a
conversation between your child and the researcher. There are no wrong or right answers.
Your child does not have to talk about any topics that they do not want to. Your child can stop
the interview at any time, without having to explain why.
We would like to audio record these interviews, if this is OK with you and your child. The
interview will take place somewhere that your child feels comfortable.
What will happen at YTB meetings?
At a YTB meeting your child and the other YTB members will:
Learn about trials and how they work

Work out ways to ask other children and young people who are on the trial about their
experiences
Learn about how to be an advocate – so someone that speaks for other people – and
then do this at meetings with people who run clinical trials
Be creative and design ways to get messages about the trial to the children and young
people who are part of it
Decide what is important and how you are going to tell this to either the people
running the trial or to children on the trial
Help to design how YTBs can work well in the future

We are asking you to think about whether you would like your child to be involved because
they are aged between 15-19 years of age.
Learning from your child
If you and your child decide that you would like them to take part, it is very important that
we learn from your child and the other YTB members. We will have activities, games and also
time to talk in an individual interview, where they will be asked about the best and the worst
things about being a member of a YTB. We want to know their ideas and opinions. We call
these ‘reflections’ because they will be telling us about what they feel and think.
Examples of what we would be writing down include what YTB members think works or
doesn’t work in a YTB and in a clinical trial and what they would like the people running the
trial to understand about what it’s like to be a young person living with HIV who is taking part
in a clinical trial.

ODYSSEY Protocol
Your child will be asked at the start of being a YTB member to agree for us to use their
reflections, we call this ‘giving consent’. If they change their mind, they can take their consent
away. We will not be angry with them and want to support them to feel happy and
comfortable. You and your child have control over all of this and it’s important to us that you
know that.
What will we do with all the information from the YTB meetings?
We would like to use this information to help us design the YTB model. What all YTB members
say in their reflections and interviews will be written down and what your child says will help
us build a YTB model where young people feel really listened to and are able to change things.
These reflections will also be used as part of the guidance we will write on how to set up YTBs
in all countries.
Will what my child says be confidential?
None of what we see, hear and write down will be linked back to your child. Everything will
be anonymised, which means it won’t have their name so that someone could link it back to
them. Anything that does have information that we can link back to them will just be seen by
members of the project team. This means that whenever we write or talk about anything they
have told us, we never use their real name. All information about them will be stored securely.
Your child will be part of a project that aims to develop a way to meaningfully involve young
people in how trials are run. The overall goal of YTBs is to improve the experiences of children
and young people participating in trials and this project is an early step in achieving this goal.
There are no risks to your child in being involved.
NO, your child does not have to take part. If you prefer for your child not to take part, that is
absolutely OK. Saying no will also not affect any of the services that your child receives. If
your child decides to take part but later changes their mind this is OK too.

ODYSSEY Protocol
YOUTH TRIAL BOARD

YTB FACILITATOR INFORMATION SHEET

and you will have a say in this. We have different countries involved in this YTB pilot project,
so we can see how this works in different settings.
Helping design YTBs

We are in the process of conducting the pilot of the YTBs in four countries and are looking to
understand the experiences of those who have been taking part and/ or running the YTBs.
We will be asking YTB participants and facilitators about their experiences of what it has been
like being involved and how they think the design and delivery of the YTB project would be
improved. We will do this by conducting individual interviews with participants and
facilitators to understand their experiences and learn from their ideas and opinions. We will
use the information that we learn to improve the YTB model and then to make a YTB toolkit.
This toolkit will tell others about what we have learnt and how to set up their own YTBs.
Before you decide whether you want to be involved, it is important that you understand what
we are doing and what being involved will mean. Please read this information sheet carefully
and ask any questions you may have.
Thank you!
What are we asking you to do?
We would like to have an interview with you about what it is like being part of a YTB as a
facilitator. This interview will be like a conversation and will last for about an hour. It will be
a conversation between you and the researcher. There are no wrong or right answers. You do
not have to talk about any topics that you do not want to. You can stop the interview at any
time, without having to explain why.

ODYSSEY Protocol
place somewhere that you feel comfortable.
We are asking you to think about whether you would like to be involved because you have
taken part in the YTB pilot project by being a facilitator. Understanding more about your
experience of doing so will be valuable to us in designing the YTB toolkit.
Learning from you
If you decide that you would like them to take part, we would like to talk to you in an individual
interview about your experiences of facilitating a YTB, what works well and what could be
improved, as well as the training needs of facilitators.
What will we do with all the information?
We would like to use this information from you, the other facilitators and participants to help
us design the YTB model and will be used as part of the guidance we will write on how to set
up YTBs in all countries.
Will what I say be confidential?
None of what you tell us in your interview will be linked back to you. This means that
whenever we write or talk about anything you have told us, we will never use your real name.
All information about you will be stored securely.
You are part of project that aims to develop a way to meaningfully involve young people in
how trials are run. The overall goal of YTBs is to improve the experiences of children and
young people participating in trials and this project is an early step in achieving this goal. We
would like to understand how we can learn from the experiences of those involved in the pilot
YTBs and how we can improve the YTB model in the future. There are no risks to you in being
involved.
NO, you do not have to take part. If you prefer not to take part, that is absolutely OK.

ODYSSEY Protocol
20 APPENDIX II TEMPLATE CONSENT AND ASSENT FORMS
PARENT/CARER – MAIN STUDY CONSENT TO SCREENING
(To be printed on local-headed paper) Study number:

(Insert version no and date) Anonymous code:
ODYSSEY: A randomised trial of dolutegravir (DTG)-based antiretroviral therapy vs. standard of

care (SOC) in children with HIV infection starting first-line or switching to second-line antiretroviral
therapy.
Please initial (or mark) box if you agree:
I have read/been read the information sheet (version ____, dated __________)
for the ODYSSEY study.
I agree to my child being assessed to see whether he/she is eligible to take part
in this study.
I understand this will involve my child being seen by the doctor who will ask
questions about my child’s health, and my child having some blood taken for
testing.
I agree that the results of these tests and an additional blood sample can be
kept by the ODYSSEY team for further tests if my child starts the study. I
understand that these results and samples will not be identified by either my or
my child’s name.
I understand that if my child cannot participate in the study, the stored blood
sample will be discarded and not used for further tests.
Parent/carer’s signature
Print name Date
(or thumbprint)
Witness’ signature
Print name Date
(if thumbprint above)
I have provided the ODYSSEY study information to the potential participant’s parent/legal guardian
in full and answered all his/her questions. To the best of my knowledge, he/she understands the
purpose, interventions, risks and benefits of this study and willingly agrees for his/her child to be
screened for the ODYSSEY study.
Signature of person
conducting the informed Print name Date
consent process
IMPORTANT: one signed original to be kept in ODYSSEY trial file by the researcher
one signed copy to be given to the parent/carer
one signed copy to be kept in the clinic file

ODYSSEY Protocol
PARENT/CARER – MAIN STUDY CONSENT TO RANDOMISATION
(To be printed on local-headed paper)

Study number:
Anonymous code:
therapy.

I have read/been read the information sheet (version ____, dated __________) for
the ODYSSEY study and I understand what will be required if my child participates in
the study.
The study has been explained to me and all my questions have been answered.
I understand that my child’s participation is voluntary and that I am free to withdraw

him or her at any time, without giving any reason, without my medical care or legal
rights or my child’s medical care or legal rights being affected.
I agree to inform the study doctor if my child starts any other new medicine during
the period of the study.
I understand that clinical information may be reviewed by properly authorised

individuals as part of the study and that such information will be treated as strictly
confidential.
I agree to allow blood samples to be taken from my child and for my child’s samples
to be stored for later testing. I understand that these results and samples will not be
identified by either my or my child’s name and that I may not be given the results of
tests performed on stored samples.
I agree to routine blood results and clinical information being included anonymously
in continued follow-up after the study has ended (identified only by study number
and date of birth).
I agree to UCL collecting information about my child from my child’s clinic for this
research study. This data may be used by UCL and other authorised research
collaborators to conduct the trial and associated sub-studies
I agree to anonymised study data being transferred to ViiV Healthcare, and to drug
agencies in other countries.
I agree for my child to participate in the ODYSSEY study
Print name Date
(or thumbprint)
Print name Date
Please turn over the page

ODYSSEY Protocol
I have provided the ODYSSEY study information to the participant’s parent/legal guardian in full and
answered all his/her questions. To the best of my knowledge, he/she understands the purpose,
interventions, risks and benefits of this study and willingly agrees for his/her child to be enrolled
into the ODYSSEY study.
Signature of person
consent process
I would/would not (please circle) like my child’s GP to be notified about participation in this study.
Signature of Parent/Guardian:______________________________Date:____________
Name of GP:
Contact address of GP: __________________________________________________

ODYSSEY Protocol
PARTICIPANT –MAIN STUDY ASSENT TO SCREENING

Anonymous code:
ODYSSEY – A randomised trial of dolutegravir (DTG)-based antiretroviral therapy vs. standard of care
(SOC) in children with HIV infection starting first-line or switching to second-line ART.
Please tick yes or no to the questions below

1. Have you read (or had read to you) the information about this study? YES NO
2. Do you understand that your doctor will check how you are and do some tests on your YES NO
blood to see if you can join the study?
3. Do you agree that if you start the study your blood samples (without your name on) can YES NO
be used during the study and stored for studies which will help us understand more about
the virus? (If you don’t start the study, we won’t use your blood samples)
4. Are you happy to be assessed to see whether you can take part in this study? YES NO
If any answers are ‘no’ or you don’t want to take part, don’t sign your name.
If you do want to take part, please sign your name below.
Participant’s signature
Print name Date
(or thumbprint)
(if thumbprint used above) Print name Date
The person who explained the study to you needs to sign too:
I have provided the ODYSSEY study information to the potential participant in full and answered all
his/her questions. To the best of my knowledge, he/she understands the purpose, interventions,
risks and benefits of this study and willingly agrees to be screened for the ODYSSEY study.
Signature of person
consent process
one signed copy to be given to the participant

ODYSSEY Protocol
PARTICIPANT- MAIN STUDY ASSENT TO RANDOMISATION

Study number:
Anonymous code:
care (SOC) in children with HIV infection starting first-line or switching to second-line ART.

2. Has somebody explained the study to you? YES NO
3. Do you understand what the study is about? YES NO
4. Have you asked all the questions you want? YES NO
5. Have your questions been answered in a way you understand? YES NO
6. Do you understand how the study might help you? YES NO
7. Do you understand the risks of taking part? YES NO
8. Do you understand it’s OK to stop taking part in the study at any time? YES NO
9. Do you understand that you cannot choose the group you will be in? YES NO
10. Are you happy to take part? YES NO
If you do want to take part, you can sign your name below.
Print name Date
(or thumbprint)


ODYSSEY Protocol
I have provided the ODYSSEY study information to the participant in full and answered all his/her
questions. To the best of my knowledge, he/she understands the purpose, interventions, risks and
benefits of this study and willingly agrees to be enrolled into the ODYSSEY study.
Signature of person
consent process

ODYSSEY Protocol
PARTICIPANT – MAIN STUDY CONSENT TO CONTINUED PARTICIPATION FOR YOUNG

PEOPLE WHO REACH THE AGE OF CONSENT WHILST IN THE TRIAL



I have read/been read the information sheet (version ____, dated __________) for the
ODYSSEY study and I understand what will be required if I continue to participate in the
study.
The study has been explained to me and my questions have been answered.
I understand that my participation is voluntary and that I am free to withdraw at any

time, without giving any reason, and without my medical care or legal rights being
affected.
I agree to inform the study doctor if I start any other new medicines during the period
of the study.

confidential.
I agree to allow blood samples to be taken and stored for later testing. I understand
that these results and samples will not be identified by my name and that I may not be
given the results of tests performed on stored samples.
I agree to routine blood results and clinical information being included anonymously in
continued follow-up after the study has ended (identified only by study number and
date of birth).
I agree to UCL collecting information about me from my clinic for this research study.
This data may be used by UCL and other authorised research collaborators to conduct
the trial and associated sub-studies.
I agree to take part in the ODYSSEY study
Print name Date
(or thumbprint)
Print name Date

ODYSSEY Protocol
benefits of this study and willingly agrees to continue to participate in the ODYSSEY study.
Signature of person
consent process

ODYSSEY Protocol
PARENT/CARER – RE-CONSENT TO THE ODYSSEY TRIAL

Study number:
Anonymous code:

therapy.

the study.


confidential.
and date of birth).
I agree to UCL collecting information about my child from my child’s clinic for this
research study. This data may be used by UCL and other authorised research
collaborators to conduct the trial and associated sub-studies
I agree for my child to continue to participate in the ODYSSEY study
Print name Date
(or thumbprint)
Print name Date

ODYSSEY Protocol
Signature of person
consent process
Name of GP:

ODYSSEY Protocol
PARTICIPANT – RE-CONSENT TO THE ODYSSEY TRIAL

Study number:
Anonymous code:

therapy.

the ODYSSEY study and I understand what will be required if I participate in the
study.

time, without giving any reason, without my medical care or legal rights being
affected.
I agree to inform the study doctor if I start any other new medicine during the period
of the study.

confidential.
that these results and samples will not be identified by my name and that I may not
be given the results of tests performed on stored samples.
and date of birth).
I agree to UCL collecting information about me from my clinic for this research
study. This data may be used by UCL and other authorised research collaborators to
conduct the trial and associated sub-studies.
I agree to continue to participate in the ODYSSEY study
Participant signature
Print name Date
(or thumbprint)
Print name Date

ODYSSEY Protocol
benefits of this study and willingly agrees to continue participation in the ODYSSEY study.
Signature of person
consent process
_

ODYSSEY Protocol
PARTICIPANT- MAIN STUDY RE-ASSENT TO THE ODYSSEY TRIAL

Study number:
Anonymous code:

10. Are you happy to continue to take part? YES NO
Print name Date
(or thumbprint)


ODYSSEY Protocol
Signature of person
consent process

ODYSSEY Protocol
PARENT/CARER – CONSENT TO EXTENDED FOLLOW-UP

Study number:
Anonymous code:
therapy.

extended follow-up within the ODYSSEY study and I understand what will be
required if my child participates.
The reason for extended follow-up has been explained to me and all my questions
have been answered.

the extended follow-up period.

confidential.
I agree to UCL collecting information on routine blood results and clinical
information on my child from my child’s clinic for the extended follow-up period.
This data may be used by UCL and other authorised research collaborators to
conduct the trial
I agree for my child to participate in the extended follow-up period for ODYSSEY
study
Print name Date
(or thumbprint)
Print name Date

ODYSSEY Protocol
I have provided the ODYSSEY extended follow-up information to the participant’s parent/legal
guardian in full and answered all his/her questions. To the best of my knowledge, he/she
understands the purpose, interventions, risks and benefits and willingly agrees for his/her child to
participate in the extended follow-up period for the ODYSSEY study.
Signature of person
consent process

ODYSSEY Protocol
PARTICIPANT – CONSENT TO EXTENDED FOLLOW-UP

Study number:
Anonymous code:
therapy.

extended follow-up within the ODYSSEY study and I understand what will be
required if I participate.
The reason for extended follow-up has been explained to me and all my questions
have been answered.

time, without giving any reason, without my medical care or legal rights being
affected.
I agree to inform the study doctor if I start any other new medicine during the
extended follow-up period.

confidential.
I agree to UCL collecting information on my routine blood results and clinical
information from my clinic for the extended follow-up period. This data may be used
by UCL and other authorised research collaborators to conduct the trial.
I agree to participate in the extended follow-up period for ODYSSEY study
Print name Date
(or thumbprint)
Print name Date

ODYSSEY Protocol
I have provided the ODYSSEY extended follow-up information to the participant in full and
interventions, risks and benefits and willingly agrees to participate in the extended follow-up period
Signature of person
consent process

ODYSSEY Protocol
PARTICIPANT – ASSENT TO EXTENDED FOLLOW-UP

Study number:
Anonymous code:

1. Have you read (or had read to you) the information about extended follow-up YES NO
for this study?
2. Has somebody explained extended follow-up for this study to you? YES NO
3. Do you understand what follow-up for the study is about? YES NO
6. Do you understand how extended follow-up might help you? YES NO
8. Do you understand that it’s OK to stop taking part in extended follow-up at any YES NO
time?
Print name Date
(or thumbprint)

ODYSSEY Protocol
Signature of person
consent process

ODYSSEY Protocol
PARENT/CARER – CONSENT TO STORAGE OF BLOOD SAMPLES FOR FUTURE TESTING

ODYSSEY: A randomised trial of dolutegravir (DTG)-based antiretroviral therapy vs. standard of care

Print name Date
(or thumbprint)
Print name Date
answered all his/her questions. To the best of my knowledge, he/she understands the purpose, risks
and benefits of blood sample storage and willingly agrees for his/her child to have their blood
samples stored for future testing.
Signature of person
consent process

ODYSSEY Protocol
PARTICIPANT - CONSENT TO STORAGE OF BLOOD SAMPLES FOR FUTURE TESTING


that these results and samples will not be identified by my name and that I may not
be given the results of tests performed on stored samples.
Print name Date
(or thumbprint)
Print name Date
questions. To the best of my knowledge, he/she understands the purpose, risks and benefits of
blood sample storage and willingly agrees to have their blood samples stored for future testing.
Signature of person
consent process

ODYSSEY Protocol
PARTICIPANT – ASSENT TO STORAGE OF BLOOD SAMPLES FOR FUTURE TESTING

(Insert version no and date) Study number:
Anonymous code:


1. Do you understand that we would like to keep some of your blood samples to YES NO
test in the future?
2. Do you understand that we will not put your name on the samples so that YES NO
other people will not know that they belong to you?
3. Do you understand that you may not be given the results from these tests? YES NO
4. Are you happy for us to keep your blood samples to test in the future? YES NO
If any answers are ‘no’, don’t sign your name.
If you are happy for us to store your blood samples to test in the future, you can sign your name
below.
Print name Date
(or thumbprint)
benefits of blood sample storage and willingly agrees to have their blood samples stored for future
testing.
Signature of person
consent process

ODYSSEY Protocol
PARENT/CARER – MAIN STUDY & WB PK 1 CONSENT TO SCREENING (3 TO <14KG)

(Insert version no and date) Study number:
Anonymous code:
therapy.
about the ODYSSEY study and the PK (blood levels) study.
in this study.
testing.
my child’s name.
I understand that if my child cannot participate in the study, the stored blood
sample will be discarded and not used for further tests.
I agree to my child taking part in the PK (blood levels) study if they enter
ODYSSEY and are allocated dolutegravir.
Print name Date
(or thumbprint)
Print name Date
Signature of person
consent process
IMPORTANT: one signed original to be kept in odyssey trial file by the researcher

ODYSSEY Protocol
PARENT/CARER – MAIN STUDY & WB PK 1 CONSENT TO RANDOMISATION (3 TO <14KG)

Study number:
Anonymous code:

therapy.
about the ODYSSEY study and the PK (blood levels) study and I understand what will
be required if my child participates in the study.


confidential.
and date of birth).
I agree for my child to participate in the ODYSSEY study.
I agree to my child taking part in the PK (blood levels) study if they are allocated
dolutegravir.
Print name Date
(or thumbprint)
Print name Date

ODYSSEY Protocol
Signature of person
consent process
Name of GP:

ODYSSEY Protocol
PARTICIPANT – MAIN STUDY & WB PK 1 ASSENT TO SCREENING (3 TO <14KG)

ODYSSEY – A randomised trial of dolutegravir (DTG)-based antiretroviral therapy vs. standard of care

1. Have you read (or had read to you) the information about this study and the PK (blood
levels) study? YES NO
2. Do you understand that your doctor will check how you are and do some tests on your YES NO
blood to see if you can join the study?
3. Do you agree that if you start the study your blood samples (without your name on) can
be used during the study and stored for studies which will help us understand more about YES NO
the virus? (If you don’t start the study, we won’t use your blood samples)
4. Are you happy to be assessed to see whether you can take part in this study? YES NO
5. Do you agree to taking part in the PK (blood levels) study? YES NO
Print name Date
(or thumbprint)
I have provided the ODYSSEY study information to the potential participant in full and answered all
risks and benefits of this study and willingly agrees to be screened for the ODYSSEY study.
Signature of person
consent process

ODYSSEY Protocol
PARTICIPANT- MAIN STUDY & WB PK 1 ASSENT TO RANDOMISATION (3 TO <14KG)



1. Have you read (or had read to you) the information about this study and the YES NO
PK (blood levels) study?
11. Do you agree to taking part in the PK (blood levels) study? YES NO
Print name Date
(or thumbprint)

ODYSSEY Protocol
Signature of person
consent process

ODYSSEY Protocol
PARENT/CARER - CONSENT TO PHARMACOKINETIC (WB PK 1) STUDY (3 TO <25KG)


the ODYSSEY weight band PK 1 (blood levels) study and I understand what will be
required if my child participates in the study.
The weight band PK 1 study has been explained to me and my questions have been
answered.
I understand that my child’s participation in this study is voluntary and that I am free
to withdraw him or her at any time, without giving any reason, without my medical
care or legal rights or my child’s medical care or legal rights being affected.
I agree for small quantities of blood to be stored with anonymised labelling so that
further work can be done to help understand more about HIV treatment. [Country
specific, delete if not applicable]
I agree for my child to participate in the ODYSSEY weight band PK 1 (blood levels)
study if they are eligible.
Print name Date
(or thumbprint)
Print name Date
I have provided the ODYSSEY WB PK 1 study information to the participant’s parent/legal guardian
purpose, interventions, risks and benefits of this study and willingly agrees for his/her child to
participate in the ODYSSEY WB PK 1 study.
Signature of person
consent process

ODYSSEY Protocol

ODYSSEY Protocol
PARTICIPANT - ASSENT TO PHARMACOKINETIC (WB PK 1) SUBSTUDY (3 TO <25KG)



1. Have you read (or had read to you) the information about the blood levels YES NO
study?
2. Has somebody explained this study to you? YES NO
3. Do you understand what this study is about? YES NO
6. Do you understand how this study might help you? YES NO
7. Do you understand the disadvantages of taking part? YES NO
9. Do you understand that if you take part in the blood levels study you will need
to come to the clinic for a whole day (over a 24 hour period) to check the level of YES NO
medicine in your blood and maybe sleep there?
Print name Date
(or thumbprint)

ODYSSEY Protocol
I have provided the ODYSSEY WB PK 1 study information to the participant in full and answered all
risks and benefits of this study and willingly agrees to participate in the ODYSSEY WB PK 1 study.
Signature of person
consent process

ODYSSEY Protocol
PARENT/CARER - CONSENT TO PHARMACOKINETIC (WB PK 2) STUDY (≥25KG)


the ODYSSEY weight band PK 2 (blood level)s study and I understand what will be
required if my child participates in the study.
The weight band PK study has been explained to me and my questions have been
answered.
further work can be done to help understand more about HIV treatment. [Country
specific, delete if not applicable]
I agree to study data including my child’s study number and age being transferred to
ViiV Healthcare, and to drug agencies in other countries.
I agree for my child to participate in the ODYSSEY weight band PK 2 (blood levels)
study if they are eligible.
Print name Date
(or thumbprint)
Print name Date
I have provided the ODYSSEY WB PK 2 study information to the participant’s parent/legal guardian
participate in the ODYSSEY WB PK 2 study.
Signature of person
consent process

ODYSSEY Protocol
PARTICIPANT - ASSENT TO PHARMACOKINETIC (WB PK 2) STUDY (≥25KG)



1. Have you read (or had read to you) the information about the blood levels study? YES NO
9. Do you understand that if you do take part in the PK (blood levels) study you will need
to come to the clinic for a whole day to check the level of medicine in your blood and YES NO
maybe sleep there?
10. Do you understand that if you do take part in the PK (blood levels) study your dose of YES NO
medicine will be changed after the first blood sampling day?
11. Do you understand that if you do take part in the PK (blood levels) study you will need
to come back to the clinic for a second full day to check the level of medicine in your YES NO
blood and maybe sleep there?
Print name Date
(or thumbprint)

ODYSSEY Protocol
I have provided the ODYSSEY WB PK 2 study information to the participant in full and answered all
risks and benefits of this study and willingly agrees to participate in the ODYSSEY WB PK 2 study.
Signature of person
consent process

ODYSSEY Protocol
PARENT/CARER - CONSENT TO PHARMACOKINETIC (TB PK) STUDY


the ODYSSEY TB PK (blood levels) study and I understand what will be required if my
child participates in the study.
The TB PK study has been explained to me and my questions have been answered.
further work can be done to help understand more about HIV and TB effective
treatment. [Country specific, delete if not applicable]
I agree for my child to participate in the ODYSSEY TB PK (blood levels) study
Print name Date
(or thumbprint)
Print name Date
I have provided the ODYSSEY TB PK study information to the participant’s parent/legal guardian in
full and answered all his/her questions. To the best of my knowledge, he/she understands the
participate in the ODYSSEY TB PK study.
Signature of person
consent process

ODYSSEY Protocol
PARTICIPANT - ASSENT TO PHARMACOKINETIC (TB PK) STUDY



1. Have you read (or had read to you) the information about the blood levels study? YES NO
9. Do you understand that you will need to come to the clinic for a whole day to YES NO
check the level of medicine in your blood?
10. Do you understand that you will need to come back to the clinic for a second YES NO
full day to check the level of drugs in your blood and maybe sleep there?
Print name Date
(or thumbprint)

ODYSSEY Protocol
I have provided the ODYSSEY TB PK study information to the participant in full and answered all
risks and benefits of this study and willingly agrees to participate in the ODYSSEY TB PK study.
Signature of person
consent process

ODYSSEY Protocol
CONSENT AND ASSENT FORMS FOR QUALITATIVE SUBSTUDY

Consent/ assent forms for in-depth interviews - IDIs (10-18 year olds)
Assent form- IDIs- 10-17 years olds
Consent form- IDIs- 18 year olds
Consent form- IDIs- parents/ carers
Consent form- IDIs- caregivers
Consent/ assent forms for in-depth interviews (DTG) - IDIs (10-19 year olds)
Assent form- IDIs- 10-17 years olds (DTG)
Consent form- IDIs- 18-19 year olds (DTG)
Consent form- IDIs- parents/ carers (DTG)
Consent / assent forms for focus group discussions - FGDs (10-19 year olds)
Assent form- FGDs- 10-17 years olds
Consent form- FGDs- 18-19 year olds
Consent form- FGDs- parents/ carers

ODYSSEY Protocol

ASSENT FORM FOR IN-DEPTH INTERVIEWS 10-17 YEAR OLDS

Please tick yes or no to answer the questions below.
1. Have you read (or had read to you) the information about this study?
YES NO
6. Do you understand it’s OK to stop taking part at any time? YES NO

7. Do you understand that you don’t have to answer any questions that you do
YES NO
not want to?
8. Is it OK if we audio record our discussions? YES NO
9. Do you understand that we will speak with you on two separate occasions? YES NO

Print name Date
(or thumbprint)
I have provided the Qualitative study information to the potential participant in full and answered
all his/her questions. To the best of my knowledge, he/she understands the purpose, interventions,
risks and benefits of this study and willingly agrees to participate in the Qualitative study.
Signature of person
consent process

ODYSSEY Protocol

CONSENT FORM FOR IN-DEPTH INTERVIEWS YOUNG PEOPLE (18 YEARS OLD)

I _____________________________________________ agree to take part in this study.
I have read and understood the information sheet on the study, version X YES NO
I have been given the opportunity to ask questions and I am satisfied with YES NO
the answers that you have given me.
I agree to my contact details being given to the study team so that they can
contact me to arrange the interview and about other study arrangement YES NO
matters.
I understand that the researcher will interview me on two separate
occasions.
This will involve them talking to them for about an hour each time about my YES NO
experience of being on second-line HIV treatment.
I agree to this interview being audio-recorded. YES NO
I know that I do not have to talk about things that I do not want to talk about.
I can stop talking to the researchers at any time and without giving a reason YES NO
for this.
I understand that everything that I talk to the researchers about is
confidential. However if the researchers are told that myself or another child
is at serious risk of harm, they may have to pass this information on to YES NO
someone else.
I agree that anonymised direct quotes from the interview may be used in the
public reporting of this study. YES NO
My questions have been answered by ……………………………………………………………
Print name Date
(or thumbprint)

ODYSSEY Protocol
Signature of person
consent process

ODYSSEY Protocol

CONSENT FORM FOR IN-DEPTH INTERVIEWS PARENT/CARERS

I _____________________________________________ agree to my child taking part in this study.
I have been given the opportunity to ask questions and I am satisfied with the YES NO
answers that you have given me.
I agree to my contact details being given to the study team so that they can YES NO
contact me to arrange the interview and about other study arrangement
matters.
I understand that the researcher will interview my child on two separate YES NO
occasions. This will involve them talking with my child for about an hour about
my child’s experience of being on second-line treatment.
I know that my child does not have to talk about things that he/she does not YES NO
want to talk about. My child can stop talking to the researchers at any time and
without giving a reason for this.
I understand that everything that my child talks to the researchers about is YES NO
confidential. However if the researchers are told that a child is at serious risk of
harm, they may have to pass this information on to someone else.
I agree that anonymised direct quotes from the interview may be used in the YES NO
public reporting of this study.
Print name Date
(or thumbprint)
I have provided the Qualitative study information to the potential participant’s parent/legal
understands the purpose, interventions, risks and benefits of this study and willingly agrees to
participate in the Qualitative study.
Signature of person
consent process

ODYSSEY Protocol

ODYSSEY Protocol

CONSENT FORM FOR IN-DEPTH INTERVIEWS WITH CAREGIVERS

I _____________________________________________ agree to taking part in this study.
matters.
I understand that the researcher will conduct an interview with me. This will YES NO
involve us talking for about an hour about what it is like caring for my child and
my child’s experience of growing up with HIV.
I know that I do not have to talk about things that I not want to talk about. I can YES NO
stop talking to the researchers at any time and without giving a reason for this.
I understand that everything that I talk to the researchers about is confidential. YES NO
However if I tell the researchers that a child is at serious risk of harm, they may
have to pass this information on to someone else.
Caregiver’s signature
Print name Date
(or thumbprint)
Signature of person
consent process

ODYSSEY Protocol

ODYSSEY Protocol

ASSENT FORM FOR IN-DEPTH INTERVIEWS 10-17 YEAR OLDS (DTG)

1. Have you read (or had read to you) the information about this study?
YES NO

7. Do you understand that you don’t have to answer any questions that you do
YES NO
not want to?

Print name Date
(or thumbprint)
Signature of person
consent process

ODYSSEY Protocol

CONSENT FORM FOR IN-DEPTH INTERVIEWS YOUNG PEOPLE (18-19 YEARS OLD) (DTG)

I _____________________________________________ agree to take part in this study.
I agree to my contact details being given to the study team so that they can
contact me to arrange the interview and about other study arrangement YES NO
matters.
I understand that the researcher will interview me that will last for about an
hour about my experience of growing up with HIV and being on HIV YES NO
treatment.
I know that I do not have to talk about things that I do not want to talk about.
I can stop talking to the researchers at any time and without giving a reason YES NO
for this.
I understand that everything that I talk to the researchers about is
confidential. However if the researchers are told that myself or another child
is at serious risk of harm, they may have to pass this information on to YES NO
someone else.
I agree that anonymised direct quotes from the interview may be used in the
public reporting of this study. YES NO
Print name Date
(or thumbprint)

ODYSSEY Protocol
Signature of person
consent process

ODYSSEY Protocol

CONSENT FORM FOR IN-DEPTH INTERVIEWS PARENT/CARERS (DTG)

matters.
I understand that the researcher will interview my child for about an hour about YES NO
my child’s experience of growing up with HIV and being on HIV treatment.
want to talk about. My child can stop talking to the researchers at any time and
without giving a reason for this.
confidential. However if the researchers are told that a child is at serious risk of
Print name Date
(or thumbprint)
Signature of person
consent process

ODYSSEY Protocol

ODYSSEY Protocol

ASSENT FORM FOR FOCUS GROUP DISCUSSIONS (10-17 YEAR OLDS)

7. Do you understand that you don’t have to answer any questions that you do YES NO
not want to?
8. Do you understand that there will be two focus groups that we would like YES NO
you to take part in?
9. Do you understand that you should not tell anyone what you hear about YES NO
other people in the focus groups, but that you can talk about it with the
researchers and clinic counsellors?
Print name Date
(or thumbprint)

ODYSSEY Protocol
Signature of person
consent process
Thank you for your help!

ODYSSEY Protocol

CONSENT FORM FOR FOCUS GROUP DISCUSSIONS (YOUNG PEOPLE OVER 18-19 YEARS)

I _____________________________________________ agree to taking part in this study.

I have read and understood the information sheet on the ODYSSEY YES NO
qualitative study, version……..
I agree to my contact details being given to the qualitative study team and YES NO
understand that they will contact me.
I understand that I am being asked to participate in two focus groups. For YES NO
each focus group this will involve the researcher talking with me and up to
seven other young people for about an hour about their experiences of being
on second-line HIV treatment.
I agree to the focus groups being audio-recorded. YES NO
I know that I do not have to talk about things that I do not want to talk about. YES NO
I understand that I can stop talking to the researchers at any time and
without
giving a reason for this.
I understand that everything that I to the group about is confidential. I YES NO
understand that I and the other participants will agree to not talk about what
anyone else says in the focus groups, except for with the researchers and
counsellors.
I agree that anonymised direct quotes from the focus groups may be used. YES NO
Print name Date
(or thumbprint)

ODYSSEY Protocol
Signature of person
consent process

ODYSSEY Protocol

CONSENT FORM FOR FOCUS GROUP DISCUSSIONS (PARENT/CARERS)

I have read and understood the information sheet on the ODYSSEY YES NO
qualitative study, version……..
I agree to my contact details being given to the qualitative study team and YES NO
understand that they will contact me should my child be selected to take part
in the study.
I understand that my child will participate in two focus groups. For each focus YES NO
group this will involve them talking with my child and up to seven other
young people for about an hour about their experiences of being on second-
line HIV treatment.
I agree to the focus groups being audio-recorded. YES NO
want to talk about. My child can stop talking to the researchers at any time
and without giving a reason for this.
confidential and that my child and other participants will agree to not talking
about what anyone else says in the focus group, except for with the
researchers and counsellors.
I understand that if the researchers are told that a child is at serious risk of YES NO
I agree that anonymised direct quotes from the focus group may be used. YES NO
Print name Date
(or thumbprint)

ODYSSEY Protocol
Signature of person
consent process

ODYSSEY Protocol
CONSENT FORMS AND ASSENT FORMS FOR YOUTH TRIAL BOARD PROJECT
Consent/ assent forms for in-depth interviews - IDIs (10-18 year olds)
Assent form - 10-17 years olds
Consent form - 18 year olds
Consent form - parents/ carers
Consent form – YTB facilitators

ODYSSEY Protocol
YOUTH TRIAL BOARD PROJECT

ASSENT FORM FOR YOUTH TRIAL BOARD PROJECT FOR YOUNG PEOPLE

I _____________________________________________ agree to taking part in this project.
I have read and understood the information sheet on the Youth Trial Board
YES NO
project, version……..
I have been given the chance to ask questions and I am happy with the answers
YES NO
that you have given me.
I understand that being a Youth Trial Board member means that what we say
and discuss in our meetings over the course of the project may be observed and YES NO
notes taken.
I understand that I am being asked to take part in an individual interview about
YES NO
my experiences participating in the Youth Trials Board project.
I understand that everything that is said in the meetings is confidential and that
YES NO
the notes will be anonymised.
I understand that at any time I can withdraw my consent for the observations
YES NO
about what I say in the meetings and the interview to be used.
I agree that anonymised direct quotes from the meetings and interview can be
used. YES NO
Print name Date
(or thumbprint)
The person who explained the project to you needs to sign too:
I have provided the Youth Trial Board project information to the potential participant in full and
interventions, risks and benefits of this study and willingly agrees to participate in the Youth Trial
Board project.
Signature of person
consent process

ODYSSEY Protocol

ODYSSEY Protocol

CONSENT FORM FOR YOUTH TRIAL BOARD PROJECT FOR YOUNG ADULT PARTICIPANTS

YES NO
I have been given the chance to ask questions and I am happy with the
YES NO
I understand that being a Youth Trial Board member means that what we
say and discuss in our meetings over the course of the project may be YES NO
observed and notes taken.
I understand that I am taking part in an individual interview about my experiences
YES NO
participating in the Youth Trials Board project.
I understand that everything that is said in the meetings and interview is

YES NO
confidential and that the notes will be anonymised.
I understand that at any time I can withdraw my consent for the

YES NO
observations about what I say in the meetings and the interview to be used.
I agree that anonymised direct quotes from the meetings and interview can
YES NO
be used.
Print name Date
(or thumbprint)
interventions, risks and benefits of this study and willingly agrees to participate in the Youth Trial
Board project.

ODYSSEY Protocol
Signature of person
consent process

ODYSSEY Protocol

CONSENT FORM FOR YOUTH TRIAL BOARD PROJECT FOR PARENTS/ GUARDIANS

YES NO
I have been given the chance to ask questions and I am happy with the
YES NO
I understand that my child being a Youth Trial Board member means that
what they say and discuss in the meetings over the course of the project YES NO
may be observed and notes taken.
I understand that my child will take part in an individual interview about their
YES NO
experiences participating in the Youth Trials Board project.
I understand that everything that is said in the meetings and interview is

YES NO
confidential and that the notes will be anonymised.
I agree that anonymised direct quotes from the meetings and interview can
YES NO
be used.
Print name Date
(or thumbprint)
I have provided the Youth Trial Board project information to the potential participant’s parent/legal
participate in the Youth Trial Board project.
Signature of person
consent process

ODYSSEY Protocol

ODYSSEY Protocol

CONSENT FORM FOR YOUTH TRIAL BOARD PROJECT FOR FACILITATORS

I have read and understood the information sheet on the Youth Trial Board project,
YES NO
version……..
I have been given the chance to ask questions and I am happy with the answers
YES NO
that you have given me.
I understand that I am taking part in an individual interview about my experiences

YES NO
participating in the Youth Trials Board project.
I understand that everything that is said in the interview is confidential and that the
YES NO
notes will be anonymised.
I understand that at any time I can withdraw my consent for what I say in the
YES NO
interview to be used.
I agree that anonymised direct quotes from interview can be used. YES NO
Print name Date
(or thumbprint)
interventions, risks and benefits of this study and willingly agrees to participate in an interview
about the the Youth Trial Board project.
Signature of person
consent process

ODYSSEY Protocol

ODYSSEY Protocol
21 APPENDIX III TEMPLATE GP LETTER
(To be printed on local headed paper).

Dear Dr ________________________________
The parents of________________________and him/herself, have agreed to participate in the

ODYSSEY study. This is a randomised multicentre international trial co-ordinated by PENTA, which is
funded by the European Commission (see www.PENTA-ID.org).
ODYSSEY aims to compare the efficacy and toxicity of antiretroviral regimens containing two NRTIs
and the new integrase inhibitor dolutegravir versus standard combination regimens containing
two/three NRTIs and either an NNRTI, a protease inhibitor or a first generation integrase inhibitor,
raltegravir. Adherence to and acceptability of the different regimens will also be compared.
The trial will enrol 700 children under 18 years of age from clinical centres in Europe, Africa, Asia,
North and South America and will include 2 groups of children: those initiating antiretroviral therapy
and those switching to a second-line regimen. All children will be followed until the last patient
recruited has completed 96 weeks of follow-up.
Your patient has been randomised to:

dolutegravir containing regimen
standard combination therapy.
I would be very grateful if you could inform me of any concomitant medication that you prescribe to
this child during the study.
I enclose a summary of the trial and a copy of the Patient Information Sheet. If you would like a copy
of the full protocol or have any comments or problem, please contact:
Dr _____________________
Enc.
Trial Summary
Patient Information Sheet

ODYSSEY Protocol
22 APPENDIX IV TEMPLATE ADHERENCE QUESTIONNAIRES

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23 APPENDIX V TEMPLATE ACCEPTABILITY QUESTIONNAIRES

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24 APPENDIX VI ADAPTED WHO CLINICAL STAGING OF HIV/AIDS FOR PATIENTS WITH

CONFIRMED HIV INFECTION
The table below summarising WHO clinical staging for children and adolescents (1); Diagnostic
criteria for these conditions, are described in Appendix VII
Children (<15 years of age) Adolescents (≥15 years of age)
Clinical Stage 1 Clinical Stage 1
Asymptomatic Asymptomatic
Persistent generalized lymphadenopathy Persistent generalized lymphadenopathy
Clinical stage 2 Clinical stage 2
Unexplained persistent Moderate unexplained weight loss

hepatosplenomegaly (<10% of presumed or measured body
Papular pruritic eruptions weight)
Fungal nail infection Recurrent respiratory tract infections
Angular cheilitis (sinusitis, tonsillitis, otitis media and
Lineal gingival erythema pharyngitis)
Extensive wart virus infection Herpes zoster
Extensive molluscum contagiosum Angular cheilitis
Recurrent oral ulcerations Recurrent oral ulceration
Unexplained persistent parotid Papular pruritic eruptions
enlargement Seborrhoeic dermatitis
Herpes zoster Fungal nail infections
Recurrent or chronic upper respiratory
tract infections (otitis media, otorrhoea,
sinusitis or tonsillitis)
Clinical Stage 3 ( *= severe WHO clinical stage 3 for the ODYSSEY trial)
Unexplained moderate malnutrition or Unexplained severe weight loss (>10% of

wasting not adequately responding to presumed or measured body weight)*
standard therapy* Unexplained chronic diarrhoea for
Unexplained persistent diarrhoea (14 longer than one month
days or more) Unexplained persistent fever (above
Unexplained persistent fever (above 37.6°C intermittent or constant,
37.5°C intermittent or constant, for longer than one month)
for longer than one month) Persistent oral candidiasis*
Persistent oral candidiasis (after first 6–8 Oral hairy leukoplakia
weeks of life)* Pulmonary tuberculosis (current)
Oral hairy leukoplakia Severe bacterial infections (such as
Acute necrotizing ulcerative gingivitis or pneumonia, empyema, pyomyositis,
periodontitis bone or joint infection, meningitis or
Lymph node tuberculosis bacteraemia)

ODYSSEY Protocol
Pulmonary tuberculosis Acute necrotizing ulcerative stomatitis,

Severe recurrent bacterial pneumonia gingivitis or periodontitis
Symptomatic lymphoid interstitial Unexplained anaemia (<8 g/dl),
pneumonitis* neutropaenia (<0.5 × 109 per litre) or
Chronic HIV-associated lung disease chronic thrombocytopaenia (<50 × 109
including bronchiectasis* per litre)
Unexplained anaemia (<8 g/dl),
neutropaenia (<0.5 × 109 per litre)and or
chronic thrombocytopaenia (<50 × 109
per litre)
Clinical Stage 4
Unexplained severe wasting, stunting or HIV wasting syndrome

severe malnutrition not responding to Pneumocystis pneumonia
standard therapy Recurrent severe bacterial pneumonia
Pneumocystis pneumonia Chronic herpes simplex infection
Recurrent severe bacterial infections (orolabial, genital or anorectal
(such as empyema, pyomyositis, bone or of more than one month’s duration or
joint infection or meningitis but visceral at any site)
excluding pneumonia) Oesophageal candidiasis (or candidiasis
Chronic herpes simplex infection of trachea, bronchi or lungs)
(orolabial or cutaneous of more than Extrapulmonary tuberculosis
one month’s duration or visceral at any Kaposi’s sarcoma
site) Cytomegalovirus infection (retinitis or
Oesophageal candidiasis (or candidiasis infection of other organs)
of trachea, bronchi or lungs) Central nervous system toxoplasmosis
Extrapulmonary tuberculosis HIV encephalopathy
Kaposi’s sarcoma Extrapulmonary cryptococcosis including
Cytomegalovirus infection: retinitis or meningitis
cytomegalovirus infection affecting Disseminated non-tuberculous
another organ, with onset at age older mycobacterial infection
than one month Progressive multifocal
Central nervous system toxoplasmosis leukoencephalopathy
(after one month of life) Chronic cryptosporidiosis (with
Extrapulmonary cryptococcosis diarrhoea)
(including meningitis) Chronic isosporiasis
HIV encephalopathy Disseminated mycosis (coccidiomycosis
Disseminated endemic mycosis or histoplasmosis)
(coccidiomycosis or histoplasmosis) Recurrent non-typhoidal Salmonella
Disseminated non-tuberculous bacteraemia
mycobacterial infection Lymphoma (cerebral or B-cell non-
Chronic cryptosporidiosis (with Hodgkin) or other solid HIV-associated
diarrhoea) tumours
Chronic isosporiasis Invasive cervical carcinoma
Cerebral or B-cell non-Hodgkin Atypical disseminated leishmaniasis
lymphoma Symptomatic HIV-associated
Progressive multifocal nephropathy or symptomatic HIV-
leukoencephalopathy associated cardiomyopathy
Symptomatic HIV-associated
nephropathy or HIV-associated
cardiomyopathy

ODYSSEY Protocol
References:
1. World Health Organization. WHO case definitions of HIV for surveillance, and revised clinical
staging and immunological classification of HIV related disease in adults and children. Geneva:
World Health Organization; 2007.

ODYSSEY Protocol
25 APPENDIX VII ADAPTED DIAGNOSTIC CRITERIA FOR WHO CLINICAL STAGING EVENTS IN
CHILDREN YOUNGER THAN 15 YEARS
The table is reproduced from WHO case definitions of HIV for surveillance and revised clinical staging
and immunological classification of HIV-related disease in adults and children (1). Definitions for
moderate (grade 3) and severe (grade 4) malnutrition are modified using definitions from WHO (1)
and CDC (2,3).
CLINICAL EVENT CLINICAL DIAGNOSIS DEFINITIVE DIAGNOSIS
Clinical Stage 1
Asymptomatic No HIV related symptoms reported and no clinical Not applicable.
signs on examination.
Persistent Persistent swollen or enlarged lymph nodes >1 cm Clinical diagnosis
generalized at two or more non-contiguous sites (excluding
lymphadenopathy inguinal) without known cause.
Clinical Stage 2
Unexplained Enlarged liver and spleen without obvious cause. Clinical diagnosis
persistent
hepatosplenomeg
aly
Papular pruritic Papular pruritic vesicular lesions. Also common in Clinical diagnosis
eruptions uninfected children: scabies and insect bites should
be excluded.
Extensive wart Characteristic warty skin lesions; small fleshy grainy Clinical diagnosis
virus infection bumps, often rough, flat on sole of feet (plantar
warts); facial, more than 5% of body area or
disfiguring.
Extensive Characteristic skin lesions: small flesh-coloured, Clinical diagnosis
molluscum pearly or pink, dome-shaped or umbilicated growths
contagiosum may be inflamed or red; facial, more than 5% of
infection body area or disfiguring. Giant molloscum may
indicate more advanced immunodeficiency
Fungal nail Fungal paronychia (painful, red and swollen nail Clinical diagnosis
infections bed) or onycholysis (painless separation of the nail
from the nail bed.) Proximal white subungual
onchomycosis is uncommon without
immunodeficiency
Recurrent oral Current event plus at least one previous episode in Clinical diagnosis
ulcerations past six months. Aphthous ulceration, typically with
a halo of inflammation & yellow-grey
pseudomembrane.
Unexplained Asymptomatic bilateral swelling that may Clinical diagnosis
persistent parotid spontaneously resolve and recur, in absence of
enlargement other known cause, usually painless
Lineal gingival Erythematous band that follows the contour of the Clinical diagnosis
erythema free gingival line; may be associated with
spontaneous bleeding
Herpes zoster Painful rash with fluid-filled blisters, dermatomal Clinical diagnosis
distribution, can be haemorrhagic on erythematous
background, and can become large and confluent.
Does not cross the midline

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Recurrent upper Current event with at least one episode in past 6 Clinical diagnosis
respiratory tract months. Symptom complex; fever with unilateral
infection face pain and nasal discharge (sinusitis) or painful
swollen eardrum (otitis media), sore throat with
productive cough (bronchitis), sore throat
(pharyngitis) and barking croup-like cough (LTB).
Persistent or recurrent ear discharge.
Clinical Stage 3
Unexplained Weight loss: low weight-for-age or weight-for-height Documented loss of body
moderate up to −2 standard deviations from the mean OR clear weight of -2 standard
malnutrition* deviation from a previous growth trajectory or deviations from the mean
documented crossing of percentile lines, not explained OR or documented
by poor or inadequate feeding and or other crossing of percentile
infections, and not adequately responding to lines,
standard management. failure to gain weight on
standard management and
no other cause identified
during investigation.
Unexplained Unexplained persistent (14 days or more) diarrhoea Confirmed by stools
persistent (loose or watery stool, three or more times daily), observed and documented
diarrhoea not responding to standard treatment. as unformed. Culture and
microscopy reveal no
pathogens.
Unexplained Reports of fever or night sweat for longer than one Confirmed by documented
persistent fever month, either intermittent or constant, with fever of >37.50 ◦C with
(>37.5oC reported lack of response to antibiotics or negative blood culture,
intermittent or antimalarial agents. No other obvious foci of disease negative malaria slide and
constant for reported or found on examination. Malaria must be normal or unchanged
longer than one excluded in malaria areas. chest X-ray, and no other
month) obvious foci of disease.
Oral candidiasis Persistent or recurring creamy white to yellow soft Confirmed by microscopy
(after first 6-8 small plaques which can be scraped off or culture.
weeks of life) (pseudomembranous), or red patches on tongue,
palate or lining of mouth, usually painful or tender
(erythematous form).
Oral hairy Fine small linear patches on lateral borders of Clinical diagnosis
leukoplakia tongue, generally bilaterally, which do not scrape
off.
Lymph node Non acute, painless "cold" enlargement of Confirmed by histology or
tuberculosis peripheral lymph nodes, localized to one region. fine needle aspirate for
May have draining sinuses. Response to standard Ziehl-Nielsen stain or
anti- tuberculosis treatment in one month. culture.
Pulmonary Nonspecific symptoms, e.g. chronic cough, fever, Confirmed by one or more
tuberculosis night sweats, anorexia and weight loss. In the older sputum positive smear for
child also productive cough and haemoptysis. acid-fast bacilli and/or
History of contact with adults with smear-positive radiographic abnormalities
pulmonary tuberculosis. No response to standard consistent with active
broad-spectrum antibiotic treatment. tuberculosis and/or
culture-positive for
Mycobacterium.

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Severe recurrent Cough with fast breathing, chest indrawing, nasal Confirmed by isolation of
bacterial flaring, wheezing, and grunting. Crackles or bacteria from appropriate
pneumonia consolidation on auscultation. Responds to course clinical specimens
of antibiotics. Current episode plus one or more in (induced sputum, BAL,
previous 6 months. lung aspirate).
Acute necrotizing Severe pain, ulcerated gingival papillae, loosening of Clinical diagnosis
ulcerative teeth, spontaneous bleeding, bad odour, and rapid
gingivitis or loss of bone and/or soft tissue.
stomatitis, or
acute necrotizing
ulcerative
periodontitis
Symptomatic No presumptive clinical diagnosis. Diagnosed by chest X-ray:
lymphocytic bilateral reticulonodular
interstitial interstitial pulmonary
pneumonitis infiltrates present for
more than two months
with no response to
antibiotic treatment and
no other pathogen found.
Oxygen saturation
persistently <90%. May
present with cor
pulmonale and increased
exercise-induced fatigue.
Characteristic histology.
Chronic HIV- History of cough productive of copious amounts of Confirmed by chest X-ray:
associated lung purulent sputum (bronchiectasis only), with or may show honeycomb
disease (including without clubbing, halitosis, and crepitations and/or appearance (small cysts)
bronchiectasis) wheezes on auscultation and/or persistent areas of
opacification and/or
widespread lung
destruction, with fibrosis
and loss of volume.
Unexplained No presumptive clinical diagnosis. Diagnosed on laboratory
anaemia (<8g/dl), testing, not explained by
or neutropaenia other non-HIV conditions,
(<0.5 x 109 per not responding to
litre) and/or standard therapy with
chronic haematinics, antimalarial
thrombocytopaeni agents or anthelmintic
a (<50 x 109 per agents as outlined in WHO
litre) Integrated Management of
Childhood Illness (IMCI)
guidelines.
Clinical Stage 4
Unexplained Persistent weight loss, stunting, wasting or Documented weight for
severe wasting, malnutrition not explained by poor or inadequate height or weight for age of
stunting or severe feeding, other infections and not adequately more than –3 standard
malnutrition not responding in two weeks to standard therapy. deviations from the mean
adequately Visible severe wasting of muscles, with or without

ODYSSEY Protocol

responding to oedema of both feet, and/or weight-for-height of –3 or documented downward
standard therapy* standard deviations from the mean or downward crossing of at least two
crossing of at least two weight percentile lines. complete weight
percentile lines with or
without oedema
Pneumocystis Dry cough, progressive difficulty in breathing, Confirmed by: cytology or
pneumonia cyanosis, tachypnoea and fever; chest indrawing or immunofluorescent
stridor. (Severe or very severe pneumonia as in microscopy of induced
WHO IMCI guidelines). Usually rapid onset especially sputum or BAL or histology
in infants under six months of age. Response to of lung tissue.
high-dose co-trimoxazole with or without
prednisolone. Chest X-ray shows typical bilateral
perihilar diffuse infiltrates
Recurrent severe Fever accompanied by specific symptoms or signs Confirmed by culture of
bacterial that localize infection. Responds to antibiotics. appropriate clinical
infection, e.g. Current episode plus one or more in previous 6 specimen.
empyema, months
pyomyositis, bone
or joint infection
or meningitis but
excluding
pneumonia
Chronic herpes Severe and progressive painful orolabial, genital, or Confirmed by culture
simplex infection; anorectal lesions caused by HSV infection present and/or histology
(orolabial or for more than one month.
cutaneous of
more than
one month's
duration or
visceral at any
site)
Oesophageal Difficulty in swallowing or pain on swallowing (food Confirmed by macroscopic
candidiasis and fluids). In young children, suspect particularly if appearance at endoscopy,
(or candidiasis of oral Candida observed and food refusal occurs microscopy of specimen
trachea, bronchi and/or difficulties or crying when feeding. from tissue or macroscopic
or lungs). appearance at
bronchoscopy or histology.
Extrapulmonary or Systemic illness usually with prolonged fever, night Confirmed by positive
disseminated sweats, and weight loss. Clinical features of organs microscopy showing acid-
tuberculosis involved, e.g. sterile pyuria, pericarditis, ascites, fast bacilli or culture of
pleural effusion, meningitis, arthritis or orchiti, Mycobacterium TB from
pericardial or abdominal blood or other relevant
specimen except sputum
or BAL. Biopsy and
histology.
Kaposi sarcoma Typical appearance in skin or oropharynx of Not required but may be
persistent, initially flat, patches with a pink or blood- confirmed by:
bruise colour, skin lesions that usually develop into - typical red-purple lesions
nodules. seen on bronchoscopy or
endoscopy;

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- dense masses in lymph
nodes, viscera or lungs by
palpation or radiology; and
- histology.
CMV retinitis or Retinitis only. Definitive diagnosis
CMV infection CMV retinitis may be diagnosed by experienced required for other sites.
affecting another clinicians: typical eye lesions on serial fundoscopic Histology. Cerebrospinal
organ, with onset examination; discrete patches of retinal whitening fluid polymerase chain
at age over 1 with distinct borders, spreading centrifugally, often reaction
month. following blood vessels, associated with retinal
vasculitis, haemorrhage and necrosis.
CNS Fever, headache, focal neurological signs, Not required but
toxoplasmosis convulsions. Usually responds within 10 days to confirmed by computed
with onset at age specific therapy. tomography (CT) scan (or
over 1 month. other neuroimaging)
showing single or multiple
lesions with mass effect or
enhancing with contrast.
Extrapulmonary Meningitis: usually subacute, fever with increasing Confirmed by CSF
cryptococcosis severe headache, meningism, confusion and microscopy (India ink or
(including behavioural changes that respond to cryptococcal Gram stain), serum or CSF
meningitis) therapy. CRAG test or culture.
HIV At least one of the following, progressing over at Confirmed by
encephalopathy least two months in the absence of another illness: neuroimaging (brain CT
- failure to attain, or loss of, developmental scan or MRI)
milestones, loss of intellectual ability; OR demonstrating atrophy
- progressive impaired brain growth demonstrated and basal ganglia
by stagnation of head circumference; OR calcification and excluding
- acquired symmetric motor deficit accompanied by other causes.
two or more of the following: paresis, pathological
reflexes, ataxia, gait disturbances.
Disseminated No presumptive clinical diagnosis. Diagnosed by:
mycosis Histology: usually
(coccidiomycosis, granuloma formation.
histoplasmosis, Isolation: antigen
penicilliosis) detection from affected
tissue; culture or
microscopy from clinical
specimen or blood culture.
Disseminated No presumptive clinical diagnosis. Nonspecific clinical
mycobacteriosis, symptoms including
other than TB progressive weight loss,
fever, anaemia, night
sweats, fatigue or
diarrhoea; plus culture of
atypical mycobacterial
species from stool, blood,
body fluid or other body
tissue, excluding lung.

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Chronic No presumptive clinical diagnosis. Confirmed by cysts
cryptosporidiosis identified on modified
Ziehl-Nielsen microscopic
examination of unformed
stool
Chronic Isospora No presumptive clinical diagnosis. Confirmed in children with
chronic diarrhoea by
microscopic examination.
Cerebral or B-cell No presumptive clinical diagnosis. Diagnosed by CNS

non-Hodgkin neuroimaging: at least one
lymphoma lesion with mass effect on
brain scan; histology of
relevant specimen
Progressive multi No presumptive clinical diagnosis. Diagnosed by progressive
focal nervous system disorder
leukoencephalopa (cognitive dysfunction, gait
thy or speech disorder, visual
loss, limb weakness and
cranial nerve palsies)
together with hypodense
white matter lesions on
neuroimaging or positive
polyomavirus Jacob
Creutzfeldt PCR on
cerebrospinal fluid
Symptomatic HIV- No presumptive clinical diagnosis. Renal biopsy
associated
nephropathy
Symptomatic HIV- No presumptive clinical diagnosis. Cardiomegaly and
associated evidence of poor left
cardiomyopathy ventricular function
confirmed by
echocardiography
* Modified definitions for moderate (grade 3) and severe (grade 4) malnutrition from WHO and CDC clinical stage classifications (1,2,3)
References:
2. Centers for Disease Control and Prevention. 1994 revised classification system for human
immunodeficiency virus infection in children less than 13 years of age. MMWR. 1994;43(RR-
12):1-10.
3. 1993 revised classification system for HIV infection and expanded surveillance case definition for
AIDS among adolescents and adults. MMWR Recommendations and reports : Morbidity and
mortality weekly report Recommendations and reports / Centers for Disease Control.
1992;41(RR-17):1-19.

ODYSSEY Protocol
26 APPENDIX VIII CRITERIA FOR WHO CLINICAL STAGING EVENTS FOR YOUNG PEOPLE 15 YEARS
AND OLDER
Criteria for WHO clinical staging events (1).

Clinical stage 1
Asymptomatic. No HIV-related symptoms reported Not applicable.
and no signs on examination.
Persistent generalized Painless enlarged lymph nodes >1 Histology.
lymphadenopathy. cm in two or more non-contiguous
sites
(excluding inguinal) in the absence
of known cause and persisting for
three months or more.
Clinical stage 2
Unexplained moderate Reported unexplained Documented weight loss
weight loss (<10% of involuntary weight loss in <10% of body weight.
body pregnancy failure to gain
weight). weight.
Recurrent upper Symptom complex, such as Laboratory studies where
respiratory unilateral face pain with nasal available, such as culture of
tract infections (current discharge (sinusitis), suitable body fluid.
event plus one or more painful inflamed eardrum (otitis
in media) or
last six-month period). tonsillopharyngitis without features
of viral infection (such as coryza or
cough).
Herpes zoster. Painful vesicular rash in dermatomal Clinical diagnosis.
distribution of a nerve supply, does
not
cross the midline.
Angular cheilitis. Splits or cracks at the angle of the Clinical diagnosis.
mouth not due to iron or vitamin
deficiency, usually respond to
antifungal treatment.
Recurrent oral Aphthous ulceration, typically Clinical diagnosis.
ulceration painful with a halo of inflammation
(two or more episodes and a yellow grey
in pseudomembrane.
last six months).
Papular pruritic Papular pruritic lesions, often with Clinical diagnosis.
eruption. marked postinflammatory
pigmentation.
Seborrhoeic dermatitis. Itchy scaly skin condition, Clinical diagnosis.
particularly affecting hairy areas
(scalp, axillae, upper
trunk and groin).
Fungal nail infection. Paronychia (painful red and swollen Fungal culture of the nail or nail
nail bed) or onycholysis (separation plate material.
of

ODYSSEY Protocol

the nail from the nail bed) of the
fingernails (white discoloration –
especially involving proximal part of
nail plate – with thickening and
separation of the nail from the nail
bed).
Clinical stage 3
Unexplained severe Reported unexplained involuntary Documented loss of more than
weight loss (more than weight loss (>10% of body weight) 10% of body weight.
10% of body weight). and visible thinning of face, waist
and extremities with obvious
wasting or body mass index <18.5
kg/m2; in pregnancy, the weight
loss may be masked.
Unexplained chronic Chronic diarrhoea (loose or watery Three or more stools observed
diarrhoea for longer stools three or more times daily) and documented as unformed,
than one month. reported for longer than one month. and two or more stool tests
reveal no pathogens.
Unexplained persistent Fever or night sweats for more than Documented fever >37.5°C with
fever one month, either intermittent or negative blood culture,
(intermittent or constant with reported lack of negative Ziehl-Nielsen stain,
constant and lasting for response to antibiotics or negative malaria slide, normal
longer than one month). antimalarial agents, without other or unchanged chest X-ray and
obvious foci of disease reported or no other obvious focus of
found on examination; malaria must infection.
be excluded in malarious areas.
Persistant oral Persistent or recurring creamy white Clinical diagnosis.
candidiasis. curd-like plaques that can be
scraped off (pseudomembranous) or
red patches on tongue, palate or
lining of mouth, usually painful or
tender (erythematous form).
Oral hairy leukoplakia. Fine white small linear or Clinical diagnosis.
corrugated lesions on lateral
borders of the tongue that do not
scrape off.
Pulmonary tuberculosis Chronic symptoms: (lasting at least Isolation of M. tuberculosis on
(current). 2–3 weeks) cough, haemoptysis, sputum culture or histology of
shortness of breath, chest pain, lung biopsy (with compatible
weight loss, fever, night sweats; symptoms).
PLUS EITHER
positive sputum smear;
OR
negative sputum smear;
AND
compatible chest radiograph
(including but not restricted to
upper lobe infiltrates, caritation,
pulmonary fibrosist shrinkage. No
evidence of extrapulmonary
disease.

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Acute necrotizing Severe pain, ulcerated gingival Clinical diagnosis.
ulcerative gingivitis or papillae, loosening of teeth,
necrotizing ulcerative spontaneous bleeding, bad odour
periodontitis. and rapid loss of bone and/or soft
tissue.
Severe bacterial Fever accompanied by specific Isolation of bacteria from
infection symptoms or signs that localize appropriate clinical specimens
(such as pneumonia, infection and response to (usually sterile sites).
meningitis, empyema, appropriate antibiotic.
pyomyositis, bone or
joint infection,
bacteraemia and severe
pelvic inflammatory
disease).
Unexplained anaemia Not presumptive clinical diagnosis. Diagnosed on laboratory testing
(<8 g/dl), neutropaenia and not explained by other non-
(<0.5 × 109 per litre) or HIV conditions;
chronic (more than one not responding to standard
month) therapy with haematinics,
thrombocytopaenia antimalarial agents or
(<50 × 109 per litre). anthelmintic agents as outlined
in relevant national treatment
guidelines, WHO Integrated
Management of Childhood
Illness guidelines or other
relevant guidelines.
Clinical stage 4
HIV wasting syndrome Unexplained involuntary weight loss Documented weight loss (>10%
(>10% baseline body weight), with of body weight);
obvious wasting or body mass index PLUS EITHER
<18.5; two or more unformed stools
PLUS EITHER negative for pathogens;
unexplained chronic diarrhoea OR
(loose or watery stools three or documented temperature of
more times daily) reported for >37.5°C with no other cause of
longer than one month; disease, negative blood culture,
OR negative malaria slide and
reports of fever or night sweats for normal or unchanged chest X-
more than one month without other ray.
cause and lack of response to
antibiotics or antimalarial agents;
malaria must be excluded in
malarious areas.
Pneumocystis Dyspnoea on exertion or Cytology or immunofluorescent
pneumonia nonproductive cough of recent microscopy of induced sputum
onset (within the past three or bronchoalveolar lavage or
months), tachypnoea and fever; histology of lung tissue.
AND
Chest X-ray evidence of diffuse
bilateral interstitial infiltrates;
AND

ODYSSEY Protocol

No evidence of bacterial
pneumonia; bilateral crepitations on
auscultation with or without
reduced air entry.
Recurrent bacterial Current episode plus one or more Positive culture or antigen test
pneumonia previous episodes in the past six of a compatible organism.
(this episode plus one or months; acute onset (<2 weeks) of
more episodes in last six severe symptoms (such as fever,
months) cough, dyspnoea, and chest pain)
PLUS new consolidation on clinical
examination or chest X-ray;
response to antibiotics.
Chronic herpes simplex Painful, progressive anogenital or Positive culture or DNA (by
virus infection orolabial ulceration; lesions caused polymerase chain reaction) of
by recurrence of herpes simplex herpes simplex virus or
(orolabial, genital or virus infection and reported for compatible cytology or
anorectal) of more than more than one month. History of histology.
one month or visceral previous episodes. Visceral herpes
infection of any simplex virus requires definitive
duration. diagnosis.
Oesophageal candidiasis Recent onset of retrosternal pain or Macroscopic appearance at
difficulty on swallowing (food and endoscopy or bronchoscopy, or
fluids) together with oral candidasis. by microscopy or histology.
Extrapulmonary Systemic illness (such as fever, night M. tuberculosis isolation or
tuberculosis sweats, weakness and weight loss). compatible histology from
Other evidence for extrapulmonary appropriate site or radiological
or disseminated tuberculosis varies evidence of miliary
by site: Pleural, pericardia, tuberculosis; (diffuse uniformly
peritoneal involvement, meningitis, distributed small miliary
mediastinal or abdominal shadows or micronodules on
lymphadenopathy or ostetis. chest X-ray).
Discrete peripheral lymph node
Mycobacterium tuberculosis
infection (especially cervical) is
considered a less severe form of
extrapulmonary tuberculosis.
Kaposi sarcoma Typical gross appearance in skin or Macroscopic appearance at
oropharynx of persistent, initially endoscopy or bronchoscopy, or
flat, patches with a pink or by histology.
violaceous colour, skin lesions that
usually develop into plaques or
nodules.
Cytomegalovirus Retinitis only: may be diagnosed by Compatible histology or
disease experienced clinicians. Typical eye cytomegalovirus demonstrated
(other than liver, spleen lesions on fundoscopic examination: in cerebrospinal fluid by culture
or lymph node) discrete patches of retinal hitening or DNA (by polymerase chain
with distinct borders, spreading reaction).
centrifugally, often following blood
vessels, associated with retinal
vasculitis, haemorrhage and
necrosis.

ODYSSEY Protocol

Central nervous system Recent onset of a focal nervous Positive serum toxoplasma
toxoplasmosis system abnormality consistent with antibody AND (if available)
intracranial disease or reduced level single or multiple intracranial
of consciousness mass lesion on neuroimaging
AND (computed tomography or
response within 10 days to specific magnetic resonance imaging).
therapy.
HIV encephalopathy Disabling cognitive and/or motor Diagnosis of exclusion: and (if
dysfunction interfering with available) neuroimaging
activities of daily living, progressing (computed tomography or
over weeks or months in the magnetic resonance imaging).
absence of a concurrent illness or
condition other than HIV infection
that might explain the findings.
Extrapulmonary Meningitis: usually subacute, fever Isolation of Cryptococcus
cryptococcosis with increasing severe headache, neoformans from
(including meningitis) meningism, confusion, behavioural extrapulmonary site or positive
changes that respond to cryptococcal antigen test on
cryptococcal therapy. cerebrospinal fluid or blood.
Disseminated No presumptive clinical diagnosis. Diagnosed by finding atypical
nontuberculous mycobacterial species from
mycobacteria infection stool, blood, body fluid or other
body tissue, excluding the
lungs.
Progressive multifocal No presumptive clinical diagnosis. Progressive nervous system
leukoencephalopathy disorder (cognitive dysfunction,
gait/speech disorder, visual
loss, limb weakness and cranial
nerve palsies) together with
hypodense white matter lesions
on neuro-imaging or positive
polyomavirus JC polymerase
chain reaction on cerebrospinal
fluid.
Chronic No presumptive clinical diagnosis. Cysts identified on modified
cryptosporidiosis Ziehl-Nielsen stain microscopic
(with diarrhoea lasting examination of unformed stool.
more than one month)
Chronic isosporiasis No presumptive clinical diagnosis. Identification of Isospora.
Disseminated mycosis No presumptive clinical diagnosis. Histology, antigen detection or
(coccidiomycosis or culture from clinical specimen
histoplasmosis) or blood culture.
Recurrent non-typhoid No presumptive clinical diagnosis. Blood culture.
Salmonella bacteraemia
Lymphoma (cerebral or No presumptive clinical diagnosis. Histology of relevant specimen

B-cell non-Hodgkin) or, for central nervous system
tumours, neuroimaging
techniques.
Invasive cervical No presumptive clinical diagnosis. Histology or cytology.
carcinoma

ODYSSEY Protocol

Atypical disseminated No presumptive clinical diagnosis. Diagnosed by histology
leishmaniasis (amastigotes visualized) or
culture from any appropriate
clinical specimen.
Symptomatic HIV- No presumptive clinical diagnosis. Renal biopsy.
associated nephropathy
Symptomatic HIV- No presumptive clinical diagnosis. Cardiomegaly and evidence of
associated poor left ventricular function
cardiomyopathy confirmed by
echocardiography.
References:

ODYSSEY Protocol
27 APPENDIX IX ADAPTED DAIDS TOXICITY GRADINGS
The toxicity grading table is adapted from the Division of AIDS (DAIDS) Table for Grading the Severity
of Adult and Pediatric Adverse Events, Version 2.0. [November 2014]. Available from:
http://rsc.tech-res.com/docs/default-source/safety/daids_ae_grading_table_v2_nov2014.pdf (1).
The changes from the previous version of the DAIDS Table are highlighted in yellow.
Neutrophil grading for children aged >7 days, are based on WHO 2010 guidelines (2) recognising the
lower normal levels in African populations. These are highlighted in grey.
General Instructions:
If the need arises to grade a clinical adverse event (AE) that is not identified in the DAIDS AE Grading
Table, use the category “Estimating Severity Grade” located at the top of the table.
If the severity of an AE could fall under either one of two grades (e.g. the severity of an AE could be
either Grade 2 or Grade 3) select the higher of the two grades for the AE.
Definitions:
Basic self-care functions Adults: Activities such as bathing, dressing, toileting, transfer or
movement, continence, and feeding.
Young children: Activities that are age and culturally appropriate,
such as feeding one’s self with culturally appropriate eating
implements.
Chemical pregnancy A pregnancy in which a positive pregnancy test is followed by a
negative pregnancy test without evidence of a clinical pregnancy
loss.
Disability A substantial disruption of a person’s ability to conduct normal life
functions.
Intervention Medical, surgical, or other procedures recommended or provided
by a healthcare professional for the treatment of an adverse event.
Hospitalisation Does not include the following hospital admissions: under 24
hours, unrelated to an adverse event (e.g., for labour and delivery,
cosmetic surgery, social or administrative for temporary placement
[for lack of a place to sleep]), protocol-specified, and for diagnosis
or therapy of a condition that existed before the receipt of a study
agent and which has not increased in severity or frequency.
LLN Lower limit of normal
Medical intervention Use of pharmacologic or biologic agent(s) for treatment of an AE
NA Not applicable
Operative intervention Surgical OR other invasive mechanical procedures.
ULN Upper limit of normal
Usual social & functional activities Activities which adults and children perform on a routine basis and
those which are part of regular activities of daily living, for
example:
Adults: Adaptive tasks and desirable activities, such as going to
work, shopping, cooking, use of transportation, or pursuing a
hobby.
Young children: Activities that are age and culturally appropriate,
such as social interactions, play activities, or learning tasks.

ODYSSEY Protocol
PARAMETER GRADE 1 GRADE 2 GRADE 3 GRADE 4

MILD MODERATE SEVERE POTENTIALLY
LIFE-THREATENING
CLINICAL CONDITIONS: ESTIMATING SEVERITY GRADE FOR PARAMETERS NOT IDENTIFIED IN THE GRADING TABLE
Clinical adverse event Symptoms causing no Symptoms causing Symptoms causing Symptoms causing
NOT identified or minimal greater than minimal inability to perform inability to perform basic
elsewhere in this DAIDS interference with interference with usual usual social & functional self-care functions OR
AE grading table usual social & social & functional activities Medical or operative
functional activities activities intervention indicated to
prevent permanent
impairment, persistent
disability, or death
MAJOR CLINICAL CONDITIONS
CARDIOVASCULAR
Arrhythmia No symptoms AND No No symptoms AND Non-life-threatening Life-threatening
(by ECG or physical intervention indicated Non-urgent symptoms AND Non- arrhythmia OR Urgent
examination) intervention indicated urgent intervention intervention indicated
indicated
Specify type, if
applicable
Blood Pressure 140 to < 160 mmHg ≥ 160 to < 180 mmHg ≥ 180 mmHg systolic OR Life-threatening
Abnormalities1 systolic OR 90 to < 100 systolic OR ≥ 100 to < ≥ 110 mmHg diastolic consequences in a
Hypertension (with mmHg diastolic 110 mmHg diastolic participant not
the lowest reading previously diagnosed
taken after repeat with hypertension (e.g.,
testing during a visit) malignant hypertension)
OR Hospitalization
≥ 18 years of age
indicated
< 18 years of age > 120/80 mmHg ≥ 95th to < 99th ≥ 99th percentile + 5 Life-threatening
percentile + 5 mmHg mmHg adjusted for age, consequences in a
adjusted for age, height, and gender participant not
height, and gender (systolic and/or diastolic) previously diagnosed
(systolic and/or with hypertension (e.g.,
diastolic) malignant hypertension)
OR Hospitalization
indicated
Hypotension No symptoms Symptoms corrected Symptoms AND IV fluids Shock requiring use of
with oral fluid indicated vasopressors or
replacement mechanical assistance to
maintain blood pressure
Cardiac Ischemia or NA NA New symptoms with Unstable angina OR
Infarction ischemia (stable angina) Acute myocardial
OR New testing infarction
Report only one
consistent with ischemia
Heart Failure No symptoms AND Symptoms with mild to Symptoms at rest or Life-threatening
Laboratory or cardiac moderate activity or with minimal activity or consequences OR Urgent
imaging abnormalities exertion exertion (e.g., intervention indicated
hypoxemia) OR (e.g., vasoactive
Intervention indicated medications, ventricular
(e.g., oxygen) assist device, heart
transplant)
Hemorrhage NA Symptoms AND No Symptoms AND Life-threatening
(with significant acute transfusion indicated Transfusion of ≤ 2 units hypotension OR
blood loss) packed RBCs indicated Transfusion of > 2 units
packed RBCs (for
children, packed RBCs >
10 cc/kg) indicated

ODYSSEY Protocol

LIFE-THREATENING
Prolonged PR Interval
or AV Block
Report only one
> 16 years of age PR interval 0.21 to < PR interval ≥ 0.25 Type II 2nd degree AV Complete AV block
0.25 seconds seconds OR Type I 2nd block OR Ventricular
degree AV block pause ≥ 3.0 seconds
≤ 16 years of age 1st degree AV block Type I 2nd degree AV Type II 2nd degree AV Complete AV block
(PR interval > normal block block OR Ventricular
for age and rate) pause ≥ 3.0 seconds
Prolonged QTc 0.45 to 0.47 seconds > 0.47 to 0.50 seconds > 0.50 seconds OR ≥ 0.06 Life-threatening
Interval2 seconds above baseline consequences (e.g.,
Torsade de pointes,
other associated serious
ventricular dysrhythmia)
Thrombosis or NA Symptoms AND No Symptoms AND Life-threatening embolic
Embolism intervention indicated Intervention indicated event (e.g., pulmonary
Report only one embolism, thrombus)
DERMATOLOGICAL
Alopecia Thinning detectable by Thinning or patchy hair Complete hair loss NA
study participant (or loss detectable by
by caregiver for young health care provider
children and disabled
adults)
Bruising Localized to one area Localized to more than Generalized NA
one area
Cellulitis NA Non-parenteral IV treatment indicated Life-threatening
treatment indicated (e.g., IV antibiotics, consequences (e.g.,
(e.g., oral antibiotics, antifungals, antivirals) sepsis, tissue necrosis)
antifungals, antivirals)
Hyperpigmentation Slight or localized Marked or generalized NA NA
causing no or minimal causing greater than
interference with minimal interference
usual social & with usual social &
functional activities functional activities
Hypopigmentation Slight or localized Marked or generalized NA NA
causing no or minimal causing greater than
interference with minimal interference
usual social & with usual social &
Petechiae Localized to one area Localized to more than Generalized NA
one area
Pruritus3 Itching causing no or Itching causing greater Itching causing inability NA
(without skin lesions) minimal interference than minimal to perform usual social &
with usual social & interference with usual functional activities
functional activities social & functional
activities

ODYSSEY Protocol

LIFE-THREATENING
Rash Localized rash Diffuse rash OR Target Diffuse rash AND Extensive or generalized
lesions Vesicles or limited bullous lesions OR
Specify type, if
number of bullae or Ulceration of mucous
applicable
superficial ulcerations of membrane involving two
mucous membrane or more distinct mucosal
limited to one site sites OR Stevens-Johnson
syndrome OR Toxic
epidermal necrolysis
ENDOCRINE and METABOLIC
Diabetes Mellitus Controlled without Controlled with Uncontrolled despite Life-threatening
medication medication OR treatment modification consequences (e.g.,
Modification of current OR Hospitalization for ketoacidosis,
medication regimen immediate glucose hyperosmolar non-
control indicated ketotic coma, end organ
failure)
Gynecomastia Detectable by study Obvious on visual Disfiguring changes AND NA
participant, caregiver, inspection AND Symptoms requiring
or physician AND Causing pain with intervention or causing
Causing no or minimal greater than minimal inability to perform
interference with interference with usual usual social & functional
usual social & social & functional activities
functional activities activities
Hyperthyroidism No symptoms AND Symptoms causing Symptoms causing Life-threatening
Abnormal laboratory greater than minimal inability to perform consequences (e.g.,
value interference with usual usual social & functional thyroid storm)
social & functional activities OR
activities OR Thyroid Uncontrolled despite
suppression therapy treatment modification
indicated
Hypothyroidism No symptoms AND Symptoms causing Symptoms causing Life-threatening
Abnormal laboratory greater than minimal inability to perform consequences (e.g.,
value interference with usual usual social & functional myxedema coma)
social & functional activities OR
activities OR Thyroid Uncontrolled despite
replacement therapy treatment modification
indicated
Lipoatrophy4 Detectable by study Obvious on visual Disfiguring changes NA
participant, caregiver, inspection AND
or physician AND Causing greater than
Causing no or minimal minimal interference
interference with with usual social &
usual social & functional activities
functional activities
Lipohypertrophy5 Detectable by study Obvious on visual Disfiguring changes NA
participant, caregiver, inspection AND
or physician AND Causing greater than
Causing no or minimal minimal interference
interference with with usual social &
GASTROINTESTINAL

ODYSSEY Protocol

LIFE-THREATENING
Anorexia Loss of appetite Loss of appetite Loss of appetite Life-threatening
without decreased associated with associated with consequences OR
oral intake decreased oral intake significant weight loss Aggressive intervention
without significant indicated (e.g., tube
weight loss feeding, total parenteral
nutrition)
Ascites No symptoms Symptoms AND Symptoms recur or Life-threatening
Intervention indicated persist despite consequences
(e.g., diuretics, intervention
therapeutic
paracentesis)
Bloating or Distension Symptoms causing no Symptoms causing Symptoms causing NA
or minimal greater than minimal inability to perform
Report only one
Cholecystitis NA Symptoms AND Radiologic, endoscopic, Life-threatening
Medical intervention or operative consequences (e.g.,
indicated intervention indicated sepsis, perforation)
Constipation NA Persistent constipation Obstipation with manual Life-threatening
requiring regular use of evacuation indicated consequences (e.g.,
dietary modifications, obstruction)
laxatives, or enemas
Diarrhoea
≥ 1 year of age Transient or Persistent episodes of Increase of ≥ 7 stools per Life-threatening
intermittent episodes unformed to watery 24-hour period OR IV consequences (e.g.,
of unformed stools OR stools OR Increase of 4 fluid replacement hypotensive shock)
Increase of ≤ 3 stools to 6 stools over indicated
over baseline per 24- baseline per 24-hour
hour period period
< 1 year of age Liquid stools (more Liquid stools with Liquid stools with Life-threatening
unformed than usual) increased number of moderate dehydration consequences (e.g.,
but usual number of stools OR Mild liquid stools resulting in
stools dehydration severe dehydration,
hypotensive shock)
Dysphagia or Symptoms but able to Symptoms causing Symptoms causing Life-threatening
Odynophagia eat usual diet altered dietary intake severely altered dietary reduction in oral intake
with no intervention intake with intervention
Report only one and
indicated indicated
specify location
Gastrointestinal Not requiring Endoscopic Transfusion indicated Life-threatening
Bleeding intervention other intervention indicated consequences (e.g.,
than iron supplement hypotensive shock)
Mucositis or Stomatitis Mucosal erythema Patchy Confluent Life-threatening
pseudomembranes or pseudomembranes or consequences (e.g.,
Report only one and
ulcerations ulcerations OR Mucosal aspiration, choking) OR
specify location
bleeding with minor Tissue necrosis OR
trauma Diffuse spontaneous
mucosal bleeding
Nausea Transient (< 24 hours) Persistent nausea Persistent nausea Life-threatening
or intermittent AND resulting in decreased resulting in minimal oral consequences (e.g.,
No or minimal oral intake for 24 to 48 intake for > 48 hours OR hypotensive shock)
interference with oral hours Rehydration indicated
intake (e.g., IV fluids)

ODYSSEY Protocol

LIFE-THREATENING
Pancreatitis NA Symptoms with Symptoms with Life-threatening
hospitalization not hospitalization indicated consequences (e.g.,
indicated circulatory failure,
hemorrhage, sepsis)
Perforation NA NA Intervention indicated Life-threatening
(colon or rectum) consequences
Proctitis Rectal discomfort with Symptoms causing Symptoms causing Life-threatening
no intervention greater than minimal inability to perform consequences (e.g.,
indicated interference with usual usual social & functional perforation)
social & functional activities OR Operative
activities OR Medical intervention indicated
intervention indicated
Rectal Discharge Visible discharge Discharge requiring the NA NA
use of pads
Vomiting Transient or Frequent episodes with Persistent vomiting Life-threatening
intermittent AND No no or mild dehydration resulting in orthostatic consequences (e.g.,
or minimal hypotension OR hypotensive shock)
interference with oral Aggressive rehydration
intake indicated (e.g., IV fluids)
MUSCULOSCELETAL
Arthralgia Joint pain causing no Joint pain causing Joint pain causing Disabling joint pain
or minimal greater than minimal inability to perform causing inability to
interference with interference with usual usual social & functional perform basic self-care
usual social & social & functional activities functions
Arthritis Stiffness or joint Stiffness or joint Stiffness or joint swelling Disabling joint stiffness
swelling causing no or swelling causing causing inability to or swelling causing
minimal interference greater than minimal perform usual social & inability to perform basic
with usual social & interference with usual functional activities self-care functions
activities
Myalgia (generalized) Muscle pain causing Muscle pain causing Muscle pain causing Disabling muscle pain
no or minimal greater than minimal inability to perform causing inability to
Osteonecrosis NA No symptoms but with Bone pain with Disabling bone pain with
radiographic findings radiographic findings OR radiographic findings
AND No operative Operative intervention causing inability to
intervention indicated indicated perform basic self-care
functions
Osteopenia6
≥ 30 years of age BMD t-score -2.5 to -1 NA NA NA
< 30 years of age BMD z-score -2 to -1 NA NA NA
Osteoporosis6
≥ 30 years of age NA BMD t-score < -2.5 Pathologic fracture (e.g., Pathologic fracture
compression fracture causing life-threatening
causing loss of vertebral consequences
height)
< 30 years of age NA BMD z-score < -2 Pathologic fracture (e.g., Pathologic fracture
compression fracture causing life-threatening
causing loss of vertebral consequences
height)

ODYSSEY Protocol

LIFE-THREATENING
NEUROLOGICAL
Acute CNS Ischaemia NA NA Transient ischemic Cerebral vascular
attack accident (e.g., stroke
with neurological deficit)
Altered Mental Status Changes causing no or Mild lethargy or Confusion, memory Delirium OR Obtundation
(for Dementia, see minimal interference somnolence causing impairment, lethargy, or OR Coma
Cognitive, Behavioral, with usual social & greater than minimal somnolence causing
or Attentional functional activities interference with usual inability to perform
Disturbance below) social & functional usual social & functional
activities activities
Ataxia Symptoms causing no Symptoms causing Symptoms causing Disabling symptoms
functional activities OR activities
No symptoms with
ataxia detected on
examination
Cognitive, Behavioral, Disability causing no or Disability causing Disability causing Disability causing
or Attentional minimal interference greater than minimal inability to perform inability to perform basic
Disturbance with usual social & interference with usual usual social & functional self-care functions OR
(includes dementia and functional activities OR social & functional activities OR Specialized Institutionalization
attention deficit Specialized resources activities OR resources on a full-time indicated
disorder) not indicated Specialized resources basis indicated
on part-time basis
Specify type, if
indicated
applicable
Developmental Delay Mild developmental Moderate Severe developmental Developmental
< 18 years of age delay, either motor or developmental delay, delay, either motor or regression, either motor
cognitive, as either motor or cognitive, as determined or cognitive, as
Specify type, if
determined by cognitive, as by comparison with a determined by
applicable
comparison with a determined by developmental comparison with a
developmental comparison with a screening tool developmental screening
screening tool developmental appropriate for the tool appropriate for the
appropriate for the screening tool setting setting
setting appropriate for the
setting
Headache Symptoms causing no Symptoms causing Symptoms causing Symptoms causing
or minimal greater than minimal inability to perform inability to perform basic
interference with interference with usual usual social & functional self-care functions OR
usual social & social & functional activities Hospitalization indicated
functional activities activities OR Headache with
significant impairment of
alertness or other
neurologic function
Weakness Minimal muscle Muscle weakness Muscle weakness Disabling muscle
(includes myopathy and weakness causing no causing greater than causing inability to weakness causing
neuropathy) or minimal minimal interference perform usual social & inability to perform basic
interference with with usual social & functional activities self-care functions OR
Specify type, if
usual social & functional activities Respiratory muscle
applicable
functional activities OR weakness impairing
No symptoms with ventilation
decreased strength on
examination

ODYSSEY Protocol

LIFE-THREATENING
Neurosensory Minimal paresthesia Sensory alteration or Sensory alteration or Disabling sensory
Alteration causing no or minimal paresthesia causing paresthesia causing alteration or paresthesia
(includes paresthesia interference with greater than minimal inability to perform causing inability to
and painful usual social & interference with usual usual social & functional perform basic self-care
neuropathy) functional activities OR social & functional activities functions
No symptoms with activities
Specify type, if
sensory alteration on
applicable
examination
Seizures
New Onset Seizure
≥ 18 years of age NA NA 1 to 3 seizures Prolonged and repetitive
seizures (e.g., status
epilepticus) OR Difficult
to control (e.g.,
refractory epilepsy)
< 18 years of age Seizure lasting < 5 Seizure lasting 5 to < 20 Seizure lasting ≥ 20 Prolonged and repetitive
(includes new or minutes with < 24 minutes with < 24 minutes OR > 24 hours seizures (e.g., status
pre-existing febrile hours postictal state hours postictal state postictal state epilepticus) OR Difficult
seizures) to control (e.g.,
Pre-existing Seizure NA Increased frequency Change in seizure Prolonged and repetitive
from previous level of character either in seizures (e.g., status
control without change duration or quality (e.g., epilepticus) OR Difficult
in seizure character severity or focality) to control (e.g.,
Syncope Near syncope without Loss of consciousness Loss of consciousness NA
loss of consciousness with no intervention AND Hospitalization or
(e.g., pre-syncope) indicated intervention required
PREGNANCY, PEURPERIUM and PERINATAL
Fetal Death or Stillbirth NA NA Fetal loss occurring at ≥ NA
(report using mother’s 20 weeks gestation
participant ID)
Report only one
Preterm Delivery7 Delivery at 34 to < 37 Delivery at 28 to < 34 Delivery at 24 to < 28 Delivery at < 24 weeks
(report using mother’s weeks gestational age weeks gestational age weeks gestational age gestational age
participant ID)
Spontaneous Abortion Chemical pregnancy Uncomplicated Complicated NA
or Miscarriage8 spontaneous abortion spontaneous abortion or
(report using mother’s or miscarriage miscarriage
participant ID)
Report only one
PSCYCHIATRIC and SLEEP PROBLEMS
Insomnia Mild difficulty falling Moderate difficulty Severe difficulty falling NA
asleep, staying asleep, falling asleep, staying asleep, staying asleep, or
or waking up early asleep, or waking up waking up early
early
Psychiatric Disorders Symptoms with Symptoms with Symptoms with Threatens harm to self or
(includes anxiety, intervention not intervention indicated hospitalization indicated others OR Acute
depression, mania, and indicated OR Behavior OR Behavior causing OR Behavior causing psychosis OR Behavior
psychosis) causing no or minimal greater than minimal inability to perform causing inability to
Specify disorder

ODYSSEY Protocol

LIFE-THREATENING
Suicidal Ideation or Preoccupied with Preoccupied with Thoughts of killing Suicide attempted
Attempt thoughts of death AND thoughts of death AND oneself with partial or
No wish to kill oneself Wish to kill oneself complete plans but no
Report only one
with no specific plan or attempt to do so OR
intent Hospitalization indicated
RESPIRATORY
Acute Bronchospasm Forced expiratory Forced expiratory Forced expiratory Forced expiratory
volume in 1 second or
volume in 1 second or volume in 1 second or volume in 1 second or
peak flow reduced to ≥
peak flow 50 to < 70% peak flow 25 to < 50% peak flow < 25% OR Life-
70 to < 80% OR MildOR Symptoms with OR Symptoms causing threatening respiratory
symptoms with intervention indicated inability to perform or hemodynamic
intervention not OR Symptoms causing usual social & functional compromise OR
indicated greater than minimal activities Intubation
interference with usual
social & functional
activities
Dyspnea or Respiratory Dyspnea on exertion Dyspnea on exertion Dyspnea at rest causing Respiratory failure with
Distress with no or minimal causing greater than inability to perform ventilator support
interference with minimal interference usual social & functional indicated (e.g., CPAP,
Report only one
usual social & with usual social & activities OR Pulse BPAP, intubation)
functional activities OR functional activities OR oximetry < 90%
Wheezing OR Minimal Nasal flaring OR
increase in respiratory Intercostal retractions
rate for age OR Pulse oximetry 90
to < 95%
SENSORY
Hearing Loss
≥ 12 years of age NA Hearing aid or Hearing aid or Profound bilateral
intervention not intervention indicated
hearing loss (> 80 dB at 2
indicated kHz and above) OR Non-
serviceable hearing (i.e.,
>50 dB audiogram and
<50% speech
discrimination)
< 12 years of age > 20 dB hearing loss at > 20 dB hearing loss at > 20 dB hearing loss at ≥ Audiologic indication for
(based on a 1, 2, 3, 4, ≤ 4 kHz > 4 kHz 3 kHz in one ear with cochlear implant and
6 and 8 kHz additional speech additional speech-
audiogram) language related language related services
services indicated indicated (where
(where available) OR available)
Hearing loss sufficient to
indicate therapeutic
intervention, including
hearing aids
Tinnitus Symptoms causing no Symptoms causing Symptoms causing NA
functional activities activities with
with intervention not intervention indicated
indicated

ODYSSEY Protocol

LIFE-THREATENING
Uveitis No symptoms AND Anterior uveitis with Posterior or pan-uveitis Disabling visual loss in
Detectable on symptoms OR OR Operative affected eye(s)
examination Medicamylasal intervention indicated
Vertigo Vertigo causing no or Vertigo causing greater Vertigo causing inability Disabling vertigo causing
minimal interference than minimal to perform usual social & inability to perform basic
with usual social & interference with usual functional activities self-care functions
activities
Visual Changes Visual changes causing Visual changes causing Visual changes causing Disabling visual loss in
(assessed from no or minimal greater than minimal inability to perform affected eye(s)
baseline) interference with interference with usual usual social & functional
SYSTEMIC
Acute Allergic Reaction Localized urticaria Localized urticaria with Generalized urticaria OR Acute anaphylaxis OR
(wheals) with no intervention indicated Angioedema with Life-threatening
medical intervention OR Mild angioedema intervention indicated bronchospasm OR
indicated with no intervention OR Symptoms of mild Laryngeal edema
indicated bronchospasm
Chills Symptoms causing no Symptoms causing Symptoms causing NA
Cytokine Release Mild signs and Therapy (i.e., antibody Prolonged severe signs Life-threatening
Syndrome9 symptoms AND infusion) interruption and symptoms OR consequences (e.g.,
Therapy (i.e., antibody indicated AND Recurrence of symptoms requiring pressor or
infusion) interruption Responds promptly to following initial ventilator support)
not indicated symptomatic improvement
treatment OR
Prophylactic
medications indicated
for ≤ 24 hours
Fatigue or Malaise Symptoms causing no Symptoms causing Symptoms causing Incapacitating symptoms
or minimal greater than minimal inability to perform of fatigue or malaise
Report only one
interference with interference with usual usual social & functional causing inability to
usual social & social & functional activities perform basic self-care
functional activities activities functions
Fever
(non-axillary 38.0 to < 38.6°C or ≥ 38.6 to < 39.3°C or ≥ ≥ 39.3 to < 40.0°C or ≥ ≥ 40.0°C or ≥ 104.0°F
temperatures only) 100.4 to < 101.5°F 101.5 to < 102.7°F 102.7 to < 104.0°F
Pain10 Pain causing no or Pain causing greater Pain causing inability to Disabling pain causing
(not associated with minimal interference than minimal perform usual social & inability to perform basic
study agent injections with usual social & interference with usual functional activities self-care functions OR
and not specified functional activities social & functional Hospitalization indicated
elsewhere) activities
Specify location
Serum Sickness11 Mild signs and Moderate signs and Severe signs and Life-threatening
symptoms symptoms AND symptoms AND Higher consequences (e.g.,
Intervention indicated level intervention requiring pressor or
(e.g., antihistamines) indicated (e.g., steroids ventilator support)
or IV fluids)

ODYSSEY Protocol

LIFE-THREATENING
Underweight12
> 5 to 19 years of age NA WHO BMI z-score < -2 WHO BMI z-score < -3 WHO BMI z-score < -3
to ≤ -3 with life-threatening
consequences
2 to 5 years of age NA WHO Weight-for- WHO Weight-for-height WHO Weight-for-height
height z-score z-score < -3 z-score < -3 with life-
< -2 to ≤ -3 threatening
consequences
< 2 years of age NA WHO Weight-for- WHO Weight-for-length WHO Weight-for-length
length z-score z-score < -3 z-score < -3 with life-
< -2 to ≤ -3 threatening
consequences
Weight Loss NA 5 to < 9% loss in body ≥ 9 to < 20% loss in body ≥ 20% loss in body
(excludes postpartum weight from baseline weight from baseline weight from baseline OR
weight loss) Aggressive intervention
indicated (e.g., tube
feeding, total parenteral
nutrition)
URINARY
Urinary Tract NA Signs or symptoms of Signs or symptoms of Obstruction causing life-
Obstruction urinary tract urinary tract obstruction threatening
obstruction without with hydronephrosis or consequences
hydronephrosis or renal dysfunction
renal dysfunction
SITE REACTIONS TO INJECTIONS AND INFUSIONS
Injection Site Pain or Pain or tenderness Pain or tenderness Pain or tenderness Pain or tenderness
Tenderness causing no or minimal causing greater than causing inability to causing inability to
limitation of use of minimal limitation of perform usual social & perform basic self-care
Report only one
limb use of limb functional activities function OR
Hospitalization indicated
Injection Site Erythema
or Redness13
Report only one
> 15 years of age 2.5 to < 5 cm in ≥ 5 to < 10 cm in ≥ 10 cm in diameter OR Potentially life-
diameter OR 6.25 to < diameter OR ≥ 25 to < ≥ 100 cm2 surface area threatening
25 cm2 surface area 100 cm2 surface area OR Ulceration OR consequences (e.g.,
AND Symptoms OR Symptoms causing Secondary infection OR abscess, exfoliative
causing no or minimal greater than minimal Phlebitis OR Sterile dermatitis, necrosis
interference with interference with usual abscess OR Drainage OR involving dermis or
usual social & social & functional Symptoms causing deeper tissue)
functional activities activities inability to perform
usual social & functional
activities
≤ 15 years of age ≤ 2.5 cm in diameter > 2.5 cm in diameter ≥ 50% surface area of Potentially life-
with < 50% surface the extremity segment threatening
area of the extremity involved (e.g., upper arm consequences (e.g.,
segment involved (e.g., or thigh) OR Ulceration abscess, exfoliative
upper arm or thigh) OR Secondary infection dermatitis, necrosis
OR Phlebitis OR Sterile involving dermis or
abscess OR Drainage deeper tissue)

ODYSSEY Protocol

LIFE-THREATENING
Injection Site
Induration or Swelling
Report only one
> 15 years of age Same as for Injection Same as for Injection Same as for Injection Same as for Injection
Site Erythema or Site Erythema or Site Erythema or Site Erythema or
Redness, > 15 years of Redness, > 15 years of Redness, > 15 years of Redness, > 15 years of
age age age age
≤ 15 years of age Same as for Injection Same as for Injection Same as for Injection Same as for Injection
Site Erythema or Site Erythema or Site Erythema or Site Erythema or
Redness, ≤ 15 years of Redness, ≤ 15 years of Redness, ≤ 15 years of Redness, ≤ 15 years of
age age age age
Injection Site Pruritus Itching localized to the Itching beyond the Generalized itching NA
injection site that is injection site that is not causing inability to
relieved generalized OR Itching perform usual social &
spontaneously or in < localized to the functional activities
48 hours of treatment injection site requiring
≥ 48 hours treatment
LABORATORY
CHEMISTRY
Acidosis NA pH ≥ 7.3 to < LLN pH < 7.3 without life- pH < 7.3 with life-
threatening threatening
consequences consequences
Albumin, Low 3.0 to < LLN 30 to < LLN ≥ 2.0 to < 3.0 ≥ 20 to < < 2.0 < 20 NA
(g/dL; g/L) 30
Alkaline Phosphatase, 1.25 to < 2.5 x ULN 2.5 to < 5.0 x ULN 5.0 to < 10.0 x ULN ≥ 10.0 x ULN
High
Alkalosis NA pH > ULN to ≤ 7.5 pH > 7.5 without life- pH > 7.5 with life-
ALT or SGPT, High 1.25 to < 2.5 x ULN 2.5 to < 5.0 x ULN 5.0 to < 10.0 x ULN ≥ 10.0 x ULN
Report only one
Amylase (Pancreatic) 1.1 to < 1.5 x ULN 1.5 to < 3.0 x ULN 3.0 to < 5.0 x ULN ≥ 5.0 x ULN
or Amylase (Total),
High
Report only one
AST or SGOT, High 1.25 to < 2.5 x ULN 2.5 to < 5.0 x ULN 5.0 to < 10.0 x ULN ≥ 10.0 x ULN
Report only one
Bicarbonate, Low 16.0 to < LLN 11.0 to < 16.0 8.0 to < 11.0 < 8.0 < 8.0
(mEq/L; mmol/L) 16.0 to < LLN 11.0 to < 16.0 8.0 to < 11.0
Bilirubin > ULN with life-
Direct Bilirubin14, threatening
High consequences (e.g., signs
> 28 days of age NA NA > ULN and symptoms of liver
failure)
≤ 28 days of age ULN to ≤ 1 mg/dL > 1 to ≤ 1.5 mg/dL > 1.5 to ≤ 2 mg/dL > 2 mg/dL
Total Bilirubin, High 1.1 to < 1.6 x ULN 1.6 to < 2.6 x ULN 2.6 to < 5.0 x ULN ≥ 5.0 x ULN
> 28 days of age
≤ 28 days of age See Appendix A in See Appendix A in See Appendix A in See Appendix A in DAIDS
DAIDS 2014. DAIDS 2014. DAIDS 2014. 2014.
Total Bilirubin for Term Total Bilirubin for Term Total Bilirubin for Term Total Bilirubin for Term
and Preterm Neonates and Preterm Neonates and Preterm Neonates and Preterm Neonates

ODYSSEY Protocol

LIFE-THREATENING
Calcium, High
(mg/dL; mmol/L)
≥ 7 days of age 10.6 to < 11.5 11.5 to < 12.5 12.5 to < 13.5 ≥ 13.5
2.65 to < 2.88 2.88 to < 3.13 3.13 to < 3.38 ≥ 3.38
< 7 days of age 11.5 to < 12.4 2.88 to < 12.4 to < 12.9 3.10 to < 12.9 to < 13.5 3.23 to < ≥ 13.5 ≥ 3.38
3.10 3.23 3.38
Calcium (Ionized),
High > ULN to < 6.0 6.0 to < 6.4 6.4 to < 7.2 ≥ 7.2
(mg/dL; mmol/L) > ULN to < 1.5 1.5 to < 1.6 1.6 to < 1.8 ≥ 1.8
Calcium, Low
(mg/dL; mmol/L)
≥ 7 days of age 7.8 to < 8.4 7.0 to < 7.8 6.1 to < 7.0 < 6.1
1.95 to < 2.10 1.75 to < 1.95 1.53 to < 1.75 < 1.53
< 7 days of age 6.5 to < 7.5 6.0 to < 6.5 5.50 to < 6.0 < 5.50
1.63 to < 1.88 1.50 to < 1.63 1.38 to < 1.50 < 1.38
Calcium (Ionized), Low
(mg/dL; mmol/L) < LLN to 4.0 3.6 to < 4.0 3.2 to < 3.6 < 3.2
< LLN to 1.0 0.9 to < 1.0 0.8 to < 0.9 < 0.8
Cardiac Troponin I, NA NA NA Levels consistent with
High myocardial infarction or
unstable angina as
defined by the local
laboratory
Creatine Kinase, High 3 to < 6 x ULN 6 to < 10 x ULN 10 to < 20 x ULN ≥ 20 x ULN
Creatinine, High 1.1 to 1.3 x ULN > 1.3 to 1.8 x ULN OR > 1.8 to < 3.5 x ULN OR ≥ 3.5 x ULN OR
Increase of > 0.3 mg/dL Increase of 1.5 to < 2.0 x Increase of ≥ 2.0 x above
above baseline above baseline baseline
Creatinine Clearance15 NA < 90 to 60 ml/min or < 60 to 30 ml/min or < 30 ml/min or
or eGFR, Low ml/min/1.73 m2 OR ml/min/1.73 m2 OR ml/min/1.73 m2 OR
Report only one 10 to < 30% decrease ≥ 30 to < 50% decrease ≥ 50% decrease from
from baseline from baseline baseline or dialysis
needed
Glucose
(mg/dL; mmol/L) 110 to 125 > 125 to 250 > 250 to 500 > 500
Fasting, High 6.11 to < 6.95 6.95 to < 13.89 13.89 to < 27.75 ≥ 27.75
Nonfasting, High 116 to 160 > 160 to 250 > 250 to 500 > 500
6.44 to < 8.89 8.89 to < 13.89 13.89 to < 27.75 ≥ 27.75
Glucose, Low
(mg/dL; mmol/L)
≥ 1 month of age 55 to 64 40 to < 55 30 to < 40 < 30
3.05 to 3.55 2.22 to < 3.05 1.67 to < 2.22 < 1.67
< 1 month of age 50 to 54 40 to < 50 30 to < 40 < 30
2.78 to 3.00 2.22 to < 2.78 1.67 to < 2.22 < 1.67
Lactate, High ULN to < 2.0 x ULN ≥ 2.0 x ULN without Increased lactate with Increased lactate with pH
without acidosis acidosis pH < 7.3 without life- < 7.3 with life-
Lipase, High 1.1 to < 1.5 x ULN 1.5 to < 3.0 x ULN 3.0 to < 5.0 x ULN ≥ 5.0 x ULN

ODYSSEY Protocol

LIFE-THREATENING
Lipid Disorders
(mg/dL; mmol/L)
Cholesterol, Fasting,
High
≥ 18 years of age 200 to < 240 240 to < 300 ≥ 300 NA
5.18 to < 6.19 6.19 to < 7.77 ≥ 7.77
< 18 years of age 170 to < 200 200 to < 300 ≥ 300 NA
4.40 to < 5.15 5.15 to < 7.77 ≥ 7.77
LDL, Fasting, High 130 to < 160 160 to < 190 ≥ 190 NA
≥ 18 years of age 3.37 to < 4.12 4.12 to < 4.90 ≥ 4.90
> 2 to < 18 years of 110 to < 130 2.85 to < 130 to < 190 ≥ 190 NA
age 3.34 3.34 to < 4.90 ≥ 4.90
Triglycerides, 150 to 300 >300 to 500 >500 to < 1,000 > 1,000
Fasting, High 1.71 to 3.42 >3.42 to 5.7 >5.7 to 11.4 > 11.4
Magnesium16, Low 1.2 to < 1.4 0.9 to < 1.2 0.6 to < 0.9 < 0.6
(mEq/L; mmol/L) 0.60 to < 0.70 0.45 to < 0.60 0.30 to < 0.45 < 0.30
Phosphate, Low
(mg/dL; mmol/L)
> 14 years of age 2.0 to < LLN 1.4 to < 2.0 1.0 to < 1.4 < 1.0
0.81 to < LLN 0.65 to < 0.81 0.32 to < 0.65 < 0.32
1 to 14 years of age 3.0 to < 3.5 2.5 to < 3.0 1.5 to < 2.5 < 1.5
0.97 to < 1.13 0.81 to < 0.97 0.48 to < 0.81 < 0.48
< 1 year of age 3.5 to < 4.5 2.5 to < 3.5 1.5 to < 2.5 < 1.5
1.13 to < 1.45 0.81 to < 1.13 0.48 to < 0.81 < 0.48
Potassium, High 5.6 to < 6.0 6.0 to < 6.5 6.5 to < 7.0 ≥ 7.0
(mEq/L; mmol/L) 5.6 to < 6.0 6.0 to < 6.5 6.5 to < 7.0 ≥ 7.0
Potassium, Low 3.0 to < 3.4 2.5 to < 3.0 2.0 to < 2.5 < 2.0
(mEq/L; mmol/L) 3.0 to < 3.4 2.5 to < 3.0 2.0 to < 2.5 < 2.0
Sodium, High 146 to < 150 150 to < 154 154 to < 160 ≥ 160
(mEq/L; mmol/L) 146 to < 150 150 to < 154 154 to < 160 ≥ 160
Sodium, Low 130 to < 135 125 to < 130 121 to < 125 ≤ 120
(mEq/L; mmol/L) 130 to < 135 125 to < 135 121 to < 125 ≤ 120
Uric Acid, High 7.5 to < 10.0 10.0 to < 12.0 12.0 to < 15.0 ≥ 15.0
(mg/dL; mmol/L) 0.45 to < 0.59 0.59 to < 0.71 0.71 to < 0.89 ≥ 0.89
HAEMATOLOGY
Absolute CD4+ Count,
Low
(cell/mm3; x109cells/L) 300 to < 400 200 to < 300 100 to < 200 < 100
> 5 years of age (not 300 to < 400 200 to < 300 100 to < 200 < 100
HIV infected)
Absolute Lymphocyte
Count, Low
(cell/mm3; x109cells/L)
> 5 years of age 600 to < 650 500 to < 600 350 to < 500 < 350
(not HIV infected) 0.600 to < 0.650 0.500 to < 0.600 0.350 to < 0.500 < 0.350
Absolute Neutrophil
Count (ANC), Low17
(cells/mm3;x109cells/L)
> 7 days of age 750 –< 1,000 500 – 749 250 – 499 < 250
0.75 –<1.0 0.5 –0.749 0.25 –0.499 < 0.250
2 to 7 days of age 1,250 to 1,500 1,000 to 1,249 750 to 999 < 750
1.250 to 1.500 1.000 to 1.249 0.750 to 0.999 < 0.750

ODYSSEY Protocol

LIFE-THREATENING
≤ 1 day of age 4,000 to 5,000 3,000 to 3,999 1,500 to 2,999 < 1,500
4.000 to 5.000 3.000 to 3.999 1.500 to 2.999 < 1.500
Fibrinogen, Decreased 100 < 200 75 to < 100 50 to < 75 < 50
(mg/dL; g/L) 1.00 to < 2.00 OR 0.75 to < 1.00 OR 0.50 to < 0.75 OR < 0.50 OR < 0.25 x LLN OR
0.75 to < 1.00 x LLN ≥ 0.50 to < 0.75 x LLN 0.25 to < 0.50 x LLN Associated with gross
bleeding
Hemoglobin, Low
(g/dL; mmol/L)18
≥ 13 years of age 10.0 to 10.9 9.0 to < 10.0 7.0 to < 9.0 < 7.0
(male only) 6.19 to 6.76 5.57 to < 6.19 4.34 to < 5.57 < 4.34
≥ 13 years of age 9.5 to 10.4 8.5 to < 9.5 6.5 to < 8.5 < 6.5
(female only) 5.88 to 6.48 5.25 to < 5.88 4.03 to < 5.25 < 4.03
57 days of age to <
13 years of age 9.5 to 10.4 8.5 to < 9.5 6.5 to < 8.5 < 6.5
(male and female) 5.88 to 6.48 5.25 to < 5.88 4.03 to < 5.25 < 4.03
36 to 56 days of age 8.5 to 9.6 7.0 to < 8.5 6.0 to < 7.0 < 6.0
22 to 35 days of age 9.5 to 11.0 8.0 to < 9.5 6.7 to < 8.0 < 6.7
8 to ≤ 21 days of age 11.0 to 13.0 9.0 to < 11.0 8.0 to < 9.0 < 8.0
≤ 7 days of age 13.0 to 14.0 10.0 to < 13.0 9.0 to < 10.0 < 9.0
INR, High 1.1 to < 1.5 x ULN 1.5 to < 2.0 x ULN 2.0 to < 3.0 x ULN ≥ 3.0 x ULN
(not on
anticoagulation
therapy)
Methemoglobin 5.0 to < 10.0% 10.0 to < 15.0% 15.0 to < 20.0% ≥ 20.0%
(% hemoglobin)
PTT, High 1.1 to < 1.66 x ULN 1.66 to < 2.33 x ULN 2.33 to < 3.00 x ULN ≥ 3.00 x ULN
(not on
anticoagulation
therapy)
Platelets, Decreased 100,000 to < 124,999 50,000 to < 100,000 25,000 to < 50,000 < 25,000 < 25.000 x 109
(cells/mm3; cells/L) 100.000 x 109 to < 50.000 x 109 to < 25.000 x 109 to < 50.000
124.999 x 109 100.000 x 109 x 109
PT, High 1.1 to < 1.25 x ULN 1.25 to < 1.50 x ULN 1.50 to < 3.00 x ULN ≥ 3.00 x ULN
(not on
anticoagulation
therapy
WBC, Decreased
(cells/mm3;x109cells/L) 2,000 to 2,499 1,500 to 1,999 1,000 to 1,499 < 1,000
> 7 days of age 2.000 to 2.499 1.500 x to 1.999 1.000 to 1.499 < 1.000
≤ 7 days of age 5,500 to 6,999 4,000 to 5,499 2,500 to 3,999 < 2,500
5.500 to 6.999 4.000 to 5.499 2.500 to 3.999 < 2.500
URINALYSIS
Glycosuria Trace to 1+ or 2+ or ˃ 250 to > 2+ or > 500 mg NA
(random collection ≤ 250 mg ≤ 500 mg
tested by dipstick)

ODYSSEY Protocol

LIFE-THREATENING
Hematuria 6 to < 10 RBCs per high ≥ 10 RBCs per high Gross, with or without Life-threatening
(not to be reported power field power field clots OR With RBC casts consequences
based on dipstick OR Intervention
findings or on blood indicated
believed to be of
menstrual origin)
Proteinuria 1+ 2+ 3+ or higher NA
(random collection
tested by dipstick)
1 Blood pressure norms for children < 18 years of age can be found in: Expert Panel on Integrated Guidelines for
Cardiovascular Health and Risk Reduction in Children and Adolescents. Pediatrics 2011;128;S213; originally published
online November 14, 2011; DOI: 10.1542/peds.2009-2107C.
2 As per Bazett’s formula.
3 For pruritus associated with injections or infusions, see the Site Reactions to Injections and Infusions section (page 23).
4 Definition: A disorder characterized by fat loss in the face, extremities, and buttocks.
5 Definition: A disorder characterized by abnormal fat accumulation on the back of the neck, breasts, and abdomen.
6 BMD t and z scores can be found in: Kanis JA on behalf of the World Health Organization Scientific Group (2007).
Assessment of osteoporosis at the primary health-care level. Technical Report. World Health Organization Collaborating
Centre for Metabolic Bone Diseases, University of Sheffield, UK. 2007: Printed by the University of Sheffield.
7 Definition: A delivery of a live-born neonate occurring at ≥ 20 to < 37 weeks gestational age.
8 Definition: A clinically recognized pregnancy occurring at < 20 weeks gestational age.
9 Definition: A disorder characterized by nausea, headache, tachycardia, hypotension, rash, and/or shortness of breath.
10 For pain associated with injections or infusions, see the Site Reactions to Injections and Infusions section (page 23).
11 Definition: A disorder characterized by fever, arthralgia, myalgia, skin eruptions, lymphadenopathy, marked discomfort,
and/or dyspnea.
12 WHO reference tables may be accesed by clicking the desired age range or by accessing the following URLs:
http://www.who.int/growthref/who2007_bmi_for_age/en/ for participants > 5 to 19 years of age and
http://www.who.int/childgrowth/standards/chart_catalogue/en/ for those ≤ 5 years of age.
14 Direct bilirubin > 1.5 mg/dL in a participant < 28 days of age should be graded as grade 2, if < 10% of the total bilirubin.
15 Use the applicable formula (i.e., Cockroft-Gault in mL/min or Schwatrz in mL/min/1.73m2).
16 To convert a magnesium value from mg/dL to mmol/L, laboratories should multiply by 0.4114.
17 Neutrophil grading, are based on WHO 2010 guidelines(2) recognising the lower normal levels in African populations.
18 The conversion factor used to convert g/dL to mmol/L is 0.6206 and is the most commonly used conversion factor. For
grading hemoglobin results obtained by an analytic method with a conversion factor other than 0.6206, the result must be
converted to g/dL using the appropriate conversion factor for the particular laboratory.
19 Severity grading for total bilirubin in neonates is complex because of rapidly changing total bilirubin normal ranges in
the first week of life followed by the benign phenomenon of breast milk jaundice after the first week of life. Severity
grading in this appendix corresponds approximately to cut-offs for indications for phototherapy at grade 3 and for
exchange transfusion at grade 4.
References:
1. Division of AIDS National Institute of Allergy and Infectious Diseases National Institutes of
Health US Department of Health and Human Services. Division of AIDS (DAIDS) Table for Grading the
Severity of Adult and Pediatric Adverse Events 2014 [updated Version 2.0 November 2014]. Available
from: http://rcc.tech-res.com/docs/default-
source/safety/daids_ae_grading_table_v2_nov2014.pdf?sfvrsn=8.
2. WHO. Antiretroviral therapy for HIV infection in infants and children: Towards universal
access. Recommendations for a public health approach: 2010 revision. In: WHO, editor. 2010.

ODYSSEY Protocol
28 APPENDIX X TANNER SCALES
The Five Stages of Female Breast and Pubic Hair Development should be staged separately (1, 2).
Stage Female Breast Pubic Hair

1 Breasts during childhood. None
The breasts are flat and
show no signs of
development.
2 Breast bud stage. Milk Sparse, lightly

ducts and fat tissue pigmented, straight,
forms a small mound. medial border of labia.
3 Breasts continue to grow. Darker, beginning to

Breasts become rounder curl, increased
and fuller. amount.
4 Nipple and areola form Coarse, curly,

separate small mound. abundant but amount
Not all girls go through less than in adult.
this stage. Some skip
stage 4 and go directly to
stage 5.
5 Breast growth enters Adult feminine

final stage. Adult breast triangle, spread to
is full and round shaped. medial surface of
thighs

ODYSSEY Protocol
The Five Stages of Male Genitalia and Pubic Hair Development should be staged separately
Stage Male Genitalia Pubic Hair
1 Penis and testicles of a child. No pubichair.

Testicles between 1 and 3
milliliters in volume.
2 First signs for penis and Pubic hair beginning to grow:

testicle growth, Testicles appears sparse and downy
become larger. Testicles straight.
between 4 and 6 millilitres in
volume.
3 Penis continues to grow Pubic hair appears curlier and

getting wider and longer. coarser with increased
Testicles continue to grow pigmentation.
larger. Testicles between 7
and 16 millilitres in volume.
4 Penis continues to grow Pubic hair becomes adult type,

getting wider and longer. but less.
Testicles continue to grow
larger. Penis gland or head is
more developed. Testicles
between 12 and 24 milliliters
in volume. Testicles are about
1 1/2 inches long.
5 Penis growth enters final Pubic hair is thick spreading to
stage. Average erect penis medial thighs.
length 6 1/4 inches. 90% are 5
- 7 inches. Glans penis or head
is fully developed. Testicles
16 - 27 millilitres in volume.
Testicles are about 1-3/4
inches.
Copyright© 1998,1999 VirtualKid All Rights Reserved.

References:
1. Marshall WA, Tanner JM. Variations in pattern of pubertal changes in girls. Archives of disease in
childhood. 1969;44(235):291-303.
2. Marshall WA, Tanner JM. Variations in the pattern of pubertal changes in boys. Archives of
disease in childhood. 1970;45(239):13-23.

ODYSSEY Protocol
29 APPENDIX XI SAFE LIMITS OF BLOOD SAMPLE VOLUMES IN CHILDREN
The blood volumes taken from children for clinical and research purposes should not exceed
maximum allowable limits.
Allowable blood draw limits for children (1,2):

For healthy children:
o 3% total blood volume in a 24 hour period
o 10% total blood volume in a 30 day period
For sick/unwell children:
o 2.5% total blood volume in a 24 hour period
o 5% total blood volume in a 30 day period
Estimated total blood volume for term infants (Wt >2kg) and children is 80 ml/kg.
Table 7: Maximum allowable total blood draw volumes*
Wt, kg TBV, ml Blood draw volume in 24 hours, ml Total volume in 30 days, ml
Unwell Healthy Unwell Healthy

(2.5% TBV) (3% TBV) (5% TBV) (10% TBV)
3 240 6 7 12 24
4 320 8 10 16 32
5 400 10 12 20 40
6 480 12 14 24 48
7 560 14 17 28 56
8 640 16 19 32 64
9 720 18 22 36 72
10 800 20 24 40 80
11-15 880-1200 22-30 27-36 44-60 88-120
16-20 1280-1600 32-40 38-48 64-80 128-160
21-25 1680-2000 42-50 50-60 64-100 168-200
26-30 2080-2400 52-60 62-72 104-120 208-240
31-35 2480-2800 62-70 74-84 124-140 248-280
36-40 2880-3200 72-80 86-96 144-160 288-320
41-45 3280-3600 82-90 98-108 164-180 328-360
46-50 3680-4000 92-100 110-120 184-200 368-400
*Adapted from Jack 2001 (2).
References:
1. Howie S. Blood sample volumes in child health research: review of safe limits. Bull World
Health Organ 2011;89:46–53
Jack R. Maximum allowable total blood draw volumes. Children’s Hospital and Regional
Medical Center Laboratory, Seattle, WA. August 2001.
https://www.ucdmc.ucdavis.edu/clinicaltrials/StudyTools/Documents/Blood_Draws_Maxim
um_Allowable.doc

ODYSSEY Protocol
30 APPENDIX XII IMMUNOLOGY/VIROLOGY SUBSTUDY
INTRODUCTION AND RATIONALE

This proposal is based upon two main observations from using integrase inhibitors in clinical studies.
The first stems from the STARTMRK study (1, 2). It showed that in adults there was a progressive
increase in CD4 counts in the raltegravir arm. The reasons were unclear and it has been postulated
that it could be a negative effect of the efavirenz arm rather than a positive impact of raltegravir.
However in the recently completed REALITY study of over 1800 patients, raltegravir significantly
increased the CD4 count after 48 weeks, even though raltegravir had only been taken for the first 12
weeks of treatment (3). In further analyses by MRC CTU (not published yet), the largest effect was in
children under 17 with declining impact with increasing age and no impact in adults older than 40
years of age. This is strongly supportive of an impact of raltegravir on thymic output. Whether this is
related to a more rapid decline in viral load, the viral reservoir or a direct impact on CD4 cell dynamics
is unclear, and forms the basis for this proposed study. Other studies also show that integrase
inhibitors lead to greater increases in CD4 count than comparator regimes (1-5). The reasons for this
are unclear but may be due to an increase in naïve CD4 cells (6).
If correct, this finding could have important implications for treating HIV infected children and adults,
as it may imply that integrase inhibitors can lead to an increase in thymic output.
T-cells produced in the thymus from bone marrow derived precursor cells establish the peripheral
naïve T-cell pool during the first year of life. The export of T-cells from the thymus (thymic output)
then gradually declines from its peak at 1 year of age to much lower levels by early adulthood. In
humans, increased peripheral T-cell division with age is relied upon to maintain the naïve T-cell pool.
The relative contribution of these two mechanisms therefore changes with age. Our recent work has
demonstrated the importance of maintaining thymic output in children with HIV infection to optimise
CD4 reconstitution and we have just completed analysis in the cohort from Children with HIV Early
antiretroviral trial (CHER) (7), which shows that thymic output is the main determinant of CD4 cell
reconstitution in HIV infected infants (Payne H et al. Personal communication). Though the mechanism
is unknown, it is clear therefore that the finding of increased naïve CD4 cells in response to integrase
inhibitors may be due to increased naïve cell proliferation and/or increased thymic output.
Until recently, thymic output has been commonly estimated from T-cell receptor excision circles
(TRECS) and/or markers such as CD31 expressed on recent thymic emigrants. Because concentrations
of TREC and markers of recent thymic emigrants are confounded by peripheral T-cell division they
cannot in themselves be used as quantitative estimates of thymic output. We have established
methods using measurements of TRECs and cell division using the marker Ki67 in the total naïve CD4
T-cell population and a recently described mathematical model to obtain explicit measures of thymic
output in HIV infected patients (8). We have adapted this methodology for use in frozen cells and
propose to apply it to stored samples collected from the proposed study quantify T-cell dynamics and
assess if DTG leads to increased thymic output.

ODYSSEY Protocol
DTG may also be operating to increase CD4 cells through its effects on immune activation, possibly as
a result of ongoing low level viral replication. HIV establishes latency early after primary infection and
the resting CD4+ T cells constitute the main pool of cells responsible for persistence (9). Homeostatic
cell proliferation mechanisms as well as stochastic phenomena of cell activation by different stimuli
have been proposed as models of persistence in the presence of suppressive cART (9). However it was
recently shown that persistence is rather an active process driven by the virus aiming at its own
survival (10). Many of the cells in this pool undergo clonal expansion and strong selection of cells with
HIV integration sites in specific genes as these seem to offer a survival advantage through expansion
of infected clones (11). Eliminating the viral reservoir is the main challenge of the functional cure
agenda (12) and therapeutic strategies should incorporate qualitative and quantitative assessments
of this compartment. Integrase Strand Transfer Inhibitors (INSTIs) exhibit virological features that
suggest that these compounds are advantageous for reducing the viral reservoir in patients that
initiate treatment, as well as those commencing second-line therapy (13).
In view of the absence of resistance even when given as monotherapy (14), dolutegravir appears
particularly appealing for use in children, and the Odyssey trial offers a unique opportunity to assess
its impact in both groups of patients. There have been conflicting reports on the effect of raltegravir
on intensification of cART suggesting that there might be a temporary effect on 2LTR circles (15)
probably reflecting the absence of consensus on the role of ongoing low level viral replication as a
mechanism of replenishment of the reservoir (16). The aim of the virological component of this
substudy is to assess the dynamic impact of dolutegravir on the viral reservoir and its impact on clonal
expansion selection of infected cells when compared to SOC for treatment naïve and treatment
experienced patients.
Recent data (14, 17, 18) on the use of dolutegravir in highly experienced patients as well as its use as
part of dual therapy present us with a potential new paradigm in HIV treatment. Odyssey is therefore
expected to a) inform policies and treatment strategies in paediatric HIV b) advance our knowledge of
the viral reservoir and c) add invaluable clinical utility/validity data to the use of emerging virological
and immunological markers for estimating the size of the viral reservoir (19). It is therefore critical to
ensure storage of adequate, good quality samples (cells and plasma) in order to maximise the
potential future benefit maintaining commitment to the trial participants.
This sub-study could provide the data that shows that integrase inhibitors can lead to a greater
increase in thymic output and/or a decrease in CD4 cell death than other regimes. It could
demonstrate the use of this class of ARVs is particularly advantageous for children and would strongly
support the use of integrase inhibitors in HIV infected children.
OBJECTIVE
The objective of the substudy is to assess the impact of DTG on the mechanisms of CD4 reconstitution,
immune activation and HIV reservoir and replication.
METHODS

ODYSSEY Protocol
Blood samples for plasma will be collected at each study visit according to the trial assessment
schedule of the main ODYSSEY trial and separated into plasma prior to storage. PBMCs will be
collected at enrolment, and at 12, 48 and 96 weeks for sites participating in the immunology/virology
substudy.
Immunology assays: T-cell subsets of PBMCs (CD3, CD4 and CD45RA) and activation markers (CD38
and HLA-DR) will be stained by surface labelling. PBMCs will then be fixed and permeabilized and
stained for the intranuclear marker Ki67 and levels determined by flow cytometry. CD4+/CD45RA+ T-
cells will be isolated by negative immunoselection using magnetic beads. Genomic DNA will be
extracted using QIAamp DNA minikits (QIAGEN) and Real-time quantitative PCR (qPCR) will be carried
out to determine the number of TRECs per cell.
The method for estimating thymic output has been described (8). An explicit expression for thymic
export in terms of total naïve cell numbers, naïve cell TREC content and Ki67 expression is given as:
y(t) (t) d (t ) N(t)
(t)
dt c (t )
Thymic Export (cells day-1) =
where c is a constant representing the average TREC content of thymocytes entering the peripheral
naïve population, y(t) is the fraction of naïve CD4+ T-cells expressing Ki67, Δ is the duration of Ki67
expression, τ is the TREC concentration in the peripheral naïve CD4+ T-cell population and N(t) is the
total size of the naïve CD4+ T-cell pool. Calculations to estimate total body CD4+/CD45RA+ T-cell
numbers N(t) will be performed as previously described using estimates on the linear relationship
between blood volume and body weight to estimate total body T-cell numbers.
The impact of treatment on thymic output will be analysed using Non-Linear Mixed Effect modelling
to ascertain the impact of DTG on thymic output. The requirements for these models are to have
repeated measurements of multiple individuals over time. In addition to determining fixed effects
(average of a measure within a population) this method has the ability to estimate how an individual
differs from the average (random effects). Perhaps most importantly it can be used to assess how
factors such as treatment determine individual responses. Such an approach has been used
successfully for predicting long term CD4 counts in HIV infected children following ART (20).
We have recently completed studies in children and adults examining the impact of immune activation
in response to different ART regimes (21). We will study a range of markers in plasma and cell samples
that will be stored from baseline and at multiple time points after randomization, and then frozen at
-80oc or in liquid nitrogen respectively. Samples from Uganda will be stored locally and later
transferred to the Institute of Child Health, UCL. Samples from Zimbabwe and South African sites will
be stored locally and then transferred to the African Health Research Institute (AHRI) Laboratories for
analyses. We will analyse soluble markers (including known markers of immune activation such as
IL1ra, IL6, TNFalpha, IL10, TF, D-dimers and other markers that we have shown to be sensitive to HIV
infection) using Meso Scale Discovery assays (MesoScale Discovery, Gaithersburg, MD, US) or by ELISA
(22). Immunophentyping will be performed as previously described to measure CD45RA and CD45RO

ODYSSEY Protocol
subpopulations of CD4 and CD8 cells as well as CD31, CD38, HLA-DR and Ki67 (21). All of these assays
have been established by us and are in regular use within our laboratories (At ICH and AHRI).
Viral assays: For the reservoir assays we have developed a quantitative Total HIV-1 DNA and RNA by
digital droplet PCR as well as an ultrasensitive quantitative RNA assay (22), and whole genome
sequencing methodologies by next-generation sequencing (NGS) (23-24). A modified approach based
on an already published method will be used for estimating 2LTR-circles and integrated HIV DNA (25).
For the ODYSSEY substudy NGS of the integrase gene will be used as NGS allows increased sensitivity
in minor variant detection (26). Clonality of infection will be assessed by integration sites analysis (11).
A case-control approach with a limited number of matched patients in SOC vs DTG will be used to
detect low-level replication/seeding of the reservoirs and the replication pathway (viral replication or
T-cell division); if viral replication predominates DTG has a potential beneficial effect in reducing
reservoirs.
The results could have important implications for treating HIV infected children and adults, as higher
long term CD4 counts and smaller viral reservoirs are being extensively studied in their association
with better long-term health.
Number of patients: Based on CHER data we estimated that 350 children (175 per arm) would provide
80% power (2-sided α =0.05) to detect a treatment difference of 0.18 log10 cells in thymic output at
96 weeks, adjusting for baseline output. We will describe changes in thymic output, immune
activation biomarkers and viral reservoirs and replication.
STATISTICAL ANALYSIS PLAN

The primary outcome, thymic output at week 96, will be analysed using analysis of covariance to
compare the mean log10 output between the two treatment arms, adjusting for baseline output and
stratification factors. Secondary outcomes will be analysed by the same approach.
References:
1. DeJesus E, Rockstroh JK, Lennox JL, Saag MS, Lazzarin A, Zhao J, et al. Efficacy of raltegravir
versus efavirenz when combined with tenofovir/emtricitabine in treatment-naive HIV-1-infected
patients: week-192 overall and subgroup analyses from STARTMRK. HIV clinical trials.
2012;13(4):228-32.
2. Rockstroh JK, Lennox JL, Dejesus E, Saag MS, Lazzarin A, Wan H, et al. Long-term treatment
with raltegravir or efavirenz combined with tenofovir/emtricitabine for treatment-naive human
immunodeficiency virus-1-infected patients: 156-week results from STARTMRK. Clin Infect Dis.
2011;53(8):807-16.
3. REALITY Trial Team, editor 12-week raltegravir-intensified quadruple therapy versus triple
first-line ART reduces viral load more rapidly but does not reduce mortality in severely
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004). J Acquir Immune Defic Syndr. 2012;61(1):73-7.
5. Negredo E, Massanella M, Puertas MC, Buzon MJ, Puig J, Perez-Alvarez N, et al. Early but
limited effects of raltegravir intensification on CD4 T cell reconstitution in HIV-infected patients with
an immunodiscordant response to antiretroviral therapy. J Antimicrob Chemother.
2013;68(10):2358-62.

ODYSSEY Protocol
6. Garrido C, Rallon N, Soriano V, Lopez M, Zahonero N, de Mendoza C, et al. Mechanisms

involved in CD4 cell gains in HIV-infected patients switched to raltegravir. AIDS. 2012;26(5):551-7.
7. Cotton MF, Violari A, Otwombe K, Panchia R, Dobbels E, Rabie H, et al. Early time-limited
antiretroviral therapy versus deferred therapy in South African infants infected with HIV: results
from the children with HIV early antiretroviral (CHER) randomised trial. Lancet.
2013;382(9904):1555-63.
8. Sandgaard KS, Lewis J, Adams S, Klein N, Callard R. Antiretroviral therapy increases thymic
output in children with HIV. AIDS. 2014;28(2):209-14.
9. Chomont N, El-Far M, Ancuta P, Trautmann L, Procopio FA, Yassine-Diab B, et al. HIV
reservoir size and persistence are driven by T cell survival and homeostatic proliferation. Nat Med.
2009;15(8):893-900.
10. Rouzine IM, Weinberger AD, Weinberger LS. An evolutionary role for HIV latency in
enhancing viral transmission. Cell. 2015;160(5):1002-12.
11. Maldarelli F, Wu X, Su L, Simonetti FR, Shao W, Hill S, et al. HIV latency. Specific HIV
integration sites are linked to clonal expansion and persistence of infected cells. Science.
2014;345(6193):179-83.
12. Siliciano RF, Greene WC. HIV latency. Cold Spring Harb Perspect Med. 2011;1(1):a007096.
13. Mesplede T, Wainberg MA. Resistance against Integrase Strand Transfer Inhibitors and
Relevance to HIV Persistence. Viruses. 2015;7(7):3703-18.
14. Rojas J BJ, Lonca M, Torres B, Parera M, Gonzalez A, Mallolas J, Tricas A, Moreno L, Garcia F,
Gatell JM, Martinez E, editor Dolutegravir monotherapy in HIV-infected patients with sustained viral
suppression: a 24-week pilot study. 15th European AIDS Conference; October 2015; Barcelona.
15. Hatano H, Strain MC, Scherzer R, Bacchetti P, Wentworth D, Hoh R, et al. Increase in 2-long
terminal repeat circles and decrease in D-dimer after raltegravir intensification in patients with
treated HIV infection: a randomized, placebo-controlled trial. J Infect Dis. 2013;208(9):1436-42.
16. Kearney MF, Spindler J, Shao W, Yu S, Anderson EM, O'Shea A, et al. Lack of detectable HIV-1
molecular evolution during suppressive antiretroviral therapy. PLoS Pathog. 2014;10(3):e1004010.
17. Gubavu C, Prazuck T, Niang M, Buret J, Mille C, Guinard J, et al. Dolutegravir-based
monotherapy or dual therapy maintains a high proportion of viral suppression even in highly
experienced HIV-1-infected patients. J Antimicrob Chemother. 2016;71(4):1046-50.
18. Katlama C SC, Blanc C, Denis A, Caby F, Schneider L, Valantin MA, Tubiana R, Kirstetter M,
Valdenassi E, Peytavin G, Calvez V, Marcelin AG, editor Dolutegravir monotherapy in HIV-infected
patients with suppressed HIV viremia. 15th European AIDS Conference; 2015 October 21-24, 2015;
Barcelona.
19. Bruner KM, Hosmane NN, Siliciano RF. Towards an HIV-1 cure: measuring the latent
reservoir. Trends Microbiol. 2015;23(4):192-203.
20. Lewis J, Walker AS, Castro H, De Rossi A, Gibb DM, Giaquinto C, et al. Age and CD4 count at
initiation of antiretroviral therapy in HIV-infected children: effects on long-term T-cell reconstitution.
J Infect Dis. 2012;205(4):548-56.
21. Klein N, Sefe D, Mosconi I, Zanchetta M, Castro H, Jacobsen M, et al. The immunological and
virological consequences of planned treatment interruptions in children with HIV infection. PloS one.
2013;8(10):e76582.
22. The BREATHER (PENTA 16) Trial Group. Weekends-off efavirenz-based antiretroviral therapy
in HIV-infected children, adolescents, and young adults (BREATHER): a randomised, open-label, non-
inferiority, phase 2/3 trial. Lancet HIV. 2016;3(9):e421-30.
23. Gall A, Ferns B, Morris C, Watson S, Cotten M, Robinson M, et al. Universal amplification,
next-generation sequencing, and assembly of HIV-1 genomes. J Clin Microbiol. 2012;50(12):3838-44.
24. Hunt M, Gall A, Ong SH, Brener J, Ferns B, Goulder P, et al. IVA: accurate de novo assembly
of RNA virus genomes. Bioinformatics. 2015;31(14):2374-6.
25. Vandergeeten C, Fromentin R, Merlini E, Lawani MB, DaFonseca S, Bakeman W, et al. Cross-
clade ultrasensitive PCR-based assays to measure HIV persistence in large-cohort studies. J Virol.
2014;88(21):12385-96.

ODYSSEY Protocol
26. Fonager J, Larsson JT, Hussing C, Engsig FN, Nielsen C, Fischer TK. Identification of minority
resistance mutations in the HIV-1 integrase coding region using next generation sequencing. J Clin
Virol. 2015;73:95-100.

ODYSSEY Protocol
31 APPENDIX XIII WEIGHT BAND PHARMACOKINETIC SUBSTUDIES (WB-PK) 1 & 2
WB-PK1: Pharmacokinetics of dolutegravir in children weighing 3 to <25kg
WB-PK2: A crossover pharmacokinetics substudy of dolutegravir in children

weighing 25 to <40kg with switch to DTG 50mg QD

Dolutegravir (DTG) is recommended as an alternative to EFV 600mg third drug (to be combined with
2 NRTIs) for first-line ART in adults and adolescents in the WHO 2016 guidelines. Once DTG becomes
widely available from generic companies, the regimen is expected to be quickly adopted by most
countries, for first-line and second-line therapy (1,2). To make DTG-based regimens available for
children data on dosing according to WHO weight bands using formulations produced by generic
companies are required. DTG is currently licensed in the EU for children weighing ≥15kg and in the US
for children weighing ≥30kg based on the results of the ongoing dose-finding study, IMPAACT P1093
(3).
While IMPAACT P1093 is ongoing, ODYSSEY provides an opportunity to complement their results by
studying the dosing in children according to WHO weight bands, and in children weighing ≥25kg, to
align DTG dose with ABC/3TC fixed dose combination (FDC). The adult FDC of DTG/ABC/3TC (Triumeq,
50/600/300mg) is licensed by EMA for adults and adolescents weighing ≥40kg, whereas adult ABC/3TC
(600/300mg) is licensed by FDA/EMA for children weighing ≥25kg.
The plan for these DTG pharmacokinetic (PK) substudies are endorsed by the WHO Paediatric
Antiretrovirals Working Group (PAWG), which includes representatives from WHO, FDA and EMA as
well as the ODYSSEY and P1093 teams. The dosing and safety data from these substudies will enable
the use of formulations that are planned for manufacturing by generic companies.
Children in weight band PK substudies will be dosed with the DTG 5mg dispersible tablets (DT) or DTG
25mg, 50mg film-coated tablets. The film-coated pediatric-strength 25mg tablet and 50mg tablets
are known to have comparable bioavailability. The DTG 5mg dispersible tablets have higher
bioavailability than the film coated tablets, with the (dose-normalized) AUC(0-inf) estimated to be 1.6-
to 1.8-fold higher than that of the 50mg tablets (4,5).

The P1093 team is studying DT, which readily disperse in 2-5 mL of water or can be taken direct to
mouth. The P1093 team conducts intensive PK analyses in 10 children and sparse PK in 12 children in
age-groups of 4 weeks to 6 months, 6 months to 2 years and 2 to 6 years using 5mg DT.
In discussion with the P1093 team during the WHO PAWG meetings, it was agreed that ODYSSEY will
provide complementary PK data for corresponding WHO weight bands.
AIM OF WB-PK1 AND WB-PK2 SUBSTUDIES

ODYSSEY Protocol
To assess the pharmacokinetics, safety and tolerability of DTG in children 3-<40kg using simplified
formulations and WHO weight band-aligned dosing.
OBJECTIVES
1) To provide PK data, for children in the first three WHO weight bands (Lower WB-PK1, ongoing)
2) To provide PK data with DTG film-coated 25mg tablets in children 14-<25kg (WB-PK1, part I,
completed)
3) To provide PK data in children 14-<20kg on DTG administered as dispersible tablets and in
children 20-<25kg on DTG administered as dispersible tablets or film-coated 50mg tablets QD
(WB_PK1 part II, completed)
4) To provide PK data with DTG 50mg in children 25-<40kg (WB-PK2, completed)
5) To provide safety data for new dosing
METHODS
Study Design:
Children from ODYSSEY A or B will be enrolled into PK substudies across 7 weight bands with the aim
to have 8 children per weight band with evaluable PK data on the investigated dose.
WB-PK1 substudy: Children randomised to DTG in weight bands 3-<6kg, 6-<10kg, 10-<14kg, 14-<20kg
and 20-<25kg will have a 24h PK curve after at least one week of dolutegravir treatment. WB-PK1 part
I investigated DTG PK exposures in children 14-<20kg and 20-<25kg on once daily DTG 25mg FCT (the
study is completed). Lower WB-PK (ongoing) and WB-PK1 part II (completed) investigate DTG PK
parameters in children 3-<25kg using dispersible DTG formulations, and in children 20-<25kg using
DTG 50mg FCT.
WB-crossover-PK2 substudy: Children weighing 25-<40kg taking DTG according to the previous version
of the protocol (25mg for 25-<30kg and 35mg in 30-<40kg) have two 24h PK curves performed: the
first curve at least one week after taking their pre-switch dose and the second curve at least one week
after the switch to a 50mg tablet (the study is completed).
The plasma concentrations for DTG are assayed at the department of Pharmacy of the Radboud
University Medical Center in Nijmegen, the Netherlands. The samples are shipped to the Netherlands
in batches. A quick turnaround data analysis of PK parameters enables review of PK and short-term
safety results by ODYSSEY and ViiV experts and the IDMC.
Inclusion criteria:
Children should meet the inclusion criteria for the main trial (ODYSSEY A or ODYSSEY B) AND be
randomised to DTG, AND meet the following additional inclusion criteria for the WB-PK substudies:
Weight 3-<25kg for WB-PK1 substudies
o Weight 3-<14kg for Lower WB-PK1 substudy (ongoing)
o Weight 14-<25kg for WB-PK1 part I substudy and part II substudy (completed)
Weight 25-<40kg for WB-PK2 substudy (completed)
Exclusion criteria:
In addition to the exclusion criteria for the main trial:
Children who suffer from illnesses that could influence drug pharmacokinetics, i.e. severe
diarrhoea, vomiting, renal disease or liver disease

ODYSSEY Protocol
Children treated with concomitant medications known to have interactions with

dolutegravir
Children with current acute severe malnutrition
Number of Patients: We aim to enroll at least 8 children per weight band with evaluable PK curves
on the investigated doses. If we see large differences within a weight band for a dose/formulation we
will consider recruiting additional children in the relevant weight-band. Further PK study with
different DTG doses may be required if the main PK parameters (AUC0-24h, Ctrough or Cmax) are
substantially different compared to adults on DTG 50mg QD.
Clinical Sites: The PK substudies are undertaken at clinical sites in Uganda (JCRC Kampala, JCRC
Mbarara and Baylor), South Africa (PHRU Soweto, PHRU Klerksdorp and Durban International Clinical
Research Site) and Zimbabwe (UZCRC Harare).
Clinical Procedures: Eligible children for the PK substudies are admitted to the PK unit in the morning
after an overnight fast. Medication adherence during the last 3 days prior to the PK day is ascertained
ensuring that none of the doses were missed. PK blood samples are taken via an i.v. cannula. For each
24 h curve, blood samples are taken at t=0 (prior to DTG dose), and at t= 1, 2, 3, 4, 6 and 24h after the
dose. Standardised meals are served during the PK day at pre-specified time points. Total blood
volume for PK samples during a 24-hour PK day is approximately 6-20 ml for all children across 7
different weight bands between 3kg and ≤40kg and is within the limits of maximum allowable total
blood draw volumes over 24 hours for children (see Appendix XI). The details are outlined in the MOP.
Safety Assessments: Children in the PK substudies are reviewed at 2, 4 and 12 weeks after starting
on DTG or changing to the higher dose. Where scheduled visits for the main protocol do not coincide
children should attend for additional visits. The safety assessments at these visits include: clinical
assessment, collection of bloods to assess haematology and biochemistry safety parameters and
acceptability and sleep questionnaires. Additional safety blood tests or investigations may be
performed if clinically indicated to investigate symptoms or monitor emergent laboratory test
abnormalities. Adverse events (as at standard follow-up visits) should be reported on the case report
form. Adverse events (clinical and laboratory) should be graded using the 2014 Division of AIDS toxicity
grading tables (see Appendix IX). Notable events (pregnancy, liver toxicity meeting DTG stopping
criteria, ABC hypersensitivity reactions and possible suicidality-related adverse events), grade 3 and 4
clinical and laboratory events, and all events resulting in change of ART, should be reported on the
main trial Event Form, including relationship with DTG or other antiretrovirals. Serious adverse events,
defined according to ICH GCP, and notable events (pregnancy, liver toxicity meeting DTG stopping
criteria, ABC hypersensitivity reactions and possible suicidality-related adverse events) should be
reported to the CTU within 24 hours of the sites being aware.
Design Overview and Dose Rationale: WB-PK 1 substudy investigates PK of DTG in children 3-<25kg.
It has four components:
Lower WB-PK: PK of DTG in children in the three lower WHO weight bands 3-<6kg, 6-<10kg
and 10-<14kg using DTG dispersible tablets QD
WB-PK1 part I: PK of DTG in children 14-<20kg and 20-<25kg using DTG film-coated tablets at
25mg QD

ODYSSEY Protocol
WB-PK1 part II: PK of DTG administered as dispersible tablets in children 14-<20kg and 20-
<25kg QD or film-coated 50mg tablets QD in children 20-<25kg
The doses in these substudies provide a range from 0.8 to 3.6mg/kg/day (tables 8a – 8c). DTG doses
up to 2mg/kg were shown to be safe in adults (see below). Infants ≥6 months old at the lower end of
the first two weight bands on dispersible tablets and children in the 14-<20kg and 20-<25kg weight
bands on DTG 50mg FCT receive DTG dose of >2mg/kg but for a limited time as they gain weight
rapidly.
WB-PK1 part I investigated DTG 25mg film-coated tablet in children 14-<25kg. This substudy is
completed. The results showed that DTG 25mg QD given as FCT to children 14-<20kg and 20-<25kg
(table 8a) produced lower DTG Ctrough and AUC0-24h compared to fasted adults on DTG 50mg QD (6).
Table 8a: Dolutegravir dosing in WB-PK1 part I substudy (completed)

Administered DTG once daily (formulations and
WHO daily dose, mg)
DTG dose, mg/kg
Wt bands, kg
5mg dispersible tablet 25mg tablet
14-<20 1 (25mg) 1.25-1.8

20-<25 1 (25mg) 1.0-1.25
WB-PK1 part II substudy (table 8b) investigate higher doses for the 14-<20kg and 20-<25kg to match
the PK parameters in adults. The preliminary results showed that both DTG 30mg DT and 50mg FCT
in children 20-<25kg produced GM Ctrough comparable to values in adults on DTG 50mg QD and GM
AUC0-24h in between reference values in adults on DTG 50mg QD and BID doses. GM Cmax on both doses
exceeded adult GM reference values on DTG 50mg QD and BID. Ongoing safety monitoring is
reassuring. The results will be presented at CROI 2019 (late-breaker abstract accepted [44]).
Lower WB-PK1 substudy assesses the doses for the three lowest weight bands (3-<14kg) using
dispersible tablets based on preliminary results of P1093 (table 8b). The study is ongoing.
Table 8b: Dolutegravir dosing in Lower WB-PK1 and WB-PK1 part II substudies
Administered DTG once daily (formulations and
WHO daily dose, mg)
DTG dose, mg/kg
Wt bands, kg
5mg dispersible tablet 50mg tablet
3-<6 1 (5mg) / 2 (10mg)* 0.8-1.7 / 1.7-3.3

6-<10 3 (15mg)* 1.5-2.5
10-<14 4 (20mg)* 1.4-2.0
14-<20 5 (25mg) 1.25-1.8
20-<25 6 (30mg)§ 1 (50mg)§ 1.2-2.5
. Infants <6 months of age will receive DTG 5mg QD while infants ≥6 months of age will receive DTG 10mg QD, both as dispersible tablets.
*Dose may be modified based on data from the ongoing P1093 study and the data from this study.
§ Children 20-<25kg will receive either DTG 30mg QD (six 5mg dispersible tablets) or DTG 50mg QD (one 50mg film-coated tablet) depending
on site. Participants at UZCRC (Zimbabwe), Baylor (Uganda) and PHRU sites in Soweto and Matlosana (South Africa) will receive dispersible
DTG 30mg whilst those at JCRC sites in Lubowa and Mbarara (Uganda) and Durban International Clinical Research Centre (South Africa) will
receive film-coated DTG 50mg.

ODYSSEY Protocol
Based on population PK modelling and the available results from P1093 and the ODYSSEY WB-PK1
substudies, the proposed DTG doses are predicted to result in GM Ctrough values that exceed antiviral
target concentrations across all weight bands. The predicted GM C trough and AUC0-24h exposures for
children are expected to be in between values observed in adults receiving 50mg QD and BID used in
the SPRING-1 and VIKING studies respectively (7-9). However, given the greater PK variability in
children, wide confidence intervals are expected and paediatric exposures on the upper limit of the
confidence interval are expected to exceed those observed in adults. In the 3-<6kg weight band we
aim to provide some PK data on the 10mg DT which could align with future FDCs. Following discussions
with ViiV we will initially use a lower dose in the youngest children (<6 months) where exposures may
be highest. Depending on the results further PK substudies evaluating different DTG doses and
formulations may be required to achieve optimal and pragmatic dosing in children.

For children aged 6-<12 years, initially two doses aligning with P1093 were taken forward for use in
ODYSSEY (protocol version 2.0): 25mg for children 25-<30kg, and 35mg for children 30-<40kg.
However, issues with this dosing pose some challenges for wide implementation of DTG-based
regimens for children ≥25kg:
For a WHO weight band 25-<35kg, two different doses of 25mg and 35mg are used which is
impractical for implementation in countries using WHO weight bands.
Generic companies produce scored 50mg tablets and 5 mg tablets, therefore the dose of 35mg
can only be made with separate 5mg tablets (7 tablets) or with half of one 50mg tablet plus
two 5mg tablets. Both options will be inconvenient for families and difficult for programs.
In addition the ABC/3TC fixed dose formulation is licensed at the adult dose (600/300mg QD)
in children ≥25kg, while the ABC/3TC/DTG co-formulated combination (Triumeq) is licensed
in children ≥40kg. To align paediatric and adult treatment regimens it would be useful if
Triumeq could be given to children ≥25kg. This would mean that children in this weight band
receive a DTG dose of 1.25-2 mg/kg/day which is similar to the daily dose currently
recommended in treatment-experienced adults i.e. 50mg BID (100mg/day). Adult studies
reported that QD and BID administration had similar tolerability and toxicity (7, 10-13).
The weight band crossover PK2 substudy (WB-PK2) was set up to investigate PK of DTG in children
weighing 25-<40kg on the currently used doses (25mg for 25-<30kg, and 35mg for 30-<40kg) and after
a switch to DTG 50mg. The initial doses provided a range from 0.8 to 1.17mg/kg/day; after the switch
the dose ranged from 1.25 to 2mg/kg/day. The cross-over study design took advantage of the fact that
ODYSSEY was already open in the 25-<40kg weight band and allowed within-participant comparisons
of PK parameters between licensed doses and new proposed doses of DTG.
The results presented at the 10th International Workshop on HIV Pediatrics in Amsterdam, showed
that the new dose of DTG 50mg QD provided DTG Ctrough and AUC exposures comparable to fasted
adults on DTG 50mg QD and Cmax has not exceeded Cmax in adults on DTG 50mg BID (14). The dose was
seen to be safe and acceptable for children within the 25-<40kg weight bands. Following this, children
in the main trial weighing 25-<40kg were switched to DTG 50mg QD as per previous version of the
protocol.

ODYSSEY Protocol
Sparse PK sampling will be done in a subset of children on stored plasma samples collected in the
main trial to correlate with long term tolerability data (See Trial Assessment Schedule).
Retrospective data on viral loads will enable PK/PD analyses.

Review of tolerability and toxicity data: The PK results and clinical and laboratory events will be
reviewed by ODYSSEY and ViiV experts and the IDMC.
Drug levels (particularly Cmax) are anticipated to be higher than BID adult drug levels and levels in
children treated with lower doses. It is therefore important to monitor tolerability and toxicity,
particularly in the first month on treatment. Adverse events and treatment discontinuations will
be described in detail and summarised using descriptive statistics. Comparisons will be made with
data from P1093, ODYSSEY data (outside of the substudies) and adult studies (Table 9) using
descriptive statistics with attention to weight and time on treatment.
All available clinical and laboratory safety data and PK data will be reviewed by the IDMC who, if
there are concerns in any of the weight bands, may recommend to the TSC to extend follow up of
children in specified weight bands enrolled to the PK substudies or to recruit additional children
in the weight band before decisions for dosing in the main trial are made. The IDMC will continue
reviewing safety data during the duration of the randomised phase of the trial.
Table 9: Pharmacokinetic parameters for dolutegravir in literature

Ctrough/
AUC0-tau AUC0-24 C0
Studies Cmax (mg/L Tmax (h) T1/2 (h) C12h/C24h Reference
(h*mg/L) (h*mg/L) (mg/L)
(mg/L)
Adults DTG 50 mg QD (fasted, DTG monotherapy, 2.00
43.4 (20) 3.34 (16) 12.0 (22) 0.83 (26) Min 2011 (12)
n=10) (0.97-4.0)
Van Lunzen
Adults DTG 50 mg QD (SPRING-1, n=15) 48.1 (40) 3.40 (27) 1.20 (62)
2013 (10)
2.00 3.20 VIKING
Adults DTG BID 50 mg (VIKING-3, n=180) 93.4 (50) 5.41 (40) 2.72 (70)
(0-7.87) (69) (ING112961) (8)
Healthy adults DTG 50 mg BID (fasted, n=12) 46.3 (55) 92.7 (55) 5.55 (49) 9.5 (48) 2.41 (77) Dooley 2013(13)
12-<18 year olds 3.00 Viani et al, 2015
43.1 (46) 3.48 (38) 11.9 (43) 0.90 (59)
DTG 50 mg QD (n=10) (1.0-6.0) (15)
6-<12 year olds, DTG 25mg in 20-<30kg (n=4), DTG
Viani et al, 2014
35mg in 30-<40kg (n=2) and DTG 25-50mg QD in 50.5 (63) 0.92 (89)
(16)
>40kg(n=5)
2-<6 year olds DTG ~0.8mg/kg DTG QD (granules)
44.4 (36) 0.51 (68) Ruel 2017 (17)
(n=10)
Table entries are geometric mean (CV%) and for Tmax median (range)
Analysis of PK data: Pharmacokinetic parameters (AUC 0-24, Vd, CL, t1/2) will be calculated using
WinNonlin/Phoenix (Pharsight Corporation, CA, USA). Cmax, Tmax and Cmin will be determined from
observed concentration time data. Geometric Mean and 95% confidence intervals will be estimated
for pharmacokinetic parameters of DTG (except for Tmax). Descriptive statistics for the plasma
concentrations of DTG will be evaluated.
In WB-PK2, current DTG dose (25mg or 35 mg) and 50mg DTG will be compared in all children with
two evaluable PK curves. Within-patient ratios of AUC0-24, Cmax and C min for current dose versus 50mg
DTG will be calculated. Overall GMRs (geometric mean ratios) for current dose versus 50mg DTG
daily will be calculated after log-transformation of the within-patient ratios and 95% CI for the GMR
will be calculated using the t-distribution.
SUBSEQUENT DOSING IN THE MAIN TRIAL

Based on available PK and safety data from P1093 and the ODYSSEY WB-PK substudies, doses in the
main ODYSSEY trial for children 3-<14kg are being reviewed and, if necessary, modified (with further

ODYSSEY Protocol
PK and safety data if required) leading to a decision on the appropriate DTG dose for children in these
weight bands. (Appendix XIX).
References:
1. Third Conference on Antiretroviral Drug Optimization (CADO III). Johannesburg, SA, Nov 29-
Dec 1, 2017
2. WHO. Paediatric Antiretroviral Drug Optimization (PADO) Meeting 3. 6-7 December 2016.
WHO. Available from: http://www.who.int/hiv/pub/meetingreports/paediatric-arv-
optimization-pado3/en/index7.html.
3. NCT01302847. Safety of and immune response to dolutegravir in HIV-1 infected infants,
children, and adolescents (IMPAACT P1093) [Internet]. Available from:
https://clinicaltrials.gov/ct2/show/NCT01302847.
4. Patel P, Song I, Borland J, et al. Relative bioavailability of a paediatric granule formulation of
the HIV integrase inhibitor dolutegravir in healthy adult subjects. Antivir Ther. 2014;19(3):229-
33.
5. Buchanan AM, Holton M, Conn I, Davies M, Choukour M, Wynne BR. Relative Bioavailability
of a Dolutegravir Dispersible Tablet and the Effects of Low- and High-Mineral-Content Water
on the Tablet in Healthy Adults. Clin Pharmacol Drug Dev. 2017 Nov;6(6):577-583.
6. Bollen PDJ, Turkova A, Mujuru H, Musiime V, Amuge P, Lugemwa A, Colbers A, J Spyer MJ,
Lensen S, Moore CL, Hakim J, Kity C, Bbuye D, Atwine L, Giaquinto C, Ford D, Gibb DM, Burger
DM, and the ODYSSEY trial team. Steady-state pharmacokinetics and early safety data in HIV-
infected African children weighing 14 to <25kg on film-coated dolutegravir 25mg tablets in
the ODYSSEY trial. 10th International Workshop on HIV Pediatrics, Amsterdam, the
Netherlands, 20-21 July 2018, abstract 22
7. Eron JJ, Clotet B, Durant J, et al. Safety and efficacy of dolutegravir in treatment-experienced
subjects with raltegravir-resistant HIV type 1 infection: 24-week results of the VIKING Study. J
Infect Dis. 2013 Mar 1;207(5):740-8.
8. Castagna A, Maggiolo F, Penco G, et al. Dolutegravir in antiretroviral-experienced patients
with raltegravir- and/or elvitegravir-resistant HIV-1: 24-week results of the phase III VIKING-3
study. J Infect Dis. 2014 Aug 1;210(3):354-62.
9. Akil B, Blick G, Hagins DP, et al. Dolutegravir versus placebo in subjects harbouring HIV-1
with integrase inhibitor resistance associated substitutions: 48-week results from VIKING-4,
a randomized study. Antivir Ther. 2015;20(3):343-8.
10. van Lunzen J, Maggiolo F, Arribas JR, Rakhmanova A, Yeni P, Young B, et al. Once daily
dolutegravir (S/GSK1349572) in combination therapy in antiretroviral-naive adults with HIV:
planned interim 48 week results from SPRING-1, a dose-ranging, randomised, phase 2b trial.
The Lancet infectious diseases. 2012;12(2):111-8.
11. Raffi F, Jaeger H, Quiros-Roldan E, et al. Once-daily dolutegravir versus twice-daily raltegravir
in antiretroviral-naive adults with HIV-1 infection (SPRING-2 study): 96 week results from a
randomised, double-blind, non-inferiority trial. Lancet Infect Dis. 2013 Nov;13(11):927-35.
12. Min S, Sloan L, DeJesus E, Hawkins T, McCurdy L, Song I, et al. Antiviral activity, safety, and
pharmacokinetics/pharmacodynamics of dolutegravir as 10-day monotherapy in HIV-1-
infected adults. AIDS. 2011;25(14):1737-45.
pharmacokinetics of the HIV integrase inhibitor dolutegravir given twice daily with rifampin
or once daily with rifabutin: results of a phase 1 study among healthy subjects. J Acquir
Immune Defic Syndr. 2013;62(1):21-7.
14. Turkova A, Bollen PDJ, Kaudha E, Chidziva E, Lugemwa A, Kekitiinwa A, Parker A, Shakeshaft
C, Montero S, Colbers A, Nanduudu A, Mujuru H, Makumbi S, Amuge P, Rojo P, Ford D, Burger
DM, Gibb DM, and the ODYSSEY trial team. Steady-state pharmacokinetics and early safety

ODYSSEY Protocol
data in HIV-infected African children weighing ≥25kg after switching to 50mg film-coated
dolutegravir tablets in the ODYSSEY trial. 10th International Workshop on HIV Pediatrics,
Amsterdam, the Netherlands, 20-21 July 2018, abstract 03
15. Viani RM, Alvero C, Fenton T, Acosta EP, Hazra R, Townley E, et al. Safety, Pharmacokinetics
and Efficacy of Dolutegravir in Treatment-experienced HIV-1 Infected Adolescents: Forty-
eight-week Results from IMPAACT P1093. The Pediatric infectious disease journal.
2015;34(11):1207-13.
16. Viani R. IMPAACT 1093: Safety Pharmacokinetics and Efficacy of Dolutegravir in Treatment
Experienced HIV + Children. P901. CROI 2014
17. Ruel T. Dolutegravir pharmacokinetics, safety and efficacy in HIV+ children 2 to < 6 years old.
P806. CROI 2017.

ODYSSEY Protocol
32 APPENDIX XIV PHARMACOKINETIC SUBSTUDY IN PARTICIPANTS RECEIVING RIFAMPICIN AS

PART OF ANTI-TB TREATMENT OR TB PREVENTION THERAPY WHILE ON DTG:
TB-PK substudy: pharmacokinetics of dolutegravir co-administered with

rifampicin

Rifampicin significantly lowers dolutegravir plasma concentrations. The mechanism behind this
interaction is increased enzyme activity of UDP-glucuronosyltransferase (UGT) caused by rifampicin
resulting in increased metabolism and elimination of dolutegravir. It has been shown in HIV-infected
and uninfected adults receiving rifampicin that increasing dolutegravir dose to 50mg BID results in a
similar exposure compared with dolutegravir 50mg QD without rifampicin (1,2). A recent study
showed DTG was effective and well-tolerated in HIV/TB co-infected adults receiving rifampicin-based
TB treatment (2). Furthermore, in adults with resistant HIV, who received dolutegravir 50mg BID
without rifampicin, there was no added toxicity (3). Based on the above, we expect that the exposure
to dolutegravir in children with their daily dose doubled (per protocol dose given BID) while on
rifampicin will be comparable to QD dosing without rifampicin and with no additional safety problems.
The dolutegravir dose will need to remain BID for 2 weeks after the last dose of rifampicin has been
given as the enzyme inducing effect of rifampicin slowly fades away after discontinuing the drug (1).
AIM
To estimate the impact of rifampicin on dolutegravir plasma concentrations in children.
METHODS
Study Design:
The PK substudy is set up in a crossover design in order to estimate the impact of rifampicin on the
plasma pharmacokinetics of dolutegravir within a child. A first 12h PK curve of dolutegravir with
rifampicin co-administration (TB-PK1) and a second 24h PK-curve without rifampicin co-administration
(TB-PK2) will be recorded for each child. TB-PK1 will take place within the last month of rifampicin co-
administration. Rifampicin treatment will then be stopped at the TB treatment completion,
dolutegravir BID dosing will be continued for another 2 weeks and then reduced to QD. At least 2
weeks after resuming QD dosing of dolutegravir a ‘steady-state’ for dolutegravir will be reached and
a second PK-curve (TB-PK2) will be recorded in the same child (Figure 1).
Figure 1. Dolutegravir dosing and timing of TB- PK1 and TB-PK2
Last month of co-

2 weeks 2 weeks
administration
R + DTG BID DTG BID DTG BID DTG QD DTG QD DTG QD
TB-PK1 TB-PK2
Figure 1: (24h curve)
(12h curve)
R= rifampicin, BID= twice daily dosing, QD= once daily dosing.

ODYSSEY Protocol
The plasma concentrations for dolutegravir and rifampicin will be assayed at the department of
Clinical Pharmacy of the Radboud University Medical Center in Nijmegen, The Netherlands.
Inclusion criteria:
Children should meet the inclusion criteria for the main trial (ODYSSEY A or ODYSSEY B) AND:
Receive DTG as part of their ART
Receive rifampicin as part of anti-TB treatment or TB prevention therapy
Exclusion Criteria:
In addition to the exclusion criteria for the main trial:
Illnesses that could influence drug pharmacokinetics, i.e. severe diarrhoea, vomiting, renal
disease or liver disease
Concomitant medications known to have interactions with dolutegravir
Acute severe malnutrition at the time of PK days
Before enrolling in the TB-PK substudy, parents/carers of HIV-infected children and adolescents will
be given an information sheet about the substudy and asked to give written consent before any
substudy-specific procedures are performed.
Number of Patients: 12 children (6 children aged ≥ 6 to <12 years old and 6 children aged 12 to <18
years old) will be included in this PK substudy in order to achieve 10 evaluable subjects. The sample
size calculation is outlined elsewhere (1). This number may need to be increased if intersubject
variability of dolutegravir PK parameters in children appears to be larger than the 33% reported in
non HIV-infected adults or if less than 2 children per WHO weight band have evaluable PK data. In
addition, younger children <6 years on DTG-based ART who are diagnosed with TB or TB infection
and treated with rifampicin-containing regimen will be recruited, however small numbers are
expected at the PK sites.
Clinical Sites: The PK substudies will be undertaken at clinical sites in Uganda, South Africa, and
Zimbabwe
Clinical Procedures: Eligible children for the PK substudies will be admitted to the PK unit in the
morning after an overnight fast. Medication adherence during the last 3 days prior to the PK day will
be confirmed ensuring that none of the doses were missed. Dolutegravir and rifampicin will be given
at the same time. PK blood samples will be taken via an i.v. cannula. Dolutegravir concentrations will
be measured at t=0 (prior to the dose), and at t= 1, 2, 3, 4, 6, 12 or 24h (after the dose). Rifampicin
concentrations will be measured at t=0, 2, 4, and 6h for children weighing ≥6kg. For children weighing
3-<6kg only one rifampicin PK sample at t=2hr will be taken, the time points for DTG samples remain
the same. Standardized meals will be served during the PK day at pre-specified time points. Total blood
volume drawn for each PK curve will be between 6 to 25 ml depending on the weight of the child. The
blood volumes will be within the limits of maximum allowable total blood draw volumes over 24 hours
for children (see Appendix XI). The procedure details will be outlined in the MOP.

ODYSSEY Protocol
Safety Assessments: As per the main trial protocol. The clinical examination at each visit will explicitly
prompt for symptoms relating to possible drug toxicities. Blood will be drawn at trial visits to assess
laboratory safety parameters as per the main Trial Assessment Schedule. Additional safety blood tests
or investigations may be performed as guided by clinical decision to investigate symptoms or monitor
emergent laboratory test abnormalities as clinically indicated. Adverse events will be reported on the
case report form. Adverse events (clinical and laboratory) will be graded using the 2014 Division of
AIDS toxicity grading tables (see Appendix IX). Grade 3 and 4 clinical and laboratory events, and all
events resulting in change of ART, will be reported on the main trial CRFs and relationship with
medications, the child is taking at the time, will be evaluated. Serious adverse events, defined
according to ICH GCP, and notable events (pregnancy, liver toxicity meeting DTG stopping criteria, ABC
hypersensitivity reactions and possible suicidality-related adverse events) will be reported to the CTU
within 24 hours of the sites being aware.

Pharmacokinetic parameters (AUC0-tau, AUC0-24, Vd, CL, t1/2) will be calculated using WinNonlin/Phoenix
(Pharsight Corporation, CA, USA). Cmax, Tmax and Cmin will be determined from observed concentration
time data. Geometric Means and 95% confidence intervals will be estimated for pharmacokinetic
parameters (except for Tmax) of dolutegravir at TB PK1 and TB PK2and rifampicin at TB PK1. The results
will be compared to the published adult data (1).
BID DTG (with RIF) and QD DTG will be compared in all children with two evaluable PK curves. Within-
patient ratios of AUC0-24, Cmax and C min for BID DTG (with RIF) versus QD DTG will be calculated. Overall
GMRs (geometric mean ratios) for BID DTG versus QD DTG daily will be calculated after log-
transformation of the within-patient ratios and 95% CI for the GMR will be calculated using the t-
distribution.
Descriptive statistics (mean (SD) and median (IQR) for the plasma concentrations of DTG and RIF will
also be evaluated.
References:
2013;62(1):21-7.
2. Dooley K, Kaplan R, Mwelase T, Grinsztejn B, Ticona E, Lacerda M, et al. Safety and efficacy
of dolutegravir-based ART in TB/HIV co-infected adults at week 48. 22nd International AIDS
Conference, Amsterdam, the Netherlands, 23-27 July 2018, abstract TUAB0206.
antiretroviral-experienced patients with raltegravir- and/or elvitegravir-resistant HIV-1: 24-week
results of the phase III VIKING-3 study. J Infect Dis. 2014;210(3):354-62.

ODYSSEY Protocol
33 APPENDIX XV QUALITATIVE SUBSTUDY
Optimising adherence to HIV treatment
RATIONALE
It is known that adherence to chronic illness treatment drops off in adolescence and unfortunately
HIV is no exception (1). Consequently, a primary reason that a young person may need to be moved
onto second-line treatment is because they have failed first line treatment due to adherence
problems. Our previous research has shown that adherence problems in this population are
predominately caused by social and relational challenges and rarely due to a lack of knowledge about
the need to take ART (2, 3).
Three key issues are associated with initiation of the second-line ART in young people. Firstly, the
increased risk of mortality due to therapeutic and virological failure. Secondly, the socially complex
reasons behind problematic ART adherence in HIV paediatric populations in general (2-6). Thirdly, the
awareness that second-line ART has long been used as a deterrent, or threat, to enforce adherence to
first line treatment in young people which may not be helpful (5). Children and young people reported
being told by clinic staff and their carers about how much harder second-line treatment would be to
take, for example because of the pill burden, size of pills and side effects, and that they have no further
therapeutic alternative(2). Hence, whilst existing challenges to adherence are unlikely to have
resolved for those young people moving on to second-line treatment, they might also be dealing with
potentially more challenging second-line regimens and the awareness that these are, effectively, their
‘last option’.
The intervention arms of ODYSSEY involve participants being put onto dolutegravir. There has been a
recent WHO alert raising concerns about the possible risks of taking dolutegravir during pregnancy for
increased chances giving birth to a baby with spinal bifida. The trial sites are conducting specialised
counselling to advise participants in the intervention arm about this recent alert about Doluegravir.
This will involve clinic staff explaining the nature of the risks and counselling female participants who
may be sexually active to take contraception.
AIMS
1. To explore how moving onto second-line treatment affects young people’s treatment
engagement and identify how best to support them to maintain optimal treatment
adherence.
2. To explore young people and their caregivers’ understanding of the dolutegravir (DTG) alert
and their sexual and reproductive health (SRH) needs within the context of the ODYSSEY trial.
OBJECTIVES
1. To understand the experiences of young people moving onto second-line ART, including the
acceptability and effects of an altered pill burden and other treatment changes where
applicable.
2. To explore their capacity and engagement in adhering to their second-line treatment and
whether and how this changes over time, including whether this differs across both arms in
ODYSSEY B.

ODYSSEY Protocol
3. To conduct anonymised, comparative analysis with trial data on self-reported adherence in

order to triangulate results and contribute to improving questionnaire measurements for data
collected in the trial.
4. To consider what narratives circulate around second-line treatment and what effect this has
on young people’s perceptions of their health and well-being in the present and the future.
5. To identify what support is needed and can be put in place to strengthen young people’s
ability to maintain optimal adherence to second-line treatment.
6. To assess trial participants’ understandings of the DTG alert and explore the impact of related
discussions on their understanding of the trial and SRH.
7. To describe the attitudes of caregivers to supporting the needs of adolescents living with HIV,
in particular in relation to trial participation, adherence as well as sexual and reproductive
health information.
METHODS
This is a 36 month qualitative study conducted in two trial sites, at JCRC in Uganda and at the University
of Zimbabwe, Harare in Zimbabwe, employing longitudinal qualitative methods.
In each site we will conduct:
1) 2 in-depth individual interviews – at approximately 3 and 12 months after initiation onto second-
line treatment
2) a series of focus group discussions with trial participants at different stages of the trial
3) consultations with a Youth Trial Board currently being set up in participating countries (through a
separately ViiV-funded project) to develop our dissemination materials.
4) in-depth interviews with trial participants to explore the influence of discussions around the DTG
alert.
5) in-depth interviews with caregivers of trial participants
Inclusion criteria for in-depth interviews and focus group with young people:
Participants enrolled in ODYSSEY trial
Age 10-19 years
Participants have known about their HIV status for a minimum of six months before
participating in the qualitative study
Inclusion criteria for in-depth interviews with caregivers:

Caregiver of young person enrolled in the ODYSSEY trial and qualitative study
The young person has given consent for their caregiver to be approached to participate.
Number of Patients: Up to 60 participants will be included in the study in total. A sample size of 60
participants is appropriate to explore specific qualitative questions in the two sites identified for the
qualitative substudy. We will adopt a purposive sampling approach to identify and recruit up to 30
participants in each site. Participants will be invited from both the intervention and standard of care
arms across the ODYSSEY trial. We will obtain separate assents/consents (together with caregiver
consents for participants aged under 18 years old) for this research. There is a patient information
sheet, informed consent form and assent form for the in-depth interviews and a separate set of

ODYSSEY Protocol
information and consent/assent forms for the focus groups. Additional consent will be collected for
the third round of interviews.
Number of Caregivers: In addition, up to 30 caregivers (15/site) will be recruited to participate in

individual in-depth interviews to explore their experience of supporting a young person living with
HIV, as well as their attitudes to trial participation and SRH informational needs of young people living
with HIV. Young people already participating in the qualitative study will be asked if they are
comfortable with their caregivers being invited to participate in the qualitative study. A purposive
sampling approach will be adopted to identify potential caregivers to be included within the trial,
reflecting key sampling dimensions of interest. Subject to the young person’s agreement, their
caregivers will then be invited to participate.
Data collection:
Individual interviews:
Baseline interviews will be conducted approximately three months from starting second-line therapy;
participants will be interviewed individually. This interview will be organised within the early stages of
their initiation into the trial and will particularly explore their expectations and early experiences of
second-line treatment and their reported adherence behaviour.
The second individual interview will be conducted with the same participants, approximately nine
months after the first interview, to explore how they are adapting to and managing their second-line
treatment.
A third round of interviews (maximum of 20 per site) will be conducted with a purposively selected
sample to explore the influence of DTG-alert related conversations on their understanding,
experiences of and attitudes towards trial participation, the DTG risk and more broadly sexual and
reproductive health. Participants taking part in these DTG-related interviews will be selected from
within the existing qualitative sample (this will be done as third interview) and others from within the
trial population (their first interview). The sample will be selected to ensure maximum
representativeness of the trial population. Key sampling characteristics will be gender (both male and
female will be involved); age; and trial arm.
A maximum of 15 caregiver interviews per site will be conducted to better understand the attitudes
towards and experiences in supporting the needs of adolescents living with HIV, in particular in
relation to trial participation and treatment adherence. In these interviews we will also ask caregivers
about their experiences of supporting adolescents growing up with HIV and their opinions towards
the provision of sexual and reproductive health information to adolescents living with HIV.
Focus group discussions:

Two sets of focus group discussions will be held with groups of young people and will include
subsamples of those who have participated in the interview phases and trial participants not yet
involved in the qualitative substudy. The group compositions will be decided by the research team
who will take into account local considerations around gender, age and whether young people are
known to each other.
The first set of focus groups will be held at approximately months 14-18 from trial start, to explore the
participant’s perspectives on the acceptability and sleep questionnaires completed at the beginning
of the trial. There will be 5-8 participants in each focus group and we plan to hold up to 3 focus groups

ODYSSEY Protocol
in each site. The results of these discussions will be fed back to the trial team and clinicians and may
inform the design of data collection tools for the remaining duration of the trial, and for future use in
trials with paediatric HIV populations.
A final set of focus groups will be held up to approximately 3-6 months after the completion of the
final interviews. During these focus groups, we will feedback and discuss our preliminary findings with
the young people as well as discuss their experience of DTG related discussions and their attitudes
towards their SRH informational needs. This will serve not only as an opportunity to refine and validate
our findings from the data collected so far, but also to discuss and plan how we disseminate our
findings both to key stakeholders and young people themselves.
Subject to feasibility and timing we will seek the collaboration of the linked ODYSSEY Youth Trial Board
in the design, development and dissemination of any youth-targeted materials.
DATA ANALYSIS
All the data will be audio recorded, transcribed verbatim and translated. These transcripts will be
checked by the local researchers and the PI/co-investigators, who will discuss each interview with the
research team, checking for completeness and emerging themes to be explored in later interviews.
Data will be stored securely on the MRC/UVRI/JCRC servers in Uganda and on the CeSHHAR servers in
Zimbabwe.
Data analysis will be conducted by the local researchers in collaboration with the PI and co-
investigators. A thematic coding framework, informed by the study objectives will be developed after
the first interview by the study team, so that emerging findings can inform the thematic coding
framework. This framework will be used for coding the study data, with constant comparison across
the team to ensure consistency in coding.
The qualitative data, both from the in-depth interviews and the focus group discussions, will be subject
to a thematic analysis with coding undertaken accompanied by the iterative development of analytical
memos. This will involve comprehensive analysis of the data by case to examine how reported
adherence behaviour may change over time and to account for these reported changes. Once the
interviews and focus group data have been analysed separately, a comparative analyses of both will
be conducted to maximise the benefit of using mixed qualitative methods. The team have
considerable experience of collecting and analysing dyad data (from the young person and related
caregiver). These dyad data will be analysed together to explore important relational concerns and
experience. However, these data will only be presented in dyad form if it can be done in such a way
that does not enable deductive disclosure.
In addition, a comparative analysis of the qualitative data and the quantitative adherence data to
compare how young people describe their adherence in the qualitative study and how they report it
within the trial will be performed, and where appropriate anonymised cases will be examined in more
detail.
References:
1. Nachega JB, Hislop M, Nguyen H, Dowdy DW, Chaisson RE, Regensberg L, et al. Antiretroviral
therapy adherence, virologic and immunologic outcomes in adolescents compared with adults in
southern Africa. J Acquir Immune Defic Syndr. 2009;51(1):65-71.

ODYSSEY Protocol
2. Kawuma R, Bernays S, Siu G, Rhodes T, Seeley J. 'Children will always be children': exploring
perceptions and experiences of HIV-positive children who may not take their treatment and why
they may not tell. African journal of AIDS research : AJAR. 2014;13(2):189-95.
3. Bernays S, Paparini S, Gibb D, Seeley J. When information does not suffice: young people
living with HIV and communication about ART adherence in the clinic. Vulnerable Child Youth Stud.
2016;11(1):60-8.
4. Bernays S, Jarrett P, Kranzer K, Ferrand RA. Children growing up with HIV infection: the
responsibility of success. Lancet. 2014;383(9925):1355-7.
5. Bernays S, Seeley J, Rhodes T, Mupambireyi Z. What am I 'living' with? Growing up with HIV
in Uganda and Zimbabwe. Sociology of health & illness. 2015;37(2):270-83.
6. Mupambireyi Z, Bernays S, Bwakura-Dangarembizi M, Cowan FM. "I don't feel shy because I
will be among others who are just like me...": The role of support groups for children perinatally
infected with HIV in Zimbabwe. Child Youth Serv Rev. 2014;45:106-13.

ODYSSEY Protocol
34 APPENDIX XVI YOUTH TRIAL BOARD PROJECT
A multi-country model of user involvement to engage adolescents living with

HIV in the development and delivery of paediatric clinical trials
RATIONALE
Patient participation and involvement in clinical trials and studies has been shown to improve the
patient’s experience and ensure a better quality of trial or study (1, 2). The inclusion of children and
adolescents in these trials needs a higher level of support than their adult counterparts and although
this presents particular challenges there is a significant need for effective research to be done with
this key group (3, 4). However, children and adolescents growing up with HIV are a group whose voices
are often not heard (5). This is due to a number of factors, such as not informing the child about their
HIV diagnosis, stigma and fear. Coupled with the continuing challenges in including young people in
clinical research in general, this group are commonly not involved in research in a meaningful way.
Current provision tends to rely on one young person’s inclusion on a trial committee and is often
inadequate to ensure young people are genuinely represented. More proactive models of
engagement are urgently needed to improve user involvement.
AIM
The aim of this project is to develop a simple low-cost model of meaningful engagement and
participation of adolescent patient representatives in paediatric clinical trials and research studies.
OBJECTIVES
1. To conduct a literature review of the available evidence about existing participation models
for young people in clinical research to inform the design.
2. To work with young people living with HIV and key stakeholders to design and pilot a user
engagement model (participation model) for including young people in development, delivery
and dissemination of the ODYSSEY trial.
3. To include practical communication strategies between trialists and young people throughout
the process.
4. To ensure the relevance and applicability of the participation model in low and high income
settings.
5. Once piloted, to integrate the model into future adolescent trial to ensure its ongoing
application and refinement and to secure its sustainability.
6. To identify how this model can be adapted to be used in other clinical trials and research
outside of HIV to maximise its generalisability.
METHODS
A model of meaningful engagement and participation of children living with HIV in the development
and delivery of a paediatric clinical trial, using ODYSSEY trial as an example, will be developed and
piloted in 4 countries participating in ODYSSEY: the UK, South Africa, Uganda and Zimbabwe for 2
years. Those children involved will be living with HIV, aged between 15-19. They will be recruited
through a set criteria to ensure they represent the country demographic of children living with HIV
(gender, ethnicity, social circumstances).
Stage 1: Developing the model

A literature review will be conducted to identify and review the published and grey English language
literature on involving young people in clinical trials. Once this review has been completed, a
consultation phase with partners in the four sites (based in South Africa, UK, Uganda and Zimbabwe)

ODYSSEY Protocol
and other key individuals (young people living with HIV and experts with knowledge and experience
in this field) who are able to advise us on our approach will be performed.
Stage 2: Piloting the model, including ongoing reflection (2 years)

The model will involve establishment of a Youth Trial boards (YTB), groups of up to 8 young people in
four countries; the UK, Uganda, South Africa and Zimbabwe. Consent will be obtained from legal
guardians and assent/consent depending on their age from the participants prior to any involvement
in this project. Following this, each YTB will meet in-country a number of times a year for the duration
of the YTB project. Opportunities to link YTB groups together through face to face or virtual meetings
will be pursued. The groups will be facilitated by individuals skilled in working with young people and
in research, with local NGO involvement in some sites. Each YTB will receive training to ensure
understanding of clinical trials, understand their role and support their participation. The in-country
staff will work closely with researchers from PENTA and London School of Hygiene and Tropical
Medicine, to ensure that there is effective communication between the sites and across the project
team. This will also ensure that there is similarity in the roll out of the pilot model across the sites and
that information is shared. Participant observations of the group meetings will be arranged in order
to see ways to improve the model and to ensure that we are consistently capturing the ideas and
opinions of the young people involved. Once the YTBs are established in each country consent will be
sought to conduct individual interviews with YTB member and facilitators to understand their
experiences of taking part in a YTB and to gather their ideas about what they have enjoyed, works well
and how the YTB model could be improved further. This will inform the guidance that we produce
alongside the model.
Stage 3: Beyond ODYSSEY trial

Once the YTB groups have an understanding of how ODYSSEY and clinical trials work in general, they
will then be involved at the development stage of a new clinical trial. When the model is finalised, it
can be used by other investigators inside and outside paediatric HIV trials and studies.
Inclusion criteria: Young people aged 15-19 years who are fully aware of their positive HIV status.
Number of Patients: At least 32 young people across the four sites. These young people will be
purposively selected by each in-country team to broadly represent the characteristics of the clinic/
population group.
Project Timeline: 40 months
Anticipated Enrolment Rate: From Spring 2017
Output: A patient participation model in clinical trials for adolescents will be designed and piloted. At
the end of the project this model will then be adopted and applied to new clinical trials as
opportunities arise.
DATA ANALYSIS
Throughout the project, YTB meetings will be observed and participant observation and field notes
will be taken. This will form the basis for our reflections on the process of developing and shaping the
model. Individual in-depth interviews will be audio recorded and summarised. These data will be
analysed using a thematic analysis approach with the supervision of LSHTM researchers.
References:
1. Moorcraft, S. Y., Marriott, C., Peckitt, C. , Cunnighman, D., Chau, I., Starling, N., Watkins, D.,
& Rao, S. Patients’ willingness to participate in clinical trials and their views on aspects of
cancer research: results of a prospective patient survey. Trials. 2016; 17: 17.
2. Institute of Medicine (US) Committee on Cancer Clinical Trials and the NCI Cooperative Group
Program; Nass SJ, Moses HL, Mendelsohn J, editors. A National Cancer Clinical Trials System

ODYSSEY Protocol
for the 21st Century: Reinvigorating the NCI Cooperative Group Program. Washington (DC):
National Academies Press (US); 2010. 4, Physician and Patient Participation in Cancer Clinical
Trials. Available from: https://www.ncbi.nlm.nih.gov/books/NBK220370/
3. Moore L, and Kirk S. ‘A Literature Review of Children’s and Young People’s Participation in
Decisions Relating to Health Care’. Journal of Clinical Nursing 19, no. 15/16 (August 2010):
2215–25.
4. Cherrill, J., Hudson, H., Cocking, C., Unsworty, V., Franck, L., Fakis, A., McIntyre, J. & Choonara,
I. Clinical trials: the viewpoint of children with a chronic illness compared with healthy
children. Archives of Disease in Childhood 2010; 95:229-232
5. Clacherty, G. & Donald, D. Child participation in research: reflections on ethical challenges in
the southern African context. African Journal Of AIDS Research 2007; 6: 147-156.

ODYSSEY Protocol
35 APPENDIX XVII ODYSSEY STRUCTURE

ODYSSEY Protocol
36 APPENDIX XVIII FOLATE AND VITAMIN B12 SUBSTUDY
Folate and vitamin B12 status among children and adolescents in the ODYSSEY
trial

Recent concerns have been raised about the use of dolutegravir (DTG) in pregnant women.
In a preliminary unscheduled analysis of an ongoing NIH-funded birth surveillance study in
Botswana, an increased risk of neural tube defects (NTDs) among infants of women who
became pregnant while taking DTG-based regimens has been reported (1-3). It is well known
that maternal folate and/or vitamin B12 deficiency increases the risk of NTDs however it is
unknown whether DTG may affect folate or B12 levels.
ODYSSEY provides an opportunity to compare folate and B12 levels in participants on DTG
versus non DTG regimens to determine if there is an association between DTG and folate
status.
Folate and vitamin B12 play a critical role in DNA and RNA synthesis. Folate-requiring
reactions include the reactions involved in amino acid metabolism, purine and pyrimidine
synthesis, and the formation of the primary methylating agent, S-adenosylmethionine (4).
The key folate metabolite is tetrahydrofolate (THF). Folate coenzymes are compartmentalized
between the cytosol and the mitochondria and they cannot be transported between
compartments (4). Folate one-carbon (1C) metabolism serves to activate and transfer 1C units
for biosynthetic processes. As 1C-loaded folates are known not to transfer across intracellular
membranes, the 1C-carrying metabolite THF must be generated in both the mitochondria and
cytosol. Formate, a small 1C metabolite produced in the mitochondria, enters the cytosol and
provides 70% of the cell’s 1C units. Both pyrimidines and purines (DNA building blocks) require
folate 1C metabolism for their synthesis. Similarly, DNA methylation, which is involved in gene
expression regulation, is folate 1C-dependent.
Cobalamin (vitamin B12) serves as a coenzyme in the methionine synthase reaction required
for the conversion of 5-methyltetrahydrofolate (5-methyl-THF) to THF, an active folate form
participating in folate-dependent enzymatic reactions. In its absence, folate is "trapped" as 5-
methyl-THF, therefore, vitamin B12 deficiency reduces the regeneration of THF required for
DNA synthesis, which may result in a secondary folate deficiency and impair cell division (5).
DNA synthesis impairment due to folate and/or vitamin B12 deficiency leads to arrest of the
red blood cell division at the G2 growth stage, continuation of cell growth and increased mean
cell volume (MCV) (macrocytosis). The red cell MCV, therefore, could be an indicator of folate
or B12 deficiency.
Different medications (e.g. methotrexate, trimethoprim, phenytoin, antimalarials, antacids)

may cause or contribute to folate and/or B12 deficiency by various mechanisms, including
decreased absorption (due to reduction of gastric acid or competion for the receptors on
intestinal mucosal cells), effect on enzymes involved in folate metabolism or inhibition of
cellular utilisation of folate. Since NT development requires both rapid cell proliferation and
gene expression regulation, then 1C metabolism is crucial for this embryonic event, and could
represent the cellular process that becomes disturbed by DTG, leading to NTDs.

ODYSSEY Protocol
Folate status can be measured using plasma (or serum) and red blood cell (RBC) folate levels.
The plasma or serum folate level is an informative biomarker of short-term folate status. It
reflects a recent folate intake and is sensitive to dietary changes or action of folate-decreasing
medications. RBC folate level tend to reflect long-term folate status and estimates the folate
stores over the last 3-4 months (5).
ODYSSEY provides an opportunity to compare folate levels in participants on DTG versus non
DTG regimens to determine if there is a potential association between DTG and folate /B12
status.
AIM
To compare folate and B12 levels among children and adolescents randomized to a DTG
containing ART regimen versus those on SOC ART regimen
OBJECTIVES
1. To compare red cell folate level at 96 weeks or later in participants randomized to
DTG versus participants randomized to SOC (Primary objective)
2. To compare change in plasma folate level from baseline to week 4 in participants
randomized to DTG versus participants randomized to SOC
3. To compare change in MCV levels from baseline to weeks 48 and 96 in participants
randomized to DTG versus participants randomized to SOC
4. To compare vitamin B12 serum level at 96 weeks or later in participants randomized
to DTG versus participants randomized to SOC
METHODS
Folate and B12 will be assayed in children enrolled in ODYSSEY at sites in Uganda who were
aged ≥6 years at enrolment (if required the substudy may also extended to other sites).
Red cell folate and B12 will be assayed in prospectively collected samples using the same
blood draw as for other scheduled blood tests in the trial at 96 weeks or later (for patients
who have passed their 96 week visit the samples will be collected at their first visit after the
substudy opens). Where assays cannot be done in real time, the blood samples will be stored
for subsequent testing. Plasma folate levels will be assayed at baseline and at 4 weeks after
commencing ART using plasma samples that are routinely stored as part of the main ODYSSEY
protocol.
Testing plasma folate levels before and after ART initiation will allow us to evaluate the impact
of treatment on folate levels within an individual.
Blood samples and assays

EDTA whole blood samples and serum are routinely collected in the ODYSSEY study and
plasma samples are stored. MCV is captured as part of the haematology assays at screening,
week 0, 24 and then every 24 weeks, and these data are available to analyse the differences
in MCV between the arms. The plasma and whole blood folate levels will be performed on

ODYSSEY Protocol
the cobas e 411 instrument (Roche diagnostics, Manheim). The Elecsys Folate assay will be
used for the determination of folate in plasma, and the Folate RBC Hemolyzing Reagent will
be used in conjunction with the Elecsys Folate RBC assay for the determination of folate in
erythrocytes. Plasma B12 levels will be performed on the cobas e 411 instrument (Roche
diagnostics, Manheim). The Elecsys Vitamin B12 II electrochemiluminescence immunoassay
will be used for the determination of B12 in plasma.
Substantial variation between folate assays used in different laboratories exists, therefore
testing will be centralised.
SAMPLE SIZE AND STATISTICAL ANALYSIS PLAN
The sample size is based on objectives 1 and 2. Since plasma folate levels and red blood cell
folate levels in children in Africa are unknown we have assumed that a difference of half a
standard deviation or more between groups may be clinically relevant.
1. Comparison of red blood cell folate level at week 96 (or later): To detect a difference
of half a standard deviation in folate levels between DTG and SOC arms, with 80%
power at the 5% level of significance, a sample size of 124 children is required (62 in
each treatment arm).
2. Comparison of plasma folate levels at week 4: To detect a difference of half a standard
deviation in folate levels between DTG and SOC arms, adjusting for baseline levels,
using one pre-treatment and one post-treatment measure (assuming correlation
between pre- and post-treatment levels of 0.3, with 80% power at the 5% level of
significance, a sample size of 116 children is required (58 in each treatment arm).
Increasing the sample size to 140 children (70 in each arm) will allow for 10% of samples being
potentially unanalysable for any reason.
Mean red blood cell folate levels and B12 at week 96 (or later) will be compared between the
two randomised groups in an intention-to-treat analysis. In an as treated analysis we will look
at the difference between groups depending on the ART received at the time of the sample.
Mean plasma folate levels at 4 weeks will be compared between the two randomised groups
with adjustment for values at randomisation by analysis of covariance (ANCOVA).
Mean MCV levels at 48 and 96 weeks will be compared between the two randomised groups
with adjustment for values at randomisation by ANCOVA. In as treated analysis we will also
look at the difference between groups depending on the ART received at the time of the
sample
References:
1. Zash R, Holmes L, Makhema J, Diseko M, Jacobson DL, Mayondi G, Mmalane M,
Mofenson L, Gaolathe T, Petlo C, Essex M, Lockman S and Shapiro RL. Surveillance
for neural tube defects following antiretroviral exposure from conception, the
Tsepamo study (Botswana). AIDS 2018. Amsterdam, the Netherlands, 23–27 July
2018. Symposia session TUSY15.
http://programme.aids2018.org/Programme/Session/1589
2. World Health Organization. Statement on DTG. May 18, 2018; Geneva.

ODYSSEY Protocol
3. FDA Drug Safety Communication: FDA to evaluate potential risk of neural tube birth
defects with HIV medicine dolutegravir (Juluca, Tivicay, Triumeq). May 18, 2018.
4. Bailey LB, Gregory JF 3rd. Folate Metabolism and requirements. J Nutr 1999; 129:
779-82. Available: https://doi.org/10.1093/jn/129.4.779
5. Bailey LB, Hausman DB. Folate status in women of reproductive age as basis of
neural tube defect risk assessment. Ann N Y Acad Sci 2018;1414(1):82-95.

ODYSSEY Protocol
37 APPENDIX XIX DOLUTEGRAVIR DOSING IN THE ODYSSEY TRIAL ACROSS DIFFERENT PROTOCOL VERSIONS
ODYSSEY v2.0* ODYSSEY v3.0 ODYSSEY v4.0 ODYSSEY v5.0 onwards

Main trial Main trial WB PK substudy WB PK substudy Main trial WB PK substudy
Main trial participants
participants participants participants participants participants participants
3-<6kg - - - 5mg or 10mg DT - 5mg or 10mg DT
6-<10kg - - - 15mg DT - 15mg DT
10-<14kg - - - 20mg DT - 20mg DT
§
14-<15kg - - 25mg 25mg 25mg DT 25mg DT 25mg DT N/A
15-<20kg 20mg* 20mg
25mg 30mg DT or
20-<25kg 25mg 25mg 25mg 30mg DT or 50mg† 50mgπ N/A
50mg¥
25-<30kg 25mg 25mg 50mg** 50mg 25mg 50mg** NA 50mg NA
≥40kg 50mg 50mg NA 50mg NA 50mg NA
Infants <6 months of age receive DTG 5mg QD while infants ≥6 months of age receive DTG 10mg QD, both as dispersible tablets.
* In May 2017 the EMA licensed the use of 20mg DTG in children 15 - <20kg and ≥6years, following this, children were able to be recruited in this weight and age-band.
** From 1st of April 2018, after ethics notification, sites following protocol version 3.0 and above were recommended to increase the DTG dose of children 25 - <40kg to 50mg
FCT QD at their next scheduled study visit based on the results of the WB-PK2. WB-PK2 participants remained on DTG 50mg with ongoing follow-up. Non-PK participants
recruited after implementation were initiated on the 50mg film-coated DTG dose.
† Both doses are examined in WB-PK1 part II substudy in this weight-band.
§ Children 15 - <20kg previously receiving DTG 20mg QD were changed to DTG film-coated 25mg tablets upon the approval of protocol v4.0. Subsequently all children 14-<20kg
changed to DTG 25mg QD dispersible tablets following the review of WB-PK1 part I results and approval by the relevant ethical and regulatory authorities.
¥ Children 20 - <25kg previously receiving DTG 25mg QD as one 25mg film-coated tablet changed to either DTG 30mg QD dispersible tablets or DTG 50mg QD (film-coated tablet)
depending on site following the review of WB-PK1 part I results and approval by the relevant ethical and regulatory authorities.
π Following the review of PK and safety data children 20-<25kg receiving DTG 30mg dispersible tablets should be switched to DTG 50mg film-coated tablets. Those who prefer to
remain on DTG 30mg DT will be able to do so until they move weight band.
DT=dispersible, otherwise film coated tables

ODYSSEY Protocol
38 APPENDIX XX ARRANGEMENTS FOR THE EXTENDED FOLLOW-UP OF ODYSSEY PARTICIPANTS
GENERAL INFORMATION
This appendix details planned extended follow-up for all children participating in the ODYSSEY
(PENTA 20) trial.
Objectives are two-fold:
1. to provide safety data for ViiV Healthcare for participants who, in the opinion of the
treating physician, continue to derive benefit from dolutegravir and receive
dolutegravir from ViiV Healthcare where it is not available through their country’s
national HIV treatment programme;
2. to monitor long-term safety and effectiveness of dolutegravir versus standard of care
(at selected sites, subject to sufficient funding).
All children who entered the main trial (weighing ≥14kg) will attend their end of study visit
for the randomised phase on/after 24 April 2020 (when the last patient recruited into the
main trial reaches 96 weeks follow-up). Children recruited weighing <14kg will be asked to
attend their 96 week follow-up visit at/after 96 weeks from their randomisation visit and this
will be their end of study visit for the randomised phase; they should move to the extended
follow-up only after their 96 week visit is completed. The baseline visit for the extended
follow-up will be the end of study visit for the randomised phase of the trial.
At the end of study visit for the randomised phase children and carers will be asked to consent
to extended follow-up. Children’s visit schedules (at least 6 monthly) and care will be as per
local clinic guidelines. In addition to routine care, clinics will be asked to continue collecting
urine dipsticks, Sleep and Mood Questionnaire data, waist and hip circumferences and
bioelectric impedance analysis (BIA) measurements (the latter only at the sites where BIA
machines are available) as per the Assessment schedule below. Pregnancy tests will also be
required at every visit for females of childbearing potential. Clinicians will be able to change
ART according to local supplies and/or in the patient’s best interest. Laboratory tests will be
according to local practice.
Children on DTG at the end of the randomised phase will be moved to local DTG where
available (up to 6 months’ supply of trial DTG will be provided for transition). Provided
consent is given for extended follow-up, ViiV Healthcare DTG 5mg DT can continue to be
provided for participants <20kg in South Africa, Uganda and Zimbabwe who are receiving DTG
5mg DT at their end of study visit for the randomised phase until DTG DTs are available locally
or participants move to DTG FCTs or stop benefiting from DTG-based ART (i.e. require
switching to another regimen). Similarly, provided consent is given for extended follow-up,
ViiV Healthcare DTG 50mg FCT can continue to be provided for participants in Thailand
receiving DTG 50mg FCT at their end of study visit for the randomised phase.
At each routine clinic visit during extended follow-up, a shortened version of the trial follow-
up CRF will be completed. Serious adverse events must be reported to MRC CTU within 24
hours of the investigator becoming aware of the event. Annually we will collect participant
and carer data on sleep and mood.
Participants receiving ViiV Healthcare DTG must remain in follow-up while this continues or
they can no longer take ViiV Healthcare DTG provided for the trial. Follow-up of other
participants will be at selected sites for 3 years after the randomisation phase is completed

ODYSSEY Protocol
(until May 2023) providing sufficient funding is available. If sufficient funding cannot be
sourced then follow-up of these participants (those not receiving ViiV Healthcare DTG) will
finish at their study visit for the end of the randomised phase on/after 24 April 2020.
ASSESSMENT SCHEDULE FOR EXTENDED FOLLOW- UP
Further follow-up
Study visit at end of End of extended follow-
WEEK (minimum of every 6
randomised phase up visit
months)
Informed consent for
X
extended follow-up
History and clinical
X As per local practice As per local practice
assessment a
Tanner scale X N/A N/A
Lipodystrophy assessment X N/A N/A
Drug supply to next visit X As per local practice As per local practice
HIV-1 RNA viral load X As per local practice As per local practice
HIV-1 resistance tests As per local practice As per local practice
T cell lymphocyte subsets X As per local practice As per local practice
Biochemistry b X As per local practice As per local practice
Haematology X As per local practice As per local practice
Lipids/glucose b X As per local practice As per local practice
Bone profile b X As per local practice As per local practice
Urine dipstick X Annual Annual
Quality of Life
X N/A N/A
questionnaire c
Pregnancy test d X Every clinic visit X
Plasma storage X N/A N/A
Adherence questionnaire X N/A N/A
Acceptability, sleep &
Xd Annual d Xd
mood questionnaire e
N/A as full lipodystrophy
Body composition
assessment should be Annual Annual
assessment f
performed at this visit
(a) Clinical assessment: including presence of adverse events and change in HIV disease stage.
(b) Frequency of blood tests will be as per local practice but some specific tests above routine care may be
required, subject to funding. These will be as per the trial assessment schedule for the randomised phase.
No additional tests will be performed in extended follow-up that were not performed during the
randomised phase.
(c) In children aged 8 or over
(d) Pregnancy test for females of childbearing potential only
(e) The full acceptability, sleep and mood questionnaire should be completed at the end of study visit for the
randomised phase, however, only the sleep and mood section should be completed for the extended follow-
up period. The sleep and mood section is only required to be completed for participants ≥6 years old.
(f) Weight, height, waist and hip circumferences and BIA measurements at the sites where BIA machines are
available. Replaces previously collected Lipodystrophy assessment data.

ODYSSEY Protocol
SAFETY REPORTING
Any event fulfilling the criteria of an SAE should be reported within 24 hours of the site team
becoming aware of the event. Other adverse events and pregnancies should be submitted
within one week of the site team becoming aware of the event.
CO-ENROLMENT
Co-enrolment in other studies is allowed. Centres should also adhere to local guidelines
concerning co-enrolment in other trials.

ODYSSEY (PENTA 20):
A randomised trial of dolutegravir
(DTG)-based antiretroviral therapy vs.
standard of care (SOC) in children with
HIV infection starting first-line or
switching to second-line ART.
Version: 2.0
Date: 6th March 2015
EUDRACT #: 2014-002632-14
NCT #: NCT02259127
Authorised by:
Name: Professor Ian Weller

Role: Chair ODYSSEY Trial Steering Committee
Signature:
Date: 20th March 2015
Name: Professor Carlo Giaquinto

Role: Chair, PENTA Foundation
ODYSSEY Protocol
th
Version 2.0; 6 March 2015
GENERAL INFORMATION
The trial will be co-ordinated and monitored by the UK Medical Research Council (MRC) Clinical
Trials Unit at University College London (UCL), (hereafter referred to as MRC CTU) in collaboration
with INSERM-ANRS SC10-US019, France (INSERM-ANRS) and the Program for HIV Prevention and
Treatment, Thailand (PHPT). Liaison between these Clinical Trials Units (CTUs) and clinical centres in
each country will be similar to that organised for other trials conducted by the Paediatric European
Network for the treatment of AIDS (PENTA), with a combination of direct liaison with a CTU (see
Section 2.3) and liaison via a local co-ordinating centre. Clinical centres in South Africa, Uganda and
Zimbabwe will be coordinated by MRC CTU; clinical centres in US, Uganda and South Africa joining
the trial from the International Maternal Pediatric Adolescent AIDS Clinical Trials Network (IMPAACT,
US) will also be coordinated through MRC CTU. The trial will be supervised by the ODYSSEY Trial
Management Group (TMG) who will report to the ODYSSEY Trial Steering Committee (TSC) (see
Appendix XIV for the committee structure within PENTA). The TSC may decide to terminate the trial
for any reason including the recommendation of the Independent Data Monitoring Committee
(IDMC).
This document was constructed using the MRC CTU Protocol Template Version 3.1. The protocol
should not be used as an aide-memoire or guide for the treatment of other children or young people
with HIV infection. Every care was taken in its drafting, but corrections or amendments may be
necessary. These will be circulated to the registered investigators in the trial, but centres entering
participants for the first time are advised to contact one of the co-ordinating CTUs to confirm they
have the most up-to-date version. Clinical problems relating to this trial should be addressed with
the relevant CTU.
COMPLIANCE
The trial will be conducted in accordance with the protocol, EU Clinical Trials Directive 2001/20/EC
Article 2, the principles of Good Clinical Practice (GCP) as laid down by the ICH topic E6 (Note for
Guidance on GCP), applicable national regulations and national data protection legislation.
SPONSOR
Paediatric European Network for Treatment of AIDS (PENTA) Foundation.
CHIEF INVESTIGATORS
Dr Pablo Rojo, Hospital 12 de Octubre, Madrid, Spain

Professor Diana M Gibb, MRC CTU at UCL, London, UK
FUNDING
This study is funded by ViiV Healthcare. MRC CTU at UCL and INSERM SC10 are supported by the
MRC (UK) and INSERM-ANRS (France) respectively. INSERM-ANRS supports the trial in France.
PENTA Foundation and EuroCoord provide support to sites in Europe.
ODYSSEY (PENTA 20) Page ii

ODYSSEY Protocol
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AUTHORISATIONS AND APPROVALS
This trial will be submitted for approval by Research Ethics Committees/Institutional Review Boards
and by all required regulatory authorities in each of the participating countries.
TRIAL REGISTRATION
This trial has been registered with EudraCT, ISRCTN and Clinicaltrials.gov.
RANDOMISATIONS
For those sites randomising directly, training will be provided for DIRECT
RANDOMISATION ONLINE as part of the site initiation and database training. Individual
passwords will be provided.
Alternatively, sites can fax or send by password protected email the Randomisation CRF to
the relevant CTU:
MRC CTU, Monday to Friday 09:00 to 17:00
Tel: +44 (0) 20 7670 4825
Fax: +44 (0) 20 7670 4814
Email: penta.mrcctu@ucl.ac.uk
Inserm-ANRS, Monday to Friday 09:00 to 17:00

Tel: + 33 1 45 59 50 83 / 52 55
Fax: + 33 1 46 58 72 93
PHPT, Monday to Friday 09:00 to 18:00

Tel: +66 (0) 53 814 633 ext. 710
Fax: +66 53 814 269
Email: suwalai@phpt.org
SAE REPORTING
Within 24 hours of becoming aware of an SAE, please fax or email a
completed SAE form to the relevant CTU. Please ensure that an acknowledgment of
MRC CTU: fax: +44 (0) 20 7670 4814 or email: penta.mrcctu@ucl.ac.uk
PHPT: fax: +66 53 814 269 or email: suwalai@phpt.org
ODYSSEY (PENTA 20) Page iii

ODYSSEY Protocol
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SPONSOR
PENTA FOUNDATION, ITALY: PENTA Foundation

Torre della Ricerca Pediatrica Corso Stati Uniti 4
Padova, 35127, Italy
Tel: +39 049 821 5447
STAFF:
Chair: Carlo Giaquinto
Project Manager: Luigi Comacchio
ODYSSEY (PENTA 20) Page iv

ODYSSEY Protocol
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TRIAL ADMINISTRATION AND MAIN CONTACTS
Please direct all queries to the relevant CTU (see contacts below) in the first instance.
MRC CTU, UK: MRC CTU at UCL

Aviation House, 125 Kingsway
London, WC2B 6NH, UK
Tel: +44 (0) 207 670 4700
STAFF:
Programme Diana M Gibb, MD, MSc
Lead:
Clinical Project Margaret Thomason, PhD, MSc
Manager:
Trial Manager: Anna Parker, PhD
Data Managers: Samuel Montero, BSc
Joanna Calvert, BSc
Trial Statistician: Angela Crook, PhD
Aimee Nunn, MSc
Trial Physician: Anna Turkova, MRCPCH
SITES:
Germany, Ireland, Italy, Netherlands, Russia, Sweden, Ukraine, UK, (as listed on www.penta-id.org)
Collaborating Centres
Torsak Bunupuradah, MD The HIV Netherlands Australia Thailand Research
Collaboration (HIV-NAT), 104 Rajdumri Road,
Pathumwan, Bangkok 10330, Thailand
James Gita Hakim, FRCP University of Zimbabwe Clinical Research Centre
Kusum Nathoo, MBChB, MRCP, MSc (UZCRC),
Hilda Angela Mujuru, MBChB, MMed, Box A1578 Avondale, Harare, Zimbabwe
MSc
Mutsa Bwakura-Dangarembizi, MBChB,
MMed,MSc
Cissy Kityo Mutuluuza, MSc, MBChB Joint Clinical Research Centre (JCRC),Plot 101
Victor Musiime, MBChB, MMED, PhD Lubowa Estates, off Entebbe road, Kampala,
Hilda Kizito, MBChB, MMED Uganda
Adeodata Kekitiinwa MBChB MMED Baylor College of Medicine Bristol Myers Squibb
Children’s Clinical Centre of Excellence, Block 5,
Mulago Hospital, P.O. Box 72052, Kampala, Uganda
Mark F. Cotton, FCPaed (SA), M.Med Children’s Infectious Diseases Clinical Research
(Paed), PhD, DCH (SA), DTM&H Unit (KID-CRU),
University of Stellenbosch, Tygerberg Children’s
Hospital, Ward J8, Francie van Zijl Avenue, Parow,
7505, Cape Town, South Africa
ODYSSEY (PENTA 20) Page v

ODYSSEY Protocol
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Jonathan Bernheimer, MD, MSc, The Paediatric and Adolescent Care Clinic (PACC)
DTM&H, FAAP Medecins Sans Frontieres (MSF) / Doctors Without
Borders
Khayelitsha, South Africa
Avy Violari, MD, FCPaed (SA) Chris Hani Baragwanath Hospital: Perinatal HIV
Research Unit, Chris Hani Baragwanath Hospital,
P.O. Box 114, Diepkloof, 1864, Soweto, South
Africa
Perinatal HIV Research Unit, Klerksdorp/Tsepong

Hospital Complex
Klerksdorp, South Africa
Pat Flynn, MD Department of Infectious Diseases, St Jude
Children’s Research Hospital, 262 Danny Thomas
Place, Memphis, TN 38105, US
INSERM-ANRS, FRANCE: 16 Avenue Paul Vaillant Couturier

Villejuif Cedex, 94807, France
Tel: +33 1 4559 5255
STAFF:
Project leader: Alexandra Compagnucci, MD
Trial Managers: Yoann Riault, MSc
Mbaye Ndiaye, MSc
Senior Trial Yacine Saidi, PhD
Manager:
SITES:
Argentina, Belgium, Brazil, Denmark, France, Portugal, Poland, Romania, Spain and Switzerland (as
listed on www.penta-id.org)
PHPT, THAILAND: PHPT-IRD 174

187/10, Changklan Road, Changklan,
Muang, 50100 Chiang Mai, Thailand
Tel: + 66 (0) 53 4 633 ext. 631
Email: tim.cressey@phpt.org
STAFF:
Project leader: Tim Cressey, PhD
Trial Manager: Suwalai Chalermpantmetagul
SITES:
Participating PHPT Centres in:
Thailand
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IMPAACT, US: IMPAACT Operations Center

FHI 360
359 Blackwell Street, Ste 200
Durham, NC27701, US
Email: IMPAACT.OperationsCenter@fstrf.org
STAFF:
Co-ordinator: Elaine Abrams, MD
Clinical Trials Katie McCarthy, MPH
Specialist:
SITES:
Collaborating Centres in:
South Africa and Uganda
Lee Fairlie, MD Shandukani Research Centre; Shandukani Research
Centre (Wits RHI), University of the Witwatersrand,
Hillbrow Health Precinct, Hugh Solomon Building,
Esselen Street, Hillbrow 2001, Johannesburg, South
Africa
Linda N. Barlow-Mosha, MD, MPH, FAAP Makerere University – John Hopkins University
Philippa Musoke, MD Research Collaboration, Upper Mulago Hill Road,
MU-JHU Research House, Old Mulago Hill, P.O. Box
23491, Kampala, Uganda
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Protocol expert: Pharmacology

864 Department of Clinical Pharmacy and Nijmegen Institute for Infection, Inflammation and
Immunity (N4i),
Radboud Univ, Nijmegen Med. Ctr. Nijmegen Geert Grooteplein 10, 6525 GA Nijmegen,
The Netherlands.
David Burger, PhD Email: david.burger@radboudumc.nl
Immunology/Virology Committee
Nigel Klein, BSc, MBBS, UCL Institute of Child Health, Email: n.klein@ucl.ac.uk
MRCP, PhD, FRCPCH London, UK
Anita De Rossi, PhD University of Padova, Italy Email: anita.derossi@unipd.it
Eleni Nastouli, FRCPCH, UCL Division of Infection & Immunity Email: e.nastouli@ucl.ac.uk
FRCPath
Maria Angeles Munoz Hospital General, Madrid, Spain Email:
Fernandez, PhD mmunoz@trasto.cbm.uam.es
Other members to be confirmed
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SUMMARY OF TRIAL
SUMMARY INFORMATION TYPE SUMMARY DETAILS

ACRONYM ODYSSEY (Once daily dolutegravir based ART in young people vs.
standard therapy)
Long Title of Trial A randomised trial of dolutegravir (DTG)-based antiretroviral therapy
vs. standard of care (SOC) in children with HIV infection starting first-
line or switching to second-line ART (PENTA 20)
Version 2.0
Date 6th March 2015
ISRCTN # ISRCTN91737921
EudraCT # 2014-002632-14
NCT # NCT02259127
Study Design An open-label, multi-centre, randomised (1:1), non-inferiority, Phase
II/III, 96-week, 2-arm clinical trial to compare the efficacy and toxicity
of DTG plus 2 NRTI vs. standard of care (SOC) in HIV-infected children
aged less than 18 years who are starting first-line ART (ODYSSEY A) or
switching to second-line ART (ODYSSEY B).
Type of Participants to HIV-1 infected children younger than 18 years planning to start first-
be Studied line or second-line antiretroviral therapy
Setting International
Interventions to be DTG + 2 NRTI (DTG arm) vs. SOC (SOC arm) in first-line and second-line
Compared antiretroviral regimens
Study Hypothesis DTG + 2 NRTIs is non-inferior to SOC (NNRTI or PI + 2 or 3 NRTIs) in
terms of efficacy and superior in terms of toxicity profile
Primary Outcome Difference in proportion with failure (clinical or virological) at 96
Measure(s) weeks, estimated using time to the first occurrence of any of the
following components:
Insufficient virological response defined as <1 log10 drop at week 24
Viral load (VL)>400 c/ml at or after 36 weeks confirmed by next visit
Any new or recurrent AIDS defining event (WHO 4) or severe WHO 3
event, adjudicated by the Endpoint Review Committee
Secondary Outcome Secondary efficacy outcomes:
Measure(s) Difference in proportion with clinical or virological failure (as
defined above) over 48 weeks
Time to any new or recurrent AIDS defining event (WHO 4) or
severe WHO 3 event after 24 weeks from randomisation,
adjudicated by the Endpoint Review Committee
Proportion of children with VL suppression <50 c/ml at 48 and 96
weeks
Proportion of children with VL suppression <400 c/ml at 48 and 96
weeks
Rate of clinical events over 96 weeks: WHO 4, severe WHO 3 events
and death
Change in CD4 count and percentage from baseline to weeks 48
and 96
Change in CD4 / CD8 ratio from baseline to weeks 48 and 96
Proportion developing new resistance mutations in those with viral
load >1000 c/ml
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Secondary safety outcomes:

Change in total cholesterol, triglycerides and lipid fractions (LDL,
HDL) from baseline to weeks 48 and 96. These safety outcomes will
be used to formally assess superiority of DTG arm vs SOC arm
Incidence of new clinical and laboratory grade 3 and 4 adverse
events
Incidence of adverse events (of any grade) leading to treatment
modification
Other secondary outcomes:
Quality of life
Randomisation Children starting first- and second-line ART will be randomised
separately (both in 1:1 ratio) :
DTG + 2 NRTIs
SOC (defined as PI or NNRTI + 2 or 3 NRTIs)
DTG + 2 NRTI
SOC (defined as PI or NNRTI or raltegravir + 2 NRTIs)
Number of Participants 700 HIV-1 infected children, including 310 children starting first-line
to be Studied (ODYSSEY A) and 390 starting second-line ART (ODYSSEY B)
Duration Participants will be enrolled over 72-96 weeks. All participants will be
followed until the last recruited participant reaches week 96
Ancillary The following sub-studies will be performed in selected sites:
Studies/Substudies Pharmacokinetics (PK) in participants developing TB while on DTG
Full PK curves will be undertaken in at least 10 children receiving DTG
and rifampicin; curves will be repeated in the same children after
completion of TB therapy
Immunology/virology substudy
Mechanisms of CD4 reconstitution, immune activation, HIV reservoir
and replication will be compared between DTG vs. SOC arms
Sponsor PENTA Foundation
Funder Funded by ViiV Healthcare and the PENTA Foundation. MRC CTU at
UCL and INSERM SC10 are supported by the MRC (UK) and INSERM-
ANRS (France) respectively; INSERM-ANRS supports the trial in France;
Eurocoord provide support for the sites in Europe
Partners MRC CTU at UCL, INSERM-ANRS, PHPT, IMPAACT, Eurocoord, PENTA
Chief Investigator Pablo Rojo and Diana M Gibb
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TRIAL SCHEMA
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TRIAL ASSESSMENT SCHEDULE
WEEK Screening Randomisation (2) 4 12 24 36 48 60 72 84 96 Further follow-up End of

a
0 study visit
Patient information sheet and
X
consent for screening
Informed consent for trial
X
enrolment
History and clinical assessment b X X (X) X X X X X X X X X Every 12 weeks X
Tanner scale c X X X X X Every 24 weeks X
Lipodystrophy assessment X X X Every 48 weeks
Drug supply to next visit X (X) X X X X X X X X X Every 12 weeks
HIV-1 RNA viral load d Xd (X) (X) (X) (X) (X) (X) (X) (X) (X) (X) (X) As per local practice Xd
T cell lymphocyte subsets e X X X X X (X) X (X) X (X) X As per local practice X
Biochemistry f X (X) (X) X (X) X (X) X (X) X (X) X As per local practice X
Haematology g X X (X) X (X) X (X) X (X) X (X) X As per local practice X
Lipids/glucose h X (X) X X Every 48 weeks X
Bone profile i (X) (X) (X) Every 48 weeks
Urine dipstick j X X X Every 48 weeks X
EQ-5D questionnaire c X X X X X Every 48 weeks X
Pregnancy test k X Xk X X X X Every 24 weeks X
Plasma storage l X X (X) X X X X X X X X X Every 24 weeks X
Cell storage m Xm Xl (Xm) Xm Xm Xm Xl
Adherence questionnaire Xn X X X X X X X X X Every 12 weeks X
Acceptability questionnaire X X X X X Every 24 weeks X
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Notes:
( ) Optional, not mandatory
Darker shaded boxes indicate visits where overnight fasting is required for blood lipids/glucose.
A total of 10-15 ml blood should be collected at each visit depending upon the size of the child.
a. Randomisation visit should take place within 4 weeks after the screening visit, ideally within 2 weeks
b. Clinical assessment: including height, weight (and adjustment of drug doses accordingly) and mid upper arm circumference (MUAC), change in HIV
disease stage, clinical events and presence of adverse events
c. In children aged 8 or over
d. Real-time viral loads will be measured on all children in ODYSSEY B at screening visit. For children recruited in ODYSSEY A, this is not mandatory.
Thereafter in both ODYSSEY A and B, viral loads should be measured locally at sites according to the routine frequency, where viral loads are not
measured in real time, they will be run retrospectively in batches on stored plasma
e. CD4 and CD8 percentage and absolute, total lymphocyte count. In addition, immunophenotyping (IPT) on the same blood draw will be done at the sites
participating in the immunology/virology substudy, and where IPT tests are available. At the other sites IPT will be done on the cell storage samples.
f. Biochemistry: creatinine, bilirubin, ALT or AST
g. Haematology: Hb, MCV, WBC, lymphocytes, neutrophils, platelets
h. Lipids/Glucose: triglycerides, cholesterol (total, HDL, LDL), glucose (overnight fasting required at randomisation and weeks 24 and 48, and then every
48 weeks)
i. Bone profile: calcium, phosphate, alkaline phosphatase
j. Urine dipstick: for protein and glucose, performed at randomisation and then every 48 weeks and at end of study visit
k. Pregnancy test: urine sample; the test should be performed for all females of childbearing potential at screening, randomisation and then weeks 24, 48
and every 24 weeks. Also at other time-points if required.
l. Plasma and cell storage: for retrospective HIV-1 RNA viral load, resistance testing where not routinely available locally and immunology substudy. See
Manual of Operations for more detail.
m. Cells will be stored at selected sites
n. Baseline adherence questionnaire for patients screened for Odyssey B
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CONTENTS
GENERAL INFORMATION ................................................................................................................... II
SUMMARY OF TRIAL ......................................................................................................................... IX
TRIAL SCHEMA ................................................................................................................................. 11
TRIAL ASSESSMENT SCHEDULE ........................................................................................................ 12
CONTENTS ....................................................................................................................................... 14
ABBREVIATIONS............................................................................................................................... 18
1 BACKGROUND ..................................................................................................................... 21
1.1 DTG ADULT TRIALS.................................................................................................................. 21
1.2 DTG IN CHILDREN.................................................................................................................... 22
1.3 FIRST- AND SECOND-LINE ART OPTIONS FOR CHILDREN: THE PLACE OF DTG ...................................... 23
1.4 DTG WITH ANTI-TUBERCULOSIS (TB) THERAPY ............................................................................. 24
1.5 MARKETING AUTHORISATION ..................................................................................................... 24
1.6 RATIONALE AND OBJECTIVES............................................................................................... 24
2 SELECTION OF SITES/CLINICIANS ......................................................................................... 26

2.1 SITE /INVESTIGATOR INCLUSION CRITERIA ..................................................................................... 26
2.2 APPROVAL AND ACTIVATION...................................................................................................... 26
2.3 SITE MANAGEMENT ................................................................................................................. 27
3 SELECTION OF PATIENTS ...................................................................................................... 28

3.1 PATIENT INCLUSION CRITERIA..................................................................................................... 28
3.1.1 All patients:.......................................................................................................................... 28
3.1.2 Additional criteria for ODYSSEY A: ........................................................................................ 28
3.1.3 Additional criteria for ODYSSEY B: ........................................................................................ 29
3.2 PATIENT EXCLUSION CRITERIA .................................................................................................... 29
3.3 CONSIDERATIONS FOR USE OF DIFFERENT NRTI .................................................................. 29
3.3.1 ABC-containing products ...................................................................................................... 29
3.4 NUMBER OF PATIENTS .............................................................................................................. 30
3.5 CO-ENROLMENT GUIDELINES...................................................................................................... 31
3.6 SCREENING PROCEDURES & PRE-RANDOMISATION INVESTIGATIONS ................................................. 31
3.6.1 Screening visit ...................................................................................................................... 31
4 REGISTRATION & RANDOMISATION .................................................................................... 32

4.1 RANDOMISATION PRACTICALITIES ............................................................................................... 32
4.2 CO-ENROLMENT GUIDELINES...................................................................................................... 33
5 TREATMENT OF PATIENTS ................................................................................................... 34

5.1 INTRODUCTION ....................................................................................................................... 34
5.2 SOC ARM .............................................................................................................................. 34
5.2.1 SOC ODYSSEY A .................................................................................................................... 35
5.2.2 SOC ODYSSEY B .................................................................................................................... 35
5.3 DTG ARM .............................................................................................................................. 36
5.3.1 DTG ...................................................................................................................................... 37
5.3.2 Fixed dose combination of DTG, ABC and 3TC ...................................................................... 37

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5.4 DISPENSING ............................................................................................................................ 37

5.5 DOSE MODIFICATIONS, INTERRUPTIONS & DISCONTINUATIONS ........................................................ 38
5.5.1 Dose Modifications, Interruptions & Discontinuations of antiretroviral drugs....................... 38
5.5.2 Dose Modifications, Interruptions & Discontinuations of DTG .............................................. 39
5.6 ACCOUNTABILITY & UNUSED DRUGS /DEVICES .............................................................................. 40
5.7 COMPLIANCE & ADHERENCE ...................................................................................................... 40
5.8 OVERDOSE OF TRIAL MEDICATION .............................................................................................. 40
5.9 PROTOCOL TREATMENT DISCONTINUATION .................................................................................. 40
5.10 NON-TRIAL TREATMENT ............................................................................................................ 41
6 ASSESSMENTS & FOLLOW-UP .............................................................................................. 42

6.1 TRIAL ASSESSMENT SCHEDULE .................................................................................................... 42
6.2 PROCEDURES FOR ASSESSING EFFICACY ........................................................................................ 43
6.2.1 Clinical: ................................................................................................................................ 43
6.2.2 Immunology: ........................................................................................................................ 43
6.2.3 Viral load testing: ................................................................................................................. 43
6.2.4 Resistance testing ................................................................................................................ 44
6.3 PROCEDURES FOR ASSESSING SAFETY .......................................................................................... 44
6.4 PROCEDURES FOR ASSESSING QUALITY OF LIFE .............................................................................. 44
6.5 ADHERENCE ASSESSMENTS ........................................................................................................ 44
6.6 MANAGEMENT OF PARTICIPANTS WITH TREATMENT FAILURE ........................................... 45
6.7 MANAGEMENT OF CHILDREN DIAGNOSED WITH TUBERCULOSIS (TB) .................................................. 45
6.7.1 Management of children with tuberculosis in the DTG arm .................................................. 45
6.7.2 Management of children with tuberculosis in the SOC arm .................................................. 45
6.8 MANAGEMENT OF PREGNANCY .................................................................................................. 46
6.9 EARLY STOPPING OF FOLLOW-UP................................................................................................. 47
6.10 PARTICIPANT TRANSFERS........................................................................................................... 47
6.11 END OF TRIAL.......................................................................................................................... 47
7 SAFETY REPORTING ............................................................................................................. 49

7.1 DEFINITIONS ........................................................................................................................... 49
7.1.1 Medicinal Products .............................................................................................................. 50
7.1.2 Adverse Events..................................................................................................................... 50
7.1.3 exempted Adverse Events .................................................................................................... 50
7.1.4 Disease-related Events ......................................................................................................... 50
7.1.5 Other Study-specific Requirements ...................................................................................... 50
7.2 OTHER NOTABLE EVENTS .......................................................................................................... 51
7.2.1 Pregnancy ............................................................................................................................ 51
7.3 INVESTIGATOR RESPONSIBILITIES ................................................................................................ 51
7.3.1 Investigator Assessment....................................................................................................... 51
7.3.2 Notification Procedure ......................................................................................................... 53
7.4 CTU RESPONSIBILITIES.............................................................................................................. 54
8 QUALITY ASSURANCE & CONTROL ...................................................................................... 55

8.1 RISK ASSESSMENT.................................................................................................................... 55
8.2 CENTRAL MONITORING AT MRC CTU ......................................................................................... 55
8.3 ON-SITE MONITORING.............................................................................................................. 55
8.3.1 Direct Access to Participant Records .................................................................................... 56
8.3.2 Confidentiality ..................................................................................................................... 56
9 STATISTICAL CONSIDERATIONS ........................................................................................... 57

9.1 METHOD OF RANDOMISATION ................................................................................................... 57
9.2 OUTCOME MEASURES .............................................................................................................. 57

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9.2.1 Primary efficacy outcome (over 96 weeks) ........................................................................... 57

9.2.2 Secondary efficacy outcomes ............................................................................................... 57
9.2.3 Secondary safety outcomes.................................................................................................. 57
9.2.4 Other secondary outcomes .................................................................................................. 58
9.3 SAMPLE SIZE ........................................................................................................................... 58
9.4 INTERIM MONITORING & ANALYSES............................................................................................ 58
9.5 ANALYSIS PLAN (BRIEF) ............................................................................................................ 58
10 ANCILLARY STUDIES............................................................................................................. 60
10.1 IMMUNOLOGY / VIROLOGY SUBSTUDY........................................................................................... 60
10.2 PHARMACOKINETIC SUBSTUDY IN PARTICIPANTS DEVELOPING TB WHILE ON DTG: ............................... 60
11 REGULATORY & ETHICAL ISSUES.......................................................................................... 61

11.1 COMPLIANCE .......................................................................................................................... 61
11.1.1 Regulatory Compliance ........................................................................................................ 61
11.1.2 Site Compliance ................................................................................................................... 61
11.1.3 Data Collection & Retention ................................................................................................. 61
11.2 ETHICAL CONDUCT OF THE STUDY ............................................................................................... 61
11.2.1 Ethical Considerations .......................................................................................................... 61
11.2.2 Ethical Approvals.................................................................................................................. 62
11.3 COMPETENT AUTHORITY APPROVALS .......................................................................................... 63
11.4 OTHER APPROVALS .................................................................................................................. 63
12 INDEMNITY .......................................................................................................................... 64
13 FINANCE .............................................................................................................................. 65
14 OVERSIGHT & TRIAL COMMITTEES ...................................................................................... 66

14.1 TRIAL MANAGEMENT GROUP (TMG) .......................................................................................... 66
14.2 TRIAL STEERING COMMITTEE (TSC)............................................................................................. 66
14.3 INDEPENDENT DATA MONITORING COMMITTEE (IDMC] ................................................................ 66
14.4 ENDPOINT REVIEW COMMITTEE .................................................................................................. 66
14.5 ROLE OF STUDY SPONSOR ......................................................................................................... 66
15 PUBLICATION....................................................................................................................... 67
15.1 PUBLICATION .......................................................................................................................... 67
15.2 FEEDBACK TO PARTICIPANTS....................................................................................................... 67

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16 PROTOCOL AMENDMENTS .................................................................................................. 68
17 REFERENCES ........................................................................................................................ 70
APPENDIX I TEMPLATE INFORMATION SHEETS ............................................................................... 73
APPENDIX II TEMPLATE CONSENT AND ASSENT FORMS ................................................................. 92
APPENDIX III TEMPLATE GP LETTER .............................................................................................. 104
APPENDIX IV TEMPLATE ADHERENCE QUESTIONNAIRES .............................................................. 105
APPENDIX V TEMPLATE ACCEPTABILITY QUESTIONNAIRES: ODYSSEY A ....................................... 109
APPENDIX VI TEMPLATE ACCEPTABILITY QUESTIONNAIRE: ODYSSEY B ........................................ 112
APPENDIX VII ADAPTED WHO CLINICAL STAGING OF HIV/AIDS FOR PATIENTS WITH CONFIRMED
HIV INFECTION ............................................................................................................................... 115
APPENDIX VIII ADAPTED DIAGNOSTIC CRITERIA FOR WHO CLINICAL STAGING EVENTS IN
CHILDREN YOUNGER THAN 15 YEARS ............................................................................................ 117
APPENDIX IX CRITERIA FOR WHO CLINICAL STAGING EVENTS FOR YOUNG PEOPLE 15 YEARS AND
OLDER 123
APPENDIX X ADAPTED DAIDS TOXICITY GRADINGS ...................................................................... 129
APPENDIX XI TANNER SCALES ....................................................................................................... 147
APPENDIX XII IMMUNOLOGY SUBSTUDY....................................................................................... 149
APPENDIX XIII SUBSTUDY PHARMACOKINETIC SUBSTUDY IN PARTICIPANTS DEVELOPING TB

WHILE ON DTG:.............................................................................................................................. 151
APPENDIX XIV ODYSSEY STRUCTURE ............................................................................................ 152
APPENDIX XV REFERENCES ............................................................................................................ 153

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ABBREVIATIONS
ABC Abacavir
AE Adverse Event
ANRS National Agency for Research (France)
AR Adverse Reaction
ART Antiretroviral Therapy
ARV Antiretrovirals
ATV Atazanavir
AUC Area Under Curve
BID Twice Daily
bPI Boosted Protease Inhibitor
c/ml Copies per ml
CDC Centres for Disease Control
CI Confidence Interval
CI Chief Investigator
CRF Case Report Form
CTA Clinical Trials Authorisation (Europe)
CTU Clinical Trials Unit (MRC, INSERM-ANRS, PHPT - as appropriate for the country)
d4T Stavudine
DRV/r Darunavir/ritonavir
DSMS Drug Supply Management System
DSUR Development Safety Update Report
DTG Dolutegravir
EFV Efavirenz
EMA European Medicines Agency
EQ-5D EuroQol. EQ-5D™ A standardised instrument for use as a measure of health outcome.
http:/ /www.euroqol.org/about-eq-5d.html
ERC Endpoint Review Committee
EU European Union
EUDRACT European Union Drug Regulatory Agency Clinical Trial
FDA Food and Drug Administration
FDC Fixed Dose Combination
FTC Emtricitabine
HAART Highly Active Antiretroviral Therapy

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HBV Hepatitis B Virus

HDL High-Density Lipoproteins
HIV Human Immunodeficiency Virus
HIV NAT HIV Netherlands Australia Thailand Research Collaboration
HSR Hypersensitive Reaction
IB Investigator’s Brochure
ICH GCP International Conference on Harmonisation (of Technical Requirements for
Registration of Pharmaceuticals for Human Use) Good Clinical Practice
IDMC Independent Data Monitoring Committee
IMP Investigational Medical Product
IMPAACT International Maternal Paediatric Adolescents AIDS Clinical Trials
INI Integrase Inhibitor
INSERM-ANRS Institut National de la Santé et de la Recherche Médicale
INSERM-ANRS Institut National de la Santé et de la Recherche Médicale Service Commun 10 –
SC10-US019 Unité de Services 019
ISF Investigator Site File
ISRCTN International Standard Randomised Controlled Trial Number
LDL Low-Density Lipoproteins
LPV/r Lopinavir/ritonavir
MOP Manual of Operations
MRC CTU Medical Research Council Clinical Trials Unit at UCL (UK)
MUAC Mid Upper Arm Circumference
NHS National Health Service (UK)
NNRTI Non-nucleoside Reverse Transcriptase Inhibitor
NRTI Nucleoside Reverse Transcriptase Inhibitor
OD Once daily
PENTA Paediatric European Network for Treatment of AIDS
PHPT Program for HIV Prevention and Treatment (Thailand)
PI Protease Inhibitor
PIS Patient information Sheet
PK Pharmacokinetics
pMTCT Prevention of Mother to Child Transmission
QA Quality Assurance
QC Quality Control
R&D Research & Development

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RAL Raltegravir
SAE Serious Adverse Event
SAP Statistical Analysis Plan
SAR Serious Adverse Reaction
SOC Standard Of Care (defined as the antiretroviral regimen routinely prescribed at a
particular site for an ART-naïve or for an ART-experienced patient)
SPF Summary of Product Characteristics
SSA Sub-Saharan Africa
SUSAR Suspected Unexpected Serious Adverse Reaction
TAM Thymidine Analogue resistance Mutation
TB Tuberculosis
TDF Tenofovir
TDM Therapeutic Drug Monitoring
TMF Trial Master File
TMG Trial Management Group
TSC Trial Steering Committee
UAR Unexpected Adverse Reaction
ULN Upper Limit of Normality
VL Viral Load
ZDV Zidovudine
3TC Lamivudine

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1 BACKGROUND
With the development of new antiretroviral drugs (ARVs), including new drug classes, which offer
simplified, more potent options for first- and second-line therapy with fewer adverse effects in
adults, there is a need to evaluate their place in paediatric HIV treatment.
Unique issues for HIV-infected children include: potential for perinatal transmission of viruses
resistant to antiretroviral therapy (ART) regimens taken by mothers during pregnancy and
breastfeeding; special consideration of adverse events as children take drugs during growth and
development and will be on them for much longer than adults; and the need for age appropriate
once daily formulations, preferably fixed dose scored dispersible combinations which may require
different ratios of drugs from those used in adults.
Globally, more than 90% of HIV-infected children live in Sub Saharan Africa (SSA) and overall
coverage among children in need of ART lags considerably behind adults at only 34% (compared with
65% in adults) in 2012 (1). Rapid disease progression and high early mortality require that ART is
started early in life and many children still die before they are diagnosed. Children <3 years in
low/middle income countries are taking either non-nucleoside reverse transcriptase inhibitors
(NNRTI)-based ART (e.g. most African countries, India, Eastern Europe) or protease inhibitor (PI)
(lopinavir/ritonavir, LPV/r)-based ART (South Africa; some centres of excellence in SSA). Children >3
years in SSA, including South Africa, start NNRTI-based ART. In both well-resourced and resource-
limited settings, there is a need for alternative first- and second-line regimens which can be given in
the face of possible transmitted resistance (from prevention of mother to child transmission pMTCT)
or resistance arising from first-line ART, whether PI or NNRTI based. New regimens need to be
potent, durable, non-toxic and available in acceptable once daily formulations with correct drug
ratios. Ideally regimens should be robust with a high barrier to resistance, have minimal cross-
resistance and minimal interactions with anti-tuberculosis drugs.
Dolutegravir (DTG) is a new integrase inhibitor (INI) with the advantage of once daily dosing, a good
short-term safety profile, low pharmacokinetic variability, few drug-to-drug interactions, rapid and
robust virological response with an optimised background treatment, a distinct resistance profile
from raltegravir, a high genetic barrier to resistance and high potency at a low milligram dose.
Combination regimens with DTG will therefore be attractive for children starting first-line ART and
for those switching to second-line for reasons of toxicity or failure.
1.1 DTG ADULT TRIALS
There are encouraging efficacy and safety data from Phase II and III studies of DTG in adults (2-6)
with reassuring safety data reported at 96 week endpoints (2-4). SPRING-2, SINGLE and FLAMINGO
Phase III studies were conducted on treatment-naïve adults. SPRING-2 showed that DTG once daily
(OD) is non-inferior to twice daily (BID) raltegravir in combination with ABC+3TC or TDF+FTC at 96
weeks, and superior in patients with VL >100,000 c/ml (3). SINGLE compared DTG in combination
with ABC+3TC to efavirenz (EFV) in combination with TDF+FTC. Results showed that the DTG
combination is superior in efficacy and safety at 48 weeks and are consistent for patients with VL
</>100,000 c/ml and CD4 count </>200 cells/mm3 (6). A subsequent analysis of bone marker
changes at 48 weeks demonstrated that DTG+ABC+3TC was associated with significantly smaller
changes compared to Atripla (EFV/TDF/FTC) indicating more active bone turnover in patients on
Atripla, which may correlate with the known TDF-associated effect on bone mineral density over
time (7).

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FLAMINGO, an open-label, non-inferiority trial compared DTG with darunavir (DRV) boosted with
ritonavir (/r) plus investigator-selected TDF+FTC or ABC+3TC in previously untreated adults. The trial
showed that DTG was superior to DRV/r at 48 and 96 weeks (8, 9). The difference was most
pronounced in participants with baseline viral load ≥100,000 c/ml. There was no treatment-
emergent resistance to study drugs (8). Patients randomised to DTG had better lipid profiles with
significantly less grade 2 or above low-density lipoprotein cholesterol results (2% versus 7%,
p<0.001).
A recently presented systematic review and meta-analysis compared virological efficacy (HIV-1 RNA
<50 c/ml) and CD4 change on DTG-based ART compared with other recommended third agents for
the first-line treatment of HIV-infected patients. The results showed that DTG has a higher
probability of virological suppression than all guideline recommended third agents (EFV, rilpivirine,
atazanavir (ATV)/r, DRV/r and LPV/r) and compared to EFV, ATV/r and LPV/r it also has better CD4
cell responses from baseline to week 48 (10).
The studies in treatment-experienced adult patients also showed very encouraging results. SAILING,
a Phase III trial in treatment-experienced, INI-naïve patients, with at least two-class drug resistance,
compared OD DTG- versus raltegravir-based ART combined with no more than 2 other agents, one of
which was fully active: by 48 weeks, 71% vs. 64% patients reached undetectable viral load (11).
VIKING-3, a Phase II study on safety and efficacy of BID DTG in highly treatment-experienced
patients with previous resistance to INI and 2 other classes (70% patients had mutations to PIs),
showed that 69% reached undetectable viral load at 24 weeks and 56% at 48 weeks of treatment.
Only 3% of patients discontinued treatment due to adverse events (12).
In order to inform the ODYSSEY design, an exploratory analysis of subjects receiving DTG plus 1-2
NRTIs in SAILING was conducted (personal communication from the SAILING team). None of the 32
subjects in the DTG arm, who received an NRTI-based background regimen, experienced protocol
defined virological failure by week 48, including no cases of virological failure in 13 subjects receiving
less than 2 fully active NRTIs by phenotype (12 received one fully active NRTI and 1 received two
inactive NRTIs)(13). Based on this exploratory analysis, DTG + 2 NRTIs appears to have good activity
through 48 weeks in treatment-experienced patients when at least one of the NRTIs was fully active
by phenotype. However, because of the small sample size, an increased risk of virological failure in
subjects receiving DTG with less than 2 fully active NRTIs cannot be ruled out based on these data
alone.
1.2 DTG IN CHILDREN
A paediatric dose-finding Phase I/II study is ongoing. The study is enrolling treatment-experienced
children failing their regimen. Children were started on DTG with an optimized background regimen
containing at least one fully active antiretroviral drug (13, 14). The results are available for older
children. In children aged 12-18 years the PK study showed that an adult dose of 50 mg can be used
(13). Recently presented week 48 data showed that 74% children (95% CI 52% to 90%) achieved
viral load of <400 c/ml (14). DTG was well tolerated with two patients experiencing grade 3
laboratory adverse events, which were evaluated as not related to DTG. There were no drug-related
clinical adverse events, no grade 3 or 4 clinical events, and no serious adverse events. The 24 week
results of the PK, safety and virological efficacy study in children 6 to 12 years of age showed
adequate AUC24 and C24 with the dose of ~1 mg/kg (16). Three subjects experienced grade 3
laboratory events all of which were deemed unrelated to DTG. There were no grade 4 AEs, SAEs or
study discontinuations secondary to AEs (15). The study on younger children is ongoing.

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1.3 FIRST- AND SECOND-LINE ART OPTIONS FOR CHILDREN: THE PLACE OF DTG
DTG-based treatment with two NRTIs offers a potent regimen, with advantages of low toxicity, and
the potential for once daily dosing. The rapid virological response observed following initiation of
ART with DTG-based ART will be highly relevant for children with very high viral loads, which is
commonly observed in younger children. DTG has high potency at a low milligram dose, and
therefore it could be particularly attractive for young children in both well-resourced and resource-
limited settings, who have limited options and may be more likely to be infected with resistant
viruses through mother-to-child transmission (MTCT). In resource-limited countries, a DTG-based
regimen has the potential to be potent. This is important in children exposed and resistant to
NNRTIs (in particular, single dose nevirapine (NVP)) for prevention of MTCT as there is no cross-
resistance with NNRTIs. Preliminary studies have shown that the taste of paediatric granules is
acceptable (16) and a dispersible tablet formulation is also in preparation. A DTG-based first-line
regimen is likely to be better tolerated and logistically advantageous for ART programmes currently
using liquid LPV/r, as well as needing to be dosed once rather than twice daily.
The choice of NRTI backbone depends on the child’s age, history of previous NRTI exposure (for ART
experienced children) and drug availability in a country. The combination of abacavir (ABC) +
lamivudine (3TC) is already frequently used as a preferred first-line nucleoside reverse transcriptase
inhibitors (NRTI) ‘backbone’ and tenofovir disoproxil fumarate (TDF) + emtricitabine (FTC) or TDF +
3TC are increasingly being used in older children (TDF recently received regulatory approval by both
Food and Drug Administration (FDA) and European Medicines Agency (EMA) for children >2 years of
age). Furthermore, there are reasons to use ABC or TDF as part of a first-line regimen as resistance
to both these drugs follows the same ‘resistance pathway’ and does not affect potency to
zidovudine (ZDV) for second-line (and in fact may result in hyper-susceptibility to ZDV), whereas
using ZDV in first-line typically results in accumulation of thymidine analogue resistance mutations
(TAMs) which may limit second-line NRTI options. The most recent WHO 2013 guidelines
recommend ABC or ZDV as part of first-line ART; if ZDV is used in first-line, then ABC + 3TC are
recommended in second-line. PK data from PENTA trials (17, 18) and most recently, 96-week viral
load and clinical efficacy data as well as safety data from the paediatric ARROW trial, have shown
that once daily dosing with ABC + 3TC is non-inferior to twice daily in terms of viral load suppression,
safety and clinical efficacy (19). Thus, with ABC + 3TC, DTG has the potential to be part of a potent,
safe and simple fixed dose combination (FDC) for both first- and second-line ART in children.
DTG can be used as part of a second-line regimen in children failing first-line PI-based therapy;
despite the presence of viral rebound for long periods, the NRTI backbone remains relatively
protected in the presence of a boosted PI (bPI). No TAMs developed in children failing LPV/r-based
first line ART in a large paediatric study (CHER) (20) and only 3/22 (14%) developed ≤2 TAMs and
none developed >2 TAMs in the PENPACT1 trial when switch was delayed until children had viral
load (VL) >30,000 c/ml (21). Children failing NNRTI-based regimens developed TAMs more
frequently. The PENPACT1 study showed that 3/20 (15%) children who were randomised to switch
their first-line ART at VL of 1000 c/ml developed one TAM, whereas children randomised to switch at
VL of 30,000 c/ml developed TAMs at higher rates: 9/22 (41%) developed ≥1 TAM, 5/22 (23%) ≥2
TAMs and 4/22 (18%) had 3 TAMs (21). In small studies in Uganda nearly 10% of children developed
a first TAM by 6 months of early virological failure on NNRTI-based regimen (22, 23) and 9%
developed 2 TAMs by 12 months of virological failure(23). The presence of no more than two TAMs
is expected to reasonably retain ABC potency. Therefore, for children in resource-limited countries
in whom ZDV has been used first-line and VL and resistance testing are not available, it might still be
expected that ABC potency might not be unduly compromised when used with DTG (which itself has
a high barrier to resistance) and that this regimen might have similar potency and greater
acceptability compared with a bPI-based second-line regimen. Patients who are failing ABC + 3TC or
stavudine (d4T) + 3TC containing first-line ART are at risk of accumulating the K65R mutation and

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thus susceptibility to ABC or TDF containing second-line ART may be reduced. Variable rates of
acquiring the K65R mutation are reported in paediatric trials. In the PENPACT1 trial 1/14 children on
ABC + 3TC developed the K65R mutation (24). A multi-centre study in sub-Saharan Africa found that
K65R occurred in 3/20 (15%) and 13/47 (28%) adults failing on d4T-or TDF-containing ART
respectively, after 12 months of virological failure (24). However, the majority of patients switching
empirically to ZDV, ABC or TDF-containing ART would be expected to have at least 2 active drugs
with a DTG-based regimen, and therefore to have an effective ART regimen. Supporting this, adult
studies from Africa showed high rates of virological re-suppression with empirically prescribed and
re-cycled second-line ART even when switching ART very late (25-27). Of note, DTG can be used in
liver and renal impairment without dose modification (28, 29).
1.4 DTG WITH ANTI-TUBERCULOSIS (TB) THERAPY
A PK study of co-administration of DTG with rifampicin in healthy adult volunteers showed that BID
DTG overcomes the induction effect of rifampicin (30) and therefore can be used in HIV/TB co-
infection. It will be important to study the DTG PK in children on ART who require anti-TB treatment
with rifampicin, as in many settings TB is common in HIV-infected children, even when on ART.
1.5 MARKETING AUTHORISATION
DTG was approved by the FDA in August 2013 and by the EMA in January 2014 for the treatment of
adults and adolescents > 12 years of age naïve to integrase inhibitors. A single tablet of DTG + 3TC +
ABC has been developed, providing an attractive option of a one-pill once daily regimen for older
children >12 years. A PK study in healthy volunteers demonstrated that FDC DTG 50mg/ABC
600mg/3TC 300mg is bioequivalent to DTG alone in combination with ABC/3TC (31, 32). This FDC
has been recently approved for adults by FDA and for adults and children > 12 years by EMA.. The
dose finding and safety assessment study in younger children is ongoing (15).
1.6 RATIONALE AND OBJECTIVES
DTG is a new drug which offers the potential to be highly effective, safe and simple when used as
part of first- or second-line ART regimens. Following adult Phase II/III trials, DTG needs evaluation to
determine its place as first-line and second-line therapy in adolescent and paediatric HIV treatment.
Standard ART for children is a NNRTI or bPI, plus 2 NRTI and where possible fixed drug combinations
(FDC) are preferred to support adherence. Adult US and European guidelines now recommend
integrase inhibitors as part of first-line regimens. In contrast, current options for paediatric 1st and
2nd line ART are fewer although raltegravir-based ART is being used in some clinics, generally for
second-line, following LPV/r based regimens. Concerns have been raised about the potency of NVP-
based ART in infants (33), and EFV is not readily available for children <3 years. Neither EFV nor NVP
are available in a 3-drug once-daily FDC for children. The only available FDC for adolescents is EFV,
TDF with either emtricitabine (Atripla) or 3TC (generic). With currently used doses, EFV may cause
significant neuropsychological side effects (34). Similarly, the only available bPI for young children is
LPV/r, an unpleasant tasting liquid requiring a cold chain. LPV/r tablets for children are relatively
large and need to be swallowed whole or they lose bioavailability. Two other PIs, ATV and DRV, are
available for older children in high-income countries but need to be boosted with ritonavir tablets.
Finally, TDF, a preferred NRTI in adults, has only recently been licensed for children and concerns
remain about long-term renal and bone toxicity in growing children.

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DTG with two NRTIs will potentially offer a potent and safe regimen for both ART-naïve and ART-
experienced children and is available as a FDC with ABC and 3TC for children >12 years.
No randomised trial has been undertaken comparing this new regimen with standard of care in
children, who potentially have more to gain in terms of minimising long term HIV and ART
complications, improving long-term adherence to medication and gaining better quality of life than
adults.
ODYSSEY will be a pragmatic strategy trial evaluating the efficacy and safety of once daily DTG-based
ART compared with standard of care in children and adolescents starting first- or second-line ART in
resource-limited and well-resourced settings.

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2 SELECTION OF SITES/CLINICIANS
The trial sponsor has overall responsibility for site and investigator selection.
2.1 SITE/INVESTIGATOR INCLUSION CRITERIA
Clinical sites invited to enrol children and young people in ODYSSEY will usually have previously
collaborated in trials with the MRC CTU, INSERM-ANRS, PHPT or IMPAACT. In the case of a new site
wishing to participate, the site will need to demonstrate sufficient resources to conduct clinical trial
research with children and young people.
The principal investigator will sign an Investigator’s Agreement for that institution on behalf of all
staff at that site who will be working on the ODYSSEY trial. The principal investigator will sign to
confirm that:
The institution has an adequate number of qualified staff and adequate facilities for the
foreseen duration of the trial to conduct the trial properly and safely.
All staff assisting with the trial are adequately informed about the protocol, the
investigational products and their trial-related duties.
The trial will be conducted in accordance with the current protocol and changes will only be
made when necessary to protect the safety, rights or welfare of participants.
The trial will be conducted in compliance with the principles of ICH GCP and applicable
regulatory requirements.
The institution will permit monitoring and auditing by the relevant CTU and inspection by
the appropriate regulatory authorities. Direct access will be made available to all trial-
related sites, data/documents and reports.
The institution will maintain an Investigator Site File (ISF), which will contain essential
documents for the conduct of the trial.
All trial data will be submitted in a timely manner and as described in the protocol.
All Serious Adverse Events (SAEs) will be reported to the relevant CTU within 24 hours of the
investigator becoming aware of the event. The initial SAE report shall be promptly followed
by detailed follow up reports.
All employees, students or agents engaged in the research shall maintain the confidentiality
of information.
No data on trial participants will be disclosed without the approval of the Trial Steering
Committee (TSC).
All trial-related documents will be retained for at least 15 years after the completion of the
trial.
In addition to the points above and in compliance with the principles of ICH GCP, all institutions
participating in the trial will complete a delegation log and forward this to the CTU. Each person
working on the ODYSSEY trial must complete a section of this log and indicate their responsibilities
as agreed with the principal investigator. The CTU must be immediately notified of any changes to
trial personnel and/or their responsibilities. An up-to-date copy of this log must be stored in the ISF
at the institution and also in the Trial Master File (TMF) at the CTU.
2.2 APPROVAL AND ACTIVATION
MRC CTU, INSERM-ANRS or PHPT staff will visit new sites prior to the trial commencing at that site in
order to carry out a site and lab risk assessment and set-up visit. This visit should be attended by the

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principal investigator at that site (the clinician), the clinic nurse(s), and representatives from the
laboratory and pharmacy and any other staff who will be involved in the ODYSSEY trial. At the trial
set-up visit the trial management staff should ensure that the following minimum criteria are met
before the site enrols participants into the trial:
The clinician should be experienced in the management of children/young people with HIV
or work in close contact with a specialist HIV unit/site.
Staff involved in the trial must have training in Good Clinical Practice (GCP).
Pharmacy staff are able to keep detailed records of the trial medications prescribed.
There exists good communication between all of the above departments.
Laboratories have quality certification procedures, are enrolled with an EQA program and
have the capacity to run the trial scheduled assays/store trial samples.
Training will be provided for all sites participating in ODYSSEY. Where sites have participated in
previous PENTA trials, site initiation training may be conducted via web conferencing or similar.
Training in the use of ABC will be included in the site initiation.
2.3 SITE MANAGEMENT
Sites in the United Kingdom and Ireland are managed by the MRC CTU. Sites in Germany, Italy,
Netherlands, Russia, South Africa, Sweden, Thailand (HIV-NAT), Ukraine, Uganda, US and Zimbabwe
are managed by the MRC CTU together with national co-ordinators and local monitors. This includes
those sites in South Africa and Uganda that are supported by IMPAACT. Sites in France are managed
by INSERM-ANRS; sites in Argentina, Belgium, Brazil, Denmark, Portugal, Poland, Romania, Spain and
Switzerland are managed by INSERM-ANRS together with national co-ordinators and local monitors.
PHPT sites in Thailand are managed directly by PHPT.

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3 SELECTION OF PATIENTS
Participants will be selected by medical investigators at the participating sites, who should be aware
of eligibility criteria in advance of screening participants for the trial.
Eligible participants (or carers, as appropriate) must:
Be able to understand and comply with protocol requirements, instructions, and restrictions
Be likely to complete the study as planned
Be considered appropriate candidates for participation in an investigative clinical trial with
oral medication
The eligibility criteria are the standards used to ensure that only medically appropriate participants
are considered for this study. Participants not meeting the criteria should not join the study. For the
safety of the participants, as well as to ensure that the results of this study can be useful for making
treatment decisions regarding other children and adolescents with HIV, it is important that no
exceptions be made to these criteria for admission to the study.
Participants will be considered eligible for enrolment in this trial only if they fulfil all the inclusion
criteria and none of the exclusion criteria as defined below.
3.1 PATIENT INCLUSION CRITERIA
3.1.1 ALL PATIENTS:

Children <18 years with confirmed HIV-1 infection and DTG dose known for the child’s
age/weight-band*
Girls who have reached menses must have a negative pregnancy test at screening and
randomisation and be willing to adhere to effective methods of contraception if sexually
active
Children with co-infections who need to start ART can be enrolled into ODYSSEY according to
local/national guidelines
Parents/carers and children, where applicable, willing to adhere to a minimum of 96 weeks'
follow-up
*Recruitment will start from children aged ≥6 and <18 years for whom dosing information and
formulations are currently available. Additional formulations for younger children will become
available during the trial and dosing information will be updated.
3.1.2 ADDITIONAL CRITERIA FOR ODYSSEY A:

Planning to start first-line ART

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3.1.3 ADDITIONAL CRITERIA FOR ODYSSEY B:

Planning to start second-line ART defined as switch of at least 2 ART drugs due to treatment
failure
Treated with only one previous ART regimen. Single drug substitutions for toxicity or
simplification are allowed.
In settings where resistance tests are routinely available, at least one new active NRTI from
TDF, ABC or ZDV should have preserved activity based on cumulative results of resistance
tests within 3 months (see Section 5.2.2)
In settings where resistance tests are not routinely available, children who are due to switch
according to national guidelines should have at least one new NRTI predicted to be available
from TDF, ABC or ZDV (see Section 5.2.2)
Viral load >1000 c/ml at screening visit
See Section 3.3 for additional considerations for inclusion in the study depending on NRTI
backbone.
3.2 PATIENT EXCLUSION CRITERIA
History or presence of known allergy or some other contraindication to the study drugs or
their components
Alanine aminotransferase (ALT) ≥5 times the upper limit of normal (ULN), OR ALT ≥3xULN
and bilirubin ≥2xULN
Patients with severe hepatic impairment or unstable liver disease (as defined by the
presence of ascites, encephalopathy, coagulopathy, hypoalbuminaemia, oesophageal or
gastric varices, or persistent jaundice), known biliary abnormalities (with the exception of
Gilbert's syndrome or asymptomatic gallstones)
Evidence of lack of susceptibility to integrase inhibitors or more than a 2-week exposure to
antiretrovirals of this class
Contraindications to proposed available NRTI backbone (see Section 3.3).
3.3 CONSIDERATIONS FOR USE OF DIFFERENT NRTI
3.3.1 ABC-CONTAINING PRODUCTS
HLA-B*5701 testing
In countries where HLA-B*5701 screening is considered standard of care and HLA-B*5701 status is
unknown (even if the subject has previously tolerated ABC), investigators must test for HLA-B*5701
and the results of the test must be received prior to starting ABC. Children who are HLA-B*5701
positive must not be given ABC.
In countries where HLA-B*5701 screening is not considered standard of care, investigators must
obtain a complete history of previous exposure to ABC-containing products. In cases requiring

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discontinuation of abacavir, they should evaluate for the possibility of a clinically suspected
hypersensitivity reaction (HSR). If the possibility of a HSR cannot be ruled out then treatment with
any ABC-containing product should not be started, due to the risk for a potential life-threatening and
sometimes fatal re-challenge reaction. Where participants have previously tolerated treatment with
ABC, restarting ABC treatment as part of this study must be done in a setting where medical
assistance is readily available.
The use of ABC-containing products in participants should be in accordance with the corresponding
local product information.
3TC-, FTC- and TDF-containing products
HBV-co-infected patients
Patients known to have chronic HBV infection (HBsAg positive OR anti-HBc positive with HBV DNA
present) should be treated with TDF ideally in combination with either 3TC or FTC. Monotherapy
with either 3TC or FTC for treatment of HBV is not recommended, and 3TC should not be used in
combination with FTC. In young patients for whom TDF is not available, consideration should be
given to use of 3TC- or FTC-sparing regimens to avoid development of 3TC or FTC resistance in HBV.
Some participants with chronic HBV disease may experience clinical or laboratory evidence of
recurrent hepatitis upon discontinuation of 3TC, FTC or TDF. If 3TC, FTC or TDF is discontinued in
participants co-infected with HBV, periodic monitoring of liver chemistry tests should be considered.
Renal impairment
The use of TDF is not recommended in children with renal impairment. TDF should be discontinued
in children who develop renal impairment on TDF therapy.
In patients with moderate-severe renal impairment and creatinine clearance <50 ml/min, the dose
of 3TC or FTC should be adjusted in accordance with the local product information.
ZDV-containing products
Patients with either of the following haematology results at screening should not receive ZDV-
containing products:
Haemoglobin (Hb) concentration <7.5 g/dL or 4.65 mmol/L
Absolute neutrophil count <500/mm3 or 0.5 x 109 /L
Alternative causes for anaemia and/or neutropenia, such as concurrent bacterial, mycobacterial or
fungal infection, malaria, helminthiasis, malignancy and/or malnutrition should be investigated. ZDV
should be substituted with an alternative NRTI if alternative causes for anaemia and/or neutropenia
cannot be identified.
3.4 NUMBER OF PATIENTS
700 children will be enrolled over 96 weeks. This will include 310 children starting first-line
(ODYSSEY A) and 390 children starting second-line ART (ODYSSEY B). Children will be recruited from
clinical centres in Africa, Europe, Asia, North and South America.

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Co-enrolment in previous or future trials is considered in Section 4.2.
3.6 SCREENING PROCEDURES & PRE-RANDOMISATION INVESTIGATIONS
3.6.1 SCREENING VISIT

At screening, parents/carers of HIV-infected children and adolescents will be given an information
sheet about the ODYSSEY trial and asked to give written consent for screening before any trial-
specific procedures are performed or any blood is taken for the trial (see Appendices I - II).
Signed screening consent forms must be kept by the investigator in the ISF, a copy in the child's
clinical records and a copy given to the participant or family.
At this visit the patient will be allocated a Trial Number and an anonymous code taken from a
sequential list included in the ISF.
Screening procedures will include a clinical assessment, T cell lymphocyte subsets (including total
lymphocytes, CD4, CD8), haematology, biochemistry (see Trial Assessment Schedule, page x) and
plasma/cell storage. Stored samples will be discarded if the patient is not randomised into the
study; real-time HIV-1 RNA viral load is required for ODYSSEY B. Girls who have started menses will
be given information about the risks of pregnancy in the trial and advised on how to avoid
pregnancy. A pregnancy test will be performed at screening in girls who have started menses. Any
female participant found to be pregnant will not be eligible for the trial.
For children being screened for ODYSSEY B, i.e. children requiring a switch to second-line ART, the
parent/carer, or any young person who administers their own medication, should complete an
adherence questionnaire (See Appendix IV).
As soon as the results are received and eligibility has been confirmed, the Screening Form with
confirmation of eligibility and receipt of informed consent, clinical history and assessment,
haematology, biochemistry, previous immunology and virology should be entered on the trial
database or sent to the appropriate CTU. Eligibility for the study will be confirmed and the
randomisation visit should be scheduled within 4 weeks after the screening visit.

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4 REGISTRATION & RANDOMISATION
Randomisation should take place within 4 weeks after the screening visit, ideally within 2 weeks.
The participant’s eligibility for enrolment will be confirmed, including the results of screening
laboratory tests. Participants or carers must confirm that they have read the relevant patient
information sheets (see Appendix I). Written informed consent to enter into the trial and be
randomised must then be obtained from parents/carers after explanation of the aims, methods,
benefits and potential hazards of the trial (see Appendix II). Older children should give assent to trial
participation if they know their HIV status. Signed trial consent forms must be kept by the
investigator and documented in the CRF, a copy stored in the clinical records and a copy given to the
participant or family. It must be made completely and unambiguously clear that the participant (or
parent/carer of a child) is free to refuse to participate in all or any aspect of the trial, at any time and
for any reason, without compromising the care of the child.
The randomisation process will be securely embedded within the database, a web-based system
controlled through an authorised user name and password. Selected sites will be able to randomise
patients directly. An option to fax the Randomisation Form to the appropriate CTU, who will
perform the randomisation, will also be available. Patients will be randomised to DTG or SOC arms
in a 1:1 ratio (see Section 4.1 below).
Enrolment assessments will be performed as summarised in the Trial Assessment Schedule. Blood
should be taken for plasma storage. Cells will be stored in sites with this capacity. A repeat
pregnancy test should be performed in girls who have started menses. Any female participant found
to be pregnant will not be eligible for the trial.
The clinician should complete the Trial Entry Form and send to the appropriate CTU, together with
the completed questionnaires, once all the laboratory results are available, or enter the CRF data
directly onto the secure web-based trial database.
A clinic visit should be scheduled for 4 weeks after the week 0 visit (week 4 visit). At the sites where
children are routinely seen at 2 weeks after the start of new ART, this can be included as additional
visit and procedures undertaken as per the Trial Assessment Schedule.
4.1 RANDOMISATION PRACTICALITIES
The participant (child) and carer should be physically present together with a study clinician at the
time of randomisation.
To randomise a participant, the information contained on a completed Randomisation Form will be

entered into the online trial database accessible from the CTU (or the clinical site if appropriate) to
automatically check for eligibility. Only those with completed and verified screening forms on the
database will be able to be randomised. The details of the participant’s treatment allocation and
trial number will be notified to clinical staff.
If a centre’s internet connection to the database is unavailable at the time of randomisation, the
participant’s details can be provided to staff at the relevant CTU by fax or by telephone. At the CTU,
staff will verify eligibility and perform the randomisation using the online system. The details of the
participant’s treatment allocation and trial number will be notified to the trial team at the site by fax
or phone, with follow-up confirmation.

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The clinician should complete a prescription with the participant's details and ART regimen as
allocated. The pharmacist or pharmacy technician should ensure that the participant and/or carers
know how to take/administer the different drugs before they leave the clinic.
RANDOMISATIONS THROUGH A CTU

To randomise fax or send by password protected email the Randomisation CRF to the
relevant CTU:
MRC CTU, UK, Monday to Friday 9:00 AM to 17:00
Tel: +44 (0) 20 7670 4825
Fax: +44 (0) 20 7670 4814
Inserm-ANRS, France, Monday to Friday 9:00 AM to 17:00

Tel: + 33 1 45 59 50 83 / 52 55
Fax: + 33 1 46 58 72 93
PHPT, Thailand, Monday to Friday 9:00 AM to 18:00

Tel: +66 (0) 53 814 633 ext 710
Fax: +66 53 814 269
Email: kanchana.than-in-at@phpt.org
For those sites randomising directly, training will be provided as part of the site initiation and
database training. Individual passwords will be provided.
ENROLMENT OF MULTIPLE PARTICIPANTS FROM THE SAME FAMILY INTO THE TRIAL
If more than one child from a family is to be enrolled at the same time in the same strata (ODYSSEY
A or ODYSSEY B) they will be allocated to the same arm to facilitate their care (please refer to
Manual of Operations).
Co-enrolment in compatible studies is allowed by the protocol but must first be approved by the
CTU with previous discussion within the TMG. Centres should also adhere to local guidelines
concerning co-enrolment in other trials.

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5 TREATMENT OF PATIENTS
5.1 INTRODUCTION
Participants will be enrolled in two different strata depending on their previous ART experience:
ODYSSEY A: children starting first-line ART
ODYSSEY B: children starting second-line ART.
Within each strata, children will be randomised 1:1 to either DTG-based ART (DTG arm) or standard
of care (PI-, or NNRTI- or RAL-based ART; SOC arm).
DTG (including Triumeq, as appropriate), ABC, 3TC, ZDV, Kivexa and Combivir will be provided by ViiV
for the duration of the ODYSSEY trial. After the end of the trial DTG will be provided by ViiV for
those children randomised to the DTG arm until it is available and recommended for children in their
country of residence.
5.2 SOC ARM
All participants in the SOC arm will receive ART including either an NNRTI (NVP or EFV), a bPI (LPV/r,
ATV/r, DRV/r) or RAL plus two (or three (ODYSSEY A only) NRTIs following international (WHO(35),
PENTA, US), national or local recommendations for first- or second-line therapy. The exact choice of
antiretrovirals will be made by the treating clinician, but should take into account what is being used
in national programmes, as this will ensure that participants can stay on the same regimens long-
term. Inclusion of different first-line regimens in the trial increases generalisability, and will form a
pre-planned subgroup analysis population.
All parents/carers of children receiving ABC will receive warning cards and additional information
about this drug and action to be taken in the event of hypersensitivity reaction.

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Most common SOC options for drug regimens for ODYSSEY A (Table 1) and ODYSSEY B (Table
2).
Table 1. ART in ODYSSEY A Table 2. ART in ODYSSEY B
ODYSSEY B
ODYSSEY A
(Second line treatment)
(First line treatment)
First line ART received Options for second line ART
NNRTIa + ABC + 3TC
NNRTIa + ZDV + 3TC

NNRTIa + 2NRTI bPIb + 2NRTId
NNRTIa + TDF + 3TC or FTC
c
NVP + ZDV + ABC + 3TC bPIb + 2NRTId
NVP + ZDV + ABC + 3TC
DRV/r (or ATV/r) + 2NRTId
bPIb + ABC + 3TC LPV/r + 2NRTI
a
Or NNRTI + 2NRTI
d
Or RAL + 2NRTId
bPIb + ZDV + 3TC DRV/r + 2NRTId
ATV/r + 2NRTI Or NNRTIa + 2NRTId
a. NNRTI: EFV or nevirapine Or RAL + 2 NRTId
b. bPI: LPV/r, ATV/r or DRV/r
c. For infants and children aged less than 3 years, at the sites where initiation of ART with this regimen is routinely
used
d. NRTI for second line - at least one new NRTI with preserved activity (measured by resistance tests or presumed
from the history of previous ART) from ABC, TDF or ZDV should be chosen. DDI may be used where no other
drugs are available.
The doses of antiretrovirals should be in accordance to those recommended in the product

information or according to international (WHO, PENTA, US)/national guidelines as appropriate for
the country. Doses should be recalculated at every visit (until the adult dose is reached).
See Section 3.3 for additional considerations that investigators should take into account before
selecting and initiating the NRTI backbone.
5.2.1 SOC ODYSSEY A

SOC first-line ART varies across the sites and countries in ODYSSEY. See Table 1 for most likely ART
options. The choice of ART regimen will be based on International (WHO, PENTA, US)/National
guidelines. D4T may still be an option for young children in whom ZDV and ABC are contraindicated
and if it is included in the national guidelines.
5.2.2 SOC ODYSSEY B

For all children failing their first-line regimen, adherence issues should be addressed prior to
switching.

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The choice of second-line ART will be based on international (WHO, PENTA, US) or national
guidelines. In countries, where resistance tests are routinely performed, these results should be
taken into account.
In general, children with treatment failure on an NNRTI-based regimen are switched to a bPI-based
regimen. Children experiencing treatment failure on bPI-based ART may be switched to a more
potent bPI (for example change of LPV/r to DRV/r in children >3 years) or to an NNRTI-based or RAL-
based regimen if adherence can be assured.
The NRTI choice in children who are starting second-line ART will depend on the history of previously
used NRTIs and the resistance profile, if routinely performed. The decision will be made by the
treating clinician.
All carers of children starting ABC will receive warning cards and additional information about this
drug. In the countries where the HLA-B*5701 testing is routinely performed, the results of the test
should be received prior to starting ABC. Children who are HLA-B*5701 positive should not be given
ABC.
The following should be considered:
1. In countries, where resistance tests are routinely performed, at least one active NRTI from
TDF, ABC or ZDV should be chosen based on all resistance test results in the child (historic
and recent). The interpretation of the mutations will be based on the up-to-date version of
the Stanford HIV Drug Resistance Database (http:/ /hivdb.stanford.edu/). If the child has
been on ZDV or D4T first-line, and ABC or TDF are in the planned SOC for second-line, then
no more than two TAMs or one TAM + M184V are allowed. If the chosen regimen contains
ABC or TDF no presence (historic or recent) of K65R mutation is allowed.
2. In countries where resistance tests are not routinely performed, clinicians should follow
national/WHO Guidelines. At least one new NRTI with presumed preserved activity (from
ABC, TDF or ZDV) should be chosen.
Didanosine or d4T may be used in second-line where no other drugs are available. The planned SOC
regimen to be used if randomised to SOC should be recorded on the screening CRF. Treatment
should start on the day of randomisation or the following morning.
Treatment will be open-label and will be dispensed at randomisation for 4 weeks and then at
maximum 12 weekly intervals. Where drug has been supplied for the trial, it will be stored
separately from routine clinic drug supplies in a designated section at the study site.
5.3 DTG ARM
Children randomised to the DTG-containing regimen (DTG-arm) will receive DTG plus 2 NRTIs, with
at least one NRTI having preserved activity. The choice of NRTI will be at the clinician’s discretion
and depend on guidelines and drug availability (See Section 5.2 above on choice of NRTI backbone
for the first- and second-line ART in the participating sites).
For children starting second-line ART, the same considerations should be given to addressing
adherence and simplification of ART, including once daily regimens where possible, as outlined in the
previous section (Section 5.2.2).

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Options for drug regimens for ODYSSEY A:
DTG + ABC + 3TC

DTG + ZDV + 3TC
DTG + TDF + 3TC or FTC
Options for drug regimens for ODYSSEY B:
DTG + 2NRTI
At least one of the NRTIs from ABC, TDF or ZDV should have preserved activity (measured by
resistance tests or presumed from the history of previous ART. Didanosine or d4T may be used
where the listed NRTIs are contraindicated or not available.
5.3.1 DTG
Dosing will be once daily and will be determined according to weight bands (used in WHO HIV
treatment guidelines (35) as in the table below.
Table 3. DTG dosing according to weight bands1

Wt bands1, kg 20-24.9 25-29.9 30-34.9 35-39.9 >40
Dose
Daily dose 25 mg 25 mg 35 mg 35 mg 50 mg
Tablets
10 mg - - 1 1 -
25 mg 1 1 1 1 -
50 mg - - - - 1
1. The dose-finding study for children younger than 6 years of age and weighing <20 kg is ongoing; children of this
age/weight will be recruited in the study when the dosing information will be available.
5.3.2 FIXED DOSE COMBINATION OF DTG, ABC AND 3TC

For all children >12 years (>40 kg), whether ART-naïve or ART-experienced (with chosen NRTI
backbone ABC + 3TC), a three drug fixed dose combination tablet containing DTG 50 mg + ABC 600
mg + 3TC 300 mg can be provided.
5.4 DISPENSING
For all trial drugs, the designated trial pharmacist or nurse will confirm receipt of supplies prior to
the commencement of the trial. Inventories will be conducted regularly, and logs returned to the
appropriate CTU.
All drugs dispensed to participants will be recorded on a dispensing log or logged online. At each
site, a named person (trial pharmacist or research nurse) must maintain complete records of all
medication dispensed and returned.
Throughout the treatment period, carers will be provided with a supply of drugs sufficient to last
until the next clinic visit and will be requested to return all empty container packs and to bring any
container packs in use or unused to the follow-up clinic.

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On no account should any drug assigned to a participant be used by anyone else. Unused drug must
be returned to the site if a participant withdraws from treatment.
5.5 DOSE MODIFICATIONS, INTERRUPTIONS & DISCONTINUATIONS
5.5.1 DOSE MODIFICATIONS, INTERRUPTIONS & DISCONTINUATIONS OF ANTIRETROVIRAL DRUGS

For both arms, should the study clinician believe ART should be interrupted, discontinued, or that a
change in treatment is necessary, then the relevant CTU should be notified.
If simplification of the ART regimen is deemed necessary for clinical reasons during follow-up, this
may be allowed, but must be discussed with the appropriate CTU. Switching of the current ART
regimen should only occur if there is immunological, virological or clinical failure (according to local
clinical practice), at which point a new regimen should be chosen. Resistance tests or Therapeutic
Drug Monitoring (TDM) may be used to inform change of regimen, according to local clinical
practice.
Toxicity will be managed in both randomised arms according to standard clinical practice. Blood
tests additional to those described in the trial schedule may be requested at any time for clinical
management of the participant. Wherever possible and appropriate, side effects will initially be
managed by symptomatic measures and administration of appropriate (non-contraindicated)
medication. Interruption or substitution of drugs should be avoided except in the event of grade 3
or 4 toxicity that is considered at least possibly related to one or more of the ARVs. Wherever
possible, an alternative ARV should be substituted from the same class in order to maintain the
participant’s randomised treatment strategy.
Management of adverse events/toxicity should generally follow the criteria below, but clinicians
should use their clinical judgment as to the best management for an individual participant. If in
doubt, contact the relevant CTU to obtain advice.
NOTE: In the event of a discontinuation of an ABC-containing product for any reason (aside from
possible hypersensitivity), re-initiation of this drug should be undertaken with caution. The
investigator must obtain a complete history of the events surrounding the discontinuation of the
ABC-containing product and evaluate for the possibility of a clinically suspected hypersensitivity
reaction (HSR) to ABC. Regardless of a subject’s HLA-B*5701 status, if a hypersensitivity reaction
cannot be excluded, then ABC must not be restarted.
Grade 1 and 2
Continue ARVs
Manage using symptomatic measures and other concomitant medication, if appropriate
Raised serum aminotransferase ≥3xULN and total serum bilirubin level ≥2xULN (or coagulopathy
(INR >1.5) without hyperbilirubinemia) may indicate idiosyncratic drug induced liver injury (36) .
Follow recommendations for Grade 3 or 4 toxicity events as outlined below.
Grade 3 or 4:
Request laboratory results and repeat confirmatory laboratory results within 72 hours if
relevant
Continue study drugs pending receipt of the confirmatory laboratory tests/repeat
observations, unless there is an immediate need to substitute ART
Continue to work-up to exclude other causes

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Following confirmation of toxicity, and lack of other cause data:

if the child is not too sick, substitute ART immediately
otherwise, stop all drugs and restart with substituted drugs when the child has
improved,
stagger stop NNRTI wherever possible to avoid functional monotherapy and risk of
resistance (as per PENTA/national guidelines)
5.5.2 DOSE MODIFICATIONS, INTERRUPTIONS & DISCONTINUATIONS OF DTG

5.5.2.A Liver toxicity
Stopping criteria based on liver function test thresholds have been designed to assure participant
safety during administration of the medication and the follow-up period. DTG should be substituted
if any of the following criteria are met:
ALT ≥3xULN and bilirubin ≥2xULN
ALT ≥5xULN and symptoms of acute hepatitis or hypersensitivity (fatigue, nausea, vomiting,
right upper quadrant pain, fever, rash or eosinophilia)
ALT ≥ 5xULN for more than 2 weeks with bilirubin <2xULN and no symptoms of acute
hepatitis or hypersensitivity
ALT ≥8xULN
Participants who develop ALT ≥5xULN should be followed weekly until resolution or stabilization
(ALT <5xULN on 2 consecutive evaluations).
When liver chemistry stopping criteria are met, investigator must:

Notify the relevant CTU of the event by e-mail within 24 hours of its occurrence and
complete an SAE form (see 7.1.5.A). Additional information will be then requested from the
sites.
Discontinue DTG and substitute for an appropriate alternative (the child will continue follow
up in the study). If uncertain, then the investigator must contact the CTU.
Participants should not restart DTG due to the risk of a recurrent reaction.
5.5.2.B Allergic reaction or rash
Participants may continue DTG for grade 1 or 2 allergic reactions or rash at the discretion of the
investigator. Consideration should be made as to whether another ARV or another drug maybe
causing the reaction. The carer/participant should be advised to contact the investigator
immediately if there is any worsening of symptoms if mucosal involvement develops or if further
systemic signs or symptoms develop. Antihistamines, topical corticosteroids, or antipruritic agents
may be prescribed.
Participants with grade ≥2 rash that is associated with an increase in ALT OR grade ≥3 allergic
reactions or rash that are considered to be possibly or probably related to DTG should permanently
discontinue DTG and substitute with an appropriate alternative; the participant will remain in the
study. Investigators should contact the CTU to discuss cases if there is any uncertainty about the
course of action. Participants should be treated as clinically appropriate and follow-up of the AE
should be reported on CRFs as appropriate.
Participants receiving an ABC-containing product should be evaluated for the possibility of a clinically
suspected HSR and managed appropriately as outlined in the local product information, regardless
of a subject’s HLA-B*5701 status.

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5.6 ACCOUNTABILITY & UNUSED DRUGS/DEVICES
Procedures for drug shipping, labelling, resupply, accountability and destruction will be detailed in
the ODYSSEY Pharmacy MOP. Drug accountability will be regularly monitored and the remaining
stocks checked against the amounts dispensed.
5.7 COMPLIANCE & ADHERENCE
Compliance to ART will be assessed by pill counts and short participant-reported adherence
questions at study visits (see Appendix IV). The importance of adherence should be reinforced at
each visit. Non-adherence should prompt the study clinician to identify and address the cause(s)
(e.g. side effects, social challenges).
An acceptability questionnaire at weeks 4, 24, 48, 72 and 96 will elicit participant opinions about the
different regimens, particularly with regard to pill burden; complexity and stigma (see Appendices V-
VI).
5.8 OVERDOSE OF TRIAL MEDICATION
All participants/carers should be counselled about the importance of taking/administering the

medications as prescribed. It is particularly important that participants and carers understand how
many pills of which type they should be given. Participants must be told to contact the clinic
immediately if they take too much medication. If the overdose fits the criteria of an SAE (see Section
7.1) it should be reported appropriately.
5.9 PROTOCOL TREATMENT DISCONTINUATION
In consenting to the trial, participants and carers are consenting to trial treatment, trial follow-up
and data collection. However, an individual participant may stop treatment early for any of the
following reasons:
(i) Unacceptable toxicity (clinical or laboratory) or adverse event

(ii) Disease progression necessitating change of regimen
(iii) Virological failure
(iii) Withdrawal of consent for treatment by the participant or carer
As the child’s participation in the trial is entirely voluntary, they or their carer may choose to
discontinue the trial treatment at any time without penalty or loss of benefits to which they are
otherwise entitled.
Although the participant and/or carer are not required to give a reason for discontinuing their trial
treatment, reasonable effort should be made to establish this reason while fully respecting the
participant’s rights.
Participants should remain in the trial for the purpose of follow-up and data analysis (unless the
participant or carer withdraws their consent from all stages of the trial). Data will be kept and
included for participants who stop follow-up early, up to the point of exit.

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5.10 NON-TRIAL TREATMENT
Families and participants should be advised to notify their clinician of any current or proposed
concomitant medication, whether prescribed or over-the-counter. All necessary concomitant
medications are allowed and will be recorded in the study CRFs.

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6 ASSESSMENTS & FOLLOW-UP
Trial visit schedules will be prepared for each participant at randomisation, and participants should
be followed on the same schedule even if their trial medication is discontinued. The target dates for
trial visits are determined by the date of randomisation and are not affected by subsequent events.
The schedule sent or generated after randomisation defines visit dates (with windows) necessary for
data collection, but the participant may be seen more frequently for clinical care as needed.
Participants should attend on the scheduled day whenever possible, unless agreed in advance with
the clinic. Clinics may choose to re-schedule visits to allow for public holidays or other unavoidable
circumstances that affect the scheduled visit date. During the treatment period, if participants are
unable to attend on the day, every effort should be made to complete the visit as soon as possible
and within 14 days of the scheduled date. If a scheduled visit is missed without notice then the
research team should endeavour to contact the participant by phone or by home visit.
If a participant is more than 14 days late for a scheduled study visit (during the treatment period), an
additional visit will be performed as soon as possible, including the appropriate assessments that
were specified in the trial schedule for the visit week that was missed.
6.1 TRIAL ASSESSMENT SCHEDULE
All participants will be seen at screening, enrolment (randomisation, week 0) and then at weeks 4,
12, 24, 36, 48, 60, 72, 84 and at week 96 (see Trial Assessment Schedule). All participants should
then be followed-up in clinic every 12 weeks until the last participant enrolled reaches week 96.
Clinical assessment at week 2 is optional for the sites with the standard practice to review
participants at 2 weeks after starting new antiretrovirals.
A full clinical assessment and the following will be undertaken as specified in the Trial Assessment
Schedule:
Medical history since last visit including intercurrent illnesses, all AEs, signs and symptoms of
HIV disease with WHO stage on every visit
Weight, height and mid-upper arm circumference (MUAC) on every visit
Viral load as per local practice (in ODYSSEY B viral load must be measured at screening)
Haematology at screening, weeks 0, 4, 24, 48, 72 and 96
T cell lymphocyte subsets at screening, weeks 0, 4, 12, 24, 48, 72 and 96
Plasma storage at screening, week 0, 4, 12 and then 12 weekly
Cell storage at the selected sites at screening, week 0, 12, 48, and 96
Biochemistry at screening, week 4, 24, 48, 72 and 96 and if indicated or if required by local
practice. Participants should be fasting at week 0, 48 and 96 in order to obtain fasting lipids
and glucose values
Bone profile (optional) at randomisation, week 48, 96 and then 48 weekly at the sites where
these tests are done routinely
Urine dipstick at randomisation, week 48 and 96
Tanner scales (see Appendix XI) should be completed at week 0 and repeated every 24
weeks until the end of the study in children aged 8 or over.
Lipodystrophy clinical assessment should be performed at week 0 and repeated at weeks 48
and 96.
Pregnancy tests should be performed for all females of childbearing potential at screening,
randomisation and every 24 weeks until the end of the trial and at other time-points if
required. All boys and girls of reproductive age will be given continuing advice about

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avoiding pregnancy. If a pregnancy test performed during the trial is positive, please notify
the appropriate CTU, following procedures detailed in Sections 6.8 and 7.2.1.
In addition at each visit the following should be recorded:

Assessment of adherence to ART by adherence questionnaire while the participant is on
treatment
Changes in ART and other concomitant medication
All adverse events since the last protocol visit, including haematological abnormalities,
pancreatitis, diarrhoea, clinical lipodystrophy, acute illnesses
Change in HIV disease stage since last protocol visit
Inpatient and outpatient attendances with any documented test results
The next supply of drugs to last until the next clinic visit will be dispensed. Prescriptions of ART and
any alterations to prescribed doses should be recorded on the CRF. Doses should be checked at
every visit and adjusted for body surface area, or weight as appropriate.
Additional study visits, for example if the child develops drug toxicity or other clinical events should
be recorded using appropriate forms. At such visits, laboratory tests should be performed as
clinically indicated. Participants will also be given a patient card with the contact details for the trial
research team at their site and information on ABC hypersensitivity if receiving ABC.
For the frequency of the assessments after week 96, see the Trial Assessment Schedule.
6.2 PROCEDURES FOR ASSESSING EFFICACY
6.2.1 CLINICAL:
A symptom checklist and targeted physical examination (to evaluate any reported symptoms) will be
performed at each visit. Hospital admissions will be solicited at all visits. Where there is any clinical
suspicion of a WHO Stage 3 or 4 disease event, centres will endeavour to investigate to the full
extent possible given local availability of imaging and laboratory investigations (particularly
microbiology) in order to establish a clear diagnosis of the event. The lists of WHO stages and
diagnostic criteria are provided (see Appendices VII-IX). The site will report the event and the clinical
investigations that support the diagnosis in order to enable an independent evaluation of the event.
An endpoint review committee will review all clinical endpoints to ensure that they satisfy the
diagnostic criteria.
6.2.2 IMMUNOLOGY:
Blood will be collected according to the trial assessment schedule for the determination of total and
percentage CD4 and CD8 T cell counts. The T cell subsets will be measured using the standard assay
in the laboratory operating at each site according to quality-assured procedures.
6.2.3 VIRAL LOAD TESTING:

At sites where plasma HIV viral load (VL) is routinely measured every 12-16 weeks, VL should be
measured at screening, week 4, 12, 24 and then every 12 weeks until the end of the trial.
At the sites where VLs are not routinely measured every 12-16 weeks, real-time viral load should be
measured at the screening visit for participants in ODYSSEY B and then according to the local routine
practice. Viral loads will be measured retrospectively on plasma samples stored at enrolment
(ODYSSEY A), week 4, 12, 24, and then every 12 weeks until the end of the trial. Retrospective VL
measurements will be done in batches using the same assay (lower limit of detection of no greater

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than 50 c/ml) in one or more designated PENTA laboratories. The Independent Data Monitoring
Committee (IDMC) (Section 14.3) will review VL results on all patients.
If the participant meets the definition of treatment failure during the trial (WHO 2013 guidelines),
and the treating physician wishes to modify treatment, they may perform a VL test at their site, to
confirm treatment failure prior to switch. In this situation the management of the participant will be
discussed with the appropriate CTU and the trial Clinical Advice Group.
6.2.4 RESISTANCE TESTING

At sites where genotypic resistance testing is part of routine care, test results should be run on the
latest sample while the child is still on the same treatment. At sites where genotypic resistance
testing is not a part of routine care baseline samples will be tested retrospectively to assess
background regimen activity at baseline and batched genotypic resistance testing will be performed
on the samples with viral load >1000 c/ml. Additional resistance tests will be performed on stored
plasma samples in selected participants at the end of the trial to define in more detail the pattern of
resistance development.
Drug resistance mutations will be classified using the Stanford database algorithm. The results of all
resistance tests performed in individual participants will be given to the treating physician after the
last participant has completed 96 weeks follow-up, or as soon thereafter as results become
available.
6.3 PROCEDURES FOR ASSESSING SAFETY
The clinical examination at each visit will explicitly prompt for symptoms relating to possible drug
toxicities. Blood will be drawn at trial visits to assess laboratory safety parameters as per the Trial
Assessment Schedule. Additional safety blood tests or investigations may be performed to
investigate symptoms or monitor emergent laboratory test abnormalities as clinically indicated.
Adverse events will be reported on the case report form. Adverse events (clinical and laboratory)
will be graded using the 2004 Division of AIDS toxicity grading scale (see Appendix X). Grade 1 and 2
clinical events do not need to be reported unless resulting in a change of ART regimen. Serious
adverse events will be defined according to ICH GCP, and should be reported to the CTU within 24
hours of the site being aware (see Section 7 - Safety Reporting). All adverse events meeting the
definitions above should be reported on study CRFs, regardless of their relationship to HIV.
6.4 PROCEDURES FOR ASSESSING QUALITY OF LIFE
Quality of life (EQ-5D) questionnaires (http:/ /www.euroqol.org/about-eq-5d.html) should be

completed by all children aged 8 or over, regardless of which arm they are in, at randomisation
(week 0), 12, 24 weeks and then every 48 weeks.
6.5 ADHERENCE ASSESSMENTS
Adherence issues should be addressed with potential participants in ODYSSEY B before screening for
the trial and an adherence questionnaire should be completed at the screening visit. At 4 and 12
weeks and thereafter every 12 weeks, carers and children, where appropriate, will be asked to
complete an adherence questionnaire. This will include questions about adherence to all the
antiretrovirals.

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6.6 MANAGEMENT OF PARTICIPANTS WITH TREATMENT FAILURE
In settings where viral load measurement is part of routine care, viral loads will be measured
locally. Participants experiencing virological failure should have reasons for virological
failure investigated as per local practice (addressing problems with adherence, adequate
dosing, drug interactions, and if available, drug levels, resistance mutations) prior to
decisions being made about switching ART. ART management decisions (discontinuation of
the previous regimen, change to the new regimen) should also be made by the treating
clinician as per accepted local practice. Advice from the Clinical Advice Group should be
sought and the CTU also contacted. The participant should continue to be seen 12 weekly
until the end of the trial (see Trial Assessment Schedule). Participants should follow local
practice at subsequent visits. CRFs should be completed at each follow up visit.
In settings where viral load measurement is not routine care, the efficacy of treatment will
be monitored using clinical assessment and local CD4 cell counts/percentage. Therapy will
be maintained according to the randomised strategy until there is clinical or immunological
failure, defined for the protocol as after at least 36 weeks on the allocated regimen. Where
available, a targeted viral load should be done to confirm treatment failure prior to switch.
If the treating clinician decides to switch therapy, then the next regimen should be given
according to guidelines and paediatrician choice and based on the local availability of
antiretrovirals; advice can also be obtained from the Clinical Advice Group. The clinician can
at any stage give alternative treatment to that specified in the protocol if it is considered to
be in the participant’s best interest. However this should be discussed first with the CTU.
6.7 MANAGEMENT OF CHILDREN DIAGNOSED WITH TUBERCULOSIS (TB)
Participants developing TB should commence TB treatment following national guidelines (usually

rifampicin, isoniazid, pyrazinamide, and ethambutol). Where available, cultures should be tested for
sensitivity to first-line anti-TB drugs and regimens modified on the basis of these results.
Participants may need to be referred to the national TB treatment programme in order to access
anti-tuberculosis medication, and close liaison between the trial team and the TB treatment
providers will be required.
6.7.1 MANAGEMENT OF CHILDREN WITH TUBERCULOSIS IN THE DTG ARM

DTG pharmacokinetics are influenced by concomitant treatment with rifampicin. This interaction
can be overcome by doubling the dose of DTG, i.e. ̴1 mg/kg BID.
In a child with TB on rifampicin, the DTG dose needs to be increased from OD to BID and remain BID
until 2 weeks after the last dose of rifampicin has been given (the enzyme inducing effect of
rifampicin slowly fades away after discontinuing the drug).
At least 10 children in the DTG arm with TB will be invited to participate in the TB substudy for
children on DTG and rifampicin (see Section 10.2 and Appendix XIII).
6.7.2 MANAGEMENT OF CHILDREN WITH TUBERCULOSIS IN THE SOC ARM

As rifampicin interacts with the ARVs, including PIs and NNRTIs, change of regimen may be needed
for co-infected children in SOC arm. Guidance on the choice of ART for children with TB can be
found in the WHO 2013 guidelines (1) and in national guidelines and may differ between countries.
Children who are on EFV-based ART can continue on the same regimen while those (>3 years)
receiving NVP should be switched to EFV. Children receiving LPV/r-based ART can continue on their

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regimen if they receive super-boosted ritonavir (increasing ritonavir to achieve a LPV/r ratio of 1:1),
or they can be switched to EFV (if >3 years). As an alternative, children receiving NVP or LPV/r with
rifampicin may change to triple NRTI (ZDV + 3TC + ABC) (37) or the NVP dose should be increased to
the maximum recommended, i.e. 200 mg/m2 BD (1). In order to obtain better exposure in younger
children, the maintenance dose can be further increased by 20-30% after two weeks of starting (H
Lyall, S Welch, unpublished data). CTUs should be notified and advice sought from the Clinical
Advice Group.
6.8 MANAGEMENT OF PREGNANCY
Reproductive toxicity is not considered to be a risk for DTG, based on findings in animal reproductive
studies and the limited cases of pregnancy reported from clinical trials to date. However, no studies
of DTG in pregnant girls have so far been reported, and pregnant girls have been excluded from
randomised clinical trials conducted so far.
All eligible girls with childbearing potential will be counselled about the potential risks associated
with pregnancy during the trial and the uncertainty of long-term effects of antiretroviral therapy on
the infant. If the girl then chooses to enter the trial, she will be advised to use reliable contraception
and to report to the study site staff as soon as possible if there is a possibility of pregnancy.
Pregnancy testing will be undertaken at screening and randomisation in girls who have reached
menses. If pregnant, she will be ineligible for the trial. For randomised females who have reached
menses, pregnancy tests will be repeated 24 weekly. Females will be encouraged to disclose missed
menses; if this happens, a pregnancy test should be done.
Given that DTG is a new drug with few data on safety during pregnancy, it is generally recommended
that DTG should be discontinued and alternative ART given if a female participant becomes
pregnant. However, the clinician should use his/her judgement about whether benefits of
continuing a pregnant woman on DTG-containing products are deemed to outweigh the risks (e.g.,
individual cases from study populations with limited treatment options, or risk of poor adherence on
alternative ART regimen, especially if pregnancy comes to light late and near to the time of delivery).
Where local regulatory regulations allow, the woman may continue DTG and the case should be
discussed with the CTU. Pregnant participants should be encouraged to remain in the study whether
or not their ART regimen is changed at this time.
Pregnant participants should receive counselling about their options and receive support to make
decisions about continuing pregnancy. For females on DTG who become pregnant, advice on breast-
feeding will be given according to local or national lactation and treatment guidelines and standard
of care. All infants will receive infant prophylaxis according to the current local standard of care.
Any pregnancy that occurs during study participation must be reported as a notable event on an SAE
form (See Section 7). The pregnancy must be followed up to determine outcome (including
premature termination) and status of mother and child, which must also be reported to the CTU.
Pregnancy complications and elective terminations for medical reasons must be reported as an AE or
SAE as appropriate. Spontaneous abortions must be reported as an SAE. Any SAE occurring in
association with a pregnancy brought to the investigator´s attention after the participant has
completed the study and considered by the investigator as possibly related to the investigational
product, should also be reported as an SAE. Pregnancies will be reported to the Antiretroviral
Pregnancy Register.

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6.9 EARLY STOPPING OF FOLLOW-UP
If a participant or their carer chooses to discontinue the trial treatment, the participant should
continue to be followed until the end of the trial providing the participant and their carer are willing;
that is, they should be encouraged not to leave the trial. However, if the participant and/or carer do
not wish to remain on trial follow-up, they should be offered the option of continuing with routine
follow up and permission to collect minimal routine outcomes from the patient’s notes should be
requested. If they do not wish to provide information about routine follow up, their decision must
be respected and the patient will be withdrawn from the trial completely. The CTU should be
informed of this in writing using the appropriate documentation.
If the medical data collected during the participant's time in the trial are kept for research and
analysis purposes, they can be further anonymised if necessary. Consent for future (but not past)
use of stored samples already collected can be refused when leaving the trial early (but this should
be discouraged and should follow a discussion with the patient/carer).
Participants and carers may change their minds about stopping trial follow-up at any time and re-
consent to re-enter participation in the trial.
Participants who stop trial follow-up early will not be replaced, as the total sample size includes an
adjustment for losses to follow-up.
6.10 PARTICIPANT TRANSFERS
If a participant moves from the area, reasonable efforts should be made to continue their follow-up,
e.g. by them continuing to come for visits providing the site has sufficient resources, or by
conducting nurse only visits over the telephone and providing drugs and clinical care at a local clinic.
If a local site is conducting the trial, the participant can be transferred there; a copy of the
participant’s CRFs should be provided to the new site and the parent/carer will need to sign a new
consent form. Once this has been done, the new site will take over responsibility for the participant;
until this has been done, responsibility for the participant lies with the original site.
If none of the above options are possible, then the participant should be considered as lost to
follow-up. The participant and/or carer may or may not choose to formally register this as a
withdrawal of consent.
6.11 END OF TRIAL
The trial will be considered closed when the last patient to be enrolled reaches 96 weeks of follow-
up, all data has been entered in the database and queries have been resolved. For all other patients
the exit visit will be their scheduled visit immediately prior to this. However, results will not be
available for approximately 6 months after the end of the trial once all data have been received and
analysed by the CTUs. The date of the expected end of the trial will be communicated to the
participating centres approximately 3-6 months before the trial ends. The sponsor, or the sponsor’s
representative in each country, will notify the national regulatory body and ethics committee of the
end of the trial. The Principal Investigator at each site will be responsible for notifying local ethics
boards and any other local bodies, such as R&D departments. The TSC may decide to continue
further observational follow-up of all patients enrolled in the trial. If long term follow-up of the trial
is indicated, ethical opinion will be sought.

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After the end of the trial DTG will be provided by ViiV for those children randomised to the DTG arm
until it is available and recommended for children in their country of residence.

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7 SAFETY REPORTING
The principles of ICH GCP require that both investigators and sponsors follow specific procedures
when notifying and reporting adverse events or reactions in clinical trials. These procedures are
described in this section of the protocol. Section 7.1 lists definitions, Section 7.3 gives details of the
investigator responsibilities and Section 7.4 provides information on MRC CTU responsibilities.
7.1 DEFINITIONS
The definitions of the EU Directive 2001/20/EC Article 2 based on the principles of ICH GCP apply to
this trial protocol. These definitions are given in Table 4.
Table 4: Definitions
TERM DEFINITION
Adverse Event (AE) Any untoward medical occurrence in a patient or clinical trial
subject to whom a medicinal product has been administered
including occurrences that are not necessarily caused by or
related to that product.
Adverse Reaction (AR) Any untoward and unintended response to an investigational
medicinal product related to any dose administered.
Unexpected Adverse Reaction (UAR) An adverse reaction, the nature or severity of which is not
consistent with the information about the medicinal product in
question set out in the Summary of Product Characteristics (SPC)
or Investigator Brochure (IB) for that product.
Serious Adverse Event (SAE) or Serious Respectively any adverse event, adverse reaction or unexpected
Adverse Reaction (SAR) or Suspected adverse reaction that:
Unexpected Serious Adverse Reaction Results in death
(SUSAR) Is life-threatening*
Requires hospitalisation or prolongation of existing
hospitalisation**
Results in persistent or significant disability or
incapacity
Consists of a congenital anomaly or birth defect
Is another important medical condition***
*The term life-threatening in the definition of a serious event refers to an event in which the patient
is at risk of death at the time of the event; it does not refer to an event that hypothetically
might cause death if it were more severe, for example, a silent myocardial infarction.
**Hospitalisation is defined as an inpatient admission, regardless of length of stay, even if the

hospitalisation is a precautionary measure for continued observation. Hospitalisations for a
pre-existing condition, that has not worsened or for an elective procedure do not constitute
an SAE.
*** Medical judgement should be exercised in deciding whether an AE or AR is serious in other

situations. The following should also be considered serious: important AEs or ARs that are not
immediately life-threatening or do not result in death or hospitalisation but may jeopardise
the subject or may require intervention to prevent one of the other outcomes listed in the
definition above; for example, a secondary malignancy, an allergic bronchospasm requiring

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intensive emergency treatment, seizures or blood dyscrasias that do not result in

hospitalisation or development of drug dependency.
7.1.1 MEDICINAL PRODUCTS

An investigational medicinal product (IMP) is defined as the tested investigational medicinal product
and the comparators used in the study (EU guidance ENTR/CT 3, April 2006 revision). In ODYSSEY
DTG is the IMP.
Adverse reactions include any untoward or unintended response to drugs. Reactions to the IMP or
the other antiretrovirals should be reported appropriately.
7.1.2 ADVERSE EVENTS

Adverse Events include:
An exacerbation of a pre-existing illness
An increase in frequency or intensity of a pre-existing episodic event or condition
A condition (even though it may have been present prior to the start of the trial) detected
after trial drug administration
Continuous persistent disease or a symptom present at baseline that worsens following
administration of the study treatment
7.1.3 EXEMPTED ADVERSE EVENTS

Adverse Events do not include:
Medical or surgical procedures; the condition that leads to the procedure is the adverse
event
Pre-existing disease or a condition present before treatment that does not worsen
Hospitalisations where no untoward or unintended response has occurred, e.g., elective
cosmetic surgery, social admissions
Overdose of medication without signs or symptoms
Grade 1 or 2 events which do not result in any changes to ART
7.1.4 DISEASE-RELATED EVENTS

All adverse events meeting the definitions above should be reported on study CRFs, regardless of
their relationship to HIV and should be graded. In particular, all deaths should be reported as fatal
SAEs.
7.1.5 OTHER STUDY-SPECIFIC REQUIREMENTS
7.1.5.A Liver events

All suspected cases of drug induced liver injury (as outlined in Section 5.5.2) should be reported as
an SAE. Additional information will be then requested from the sites. Any results of liver
investigations, including liver biopsy and/or imaging should be reported.
7.1.5.B ABC Hypersensitivity reaction (HSR)

Clinically suspected ABC HSR meeting one of the International Conference on Harmonization (ICH)-
E2A definitions of seriousness should be reported as an SAE (see Table 4). Additional information
will be requested from the sites and should be completed within one week of the onset of the
hypersensitivity reaction.

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7.1.5.C Suicidal Ideation or Behaviours

A possible suicidality-related adverse event (PSRAE), which is considered by the Investigator to meet
International Conference on Harmonisation (ICH)-E2A definitions for seriousness (see Table 4),
should be reported as an SAE. A PSRAE may include, but is not limited to, an event that involves
suicidal ideation, a preparatory act toward imminent suicidal behaviour, a suicide attempt, or a
completed suicide. The investigator will exercise his or her medical and scientific judgment in
deciding whether an event is possibly suicide-related. Following SAE report, the Investigator will be
requested to collect additional information which should be reported to the relevant CTU within one
week of the investigator diagnosing a possible suicidality-related adverse event.
7.2 OTHER NOTABLE EVENTS
7.2.1 PREGNANCY
Pregnancy occurring during participation in ODYSSEY should be reported as a notable event on an
SAE form and sent to the relevant CTU within 24 hours of the site being aware of the pregnancy (see
Section 6.8). All pregnancies will be reported to ViiV and registered with the Antiretroviral
Pregnancy Register.
Any pregnancy that occurs in a trial participant will be followed to termination or to term and
reported in the specific Pregnancy Outcome form. The clinical team responsible will be informed of
the mother’s participation in the trial and will be asked to inform the relevant CTU if there is any
suspicion of any adverse effect of the trial medication. Any event fulfilling the criteria of an SAE (e.g.
congenital abnormality or birth defect) should be reported on an SAE form.
Follow-up of a child born to the partner of a male participant (who was taking trial treatment at the
time of conception) will be according to local practice.
At the end of pregnancy, the investigator will complete a Pregnancy Outcome CRF.
7.3 INVESTIGATOR RESPONSIBILITIES
All grade 3 and above clinical AEs should be reported in the relevant section of the Follow up CRF.
Grade 2 clinical AEs should be reported only if they result in change of ART. All ARs, whether
expected or not, should be recorded in the participant’s medical notes and reported on the Follow-
up Form and sent to the relevant CTU. SAEs and SARs and notable events should be reported to the
relevant CTU within 24 hours of the site becoming aware of the event.
7.3.1 INVESTIGATOR ASSESSMENT
7.3.1.A Seriousness
When an AE or AR occurs, the investigator responsible for the care of the patient must first assess
whether or not the event is serious using the definition given in Table 4. If the event is serious, then
an SAE Form must be completed and the CTU notified within 24 hours.
7.3.1.B Severity or Grading of Adverse Events

The severity of all AEs and/or ARs (serious and non-serious) in this trial should be graded using the
toxicity grading in Appendix X.

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7.3.1.C Causality
The investigator must assess the causality of all serious events or reactions in relation to the trial
therapy using the definitions in Table 5. There are five categories: unrelated, unlikely, possible,
probable, and definitely related. If the causality assessment is unrelated or unlikely to be related,
the event is classified as an SAE. If the causality is assessed as possible, probable or definitely
related, then the event is classified as an SAR.
Table 5: Assigning Type of SAE through Causality

RELATIONSHIP DESCRIPTION SAE TYPE
Unrelated There is no evidence of any causal relationship. Unrelated SAE
Unlikely There is little evidence to suggest that there is a causal Unrelated SAE
relationship (for example, the event did not occur within a
reasonable time after administration of the trial medication).
There is another reasonable explanation for the event (for
example, the patient’s clinical condition, and other concomitant
treatment).
Possible There is some evidence to suggest a causal relationship (for SAR

example, because the event occurs within a reasonable time
after administration of the trial medication). However, the
influence of other factors may have contributed to the event (for
example, the patient’s clinical condition, and other concomitant
treatments).
Probable There is evidence to suggest a causal relationship and the SAR

influence of other factors is unlikely.
Definitely There is clear evidence to suggest a causal relationship and other SAR
possible contributing factors can be ruled out.
If an SAE is considered to be related to an antiretroviral and drug is stopped or the dose modified,
refer to Section 5.5.
7.3.1.D Expectedness
An unexpected adverse reaction is one not previously reported in the current Summary of Product
Characteristics (SPC) or one that is more frequent or more severe than previously reported. The
definition of an unexpected adverse reaction (UAR) is given in Table 5. If a SAR is assessed as being
unexpected, it becomes a SUSAR. If there is at least a possible involvement of the trial treatment,
the Investigator should make an initial assessment of the expectedness of the event. The Sponsor
will have the final responsibility for determination of expectedness (for reporting purposes), and this
decision will be made on the basis of the above definition and the information provided by the
Investigator. Please see the Manual of Operations for a summary of expected toxicities for ARVs.
7.3.1.E Notification
The relevant CTU should be notified of all SAEs within 24 hours of the investigator becoming aware
of the event.
Investigators should notify the relevant CTU of all SAEs occurring from the time of randomisation
until the end of the trial. Any subsequent events that may be attributed to treatment should also be
reported to national reporting schemes where relevant.

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7.3.2 NOTIFICATION PROCEDURE

1. The SAE Form must be completed by an investigator (a clinician named on the Signature List
and Delegation of Responsibilities Log who is responsible for the participant’s care), with
due care being paid to the grading, causality and expectedness of the event as outlined
above. In the absence of an investigator, the form should be completed and signed by a
member of the site trial team and faxed or emailed as appropriate. An investigator should
subsequently check the SAE Form, make changes as appropriate, sign and then re-fax to the
CTU as soon as possible. The initial report must be followed by detailed, written reports as
appropriate.
2. The minimum criteria required for reporting an SAE are the trial number and partial date of
birth, name of investigator reporting, the event and why the event is considered serious.
3. Follow-up: participants must be followed up until clinical recovery is complete and

laboratory results have returned to normal or baseline, or until the event has stabilised. A
further SAE Form, indicated as ‘Follow-up’ should be completed and faxed to the relevant
CTU as information becomes available. Extra, annotated information and/or copies of test
results may be provided separately. The participant must be identified by trial number,
anonymous code, and date of birth only. The participant’s name should not be used on any
correspondence and should be deleted from any test results.
4. Staff should follow their institution’s procedure for local notification requirements.

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7.4 CTU RESPONSIBILITIES
Medically-qualified staff at the CTUs will review all SAE reports received. The causality assessment
given by the local investigator at the hospital cannot be overruled; in the case of disagreement, both
opinions will be provided in any subsequent reports.
The CTUs are undertaking the duties of trial sponsor and are responsible for the reporting of SAEs to
the relevant regulatory authorities and research ethics committees of any countries in which the
trial is taking place, as appropriate. This responsibility may be delegated to country principal
investigators for relevant reporting requirements in individual countries.
The relevant CTU will also keep all investigators informed of any safety issues that arise during the
course of the trial.
CTUs will prepare annual Development Safety Update Reports (DSURs) on behalf of the sponsor
which will be submitted to the Competent Authorities and Ethics Committees in each country
participating in the trial.
Viiv Healthcare will also be notified of all reportable (serious and unexpected and drug-
related/unknown relationship) events. The CTUs will also provide Viiv Healthcare with a copy of the
DSUR.

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8 QUALITY ASSURANCE & CONTROL
8.1 RISK ASSESSMENT
The Quality Assurance (QA) and Quality Control (QC) considerations have been based on a formal
Risk Assessment, which acknowledges the risks associated with the conduct of the trial and how to
address them with QA and QC processes. QA includes all the planned and systematic actions
established to ensure the trial is performed and data generated, documented and/or recorded and
reported in compliance with the principles of ICH GCP and applicable regulatory requirements. QC
includes the operational techniques and activities done within the QA system to verify that the
requirements for quality of the trial-related activities are fulfilled. This Risk Assessment has been
reviewed by the MRC CTU Research Governance Committee (RGC) and has led to the development
of a Monitoring Plan, which will be kept separately.
8.2 CENTRAL MONITORING AT MRC CTU
Where local staff have successfully completed training on the trial database, data will be entered
into the trial database directly at the clinical site. The site will retain the original CRF. Data stored
on the central database will be checked at the CTU for missing or unusual values (range checks) and
checked for consistency within participants over time. If any such problems are identified, the site
will be contacted and asked to verify or correct the entry. Changes will be made on the original CRF
and entered into the database at the site. The CTU will also send reminders for any overdue and/or
missing data with the regular inconsistency reports of errors.
Alternatively sites can send completed CRFs to the CTU for data entry. Data received at CTUs will be
checked and if problems are identified, a missing data report of the problematic data will be sent to
the local site by secure e-mail for checking and confirmation or correction, as appropriate – any data
which are changed should be crossed through with a single line, dated and initialled. The amended
data should be returned to the appropriate CTU and the amended data should also be filed in the
notes at site. The CTUs will send reminders for any overdue and missing data.
Other essential trial issues, events and outputs will be detailed in the Monitoring and Quality
Management Plans that are based on the trial-specific Risk Assessment.
8.3 ON-SITE MONITORING
The agreement with each principal investigator will include permission for trial-related monitoring,
audits, ethics committee review and regulatory inspections by providing direct access to source
data/documents. Consent from parents/carers and children, if appropriate, for direct access to data
will also be obtained.
Staff from the CTUs or local monitors will visit clinical sites to validate and monitor data. The
frequency, type and intensity for routine monitoring and the requirements for triggered monitoring
will be detailed in the Monitoring Plans. The Monitoring Plan will also detail the procedures for
review and sign-off. Monitors will:
verify completeness of the Investigator Site File

confirm adherence to protocol
review eligibility verification and consent procedures

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look for missed clinical event reporting

verify completeness, consistency and accuracy of data being entered on CRFs
evaluate drug accountability
evaluate laboratory procedures and sample storage
provide additional training as needed
The monitors will require access to all patient medical records including, but not limited to,
laboratory test results and prescriptions. The investigator (or delegated deputy) should work with
the monitor to ensure that any problems detected are resolved.
8.3.1 DIRECT ACCESS TO PARTICIPANT RECORDS

Personal medical data will be reviewed at clinical centres by properly authorised individuals from the
CTUs as part of monitoring and/or audit of the trial, but such information will be treated as strictly
confidential and will in no circumstances be made publicly available. The following data will be
validated from source documents:
Eligibility and signed consent
All baseline data
New or recurrent WHO 4 event or death or severe WHO 3 event
All SAEs
All HIV-1 RNA viral loads >400 c/ml until the primary endpoint is reached
A random sample of clinical records*
A random sample of T cell subset measurements*
A random sample of laboratory results*
A random sample of original records of antiretroviral prescriptions (with batch numbers)*
*A minimum 10% of records (or 1 child, where this is greater) per site.
8.3.2 CONFIDENTIALITY
The investigator must assure that the participant’s anonymity will be maintained. On all CRFs and
specimens, participants must not be identified by their name. The investigator will be asked to keep
a separate Confidential Trial Register which matches the participant’s trial number with their name
and should be maintained by the investigator in strict confidence.

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9 STATISTICAL CONSIDERATIONS
9.1 METHOD OF RANDOMISATION
Randomisation will be stratified by:

routine availability of resistance tests vs. non availability of resistance tests
bPI/non-bPI-based ART offered as SOC
The randomisation lists will be prepared by staff at the MRC CTU under the direction of the trial
statistician. The randomisation lists will be generated by random permuted blocks and will be
securely incorporated within the web-enabled trial database. Randomisation will not take place
until after informed consent has been confirmed and the participant is ready to receive therapy.
9.2 OUTCOME MEASURES
The primary comparison for the study is to compare DTG-based regimen versus SOC for the primary
efficacy outcome in the combined population (naïve and experienced); subpopulation analyses
(ODYSSEY A and ODYSSEY B) are key secondary comparisons.
9.2.1 PRIMARY EFFICACY OUTCOME (OVER 96 WEEKS)

Difference in the probability of virological or clinical failure at 96 weeks, estimated by Kaplan-Meier
methods using time to the first occurrence of any of the following components (note, this does not
mean VL must be performed in real time):
Insufficient virological response defined as <1 log10 drop at week 24
VL >400 c/ml at or after 36 weeks confirmed by next visit
Any new or recurrent AIDS defining event (WHO 4) or severe WHO 3 events, confirmed by
the Endpoint Review Committee
9.2.2 SECONDARY EFFICACY OUTCOMES

Difference in proportion with clinical or virological failure (as defined above) over 48 weeks
Time to any new or recurrent AIDS defining event (WHO 4) or severe WHO 3 events,
confirmed by the Endpoint Review Committee
Proportion of children with VL ≥50 c/ml at 48 and 96 weeks
Proportion of children with VL ≥400 c/ml at 48 and 96 weeks
Proportion developing new resistance mutations with a subgroup analysis according to the
activity of the background regimen
9.2.3 SECONDARY SAFETY OUTCOMES

Change in total cholesterol, triglycerides and lipid fractions (LDL, HDL) from baseline to
weeks 48 and 96 (these safety outcomes will be used to formally assess superiority of DTG
based regimen vs. SOC)

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9.2.4 OTHER SECONDARY OUTCOMES

Quality of life (as assessed by patient completed questionnaires)
Adherence and acceptability (as assessed by patient completed questionnaires)
9.3 SAMPLE SIZE
Based on previous HIV studies a non-inferiority margin (delta) of 10-12% is considered acceptable.
Assuming a failure rate of 18% overall (both first-line and second-line children combined) in the DTG
arm and SOC arm by 96 weeks and allowing for 10% loss to follow up, 700 children will provide 90%
power to exclude (at two-sided 5% significance level) a difference of more than 10% between the
two arms. If the upper bound of the two-sided 95% confidence limit for the difference in the
proportion failing (DTG – SOC) is less than 10% (the margin of non-inferiority) the DTG-regimen will
be considered to be non-inferior to the SOC.
Enrolling 310 first-line ART and 390 second-line ART children will provide 80% power to exclude a
difference of more than 12% between the DTG and SOC arms in both subgroups, assuming a failure
rate of 15% in ART-naïve (based on previous trials, including the recent ARROW trial (36) in Africa),
and 20% in ART-experienced with loss to follow up of 10%.
9.4 INTERIM MONITORING & ANALYSES
An IDMC Charter will be drawn up that describes the membership of the IDMC, relationships with
other committees, terms of reference, decision-making processes, and the timing and frequency of
interim analyses (with a description of stopping rules and/or guidelines). The IDMC will meet within
6 months after the trial opens; although the IDMC will in general meet annually, the frequency of
subsequent meetings will be determined by the IDMC and could be more frequent if they deem
necessary. The IDMC can recommend premature closure or reporting of the trial, or that
recruitment be discontinued or modified. Such recommendations would be made if, in the view of
the IDMC, there is proof beyond reasonable doubt that one of the allocated strategies is better than
its comparator in terms of a difference of clinically significant magnitude in a primary outcome. The
guiding statistical criteria for “proof beyond reasonable doubt” is a Haybittle-Peto type rule based on
the 99.9% confidence interval of the relative hazard of death in each interim analysis.
9.5 ANALYSIS PLAN (BRIEF)
For the primary analysis, the two treatment groups (DTG and SOC) will be compared in terms of the
cumulative probability of clinical or virological failure by week 96 (CPF96) (as defined above) as
estimated by the Kaplan-Meier method, adjusting for stratification factors. DTG will be considered
non-inferior to SOC if the upper limit of the 95% confidence interval of the difference in CPF96 (DTG-
SOC) is less than the non-inferiority margin of 10%. The number and percentage of participants with
at least one component of the primary endpoint and the number and percentage for each
component will be summarised.
Secondary analyses will summarise the rate of the composite primary endpoint per 100 person years
by treatment group, and a treatment hazard ratio (HR: DTG to SOC) plus two-sided 95% confidence
interval estimated by a Cox proportional hazards model. The primary analysis is by intention to treat
and includes all randomised participants. A sensitivity analysis will be done with the per protocol
population, censoring events after a participant stops the initial randomised trial treatment.

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The secondary endpoints of change in total cholesterol, triglycerides and lipid fractions (LDL, HDL)
from baseline to weeks 48 and 96 will be analysed using analysis of covariance to compare the
change in mean level between the two arms, adjusting for baseline value and stratification factors.
These analyses will be carried out on all randomised participants (intention to treat) and will assess
the superiority of DTG compared to SOC for this parameter.
Intention to treat analyses including all randomised participants will be performed for all other
endpoints using the following statistical methods:
Descriptive statistics for the summary of baseline characteristics
Fishers Exact test and logistic regression for the analysis of binary variables
Analysis of variance and linear regression models for the analysis of continuous variables,
adjusting for baseline
Poisson regression for the analysis of incidence of clinical/adverse events
Log-rank test and Cox proportional hazard model for the analysis of time to event variables
Clinical and adverse events will be summarised by body system using MedDRA coding levels System
Organ Class and Preferred Term (PT).
Full details of all analyses will be provided in the Statistical Analysis Plan (SAP). This will include any
additional pre-planned subgroup analyses such as specific SOC ART.

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10 ANCILLARY STUDIES
10.1 IMMUNOLOGY/VIROLOGY SUBSTUDY
To compare mechanisms of CD4 reconstitution, immune activation and HIV reservoir and replication
in DTG vs. SOC arms.
Consent will be requested for blood storage on all participants. PBMCs will be stored in sites with
this capability.
For further information see Appendix XII.
10.2 PHARMACOKINETIC SUBSTUDY IN PARTICIPANTS DEVELOPING TB WHILE ON DTG:
Full PK curves will be undertaken in at least 10 children receiving DTG and rifampicin; curves will be
repeated in the same children after completion of TB therapy.
Where a child develops TB, separate consent for this substudy will be sought from participants
and/or carers as appropriate.
For further information see Appendix XIII.

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11 REGULATORY & ETHICAL ISSUES
11.1 COMPLIANCE
11.1.1 REGULATORY COMPLIANCE

The trial complies with the principles of the Declaration of Helsinki of 2013.
It will also be conducted in compliance with the approved protocol, the principles of Good Clinical
Practice (GCP) as laid down by the European Commission Directive 2005/28/EC with the
implementation in national legislation in countries in the EU and subsequent amendments and
appropriate data protection and regulatory legislation in participating countries, the UK Data
Protection Act (DPA UCL’s number Z6364106), and the National Health Service (NHS) Research
Governance Framework for Health and Social Care (RGF).
11.1.2 SITE COMPLIANCE

The site will comply with the above and with the principles of GCP as laid down by the ICH topic E6
(Note for Guidance on GCP), Commission Directive 2005/28/EC (the European Directive 2001/20/EC
[where applicable]) and applicable national regulations. An agreement will be in place between the
site, PENTA and the appropriate CTU, setting out respective roles and responsibilities (see Section 13
- Finance).
The site will inform the relevant CTU as soon as they are aware of a possible serious breach of
compliance, so that the CTU can report this breach if necessary within 7 days as per the relevant
regulatory requirements. For the purposes of this regulation, a 'serious breach' is one that is likely
to affect to a significant degree:
• The safety or physical or mental integrity of the participants in the trial, or
• The scientific value of the trial
11.1.3 DATA COLLECTION & RETENTION

CRFs, clinical notes and administrative documentation should be kept in a secure location (for
example, locked filing cabinets in a room with restricted access). During this period, all data should
be accessible to the competent or equivalent authorities, the Sponsor, (and other relevant parties)
with suitable notice. The data may be subject to an audit by the competent authorities.
11.2 ETHICAL CONDUCT OF THE STUDY
11.2.1 ETHICAL CONSIDERATIONS

Participation in a randomised controlled trial means that the participant and/or their carer as
appropriate, agree to randomisation but neither the participant, carer nor clinician are able to
choose all aspects of the participant's treatment. Participants will receive different treatments and
toxicities are different by arm; this will be explained to children/families. The risks of HIV-1 viral load
rebound due to a possibly less potent regimen and the use of a novel agent will be explained to
children/families. Consent will be sought from parents/carers and from participants where allowed
by national regulations. Participants not able to consent for themselves, but deemed able to
understand about the trial, will be asked to assent.
As described above, the main risks to the participants are from the potential toxicity from integrase
inhibitors. However, this possibility needs to be balanced against the risks from SOC ART. In
addition, the trial will evaluate the net clinical/virological risk-benefit comparing DTG with SOC.

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11.2.1.A Safety Profile of DTG

DTG has been taken by large numbers of adults in Phase III trials, and is licensed for the treatment of
HIV infection in adults and adolescents aged 12 and above weighing at least 40 kg. At the present
time there is limited experience with the use of this drug in the paediatric population. Standard
procedures are in place to record Serious Adverse Events arising from the use of DTG (or any study
drug) in the trial, and such events will be evaluated and reported to ethics committees and
regulatory agencies within specified timelines. The IDMC will closely monitor Serious Adverse Events
and grade 3 and 4 events occurring during the trial in all treatment groups and will be able to advise
appropriate action if there is a pattern of serious toxicity emerging from one or more of the drugs.
11.2.1.B Burden of investigations

The follow-up study visits coincide with the usual frequency of visits for routine clinical care. Two
extra visits are scheduled at the start of the trial to monitor participant’s safety and adherence to
medication. Additional tests (over and above routine care) may be required.
11.2.1.C Post-trial treatment

Provision of DTG for participants randomised to receive DTG and who are continuing to derive
benefit will continue after the study until DTG is locally approved and available for the child’s age
and weight band. Safety follow-up of those participants receiving DTG after the study will be
performed.
11.2.1.D Informing potential trial participants of possible benefits and known risks
Participants and carers will be informed fully of known risks and possible benefits by means of a
patient information sheet and this will be reinforced by discussions with the trial research teams at
the individual sites prior to enrolment.
11.2.1.E Confidentiality
Participants’ confidentiality will be maintained throughout the trial. Patient data will be identified
by the trial number and a 4 letter computer generated anonymous code, month and year of birth
and sex; samples sent to central testing facilities will be identified only by the trial number and a 4
letter computer generated anonymous code.
11.2.2 ETHICAL APPROVALS

Before initiation of the trial at each clinical site, the protocol, all informed consent forms, and
information materials to be given to the prospective participant and carer will be submitted to
national/local ethics committees for approval as required. Any further amendments will be
submitted and approved by each ethics committee.
The rights of the participant and carer to refuse to participate in the trial without giving a reason
must be respected. After the participant has entered into the trial, the clinician must remain free to
give alternative treatment to that specified in the protocol, at any stage, if he/she feels it to be in the
best interest of the participant. The reason for doing so, however, should be recorded; the
participant will remain within the trial for the purpose of follow-up and for data analysis by the
treatment option to which they have been allocated. Similarly, the carer/participant must remain
free to change their mind at any time about the protocol treatment and trial follow-up without
giving a reason and without prejudicing his/her further treatment.

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11.3 COMPETENT AUTHORITY APPROVALS
This protocol will be submitted to the national competent or equivalent authority in each country
where the trial will be conducted.
This is a Clinical Trial of an Investigational Medicinal Product (IMP) as defined by the EU Directive
2001/20/EC. Therefore, a CTA is required in the EU. In countries outside of the EU, local and
national regulatory requirements will be followed.
The EudraCT number for the trial is 2014-002632-14.
The progress of the trial and safety issues will be reported to the competent authority, regulatory
agency or equivalent in accordance with local requirements and practices in a timely manner.
Safety reports, including expedited reporting and SUSARs will be submitted to the competent
authorities in accordance with each authority’s requirements in a timely manner.
11.4 OTHER APPROVALS
The protocol will be submitted by those delegated to do so to the relevant R&D department of each
participating site or to other local departments for approval as required in each country. A copy of
the local R&D approval (or other relevant approval as above) and of the PIS and Consent Form (CF)
on local headed paper should be forwarded to the relevant CTU before any participants are
screened for eligibility.

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12 INDEMNITY
In consideration of the agreement by the Principal Investigator at each centre to supervise the trial,
the PENTA Foundation undertakes to indemnify the Principal Investigator at each centre and the
institutions which participate in the trial and their employees and agents in respect of any claims
made against them by any third party which arises out of or as a result of the supervision or conduct
of the trial (including any claim arising in respect of the technical procedures described in the
protocol which participants would not have been exposed but for their participation in the trial).
Full details of the Indemnity agreement are given in a separate document. Cover against claims
arising from medical negligence is not included.

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13 FINANCE
Research support will be provided to the clinical centres for additional visits. In some specific cases
and agreed by national ethics bodies, transport facilities, payments or vouchers will be given to
participants or their families in compensation for the time spent in clinic particularly during
substudies.
In some countries and as required by national legislation the health service cost of all protocol visits
will be covered by the sponsor or sponsor’s representative.
DTG (including Triumeq, as appropriate), ABC, 3TC, ZDV, Kivexa and Combivir will be provided by Viiv
Healthcare.

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14 OVERSIGHT & TRIAL COMMITTEES
There are a number of committees involved with the oversight of the trial. These committees are
detailed below, and the relationship between them is shown (see Appendix XIV).
14.1 TRIAL MANAGEMENT GROUP (TMG)
A Trial Management Group (TMG) will be formed comprising Chief Investigator(s), other lead
investigators (clinical and non-clinical) and members of the CTUs: MRC CTU, INSERM-ANRS, PHPT
and IMPAACT. The TMG will be responsible for the day-to-day running and management of the trial.
It will meet monthly during the recruitment phase and thereafter at least every other month.
14.2 TRIAL STEERING COMMITTEE (TSC)
The trial will be supervised by the ODYSSEY TMG who will report to the ODYSSEY Trial Steering
Committee (TSC). The TSC has membership from the TMG plus independent members, including the
Chair. The role of the TSC is to provide overall supervision for the trial and provide advice through
its independent Chair. The ultimate decision for the continuation of the trial lies with the TSC.
Further details of TSC functioning are presented in the TSC Charter. The ODYSSEY TSC may decide to
terminate the trial for any reason including the recommendation of the Independent Data
Monitoring Committee (IDMC).
14.3 INDEPENDENT DATA MONITORING COMMITTEE (IDMC]
The Independent Data Monitoring Committee (IDMC) which oversees all PENTA trials will be the only
group who sees the confidential, accumulating data for the trial. Reports to the IDMC will be
produced by the CTU statisticians. The IDMC will meet within 6 months of the trial opening; the
frequency of meetings will be dictated in the IDMC charter. The IDMC will consider data using the
statistical analysis plan (see Section 9.5) and will advise the TSC. The IDMC can recommend
premature closure or reporting of the trial, or that recruitment to any research arm is discontinued.
Further details of IDMC functioning and the procedures for interim analysis and monitoring are
provided in the IDMC Charter.
14.4 ENDPOINT REVIEW COMMITTEE
An Endpoint Review Committee will be appointed whose remit will be to determine the validity of
potential clinical endpoints in terms of meeting the standard criteria, as defined by the protocol. It
will have an independent Chair. No member will review endpoints from their own site. Terms of
reference for the Endpoint Review Committee will be drawn up.
14.5 ROLE OF STUDY SPONSOR
The sponsor of the trial is the PENTA Foundation. The management of the trial is delegated by the
sponsor to the CTUs: MRC CTU, INSERM-ANRS and PHPT.

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15 PUBLICATION
15.1 PUBLICATION
The ODYSSEY TMG will be responsible for preparing the manuscript for rapid publication. High
priority will be given to this and it would be anticipated that a report would be completed within six
months of a decision to stop the trial. The final publication will require the approval of the ODYSSEY
TMG and TSC. No other publications, including all or any part of the results, either written or verbal,
will be made before the definitive manuscript has been agreed and accepted for publication without
the prior approval of the ODYSSEY TMG and TSC. Individual clinicians must not publish data
concerning their participants that are directly relevant to questions posed by the trial until the TMG
has published its report. Responsibility for data analysis and publication for ODYSSEY will reside
within the PENTA network and be governed by PENTA policies.
The trial will be registered with the internationally accepted clinical trials register, clinicaltrials.gov.
The ISRCTN number will be attached to all publications resulting from this trial. The ODYSSEY TSC is
the custodian of the data and specimens generated from the ODYSSEY trial; ODYSSEY trial data are
not the property of individual participating investigators or health care facilities where the data were
generated.
The data derived from this clinical trial are considered the property of the ODYSSEY TSC. The
presentation or publication of any data collected by the participating investigators on
participants entered into this trial is under the direct control of the TMG and TSC (and the
IDMC before the end of the trial). This is true whether the publication or presentation is
concerned directly with the results of the trial or is associated with the trial in some other
way.
Outcome data by randomised group will not be revealed to the participating investigators
until the data collection phase and primary full analysis of the trial has been completed. This
policy safeguards against possible bias affecting the data collection. The IDMC will be
monitoring the outcome results and may recommend that the trial be stopped for safety
reasons or if a definitive answer is reached earlier than the scheduled end of the trial.
15.2 FEEDBACK TO PARTICIPANTS
At the end of the study, letters will be sent by trial sites to participants and families to inform them
when the trial will be closing.
When the trial results are available, an information sheet in lay terms will be provided for every trial
participant and carers to explain the results of the trial. This will be distributed to the Principal
Investigators at each site so that the paediatrician can discuss it with the child and/or parent/carer
to explain the outcome of the trial.

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16 PROTOCOL AMENDMENTS
Changes to protocol version 1.1 creating version 2.0 6th March 2015
Cover page: IMPAACT logo updated.
General Information: Details for collaborating centres in Klerksdorp, South Africa (PHRU) and
Memphis, US (St Jude Children’s Research Hospital) added
General Information & Section 2.3 Site Management: US removed in relation to IMPAACT and added
as a MRC collaborator.
General Information: MRC CTU at UCL staff details updated.
Trial Assessment Schedule: Timing of urine dipstick tests corrected – tests at end of study visit
added.
Trial Assessment Schedule & Section 6.4 Procedures for Assessing Quality of Life: Removal of
reference to EQ-5D-Y questionnaire, replaced with EQ-5D. EuroQol website link added to section 6.4.
Trial Assessment Schedule: Total blood volume to be collected clarified.
Abbreviations: List updated to include EQ-5D.
Section 6.8 Management of Pregnancy: Clarified that pregnant participants should be encouraged to
remain in the study even if ART regimen is changed.
Section 7.3.1.D Expectedness: Updated information on responsibilities for determination of
expectedness of serious adverse events.
Changes to protocol version 1.0 creating version 1.1 11 December 2014 (the protocol was still a
draft document at this stage but a “final” version was required for review by Viiv resulting in version
numbers taking this format. Neither protocol version 1.0 nor version 1.1 have been reviewed by an
ethics committee or competent authority).
General Information, Summary of Trial, Section 2 Selection of Sites/Clinicians & Section 14 Oversight
& Trial Committees: Details of IMPAACT involvement added.
General Information: Funding information corrected to reflect current status.
General Information: Sponsor details added.
General Information: Immunology/Virology Committee member details updated.
Summary of Trial: Updated for consistency and minor amendments for clarification.
Trial Schema, Section 5.1 Introduction & Section 5.2 SOC Arm: Addition of raltegravir to SOC arm of
ODYSSEY B.
Trial Assessment Schedule & Section 6.1 Trial Assessment Schedule: Addition of urine dipstick tests.
Trial Assessment Schedule, Section 3.1.1 Patient Inclusion Criteria, Section 6.1 Trial Assessment
Schedule & Section 6.8 Management of Pregnancy: Pregnancy test requirements clarified.
Trial Assessment Schedule: Timing of Tanner scale measurements, lipodystrophy assessments and
study drug supply clarified.
Trial Assessment Schedule: Timing of screening and randomisation visits clarified.
Abbreviations: List updated accordingly.
Section 1 Background: Updated
Section 2 Selection of Sites: General wording updated and update to laboratory requirements.
Clarified that a site and lab risk assessment will be carried out prior to site activation.
Section 3.2 Patient Exclusion Criteria: Bilirubin must be ≥2xULN.
Section 5 Treatment of Patients & Section 13 Finance: Triumeq can be provided by Viiv Healthcare as
appropriate.
Section 5.5.2.A Liver Toxicity: Stopping criteria updated to include that DTG should be substituted if
ALT ≥3xULN and bilirubin ≥2xULN, or that ALT ≥5xULN for more than 2 weeks with bilirubin <2xULN
and no symptoms of acute hepatitis or hypersensitivity.
Section 6.2.2 Immunology, Section 8.3.1 Direct Access to Participant Records & Section 9.2.2
Secondary Efficacy Outcomes: Clarification that total and percentage CD8 T cell counts should also

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be measured and access will be required to a random sample of this data. This data will be used to
provide CD4/CD8 ratios required as a secondary efficacy outcome.
Section 6.2.4 Resistance Testing: At sites where genotypic resistance testing is not performed as
standard of care baseline samples will be tested retrospectively and batched genotypic resistance
testing will be performed on samples with viral load >1000 c/ml.
Section 6.7.1 Management of Children with Tuberculosis in the DTG Arm & Section 10.2
Pharmacokinetic Substudy in Participants Developing TB while on DTG: At least 10 children with TB
receiving DTG and rifampicin will be invited to participate in the PK substudy.
Section 6.8 Management of Pregnancy: Clarification that all infants born to female participants will
receive infant prophylaxis according to current local standard of care.
Section 6.8 Management of Pregnancy: Clarification that any pregnancy that occurs during study
participation must be reported as a notable event.
Section 6.10 Participant Transfers: Patients can continue to attend visits at original site if sufficient
resources are available, or nurse only telephone visits can be conducted with drugs and clinical care
provided at a local clinic. Participant should be considered lost to follow-up if none of the options
are possible.
Section 7.4 CTU Responsibilities: Modified for general applicability. CTUS are responsible for
reporting of SAEs to relevant regulatory authorities and research ethics committees. This
responsibility may be delegated to country principal investigators.
Section 8.3 On-Site Monitoring: Monitors will evaluate laboratory procedures and sample storage.
Section 9 Statistical Considerations: Randomisation will be stratified by bPI/non-bPI-base ART
offered as SOC (to include RAL).
Section 13 Finance: Drugs provided by Viiv Healthcare corrected.
Minor corrections

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5. Eron JJ, Clotet B, Durant J, Katlama C, Kumar P, Lazzarin A, et al. Safety and efficacy of
dolutegravir in treatment-experienced subjects with raltegravir-resistant HIV type 1 infection: 24-
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7. Tebas P KP, Hicks C. 48 week bone marker changes with dolutegravir plus
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ICAAC; Denver2013.
8. Molina JM, Clotet B, van Lunzen J, Lazzarin A, Cavassini M, Henry K, et al. Once-daily
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9. Clotet B, Feinberg J, van Lunzen J, Khuong-Josses MA, Antinori A, Dumitru I, et al. Once-daily
dolutegravir versus darunavir plus ritonavir in antiretroviral-naive adults with HIV-1 infection
(FLAMINGO): 48 week results from the randomised open-label phase 3b study. Lancet. 2014.
10. Patel DA SS, Tang WY, et al., editor. 48-Week Efficacy of Dolutegravir Relative to Commonly
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Dolutegravir versus raltegravir in antiretroviral-experienced, integrase-inhibitor-naive adults with
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Antiretroviral-Experienced Patients With Raltegravir- and/or Elvitegravir-Resistant HIV-1: 24-Week
Results of the Phase III VIKING-3 Study. J Infect Dis. 2014.
13. Demarest JFUM, St Clair M, Dorey D, Almond S, R. Cuffe R, Brown D, Nichols G. . DTG-
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14. Viani RM CA, Fenton T, et al., editor. Safety and efficacy of dolutegravir (DTG; GSK1349572)
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15. Viani RM AC, Fenton T, et al., editor. Safety pharmakokinetics and efficacy of dolutegravir in
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19. Musiime V. KP, Naidoo-James B et al. , editor. Randomised comparison of Once- vs. Twice-
daiy Abacavir and Lamivudine among 669 HIV+ Children in the Anti-Retroviral Research for Watoto
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Atlanta GA.
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therapy and mortality among HIV-infected infants. The New England journal of medicine.
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21. Harrison L MA, Fiscus S, Saidi Y, Nastouli E, Harper L, Compagnucci A, Babiker A, McKinney
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RNA thresholds. Conference on Retroviruses and Opportunistic Infections (CROI); 2014 3rd-6th
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22. Germanaud D, Derache A, Traore M, Madec Y, Toure S, Dicko F, et al. Level of viral load and
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23. Ruel TD, Kamya MR, Li P, Pasutti W, Charlebois ED, Liegler T, et al. Early virologic failure and
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Infectious Diseases Society of America. 2012;54(11):1660-9.
25. Fox MP, Ive P, Long L, Maskew M, Sanne I. High rates of survival, immune reconstitution, and
virologic suppression on second-line antiretroviral therapy in South Africa. J Acquir Immune Defic
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26. Paton N KC, Hoppe A, et al. . A pragmatic randomised controlled strategy trial of three
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27. Sigaloff KC, Hamers RL, Wallis CL, Kityo C, Siwale M, Ive P, et al. Second-line antiretroviral
treatment successfully resuppresses drug-resistant HIV-1 after first-line failure: prospective cohort in
Sub-Saharan Africa. J Infect Dis. 2012;205(11):1739-44.
28. Song I BJ, Savina P, Chen S, Patel P, Wajima T, Peppercorn A, Piscitelli S., editor.
Pharmacokinetics of DTG in Subjects with Moderate Hepatic Impairment. 19th Conference on
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29. Weller S, Borland J, Chen S, Johnson M, Savina P, Wynne B, et al. Pharmacokinetics of
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2013;62(1):21-7.
31. Weller S CS, Borland et al. Bioequivalence of a Dolutegravir, Abacavir and Lamivudine Fixed-
Dose Combination Tablet and the Effect of Food
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32. ING114580. S. Evaluation of the Bioequivalence of a Combined Formulated Tablet. Available
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33. Penazzato M, Prendergast A, Tierney J, Cotton M, Gibb D. Effectiveness of antiretroviral
therapy in HIV-infected children under 2 years of age. The Cochrane database of systematic reviews.
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34. Abers MS, Shandera WX, Kass JS. Neurological and psychiatric adverse effects of
antiretroviral drugs. CNS drugs. 2014;28(2):131-45.
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APPENDIX I TEMPLATE INFORMATION SHEETS
PARENT/CARER INFORMATION SHEET
ODYSSEY STUDY
Before you decide whether to take part, it is important for you and your child to understand why we
want to carry out this study and what it will mean for you both.
Please take time to read the following information and to discuss it with friends, family and with
your doctor or clinic nurse if you wish.
You are free to decide if you want your child to take part in this research study. If you choose not to
take part, this will not affect the care your child gets from your doctor or nurse.
Important to know
If you decide to take part your child will have some extra visits to the clinic at the beginning of the
study.
A computer program will choose which treatment your child will take. Neither you nor your doctor
will be able to choose which group your child is in.
Contents


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taken once a day.
ODYSSEY will see how children and adolescents taking dolutegravir as part of their anti-HIV
medicines compare to others taking different anti-HIV medicines.
Or
B. He/She is already taking one set of anti-HIV medicine and your doctor feels it is time your child
changes to a new combination.
It is totally up to you and your child whether or not he /she takes part in this study.

into the study.
If the results show that your child can participate, we will invite him/her to enter the study. We
need to know that you have fully understood the study and then we will ask you to sign a second
consent form for your child to join.
In the first 2 months you will need to come for 3 appointments. Once your doctor is happy that your
child has no side effects from the medicines and is doing well, they will change to having 3-monthly
appointments.
These visits are to make sure your child is continuing to do well. If for any reason your doctor has

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any concerns, they will change your child’s treatment in the normal way.
In addition to blood tests to check for any side effects, a small amount of extra blood will be
collected at each visit. The total amount of blood taken will be between 2 and 3 teaspoons
depending upon the age of your child. Part of this sample will be used to check the amount of virus
in the blood and the rest will be stored and used to look at how the body fights HIV. We would like
your agreement that we can store these samples anonymously (without your child’s name or exact
date of birth) for up to 15 years.
Your child will be in the study for at least 2 years. When the study ends, if your child is doing well
they may be able to remain on the same anti-HIV medicines they have been taking during the study,
but you will need to discuss this with your doctor.
medicine.
Dolutegravir group: meaning your child will take a combination of anti-HIV medicines that
includes the new medicine, dolutegravir.

We cannot promise that participating in the study will directly help your child. Compared to other
anti-HIV medicines dolutegravir may have fewer side effects and needs to be taken only once a day
which may make it easier to take medicines long-term.
as children not taking part in ODYSSEY, although your child will be watched very carefully for any
side effects and responses to the treatment. All the information we get will help children and young
people across the world with HIV and in the future it may mean your child has the chance to change
to medicines that are easier to take.
Whichever group they are in your child will have 3 extra visits to the clinic.

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common side effects in adults are headache, feeling sick or diarrhoea. There is a small chance that
dolutegravir may cause a rash, itching, vomiting, stomach pain, sleep problems, lack of energy,
feeling light headed or may affect your child’s liver (with signs of vomiting, jaundice or stomach
pain), which is why the doctor needs to follow your child closely. If your child has these signs for
more than a day you should inform your doctor straight away.

There is very little information about the effect of dolutegravir in unborn babies. If your child could
become pregnant, she will need a pregnancy test before entering the study. She will not be able to
join the study if the test shows she is pregnant. We encourage her to use effective contraceptives
and for her to let us know straightaway if at any time she thinks she may have become pregnant. If
this is confirmed with a pregnancy test her treatment will be reviewed by the doctor. She will be
able to stay in the study if she becomes pregnant.
Additional studies


Ethics Committee) to make sure that, as far as possible, the safety and wellbeing of anyone taking

The PENTA Foundation has made arrangements for compensation should your child come to any
harm from participating in this study. If your child is harmed due to someone’s negligence then you
may have reasons for legal action for compensation against the clinic where this occurred.
hospital doctor is not receiving any personal payment for carrying out this research. [Country

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specific, delete if not applicable ]
will not be used. Your child will only be identified using a study number and an anonymous code.
Your child’s clinic notes will only be made available to study staff and confidentiality will be
maintained at all times.

You and your child’s doctor will continue to make decisions about your child’s medicines once the
study has finished. If your child is in the dolutegravir group and treatment with dolutegravir appears
to be a safe and effective way of treating children and young people with HIV then they may be able
to stay on these medicines. We would also like to continue to collect routine information about your
child after the study has ended so we can look at the long term effects of the new medicines.

study?

If your child would like to join the ODYSSEY study please speak to the staff at your nearest clinic
where the study is run during your next appointment.
How to contact us?

Contact: ____________________________
Tel: ____________________________

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Visit schedule for children taking part in ODYSSEY

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PARTICIPANT INFORMATION SHEET
ODYSSEY STUDY
We are inviting you to take part in a research study
Before you decide whether to take part, it is important for you to understand why we want to carry
out this study and what it will mean for you.
Please take time to read the following information and to discuss it with friends, family and with
your doctor or clinic nurse if you wish.
You are free to decide if you want to take part in this research study. If you choose not to take part,
this will not affect the care you get from your doctor or nurse.
Important to know
If you decide to take part you will have some extra visits to the clinic at the beginning of the
study.
A computer program will choose which treatment you will take. Neither you nor your doctor
will be able to choose which group you are in.
Contents
5. What medicines will I be given?

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In adults it has been shown to be effective and safe, with few side effects and it only needs to be
taken once a day.
ODYSSEY will see how children and adolescents taking dolutegravir as part of their anti-HIV
medicines compare to others taking different anti-HIV medicines.
We are aiming to ask 700 young people, like yourself, from many countries to take part.
You have been asked to participate because:
A: You are about to start taking anti-HIV medicine for the first time
or
B: You are already taking one set of anti-HIV medicine and your doctor feels it is time you change to
a new combination
It is totally up to you whether or not you take part in this study.


If you decide to take part we will go through this information sheet together. We will give a copy to
you to keep. Your parent/carer will be asked to sign a consent form to show you have both
understood the information and agreed to have some blood tests and a check-up to see whether
you can go into the study.
If the results show that you can participate we will invite you to enter the study. We need to know
that you have fully understood the study and then we will ask your parent/carer to sign a second
consent form for you to join. We will also ask you to sign a form giving your assent to join the study.
Your health will be watched closely during the study. In the first 2 months you will need to come for
3 appointments. Once your doctor is happy that you have no side effects from the medicines and
you are doing well, you will change to having 3-monthly appointments.

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These visits are to make sure you are continuing to do well. If for any reason your doctor has any
concerns, they will change your treatment in the normal way.
In addition to blood tests to check for any side effects, a small amount of extra blood will be
collected at each visit. The total amount of blood taken will be between 2 and 3 teaspoons
depending on your age. Part of this sample will be used to check the amount of virus in the blood
and the rest will be stored and used to look at how the body fights HIV. We would like your
agreement that we can store these samples anonymously (without your name or exact date of birth)
for up to 15 years.
You will be on the study for at least 2 years. When the study ends, if you are doing well, you may be
able to remain on the treatment you have been taking during the study, but you will need to discuss
this with your doctor.
It is important that you know that this is a voluntary study so if at any time you decide that you do
not want to be involved anymore, you can stop and it will not affect the care that you receive in the
future.
5 What medicines will I be given?
If you join the study, a computer will choose which group you will be in so it is fair and we can truly
compare the treatments.
Standard of Care group: meaning you will receive the usual, nationally approved anti-HIV medicine.
Dolutegravir group: meaning you will take a combination of anti-HIV medicines that includes the
new medicine, dolutegravir.

We cannot promise that participating in the study will directly help you. Compared to other anti-HIV
medicines, dolutegravir may have fewer side effects and needs to be taken only once a day which
If you are in the ‘standard of care’ group you will receive the same anti-HIV medicines as children
not taking part in ODYSSEY although you will still be watched very carefully for any side effects and
responses to the treatment. All the information we get will help children and young people across
the world with HIV, and in the future it may mean you have the chance to change to medicines that
are easier to take.
Whichever group you are in you will have 3 extra visits to the clinic.
abdominal discomfort, diarrhoea, rash or may affect the liver. If you feel unwell, you should contact
the clinic as soon as possible.
The new medicine, dolutegravir, has been shown to be effective with few side effects in adults, but

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common side effects in adults are headache, feeling sick and diarrhea. There is a small chance that
dolutegravir may cause a rash, itching, vomiting, stomach pain, sleep problems, lack of energy,
feeling light-headed or may affect your liver (with signs of vomiting, jaundice or stomach pain),
which is why the doctor needs to follow you closely. If you have these signs for more than a day you
should inform your doctor straight away.

There is very little information about the effect of dolutegravir in unborn babies. If you could
become pregnant, you will need a pregnancy test before entering the study. You will not be able to
join the study if the test shows you are pregnant
We encourage you to use effective contraceptives and to let us know if at any time you think you
may have become pregnant. If this is confirmed with a pregnancy test your treatment will be
reviewed by the doctor. You will be able to stay in the study if you become pregnant.
and how it is affecting their wellbeing. Over the course of the study we will ask you to complete
questionnaires asking how you take your medicines, what it’s like taking medicine and how you feel
in general.
Additional studies
may talk to you about taking part.


The information about this study has been checked by an independent group of people (a
Research Ethics Committee)to make sure that as far as possible, the safety and wellbeing of
anyone taking part in the study is protected.
to review the results as they come out and will recommend if the trial is safe to continue. This is

The PENTA Foundation has made arrangements for compensation should you come to any harm
from participating in this study. If you are harmed due to someone’s negligence then you may have
reasons for legal action for compensation against the clinic where this occurred.
With your permission your GP will be informed of your participation in the study. Your hospital
doctor is not receiving any personal payment for carrying out this research. [Country specific, delete
if not applicable ]

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will not be used. You will only be identified using a study number and an anonymous code. Your
clinic notes will only be made available to study staff and confidentiality will be maintained at all
times.
If the results of this study are reported or published your name will not be used nor any information
that could be used to identify you. The study will be conducted in agreement with the country
specific data protection regulations.

You and your doctor will continue to make decisions about your medicines once the study has
finished.
If you are in the dolutegravir group and treatment with dolutegravir appears to be a safe and
effective way of treating children and young people with HIV then you may stay on these medicines.
We would also like to continue to collect your routine information after the study has ended so we
can look at the long term effects of the new medications.

course of the study?
studied. An independent committee will look at any new information and will also look at the data
collected so far in the study and decide if any changes are needed. If this happens, your doctor will
tell you about it and discuss whether you want to continue in the study. If you decide to stop taking
part in the study, your doctor will continue your regular care.
How can I join the study?

If you would like to join the ODYSSEY study please speak to the staff at your nearest clinic where the
study is run during your next appointment.
How to contact us?

Contact:_________________________
Tel:_____________________________

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Visit schedule for children taking part in ODYSSEY

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PARENT/CARER INFORMATION SHEET FOR PHARMACOKINETIC (PK) SUBSTUDY
ODYSSEY PK SUBSTUDY:
1 Why are we doing this substudy?

We hope this study will help us to find the best treatment for children like yours.
Your child has been asked to participate because he/she is part of the ODYSSEY study and is
We are aiming to ask at least 10 children and young people to take part.
It is totally up to you and your child whether or not he/she takes part in this study. It is your
right to decide not to take part if you wish.
If you do decide to take part, blood samples will be taken and stored from your child so
researchers can learn more about anti-HIV medicines. If at any point your child wants to
stop being in the study we hope that you will still allow us to use these samples. If, however,
you do not give your permission then we will destroy them.

If you do decide to take part, we will go through this information sheet together. We will
give you a copy to keep. You will be asked to sign a consent form to show you understand
the information and agree to take part.
Your child’s wellbeing will be monitored closely during the study. If for any reason, his/her
medicine needs to be changed this will be done by their doctor in the usual way.
Important to know
If you decide to take part your child will need to spend one day in hospital while taking anti-
TB medicines. At least a month after your child stops taking anti-TB medicines, he/she will
spend a second day at hospital and may need to stay overnight.

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At the start of the study your child will be taking dolutegravir and anti-TB medicines. At this
point we will take some blood samples to measure the level of dolutegravir in the blood.
Your child will be asked to come into hospital for a whole day. He/she will have nine blood
samples taken during the day (over 12 hours) to test the level of dolutegravir in their blood.
A cream with local pain-killing effect will be used to make the skin numb and a thin flexible
tube (called a cannula) will be inserted into a vein for the day to enable the blood samples
to be taken. All blood samples will be taken from the cannula so only one needle prick is
required. Each blood sample will be small (1 teaspoon), which is safe for your child’s age and
weight.
At least a month after your child has completed his/her anti-TB treatment he/she will be
asked to spend a second day at the clinic and another nine blood samples will be taken
(over 24 hours). This may require an overnight stay in hospital.
At this point the dolutegravir-anti-TB medicines substudy will end. However, usual clinic
ODYSSEY visits will continue for routine monitoring of your child’s health.

of this study will give us more information about how dolutegravir and anti-TB medicines
work together in children. It is very important that we have this information so we can make
sure that children are given the correct amount of medicine.
This information will help children and young people across the world with HIV and TB and
in the future it may mean your child has the chance to get the most appropriate amount of
medicines.
This substudy will not result in any risk to your child’s health. However, your child will have
to spend two days in hospital and may need to stay overnight on the second day.
Each day, nine small blood samples will be taken but only one needle prick will be needed
each day.

A second group (the Independent Data Monitoring Committee) will meet regularly during
the study to review the results as they come out and will recommend if the study is safe to

any harm from participating in this study. However, if your child is harmed due to
someone’s negligence then you may have reasons for legal action for compensation

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against the hospital where the negligence occurred, but you may have to pay your legal
costs.
What will happen to information about my child collected during this

substudy?
names will not be used. Your child will only be identified using a study number and an
anonymous code. Your child’s clinic notes will only be made available to study staff and
confidentiality will be maintained at all times.
If the results of this study are reported or published no information will be included that
could identify your child (no name or date of birth). The study will be conducted in
agreement with the country specific data protection regulations.
Contact: _________________________
Tel: _____________________________

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PARTICIPANT INFORMATION SHEET FOR PHARMACOKINETIC (PK) SUBSTUDY
ODYSSEY PK SUBSTUDY:
1 Why are we doing this substudy?

We hope this study will help us to find the best treatment for young people like you.
You have been asked to participate because you are part of the ODYSSEY study and are
We are aiming to ask at least 10 young people to take part.
It is totally up to you whether or not you take part in this study. It is your right to decide not
to take part if you wish.
If you do decide to take part, blood samples will be taken and stored from you so
researchers can learn more about anti-HIV medicines. If at any point you want to stop being
in the study we hope that you will still allow us to use these samples. If, however, you do
not give your permission then we will destroy them.
If you do decide to take part, we will go through this information sheet together. We will
give a copy to you to keep. Your parent/carer will then be asked to sign a consent form to
show you both understand the information and agree to take part. We will also ask you to
sign a form giving your assent to join the substudy.
Your wellbeing will be monitored closely during the study. If for any reason your medicine
needs to be changed this will be done by your doctor in the usual way.
Important to know

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If you decide to take part you will need to spend one day in hospital while taking anti-TB
medicines. At least a month after you stop taking anti-TB medicines, you will spend a second
day at hospital and may need to stay overnight.
At the start of the study you will be taking dolutegravir and anti-TB medicines. At this point
we will take some blood samples to measure the level of dolutegravir in the blood.
You will be asked to come into hospital for a whole day. You will have nine blood samples
taken during the day (over 12 hours) to test the level of dolutegravir in your blood. A cream
with local pain-killing effect will be used to make the skin numb and a thin flexible tube
(called a cannula) will be inserted into a vein for the day to enable the blood samples to be
taken. All blood samples will be taken from the cannula, so only one needle prick is
required. Each blood sample will be small (1 teaspoon), which is safe for your age and
weight.
At least a month after you have completed your anti-TB treatment you will be asked to
spend a second day at the clinic and another nine blood samples will be taken (over 24
hours). This may require an overnight stay in hospital.
At this point the dolutegravir-anti-TB medicines substudy will end. However, usual clinic
ODYSSEY visits will continue for routine monitoring of your health.

We cannot promise that participating in the study will directly help you but the results of
this study will give us more information about how dolutegravir and anti-TB medicines work
together in children and young people. It is very important that we have this information so
we can make sure that children and young people are given the correct amount of medicine.
This information will help children and young people across the world with HIV and TB and
in the future it may mean you have the chance to get the most appropriate amount of
medicines.
This substudy will not result in any risk to your health. However, you will have to spend two
days in hospital and may need to stay overnight on the second day.
Each day, nine small blood samples will be taken but only one needle prick will be needed
each day.

A second group (the Independent Data Monitoring Committee) will meet regularly during
the study to review the results as they come out and will recommend if the study is safe to

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The PENTA Foundation has made arrangements for compensation should you come to any
harm from participating in this study. However, if you are harmed due to someone’s
negligence then you may have reasons for legal action for compensation against the
hospital where the negligence occurred, but you may have to pay your legal costs.
With your permission your GP will be informed of your participation in the study. Your
hospital doctor is not receiving any personal payment for carrying out this research.
[Country specific, delete if not applicable ]
What will happen to my information collected during this substudy?

names will not be used. You will only be identified using a study number and an anonymous
code. Your clinic notes will only be made available to study staff and confidentiality will be
maintained at all times.
If the results of this study are reported or published no information will be included that
could identify you (no name or date of birth). The study will be conducted in agreement
with the country specific data protection regulations.
Contact: _________________________
Tel: _____________________________

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APPENDIX II TEMPLATE CONSENT AND ASSENT FORMS
Study number:
PARENT/CARER – CONSENT TO SCREENING


therapy.

in this study.
testing.
my child’s name.
I understand that if I cannot participate in the study, the stored blood sample
will be discarded and not used for further tests.
Print name Date
(or thumbprint)
Print name Date
Signature of person
consent process

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Study number:
PARENT/CARER – CONSENT TO RANDOMISATION

(Insert version no and date )

therapy.

the study.

I agree to inform the study doctor if my child starts any other new medicines during

confidential.
to be stored for later testing, including genetic testing. I understand that these
results and samples will not be identified by either my or my child’s name and that I
may not be given the results of tests performed on stored samples.
and date of birth).
I agree for my child to participate in the ODYSSEY study
Print name Date
(or thumbprint)
Print name Date

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Signature of person
consent process
Name of GP:

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Study number:
PARTICIPANT- ASSENT TO RANDOMISATION



8. Do you understand it’s ok to stop taking part in the study at any time? YES NO
Print name Date
(or thumbprint)

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Signature of person
consent process

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Study number:
PARENT/CARER – CONSENT TO STORAGE OF BLOOD SAMPLES FOR FUTURE TESTING


to be stored for later testing, including genetic testing. I understand that these
results and samples will not be identified by either my or my child’s name and that I
may not be given the results of tests performed on stored samples.
Print name Date
(or thumbprint)
Print name Date
answered all his/her questions. To the best of my knowledge, he/she understands the purpose, risks
and benefits of blood sample storage and willingly agrees for his/her child to have their blood
samples stored for future testing, including possible genetic testing.
Signature of person
consent process

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Study number:
PARTICIPANT – ASSENT TO STORAGE OF BLOOD SAMPLES FOR FUTURE TESTING



1. Do you understand that we would like to keep some of your blood samples to YES NO
test in the future?
2. Do you understand that we will not put your name on the samples so that YES NO
other people will not know that they belong to you?
3. Do you understand that you may not be given the results from these tests? YES NO
4. Are you happy for us to keep your blood samples to test in the future? YES NO
If any answers are ‘no’, don’t sign your name.
If you are happy for us to store your blood samples to test in the future, you can sign your name
below.
Print name Date
(or thumbprint)

benefits of blood sample storage and willingly agrees to have their blood samples stored for future
testing.
Signature of person
consent process

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Study number:
PARENT/CARER - CONSENT TO PHARMACOKINETIC (PK) SUBSTUDY


the ODYSSEY TB PK substudy and I understand what will be required if my child
participates in the substudy.
The TB PK substudy has been explained to me and my questions have been
answered.
I understand that my child’s participation in this substudy is voluntary and that I am

free to withdraw him or her at any time, without giving any reason, without my
medical care or legal rights or my child’s medical care or legal rights being affected.
further work can be done to help understand more about HIV and TB effective
treatment. [Country specific, delete if not applicable ]
I agree for my child to participate in the ODYSSEY TB PK substudy
Print name Date
(or thumbprint)
Print name Date
I have provided the ODYSSEY TB PK substudy information to the participant’s parent/legal guardian
participate in the ODYSSEY TB PK substudy.
Signature of person
consent process

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Study number:
PARTICIPANT - ASSENT TO PHARMACOKINETIC (PK) SUBSTUDY



1. Have you read (or had read to you) the information about the substudy? YES NO
2. Has somebody explained this substudy to you? YES NO
3. Do you understand what this substudy is about? YES NO
6. Do you understand how this substudy might help you? YES NO
8. Do you understand it’s ok to stop taking part in the study at any time? YES NO
9. Do you understand that you will need to come to the hospital for a whole day YES NO
to check the level of medicines in your blood?
10. Do you understand that you will need to come back to the hospital for a YES NO
second full day to check the level of drugs in your blood and maybe sleep there?
Print name Date
(or thumbprint)

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I have provided the ODYSSEY TB PK substudy information to the participant in full and answered all
risks and benefits of this study and willingly agrees to participate in the ODYSSEY TB PK substudy.
Signature of person
consent process

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APPENDIX III TEMPLATE GP LETTER
(To be printed on local headed paper).

Dear Dr ________________________________
The parents of________________________and him/herself, have agreed to participate in the

ODYSSEY study. This is a randomised multicentre international trial co-ordinated by PENTA, which is
funded by the European Commission (see www.PENTA-ID.org).
ODYSSEY aims to compare the efficacy and toxicity of antiretroviral regimens containing two NRTIs
and the new integrase inhibitor dolutegravir versus standard combination regimens containing
two/three NRTIs and either an NNRTI, a protease inhibitor or a first generation integrase inhibitor,
raltegravir. Adherence to and acceptability of the different regimens will also be compared.
The trial will enrol 700 children under 18 years of age from clinical centres in Europe, Africa, Asia,
North and South America and will include 2 groups of children: those initiating antiretroviral therapy
and those switching to a second-line regimen. All children will be followed until the last patient
recruited has completed 96 weeks of follow-up.
Your patient has been randomised to:

dolutegravir containing regimen
standard combination therapy.
Children taking dolutegravir who develop TB during the trial may be asked to take part in a
pharmacokinetic substudy to determine their plasma levels of dolutegravir when given with
rifampicin. Further consent will be requested for this.
I would be very grateful if you could inform me of any concomitant medication that you prescribe to
this child during the study.
I enclose a summary of the trial and a copy of the Patient Information Sheet. If you would like a copy
of the full protocol or have any comments or problem, please contact:
Dr _____________________
Enc.
Trial Summary
Patient Information Sheet

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APPENDIX IV TEMPLATE ADHERENCE QUESTIONNAIRES

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APPENDIX V TEMPLATE ACCEPTABILITY QUESTIONNAIRES: ODYSSEY A

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APPENDIX VI TEMPLATE ACCEPTABILITY QUESTIONNAIRE: ODYSSEY B

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APPENDIX VII ADAPTED WHO CLINICAL STAGING OF HIV/AIDS FOR PATIENTS WITH CONFIRMED
HIV INFECTION
WHO clinical staging (1-3); Diagnostic criteria for these conditions, are described in Appendix IX
Clinical Stage 1 Clinical Stage 1
Asymptomatic Asymptomatic
Persistent generalized lymphadenopathy Persistent generalized lymphadenopathy
Clinical stage 2 Clinical stage 2
Unexplained persistent Moderate unexplained weight loss

hepatosplenomegaly (<10% of presumed or measured body
Papular pruritic eruptions weight)
Fungal nail infection Recurrent respiratory tract infections
Angular cheilitis (sinusitis, tonsillitis, otitis media and
Lineal gingival erythema pharyngitis)
Extensive wart virus infection Herpes zoster
Extensive molluscum contagiosum Angular cheilitis
Recurrent oral ulcerations Recurrent oral ulceration
Unexplained persistent parotid Papular pruritic eruptions
enlargement Seborrhoeic dermatitis
Herpes zoster Fungal nail infections
Recurrent or chronic upper respiratory
tract infections (otitis media, otorrhoea,
sinusitis or tonsillitis)
Unexplained moderate malnutrition or Unexplained severe weight loss (>10% of

wasting not adequately responding to presumed or measured body weight)*
standard therapy* Unexplained chronic diarrhoea for longer
Unexplained persistent diarrhoea (14 than one month
days or more) Unexplained persistent fever (above
Unexplained persistent fever (above 37.6°C intermittent or constant,
37.5°C intermittent or constant, for longer than one month)
for longer than one month) Persistent oral candidiasis*
Persistent oral candidiasis (after first 6–8 Oral hairy leukoplakia
weeks of life)* Pulmonary tuberculosis (current)
Oral hairy leukoplakia Severe bacterial infections (such as
Acute necrotizing ulcerative gingivitis or pneumonia, empyema, pyomyositis,
periodontitis bone or joint infection, meningitis or
Lymph node tuberculosis bacteraemia)
Pulmonary tuberculosis Acute necrotizing ulcerative stomatitis,

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Severe recurrent bacterial pneumonia gingivitis or periodontitis

Symptomatic lymphoid interstitial Unexplained anaemia (<8 g/dl),
pneumonitis* neutropaenia (<0.5 109 per litre) or
Chronic HIV-associated lung disease chronic thrombocytopaenia (<50 109
including bronchiectasis* per litre)
Unexplained anaemia (<8 g/dl),
neutropaenia (<0.5 109 per litre)and or
chronic thrombocytopaenia (<50 109
per litre)
Clinical Stage 4
Unexplained severe wasting, stunting or HIV wasting syndrome

severe malnutrition not responding to Pneumocystis pneumonia
standard therapy Recurrent severe bacterial pneumonia
Pneumocystis pneumonia Chronic herpes simplex infection
Recurrent severe bacterial infections (orolabial, genital or anorectal
(such as empyema, pyomyositis, bone or of more than one month’s duration or
joint infection or meningitis but excluding visceral at any site)
pneumonia) Oesophageal candidiasis (or candidiasis
Chronic herpes simplex infection of trachea, bronchi or lungs)
(orolabial or cutaneous of more than one Extrapulmonary tuberculosis
month’s duration or visceral at any site) Kaposi’s sarcoma
Oesophageal candidiasis (or candidiasis Cytomegalovirus infection (retinitis or
of trachea, bronchi or lungs) infection of other organs)
Extrapulmonary tuberculosis Central nervous system toxoplasmosis
Kaposi’s sarcoma HIV encephalopathy
Cytomegalovirus infection: retinitis or Extrapulmonary cryptococcosis including
cytomegalovirus infection affecting meningitis
another organ, with onset at age older Disseminated non-tuberculous
than one month mycobacterial infection
Central nervous system toxoplasmosis Progressive multifocal
(after one month of life) leukoencephalopathy
Extrapulmonary cryptococcosis (including Chronic cryptosporidiosis (with
meningitis) diarrhoea)
HIV encephalopathy Chronic isosporiasis
Disseminated endemic mycosis Disseminated mycosis (coccidiomycosis
(coccidiomycosis or histoplasmosis) or histoplasmosis)
Disseminated non-tuberculous Recurrent non-typhoidal Salmonella
mycobacterial infection bacteraemia
Chronic cryptosporidiosis (with Lymphoma (cerebral or B-cell non-
diarrhoea) Hodgkin) or other solid HIV-associated
Chronic isosporiasis tumours
Cerebral or B-cell non-Hodgkin Invasive cervical carcinoma
lymphoma Atypical disseminated leishmaniasis
Progressive multifocal Symptomatic HIV-associated
leukoencephalopathy nephropathy or symptomatic HIV-
Symptomatic HIV-associated associated cardiomyopathy
nephropathy or HIV-associated
cardiomyopathy

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APPENDIX VIII ADAPTED DIAGNOSTIC CRITERIA FOR WHO CLINICAL STAGING EVENTS IN
CHILDREN YOUNGER THAN 15 YEARS
The table is adapted from WHO case definitions of HIV for surveillance and revised clinical staging
and immunological classification of HIV-related disease in adults and children (1)

Clinical Stage 1
Asymptomatic No HIV related symptoms reported and no clinical Not applicable.
signs on examination.
Persistent Persistent swollen or enlarged lymph nodes >1 cm Clinical diagnosis
generalized at two or more non-contiguous sites (excluding
lymphadenopathy inguinal) without known cause.
Clinical Stage 2
Unexplained Enlarged liver and spleen without obvious cause. Clinical diagnosis
persistent
hepatosplenomeg
aly
Papular pruritic Papular pruritic vesicular lesions. Also common in Clinical diagnosis
eruptions uninfected children: scabies and insect bites should
be excluded.
Extensive wart Characteristic warty skin lesions; small fleshy grainy Clinical diagnosis
virus infection bumps, often rough, flat on sole of feet (plantar
warts); facial, more than 5% of body area or
disfiguring.
Extensive Characteristic skin lesions: small flesh-coloured, Clinical diagnosis
molluscum pearly or pink, dome-shaped or umbilicated growths
contagiosum may be inflamed or red; facial, more than 5% of
infection body area or disfiguring. Giant molloscum may
indicate more advanced immunodeficiency
Fungal nail Fungal paronychia (painful, red and swollen nail Clinical diagnosis
infections bed) or onycholysis (painless separation of the nail
from the nail bed.) Proximal white subungual
onchomycosis is uncommon without
immunodeficiency
Recurrent oral Current event plus at least one previous episode in Clinical diagnosis
ulcerations past six months. Aphthous ulceration, typically with
a halo of inflammation & yellow-grey
pseudomembrane.
Unexplained Asymptomatic bilateral swelling that may Clinical diagnosis
persistent parotid spontaneously resolve and recur, in absence of
enlargement other known cause, usually painless
Lineal gingival Erythematous band that follows the contour of the Clinical diagnosis
erythema free gingival line; may be associated with
spontaneous bleeding
Herpes zoster Painful rash with fluid-filled blisters, dermatomal Clinical diagnosis
distribution, can be haemorrhagic on erythematous
background, and can become large and confluent.
Does not cross the midline

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Recurrent upper Current event with at least one episode in past 6 Clinical diagnosis
respiratory tract months. Symptom complex; fever with unilateral
infection face pain and nasal discharge (sinusitis) or painful
swollen eardrum (otitis media), sore throat with
productive cough (bronchitis), sore throat
(pharyngitis) and barking croup-like cough (LTB).
Persistent or recurrent ear discharge.
Clinical Stage 3
Unexplained Weight loss: low weight-for-age or weight-for-height Documented loss of body
moderate up to −2 standarddeviations from the mean OR clear weight of -2 standard
malnutrition* deviation from a previous growth trajectory or deviations from the mean
documented crossing of percentile lines, not explained OR or documented
by poor or inadequate feeding and or other crossing of percentile
infections, and not adequately responding to lines,
standard management. failure to gain weight on
standard management and
no other cause identified
during investigation.
Unexplained Unexplained persistent (14 days or more) diarrhoea Confirmed by stools
persistent (loose or watery stool, three or more times daily), observed and documented
diarrhoea not responding to standard treatment. as unformed. Culture and
microscopy reveal no
pathogens.
Unexplained Reports of fever or night sweat for longer than one Confirmed by documented
persistent fever month, either intermittent or constant, with fever of >37.50 ◦C with
(>37.5oC reported lack of response to antibiotics or negative blood culture,
intermittent or antimalarial agents. No other obvious foci of disease negative malaria slide and
constant for reported or found on examination. Malaria must be normal or unchanged
longer than one excluded in malaria areas. chest X-ray, and no other
month) obvious foci of disease.
Oral candidiasis Persistent or recurring creamy white to yellow soft Confirmed by microscopy
(after first 6-8 small plaques which can be scraped off or culture.
weeks of life) (pseudomembranous), or red patches on tongue,
palate or lining of mouth, usually painful or tender
Oral hairy Fine small linear patches on lateral borders of Clinical diagnosis
leukoplakia tongue, generally bilaterally, which do not scrape
off.
Lymph node Non acute, painless "cold" enlargement of Confirmed by histology or
tuberculosis peripheral lymph nodes, localized to one region. fine needle aspirate for
May have draining sinuses. Response to standard Ziehl-Nielsen stain or
anti- tuberculosis treatment in one month. culture.
Pulmonary Nonspecific symptoms, e.g. chronic cough, fever, Confirmed by one or more
tuberculosis night sweats, anorexia and weight loss. In the older sputum positive smear for
child also productive cough and haemoptysis. acid-fast bacilli and/or
History of contact with adults with smear-positive radiographic abnormalities
pulmonary tuberculosis. No response to standard consistent with active
broad-spectrum antibiotic treatment. tuberculosis and/or
culture-positive for
Mycobacterium.

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Severe recurrent Cough with fast breathing, chest indrawing, nasal Confirmed by isolation of
bacterial flaring, wheezing, and grunting. Crackles or bacteria from appropriate
pneumonia consolidation on auscultation. Responds to course clinical specimens
of antibiotics. Current episode plus one or more in (induced sputum, BAL,
previous 6 months. lung aspirate).
Acute necrotizing Severe pain, ulcerated gingival papillae, loosening of Clinical diagnosis
ulcerative teeth, spontaneous bleeding, bad odour, and rapid
gingivitis or loss of bone and/or soft tissue.
stomatitis, or
acute necrotizing
ulcerative
periodontitis
Symptomatic No presumptive clinical diagnosis. Diagnosed by chest X-ray:
lymphocytic bilateral reticulonodular
interstitial interstitial pulmonary
pneumonitis infiltrates present for
more than two months
with no response to
antibiotic treatment and
no other pathogen found.
Oxygen saturation
persistently <90%. May
present with cor
pulmonale and increased
exercise-induced fatigue.
Characteristic histology.
Chronic HIV- History of cough productive of copious amounts of Confirmed by chest X-ray:
associated lung purulent sputum (bronchiectasis only), with or may show honeycomb
disease (including without clubbing, halitosis, and crepitations and/or appearance (small cysts)
bronchiectasis) wheezes on auscultation and/or persistent areas of
opacification and/or
widespread lung
destruction, with fibrosis
and loss of volume.
Unexplained No presumptive clinical diagnosis. Diagnosed on laboratory
anaemia (<8g/dl), testing, not explained by
or neutropaenia other non-HIV conditions,
(<0.5 x 109 per not responding to
litre) and/or standard therapy with
chronic haematinics, antimalarial
thrombocytopaeni agents or anthelmintic
a (<50 x 109 per agents as outlined in WHO
litre) Integrated Management of
Childhood Illness (IMCI)
guidelines.
Clinical Stage 4
Unexplained Persistent weight loss, stunting, wasting or Documented weight for
severe wasting, malnutrition not explained by poor or inadequate height or weight for age of
stunting or severe feeding, other infections and not adequately more than –3 standard
malnutrition not responding in two weeks to standard therapy. deviations from the mean

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adequately Visible severe wasting of muscles, with or without or documented downward
responding to oedema of both feet, and/or weight-for-height of –3 crossing of at least two
standard therapy* standard deviations from the mean or downward complete weight
crossing of at least two weight percentile lines. percentile lines with or
without oedema
Pneumocystis Dry cough, progressive difficulty in breathing, Confirmed by: cytology or
pneumonia cyanosis, tachypnoea and fever; chest indrawing or immunofluorescent
stridor. (Severe or very severe pneumonia as in microscopy of induced
WHO IMCI guidelines). Usually rapid onset especially sputum or BAL or histology
in infants under six months of age. Response to of lung tissue.
high-dose co-trimoxazole with or without
prednisolone. Chest X-ray shows typical bilateral
perihilar diffuse infiltrates
Recurrent severe Fever accompanied by specific symptoms or signs Confirmed by culture of
bacterial that localize infection. Responds to antibiotics. appropriate clinical
infection, e.g. Current episode plus one or more in previous 6 specimen.
empyema, months
pyomyositis, bone
or joint infection
or meningitis but
excluding
pneumonia
Chronic herpes Severe and progressive painful orolabial, genital, or Confirmed by culture
simplex infection; anorectal lesions caused by HSV infection present and/or histology
(orolabial or for more than one month.
cutaneous of
more than
one month's
duration or
visceral at any
site)
Oesophageal Difficulty in swallowing or pain on swallowing (food Confirmed by macroscopic
candidiasis and fluids). In young children, suspect particularly if appearance at endoscopy,
(or candidiasis of oral Candida observed and food refusal occurs microscopy of specimen
trachea, bronchi and/or difficulties or crying when feeding. from tissue or macroscopic
or lungs). appearance at
bronchoscopy or histology.
Extrapulmonary or Systemic illness usually with prolonged fever, night Confirmed by positive
disseminated sweats, and weight loss. Clinical features of organs microscopy showing acid-
tuberculosis involved, e.g. sterile pyuria, pericarditis, ascites, fast bacilli or culture of
pleural effusion, meningitis, arthritis or orchiti, Mycobacterium TB from
pericardial or abdominal blood or other relevant
specimen except sputum
or BAL. Biopsy and
histology.
Kaposi sarcoma Typical appearance in skin or oropharynx of Not required but may be
persistent, initially flat, patches with a pink or blood- confirmed by:
bruise colour, skin lesions that usually develop into - typical red-purple lesions
nodules. seen on bronchoscopy or
endoscopy;

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- dense masses in lymph
nodes, viscera or lungs by
palpation or radiology; and
- histology.
CMV retinitis or Retinitis only. Definitive diagnosis
CMV infection CMV retinitis may be diagnosed by experienced required for other sites.
affecting another clinicians: typical eye lesions on serial fundoscopic Histology. Cerebrospinal
organ, with onset examination; discrete patches of retinal whitening fluid polymerase chain
at age over 1 with distinct borders, spreading centrifugally, often reaction
month. following blood vessels, associated with retinal
CNS Fever, headache, focal neurological signs, Not required but
toxoplasmosis convulsions. Usually responds within 10 days to confirmed by computed
with onset at age specific therapy. tomography (CT) scan (or
over 1 month. other neuroimaging)
showing single or multiple
lesions with mass effect or
enhancing with contrast.
Extrapulmonary Meningitis: usually subacute, fever with increasing Confirmed by CSF
cryptococcosis severe headache, meningism, confusion and microscopy (India ink or
(including behavioural changes that respond to cryptococcal Gram stain), serum or CSF
meningitis) therapy. CRAG test or culture.
HIV At least one of the following, progressing over at Confirmed by
encephalopathy least two months in the absence of another illness: neuroimaging (brain CT
- failure to attain, or loss of, developmental scan or MRI)
milestones, loss of intellectual ability; OR demonstrating atrophy
- progressive impaired brain growth demonstrated and basal ganglia
by stagnation of head circumference; OR calcification and excluding
- acquired symmetric motor deficit accompanied by other causes.
two or more of the following: paresis, pathological
reflexes, ataxia, gait disturbances.
Disseminated No presumptive clinical diagnosis. Diagnosed by:
mycosis Histology: usually
(coccidiomycosis, granuloma formation.
histoplasmosis, Isolation: antigen
penicilliosis) detection from affected
tissue; culture or
microscopy from clinical
specimen or blood culture.
Disseminated No presumptive clinical diagnosis. Nonspecific clinical
mycobacteriosis, symptoms including
other than TB progressive weight loss,
fever, anaemia, night
sweats, fatigue or
diarrhoea; plus culture of
atypical mycobacterial
species from stool, blood,
body fluid or other body
tissue, excluding lung.

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Chronic No presumptive clinical diagnosis. Confirmed by cysts
cryptosporidiosis identified on modified
Ziehl-Nielsen microscopic
examination of unformed
stool
Chronic Isospora No presumptive clinical diagnosis. Confirmed in children with
chronic diarrhoea by
microscopic examination.
Cerebral or B-cell No presumptive clinical diagnosis. Diagnosed by CNS

non-Hodgkin neuroimaging: at least one
lymphoma lesion with mass effect on
brain scan; histology of
relevant specimen
Progressive multi No presumptive clinical diagnosis. Diagnosed by progressive
focal nervous system disorder
leukoencephalopa (cognitive dysfunction, gait
thy or speech disorder, visual
loss, limb weakness and
cranial nerve palsies)
together with hypodense
white matter lesions on
neuroimaging or positive
polyomavirus Jacob
Creutzfeldt PCR on
cerebrospinal fluid
Symptomatic HIV- No presumptive clinical diagnosis. Renal biopsy
associated
nephropathy
Symptomatic HIV- No presumptive clinical diagnosis. Cardiomegaly and
associated evidence of poor left
cardiomyopathy ventricular function
confirmed by
echocardiography
* Modified definitions for moderate (grade 3) and severe (grade 4) malnutrition from WHO and CDC clinical
stage classifications (1,2,3)

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APPENDIX IX CRITERIA FOR WHO CLINICAL STAGING EVENTS FOR YOUNG PEOPLE 15 YEARS AND
OLDER
Criteria for WHO clinical staging events (1).

Clinical stage 1
Asymptomatic. No HIV-related symptoms reported Not applicable.
and no signs on examination.
Persistent generalized Painless enlarged lymph nodes >1 cm Histology.
lymphadenopathy. in two or more non-contiguous sites
(excluding inguinal) in the absence of
known cause and persisting for three
months or more.
Clinical stage 2
Unexplained moderate Reported unexplained Documented weight loss
weight loss (<10% of involuntary weight loss in <10% of body weight.
body pregnancy failure to gain
weight). weight.
Recurrent upper Symptom complex, such as unilateral Laboratory studies where
respiratory face pain with nasal discharge available, such as culture of
tract infections (current (sinusitis), suitable body fluid.
event plus one or more painful inflamed eardrum (otitis
in media) or
last six-month period). tonsillopharyngitis without features
of viral infection (such as coryza or
cough).
Herpes zoster. Painful vesicular rash in dermatomal Clinical diagnosis.
distribution of a nerve supply, does
not
cross the midline.
Angular cheilitis. Splits or cracks at the angle of the Clinical diagnosis.
mouth not due to iron or vitamin
deficiency, usually respond to
antifungal treatment.
Recurrent oral Aphthous ulceration, typically painful Clinical diagnosis.
ulceration with a halo of inflammation and a
(two or more episodes yellow grey pseudomembrane.
in
last six months).
Papular pruritic Papular pruritic lesions, often with Clinical diagnosis.
eruption. marked postinflammatory
pigmentation.
Seborrhoeic dermatitis. Itchy scaly skin condition, particularly Clinical diagnosis.
affecting hairy areas (scalp, axillae,
upper
trunk and groin).
Fungal nail infection. Paronychia (painful red and swollen Fungal culture of the nail or nail
nail bed) or onycholysis (separation plate material.
of

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the nail from the nail bed) of the
fingernails (white discoloration –
especially involving proximal part of
nail plate – with thickening and
separation of the nail from the nail
bed).
Clinical stage 3
Unexplained severe Reported unexplained involuntary Documented loss of more than
weight loss (more than weight loss (>10% of body weight) 10% of body weight.
10% of body weight). and visible thinning of face, waist and
extremities with obvious wasting or
body mass index <18.5 kg/m2; in
pregnancy, the weight loss may be
masked.
Unexplained chronic Chronic diarrhoea (loose or watery Three or more stools observed
diarrhoea for longer stools three or more times daily) and documented as unformed,
than one month. reported for longer than one month. and two or more stool tests
reveal no pathogens.
Unexplained persistent Fever or night sweats for more than Documented fever >37.5°C with
fever one month, either intermittent or negative blood culture, negative
(intermittent or constant with reported lack of Ziehl-Nielsen stain, negative
constant and lasting for response to antibiotics or malaria slide, normal or
longer than one month). antimalarial agents, without other unchanged chest X-ray and no
obvious foci of disease reported or other obvious focus of infection.
found on examination; malaria must
be excluded in malarious areas.
Persistant oral Persistent or recurring creamy white Clinical diagnosis.
candidiasis. curd-like plaques that can be scraped
off (pseudomembranous) or red
patches on tongue, palate or lining of
mouth, usually painful or tender
Oral hairy leukoplakia. Fine white small linear or corrugated Clinical diagnosis.
lesions on lateral borders of the
tongue that do not scrape off.
Pulmonary tuberculosis Chronic symptoms: (lasting at least Isolation of M. tuberculosis on
(current). 2–3 weeks) cough, haemoptysis, sputum culture or histology of
shortness of breath, chest pain, lung biopsy (with compatible
weight loss, fever, night sweats; PLUS symptoms).
EITHER
positive sputum smear;
OR
negative sputum smear;
AND
compatible chest radiograph
(including but not restricted to upper
lobe infiltrates, caritation, pulmonary
fibrosist shrinkage. No evidence of
extrapulmonary diseas.
Acute necrotizing Severe pain, ulcerated gingival Clinical diagnosis.

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ulcerative gingivitis or papillae, loosening of teeth,
necrotizing ulcerative spontaneous bleeding, bad odour
periodontitis. and rapid loss of bone and/or soft
tissue.
Severe bacterial Fever accompanied by specific Isolation of bacteria from
infection symptoms or signs that localize appropriate clinical specimens
(such as pneumonia, infection and response to (usually sterile sites).
meningitis, empyema, appropriate antibiotic.
pyomyositis, bone or
joint infection,
bacteraemia and severe
pelvic inflammatory
disease).
Unexplained anaemia Not presumptive clinical diagnosis. Diagnosed on laboratory testing
(<8 g/dl), neutropaenia and not explained by other non-
(<0.5 109 per litre) or HIV conditions;
chronic (more than one not responding to standard
month) therapy with haematinics,
thrombocytopaenia (<50 antimalarial agents or
109 per litre). anthelmintic agents as outlined
in relevant national treatment
guidelines, WHO Integrated
Management of Childhood
Illness guidelines or other
relevant guidelines.
Clinical stage 4
HIV wasting syndrome Unexplained involuntary weight loss Documented weight loss (>10%
(>10% baseline body weight), with of body weight);
obvious wasting or body mass index PLUS EITHER
<18.5; two or more unformed stools
PLUS EITHER negative for pathogens;
unexplained chronic diarrhoea (loose OR
or watery stools three or more times documented temperature of
daily) reported for longer than one >37.5°C with no other cause of
month; disease, negative blood culture,
OR negative malaria slide and
reports of fever or night sweats for normal or unchanged chest X-
more than one month without other ray.
cause and lack of response to
antibiotics or antimalarial agents;
malaria must be excluded in
malarious areas.
Pneumocystis Dyspnoea on exertion or Cytology or immunofluorescent
pneumonia nonproductive cough of recent onset microscopy of induced sputum
(within the past three months), or bronchoalveolar lavage or
tachypnoea and fever; histology of lung tissue.
AND
Chest X-ray evidence of diffuse
bilateral interstitial infiltrates;
AND

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No evidence of bacterial pneumonia;
bilateral crepitations on auscultation
with or without reduced air entry.
Recurrent bacterial Current episode plus one or more Positive culture or antigen test
pneumonia previous episodes in the past six of a compatible organism.
(this episode plus one or months; acute onset (<2 weeks) of
more episodes in last six severe symptoms (such as fever,
months) cough, dyspnoea, and chest pain)
PLUS new consolidation on clinical
examination or chest X-ray; response
to antibiotics.
Chronic herpes simplex Painful, progressive anogenital or Positive culture or DNA (by
virus infection orolabial ulceration; lesions caused polymerase chain reaction) of
by recurrence of herpes simplex virus herpes simplex virus or
(orolabial, genital or infection and reported for more than compatible cytology or histology.
anorectal) of more than one month. History of previous
one month or visceral episodes. Visceral herpes simplex
infection of any virus requires definitive diagnosis.
duration.
Oesophageal candidiasis Recent onset of retrosternal pain or Macroscopic appearance at
difficulty on swallowing (food and endoscopy or bronchoscopy, or
fluids) together with oral candidasis. by microscopy or histology.
Extrapulmonary Systemic illness (such as fever, night M. tuberculosis isolation or
tuberculosis sweats, weakness and weight loss). compatible histology from
Other evidence for extrapulmonary appropriate site or radiological
or disseminated tuberculosis varies evidence of miliary tuberculosis;
by site: Pleural, pericardia, peritoneal (diffuse uniformly distributed
involvement, meningitis, mediastinal small miliary shadows or
or abdominal lymphadenopathy or micronodules on chest X-ray).
ostetis. Discrete peripheral lymph
node Mycobacterium tuberculosis
infection (especially cervical) is
considered a less severe form of
extrapulmonary tuberculosis.
Kaposi sarcoma Typical gross appearance in skin or Macroscopic appearance at
oropharynx of persistent, initially flat, endoscopy or bronchoscopy, or
patches with a pink or violaceous by histology.
colour, skin lesions that usually
develop into plaques or nodules.
Cytomegalovirus disease Retinitis only: may be diagnosed by Compatible histology or
(other than liver, spleen experienced clinicians. Typical eye cytomegalovirus demonstrated
or lymph node) lesions on fundoscopic examination: in cerebrospinal fluid by culture
discrete patches of retinal hitening or DNA (by polymerase chain
with distinct borders, spreading reaction).
centrifugally, often following blood
vessels, associated with retinal
Central nervous system Recent onset of a focal nervous Positive serum toxoplasma
toxoplasmosis system abnormality consistent with antibody AND (if available) single
intracranial disease or reduced level or multiple intracranial mass

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of consciousness lesion on neuroimaging
AND (computed tomography or
response within 10 days to specific magnetic resonance imaging).
therapy.
HIV encephalopathy Disabling cognitive and/or motor Diagnosis of exclusion: and (if
dysfunction interfering with activities available) neuroimaging
of daily living, progressing over weeks (computed tomography or
or months in the absence of a magnetic resonance imaging).
concurrent illness or condition other
than HIV infection that might explain
the findings.
Extrapulmonary Meningitis: usually subacute, fever Isolation of Cryptococcus
cryptococcosis with increasing severe headache, neoformans from
(including meningitis) meningism, confusion, behavioural extrapulmonary site or positive
changes that respond to cryptococcal cryptococcal antigen test on
therapy. cerebrospinal fluid or blood.
Disseminated No presumptive clinical diagnosis. Diagnosed by finding atypical
nontuberculous mycobacterial species from
mycobacteria infection stool, blood, body fluid or other
body tissue, excluding the lungs.
Progressive multifocal No presumptive clinical diagnosis. Progressive nervous system
leukoencephalopathy disorder (cognitive dysfunction,
gait/speech disorder, visual loss,
limb weakness and cranial nerve
palsies) together with
hypodense white matter lesions
on neuro-imaging or positive
polyomavirus JC polymerase
chain reaction on cerebrospinal
fluid.
Chronic No presumptive clinical diagnosis. Cysts identified on modified
cryptosporidiosis Ziehl-Nielsen stain microscopic
(with diarrhoea lasting examination of unformed stool.
more than one month)
Chronic isosporiasis No presumptive clinical diagnosis. Identification of Isospora.
Disseminated mycosis No presumptive clinical diagnosis. Histology, antigen detection or
(coccidiomycosis or culture from clinical specimen or
histoplasmosis) blood culture.
Recurrent non-typhoid No presumptive clinical diagnosis. Blood culture.
Salmonella bacteraemia
Lymphoma (cerebral or No presumptive clinical diagnosis. Histology of relevant specimen

B-cell non-Hodgkin) or, for central nervous system
tumours, neuroimaging
techniques.
Invasive cervical No presumptive clinical diagnosis. Histology or cytology.
carcinoma
Atypical disseminated No presumptive clinical diagnosis. Diagnosed by histology
leishmaniasis (amastigotes visualized) or
culture from any appropriate

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clinical specimen.
Symptomatic HIV- No presumptive clinical diagnosis. Renal biopsy.
associated nephropathy
Symptomatic HIV- No presumptive clinical diagnosis. Cardiomegaly and evidence of
associated poor left ventricular function
cardiomyopathy confirmed by echocardiography.

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APPENDIX X ADAPTED DAIDS TOXICITY GRADINGS
The toxicity grading table is adapted from Division of AIDS Table for Grading the Severity of Adult
and Paediatric Adverse Events (published December 2004, clarification August 2009 (4). Neutrophil
grading, are based on WHO guidelines (5) and NIH Paediatric toxicity tables (6) recognising the
lower normal levels in African populations.
General Instructions:
If the need arises to grade a clinical adverse event (AE) that is not identified in the DAIDS AE Grading
Table, use the category “Estimating Severity Grade” located at the top of the table.
If the severity of an AE could fall under either one of two grades (e.g. the severity of an AE could be
either Grade 2 or Grade 3) select the higher of the two grades for the AE.
Definitions:
Basic Self-care Functions Adults and older children:
Activities such as bathing, dressing, toileting,
transfer/movement, continence, and feeding.
Young children:
Activities that are age and culturally appropriate (e.g., feeding
self with culturally appropriate eating implement).
LLN Lower limit of normal
Medical Intervention Use of pharmacologic or biologic agent(s) for treatment of an
AE
NA Not Applicable
Operative Intervention Surgical OR other invasive mechanical procedures.
ULN Upper limit of normal
Usual Social & Functional Activities Adults and young people:
Adaptive tasks and desirable activities, such as going to work,
shopping, cooking, use of transportation, pursuing a hobby,
etc.
Children:
Activities that are age and culturally appropriate (e.g., social
interactions, play activities, learning tasks, etc.).

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CLINICAL
LIFE-THREATENING
ESTIMATING SEVERITY GRADE
Clinical adverse Symptoms causing Symptoms causing Symptoms causing Symptoms causing
event NOT identified no or minimal greater than minimal inability to perform inability to perform
elsewhere in this interference with interference with usual social & basic self-care
DAIDS AE grading usual social & usual social & functional activities functions OR Medical
table functional activities functional activities or operative
to prevent permanent
impairment, persistent
disability, or death
SYSTEMIC
Acute systemic Localized urticaria
Localized urticaria Generalized urticaria Acute anaphylaxis OR
allergic reaction (wheals) with nowith medical OR Angioedema with Life-threatening
medical intervention
intervention medical intervention bronchospasm OR
indicated indicated OR Mild indicated OR laryngeal edema
angioedema with no Symptomatic mild
medical intervention bronchospasm
indicated
Chills Symptoms causing Symptoms causing Symptoms causing NA
no or minimal greater than minimal inability to perform
interference with interference with usual social &
usual social & usual social & functional activities
Fatigue Symptoms causing Symptoms causing Symptoms causing Incapacitating fatigue/
Malaise no or minimal greater than minimal inability to perform malaise symptoms
interference with interference with usual social & causing inability to
usual social & usual social & functional activities perform basic self-care
functional activities functional activities functions
Fever (nonaxillary) 37.7 – 38.6°C 38.7 – 39.3°C 39.4 – 40.5°C > 40.5°C
Pain (indicate body Pain causing no or Pain causing greater Pain causing inability Disabling pain causing
site) minimal interference than minimal to perform usual social inability to perform
DO NOT use for pain with usual social & interference with & functional activities basic self-care
due to injection (See functional activities usual social & functions OR
Injection Site functional activities Hospitalization (other
Reactions: Injection than emergency room
site pain) visit) indicated
See also Headache,
Arthralgia, and
Myalgia

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CLINICAL
LIFE-THREATENING
Unintentional weight NA 5 – 9% loss in body 10 – 19% loss in body 20% loss in body
loss weight from baseline weight from baseline weight from baseline
OR Aggressive
[e.g., tube feeding or
total parenteral
nutrition (TPN)]
INFECTION
Infection (any other Localized, no Systemic Systemic antimicrobial Life-threatening
than HIV infection) systemic antimicrobial treatment indicated consequences (e.g.,
antimicrobial treatment indicated AND Symptoms septic shock)
treatment indicated OR Symptoms causing inability to
AND Symptoms causing greater than perform usual social &
causing no or minimal interference functional activities
minimal interference with usual social & OR Operative
with usual social & functional activities intervention (other
functional activities than simple incision
and drainage)
indicated
INJECTION SITE REACTIONS
Injection site pain Pain/tenderness Pain/tenderness Pain/tenderness Pain/tenderness
(pain without causing no or limiting use of limb causing inability to causing inability to
touching) minimal limitation of OR Pain/tenderness perform usual social & perform basic self-care
Or use of limb causing greater than functional activities function OR
Tenderness (pain minimal interference Hospitalization (other
when area is with usual social & than emergency room
touched) functional activities visit) indicated for
management of
pain/tenderness
Injection site reaction (localized)
Adult > 15 years Erythema OR Erythema OR Ulceration OR Necrosis (involving
Induration Induration OR Edema Secondary infection dermis and deeper
of 5x5 cm – 9x9 cm > 9 cm any diameter OR Phlebitis OR Sterile tissue)
(or 25 cm2 – 81cm2) (or > 81 cm2) abscess OR Drainage
Paediatric 15 Erythema OR Erythema OR Erythema OR Necrosis (involving
years Induration OR Induration OR Edema Induration OR Edema dermis and deeper
Edema present but > 2.5 cm diameter involving tissue)
2.5 cm diameter but < 50% surface 50% surface area of
area of the extremity the extremity segment
segment (e.g., upper (e.g., upper arm/thigh)
arm/thigh) OR Ulceration OR
Secondary infection
OR Phlebitis OR Sterile
abscess OR Drainage

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CLINICAL
LIFE-THREATENING
Pruritis associated Itching localized to Itching beyond the Generalized itching NA
with injection injection site AND injection site but not causing inability to
See also Skin: Pruritis Relieved generalized OR perform usual social &
(itching - no skin spontaneously or Itching localized to functional activities
lesions) with < 48 hours injection site
treatment requiring 48 hours
treatment
SKIN – DERMATOLOGICAL
Alopecia Thinning detectable Thinning or patchy Complete hair loss NA
by study participant hair loss detectable
(or by caregiver for by health care
young children and provider
disabled adults)
Cutaneous reaction – Localized macular Diffuse macular, Diffuse macular, Extensive or
rash rash maculopapular, or maculopapular, or generalized bullous
morbilliform rash OR morbilliform rash with lesions OR Stevens-
Target lesions vesicles or limited Johnson syndrome OR
number of bullae OR Ulceration of mucous
Superficial ulcerations membrane involving
of mucous membrane two or more distinct
limited to one site mucosal sites OR Toxic
epidermal necrolysis
(TEN)
Hyperpigmentation Slight or localized Marked or NA NA
generalized
Hypopigmentation Slight or localized Marked or NA NA
generalized
Pruritis (itching – no Itching causing no or Itching causing Itching causing NA
skin lesions) minimal interference greater than minimal inability to perform
(See also Injection with usual social & interference with usual social &
Site Reactions: functional activities usual social & functional activities
Pruritis associated functional activities
with injection)
CARDIOVASCULAR
Cardiac arrhythmia Asymptomatic AND Asymptomatic AND Symptomatic, non-life- Life-threatening
(general) No intervention Non-urgent medical threatening AND Non- arrhythmia OR Urgent
(By ECG or physical indicated intervention urgent medical intervention indicated
exam) indicated intervention indicated
Cardiac- NA NA Symptomatic ischemia Unstable angina OR
ischemia/infarction (stable angina) OR Acute myocardial
Testing consistent infarction
with ischemia

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CLINICAL
LIFE-THREATENING
Hemorrhage NA Symptomatic AND Symptomatic AND Life-threatening
(significant acute No transfusion Transfusion of 2 hypotension OR
blood loss) indicated units packed RBCs (for Transfusion of > 2
children 10 cc/kg) units packed RBCs (for
indicated children > 10 cc/kg)
indicated
Hypertension
Adult > 17 years > 140 – 159 mmHg 160 – 179 mmHg ≥180 mmHg systolic Life-threatening
(with repeat systolic systolic OR consequences (e.g.,
testing at same OR OR ≥110 mmHg diastolic malignant
visit) > 90 – 99 mmHg 100 – 109 mmHg hypertension) OR
diastolic diastolic Hospitalization
indicated (other than
emergency room visit)
Paediatric 17 NA 91st – 94th ≥ 95th percentile Life-threatening
years percentile adjusted adjusted for age, consequences (e.g.,
(with repeat for age, height, and height, and gender malignant
testing at same gender (systolic (systolic and/or hypertension) OR
visit) and/or diastolic) diastolic) Hospitalization
Hypotension NA Symptomatic, Symptomatic, IV fluids Shock requiring use of
corrected with oral indicated vasopressors or
fluid replacement mechanical assistance
to maintain blood
pressure
Pericardial effusion Asymptomatic, small Asymptomatic, Effusion with non-life Life-threatening

effusion requiring no moderate or larger threatening consequences (e.g.,
intervention effusion requiring no physiologic tamponade) OR
intervention consequences OR Urgent intervention
Effusion with non- indicated
urgent intervention
indicated
Prolonged PR interval
Adult > 16 years PR interval PR interval Type II 2nd degree AV Complete AV block
0.21 – 0.25 sec > 0.25 sec block OR Ventricular
pause > 3.0 sec
Paediatric ≤ 16 1st degree AV block Type I 2nd degree AV Type II 2nd degree AV Complete AV block
years (PR > normal for age block block
and rate)
Prolonged QTc

ODYSSEY Protocol
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CLINICAL
LIFE-THREATENING
Adult > 16 years Asymptomatic, QTc Asymptomatic, QTc Asymptomatic, QTc Life-threatening
interval 0.45 – 0.47 interval 0.48 – 0.49 interval 0.50 sec OR consequences, e.g.
sec OR Increase sec OR Increase in Increase in interval Torsade de pointes or
interval < 0.03 sec interval 0.03 – 0.05 0.06 sec above other associated
above baseline sec above baseline baseline serious ventricular
dysrhythmia
Paediatric ≤ 16 Asymptomatic, QTc Asymptomatic, QTc Asymptomatic, QTc Life-threatening
years interval 0.450 – interval 0.465 – interval 0.480 sec consequences, e.g.
0.464 sec 0.479 sec Torsade de pointes or
other associated
serious ventricular
dysrhythmia
Thrombosis/embolis NA Deep vein Deep vein thrombosis Embolic event (e.g.,
m thrombosis AND No AND Intervention pulmonary embolism,
intervention indicated (e.g., life-threatening
indicated (e.g., anticoagulation, lysis thrombus)
anticoagulation, lysis filter, invasive
filter, invasive procedure)
procedure)
Vasovagal episode Present without loss Present with NA NA
(associated with a of consciousness transient loss of
procedure of any consciousness
kind)
Ventricular NA Asymptomatic New onset with Life-threatening
dysfunction diagnostic finding symptoms OR congestive heart
(congestive heart AND intervention Worsening failure
failure) indicated symptomatic
congestive heart
failure
GASTROINTESTINAL
Anorexia Loss of appetite Loss of appetite Loss of appetite Life-threatening
without decreased associated with associated with consequences OR
oral intake decreased oral intake significant weight loss Aggressive
without significant intervention indicated
weight loss [e.g., tube feeding or
total parenteral
nutrition (TPN)]
Comment: Please note that, while the grading scale provided for Unintentional Weight Loss may be used as a
guideline when grading anorexia, this is not a requirement and should not be used as a substitute for clinical
judgment.
Ascites Asymptomatic Symptomatic AND Symptomatic despite Life-threatening
Intervention intervention consequences
indicated (e.g.,
diuretics or
therapeutic
paracentesis)

ODYSSEY Protocol
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CLINICAL
LIFE-THREATENING
Cholecystitis NA Symptomatic AND Radiologic, Life-threatening
Medical intervention endoscopic, or consequences (e.g.,
indicated operative intervention sepsis or perforation)
indicated
Constipation NA Persistent Obstipation with Life-threatening
constipation manual evacuation consequences (e.g.,
requiring regular use indicated obstruction)
of dietary
modifications,
laxatives, or enemas
Diarrhea
Adult and Transient or Persistent episodes Bloody diarrhea OR Life-threatening
Paediatric 1 year intermittent of unformed to Increase of ≥ 7 stools consequences (e.g.,
episodes of watery stools OR per 24-hour period OR hypotensive shock)
unformed stools OR Increase of 4 – 6 IV fluid replacement
Increase of ≤ 3 stools stools over baseline indicated
over baseline per per 24-hour period
24-hour period
Paediatric < 1 year Liquid stools (more Liquid stools with Liquid stools with Liquid stools resulting
unformed than increased number of moderate dehydration in severe dehydration
usual) but usual stools OR Mild with aggressive
number of stools dehydration rehydration indicated
OR Hypotensive shock
Dysphagia- Symptomatic but Symptoms causing Symptoms causing Life-threatening
Odynophagia able to eat usual diet altered dietary intake severely altered reduction in oral
without medical dietary intake with intake
intervention medical intervention
indicated indicated
Mucositis/stomatitis Erythema of the Patchy Confluent Tissue necrosis OR
(clinical exam) mucosa pseudomembranes pseudomembranes or Diffuse spontaneous
Indicate site (e.g., or ulcerations ulcerations OR mucosal bleeding OR
larynx, oral) Mucosal bleeding with Life-threatening
See Genitourinary minor trauma consequences (e.g.,
for Vulvovaginitis aspiration, choking)
See also Dysphagia-
Odynophagia and
Proctitis
Nausea Transient (< 24 Persistent nausea Persistent nausea Life-threatening
hours) or resulting in resulting in minimal consequences (e.g.,
intermittent nausea decreased oral intake oral intake for > 48 hypotensive shock)
with no or minimal for 24 – 48 hours hours OR Aggressive
interference with rehydration indicated
oral intake (e.g., IV fluids)

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CLINICAL
LIFE-THREATENING
Pancreatitis NA Symptomatic AND Symptomatic AND Life-threatening
Hospitalization not Hospitalization consequences (e.g.,
indicated (other than indicated (other than circulatory failure,
emergency room emergency room visit) hemorrhage, sepsis)
visit)
Proctitis (functional- Rectal discomfort Symptoms causing Symptoms causing Life-threatening
symptomatic) AND No intervention greater than minimal inability to perform consequences (e.g.,
Also see indicated interference with usual social & perforation)
Mucositis/stomatitis usual social & functional activities
for clinical exam functional activities OR Operative
OR Medical intervention indicated
intervention
indicated
Vomiting Transient or Frequent episodes of Persistent vomiting Life-threatening
intermittent vomiting with no or resulting in orthostatic consequences (e.g.,
vomiting with no or mild dehydration hypotension OR hypotensive shock)
minimal interference Aggressive
with oral intake rehydration indicated
(e.g., IV fluids)
NEUROLOGIC
Alteration in Alteration causing Alteration causing Alteration causing Behavior potentially
personality-behavior no or minimal greater than minimal inability to perform harmful to self or
or in mood (e.g., interference with interference with usual social & others (e.g., suicidal
agitation, anxiety, usual social & usual social & functional activities and homicidal ideation
depression, mania, functional activities functional activities or attempt, acute
psychosis) psychosis) OR Causing
inability to perform
basic self-care
functions
Altered Mental Changes causing no Mild lethargy or Confusion, memory Delirium OR
Status or minimal somnolence causing impairment, lethargy, obtundation, OR coma
For Dementia, see interference with greater than minimal or somnolence causing
Cognitive and usual social & interference with inability to perform
behavioral/attention functional activities usual social & usual social &
al disturbance functional activities functional activities
(including dementia
and attention deficit
disorder)
Ataxia Asymptomatic ataxia Symptomatic ataxia Symptomatic ataxia Disabling ataxia
detectable on exam causing greater than causing inability to causing inability to
OR Minimal ataxia minimal interference perform usual social & perform basic self-care
causing no or with usual social & functional activities functions
minimal interference functional activities
with usual social &

ODYSSEY Protocol
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CLINICAL
LIFE-THREATENING
Cognitive and Disability causing no Disability causing Disability causing Disability causing
behavioral/attention or minimal greater than minimal inability to perform inability to perform
al disturbance interference with interference with usual social & basic self-care
(including dementia usual social & usual social & functional activities functions OR
and attention deficit functional activities functional activities OR Specialized Institutionalization
disorder) OR Specialized OR Specialized resources on a full- indicated
resources not resources on part- time basis indicated
indicated time basis indicated
CNS ischemia NA NA Transient ischemic
Cerebral vascular
(acute) attack accident (CVA, stroke)
with neurological
deficit
Developmental delay Mild developmental Moderate Severe developmental Developmental
– Paediatric 16 delay, either motor developmental delay, delay, either motor or regression, either
years or cognitive, as either motor or cognitive, as motor or cognitive, as
determined by cognitive, as determined by determined by
comparison with a determined by comparison with a comparison with a
developmental comparison with a developmental developmental
screening tool developmental screening tool screening tool
appropriate for the screening tool appropriate for the appropriate for the
setting appropriate for the setting setting
setting
Headache Symptoms causing Symptoms causing Symptoms causing Symptoms causing
no or minimal greater than minimal inability to perform inability to perform
interference with interference with usual social & basic self-care
usual social & usual social & functional activities functions OR
functional activities functional activities Hospitalization
OR Headache with
significant impairment
of alertness or other
neurologic function
Insomnia NA Difficulty sleeping Difficulty sleeping Disabling insomnia
causing greater than causing inability to causing inability to
minimal interference perform usual social & perform basic self-care
with usual social & functional activities functions
Neuromuscular Asymptomatic with Muscle weakness Muscle weakness Disabling muscle
weakness decreased strength causing greater than causing inability to weakness causing
(including myopathy on exam OR Minimal minimal interference perform usual social & inability to perform
& neuropathy) muscle weakness with usual social & functional activities basic self-care
causing no or functional activities functions OR
minimal interference Respiratory muscle
with usual social & weakness impairing
functional activities ventilation

ODYSSEY Protocol
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CLINICAL
LIFE-THREATENING
Neurosensory Asymptomatic with Sensory alteration or Sensory alteration or Disabling sensory
alteration (including sensory alteration paresthesia causing paresthesia causing alteration or
paresthesia and on exam or minimal greater than minimal inability to perform paresthesia causing
painful neuropathy) paresthesia causing interference with usual social & inability to perform
no or minimal usual social & functional activities basic self-care
interference with functional activities functions
usual social &
Seizure Seizure, generalized Seizure, generalized Seizure, generalized Seizure, generalized
– Paediatric < 18 onset with or onset with or onset with or without onset with or without
years without secondary without secondary secondary secondary
generalization, generalization, generalization, lasting generalization,
lasting < 5 minutes lasting 5 – 20 > 20 minutes requiring intubation
with < 24 hours post minutes with and sedation
ictal state < 24 hours post ictal
state
Syncope (not NA Present NA NA
associated with a
procedure)
Vertigo Vertigo causing no Vertigo causing Vertigo causing Disabling vertigo
interference with interference with usual social & perform basic self-care
usual social & usual social & functional activities functions
RESPIRATORY
Bronchospasm FEV1 or peak flow FEV1 or peak flow FEV1 or peak flow Cyanosis OR FEV1 or
(acute) reduced to 50 – 69% 25 – 49% peak flow < 25% OR
70 – 80% Intubation
Dyspnea or respiratory distress
Adult ≥ 14 years Dyspnea on exertion Dyspnea on exertion Dyspnea at rest Respiratory failure
with no or minimal causing greater than causing inability to with ventilatory
interference with minimal interference perform usual social & support indicated
usual social & with usual social & functional activities
Paediatric < 14 Wheezing OR Nasal flaring OR Dyspnea at rest Respiratory failure
years minimal increase in Intercostal causing inability to with ventilatory
respiratory rate for retractions OR Pulse perform usual social & support indicated
age oximetry 90 – 95% functional activities
OR Pulse oximetry <
90%
MUSCULOSKELETAL
Arthralgia Joint pain causing no Joint pain causing Joint pain causing Disabling joint pain
See also Arthritis or minimal greater than minimal inability to perform causing inability to

ODYSSEY Protocol
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CLINICAL
LIFE-THREATENING
Arthritis Stiffness or joint Stiffness or joint Stiffness or joint Disabling joint stiffness
See also Arthralgia swelling causing no swelling causing swelling causing or swelling causing
or minimal greater than minimal inability to perform inability to perform
interference with interference with usual social & basic self-care
Bone Mineral Loss
Paediatric < 21 BMD z-score BMD z-score < -2.5 Pathological fracture Pathologic fracture
years -2.5 to -1.0 (including loss of causing life-
vertebral height) threatening
consequences
Myalgia Muscle pain causing Muscle pain causing Muscle pain causing Disabling muscle pain
(non-injection site) no or minimal greater than minimal inability to perform causing inability to
Osteonecrosis NA Asymptomatic with Symptomatic bone Disabling bone pain
radiographic findings pain with radiographic with radiographic
AND No operative findings OR Operative findings causing
intervention intervention indicated inability to perform
indicated basic self-care
functions
GENITOURINARY
Cervicitis Symptoms causing Symptoms causing Symptoms causing Symptoms causing
(symptoms) no or minimal greater than minimal inability to perform inability to perform
(For use in studies interference with interference with usual social & basic self-care
evaluating topical usual social & usual social & functional activities functions
study agents) functional activities functional activities
For other cervicitis
see Infection:
Infection (any other
than HIV infection)
Cervicitis Minimal cervical Moderate cervical Severe cervical Epithelial disruption

(clinical exam) abnormalities on abnormalities on abnormalities on > 75% total surface
(For use in studies examination examination examination
evaluating topical (erythema, (erythema, (erythema,
study agents) mucopurulent mucopurulent mucopurulent
For other cervicitis discharge, or discharge, or discharge, or friability)
see Infection: friability) OR friability) OR OR Epithelial
Infection (any other Epithelial disruption Epithelial disruption disruption
than HIV infection) < 25% of total of 25 – 49% total 50 – 75% total surface
surface surface

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CLINICAL
LIFE-THREATENING
Inter-menstrual Spotting observed Inter-menstrual Inter-menstrual Hemorrhage with life-
bleeding (IMB) by participant OR bleeding not greater bleeding greater in threatening
Minimal blood in duration or duration or amount hypotension OR
observed during amount than usual than usual menstrual Operative intervention
clinical or menstrual cycle cycle indicated
colposcopic
examination
Urinary tract NA Signs or symptoms of Signs or symptoms of Obstruction causing
obstruction (e.g., urinary tract urinary tract life-threatening
stone) obstruction without obstruction with consequences
hydronephrosis or hydronephrosis or
renal dysfunction renal dysfunction
Vulvovaginitis Symptoms causing Symptoms causing Symptoms causing Symptoms causing
(symptoms) no or minimal greater than minimal inability to perform inability to perform
(Use in studies interference with interference with usual social & basic self-care
evaluating topical usual social & usual social & functional activities functions
study agents) functional activities functional activities
For other
vulvovaginitis see
Infection: Infection
(any other than HIV
infection)
Vulvovaginitis Minimal vaginal Moderate vaginal Severe vaginal Vaginal perforation OR

(clinical exam) abnormalities on abnormalities on abnormalities on Epithelial disruption
(Use in studies examination OR examination OR examination OR > 75% total surface
evaluating topical Epithelial disruption Epithelial disruption Epithelial disruption
study agents) < 25% of total of 25 - 49% total 50 - 75% total surface
For other surface surface
vulvovaginitis see
Infection: Infection
(any other than HIV
infection)
OCULAR/VISUAL
Uveitis Asymptomatic but
Symptomatic Posterior or pan- Disabling visual loss in
detectable on exam
anterior uveitis OR uveitis OR Operative affected eye(s)
Medical intervention intervention indicated
indicated
Visual changes (from Visual changes Visual changes Visual changes causing Disabling visual loss in
baseline) causing no or causing greater than inability to perform affected eye(s)
minimal interference minimal interference usual social &
with usual social & with usual social & functional activities
ENDOCRINE/METABOLIC

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CLINICAL
LIFE-THREATENING
Abnormal fat Detectable by study Detectable on Disfiguring OR Obvious NA
accumulation participant (or by physical exam by changes on casual
(e.g., back of neck, caregiver for young health care provider visual inspection
breasts, abdomen) children and
disabled adults)
Diabetes mellitus NA New onset without New onset with Life-threatening
need to initiate initiation of consequences (e.g.,
medication OR medication indicated ketoacidosis,
Modification of OR Diabetes hyperosmolar non-
current medications uncontrolled despite ketotic coma)
to regain glucose treatment
control modification
Gynecomastia Detectable by study Detectable on Disfiguring OR Obvious NA
participant or physical exam by on casual visual
caregiver (for young health care provider inspection
children and
disabled adults)
Hyperthyroidism Asymptomatic Symptomatic causing Symptoms causing Life-threatening
greater than minimal inability to perform consequences (e.g.,
interference with usual social & thyroid storm)
functional activities OR Uncontrolled
OR Thyroid despite treatment
suppression therapy modification
indicated
Hypothyroidism Asymptomatic Symptomatic causing Symptoms causing Life-threatening
greater than minimal inability to perform consequences (e.g.,
interference with usual social & myxedema coma)
functional activities OR Uncontrolled
OR Thyroid despite treatment
replacement therapy modification
indicated
Lipoatrophy Detectable by study Detectable on Disfiguring OR Obvious NA
(e.g., fat loss from participant (or by physical exam by on casual visual
the face, extremities, caregiver for young health care provider inspection
buttocks) children and
disabled adults)

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LABORATORY
LIFE-THREATENING
HAEMATOLOGY Standard International Units are listed in italics
Absolute CD4+ 300 – 400/mm3 200 – 299/mm3 100 – 199/mm3 < 100/mm3
count 300 – 400/µL 200 – 299/µL 100 – 199/µL < 100/µL
– Adult and
Paediatric
> 13 years
(HIV negative only)
Absolute 600 – 650/mm3 500 – 599/mm3 350 – 499/mm3 < 350/mm3
lymphocyte count 0.600 x 109 – 0.500 x 109 – 0.350 x 109 – < 0.350 x 109/L
– Adult and 0.650 x 109/L 0.599 x 109/L 0.499 x 109/L
Paediatric
> 13 years
(HIV negative only)
Comment: Values in children ≤ 13 years are not given for the two parameters above because the absolute counts
are variable
Absolute neutrophil count (ANC) §
Adult and 750 –< 1,000/mm3 500 – 749/mm3 250 – 499/mm3 < 250/mm3
Paediatric, 0.75 x 109 – 0.5 x 109 – 0.25 x 109 – < 0.250 x 109/L
> 7 days <1.0. x 109/L 0.749 x 109/L 0.499 x 109/L
Infant †, 2 – 7 1,250 – 1,500/mm3 1,000 – 1,249/mm3 750 – 999/mm3 < 750/mm3
days 1.250 x 109 – 1.000 x 109 – 0.750 x 109 – < 0.750 x 109/L
1.500 x 109/L 1.249 x 109/L 0.999 x 109/L
Infant †, 1 day 4,000 – 5,000/mm3 3,000 – 3,999/mm3 1,500 – 2,999/mm3 < 1,500/mm3
4.000 x 109 – 3.000 x 109 – 1.500 x 109 – < 1.500 x 109/L
5.000 x 109/L 3.999 x109/L 2.999 x 109/L
Fibrinogen, 100 – 200 mg/dL 75 – 99 mg/dL 50 – 74 mg/dL < 50 mg/dL
decreased 1.00 – 2.00 g/L 0.75 – 0.99 g/L 0.50 – 0.74 g/L < 0.50 g/L
OR OR OR OR
0.75 – 0.99 x LLN 0.50 – 0.74 x LLN 0.25 – 0.49 x LLN < 0.25 x LLN
OR
Associated with gross
bleeding
Haemoglobin (Hgb)
Comment: The Hgb values in mmol/L have changed because the conversion factor used to convert g/dL to mmol/L
has been changed from 0.155 to 0.6206 (the most commonly used conversion factor). For grading Hgb results
obtained by an analytic method with a conversion factor other than 0.6206, the result must be converted to g/dL
using the appropriate conversion factor for that lab.
Adult and 8.5 – 10.0 g/dL 7.5 – 8.4 g/dL 6.50 – 7.4 g/dL < 6.5 g/dL
Paediatric 5.24 –6.23 mmol/L 4.62-5.23 mmol/L 4.03-4.61 mmol/L < 4.03 mmol/L
57 days
(HIV positive
only)

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LABORATORY
LIFE-THREATENING
Adult and 10.0 – 10.9 g/dL 9.0 – 9.9 g/dL 7.0 – 8.9 g/dL < 7.0 g/dL
Paediatric 6.18 – 6.79 mmol/L 5.55 – 6.17 mmol/L 4.34 – 5.54 mmol/L < 4.34 mmol/L
57 days OR OR OR
(HIV negative Any decrease Any decrease Any decrease
only) 2.5 – 3.4 g/dL 3.5 – 4.4 g/dL 4.5 g/dL
1.58 – 2.13 mmol/L 2.14 – 2.78 mmol/L 2.79 mmol/L
Comment: The decrease is a decrease from baseline
Infant †, 36 – 56 8.5 – 9.4 g/dL 7.0 – 8.4 g/dL 6.0 – 6.9 g/dL < 6.00 g/dL
days 5.24 – 5.86 mmol/L 4.31 – 5.23 mmol/L 3.72 – 4.30 mmol/L < 3.72 mmol/L
(HIV positive or
negative)
Infant †, 22 – 35 9.5 – 10.5 g/dL 8.0 – 9.4 g/dL 7.0 – 7.9 g/dL < 7.00 g/dL
days 5.87 – 6.54 mmol/L 4.93 – 5.86 mmol/L 4.34 – 4.92 mmol/L < 4.34 mmol/L
(HIV positive or
negative)
Infant †, 21 12.0 – 13.0 g/dL 10.0 – 11.9 g/dL 9.0 – 9.9 g/dL < 9.0 g/dL
days 7.42 – 8.09 mmol/L 6.18 – 7.41 mmol/L 5.59 – 6.17 mmol/L < 5.59mmol/L
(HIV positive or
negative)
International 1.1 – 1.5 x ULN 1.6 – 2.0 x ULN 2.1 – 3.0 x ULN > 3.0 x ULN
Normalized Ratio of
prothrombin time
(INR)
Methemoglobin 5.0 – 10.0% 10.1 – 15.0% 15.1 – 20.0% > 20.0%
Prothrombin Time 1.1 – 1.25 x ULN 1.26 – 1.50 x ULN 1.51 – 3.00 x ULN > 3.00 x ULN
(PT)
Partial 1.1 – 1.66 x ULN 1.67 – 2.33 x ULN 2.34 – 3.00 x ULN > 3.00 x ULN
Thromboplastin
Time (PTT)
Platelets, decreased 100,000 – 50,000 – 25,000 – < 25,000/mm3
124,999/mm3 99,999/mm3 49,999/mm3 < 25.000 x 109/L
100.000 x 109 – 50.000 x 109 – 25.000 x 109 –
124.999 x 109/L 99.999 x 109/L 49.999 x 109/L
WBC, decreased 2,000 – 2,500/mm3 1,500 – 1,999/mm3 1,000 – 1,499/mm3 < 1,000/mm3
2.000 x 109 – 1.500 x 109 – 1.000 x 109 – < 1.000 x 109/L
2.500 x 109/L 1.999 x 109/L 1.499 x 109/L
CHEMISTRIES Standard International Units are listed in italics
Acidosis NA pH < normal, but pH < 7.3 without life- pH < 7.3 with life-
7.3 threatening threatening
Albumin, serum, 3.0 g/dL – < LLN 2.0 – 2.9 g/dL < 2.0 g/dL NA
low 30 g/L – < LLN 20 – 29 g/L < 20 g/L
Alkaline 1.25 – 2.5 x ULN† 2.6 – 5.0 x ULN† 5.1 – 10.0 x ULN† > 10.0 x ULN†
Phosphatase

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LABORATORY
LIFE-THREATENING
Alkalosis NA pH > normal, but pH > 7.5 without life- pH > 7.5 with life-
7.5 threatening threatening
ALT (SGPT) 1.25 – 2.5 x ULN 2.6 – 5.0 x ULN 5.1 – 10.0 x ULN > 10.0 x ULN
AST (SGOT) 1.25 – 2.5 x ULN 2.6 – 5.0 x ULN 5.1 – 10.0 x ULN > 10.0 x ULN
Bicarbonate, 16.0 mEq/L – < LLN 11.0 – 15.9 mEq/L 8.0 – 10.9 mEq/L < 8.0 mEq/L
serum, low 16.0 mmol/L – < LLN 11.0 – 15.9 mmol/L 8.0 – 10.9 mmol/L < 8.0 mmol/L
Comment : Some laboratories will report this value as Bicarbonate (HCO3) and others as Total Carbon Dioxide
(CO2). These are the same tests, values should be graded according to the ranges for Bicarbonate as listed above.
Bilirubin (Total)
Adult and 1.1 – 1.5 x ULN 1.6 – 2.5 x ULN 2.6 – 5.0 x ULN > 5.0 x ULN
Paediatric > 14
days
Infant †, ≤ 14 NA 20.0 – 25.0 mg/dL 25.1 – 30.0 mg/dL > 30.0 mg/dL
days 342 – 428 µmol/L 429 – 513 µmol/L > 513.0 µmol/L
(non-hemolytic)
Infant †, ≤ 14 NA NA 20.0 – 25.0 mg/dL > 25.0 mg/dL
days 342 – 428 µmol/L > 428 µmol/L
(hemolytic)
Calcium, serum, high (corrected for albumin)
Adult and 10.6 – 11.5 mg/dL 11.6 – 12.5 mg/dL 12.6 – 13.5 mg/dL > 13.5 mg/dL
Paediatric 2.65 – 2.88 mmol/L 2.89 – 3.13 mmol/L 3.14 – 3.38 mmol/L > 3.38 mmol/L
≥ 7 days
Infant †, < 7 days 11.5 – 12.4 mg/dL 12.5 – 12.9 mg/dL 13.0 – 13.5 mg/dL > 13.5 mg/dL
2.88 – 3.10 mmol/L 3.11 – 3.23 mmol/L 3.245 – 3.38 mmol/L > 3.38 mmol/L
Calcium, serum, low (corrected for albumin)
Adult and 7.8 – 8.4 mg/dL 7.0 – 7.7 mg/dL 6.1 – 6.9 mg/dL < 6.1 mg/dL
≥ 7 days
Infant †, < 7 days 6.5 – 7.5 mg/dL 6.0 – 6.4 mg/dL 5.50 – 5.90 mg/dL < 5.50 mg/dL
1.63 – 1.88 mmol/L 1.50 – 1.62 mmol/L 1.38 – 1.51 mmol/L < 1.38 mmol/L
Comment: Do not adjust Calcium, serum, low or Calcium, serum, high for albumin
Cardiac troponin I NA NA NA Levels consistent with
(cTnI) myocardial infarction or
unstable angina as
defined by the
manufacturer
Cardiac troponin T NA NA NA 0.20 ng/mL
(cTnT) OR
Levels consistent with
myocardial infarction or
unstable angina as
defined by the
manufacturer
Cholesterol (fasting)

ODYSSEY Protocol
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LABORATORY
LIFE-THREATENING
Adult ≥ 18 years 200 – 239 mg/dL 240 – 300 mg/dL > 300 mg/dL NA
5.18 – 6.19 mmol/L 6.20 – 7.77 mmol/L > 7.77 mmol/L
Paediatric < 18 170 – 199 mg/dL 200 – 300 mg/dL > 300 mg/dL NA
years 4.40 – 5.15 mmol/L 5.16 – 7.77 mmol/L > 7.77 mmol/L
Creatine Kinase 3.0 – 5.9 x ULN† 6.0 – 9.9 x ULN† 10.0 – 19.9 x ULN† 20.0 x ULN†
Creatinine 1.1 – 1.3 x ULN† 1.4 – 1.8 x ULN† 1.9 – 3.4 x ULN† 3.5 x ULN†
Glucose, serum, high
Nonfasting 116 – 160 mg/dL 161 – 250 mg/dL 251 – 500 mg/dL > 500 mg/dL
Fasting 110 – 125 mg/dL 126 – 250 mg/dL 251 – 500 mg/dL > 500 mg/dL
Glucose, serum, low
Adult and 55 – 64 mg/dL 40 – 54 mg/dL 30 – 39 mg/dL < 30 mg/dL
≥ 1 month
Infant †, < 1 50 – 54 mg/dL 40 – 49 mg/dL 30 – 39 mg/dL < 30 mg/dL
month 2.78 – 3.00 mmol/L 2.22 – 2.77 mmol/L 1.67 – 2.21 mmol/L < 1.67 mmol/L
Lactate ULN - < 2.0 x ULN 2.0 x ULN without Increased lactate with Increased lactate with
without acidosis acidosis pH < 7.3 without life- pH < 7.3 with life-
LDL cholesterol (fasting)
Paediatric > 2 - < 110 – 129 mg/dL 130 – 189 mg/dL ≥ 190 mg/dL NA
18 years 2.85 – 3.34 mmol/L 3.35 – 4.90 mmol/L ≥ 4.91 mmol/L
Lipase 1.1 – 1.5 x ULN 1.6 – 3.0 x ULN 3.1 – 5.0 x ULN > 5.0 x ULN
Magnesium, serum, 1.2 – 1.4 mEq/L 0.9 – 1.1 mEq/L 0.6 – 0.8 mEq/L < 0.60 mEq/L
low 0.60 – 0.70 mmol/L 0.45 – 0.59 mmol/L 0.30 – 0.44 mmol/L < 0.30 mmol/L
Pancreatic amylase 1.1 – 1.5 x ULN 1.6 – 2.0 x ULN 2.1 – 5.0 x ULN > 5.0 x ULN
Phosphate, serum, low
Adult and 2.5 mg/dL – < LLN 2.0 – 2.4 mg/dL 1.0 – 1.9 mg/dL < 1.00 mg/dL
Paediatric 0.81 mmol/L – < LLN 0.65 – 0.80 mmol/L 0.32 – 0.64 mmol/L < 0.32 mmol/L
> 14 years
Paediatric 1 year 3.0 – 3.5 mg/dL 2.5 – 2.9 mg/dL 1.5 – 2.4 mg/dL < 1.50 mg/dL
– 14 years 0.97 – 1.13 mmol/L 0.81 – 0.96 mmol/L 0.48 – 0.80 mmol/L < 0.48 mmol/L
Paediatric < 1 3.5 – 4.5 mg/dL 2.5 – 3.4 mg/dL 1.5 – 2.4 mg/dL < 1.50 mg/dL
year 1.13 – 1.45 mmol/L 0.81 – 1.12 mmol/L 0.48 – 0.80 mmol/L < 0.48 mmol/L
Potassium, serum, 5.6 – 6.0 mEq/L 6.1 – 6.5 mEq/L 6.6 – 7.0 mEq/L > 7.0 mEq/L
high 5.6 – 6.0 mmol/L 6.1 – 6.5 mmol/L 6.6 – 7.0 mmol/L > 7.0 mmol/L
Potassium, serum, 3.0 – 3.4 mEq/L 2.5 – 2.9 mEq/L 2.0 – 2.4 mEq/L < 2.0 mEq/L
low 3.0 – 3.4 mmol/L 2.5 – 2.9 mmol/L 2.0 – 2.4 mmol/L < 2.0 mmol/L
Sodium, serum, 146 – 150 mEq/L 151 – 154 mEq/L 155 – 159 mEq/L 160 mEq/L
high 146 – 150 mmol/L 151 – 154 mmol/L 155 – 159 mmol/L 160 mmol/L

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LABORATORY
LIFE-THREATENING
Sodium, serum, low 130 – 135 mEq/L 125 – 129 mEq/L 121 – 124 mEq/L 120 mEq/L
130 – 135 mmol/L 125 – 129 mmol/L 121 – 124 mmol/L 120 mmol/L
Triglycerides NA 500 – 750 mg/dL 751 – 1,200 mg/dL > 1,200 mg/dL
(fasting) 5.65 – 8.48 mmol/L 8.49 – 13.56 mmol/L > 13.56 mmol/L
Uric acid 7.5 – 10.0 mg/dL 10.1 – 12.0 mg/dL 12.1 – 15.0 mg/dL > 15.0 mg/dL
URINALYSIS Standard International Units are listed in italics
Hematuria 6 – 10 RBC/HPF > 10 RBC/HPF Gross, with or without Transfusion indicated
(microscopic) clots OR with RBC
casts
Proteinuria, 1+ 2–3+ 4+ NA
random collection
Proteinuria, 24 hour collection
Adult and 200 – 999 mg/24 h 1,000 – 1,999 mg/24 2,000 – 3,500 mg/24 h > 3,500 mg/24 h
Paediatric 0.200 – 0.999 g/d h 2.000 – 3.500 g/d > 3.500 g/d
10 years 1.000 – 1.999 g/d
Paediatric > 3 mo 201 – 499 mg/m2/24 500 – 799 800 – 1,000 > 1,000 mg/ m2/24 h
- h mg/m2/24 h mg/m2/24 h > 1.000 g/d
< 10 years 0.201 – 0.499 g/d 0.500 – 0.799 g/d 0.800 – 1.000 g/d
§ Neutrophil grading, are based on WHO guidelines (5) and NIH Paediatric toxicity tables (6)
recognising the lower normal levels in African populations.
Values are for term infants. Preterm infants should be assessed using local normal ranges.
†Use age and sex appropriate values (e.g., bilirubin), including preterm infants.

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APPENDIX XI TANNER SCALES
The Five Stages of Female Breast and Pubic Hair Development

Breast and pubic hair development should be staged separately (7, 8).
Stage Female Breast Pubic Hair

1 Breasts during childhood. None
The breasts are flat and
show no signs of
development.
2 Breast bud stage. Milk Sparse, lightly

ducts and fat tissue pigmented, straight,
forms a small mound. medial border of labia.
3 Breasts continue to grow. Darker, beginning to

Breasts become rounder curl, increased
and fuller. amount.
4 Nipple and areola form Coarse, curly,

separate small mound. abundant but amount
Not all girls go through less than in adult.
this stage. Some skip
stage 4 and go directly to
stage 5.
5 Breast growth enters Adult feminine

final stage. Adult breast triangle, spread to
is full and round shaped. medial surface of
thighs

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The Five Stages of Male Genitalia and Pubic Hair Development

Genitalia and Pubic hair should be staged separately
Stage Male Genitalia Pubic Hair
1 Penis and testicles of a child. No pubic hair.

Testicles between 1 and 3
milliliters in volume.
2 First signs for penis and Pubic hair beginning to grow:

testicle growth, Testicles appears sparse and downy
become larger. Testicles straight.
between 4 and 6 millilitres in
volume.
3 Penis continues to grow Pubic hair appears curlier and

getting wider and longer. coarser with increased
Testicles continue to grow pigmentation.
larger. Testicles between 7
and 16 millilitres in volume.
4 Penis continues to grow Pubic hair becomes adult type,

getting wider and longer. but less.
Testicles continue to grow
larger. Penis gland or head is
more developed. Testicles
between 12 and 24 milliliters
in volume. Testicles are about
1 1/2 inches long.
5 Penis growth enters final Pubic hair is thick spreading to

stage. Average erect penis medial thighs.
length 6 1/4 inches. 90% are 5
- 7 inches. Glans penis or head
is fully developed. Testicles
16 - 27 millilitres in volume.
Testicles are about 1-3/4
inches.
Copyright© 1998,1999 VirtualKid All Rights Reserved.

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APPENDIX XII IMMUNOLOGY SUBSTUDY
RATIONALE
Recent studies in adults show that integrase inhibitors lead to greater increases in CD4 count than
comparator regimes (9-12). The reasons for this are unclear but may be due to an increase in naïve
CD4 cells (13). If correct, this finding could have important implications for treating HIV infected
children and adults, as it may imply that integrase inhibitors can lead to an increase in thymic
output.
T-cells produced in the thymus from bone marrow derived precursor cells establish the peripheral
naïve T-cell pool during the first year of life. The export of T-cells from the thymus (thymic output)
then gradually declines from its peak at 1 year of age to much lower levels by early adulthood. In
humans, increased peripheral T-cell division with age is relied upon to maintain the naïve T-cell pool.
The relative contribution of these two mechanisms therefore changes with age. Our recent work has
demonstrated the importance of maintaining thymic output in childen with HIV infection to optimise
CD4 reconstitution ((14, 15)). It is clear therefore that the finding of increased naïve CD4 cells in
response to integrase inhibitors may be due to increased naïve cell proliferation and/or increased
thymic output.
Until recently, thymic output has been commonly estimated from T-cell receptor excision circles
(TRECS) and/or markers such as CD31 expressed on recent thymic emigrants. Because
concentrations of TREC and markers of recent thymic emigrants are confounded by peripheral T-cell
division they cannot in themselves be used as quantitative estimates of thymic output. We have
established methods using measurements of TRECs and cell division using the marker Ki67 in the
total naïve CD4 T-cell population and a recently described mathematical model to obtain explicit
measures of thymic output in HIV infected patients (16). We have adapted this methodology for use
in frozen cells and propose to apply it to stored samples collected from the proposed study quantify
T-cell dynamics and assess if DTG leads to increased thymic output.
We have developed a model of CD4 reconstitution in children and adults which allows longitudinal
CD4 data collected following ART initiation to be used to quantify T-cell dynamics, including
producing an estimate of thymic activity. It has been examined with real data and provides good
estimates of thymic output. Longitudinal CD4 counts from patients starting ART regimes including
and excluding an INI could therefore be used to investigate their potential effects on thymic activity,
when cells or more detailed immunophenotypic data are not available (Lewis et al. in preparation).
DTG may also be operating to increase CD4 cells through its effects on immune activation, possibly
as a result of ongoing low level viral replication. A recent study has shown that in adults, Raltegravir
reduces D-dimers, but increases 2-Long terminal Repeat Circles (2-LTR) indicating its effects on
ongoing low level viral replication (17). The impact of DTG on immune activation has so far been
restricted to adults.
PLAN OF INVESTIGATION
The objective of the substudy is to assess the impact of DTG on the mechanisms of CD4
reconstitution, immune activation and HIV reservoir and replication.
PBMCs will be collected at baseline and at 12, 48 and 96 weeks and stained for T-cell surface
markers with CD3, CD4 and CD45RA in FACS buffer. After surface labelling, PBMCs will be fixed and
permeabilized and then stained for the intranuclear marker Ki67. CD4+/CD45RA+ T-cells will be
isolated by negative immunoselection using magnetic beads. Genomic DNA will be extracted using
QIAamp DNA minikits (QIAGEN) and Real-time quantitative PCR (qPCR) will be carried out to

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determine the number of TRECs per cell. The method for estimating thymic output has been
described (13). An explicit expression for thymic export in terms of total naïve cell numbers, naïve
cell TREC content and Ki67 expression is given as:
y(t) (t) d (t) N(t)
(t) = +
Thymic Export (cells day-1) = dt c (t)
where c is a constant representing the average TREC content of thymocytes entering the peripheral
naïve population, y(t) is the fraction of naïve CD4+ T-cells expressing Ki67, Δ is the duration of Ki67
expression, τ is the TREC concentration in the peripheral naïve CD4+ T-cell population and N(t) is the
total size of the naïve CD4+ T-cell pool. Calculations to estimate total body CD4+/CD45RA+ T-cell
numbers N(t) will be performed as previously described using estimates on the linear relationship
between blood volume and body weight to estimate total body T-cell numbers.
The impact of treatment on thymic output will be analysed using Non-Linear Mixed Effect modeling
to ascertain the impact of DTG on thymic output. The requirements for these models are to have
repeated measurements of multiple individuals over time. In addition to determining fixed effects
(average of a measure within a population) this method has the ability how an individual differs from
the average (random effects). Perhaps most importantly it can be used to assess how factors such as
treatment determine individual responses. Such an approach has been used successfully for
predicting long term CD4 counts in HIV infected children following ART (14).
The impact of DTG on immune activation, viral reservoirs including total and episomal DNA in sub-
populations of CD4 T cells will be determined as previously described (12, 18)
We will therefore measure 1) cellular and soluble markers of immune activation (HLA-DR and CD38,
D-dimers, TNFa and hsCRP – we are currently assessing the influence of ART on immune activation
using a panel of 19 markers and these studies will inform the choice of markers of immune
activation used in the proposed study) and 2) proviral DNA, 2-LTRs and cell associated RNA using
methods already established in our laboratories (18). The results could have important implications
for treating HIV infected children and adults, as higher long term CD4 counts and smaller viral
reservoirs are being extensively studied in their association with better long-term health.
We are planning to enrol 300 children in the substudy to describe the changes in thymic output,
immune activation biomarkers and viral reservoirs and replication. Previous studies have reported
significant changes in related parameters in fewer than 50 patients.

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APPENDIX XIII SUBSTUDY PHARMACOKINETIC SUBSTUDY IN PARTICIPANTS DEVELOPING TB

WHILE ON DTG:
DTG pharmacokinetics are influenced by concomitant treatment with rifampicin. This interaction can
be compensated by administering DTG in a double dose, i.e. 50mg BID for adults (19). If in children
the dose is 1 mg/kg QD without rifampicin, it needs to be 1 mg/kg BID with rifampicin.
Full PK curves will be undertaken in 10 children receiving DTG and rifampicin; curves will be repeated
in the same children after completion of TB therapy
For children starting or already on DTG in this study who are treated for TB with rifampicin
containing regimen , the DTG dose should be 1 mg/kg BID. During the last week of rifampicin
administration a 12h pharmacokinetic curve will be recorded to determine pharmacokinetic
parameters of DTG and rifampicin (sampling at t=0 (prior to the dose), and t=1, 2, 3, 4, 5, 6, 8, and
12h after the dose). The DTG dose should remain BID until 2 weeks after the last dose of rifampicin
because the enzyme inducing effect of rifampicin slowly fades away after discontinuing the drug.
The DTG dose should be reduced to QD the following day. At least 2 weeks after resuming QD dosing
of DTG (so at least 4 weeks after the last dose of rifampicin), a 24h pharmacokinetic curve will be
undertaken to determine DTG pharmacokinetics without rifampicin. Sampling will be at t=0 (prior to
dose), 1, 2, 3, 4, 5, 6, 8, and 24h.
10 children will be included in this PK substudy (see sample size calculation by Dooley et al. (19));
this number may need to be increased if intersubject variability in DTG PK in children appears to be
larger than the 33% reported in adults).

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APPENDIX XIV ODYSSEY STRUCTURE

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APPENDIX XV REFERENCES
staging and immunological classification of HIV related disease in adults and children. Geneva: World
Health Organization, 2007.
2. Centers for Disease Control and Prevention. 1994 revised classification system for human
immunodeficiency virus infection in children less than 13 years of age. MMWR. 1994;43(RR-12):1-10.
3. 1993 revised classification system for HIV infection and expanded surveillance case
definition for AIDS among adolescents and adults. MMWR Recommendations and reports :
Morbidity and mortality weekly report Recommendations and reports / Centers for Disease Control.
1992;41(RR-17):1-19. Epub 1992/12/18.
4. DAIDS. Division of AIDS table for grading the severity of adult and paediatric adverse events.
. Bethesda, MD. USA.2004.
5. World Health Organization. Antiretroviral therapy for HIV infection in infants and children:
towards universal access. Recommendations for a public health approach (2010 revision). [14th
September 2010]; Available from:
http:/ /www.who.int/hiv/pub/paediatric/infants2010/en/index.html.
6. (DMID). NDoMaID. Pediatric toxicity tables November 2007. 2007.
7. Marshall WA, Tanner JM. Variations in pattern of pubertal changes in girls. Archives of
disease in childhood. 1969;44(235):291-303. Epub 1969/06/01.
8. Marshall WA, Tanner JM. Variations in the pattern of pubertal changes in boys. Archives of
disease in childhood. 1970;45(239):13-23. Epub 1970/02/01.
9. Rockstroh JK, Lennox JL, Dejesus E, Saag MS, Lazzarin A, Wan H, et al. Long-term treatment
with raltegravir or efavirenz combined with tenofovir/emtricitabine for treatment-naive human
immunodeficiency virus-1-infected patients: 156-week results from STARTMRK. Clinical infectious
diseases : an official publication of the Infectious Diseases Society of America. 2011;53(8):807-16.
Epub 2011/09/17.
10. DeJesus E, Rockstroh JK, Lennox JL, Saag MS, Lazzarin A, Zhao J, et al. Efficacy of raltegravir
versus efavirenz when combined with tenofovir/emtricitabine in treatment-naive HIV-1-infected
patients: week-192 overall and subgroup analyses from STARTMRK. HIV clinical trials.
2012;13(4):228-32. Epub 2012/08/02.
11. Gotuzzo E, Markowitz M, Ratanasuwan W, Smith G, Prada G, Morales-Ramirez JO, et al.
Sustained efficacy and safety of raltegravir after 5 years of combination antiretroviral therapy as
initial treatment of HIV-1 infection: final results of a randomized, controlled, phase II study (Protocol
004). J Acquir Immune Defic Syndr. 2012;61(1):73-7. Epub 2012/06/30.
12. Negredo E, Massanella M, Puertas MC, Buzon MJ, Puig J, Perez-Alvarez N, et al. Early but
limited effects of raltegravir intensification on CD4 T cell reconstitution in HIV-infected patients with
an immunodiscordant response to antiretroviral therapy. The Journal of antimicrobial
chemotherapy. 2013;68(10):2358-62. Epub 2013/05/17.
13. Garrido C, Rallon N, Soriano V, Lopez M, Zahonero N, de Mendoza C, et al. Mechanisms
involved in CD4 cell gains in HIV-infected patients switched to raltegravir. AIDS. 2012;26(5):551-7.
Epub 2012/01/03.
14. Lewis J, Walker AS, Castro H, De Rossi A, Gibb DM, Giaquinto C, et al. Age and CD4 count at
initiation of antiretroviral therapy in HIV-infected children: effects on long-term T-cell reconstitution.
J Infect Dis. 2012;205(4):548-56. Epub 2011/12/30.
15. Picat MQ, Lewis J, Musiime V, Prendergast A, Nathoo K, Kekitiinwa A, et al. Predicting
patterns of long-term CD4 reconstitution in HIV-infected children starting antiretroviral therapy in
sub-Saharan Africa: a cohort-based modelling study. PLoS medicine. 2013;10(10):e1001542. Epub
2013/11/10.

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16. Sandgaard KS, Lewis J, Adams S, Klein N, Callard R. Antiretroviral therapy increases thymic
output in children with HIV. AIDS. 2014;28(2):209-14. Epub 2013/09/28.
17. Hatano H, Strain MC, Scherzer R, Bacchetti P, Wentworth D, Hoh R, et al. Increase in 2-long
terminal repeat circles and decrease in D-dimer after raltegravir intensification in patients with
treated HIV infection: a randomized, placebo-controlled trial. J Infect Dis. 2013;208(9):1436-42. Epub
2013/08/27.
18. Klein N, Sefe D, Mosconi I, Zanchetta M, Castro H, Jacobsen M, et al. The immunological and
virological consequences of planned treatment interruptions in children with HIV infection. PloS one.
2013;8(10):e76582. Epub 2013/11/07.
2013;62(1):21-7.

ODYSSEY (PENTA 20)
A randomised trial of dolutegravir (DTG)-based antiretroviral therapy vs. standard
of care (SOC) in children with HIV infection starting first-line or switching to second-
line ART (PENTA 20)
EUDRACT #: 2014-002632-14
NCT #: NCT02259127
Version Number and Date: 5.0 19 January 2021

Supersedes version: 4.2 19 January 2021
Author Position Initial Date
Dr Ellen White Delegated 19/01/2021
Statistician
Approved by
Dr Deborah Ford Trial Statistician 19/01/21
Professor Diana Chief 19/01/21

Gibb Investigator
Version Date Who Comments

0.1 6March2016 Angela Crook Protocol Version 2.0
Aimee Nunn
0.2 15June2016 Cecilia Moore First Draft
0.3 08August2016 Cecilia Moore Second Draft, in response to A. Babiker and D. Ford’s
comments.
0.4 12Jan2017 Cecilia Moore Third Draft, on the basis of amendments made to the
protocol
0.5 06Mar2017 Cecilia Moore Fourth Draft, on the basis of comments from D. Ford
0.6 16Mar2017 Cecilia Moore Fifth Draft, on the basis of comments from A. Babiker
0.7 20Mar2017 Cecilia Moore Sixth Draft, on the basis of comments from D. Gibb
0.8 03Apr2017 Cecilia Moore Seventh Draft, on the basis of comments from A. Turkova
1.0 05Apr2017 Cecilia Moore Converted to final version for circulation
1.1 28Oct2018 Cecilia Moore Update on basis of Protocol version 4.0 release
Inclusion of children 3-<14kg with
randomisation stratified by weight band and
ODYSSEY A/B.
Changes made to the definition of one component of the
primary endpoint
Failure defined by <1 log10 drop at week 24
modified to failure for <1 log10 drop at week
24 and switch to second/third line ART for
treatment failure. Approved by IDMC
(19/02/2018); see meeting documents.
Methods clarified with respect to missing VL data at week
24
Modification of definition of ART modifying adverse event
Corrected baseline viral load calculation
Changes made to presentation of lipid changes based on
feedback from second IDMC meeting (19/02/2018)
Add total cholesterol/HDL ratio and non-HDL
Add presentation of A/B separately if indication
of interaction effect
Modification made to the calculation of virological failure
time and censoring time for primary endpoint.
Addition of sensitivity analysis for the primary endpoint.
Addition of analysis of sleep and mood questionnaires
Modification to method of analysis of VL <50 c/ml and VL
<400 c/ml at cross-sectional time points
1.2 22Nov2018 Debbie Ford Clarifications made following review by ViiV
Naomi Givens – Director, Statistics
Ralph DeMasi – Head of Statistics
Judy Hopking – Principal Statistician
2.0 03Dec2018 Cecilia Moore Converted to final version for circulation
2.1 30Jan2019 Cecilia Moore Modification to the presentation of results if indication of
interaction effect following review by IDMC members at
the third IDMC meeting (14Dec2018)
Results in A/B and Total population will be
presented irrespective of interaction effect
2.2 10June2019 Becky Turner Bayesian approach for analysis of children <14kg at
randomisation added
3.0 14November2019 Debbie Ford Clarifications added around testing multiple outcomes.
Reviewed by Abdel Babiker.
3.1 17September2020 Debbie Reviewed for changes needed due to extended follow-up
Ford/Ellen White in Thailand/Africa post randomised phase
Modified to allow for end of randomised phase visits
taking place outside the original window
Clarification around resistance analysis
Added COVID-19 as a notable event
4.0 29 September 2020 Ellen White Converted to final version for circulation
4.1 18 January 2021 Ellen White Clarification around adverse event analysis
Clarification around sensitivity analyses
Clarification around grade 3/4 AEs which include all AEs
grade ≥3
4.2 19 January 2021 Ellen White Updated based on Debbie Ford’s comments
5.0 19 January 2021 Ellen White Converted to final version for circulation
ODYSSEY Analysis Plan, version 5.0 2

1. BACKGROUND AND DESIGN ....................................................................................................................... 4
1.1 BACKGROUND AND AIMS ................................................................................................................................4
1.1.1 Hypothesis ............................................................................................................................................4
1.2 TRIAL DESIGN ................................................................................................................................................4
FIGURE 1. TRIAL SCHEMA .............................................................................................................................................5
1.3 PATIENT SELECTION ........................................................................................................................................6
1.3 TRIAL INTERVENTIONS.....................................................................................................................................6
1.4 DURATION OF TRIAL .......................................................................................................................................7
1.5 METHOD OF RANDOMISATION .........................................................................................................................7
1.6 SAMPLE SIZE CALCULATIONS .............................................................................................................................8
2. OUTCOME MEASURES ............................................................................................................................... 8
2.1 PRIMARY EFFICACY OUTCOME ..........................................................................................................................8
2.2 SECONDARY EFFICACY OUTCOMES .....................................................................................................................8
2.3 SECONDARY SAFETY OUTCOMES ........................................................................................................................8
2.4 OTHER SECONDARY OUTCOMES ........................................................................................................................8
3. ANALYSIS POPULATIONS............................................................................................................................ 9
4. DERRIVATION OF DATA TO BE ANALYSED .................................................................................................. 9

4.1 DEFINITION OF BASELINE .................................................................................................................................9
4.2 DEFINITION OF FOLLOW-UP TIME ...................................................................................................................10
4.3 DEFINITION OF NOMINAL WEEK FOR LABORATORY MEASUREMENT AND OTHER CLINICAL PARAMETERS........................10
4.4 DEFINITION OF TREATMENT CHANGES .............................................................................................................10
4.5 HANDLING OF VIRAL LOAD DATA ....................................................................................................................11
4.6 TRIAL CENSORING DATE AND ENDPOINT DETERMINATION ...................................................................................12
A) PARTICIPANTS ≥14KG .......................................................................................................................................12
4.7 STRATIFICATION VARIABLES ...........................................................................................................................12
4.8 DEFINITION OF NEW RESISTANCE MUTATIONS ..................................................................................................13
4.9 HANDLING ADVERSE EVENTS .........................................................................................................................13
5. ANALYSIS PRINCIPLES .............................................................................................................................. 13
6. ANALYSIS DETAILS.................................................................................................................................... 14
6.1 ENROLMENT AND ELIGIBILITY .........................................................................................................................14
6.2 BASELINE CHARACTERISTICS ...........................................................................................................................15
6.3 FOLLOW-UP ............................................................................................................................................... 16
6.4 ANTIRETROVIRAL THERAPY RECEIVED...............................................................................................................16
6.5 AVAILABILITY OF HIV-1 RNA MEASUREMENTS .................................................................................................17
6.6 PRIMARY EFFICACY OUTCOME........................................................................................................................17
6.6.1 Sensitivity analyses for the primary endpoint ....................................................................................17
6.6.2 Subgroup analyses for the primary endpoint .....................................................................................17
6.7 SECONDARY EFFICACY ANALYSES .................................................................................................................... 18
6.8 SECONDARY SAFETY OUTCOMES .....................................................................................................................19
6.9 OTHER SECONDARY OUTCOMES .....................................................................................................................20
6.10 OTHER OUTCOMES ......................................................................................................................................20
6.11 TESTING MULTIPLE OUTCOMES .......................................................................................................................21
7. SUBGROUP ANALYSES.............................................................................................................................. 21
7.1 ANALYSES BY DOSE AND WEIGHT-BAND ...........................................................................................................21
8. ANCILLARY STUDIES AND SUBSTUDIES..................................................................................................... 21
APPENDIX I ....................................................................................................................................................... 23

1. BACKGROUND AND DESIGN
1.1 Background and Aims
With the development of new antiretroviral drugs (ARVs), including new drug classes, which offer simplified, more
potent options for first- and second-line therapy with fewer adverse effects in adults, there is a need to evaluate
their place in paediatric HIV treatment.
Unique issues for HIV-infected children include: potential for perinatal transmission of viruses resistant to
antiretroviral therapy (ART) regimens taken by mothers during pregnancy and breastfeeding; special consideration
of adverse events as children take drugs during growth and development and will be on them for much longer than
adults; and the need for age appropriate once daily formulations, preferably fixed dose scored dispersible
combinations which may require different ratios of drugs from those used in adults.
Globally, more than 80% of HIV-infected children live in Sub Saharan Africa (SSA). Although there has been
substantial improvement in ART coverage over the last few years, only half of children in need of treatment have
access to ART (1, 2). Rapid disease progression and high early mortality require that ART is started early in life and
many children still die before they are diagnosed. Children <3 years in low/middle income countries are taking either
non-nucleoside reverse transcriptase inhibitors (NNRTI)-based ART (e.g. most African countries, India, Eastern
Europe) or ritonavir boosted protease inhibitor (bPI) lopinavir/ritonavir (LPV/r)-based ART (South Africa; some
centres of excellence in SSA). Children >3 years in SSA, including South Africa, start NNRTI-based ART. In both
well-resourced and resource-limited settings, there is a need for alternative first- and second-line regimens which
can be given in the face of possible transmitted resistance (from prevention of mother to child transmission pMTCT)
or resistance arising from first-line ART, whether PI or NNRTI based. New regimens need to be potent, durable,
non-toxic and available in acceptable once daily formulations with correct drug ratios. Ideally regimens should be
robust with a high barrier to resistance, have minimal cross-resistance and minimal interactions with anti-tuberculosis
drugs.
Dolutegravir (DTG) is a second-generation integrase inhibitor (INSTI) with the advantage of once daily dosing, a
good short-term safety profile, low pharmacokinetic variability, few drug-to-drug interactions, rapid and robust
virological response with an optimised background treatment, a distinct resistance profile from raltegravir, a high
genetic barrier to resistance and high potency at a low milligram dose. Combination regimens with DTG will therefore
be attractive for children starting first-line ART and for those switching to second-line for reasons of toxicity or failure.
ODYSSEY will be a pragmatic strategy trial evaluating the efficacy and safety of once daily DTG-based ART compared
with standard of care in children and adolescents starting first- or second-line ART in resource-limited and well-
resourced settings.
1.1.1 Hypothesis
DTG + 2 NRTIs is non-inferior to SOC (NNRTI or PI or INSTI + 2 or 3 NRTIs) in terms of efficacy and superior in
terms of toxicity profile.
1.2 Trial design

ODYSSEY is an open-label, multi-centre, randomised (1:1), non-inferiority, Phase II/III, 96-week, 2-arm clinical trial.

Figure 1. Trial Schema
Note:
At least 60 additional children weighing 3-<14kg will be enrolled and followed up for 96 weeks
1.3 Patient selection
Eligible participants are HIV-1 infected children younger than 18 years planning to start first-line or second-line
antiretroviral therapy. Additional inclusion criteria are as follows:
Children ≥28 days and <18 years weighing ≥3kg with confirmed HIV-1 infection*
Girls who have reached menses must have a negative pregnancy test at screening and randomisation and be
willing to adhere to effective methods of contraception if sexually active
Children with co-infections who need to start ART according to local/national guidelines
Parents/carers and children, where applicable, willing to adhere to a minimum of 96 weeks' follow-up
*Recruitment opened in children ≥6 years and <18 years weighing ≥20kg (Protocol version 2.0). In February 2017
the EMA approved DTG for children ≥6 years down to 15kg (with a 20mg QD dose for children weighing 15-<20kg).
Following this, in May 2017, ODYSSEY opened for recruitment of these children across all sites (Version 2.0). Version
3.0 included recruitment of children ≥14kg (with no age restriction) with a lead-in PK sub-study for children weighing
14 to <20kg. Version 4.0 allows for recruitment of children ≥3kg and ≥28 days; children weighing 3 to <14kg must
be willing to participate in a lead-in PK substudy to enter the trial. Throughout the trial eligibility will be based in
both arms on availability of DTG dose given age/weight band.
Additionally for ODYSSEY A, participants must be planning to start first-line ART.
Additionally for ODYSSEY B, participants must be:

Planning to start second-line ART defined as either: (i) switch of at least 2 ART drugs due to treatment
failure; or (ii) switch of only the third agent due to treatment failure where drug sensitivity tests show no
mutations conferring NRTI resistance
Treated with only one previous ART regimen. Single drug substitutions for toxicity, simplification, changes
in national guidelines or drug availability are allowed
In settings where resistance tests are routinely available, at least one active NRTI from TDF/TAF, ABC or
ZDV should have preserved activity based on cumulative results of resistance tests
In settings where resistance tests are not routinely available, children who are due to switch according to
national guidelines should have at least one new NRTI predicted to be available from TDF/TAF, ABC or ZDV
Viral load ≥500 c/ml* at screening visit or within 4 weeks prior to screening
* Protocol version 3.0 onwards (viral load ≥1000 c/ml in protocol version 2.0)
Exclusion criteria are as follows:

History or presence of known allergy or contraindications to DTG
History or presence of known allergy or contraindications to proposed available NRTI backbone or proposed
available SOC third agent.
Alanine aminotransferase (ALT) ≥5 times the upper limit of normal (ULN) or ALT ≥3xULN and bilirubin
≥2xULN
Patients with severe hepatic impairment or unstable liver disease (as defined by the presence of ascites,
encephalopathy, coagulopathy, hypoalbuminaemia, oesophageal or gastric varices, or persistent jaundice),
known biliary abnormalities (with the exception of Gilbert's syndrome or asymptomatic gallstones)
Evidence of lack of susceptibility to integrase inhibitors or more than a 2-week exposure to antiretrovirals
of this class
1.3 Trial interventions

Children starting first- and second-line ART will be randomised separately (both in 1:1 ratio):
1. DTG + 2 NRTIs
2. SOC (defined as PI, NNRTI or INSTI+ 2 or 3 NRTIs)

1. DTG + 2 NRTI
2. SOC (defined as PI, NNRTI or INSTI + 2 NRTIs)
1.4 Duration of trial

A minimum of 700 children will be enrolled over 96-120 weeks. This will include ≥310 children starting first-line
(ODYSSEY A) and ≥390 children starting second-line ART (ODYSSEY B). After this target is reached the end of main
trial recruitment date will be defined. Recruitment will then stop for children ≥14kg. Recruitment will continue in the
3 lower weight bands (3-<6kg, 6-<10kg and 10-<14kg) until at least 20 children are recruited in each weight band.
Follow-up for children recruited up to the end of main trial recruitment date will continue until the last child recruited
in the main trial has completed 96 weeks follow-up (herein referred to as the end of the main trial, 24th April 2020);
each participant in the main trial will then have a final trial visit. Analysis of the main trial will be conducted at this
time.
Each of the children recruited in the lower weight bands (<14kg) after the end of main trial recruitment date will
continue to be followed up for 96 weeks (from their date of randomisation); we will ask sites to schedule their 96
week visit for on/after 96 weeks and the trial will remain open until this follow-up is complete.
Note: in practice there was no overlap of recruitment of children ≥14kg (n=707) and recruitment of children <14kg
(N=85) hence children randomised ≥14kg to 22/June/2018 constitute the main trial population.
Protocol version 6.0 allows for extended follow-up in African and Thai sites of ODYSSEY participants post end of
randomised follow-up; European sites are not participating in extended follow-up. For each participant their end of
randomised phase visit can be identified by a question on the follow-up form.
Due to the COVID-19 pandemic (March 2020 onwards), and uncertainty about how it would evolve and ability of
clinics to conduct face-to-face visits, sites were advised they could conduct end of randomised phase visits for the
main trial outside of the pre-defined window (24th April 2020 (96 weeks from date last participant recruited ≥14kg)
–30 June 2020) for participants who had completed 96 weeks follow-up. This resulted in one child being seen early
in Europe and exiting from the trial on 6th April 2020 before the last participant reached 96 weeks (trial censoring
date_24th April 2020). In Thailand and Africa, many participants were kept in follow-up after 30 June 2020 to ensure
continued drug supply and until a face-to-face visit could be done; sites were subsequently asked to complete end
of randomised phase visits for participants recruited weighing ≥14kg by end November 2020.
To ensure continued care and drug supply for children recruited <14kg (who were not due to reach 96 weeks prior
to May 2020 at the earliest), sites were advised to retain all children <14kg in the randomised phase of the trial until
advised otherwise.
During COVID-19, phone visits were conducted for some participants; this information was captured and sites were
asked to ensure the week 96 and the end of randomised phase visit were in person.
1.5 Method of Randomisation

Randomisation of children weighing ≥14kg will be stratified by:
Antiretroviral treatment: naïve or experienced (ODYSSEY A or ODYSSEY B)
Routine availability at site of resistance tests vs. non availability of resistance tests, for children failing
treatment
bPI vs. non-bPI ART offered as SOC*
NRTI backbone* : ABC/3TC or ABC/3TC/ZDV vs. TDF/3TC or TDF/FTC or TAF/3TC or TAF/FTC vs. Other
Randomisation of children weighing 3-<14kg will be performed separately stratified by

weight band at randomisation: 3-<6kg vs. 6-<10kg vs. 10-<14kg
Randomisation lists will be generated using permuted blocks of varying size.
* chosen prior to randomisation

1.6 Sample size calculations
Based on previous HIV studies a non-inferiority margin (delta) of 10-12% is considered acceptable1,2. Assuming a
failure rate of 18% overall (both first-line and second-line children combined) in the DTG arm and SOC arm by 96
weeks and allowing for 10% loss to follow up, 700 children will provide 90% power to exclude (at two-sided 5%
significance level, or equivalently at one-sided 2.5% significance level) a difference of more than 10% between the
two arms. If the upper bound of the two-sided 95% confidence limit for the difference in the proportion failing (DTG
– SOC) is less than 10% (the margin of non-inferiority) the DTG-regimen will be considered to be non-inferior to the
SOC.
Enrolling 310 first-line ART and 390 second-line ART children will provide 80% power to exclude a difference of more
than 12% between the DTG and SOC arms in both subgroups, assuming a failure rate of 15% in ART-naïve (based
on previous trials, including the recent ARROW trial (36) in Africa), and 20% in ART-experienced with loss to follow
up of 10%.
2. OUTCOME MEASURES
2.1 Primary efficacy outcome
The primary outcome is the difference in the cumulative probability of virological or clinical failure by 96 weeks,
estimated by Kaplan-Meier methods using time to the first occurrence of any of the following components:
Insufficient virological response defined as <1 log10 drop at week 24 (or not <50 at week 24 if VL<500 at
baseline) and switch to second/third-line treatment for treatment failure
VL ≥400 c/ml at or after 36 weeks confirmed by next visit
Any new or recurrent AIDS defining event (WHO 4) or severe WHO 3 event*, confirmed by the Endpoint
Review Committee
The primary comparison for the study is to compare DTG-based regimen versus SOC for the primary efficacy outcome
in the combined population (naïve and experienced) adjusted for stratification variables; subpopulation analyses
(ODYSSEY A and ODYSSEY B) are key secondary comparisons.
* For definitions of AIDS defining event (WHO 4) and severe WHO 3 events for the ODYSSEY trial see Appendix I
2.2 Secondary efficacy outcomes
Proportion with clinical or virological failure (as defined above) by 48 weeks

Time to any new or recurrent AIDS defining event (WHO 4) or severe WHO 3 event, confirmed by the Endpoint
Review Committee
Proportion with VL <50 c/ml at 48 and 96 weeks
Proportion with VL <400 c/ml at 48 and 96 weeks
Change in CD4 count (actual values and percentage) and CD4/CD8 ratio from baseline to weeks 48 and 96
2.3 Secondary safety outcomes
Change in total cholesterol, triglycerides and lipid fractions (LDL, HDL) from baseline to weeks 48 and 96
Incidence of new clinical and laboratory grade 3 and 4 adverse events*
*In ODYSSEY, deaths were coded as grade 4 events.
2.4 Other secondary outcomes
Quality of life

3. ANALYSIS POPULATIONS
Intent-to-treat population
The intent-to-treat population will include all randomised patients, except those considered randomised in error.
Randomisation in error will be judged by the participant meeting a major violation of the eligibility criteria including
the patient was HIV negative or the patient was randomised at a time when the dolutegravir dose was not known
for the patient’s weight (and patient not participating in PK); and will not depend on treatment allocation or post-
randomisation follow-up.
Per protocol population

Participants who did not meet the eligibility criteria or where there was a major protocol deviation, e.g. site prescribed
incorrect drug, will also be excluded from this population. Changes to the third agent (i.e. the non-NRTI component,
including adding an additional third agent) for toxicity, failure or pregnancy will be defined as a change in therapy
and participants will be censored at this date. Any stop in regimen for >31 days will be defined as stopping therapy
and participants will be censored at this date.
Intent-to-treat analyses will be performed on all patients in the ITT population and patients will be analysed according
to the study group to which they were randomised.
The primary analysis will include participants randomised prior to the end of main trial recruitment date; these include
participants weighing ≥14kg at enrolment. This analysis will take place when the last of these children reaches 96
weeks follow-up and all children have had a face-to-face visit on/after 24th April 2020.
A sensitivity analysis of the primary endpoint will be done in the per protocol population (as above) by: censoring
follow-up after a participant changes their third agent (i.e. non-NRTI component) (including adding an additional
third agent) in their initial trial regimen for toxicity, failure, protocol deviations or pregnancy; and excluding
participants who did not meet the eligibility criteria
There will be a secondary analysis of primary and secondary endpoints in all children recruited weighing<14kg (where
DTG dose is determined) when this group has completed 96 weeks follow-up. The primary endpoint will also be re-
evaluated in all children including those in the main trial and children recruited <14kg (where DTG dose is
determined) when follow-up in everyone to a minimum of 96 weeks is complete.
4. DERRIVATION OF DATA TO BE ANALYSED

4.1 Definition of Baseline
Baseline is defined as the date of randomisation.
For all variables, the day 0 measurement is defined as the latest measurement up to 42 days prior to (and including)
date of randomisation. If no such measure exists, we will use the earliest measurement after randomisation but only
up to and including 7 days after randomisation and before initiation of trial intervention.
Baseline measures of CD4, CD4 percentage, CD8, CD8 percentage and total lymphocytes will be presented as the
average of all measurements taken between -42 days and day 0.
For HIV RNA, we will use log10 transformation and take the mean of the log10 measurements between -42 days and
day 0 if available. In order to take into account measurements that are above or below the limits of detection, we
will use the following:
First VL measurement Second VL measurement Imputed baseline log10 VL*
If X~=Y: Minimum of log10(X) and log10(Y)

<X <Y
If X=Y: log10(X)
<X =Y (log10(X)+log10(Y))/2

=X <Y (log10(X)+log10(Y))/2
=X =Y (log10(X)+log10(Y))/2
*X and Y are absolute viral load measurements between -42 days and day 0
If more than two viral loads are available between -42 days and day 0 a similar approach will be used. The anti-log
of the mean log of viral loads will be taken to get absolute viral load at baseline. Baseline values for all other
laboratory measures will be presented as the day 0 measurement (as defined above).
4.2 Definition of Follow-up Time

Time will be measured from randomisation. Analyses will include all follow-up until the end of the main trial or 96
weeks as appropriate [for interim analyses the date of data freeze will be used]. For analyses by scheduled visits,
only time-points where there are at least 10 participants in each group with a measurement will be included.
4.3 Definition of Nominal Week for Laboratory Measurement and other clinical parameters
Laboratory measurements, and other clinical parameters (e.g. weight), at any nominal week are defined using exact
dates as those taken nearest to the nominal week within equally spaced windows according to the protocol visit
schedule (note that the visit schedule changes frequency). The midpoint between two scheduled visit weeks should
be taken as belonging to the latter window (see below). Where there are two values within one of these equally
spaced windows, but both equidistant from the nominal visit week, the later value will be used.
Week 4: 2≤ week <8
Week 12: 8≤ week <18
Week 24: 18≤ week <30
Week 36: 30≤ week <42
Week 48: 42≤ week <54 etc.
4.4 Definition of Treatment Changes
A strict initial regimen will be defined as strictly the regimen allocated at trial entry.
A substituted initial regimen will be defined as the strict initial regimen allowing for substitutions to the third agent
of the regimen for reasons other than toxicity, treatment failure, pregnancy or major protocol deviation (e.g. site
prescribing incorrect drug) or to the NRTI component for any reason. Permissible substitutions to the third agent
include for reasons of simplification, drug availability, patient/carer decision and increases in weight.
All reductions to NRTIs are also considered substituted initial regimen.
All changes to the third agent not defined above as a substitution to the initial regimen will be considered a change
from the initial treatment regimen. In the DTG arm, DTG should only be stopped for toxicity, failure or (at clinician’s
discretion) pregnancy.
Changes to the third agent for reasons of treatment failure will be defined as switching to second line therapy in
ODYSSEY A or third line therapy in ODYSSEY B.
Any interruptions or reductions to a regimen for less than or equal to 31 consecutive days are allowed; as long as
the total number of drugs allocated in the regimen is not increased.
A stop to the initial regimen will occur when a patient interrupts their regimen or their third agent for >31 days.
For the definition of adverse events leading to modification of ART, any reduction or substitution in therapy will be
considered a modification of ART. Interruptions to therapy where the same drugs are subsequently restarted will not
be considered a modification of ART.
We will also report adverse events leading to increased doses of ART due to concomitant medications (e.g. DTG
increase for TB treatment). We will also report pregnancies leading to ART modification.

4.5 Handling of Viral Load Data
Participants are included in ODYSSEY both from sites where HIV RNA is routinely measured at site and from sites
where HIV RNA is not routinely measured. In the latter case, HIV RNA will be measured retrospectively on plasma
samples stored at each clinic visit. Confirmatory HIV RNA measures are likely to be performed faster in sites where
HIV RNA monitoring occurs routinely. The primary endpoint includes confirmed HIV RNA≥400 c/ml at or after 36
weeks confirmed by the next visit.
For consistency across sites, where 2 consecutive HIV RNA are ≥400c/ml the date of the next scheduled visit following
the first HIV RNA ≥400 (using schedule from randomisation) will be used for calculating the time to the first
confirmed viral load measurement ≥400c/ml (primary endpoint failure date), rather than the date of the confirmatory
measure. Where a patient has an HIV RNA≥400c/ml and switches treatment for treatment failure without a
confirmatory viral load before switch, the date of the next scheduled visit following the first HIV RNA ≥400c/ml will
be used for the first confirmed viral load measurement ≥400c/ml. This should be uncommon as extra plasma is taken
if an unscheduled visit is made at the point of treatment failure. Treatment switch in itself is not a component of the
primary endpoint; thus any patient who switches treatment for immunological/clinical failure without reaching the
primary endpoint (with no HIV RNA ≥400c/ml) will not be considered a failure at time of switch.
If a HIV RNA is missing at or after 36 weeks prior to final visit this will be assumed to be <400 if the next available
viral load is <400. The table below illustrates how the primary outcome will be counted when missing visits occur.
HIV RNA before missing HIV RNA after missing Failure

Date of virological failure
visit(s) (copies/ml) visit(s) (copies/ml) status
Not applicable. Assume virally suppressed Virally

<400 <400
between visits. suppressed
Date of next scheduled visit (using

≥400* schedule from randomisation) following Viral Failure
first HIV RNA≥400
≥400 but not confirmed*
Not applicable. Assume virally suppressed Virally

<400
between visits suppressed
* Treatment switch for failure at or after an unconfirmed HIV RNA ≥ 400 c/ml will be considered as confirmation of viral failure
The primary endpoint includes insufficient virological response by week 24, defined by less than a 1 log10 drop in
viral load from baseline (or HIV RNA≥50 at week 24 when baseline HIV RNA<500) with switch to second/third line
treatment for treatment failure. A participant will be considered a failure if they switch to second or third line
treatment following insufficient virological response at week 24 without suppressing (VL<50) between week 24 and
switching therapy. Date of switching therapy will be used as the primary endpoint failure date.
If HIV RNA is missing at week 24, we will use HIV RNA measured at week 36. Participants with no baseline viral load
will be treated as meeting this endpoint if their HIV RNA ≥1000 at week 24 (week 36, if missing at 24) and the
participant switches to second/third line without suppressing first.
If a participant does not attend visits at weeks 24 and 36, they will be censored at their last visit prior to week 24
(for analysis of the primary endpoint). If a participant has attended week 24 and week 36 visits but has no viral load
data at either week and does not switch to second or third line treatment they will not be treated as meeting this
endpoint and will not be censored for analysis of the primary endpoint. We expect few/no occurrences of missing
HIV RNA at both weeks 24 and 36 (if participants are attending visits) as missing HIV RNA at week 24 will be flagged
in real time with sites.
For the cross-sectional analysis at weeks 48 and 96, only participants with non-missing VL data will be included

4.6 Trial Censoring Date and Endpoint Determination
a) Participants ≥14kg
Follow-up for children ≥14kg will continue until the last child recruited has completed 96 weeks follow-up; the main
trial censoring date is 24 April 2020. A participant will be considered lost to follow-up if he/she has not reached the
primary endpoint (clinical or virological failure) and an HIV-RNA measurement is not available at/after 24th April
2020; in this case, follow-up will be censored at the date of last HIV RNA for assessment of combined clinical and
virological failure. Participants who attended their end of randomised phase early (prior to 24 April 2020) due to
COVID-19 will be described and their follow-up censored at their end of randomised phase visit.
If a participant has both virological and clinical failure, the earliest failure date will be taken as the failure date. If an
HIV-RNA measurement is available at the end of randomised phase visit and the participant has not reached the
primary endpoint prior to or at the time of the trial censoring date then they will be censored at the trial censoring
date.
b) Participants <14kg
Follow-up for the children <14kg will be until the 96 week visit. A participant will be considered lost to follow-up if
he/she has not reached the primary endpoint (clinical or virological failure) and an HIV-RNA measurement is not
available at the 96 week visit; in this case follow-up will be censored at the date of last HIV RNA for assessment of
combined clinical and virological failure. If a participant has both virological and clinical failure, the earliest failure
date will be taken as the failure date. If an HIV-RNA measurement is available at the 96 week visit and the participant
has not reached the primary endpoint prior to or at the time of the 96 week visit date then they will be censored at
96 weeks.
4.7 Stratification Variables
Where analyses of ≥14kg participants adjust for stratification variables these will include
antiretroviral treatment [naïve or experienced (ODYSSEY A or ODYSSEY B)]
routine availability at site of resistance tests vs. non availability of resistance tests for children failing
treatment
pre-specified NRTI backbone [ABC+3TC (± ZDV) vs. TDF(or TAF)+3TC(or FTC) vs. other]
It is likely that we will have few patients falling within the ‘other’ NRTI backbone stratum; in this circumstance, we
will combine this stratum with the TDF (or TAF) + 3TC(or FTC) stratum.
Although randomisation is stratified by pre-specified use of bPI-based ART vs. other ART as SOC, this is likely to be
strongly confounded by ODYSSEY A and B stratification; in this circumstance we will adjust for ODYSSEY A vs.
ODYSSEY B and not for pre-specified use of bPI-based ART vs. other ART as SOC.
Where analyses of <14kg participants adjust for stratification variables these will include antiretroviral treatment
[naïve or experienced (ODYSSEY A or ODYSSEY B)], provided sufficient numbers allow for this.
Where analysis of all participants (≥14kg+<14kg) adjust for stratification factors the primary analysis will include
weight band (≥/<14kg) in addition to the strata identified above for the ≥14kg group and antiretroviral treatment
(ODYSSEY A/B) in the <14kg group, provided sufficient numbers allow for this
(e.g. 10 stratums:
≥14kg/ODYSSEY A/No Resistance Testing/ABC+3TC+ZDV;
≥14kg/ODYSSEY A/Resistance Testing/ABC+3TC+ZDV;
≥14kg/ODYSSEY A/No Resistance Testing/TDF/TAF+3TC/FTC or Other;
≥14kg/ODYSSEY A/Resistance Testing/ TDF/TAF+3TC/FTC or Other;
≥14kg/ODYSSEY B/No Resistance Testing/ABC+3TC+ZDV;
≥14kg/ODYSSEY B/Resistance Testing/ABC+3TC+ZDV;
≥14kg/ODYSSEY B/No Resistance Testing/TDF/TAF+3TC/FTC or Other;
≥14kg/ODYSSEY B/Resistance Testing/ TDF/TAF+3TC/FTC or Other;
<14kg/ODYSSEY A;
<14kg/ODYSSEY B).

Further we will do a secondary analysis in all participants including the stratification information used in the main
trial (ignoring weight band): antiretroviral therapy [ODYSSEY A/B]; Resistance Testing Availability [Yes/No]; and
NRTI backbone for all participants. If insufficient patients are recruited <14kg in ODYSSEY B, provided results are
similar across all patients and in ODYSSEY A with/without additional strata (stratum) for children <14kg, secondary
analyses may be presented in preference to the primary.
4.8 Definition of New Resistance Mutations
Major NRTI, PI, NNRTI and INSTI resistance will be defined according to the most current IAS list of mutations at
the time of analysis.
Activity of the background regimen will be defined according to the most current Stanford database algorithms at
time of analysis.
4.9 Handling Adverse Events
Possible serious adverse events, notable events*, immune reconstitution inflammatory syndrome (IRIS) events,
severe WHO 3 events, WHO 4 events and deaths occurring during the trial will be reviewed by an endpoint review
committee blinded to treatment arm. Interim reports will differentiate between reviewed events and events awaiting
review. Where an event has been reviewed, the review record will be used; otherwise the site report will be used.
Date event was diagnosed (with date from Form 30 for reviewed events and date of lab sample otherwise) will be
used as the date of occurrence or date of worsening for adverse and staging events, unless specified otherwise
below. An event which has a date of diagnosis or date of worsening before or on the date of randomisation will be
considered to be pre-existing at randomisation and will be excluded from analysis.
All deaths that occur after the date of randomisation up to the trial censoring date will be included as ODYSSEY
events. The “date of death” on Form 30 will be used as the date of occurrence for deaths.
SAEs will be analysed as episodes, with all components of the same clinical SAE presented as one episode (e.g.
“Anaemia+renal failure”). Date of SAE will be defined as the date that the event met the seriousness criteria (i.e.
date of death if resulted death, date of hospitalisation (from the site event Form 21) if resulted in hospitalisation).
For SAEs meeting the seriousness criteria for reasons other than death or hospitalisation, the date the main event
was diagnosed will be used.
Analyses of grade 3 or 4 AEs or adverse events leading to modification of ART/permanent discontinuation of study
drugs will consider each component as separate events.
Grade 3 or 4 AEs, ART modifying events and notable events may be reported on more than one ERC form due to
multiple SAEs (usually multiple hospital admissions) associated with the same underlying event. These can be
identified by the same date of diagnosis and event code and the use of “OT” in the event description on second (and
subsequent) ERC forms. All SAEs should be reported but the underlying event will only be counted once when
reporting grade 3 or 4 AEs, ART-modifying events or notable events.
*notable events are pregnancy, suspected case of drug induced liver injury, ABC hypersensitivity reactions, suicidal ideation or
behaviours, COVID‐19 test positive and suspected or probable COVID‐19 infection.
5. ANALYSIS PRINCIPLES
The two arms of the trial will be compared as randomised according to the intent-to-treat principle. Any participant
randomised in a wrong stratum will be included in their incorrect stratum as randomised. Analyses of the main trial
population will be performed across the whole trial population and for ODYSSEY A and B separately. Comparisons of
endpoints will be undertaken adjusted for stratification factors (see 4.7) and adjusted for ODYSSEY A versus B.
Interactions between treatment arm and ODYSSEY A/ODYSSEY B strata will be tested and reported. Irrespective of

the presence of an interaction effect, results will be presented in ODYSSEY A and B and in the total population for
all outcomes.
Analyses of participants randomised <14kg and the whole trial population (< and ≥14kg) will follow the same
principles, with adjustment for stratification factors as described under 4.7, and additional unadjusted analyses in
participants <14kg. Bayesian estimation will be used in analysis of participants <14kg, incorporating evidence
obtained from the ≥14kg participants as a prior distribution. Clinical opinion will be elicited on the relative weight to
be allocated to the prior distribution. The Bayesian analysis will be reported alongside frequentist analyses of the
<14kg participants and of the whole trial population (< and ≥14kg). If less than 80% of clinicians choose weights
within a 30% absolute range, the Bayesian analysis will be reported as a secondary analysis and the frequentist
analysis of the <14kg participants will be the primary analysis.
Analysis of the primary outcome is described under 6.6. Otherwise, descriptive statistics will be reported overall and
by randomised group, and percentages will be of non-missing values, with the number (%) of non-missing values
given if data are not complete. Statistical tests will be 2-sided and estimates will be presented with a 2-sided 95%
CI. Appropriate transformations for all variables will be applied after inspection of the data.
Time-to-event outcomes will consider time from randomisation to the event date, using Kaplan-Meier estimation.
Differences between groups in time-to-event outcomes will be tested using a stratified log-rank test and stratified
Cox proportional hazard regression models. All hazard ratios or estimates of differences between groups will be
presented with a 2-sided 95% confidence interval.
For the analysis of continuous variables, the following will be presented: by scheduled visits, the number of
participants with a measurement and the mean and standard error. Changes from baseline in each randomised group
at scheduled visits will be calculated using normal regression of absolute values (with 2-sided 95% confidence
intervals), adjusting for the baseline measurement and stratification factors. Tests for the difference between
randomised arms at each study visit will be presented. Average treatment differences through follow-up will be
estimated with 2-sided 95% confidence intervals by fitting mixed linear models with random effects for intercept and
fixed effects for treatment assignment and adjustment covariates. The mean (or median for skewed variables)
change from baseline over time will also be plotted across scheduled visits by randomised group.
Differences between treatment groups in binary outcome variables within ODYSSEY A and B strata will be tested
using Chi-squared tests or Fisher’s exact tests as appropriate; differences between treatment groups within the total
trial population will be tested using the Mantel-Haenszel Chi-squared test stratified by ODYSSEY A versus ODYSSEY
B. Logistic regression models will be used for analyses adjusting for all stratification factors (presented with 2-sided
95% CI).
HIV-related events and AEs will be tabulated by event type and body system. The total number of events and the
number of participants with at least one event will be given. Randomised groups will be compared in terms of time
to first event. Event rates (per 100 person years) will be calculated as the number of events/total person years at
risk*100 (presented with 2-sided 95%CI). Multiple events will be compared between randomised groups using
Poisson regression models adjusted for clustering within individuals.
Percentages will be reported to 0 decimal places, unless <0.5% when they will be given to one decimal place. P-
values will be given to 2 significant figures.
There will be no formal adjustment of α-values because of any interim analyses performed for IDMC meetings.
Interim analysis will use early stopping guidelines and with the expected number of interim analyses, adjustment
would make little difference in alpha.
6. ANALYSIS DETAILS
All descriptive and analytic statistics will be reported in the total population and separately for ODYSSEY A and B.
6.1 Enrolment and Eligibility

Numbers screened, randomised, not randomised including tabulation of reason for non-randomisation
Details of major and minor ineligibility and number excluded from analysis: number (%)
Enrolment by arm and A/B strata: number (%)
Enrolment by country and site: number (%)
Enrolment by stratification factors: number (%)
6.2 Baseline Characteristics
Baseline characteristics will be summarised using descriptive statistics. No statistical tests will be used to compare
treatment arms.
Demographics
Sex: number (%), male, female
Age at last birthday (years): number of patients, missing, mean, SD, median, IQR, range
Age at last birthday (years)*: number(%), 0-<2/2-<6/6-<12/ 12-<18 years
Weight (kg): number of patients, missing, mean, SD, median, IQR, range
Weight (kg)*: number(%), <14kg, 14- <20kg, 20- <25kg, 25-<30kg, 30-40kg, >40kg
Height (cm): number of patients, missing, mean, SD, median, IQR, range
BMI (kg/m2): number of patients, missing, mean, SD, median, IQR, range
Weight-for-age: median (IQR), range, number (%) in categories (<-3, -3 to <-2, -2 to <0, ≥0), missing
Height-for-age: median (IQR), range, number (%) in categories (<-3, -3 to <-2, -2 to <0, ≥0), missing
BMI-for-age: median (IQR), range, number (%) in categories (<-3, -3 to <-2, -2 to <0, ≥0), missing
MUAC (cm): number of patients, missing, mean, SD, median, IQR, range
Mode of infection: number (%), mother to child/blood product/sexual contact/ unknown/other
Ethnic origin: number (%), white/black/mixed-black+white/asian/other
EQ5D categories- mobility, self-care, usual activities, pain/discomfort, anxiety: number of patients, missing,
median, IQR, range
EQ5D Visual Scale: number of patients, missing, mean, SD, median, IQR
*more groupings may be added as required
HIV related parameters

CD4%: number of patients, missing, mean, SD, median, IQR, range
CD4%: number(%),<10%/10-<15%/15<20%/20-<25%/25-<30%/30-<40%/≥40%
CD4 absolute: number of patients, missing, mean, SD, median, IQR, range
CD4 absolute: number(%), <50/50-<100/100-<200/200-<350/350-<500/500-<1,000/1,000-
<1,500/≥1,500
CD8%: number of patients, missing, mean, SD, median, IQR, range
CD8 absolute: number of patients, missing, mean, SD, median, IQR, range
CD4/CD8 ratio: number of patients, missing, mean, SD, median, IQR, range
Log10 Viral load: number of patients, missing, mean, SD, median, IQR, range
Viral load: number (%), <400/400-<1,000/1,000-<10,000/10,000-<50,000/50,000-<100,000/100,000-
<1,000,000/≥1,000,000
History of WHO staging: number (%), 1/2/3/4
Current or past WHO 3 or 4 events: number of events [number of children] categorised by event type
Pubertal status
Tanner score, pubic hair: mean, SD, median, IQR, number (%): 1, 2, 3, 4, 5
Tanner score, female breasts: mean, SD, median, IQR, number (%): 1, 2, 3, 4, 5
Tanner score, male genitalia: mean, SD, median, IQR, number (%): 1, 2, 3, 4, 5
Laboratory data
White cell count: number of patients, missing, mean, SD, median, IQR, range
Haemoglobin: number of patients, missing, mean, SD, median, IQR, range
MCV: number of patients, missing, mean, SD, median, IQR, range
Platelets: number of patients, missing, mean, SD, median, IQR, range

Neutrophils: number of patients, missing, mean, SD, median, IQR, range
Lymphocytes: number of patients, missing, mean, SD, median, IQR, range
Creatinine: number of patients, missing, mean, SD, median, IQR, range
Total Bilirubin: number of patients, missing, mean, SD, median, IQR, range
Aspartate transaminase number of patients, missing, mean, SD, median, IQR, range
Alanine transaminase: number of patients, missing, mean, SD, median, IQR, range
Alkaline phosphatase: number of patients, missing, mean, SD, median, IQR, range
Calcium: number of patients, missing, mean, SD, median, IQR, range
Phosphate: number of patients, missing, mean, SD, median, IQR, range
Glucose: number of patients, missing, mean, SD, median, IQR, range
Triglycerides: number of patients, missing, mean, SD, median, IQR, range
LDL Cholesterol: number of patients, missing, mean, SD, median, IQR, range
HDL Cholesterol: number of patients, missing, mean, SD, median, IQR, range
Total Cholesterol: number of patients, missing, mean, SD, median, IQR, range
Urine protein: number (%) negative, trace, +, ++, +++, ++++, missing
Urine glucose: number (%) negative, trace, +, ++, +++, ++++, missing
Adherence [in ODYSSEY B Only]

Adherence at baseline, as recorded on the Adherence Questionnaire Form, will be summarised using
frequency tables and summary statistics.
Antiretroviral exposure [in ODYSSEY B Only]

Number of different drugs ever received excluding in-utero/perinatal ART exposure: median [range], All
classes/NRTI/PI/NNRTI /INSTI
Number of ODYSSEY B participants exposed to ART classes: number (%), NRTIs+NNRTIs+PIs+INSTIs/
NRTIs+NNRTIs+INSTIs only/ NRTIs+NNRTIs+PIs only /NRTIs + NNRTIs only/ NRTIs + PIs only/ NRTIs
+ INSTIs only/ NRTIs /monotherapy
Cumulative ART exposure (years): median [range], All classes/NRTI/PI/NNRTI
ART regimen prior to randomisation: number (%), NNRTI + NRTIs, bPI +NRTIs, regimen combinations
>10% will also be described
6.3 Follow-Up
Description of follow-up to trial censoring date: distribution of time from randomisation to latest follow up
(defined as date last known to be alive) in weeks, median (IQR), range
Number of patients who have died and who are confirmed as having withdrawn consent. At interim
analyses, number (%) of patients last seen in 0-12 weeks, 12-24 weeks, 24-36 weeks, 36-48 weeks and
>48 weeks prior to data freeze date, number potentially lost to follow-up (either confirmed as withdrawn or
not seen for >24 weeks). At end of trial, number (%) of patients who did not have a face-to-face visit
on/after 24th April 2020 visit; number (%) of patients who did not have a face-to-face visit on/after 24th
April 2020 and primary endpoint status is unknown, number (%) of patients (who did not have a face-to-
face visit on/after 24th April 2020) seen in 0-12 weeks, 12-24 weeks, 24-36 weeks, 36-48 weeks and >48
weeks prior to trial censoring date.
Summary of attendance at the end of randomised phase visit
Number (percentage) of scheduled study visits attended, overall and by assessment week
6.4 Antiretroviral Therapy Received
ART prescribed at randomisation: distribution of time from randomisation to prescription in days, same day,
1-3, 4-14, >14, range; reasons for gap of >14 days
Initial ODYSSEY regimen: number (%) by NRTI backbone and third agent component of regimen. Number
(%) not starting ART, starting non-protocolled ART, starting allocated regimen
Tabulation of substitutions and changes to ART regimen: number (%) on strict initial regimen, initial
regimen with substitutions, median number of substitutions, IQR, % of follow-up time spent on strict initial
or initial regimen with substitution. Number (%) changed from initial regimen: for toxicity, for treatment
failure, for pregnancy.

List of substitutions and changes in initial treatment regimen: Trial No., A/B Strata, Arm, Week, regimen
before, regimen after, reason for substitution or change
Time from randomisation to change in third agent for toxicity, failure or pregnancy will be assessed using a
log-rank test and Cox proportional hazard regression models (stratified by the stratification factors). A
hazard ratio will be presented with a 2-sided 95% confidence interval. This analysis will be done provided
there are >15 events in total.
6.5 Availability of HIV-1 RNA Measurements
Tabulation of available HIV-1 RNA measurement by visit week: number (%), available/missing.
6.6 Primary Efficacy Outcome
The primary outcome will be assessed by time to clinical or virological failure (section 2.1) (ODYSSEY A and B
combined) using Kaplan Meier curves to estimate the proportion of children failing in each arm at any time up to the
week 96 censoring date (96weeks from date of randomisation). The primary analysis will adjust for stratification
factors as described under 4.7. Secondary analyses will be done adjusting for ODYSSEY A versus B strata only. The
survival curve for each combination of strata and randomised group will be calculated using a Cox model adjusting
for stratification factors and randomised group. The average survival curve for each randomised group will be
estimated as a weighted average of the corresponding stratum-specific survival curves, with weights proportional to
the number of individuals in each stratum in the randomised group at baseline. The mean of these differences at
week 96 is the point estimate for the difference in overall survival function between DTG and SOC arm. A two sided
bias-corrected 95% CI for the difference in proportion (DTG – SOC) will be calculated with bootstrap standard errors.
Bootstrap standard errors for the risk difference will be used so that the CI of the risk difference (estimated by the
risk difference ±1.96se assuming the bootstrap distribution is approximately Normal) is bounded between -1 and
13.3 The bootstrapping will sample 1000 times and be stratified by stratification factors.
If the upper limit of the confidence interval is <10% DTG+2NRTIs will be considered non-inferior to SOC.
Secondary analyses will summarise the rate of the composite primary endpoint per 100 person years by randomised
group, a treatment HR (DTG-regimen relative to SOC-regimen) estimated by a Cox proportional hazards regression
model.
6.6.1 Sensitivity analyses for the primary endpoint

The following sensitivity analyses will be performed:
i. Restricted to the per protocol population.
ii. Excluding participants in the SOC arm who initiated ODYSSEY treatment on an integrase inhibitor.
iii. Restricted to the per protocol population (as in (i)) and excluding participants in the SOC arm who initiated
ODYSSEY treatment on an integrase inhibitor (as in (ii)).
iv. Censoring participants who have one unconfirmed HIV RNA ≥ 400 c/ml, with a treatment switch for failure
before a confirmatory HIV RNA ≥ 400 c/ml, at the first HIV RNA ≥ 400 c/ml; and censoring participants
who switched treatment for failure without reaching the primary endpoint, at time of switch.
v. Using actual dates of confirmatory viral loads (or switch for treatment failure) for date of failure.
vi. Using the date of the first VL ≥400 c/ml at or after 36 weeks for date of failure.
vii. Adjusting for calendar time corresponding to any major changes in eligibility criteria (recruitment to younger
age-groups/lower weight bands).
6.6.2 Subgroup analyses for the primary endpoint

Subgroup analyses will be performed to assess heterogeneity in differences between randomised groups according
to:
Sex
Age groups
Weight bands
Baseline HIV RNA
Baseline CD4 percent
Routine availability at site of resistance tests for children failing treatment

NRTI backbone
bPI vs non-bPI SOC regimens (if sufficient data)
6.7 Secondary Efficacy Analyses
Difference in proportion with clinical or virological failure (as defined using primary
outcome definition) by 48 weeks
The difference in the proportion of participants with clinical or virological failure by 48 weeks will be analysed in the
same way as by 96 weeks. See ‘Primary Efficacy Analysis’ for further details.

Participants with VL<50 (or <400) c/ml at 48 and 96 weeks will be compared between arms based on (i) crude
proportions and (ii) using the FDA snapshot algorithm2. The estimated difference in the proportion of suppressed
patients at weeks 48 and 96 weeks will be provided with 95% confidence interval; in the total population this will be
estimated by the Mantel-Haenszel weighted mean of proportions in ODYSSEY A and B. The Chi-squared test, Fisher’s
exact test or Mantel-Haenszel Chi-squared test will be use to assess differences between arms. Logistic regression
will be used for analyses adjusting for all stratification factors.
Rate of clinical events (WHO 4, severe WHO 3 events and death) over 96 weeks
The number of clinical events occurring during follow-up will then be tabulated by number (%) of events/people for
each clinical event separately and for one or more event. The number of children with at least one event will be
compared between arms using the Chi-squared test, Fisher’s exact test or Mantel-Haenszel Chi-squared test (as
appropriate). Logistic regression will be used for analyses adjusting for all stratification factors. Event rates will be
calculated as the number of events/total person years at risk*100 and will be reported per 100 person years including
95% CI. Poisson regression will be used to calculate the incidence rate ratios of clinical events in the DTG arm versus
SOC arm adjusted for clustering of events by individuals. The rate ratio will be given along with the 95% CI and p-
value. Hazard ratios for first events will also be calculated using Cox proportional hazard regression models.
Time to any new or recurrent AIDS defining event (WHO 4) or severe WHO 3 events confirmed by
Endpoint Review Committee
Follow-up time will be summarised and number (%) of first events will be tabulated for WHO 4 and severe WHO 3
events. Randomised groups will be compared in terms of time to first event using a log-rank test and Cox proportional
hazard regression models (stratified by the stratification factors). A hazard ratio will be presented with a 2-sided
95% confidence interval. Event rates will be calculated as the number of first events/total person years at risk*100
and will be reported per 100 person years including 95% confidence intervals.
Changes in CD4 (absolute and percentage) and CD4/CD8 ratio from baseline will be reported by scheduled visit
week. The overall baseline mean will be calculated using all those with a CD4% or CD4 absolute measurement at
baseline. Change from baseline to each of the scheduled follow-up visit weeks will be calculated using normal
regression adjusting for baseline and ODYSSEY A versus ODYSSEY B. An additional adjusted analysis will be
performed adjusting for baseline and stratification factors.
For each of the scheduled follow-up visit weeks the following will be reported:
Change from baseline, by arm: mean (SE)
Unadjusted (i.e. only adjusting for baseline and A/B strata) difference between the two arms: mean (SE),
p-value.
Adjusted (i.e. adjusting for baseline and stratification factors) difference between the two arms: mean
(SE), 95% CI, p-value.
For each analysis, a graph showing the change from baseline by week including 95% CI will be presented.
Average treatment differences through follow-up will be estimated with 2-sided 95% confidence intervals by fitting
linear mixed models with random effect for intercept and fixed effects for treatment assignment, post-randomisation
study visits and adjustment covariates (baseline level of the outcome variable and the stratification factors used in
the randomisation).
Proportion developing new resistance mutations (see Section 4.8 for definitions)
The number and % of participants with new resistance mutations by type of mutation will be described in participants
who have reached a virological component of the primary endpoint. The proportion of participants developing new
resistance mutations will be compared between arms using the Chi-squared test, Fisher’s exact test or Mantel-
Haenszel Chi-squared test, as appropriate. Logistic regression will be used for analyses adjusting for all stratification
factors. 95% confidence interval for the difference in proportion will be provided.
A walk back approach will be used to describe development of resistance from baseline.
6.8 Secondary Safety Outcomes
The following safety outcomes will be examined:
Change in total cholesterol, triglycerides and lipid fractions (LDL, HDL, total cholesterol/HDL ratio,
non-HDL) from baseline to weeks 48 and 96
For each measurement, changes from baseline will be reported by scheduled visit week. The overall baseline mean
will be calculated using all those with a measurement at baseline. Change from baseline to each of the scheduled
follow-up visit weeks will be calculated using normal regression adjusting for baseline and ODYSSEY A versus
ODYSSEY B. An additional adjusted analysis will be performed adjusting for baseline and stratification factors.
For each of the scheduled follow-up visit weeks the following will be reported:
Change from baseline, by arm: mean (SE)
Unadjusted (i.e. only adjusting for baseline and A/B strata) difference between the two arms: mean (SE),
p-value.
Adjusted (i.e. adjusting for baseline and stratification factors) difference between the two arms: mean
(SE), 95% CI, p-value.
For each analysis, a graph showing the change from baseline by week including 95% CI will be presented.
Average treatment differences through follow-up will be estimated with 2-sided 95% confidence intervals by fitting
linear mixed models with random effect for intercept and fixed effects for treatment assignment, post-randomisation
study visits and adjustment covariates (baseline level of the outcome variable and the stratification factors used in
the randomisation).
The secondary endpoints of change in total cholesterol, triglycerides and lipid fractions (LDL, HDL) will be assessed
for superiority of DTG compared to SOC. Superiority will be regarded as proven if the mean adjusted change in total
cholesterol at 96 weeks is lower in the DTG arm and the P value is <0.05.

The number (%) of events/people will be tabulated for each clinical event separately and for one or more event. The
number of children with at least one event will be compared between arms using the Chi-squared test, Fisher’s exact
test or Mantel-Haenszel Chi-squared test (as appropriate). Logistic regression will be used for analyses adjusting for
all stratification factors. Event rates will be calculated as the number of events/total person years at risk*100 and
will be reported per 100 person years including 95% CI. Poisson regression will be used to calculate the incidence
rate ratios of clinical events in the DTG arm versus SOC arm adjusted for clustering of events by individuals. The
rate ratio will be given along with the 95% CI and p-value. Hazard ratios for first events will also be calculated using
Cox proportional hazard regression models.

6.9 Other Secondary Outcomes
Quality of life
A descriptive analysis of each dimension of the EQ5D will also be undertaken at each study visit.

Carer completed and patient completed adherence and acceptability questionnaires will be analysed separately. A
descriptive analysis of adherence questionnaire will be done. The proportion of questionnaires where the
participant/carer reports missing a dose within the last week will be compared between randomised groups.
6.10 Other Outcomes
Change in biochemistry and haematology measures

Analysis of the change in biochemistry and haematology measures will be undertaken in the same way as changes
in metabolic parameters; please see “Change in total cholesterol, triglycerides and lipid fractions (LDL, HDL) from
baseline to weeks 48 and 96”.
Change in growth measures

Analysis of the change in height, weight, body mass index (BMI), and mid upper arm circumference (MUAC) will be
undertaken in the same way as changes in metabolic parameters; please see “Change in total cholesterol,
triglycerides and lipid fractions (LDL, HDL) from baseline to weeks 48 and 96”.
Incidence of notable events* or immune reconstitution inflammatory syndrome (IRIS), examined

separately.
Analysis of the incidence of notable events or IRIS will be undertaken in the same way as other events; please see
“Incidence of serious adverse events”. We will also examine incidence of IRIS in a subgroup analysis by baseline
CD4 count (≥ vs. < 200 cells per µL).
*notable events are pregnancy, suspected case of drug induced liver injury, ABC hypersensitivity reactions, suicidal ideation or
behaviours, COVID‐19 test positive and suspected or probable COVID‐19 infection.
Incidence of newly diagnosed or worsening lipodystrophy

Follow-up time will be summarised and number (%) of first events will be tabulated. Randomised groups will be
compared in terms of time to first event using a log-rank test and Cox proportional hazard regression models
(stratified by the stratification factors). A hazard ratio will be presented with a 2-sided 95% confidence interval.
Event rates will be calculated as the number of first events/total person years at risk*100 and will be reported per
100 person years including 95% confidence intervals.
Change in sleep and mood questionnaire

Carer completed and patient completed mood and sleep questionnaires will be analysed separately. For mood
symptoms, the proportion of questionnaires where the participant or carer reports a symptom will be compared
between arms over time using logistic mixed models with random effect for intercept and fixed effects for treatment
assignment, post-randomisation study visits and adjustment covariates if any (total adjusted for A and B stratification,
no adjustment in A and B). For sleep symptoms, ordinal logistic mixed models will be used to compare outcomes
across treatment arms over time with a random effect for intercept and fixed effects for treatment arm, study visits
and adjustment covariates if any (total adjusted for A and B stratification, no adjustment in A and B). Analyses will
not be adjusted for baseline levels as questionnaires were implemented after the trial had starting and a baseline
questionnaire is missing in many participants.
Descriptive outcomes in participants switching to DTG as third-line

Viral loads and clinical events in participants who experience treatment failure on second-line ART and subsequently
changed to dolutegravir-based regimen for third-line will be described.

6.11 Testing multiple outcomes
We will make no adjustment to p-values or confidence intervals to allow for testing multiple secondary outcomes.
The ODYSSEY primary outcome is a composite outcome of virological failure, clinical events (WHO 4 and severe
WHO 3 events) and death. The primary analysis is non-inferiority of DTG versus SOC. If the 95% CI for the
treatment effect (difference in proportion failing by 96 weeks (DTG-SOC)) lies below the non-inferiority margin,
then we will also test for superiority; because this is a closed test procedure there is no issue of multiplicity.
Secondary outcomes are divided in the protocol into efficacy outcomes, safety outcomes and other patient-
reported outcomes. For safety outcomes it is appropriate to test each independently since it is important to identify
any risks associated with DTG. Change in total cholesterol from baseline to week 96 has been defined as the
primary safety outcome for the assessment of superiority of DTG versus SOC.
The secondary efficacy outcomes are mostly components of the primary outcome or very closely related to the
primary outcome (virological and clinical outcomes). We will not adjust for multiple testing for these since they are
correlated with the primary outcome (so standard adjustments are conservative). Resistance and immunological
outcomes are considered exploratory and significance tests on these outcomes alone will not be used to conclude
superiority.
We will report significance tests for differences between treatment arms for patient-reported outcomes, but if we
have failed to demonstrate non-inferiority of DTG versus SOC for the primary outcome, we will not use significance
tests for these patient-reported outcomes to conclude superiority.
7. SUBGROUP ANALYSES
7.1 Analyses by Dose and Weight-band

Safety, tolerability and efficacy outcomes will also be examined by time-updated DTG dose and weight band.
8. ANCILLARY STUDIES AND SUBSTUDIES

The following substudies will be conducted in subsets of participants:
Pharmacokinetic substudy to examine DTG dosing in children <40kg
(Lower WB-PK, WB-PK1 and WB-PK2)Pharmacokinetic substudy in participants developing TB (TB-PK)
Immunology/virology substudy
Qualitative substudy
Youth Trial Board Project
Further details on these ancillary studies and substudies are given in the appendices of the trial protocol. Analysis
plans will be developed in separate documents.
PK and accompanying safety data on PK participants in the DTG arm are being analysed to support the ViiV
submission for FDA and EMA licensing of DTG dosing in children <40kg. A separate RAP (reporting and analysis plan)
will be prepared.

REFERENCES
1. Parienti J-J, Verdon R, Massari V. Methodological standards in non-inferiority AIDS

trials: moving from adherence to compliance. BMC Medical Research Methodology.
2006;6(1):46.
2. Food Drug Administration Center for Drugs Evaluation Research. Human
Immunodeficiency Virus-1 Infection: Developing Antiretroviral Drugs for Treatment -
Guidance for Industry. In. Maryland, USA: FDA; 2015.
3. Carpenter J, Bithell J. Bootstrap confidence intervals: when, which, what? A practical
guide for medical statisticians. Statistics in medicine. 2000;19(9):1141-1164.

APPENDIX I
Table 1. ADAPTED WHO CLINICAL STAGING OF HIV/AIDS FOR PATIENTS WITH CONFIRMED HIV INFECTION
Unexplained moderate malnutrition or wasting not

adequately responding to standard therapy* Unexplained severe weight loss (>10% of
Unexplained persistent diarrhoea (14 days or more) presumed or measured body weight)*
Unexplained persistent fever (above 37.5°C Unexplained chronic diarrhoea for longer than one
intermittent or constant, month
for longer than one month) Unexplained persistent fever (above 37.6°C
Persistent oral candidiasis (after first 6–8 weeks of intermittent or constant,
life)* for longer than one month)
Oral hairy leukoplakia Persistent oral candidiasis*
Acute necrotizing ulcerative gingivitis or Oral hairy leukoplakia
periodontitis Pulmonary tuberculosis (current)
Lymph node tuberculosis Severe bacterial infections (such as pneumonia,
Pulmonary tuberculosis empyema, pyomyositis,
Severe recurrent bacterial pneumonia bone or joint infection, meningitis or bacteraemia)
Symptomatic lymphoid interstitial pneumonitis* Acute necrotizing ulcerative stomatitis, gingivitis or
Chronic HIV-associated lung disease including periodontitis
bronchiectasis* Unexplained anaemia (<8 g/dl), neutropaenia
Unexplained anaemia (<8 g/dl), neutropaenia (<0.5 × 109 per litre) or chronic
(<0.5 × 109 per litre)and or chronic thrombocytopaenia (<50 × 109 per litre)
thrombocytopaenia (<50 × 109 per litre)
Clinical Stage 4
Unexplained severe wasting, stunting or severe

HIV wasting syndrome
malnutrition not responding to standard therapy
Pneumocystis pneumonia
Pneumocystis pneumonia
Recurrent severe bacterial pneumonia
Recurrent severe bacterial infections (such as
Chronic herpes simplex infection (orolabial, genital
empyema, pyomyositis, bone or joint infection or
or anorectal
meningitis but excluding pneumonia)
of more than one month’s duration or visceral at
Chronic herpes simplex infection (orolabial or
any site)
cutaneous of more than one month’s duration or
Oesophageal candidiasis (or candidiasis of trachea,
visceral at any site)
bronchi or lungs)
Oesophageal candidiasis (or candidiasis of trachea,
Extrapulmonary tuberculosis
bronchi or lungs)
Kaposi’s sarcoma
Extrapulmonary tuberculosis
Cytomegalovirus infection (retinitis or infection of
Kaposi’s sarcoma
other organs)
Cytomegalovirus infection: retinitis or
Central nervous system toxoplasmosis
cytomegalovirus infection affecting another organ,
HIV encephalopathy
with onset at age older than one month
Extrapulmonary cryptococcosis including meningitis
Central nervous system toxoplasmosis (after one
Disseminated non-tuberculous mycobacterial
month of life)
infection
Extrapulmonary cryptococcosis (including
Progressive multifocal leukoencephalopathy
meningitis)
Chronic cryptosporidiosis (with diarrhoea)
HIV encephalopathy
Chronic isosporiasis
Disseminated endemic mycosis (coccidiomycosis or
Disseminated mycosis (coccidiomycosis or
histoplasmosis)
histoplasmosis)
Disseminated non-tuberculous mycobacterial
Recurrent non-typhoidal Salmonella bacteraemia
infection
Lymphoma (cerebral or B-cell non-Hodgkin) or
Chronic cryptosporidiosis (with diarrhoea)
other solid HIV-associated tumours
Chronic isosporiasis
Invasive cervical carcinoma
Cerebral or B-cell non-Hodgkin lymphoma
Atypical disseminated leishmaniasis
Progressive multifocal leukoencephalopathy
Symptomatic HIV-associated nephropathy or
Symptomatic HIV-associated nephropathy or HIV-
symptomatic HIV-associated cardiomyopathy
associated cardiomyopathy

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Protocol

This supplement contains the following items:

2. Original protocol (version 2.0)

4. Original statistical analysis plan (version 1.0)

Name: Professor Ian Weller

Date: 8th November 2019

Name: Professor Carlo Giaquinto

Date: 11th November 2019

ODYSSEY (PENTA 20) Page ii

Professor Diana M Gibb, MRC CTU at UCL, London, UK

AUTHORISATIONS AND APPROVALS

Inserm-ANRS, Monday to Friday 09:00 to 17:00

PHPT, Monday to Friday 09:00 to 18:00

MRC CTU: fax: +44 (0) 20 7670 4814 or email: mrcctu.trial-odyssey@ucl.ac.uk

Inserm-ANRS: fax: + 33 1 46 58 72 93 or email: penta.sc10@inserm.fr

PHPT: fax: +66 53 240 913 or email: suwalai.chalermpantmetagul@phpt.org

ODYSSEY (PENTA 20) Page iii

PENTA FOUNDATION, ITALY: PENTA Foundation

ODYSSEY (PENTA 20) Page iv

TRIAL ADMINISTRATION AND MAIN CONTACTS

MRC CTU, UK: MRC CTU at UCL

ODYSSEY (PENTA 20) Page v

P.O. Box 114, Diepkloof, 1864, Soweto, South

Perinatal HIV Research Unit, Klerksdorp/Tsepong

Ward D1, Wentworth Hospital, Sidmouth Avenue

INSERM-ANRS, FRANCE: 16 Avenue Paul Vaillant Couturier

PHPT, THAILAND: PHPT/IRD

ODYSSEY (PENTA 20) Page vi

IMPAACT, US: IMPAACT Operations Center

Protocol expert: Pharmacology

Other members to be confirmed

ODYSSEY (PENTA 20) Page vii

SUMMARY INFORMATION TYPE SUMMARY DETAILS

ODYSSEY (PENTA 20) Page viii

Change in total cholesterol, triglycerides and lipid fractions (LDL,

ODYSSEY (PENTA 20) Page ix

ANRS (France) respectively; INSERM-ANRS supports the trial in France;

ODYSSEY (PENTA 20) Page x

ODYSSEY (PENTA 20) Page xi

TRIAL ASSESSMENT SCHEDULE FOR RANDOMISED PHASE OF THE TRIAL

ODYSSEY (PENTA 20) Page xii

ODYSSEY (PENTA 20) Page xiii

ODYSSEY (PENTA 20) Page xiv

GENERAL INFORMATION .............................................................................................................. II

SUMMARY OF TRIAL ................................................................................................................. VIII

TRIAL SCHEMA ........................................................................................................................... 11

TRIAL ASSESSMENT SCHEDULE FOR RANDOMISED PHASE OF THE TRIAL ...................................... 12

3 SELECTION OF PATIENTS ................................................................................................. 30

4 REGISTRATION & RANDOMISATION ............................................................................... 34

5 TREATMENT OF PATIENTS .............................................................................................. 36

ODYSSEY (PENTA 20) Page 15 of 324

5.3.1 DTG ........................................................................................................................................... 40

6 ASSESSMENTS & FOLLOW-UP ......................................................................................... 47

7 SAFETY REPORTING ........................................................................................................ 56

8 QUALITY ASSURANCE & CONTROL .................................................................................. 63

9 STATISTICAL CONSIDERATIONS ....................................................................................... 65

ODYSSEY (PENTA 20) Page 16 of 324

9.2 OUTCOME MEASURES ......................................................................................................... 65

10 ANCILLARY STUDIES ....................................................................................................... 68