Clinical Trials and Trial Design

Punnee Pitisuttithum, MBBS,DTM&H,FRCPT Faculty of Tropical Medicine, Mahidol University AIDSVACCINE Conference ,BKK Sept 13,2011

Ongoing Trials of New HIV Prevention Options worldwide

www.avac.org (May 2009)

Working on the Puzzle of Vaccine Induced Protection

HIV vaccine constructs

Recombinant protein (gp120) synthetic peptides (V3) naked DNA

Live-recombinant vectors virus-Ad5, Ad26, MVA,NYVAC Bacteria-rBCG

Whole-inactivated virus
Live-attenuated virus

Cumulative Vaccine Efficacy Over Time

Randomized, Double Blind Evaluation of Late Boost Strategies for HIV-uninfected Participants in the HIV Vaccine Efficacy Trial RV 144: Aventis Pasteur* Live Recombinant ALVAC-HIV (vCP1521) Priming with VaxGen**gp120 B/E (AIDSVAX B/E) Boosting in HIV-uninfected Thai Adults

Punnee Pitisuttithum MD,FRCPT Mahidol University

Primary Objective
Characterize and compare cellular and humoral responses in the systemic and mucosal compartments following late boosts for each strategy tested Assess the safety and tolerability of late boost regimens consisting of the RV144 combination of regimen or one component of the combination (AIDSVAX B/E or ALVAC-HIV)

Secondary Objective
Evaluate mucosal immune responses (humoral and cellular) for each boost regimen Evaluate systemic and mucosal activation of T cell target for HIV infection for each boost regimen compare innate immune responses between each boost regimen Define the residual humoral and cellular immune response since completing the primary prime-boost series within RV144

Mode of Administration:
GROUP Number of subjects Vaccine/Placebo 0 45 I 9 ALVAC-HIV + AIDSVAX B/E ALVAC-HIV placebo + AIDSVAX placebo AIDSVAX B/E AIDSVAX placebo ALVAC-HIV Week of Study 24 ALVAC-HIV + AIDSVAX B/E ALVAC-HIV placebo + AIDSVAX placebo AIDSVAX B/E AIDSVAX placebo ALVAC-HIV

45

II

9 45

III

ALVAC-HIV placebo

ALVAC-HIV placebo

Schedule of Assessments
Visit no.
week Informed Consent Test of understanding Enrollment & Randomization Vaccination & Diary card Physical exam Medical history & Vital Signs Concomitant Medications HIV Risk Reduction Counseling (pre and/or post) Urine Pregnancy Test X X X X X X X X X X X X X X X X X X X X X X X X X X X X X X X X X X X X X X X X X X X X X X X X X

2
0

3
2

4a
24

4b

5
26

6
48

6a
50

7
72

8 Exit
74

Urine dipstick, CBC, Cr., ALT STI diagnostic tests

Pap Smear HPV tests

X X
X

Others ongoing Trials (1)

Phase Trial ID Strategy Candidate No of subject Clade

I
I I I I I I

Ad26.ENVA.01
Ad5HVR48.ENVA.01 CN54gp140-hsp70 Conjugate vaccine DCVax-001 Extention HVTN 073E/SAAVI 102 HIVIS 05 HIVIS 07

Viral Vector Adeno

Viral Vector - Adeno Protein Protein Protein DNA/Viral Vector-Pox DNA/Viral Vector-Pox

Ad26.EnvA-01
Ad5HVR48. ENVA.01 CN54gp140 DCVax-001 Sub Cgp140 HIVIS-DNA/ MVA-CMDR

48
48

A
A

24 48

Ongoing Trials (2)

Phase I I I Trial ID HPTN 027 HVRF-380-131004 HVTN 073 Strategy Viral Vector Pox Protein DNA/Viral Vector-Pox DNA/Viral VectorAdeno Viral VectorAdeno/Viral VectorAdeno/DNA Candidate ALVAC-HIV vCP1521 Vichrepol SAAVI DNAC2/SAAVI MVA-C VRC-HIVDNA 016-00-VP/ VRC-HIVADV 014-00-VP VRC-HIVADV 027-00-VP/ VRC-HIVADV 038-00-VP/ VRC-HIVDNA 044-00-VP No of subject 50 15 48 C Clade

HVTN 076

45

A,B,C

Ib

HVTN 077

192

Ongoing Trials(3)
Phase Ib Trial ID HVTN 078 Strategy Candidate No of subject 80 Clade Viral Vector NYVAC-B/VRCPox/viral HIVADV038-00Vector-Adeno VP DNA/Viral VRC-HIVDNA Vector-Adeno 016-00-VP/ VRC-HIVADV 014-00-VP Viral VectorAdeno/Viral VectorAdeno /Viral Vector-Adeno Viral VectorAdeno/Viral VectorAdeno VRC-HIVADV 038-00-VP/ VRC-HIVADV 052-00-P/VRCHIVADV027-00VP VRC-HIVADV 054-VP/VRCHIVAVD014-00VP 180 A,B

HVTN 082

HVTN 083

I/II

HVTN 084

Ongoing Trials (4)

Phase I Trial ID HVTN 086, SAAVI 103 Strategy Viral Vector Pox/DNA/ Protein DNA/Viral Vector-Pox DNA/Viral VectorAdeno Candidate SAAVI MVA-C/ SAAVI DNAC2/Oligomeric gp140/MF59 pGA2/JS7 DNA/MVA/ HIV62 VRC-HIVDNA 016-00-VP/ VRC-HIVADV 014-00-VP No of subject 184 Clade

IIa

HVTN 205

225

II

HVTN 505

2,200

IAVI B001

Viral Vector- Ad35-GRIN/ Adeno/Viral ENV/Ad35VectorGRIN/ENV Adeno

56

Ongoing Trials (5)

Phase I Trial ID IAVI B002 Strategy Protein/ Protein/ Viral Vector Adeno Candidate Adjuvanted GSK investigational HIV vaccine fomulation 1 / Adjuvanted GSK investigational HIV vaccine fomulation 2/ Ad35-GRIN No of subject 140 Clade

IAVI B003

Viral Vector- Ad26.EnvAAdeno/Viral 01/Ad35-ENV VectorAdeno

Viral Vector- Measles Replicating Vector-GSK

212

MV1-F4

Ongoing Trials (6)

Phase I/II Trial ID NCHECR-AE1 Strategy DNA/Viral Vector-Pox Candidate pHIS-HIVAE/rFPV-HIVAE No of subject 8 Clade

PedVacc001& PedVacc002

Viral Vector- MVA.HIVA Pox

48

RV138; B011

Viral Vector- ALVAC-HIV Pox MN120TMG strain (vCP205)

DNA/Viral Vector-Pox Pennvax-G/ MVA-CMDR

36

RV 262

92

A,B,C, D,E

I
I

TAMOVAC-01-MZ
Three Russian HIV Vaccines

DNA/Viral Vector-Pox

HIVIS-DNA/ MVA-CMDR

24
21

Ongoing Trials (7)

Phase I Trial ID Tiantian vaccinia HIV Vaccine VRC 012 (07-10167) Strategy DNA / Viral VectorReplicating Viral VectorAdeno/Viral VectorAdeno Candidate Chinese DNA / Tiantian vaccinia VRC-HIVADV 027-00-VP/ VRCHIVADV03800-VP No of subject 80 Clade

35

VRC 015 (08-10171) VRC 016

Viral Vector- VRCAdeno HIVADV01400-VP DNA/Viral VectorAdeno VRC-HIVDMA 016-00-VP/ VRC-HIVADV 014-00-VP

31

A,B,C

24

Trial Design: Why are Phase IIb trials an important step in evaluating AIDS vaccine?
Phase I,II trials involve a small number of volunteers Safety and immunogenicity of vaccine The phase III trials require large numbers of volunteer take a long time to set up and complete be the final step before a vaccine can get approval for licensure for FDA

 Vaccine being tested will be effective To be not designed to establish the efficacy The number of volunteers is smaller, only 2-5,000 volunteers Easier to design and manage and less cost
Disadvantage Phase IIb trials are run in smaller populations, the precision of the trial is less A vaccine can not be licensed based on the results of Phase IIb testing

Why are test of concept trials especially useful for AIDS vaccines?
The first Phase IIb trial of an AIDS vaccine candidate, which is being conducted by Merck and the HIV Vaccine Trials Network. MRKAd5 in approximately 3,000 volunteers. The MRKAd5 candidate primarily generates a cellular immune response US-based Merck and GlaxoSmithKline Biologicals tested their respective vaccine candidates for human papilloma virus in Phase IIb trials.

Trial Design
Adaptive Clinical Trial Design
Test multiple candidates simultaneously, Comparing to the same placebo group in a randomized, blinded, phase IIb trial to if they are able to prevent HIV infection Adaptive trials allow investigators to modify the trial while its underway More flexibility to drop candidates that dont seem to be working It would allow investigators to rank the different candidates

Adaptive Clinical Trial Design

The trials were blindedmeaning volunteers were not aware during the trial whether they had received the vaccine or the placebo Safety Monitoring Boards (DSMB) collected and analyzed safety and efficacy data at pre-specified time points during the course of the trials and could then determine whether the trials should continue or be stopped either for safety reasons or for futility The interim data indicates that a vaccine candidate is not meeting pre-determined efficacy levels

Adaptive Clinical Trial Design

Researchers have the flexibility to shrink or drop

that arm of the study while continuing the others

Instance, in a trial population with a 4% annual HIV incidence rate and 2,000 volunteers per group To be possible to reach a decision point in approximately 20 months

Adaptive Clinical Trial Design

One important caveat of adaptive clinical trial

is that they are not suitable for licensure

More frequent interim data analyses that are conducted in adaptive trials The flexibility that researchers will have to respond to the data To reduce the overall power of the study To difficult to interpret the result