PR 138 - EQL - 2008 Research Protocol - MPA Injection - Triyasa - English Informed Consent

BIOEQUIVALENCE STUDY OF 150 MG MEDROXYPROGESTERONE ACETATE
PT Equilab International
Jl. Utan Kayu Raya No. 45, Jakarta 13120 – INDONESIA
Compound : Medroxyprogesterone acetate
Research Protocol
BIOEQUIVALENCE STUDY OF 150 MG MEDROXYPROGESTERONE

ACETATE INJECTION PRODUCED BY PT TRIYASA NAGAMAS FARMA
(DEPONEO®) IN COMPARISON WITH THE INNOVATOR INJECTION
(DEPO-CLINOVIR® 150, PFIZER-GERMANY)
Equilab Project Code : PR. 138/EQL/2008
CONFIDENTIAL : All or part of information presented in this document may be unpublished material and
should be treated as the confidential property of the Sponsor, not to be divulged to unauthorized person, in
any form, including publications and presentations, without the written consent of the Sponsor and the
Investigators.
Author :
Atika Rimainar, BSc
Principal Investigator :
Danang Agung Yunaidi, MD
Final Version
Date : December 23, 2008
Sponsor : PT Triyasa Nagamas Farma

Kawasan Industri Pulogadung
Jl. Rawa Udang No. 75
Jakarta 13920 – INDONESIA
Phone +62 21 4603104, 4602233
Fax +62 21 4602232
D. 062/EQL Final version 23/12/2008 Page 1 of 42
CONFIDENTIAL
This material is the property of the Sponsor and developed by PT Equilab International.
Do not disclose or use any section of the present document except as authorized
in writing by PT Triyasa Nagamas Farma PT Equilab International.
Study Personnel and Responsibilities
Sponsor PT Triyasa Nagamas Farma

Phone +62 21 4603104, 4602233
Fax +62 21 4602232
Study Director Effi Setiawati, Pharm, MSc

Jl. Utan Kayu Raya No. 45
Phone +62 21 85911820-22
Fax +62 21 85911818
Principal Investigator & Danang Agung Yunaidi, MD

Responsible Physician PT Equilab International
Phone +62 21 85911820-22
Fax +62 21 85911818
Medical/Clinical Investigator Danang Agung Yunaidi, MD

Phone +62 21 85911820-22
Fax +62 21 85911818
Clinical Laboratory PT Equilab International

(for screening and study) Jl. Utan Kayu Raya No. 45
Phone +62 21 85911820-22
Fax +62 21 85911818
Analytical Laboratory Manager Lucia Rat Handayani, Chem

Phone +62 21 85911820-22
Fax +62 21 85911818
CONFIDENTIAL
Study Personnel and Responsibilities (cont.)
Data Management, Atika Rimainar, BSc

Pharmacokinetics, and Statistic PT Equilab International
Analysis Jakarta 13120 – INDONESIA
Phone +62 21 85911820-22
Fax +62 21 85911818
Co-Investigators Asriningtyas P.S., Pharm, BSc

Iwan Dwi Santoso, Pharm, BSc
Gunawan Harinanto, Chem
Phone +62 21 85911820-22
Fax +62 21 85911818
Study Monitor Dra. Sorta Saulina, MBA, MM

PT Triyasa Nagamas Farma
Phone +62 21 4603104, 4602233
Fax +62 21 4602232
Quality Assurance Siti Hawa Deniati, Chem, MSc

Phone +62 21 85911820-22
Fax +62 21 85911818
CONFIDENTIAL
STATEMENT OF COMPLIANCE
Bioequivalence study of 150 mg Medroxyprogesterone acetate injection

produced by PT Triyasa Nagamas Farma (Deponeo®) in comparison with the

innovator injection (Depo-Clinovir 150, Pfizer-Germany)
Author: Atika Rimainar, BSc
Principal Danang Agung Yunaidi, MD

Investigator:
Location: PT EQUILAB INTERNATIONAL

Telephone No.: +62 21 85911820-22
I, the undersigned, have reviewed this protocol, including Appendices. I will

adhere to the Ethical and Regulatory considerations stated and will perform the
study in compliance with EQUILAB’s SOPs and according to the relevant
versions of the Declaration of Helsinki and the International Conference on
Harmonisation, GCP (CPMP/ICH/135/95).
Principal Investigator Date
CONFIDENTIAL
AGREEMENT PAGE
Bioequivalence study of 150 mg Medroxyprogesterone acetate injection

produced by PT Triyasa Nagamas Farma (Deponeo®) in comparison with
the innovator injection (Depo-Clinovir® 150, Pfizer-Germany)
Approved:
Dra. Sorta Saulina, MBA, MM Date

Quality Assurance & Control Manager /
Sponsor Representative
Danang Agung Yunaidi, MD Date

Principal Investigator &
Responsible Physician
Lucia Rat Handayani, Chem Date

Analytical Laboratory Manager
Siti Hawa Deniati, Chem, MSc Date

Quality Assurance Specialist
Effi Setiawati, Pharm, MSc Date

Study Director
CONFIDENTIAL
TABLE OF CONTENTS
Page
I. PROTOCOL SUMMARY 9
II. BACKGROUND INFORMATION 12
2.1 Background 12
2.2 Physicochemical Properties 12
2.3 Pharmacology and Toxicology 12
2.4 Pharmacokinetics 13
2.5 Adverse Event 14
III. STUDY OBJECTIVE 15
IV. STUDY DESIGN 15
V. STUDY SUBJECTS 15
5.1 Number of Subjects 15
5.2 Inclusion Criteria 16
5.3 Exclusion Criteria 16
5.4 Removal of Subject from Assessment 17
VI. STUDY MEDICATIONS 17
VII. STUDY PROCEDURES 17
VIII. DRUG ASSAY 18
8.1 Analytical Method Validation 18
8.2 Plasma Preparation 18
8.3 Sample Storage 19
8.4 Assay Method 18
8.5 Quantitation 19
8.6 Quality Control 19
IX. STUDY ANALYSIS 19
9.1 Parameters of Bioavailability 19
9.2. Statistical Analysis 20
X. ADVERSE EVENTS / TOXICITY 20
10.1 Definition of an Adverse Event 20
10.2 Serious Adverse Event 21
XI. ADMINISTRATIVE ASPECTS 21
11.1 Data Recording 21
11.2 Record Retention 21
11.3 Subject Informed Consent 21
11.4 Ethics Committee 22
11.5 Modification of the Protocol 22
11.6 Drug Storage and Accountability 22
11.7 Biological Samples 22
11.8 Protocol Deviation 22
XII. STUDY TIMEFRAME 23
XIII. REFERENCES 23
LIST OF APPENDICES
Appendix A Adverse Event(s) Form 24
Appendix B Study Flow Chart 28
Appendix C Subject Information and Informed Consent Form 30
Appendix D Declaration of Helsinki 38
CONFIDENTIAL
Abbreviations
SYMBOL MEANING
µL microlitre
AE adverse event
ALT alanine aminotransferase
AP serum alkaline phosphatase
AST aspartate aminotransferase
AUC area under the plasma concentration-time curve
bpm beats per minute
BUN blood urea nitrogen
CK creatine kinase
Cmax maximum observed plasma concentration
CRF case report form
dL decilitre
ECG electrocardiogram
EDTA ethylenediaminetetraacetic acid
FUP follow up medical examination
g gram
GCP Good Clinical Practice
GLP Good Laboratory Practice
h, hr, hrs hour(s)
Hb haemoglobin
HBsAG hepatitis b surface antigen
Hct haematocrit
HCV hepatitis c virus
HIV human immunodeficiency virus
LC-MS/MS high pressure liquid chromatography tandem mass
chromatography detector
IEC Independent Ethics Committee
IRB Institutional Review Board
kg kilogram
LDH lactate dehydrogenase
LOQ limit of quantitation
m minute(s)
MCH mean cell haemoglobin
MCHC mean cell haemoglobin concentration
MCV mean cell volume
mg milligram
min(s) minute(s)
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SYMBOL MEANING
mL millilitre
mm millimetre
mmHg millimetre mercury column
ng nanogram
RBC red blood cells
s, sec second(s)
SAE serious adverse event
t½ half-life plasma
tmax time taken to reach maximum observed plasma concentration
WBC white blood cell (count)
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I. PROTOCOL SUMMARY
Study No : PR. 138/EQL/2008
Compound under investigation : Medroxyprogesterone acetate
Title :
Bioequivalence study of 150 mg Medroxyprogesterone acetate injection produced by
PT Triyasa Nagamas Farma (Deponeo®) in comparison with the innovator injection
(Depo-Clinovir® 150, Pfizer-Germany)
Objective :
To find out whether the bioavailability of PT Triyasa Nagamas Farma’s 150 mg
Medroxyprogesterone acetate injection is equivalent to that of the innovator’s product
(Depo-Clinovir® 150, Pfizer-Germany)
Principal Investigator : Danang Agung Yunaidi, MD
Study Centre :
Study Design :
This study will be conducted in a randomized, single dose, open-labelled, parallel study.
Number of Subjects :
The study will be conducted in two study groups. Each group will involve 80 healthy adult
female subjects. Thus, the total number of 160 subjects will be made available for this
parallel study. Each group will administer with study drug (test drug or reference drug) and
the blood will be taken at various time points of blood sampling procedures. For each group,
the blood samples from 70 subjects only will be analyzed for plasma concentration of
Medroxyprogesterone acetate. 10 other subjects in each group will be made available and
the blood samples will be used for determination of Medroxyprogesterone acetate
concentrations if there are any dropouts or withdrawals.
Selection of Subjects :
a) Inclusion criteria :
Healthy female subjects that absence of significant disease or clinically significant
abnormal laboratory values or laboratory evaluation, medical history or physical
examination during the screening, between 18 and 55 years of age and have a body
mass index of 18 to 25 kg/m2; normal blood pressure (systolic 100-120 mmHg; diastolic
60-80 mmHg); normal pulse rate (60-90 bpm); non-smokers; and willing to give written
informed consent prior to their participation.
b) Exclusion criteria :
Personal/family history of allergy or hypersensitivity or contraindication to
medroxyprogesterone acetate or allied drug; pregnant or lactating women; women of
childbearing potential without adequate contraception; subjects with chronic
gastrointestinal problems; subjects with surgical or medical condition (present or history)
which might significantly alter the absorption, distribution, metabolism or excretion of the
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study drug; subjects with any major illness in the past 90 days or clinically significant
ongoing chronic medical illness e.g. Congestive Cardiac Failure (Heart failure), Hepatitis,
Hypotensive episodes, Hyperglycemia; subject has history of seizure, epilepsy or any
kind of neurological disorders, anaphylaxis or angioedema; clinically significant
haematology, blood glucose, renal and hepatic function abnormalities; positive result for
HBsAg, anti-HCV, or anti-HIV serological test; concurrent treatment with other
experimental agents; previous inclusion in a clinical trial within 3 months prior to this
study.
Subjects demographic in each group will be selected and matched as much as possible with
another group to ensure the balance of both group.
Test Drug, Dose and Mode of Administration :

150 mg Medroxyprogesterone acetate injection produced by PT Triyasa Nagamas Farma
(Deponeo®) as the test drug and 150 mg Medroxyprogesterone acetate injection
produced by Pfizer-Germany (Depo-Clinovir® 150) as the reference drug.
One mL of the injection containing 150 mg Medroxyprogesterone acetate will be
administered via intramuscular route to each subject by the responsible physician or nurse,
using a disposable syringe.
Duration of the Clinical Phase :

The duration of the clinical phase will be approximately 4 months 3 weeks.
Study Procedures :
10-mL blood sample (control) is drawn by vein puncture immediately before drug
administration. At 7.00 a.m. the subjects are administered with study drug. One group will be
injected with 1 mL of the test drug (Deponeo®) and another group will be injected with 1 mL of
the reference drug (Depo-Clinovir® 150).
The dose is injected intramuscularly deep into the gluteal muscle by the responsible
physician or nurse, using a disposable syringe. Subsequent blood samples are drawn 10 mL
each at 1, 2, 3, 4, 5, 7, 10, 14, 18, 22, 26, 30, 35, 42, 49, 63, 77, 98, 119, and 140 days after
drug administration.
Alcohol and caffeine are not allowed for 24 hours before and during the entire sampling days.
Plasma concentrantions of medroxyprogesterone acetate will be measured by liquid
chromatography with tandem mass spectrometry detection (LC-MS/MS) method.
Bioavailability Parameters and Bioequivalence Criteria :

Bioavailability parameters to be assessed are AUC (area under the drug concentration-time
curve), Cmax (maximum drug concentration in plasma) and tmax (length of time required to
reach maximum drug concentration).
Bioequivalence is concluded if the 90% confidence interval of the Test/Reference geometric

means ratio is in the range of 80-125% for AUCt and AUCinf only.
CONFIDENTIAL
STUDY TIMEFRAME (TENTATIVE) :
Dec – Jan 2008 Protocol development, application for Ethical Clearance, and BPOM
Approval
Jan – Feb 2009 Subject recruitment and screening
Mar – Sep 2009 Blood sampling and analysis of drug concentrations
Sep – Oct 2009 Data management, statistical analysis, and final report
CONFIDENTIAL
II. BACKGROUND INFORMATION
2.1 Background
Substitution of one drug formulation for another is now a common practice in clinical drug
development and clinical medicine. General methods have been established to document
that the in vivo absorption and disposition of the new formulation will be comparable with the
one it is designed to replace or to compete with. A primary element of these methods is the
in vivo bioequivalence study that is generally performed in healthy subjects. Criteria have
been established to allow the assertion that when one formulation is bioequivalent to
the comparator, both drugs are also therapeutically equivalent.
In the present study, we investigate the bioequivalence of 150 mg Medroxyprogesterone
acetate injection produced by PT Triyasa Nagamas Farma (Deponeo®) in comparison with
the reference drug (Depo-Clinovir® 150, Pfizer-Germany) after a single intramuscular dose. In
this study, we will compare the bioavailability of Medroxyprogesterone acetate of the test and
reference drug.
2.2 Physicochemical Properties
Medroxyprogesterone acetate is a synthetic progestin. It is a derivative of progesterone (17α-

hydroxyprogesterone) that differs structurally by the addition of a 6α -methyl group and a 17α
-acetate group. It is active by both parenteral and oral routes of administration.
Medroxyprogesterone acetate is a white to off-white, odorless crystalline powder that is
stable in air and that melts between 205° and 209°C. It is freely soluble in chloroform, soluble
in acetone and dioxane, sparingly soluble in alcohol and methanol, slightly soluble in ether,
and insoluble in water.
The commercially medroxyprogesterone injection is available in a sterile aqueous

suspension containing 150 mg or 400 mg medroxyprogesterone acetate per mL.
The chemical name for medroxyprogesterone acetate is 17-hydroxy-6α-methylpregn-4-ene-

3, 20-dione 17α -acetate.
The structural formula is:
Fig. 1. Molecular structure of Medroxyprogesterone acetate
2.3 Pharmacology and Toxicology
Indications and Usage

Medroxyprogesterone acetate is indicated mainly for the prevention of pregnancy. It is also
used parenterally as adjunctive and pallitative therapy for the treatment of inoperable,
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recurrent, and metastatic endometrial carcinoma. Other indications of medroxyprogesterone

acetate injection include metastatic renal cell carcinoma and paraphilia in male treatment.
Mode of Action
Medroxyprogesterone shares the pharmacologic actions of the progestins. In women with
adequate endogenous estrogen, medroxyprogesterone transform a proliferative endometrium
into a secretory one. Medroxyprogesterone inhibits the secretion of pituitary gonadotropins
thus preventing follicular maturation and ovulation and resulting in endometrial thinning;
these effects result in contraceptives activity. High doses of medroxyprogesterone inhibit
pituitary secretion of luteinizing hormone (LH) and follicle-stimulating hormone (FSH) and will
prevent cyclic gonadotropin surges that occur during the normal menstrual cycle. It has been
suggested that the drug acts at the hypothalamus since it does not suppress the release of
LH and FSH following administration of gonadotropin-releasing hormone and since basal
concentrations of LH and FSH remain within the low normal range when the drug is used as
a contraceptive. Medroxyprogesterone has antineoplastic activity against some cancers (e.g
endometrial carcinoma, renal carcinoma).
Dosage and Administration

Medroxyprogesterone acetate injection must be vigorously shaken immediately before it is
used to ensure complete suspension of the drug. The dose is injected intramuscularly deep
into the gluteal, deltoid, or anterior thigh muscle. It is not administered inadvertently to
pregnant women thus the first injection must be given only during the first 5 days of a normal
menstrual period; only within the first 5-days postpartum if not breast-feeding, and if
exclusively breast-feeding, only at the sixth postpartum week.
Intramuscular injection doses of 150 mg of medroxyprogesterone sterile aqueous
suspension every 3 months are recommended for preventing follicular maturation and
ovulation. Because of its prolonged action and the resulting difficulty in predicting the time of
withdrawal bleeding following injection, medroxyprogesterone acetate is not recommended in
secondary amenorrhea or dysfunctional uterine bleeding. In these conditions oral therapy is
recommended. For endometrial or renal carcinoma, the doses of 400 mg to 1000 mg of
medroxyprogesterone injection per week are recommended initially.
Contraindications
Medroxyprogesterone is contraindicated in patients with active thrombophlebitis or a current
or past history of thromboembolic disorders or of cerebral vascular disease or apoplexy, in
patients with undiagnosed vaginal bleeding, missed abortion, liver dysfunction or disease,
known or suspected malignancy of the genital organs including malignancy of breast, known
hypersensitivity to the drug or any ingredient in the formulation. The drug is also
contraindicated in known or suspected pregnancy or as a diagnostic test for pregnancy.
2.4 Pharmacokinetics
Absorption
Following intramuscular administration, MPA is slowly released from the injection site,
resulting in low, but persistent levels of drug and drug-related materials in the circulation. On
average, the time required to obtain a maximum concentration of MPA in the circulation is
between 4 and 20 days. Following a single 150 mg IM, medroxyprogesterone acetate
concentrations measured by an extracted radioimmunoassay procedure, increase for
approximately 2 weeks to reach peak plasma concentrations of 1-7 ng/mL.
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Circulating levels of MPA can be detected for as long as 7 to 9 months. Increasing the
injection volume of medroxyprogesterone acetate produces an increased rate of absorption
and higher serum levels; however, extent of absorption is not affected.
Distribution
Medroxyprogesterone acetate is approximately 90 to 95 percent protein bound. Volume of
distribution is reported as 20 + 3 litres. It crosses the blood-brain barrier and is secreted in
breast milk.
Metabolism
The principal metabolite of medroxyprogesterone acetate that has been identified is 6α-
methyl-6β,17α,21-trihydroxy-4-pregnene-3,20-dione-17-acetate, which is excreted in the
urine. Numerous other metabolites of medroxyprogesterone acetate have been reported;
however, these have not been well quantified. Metabolism may be influenced by the route of
administration as well as the physical state of the drug.
Excretion
The terminal half-life of medroxyprogesterone acetate is approximately 30 to 60 hours. The
elimination half-life following intramuscular administration is approximately 6 weeks,
reflecting the prolonged absorption of the drug from the intramuscular injection site. The
levels then decrease exponentially until they become undetectable (< 100 pg/mL) between
120 to 200 days following injection. Plasma clearance is reported as approximately
1600-4000 litres per day. Medroxyprogesterone acetate (as the glucuronide conjugate) is
primarily excreted in the feces, via biliary secretion.
2.5 Adverse Event
Adverse Effects
In women receiving medroxyprogesterone acetate, the most common adverse effects are
menstrual abnormalities including irregular and unpredictable menstrual bleeding pattern,
intermenstrual bleeding decrease, and amenorrhea. Weight changes (e.g. gain) also occur
commonly during contraceptive use of medrocyprogesterone acetate because it can
stimulate lipoprotein lipase activity and seems to enhance fat deposition. It also may
decrease glucose tolerance in a long-term administration.
Other adverse effects reported during contraceptive use of medroxyprogesterone include
headache, abdominal pain or discomfort, nervousness, changes in mood or libido, asthenia
(weakness or fatigue), dizziness, insomnia, depression, hot flushes, edema, rash, alopecia
or absent hair growth, acne, breast pain or tenderness, nausea, vulvovaginal disorder, and
backache.
Infrequent (in less than 1% of patients) adverse effets as associated with
medroxyprogesterone are jaundice, paresthesia, tachycardia, osteoporosis, and seizures.
There are potential adverse effects on the fetus when these drugs are administered within
the first 4 months of pregnancy.
In males receiving parenteral medroxyprogesterone for the management of paraphilia,
fatigue and weight gain occur commonly. Other adverse effects include flashes, headache,
insomnia, nausea, and phlebitis.
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Precautions and Warning

Medroxyprogesterone should be used with caution and only with careful monitoring in
patients with conditions that might be aggravated by fluid retention, such as asthma, seizure
disorders, and migraine, cardiac or renal or hepatic insufficiency. The drugs should also be
used with caution and monitored in women with a family history of breast cancer, in diabetic
patients, in patients with thromboembolic and thrombotic disorders, in patients who have
hepatic dysfunction, and in cases of vaginal bleeding. Patients who have a history of psychic
depression should be carefully observed and the drug discontinued if the depression recurs
to a serious degree. The age of the patient constitutes no absolute limiting factor although
treatment with progestin may mask the onset of the climacteric. The use of progestational
drugs during the first four months of pregnancy is not recommended. In case of ocular
disorders, medication should be discontinued pending examination if there is a sudden
partial or complete loss of vision, or if there is a sudden onset of proptosis, diplopia or
migraine. Breast feeding mother should use the drug with caution since detectable amounts
of drug have been identified in the milk of mothers receiving progestational drugs. Use of
medroxyprogesterone injection may be considered among the risk factors for development of
osteoporosis.
III. STUDY OBJECTIVE
The objective of this study is to find out whether bioavailability of 150 mg

Medroxyprogesterone acetate injection produced by PT Triyasa Nagamas Farma
(Deponeo®) is equivalent to that of the reference’s drug (Depo-Clinovir® 150, Pfizer-
Germany).
IV. STUDY DESIGN
This is a randomized, single-dose, open-labelled, parallel study involving 160 healthy

subjects.
The study will be a bioequivalence study of 150 mg Medroxyprogesterone acetate injection
produced by PT Triyasa Nagamas Farma (Deponeo®) versus the innovator product
(Depo-Clinovir®) produced by Pfizer-Germany.
The randomization schedule was in the custody of Principal Investigator.
In this parallel study, one group will be given the test drug (T) and another group will be
given the reference drug. The randomization code is tabulated for all subjects according to
block randomization with a block size of 4 (Dixon & Massey,1969, p 447).
The randomization for study drugs will be carried out at both groups.
V. STUDY SUBJECTS
5.1 Number of Subjects
The study will be conducted in two study groups. Each group will involve 80 healthy adult
female subjects. Thus, the total number of 160 subjects will be made available for this
parallel study. Each group will administer with study drug (test drug or reference drug) and
the blood will be taken at various time points of blood sampling procedures. For each group,
the blood samples from 70 subjects only will be analyzed for plasma concentration of
Medroxyprogesterone acetate. 10 other subjects in each group will be made available and
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the blood samples will be used for determination of Medroxyprogesterone acetate

concentrations if there are any dropouts or withdrawals.
The subjects are not allowed to take any drugs, two weeks before and during study for OTC,
food supplement, herbal medicine, and for prescription drug.
5.2 Inclusion Criteria
Participating subjects have to fulfill the following criteria:

1. Female subjects that absence of significant disease or clinically significant abnormal
laboratory values or laboratory evaluation, medical history or physical examination during
the screening
2. Aged 18 – 55 years inclusive
3. Non-smokers
4. Able to participate, communicate well with the investigators and willing to provide written
informed consent to participate in the study.
5. Body mass within 18 to 25 kg/m2
6. Vital signs (after 10 minutes rest) must be within the following ranges:
- Systolic blood pressure 100 – 120 mmHg
- Diastolic blood pressure 60 – 80 mmHg
- Pulse rate : 60 – 90 bpm
5.3 Exclusion Criteria
Any of the following criteria will exclude the subject from the study:
1. Personal/family history of allergy or hypersensitivity or contraindication to
medroxyprogesterone acetate or allied drug.
2. Pregnant or lactating women (urinary pregnancy test will be applied to women subjects
just before taking the study drug).
3. Any major illness in the past 90 days or clinically significant ongoing chronic medical
illness e.g. Congestive Cardiac Failure (Heart failure), Hepatitis, Hypotensive episodes,
Hyperglycemia, etc.
4. Presence of any clinically significant abnormal values during screening e.g. significant
abnormality of liver function test (ALT, alkaline phosphatase, total bilirubin ≥ 1.5 ULN),
renal function test (serum creatinine concentration ≥ 1.4 mg/dL), etc.
5. Positive Hepatitis B surface antigen (HBsAg), anti-HCV, or anti-HIV.
6. Clinically significant haematology abnormalities.
7. Clinically significant electrocardiogram (ECG) abnormalities.
8. Any surgical or medical condition (present or history) which might significantly alter the
absorption, distribution, metabolism or excretion of the study drug, e.g. gastrointestinal
disease including gastric or duodenal ulcers or history of gastric surgery
9. History of drug or alcohol abuse within 12 months prior to screening for this study.
10. Participation in any clinical trial within the past 90 days.
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11. History of any bleeding or coagulative disorders.

12. History of difficulty with donating blood or difficulty in accessibility of veins in left or right
arm.
13. A donation or loss of 500 mL (or more) of blood within 3 months before this study’s first
dosing day.
14. Intake of any prescription or non-prescription drug, food supplement or herbal medicine
within 14 days of this study’s first dosing day.
This study will be carried out in accordance to the Good Clinical Practice (GCP) standards.
Approval from the Ethics Committee will be sought prior to the conduct of the study.
Demographic for each group will be matched each other as possible with another group to
ensure the balance of both group.
5.4 Removal of Subject from Assessment
Acceptable explanations to exclude pharmacokinetic data or to exclude a subject would be

protocol violations like vomiting, diarrhea, analytical failure, absence at the time for drug
administration, pregnant during study, etc. Exclusion of data could not be accepted on the
basis of statistical analysis on for pharmacokinetic reason.
VI. STUDY MEDICATIONS
1. 150 mg Medroxyprogesterone acetate per mL (Deponeo®) produced by PT Triyasa

Nagamas Farma as the test drug.
Batch No :
Exp. Date :
2. 150 mg Medroxyprogesterone acetate injection per mL produced by Pfizer-Germany
(Depo-Clinovir® 150) as the reference drug.
Batch No :
Exp. Date :
The person responsible will record precisely the date and the time of drug administration to
the subjects. In case the study has to be discontinued, the exact date and time will be
carefully recorded.
VII. STUDY PROCEDURES
Screening
Subjects will undergo a medical examination within 14 days prior to their first dosing day.
This included assessment of physical examination, vital signs (blood pressure, pulse rate,
respiratory rate and temperature), ECG, and laboratory values of liver function (AP, ALT,
AST and total/direct bilirubin); renal function (serum creatinine and ureum); routine
hematology (haemoglobin, leucocyte count, platelet and leucocyte differential count); blood
glucose; routine urinalysis (pH, glucose, protein, and urine sediment), and immunology test
for HBsAg, anti-HCV, and anti-HIV. Pregnancy test will be performed just before taking
the drug.
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Treatment phase
The subjects are instructed to come to PT Equilab International at 6.00 a.m. at the day of
drug administration. 10-mL blood sample (control) is drawn by vein puncture immediately
before drug administration. At 7.00 a.m. the subjects are administered with study drug. One
group will be injected with 1 mL of the test drug (Deponeo®) and another group will be
injected with 1 mL of the reference drug (Depo-Clinovir® 150). The dose is injected
intramuscularly deep into the gluteal muscle by the responsible physician or nurse, using a
disposable syringe. The time of drug administration was documented in the CRF. One
physician and two nurses with sufficient qualifications and training were present at dosing
time and stayed at the site until the last subject left the study unit; thereafter they were
reachable by mobile telephone.
Subsequent blood samples are drawn 10 mL each at 1, 2, 3, 4, 5, 7, 10, 14, 18, 22, 26, 30,
35, 42, 49, 63, 77, 98, 119, and 140 days after drug administration. Blood samples (10 mL)
are collected into EDTA tubes for the measurement of plasma concentrations of
medroxyprogesterone acetate.
The subjects are under direct medical supervision during the day after administration of
medroxyprogesterone acetate. Blood pressure, pulse rate and adverse events are monitored
during the entire study.
VIII. DRUG ASSAY
8.1 Analytical Method Validation
The medroxyprogesterone acetate concentrations will be assayed using a fully validated

liquid chromatography with tandem mass spectrometry detection (LC-MS/MS) method with
respect to adequate sensitivity, specificity, linearity, recovery, and accuracy and precision
(both within and between days). The Limit of Quantitation (LOQ) of medroxyprogesterone
acetate obtained from method validation was 50 pg/mL. Stability of the samples under frozen
conditions, at room temperature, and during freeze-thaw cycles are also determined.
8.2 Plasma Preparation
Blood samples for pre-dose 10 mL and post dose (1x 10 mL) for each subject are collected in
polypropylene tubes containing EDTA by using drawing needle 22 G during study. The total
number of blood withdrawn each subjects are 220 mL, including 10 mL for screening and 210
mL during study. Blood was also withdrawn from vein by using disposable syringe if the
vacuum tube was blocked.
The pre-dose samples were collected within one hour prior to drug dosing. The post-dose
samples were collected within 1 minute of the scheduled time where the end time of
collection to the nearest minute was recorded on CRF. Any deviation above one minute is
recorded as protocol deviation.
Human blood samples are drawn and transferred into EDTA tubes. Plasma is separated by
centrifugation at 4000 rpm for 15 minutes and the plasma is transferred to a clean tube.
8.3 Sample Storage
The separated plasma is aliquot in duplicate in prelabelled polypropylene tubes during study.
These tubes were stored in sample storage room in deep freezer maintained at -20oC for
temporary storage and finally at the end of the day these tubes were transferred to a deep
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freezer maintained below -20oC for long term storage. All the plasma samples are stored at
freezer ≤ -20°C until assayed.
8.4 Assay Method
For analysis of drug concentrations, liquid chromatography with tandem mass spectrometry
detection (LC-MS/MS) method will be used.
An aliquot of human plasma sample is mixed with the internal standard working solution. The
sample mixture is extracted with an appropriate solvent and evaporated to dryness under a
gentle stream of nitrogen. The extracted residue is dissolved in a reconstitution solution.
An appropriate volume of reconstituted sample is injected to the LC-MS/MS system.
Calibration standards, controls, and samples are processed in batches.
8.5 Quantitation
One calibration curve is prepared (medroxyprogesterone acetate) by least square linear

regression (Y = aX + b; where X is the concentration of Medroxyprogesterone acetate and Y
is the peak area ratio of medroxyprogesterone acetate to the internal standard).
The concentration of medroxyprogesterone acetate in plasma sample is determined by
entering the peak area ratio of the medroxyprogesterone acetate to internal standard into the
regression line equation of the standard calibration curve of each substance.
8.6 Quality Control
QC samples in duplicate at three concentrations [one within 3x of the LLOQ (low QC), one in
the midrange (middle QC), and one approaching the high end of the range (high QC)] will be
incorporated into each run. At least 67% (four out of six) of the QC samples should be within
15% of their respective nominal (theoretical) values; 33% of the QC samples (not all
replicates at the same concentration) can be outside the ±15% of the nominal value.
IX. STUDY ANALYSIS
9.1 Parameters of Bioavailability
Bioavailability parameters to be assessed

Cmax maximum observed plasma concentration
tmax time to reach Cmax
AUCt area under plasma concentration curve from administration to last
observed concentration at time t
AUCinf area under plasma concentration vs time curve extrapolated to infinite
time
t½ terminal phase half-life time
Cmax and tmax were obtained directly from the observed data. The AUCt was calculated by the
trapezoidal method. The AUCinf was calculated as AUCt + Ct/ke, where Ct was the last
quantifiable concentration, ke was the terminal elimination rate constant and was
determined by least-squares regression analysis during the terminal log-linear phase of the
concentration–time curve. The t1/2 was calculated as 0.693/ke.
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9.2 Statistical Analysis
The statistical method for testing bioequivalence is ANOVA for 2-sequence, randomized,
parallel study comparing AUC0-t and AUC0-inf after ln transformation of the original values.
The tmax are compared using nonparametic test from the original data.
Bioequivalence is concluded if the 90% confidence interval of the Test/Reference geometric
means ratio is in the range of 80-125% with 90% power and 0.05 alpha, for AUCt and
AUC inf. This acceptance criteria is according to the Indonesian guidelines, Pedoman Uji
Bioekivalensi, Badan Pengawas Obat dan Makanan (BPOM), Jakarta, 2004 and European
Agency for the Evaluation of Medicinal Products (EMEA) guidelines, Note for Guidance on
The Investigation of Bioavailability and Bioequivalence.
EquivTest version 2.0 (Statistical Solution Ltd., Saugus, MA, USA) will be used to perform
the statistical analyses of AUCt and AUCinf using analysis of variance (ANOVA) after
transformation of the data to their natural logarithmic (ln) values. Using the error variance
(S2) obtained from the ANOVA, the 90% confidence intervals (CIs) will be calculated from the
following equation:
2
90% CI = ( X T - X R) ± t0.1(v) S2 ×
n
- X T , X R : the means of the ln transformed values for the test drug (T) and
the reference drug (R)
- S2 : the error variance obtained from the ANOVA
-n : the number of subjects
- t0.1 : the t value for 90% CI
-v : the degree of freedom of the error variance from the ANOVA
The anti ln of the above confidence intervals are the 90% Cls of the ratios of the test / the
reference geometric means.
The difference in tmax will be analyzed non-parametrically on the original data using Wilcoxon
matched-pairs test.
X. ADVERSE EVENTS / TOXICITY
10.1 Definition of an Adverse Event
Patients will be instructed by the responsible physician to report the occurrence of any
adverse event. An adverse event is any undesirable event occurred during the use of a study
drug, whether or not considered drug related, and includes any side effect, injury,
toxicity, or hypersensitivity reactions. It also includes any undesirable clinical or laboratory
change, which does not commonly occur in the patient. For adverse reaction would be
categorized as possibly related, probably, and unlikely related based on literature data and
pharmacokinetics profile. All adverse events, regardless of severity, will be followed up and
recorded by the investigator.
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10.2 Serious Adverse Event
A serious adverse event includes any event that is fatal or life-threatening, requires
inpatient hospitalisation, prolongs hospitalisation or is disabling. Death, congenital
anomaly, cancer or overdose are always considered serious.
"Life-threatening" means that the patient is at immediate risk of death from the event as it
occurred. It does not include an event that, has it occurred in a more serious form, may have
caused death.
"Requires inpatient hospitalisation" is defined as hospital admission required for treatment of
the adverse event. Hospital admission for scheduled elective surgery is not classified as a
serious adverse event.
If the adverse event is serious, it will be reported by telephone/fax within 24 hours (one
working day from the moment it is first known by the investigators) to :
Dra. Sorta Saulina, MBA, MM

Quality Assurance & Control Manager
Phone +62 21 4603104, 4602233
Fax +62 21 4602232
and in writing within 3 days. A full explanation for the discontinuation from the study will be
made on the appropriate case report form. All adverse events, regardless of severity, will be
followed up by the investigator until satisfactory resolution.
XI. ADMINISTRATIVE ASPECTS
11.1 Data Recording
Case Report Forms (CRFs) will be filled legibly using a black ball-point. The forms will be
verified against all original records (and workbooks, if applicable). A copy will be retained in
the investigator’s files, and all other copies will be given to the Sponsor.
11.2 Record Retention
Copies of all pertinent information will be retained by the responsible investigator for a period
of at least 8 years after study completion. Additional considerations will be made about
complying with applicable local laws, guidelines, etc. A study document binder will be
provided for all required study documents.
11.3 Subject Informed Consent
Prior to screening evaluation, subjects will be informed of the nature of the study and
pertinent information as to the intended purpose, possible benefits, and possible adverse
experiences. The procedures and possible hazards to which the subjects will be exposed will
be explained. An approved informed consent statement will then be read by each subject.
Before signing the informed consent form, ample time (at least 24 hours) will be provided to
the subject to decide whether or not to participate in the trial. The subject will receive a copy
of the signed informed consent statement. They may withdraw from the study at anytime
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without any reason. Verification of the signed informed consent will be noted on the study
case report form.
11.4 Ethics Committee
The protocol and the informed consent statement will be reviewed by the Ethics Committee
of the Medical Faculty, University of Indonesia. The Ethics Committee's approval will be
made in writing to the responsible investigator and a copy of this decision will be provided to
the sponsor. The Ethics Committee must be informed by the responsible investigator of the
study completion.
11.5 Modification of the Protocol
Any modification of the protocol which may have impact on the conduct of the study,
potential benefit of the study, or may affect subject safety, including changes of study
objective, study design, study population, sample size, study procedure, or significant
administrative aspects will require a formal amendment to the protocol. Such amendment will
be agreed upon by the sponsor, the responsible investigator and the Ethics Committee prior
to implementation.
Minor administrative changes of the protocol are minor corrections and/or clarifications that
have no effect on the way the study is to be conducted. These minor administrative changes
will be agreed upon by the sponsor and the responsible investigator and will be documented
in a memorandum. The Ethics Committee may be notified of the minor administrative
changes at the discretion of the responsible investigator.
11.6 Drug Storage and Accountability
The investigator will maintain accurate records of the disposition of all study drug received,
administered (including date and time) and accidentally destroyed. At the end of the study all
unused medication, including test drug and reference drug, will be returned to the sponsor.
The investigator will responsible for ensuring that the study drugs are stored in accordance
with the instructions on the label, i.e. at room temperature below 30°C and protected from
humidity.
11.7 Biological Samples
All of the remaining plasma samples will be destroyed within three months after the final
report is received by the sponsor.
11.8 Protocol Deviation
All of the protocol deviation in this study will be recorded and reported to the sponsor.
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XII. STUDY TIMEFRAME (TENTATIVE)
Dec – Jan 2008 Protocol development, application for Ethical Clearance and BPOM
Approval
Jan – Feb 2009 Subject recruitment and screening
Mar – Sep 2009 Blood sampling and analysis of drug concentrations
Sep – Oct 2009 Data management, statistical analysis, and final report
XIII. REFERENCES
1. AHFS Drug Information. Bethesda: American Society of Health-System Parmacist; 2002.

p. 3088, 3090-92.
2. Badan Pengawas Obat dan Makanan Republik Indonesia (BPOM RI), Pedoman Uji
Bioekivalensi, Jakarta. 2004.
3. Badan Pengawas Obat dan Makanan Republik Indonesia (BPOM RI), Pedoman Cara
Uji Klinik yang Baik, Jakarta. 2001.
4. Current Medication information-Depo-Provera (medroxyprogesterone acetate), injection,
suspension (Pharmacia and Upjohn). Available from: http://dailymed.nlm.nih.gov
5. Physicians’ Desk Reference. 59th ed. Montvale, NJ: Thomson PDR; 2005. p. 2717-18.
6. Hardman JG, Limbird LE, Gilman AG. Goodman & Gilman’s the Pharmacological Basis
of Therapeutics. 10th ed. New York: McGraw-Hill; 2001. p. 1620.
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APPENDIX A
ADVERSE EVENT(S) FORM
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ADVERSE EVENT(S)
STUDY NO. : Subject No.: Initials :
Please note any SERIOUS events should not be recorded on this page, but on the Serious Adverse Event
pages provided (F.161/EQL)
Are there any adverse event in this study ? Yes No
Adverse
Event
Period Period 1 Period 2 Period 1 Period 2
Onset Date / / / /
/ Time DD MON YY DD MON YY
24 hr-clock 24 hr-clock
End Date / / / / /
Time DD MON YY DD MON YY
24 hr-clock 24 hr-clock
Outcome Resolved Resolved
* If subject died, Ongoing Ongoing

please fill in
SAE form
Died* Died*
Event Intermittent No.of episode Intermittent No.of episode

Course
Constant Constant
Investigator’s signature : ______________________ Date : _____________________
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ADVERSE EVENT(S)
Please note any SERIOUS events should not be recorded on this page, but on the Serious Adverse
Event pages provided (F.161/EQL)
Cont’d
Intensity
(maximum) Mild Mild
Moderate Moderate
Severe Severe
Relation to
study drug Unrelated Unrelated
Unlikely Unlikely
Possibly related Possibly related
Probably related Probably related
Definite Definite
Corrective
Therapy Yes No Yes No
Was subject
withdrawn due Yes No Yes No
to this event?
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ADVERSE EVENT(S)
Please note any SERIOUS events should not be recorded on this page, but on the Serious Adverse Event
pages provided (F.161/EQL)
Cont’d
Do you
consider this a Yes No Yes No
serious event?
(if yes, fill in the
SAE form)
Comments : ________________________________________
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APPENDIX B
STUDY FLOW CHART
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Study Flow Chart
Study Phase Screening Study Phase 1 and 2

Study Day D-14 to D-2 Pre- 0 1 2 3 4 5 7 10 14 18 22 26 30 35 42 49 63 77 98 119 140
dose day day day day day day day day day day day day day day day day day day day day day
Informed consent x
Inclusion/exclusion criteria x
Relevant medical history/ x
current medical conditions
Physical Examination x
ECG evaluation x
Pregnancy test x x
Hepatitis and HIV sreenings x
Hematology, blood chemistry, x
Urinalysis
Vital signs & body
measurements
Body height & weight x x x x x x x x x x x x x x x x x x x x x
Body temperature x x x x x x x x x x x x x x x x x x x x x
Blood pressure/pulse x x x x x x x x x x x x x x x x x x x x x
rate
Drug administration record x
Pharmacokinetics blood x x x x x x x x x x x x x x x x x x x x x
collection
Adverse events x x x x x x x x x x x x x x x x x x x x
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in writing by PT Triyasa Nagamas Farma and PT Equilab International.
APPENDIX C
SUBJECT INFORMATION AND INFORMED CONSENT FORM
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INFORMATION AND AGREEMENT SHEET AFTER EXPLANATION

SUBJECT NUMBER:
Principal Investigator : Danang Agung Yunaidi, MD

Medical and Responsible
Physician : Danang Agung Yunaidi, MD
PT EQUILAB INTERNATIONAL
Jl. Utan Kayu Raya No. 45, Jakarta 13120 – INDONESIA
Study Number : PR. 124/EQL/2008
Compound : Medroxyprogesterone acetate
Sponsor : PT Triyasa Nagamas Farma
Tel. +62 21 4603104, 4602233
Fax. +62 21 4602232
Title of Study : Bioequivalence study of 150 mg Medroxyprogesterone
acetate injection produced by PT Triyasa Nagamas
Farma (Deponeo®) in comparison with the innovator
injection (Depo-Clinovir, Pfizer)
You are invited to participate in this study. Important for you to read and understand
clearly the information on this sheet and the appendices, that include The Condition to
Participate in this Study. All of queries about the study could be asked to the Principal
Investigator or Co-Investigator before the study begins. If you satisfy to the information
that has been given to you and will to join in this study, you will be asked to sign up the
agreement to participate in this study on the part that has been provided; and then it will
be signed up by the investigator. After signing up the agreement, you still could have
queries about the things that unclear for you.
1 WHAT IS THE OBJECTIVE OF THE STUDY?
The objective of this study is to know whether the drug absorption of 150 mg
Medroxyprogesterone acetate injection that produced by PT Triyasa Nagamas Farma
(Deponeo®) equivalent with the similar injection produced by innovator (Depo-Clinovir®, Pfiizer).
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2 WHAT IS THE INFORMATION OF INVESTIGATOR DRUG?
Medroxyprogesterone acetate injection could be used by women as contraception.
3 HOW TO CONDUCT THE STUDY?
160 healthy female subject that pass the health screening will be separated into two groups
(each group will consist of 80 subjects). One group will be given Deponeo® and another group
will be given Depo-Clinovir® 150.
The physician or nurse will inject the drug into your lower hip using disposable needle syringe.
During the study, the total of blood sampling time will be 21 points with the volume of blood
taken in each point is 2 tea spoons (10 mL).
Blood samples will be collected by the time stated in blood collecting procedure. In
each group, blood samples from 70 subjects only will be analyzed for plasma
concentration of medroxyprogesterone acetate. 10 other subjects in each group will be
made available and the blood samples will be used for determination of
medroxyprogesterone acetate concentrations if there are any subjects dropouts or
could not finish the study.
4 WHAT WOULD BE HAPPENED DURING THE STUDY?
Health screening before study
After you have signed the agreement letter to join this study, your health condition will be
examined. This examination will be conducted before the first drug administration.
These examinations are included blood collecting to detemine laboratorium values (including
hepatitis and HIV test) and urine test. After that, your heart condition will be checked by ECG
(electrocardiogram). This instrument will be patched on your chest, and you will lie down for a
minute. Body weight and height, blood pressure, pulse rate and body temperature also will be
measured. After that, you will be checked and interviewed about drug using.
If you state health and agree to follow the study rules, you will be allowed to involve in this
study.
Period of drug administration
This study is one period study with duration 4 months and 20 days. You will accept test drug
(Deponeo®, PT Triyasa Nagamas Farma) or reference drug (Depo-Clinovir® 150, Pfizer), that
will be administered by physicians or nurse on duty by injecting it on the lower hip. At the stated
day, you will be invited to come to the clinical site (PT Equilab International) at 6 a.m. You will
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be asked to perform pregnancy test to ensure that you are not in pregnant condition. You will
accept number of subject; all data and blood samples will be marked by that number.
Before receiving the drug, 10 mL of blood sample will be collected. And then, you will be
injected 1 mL of test drug (Deponeo®) or reference drug (Depo-Clinovir® 150) in the lower hip
using disposable needle syringe by physician or nurse on duty.
The blood sample for drug plasma concentration analysis will be collected a moment before
drug administration in the morning and at 1st, 2nd, 3rd, 4th, 5th, 7th, 10th, 14th, 22nd, 26th, 30th, 35th,
42nd, 49th, 63th, 77th, 98th, 119th, and 140th days after drug administration.
You could go home after blood collecting at the first dosing day. You will be instructed to come
again to Equilab on the next day of blood collecting at 6.30 a.m.
During the study day, when the investigators ask about your health condition, please report all
the changes or adverse event that you experience, although you can not distinguish whether it
is related or unrelated to the investigational drug. Also, if you feel something change on your
health condition at the other time after the study has finished, please inform to the physician or
nurse on duty.
5 WHAT ARE THE RISKS AND ADVERSE REACTIONS?
From the blood collecting procedure
Your blood samples will be collected using disposable needle syringe. The risks that related to
blood sample collected from the arms vein are the pain because of the puncture of syringe
needle, bleeding, inflammation, and blue mark that will heal within a couple days. The amount
of blood collected in this study (including health examination before study) is about 220 mL
(less than one glass of aqua).
From the drug administration
Medroxyprogesterone acetate is commonly well tolerated by body. Adverse event related to the
drug administration that had been reported are headache, nausea, gastric disorder, vomit,
weight exchange, libido exchange, menstruation exchange like decreasing or none of blood of
menstruation.
Adverse event that are encountered will be asked and noted by investigator on the available
form. If the adverse event or reactions is happened, physicians will respond and give some
treatment immediately, and you would not be charged for the treatment.
You will be given information, both oral and write immediately, if there is a new info that will
need your consideration to decide whether you will continue or stop to participate in this study.
6 CONTACT PHYSICIAN
If you have adverse events or reactions symptoms, including serious and life threatening
events, please call physicians immediately (Danang Agung Yunaidi, MD) at PT Equilab
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International, Jl. Utan Kayu Raya No. 45, Jakarta 13120, phone number 021-85911820-22,
cellular phone 08561228485, in order to get help as soon as possible.)
You are allowed to contact investigator for all additional information about the study that you
need or about your rights as study subject at anytime.
7 IS THERE ANY RESTRICTION?
Drug and Medicine :
Intake of any prescription and non-prescription drug (including vitamin, food supplement or
herbal medicine) are not allowed within 14 days before first dosing day and during the study. If
you have to use some medicines, you must to ask agreement from investigator physicians. This
condition is exception for emergency case.
Alcohol, juice, coffee, etc. : The drink that contains alcohol and coffee is not allowed within
24 hours before drug administration and until the last blood sampling time (at 140th day). For
The consuming of tea, chocolate and coke is limited only one glass every week.
Physical activity: You have to avoid heavy physical activity or sports during the study.
8 FURTHER INFORMATION ABOUT THIS STUDY
You wiil not be charged for the investigation drug and all the examination. You will receive
compensation Rp. 1.420.000,- (gross-before tax charge PPh-21 appropriate with the existing
tax rules) for participate in this study. You are free to leave this study anytime without
compulsion to give the reason. Principal investigator could drop you out from this study, if you
do not follow the instruction (page 34 – 35).
This study will not give you advantage directly, but the result will give benefit for other people.
All supported data had shown that all the risks that could be happen are able to control and
handle. This study protocol has been appraised and approved by Ethical Committee of the
Medical Faculty, University of Indonesia.
9 CONFIDENTIALITY OF DATA
Your identity in this study will be kept under controlled access. Your identity only could be
known by investigator team, ethical committee that approved this study, National Regulatory
Authority (BPOM) and sponsor/ study monitor, that have authorization.
10 HEALTH PROTECTION
In this study the treatment for all of adverse event including adverse effect or uncomfortable
reaction that appeared because of drug administration during study will be insured by PT
Equilab International. You could complaint anytime to the investigator.
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If you need further information, you could contact Danang Agung Yunaidi, MD or other
investigator team at PT Equilab International Office, Jl. Utan Kayu Raya No. 45, Jakarta 13120,
Phone number 021-85911820-22.
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THE CONDITIONS TO PARTICIPATE IN STUDY
The conditions below are the compulsory requirements for all of subject BE study to join this
study as an additional agreement:
Herewith, I declare that I do not participate to another clinical research during the last 3 months.
I also declare that I do not take other drugs.
I have responsibility to come punctual and join every instruction that is given to me by
investigator.
I am not allowed to drink alcohol, coffee, tea, chocolate, fruit juice, lemon juice, and carbonate
water, 24 hours before drug administration until the last blood sampling time.
I will not participate in sports games and do heavy physical activity 24 hours before drug
administration and all the day of blood sampling.
I do not use narcotics, psychotropic (example cannabis, cocaine) or other drugs except the
investigational drugs. I realize that drug using will be controlled a couple times during the study.
Additional medicine are not allowed to be consumed without prior consultation to investigator
physicians.
In the last day, all the finding result will be explained and discussed with physician.
Compensation that has been agreed will be given at the end of study.
If I feel suffer, sick or have an accident that related to this study, hence the participation in this
study will be terminated based on investigator physician judgment and I still can receive all of
compensation that has been agreed. If the termination of my participation in this study is due to
my incompliance or disobey to follow the investigator’s instruction, I will not get the
compensation. I have right to leave the study because of personal reason without any kind of
negative impact.
I have been instructed to not doing blood donor, 12 weeks before, during, and 6 weeks after the
last blood collecting time to prevent the significant blood loss.
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AGREEMENT SHEET AFTER EXPLANATION
Bioequivalence study of 150 mg Medroxyprogesterone acetate injection produced by PT

Triyasa Nagamas Farma (Deponeo®) in comparison with the innovator injection (Depo-
Clinovir, Pfizer)
Agreement
I had been given sufficient time (more than 24 hours before the study begin) to read this document
and understood all of information about this study clearly. All technical term had been explained to
me and my entire queries had been answered satisfyingly.
I agree to join this study. I agree to cooperation with investigator and will contact him immediately
if I suffer any unexpected and unusual symptoms during study. I realize the risk that I will get from
this study as the described in inform consent point adverse event. I agree to follow all health
examination including physical examination and several laboratory tests for blood and urine before
being involved in the study. I understand, if there is abnormal result from the examination, I will not
be involved in this study.
I realize that if I do not cooperate with the entire requirement, guide, or instruction from
investigator, I could be dropped out from this study.
I understand that my participation in this study is voluntarily and I could refuse or leave the study
anytime without any claim or disadvantages. I understand that during study, all of information that
could influence my willing to continue the study will be informed to me as soon as possible.
I had been given one copy of writing information and agreement form to participate on this study.
Full name of BE study subject

(Capital letter)
Signature of BE study subject Date (for complete by BE

study subject at agreement
time)
Full name of investigator

(Capital letter)
Signature of investigator Date
Full name of Witness

(Capital letter)
Signature of Witness Date
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APPENDIX D
DECLARATION OF HELSINKI
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World Medical Association
DECLARATION OF HELSINKI
Ethical Principles for Medical Research Involving Human Subjects
Adopted by the 18th World Medical Assembly, Helsinki, Finland, June 1964, and amended by the 29th
World Medical Assembly, Tokyo, Japan, October 1975, the 35th World Medical Assembly, Venice,
Italy, October 1983, the 41st World Medical Assembly, Hong Kong, September 1989, the 48th General
Assembly, Somerset West, Republic of South Africa, October 1996, and the 52nd WMA General
Assembly, Edinburgh, Scotland, October 2000.
A INTRODUCTION
1 The World Medical Association has developed the Declaration of Helsinki as a statement of ethical
principles to provide guidance to physicians and other participants in medical research involving human
subjects. Medical research involving human subjects includes research on identifiable human material or
identifiable data.
2 It is the duty of the physician to promote and safeguard the health of the people. The physician's
knowledge and conscience are dedicated to the fulfillment of this duty.
3 The Declaration of Geneva of the World Medical Association binds the physician with the words, "The
health of my patient will be my first consideration," and the International Code of Medical Ethics declares
that, "A physician shall act only in the patient's interest when providing medical care which might have
the effect of weakening the physical and mental condition of the patient."
4 Medical progress is based on research which ultimately must rest in part on experimentation involving
human subjects.
5 In medical research on human subjects, considerations related to the well-being of the human subject
should take precedence over the interests of science and society.
6 The primary purpose of medical research involving human subjects is to improve prophylactic,
diagnostic and therapeutic procedures and the understanding of the aetiology and pathogenesis of
disease. Even the best proven prophylactic, diagnostic, and therapeutic methods must continuously be
challenged through research for their effectiveness, efficiency, accessibility and quality.
7 In current medical practice and in medical research, most prophylactic, diagnostic and therapeutic
procedures involve risks and burdens.
8 Medical research is subject to ethical standards that promote respect for all human beings and protect
their health and rights. Some research populations are vulnerable and need special protection. The
particular needs of the economically and medically disadvantaged must be recognized. Special attention
is also required for those who cannot give or refuse consent for themselves, for those who may be
subject to giving consent under duress, for those who will not benefit personally from the research and
for those for whom the research is combined with care.
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9 Research Investigators should be aware of the ethical, legal and regulatory requirements for research
on human subjects in their own countries as well as applicable international requirements. No national
ethical, legal or regulatory requirement should be allowed to reduce or eliminate any of the protections
for human subjects set forth in this Declaration.
B BASIC PRINCIPLES FOR ALL MEDICAL RESEARCH
10 It is the duty of the physician in medical research to protect the life, health, privacy, and dignity of the
human subject.
11 Medical research involving human subjects must conform to generally accepted scientific principles, be
based on a thorough knowledge of the scientific literature, other relevant sources of information, and on
adequate laboratory and, where appropriate, animal experimentation.
12 Appropriate caution must be exercised in the conduct of research which may affect the environment, and
the welfare of animals used for research must be respected.
13 The design and performance of each experimental procedure involving human subjects should be
clearly formulated in an experimental protocol. This protocol should be submitted for consideration,
comment, guidance, and where appropriate, approval to a specially appointed ethical review committee,
which must be independent of the Investigator, the Sponsor or any other kind of undue influence. This
independent committee should be in conformity with the laws and regulations of the country in which the
research experiment is performed. The committee has the right to monitor ongoing trials. The researcher
has the obligation to provide monitoring information to the committee, especially any serious adverse
events. The researcher should also submit to the committee, for review, information regarding funding,
Sponsors, institutional affiliations, other potential conflicts of interest and incentives for subjects.
14 The research protocol should always contain a statement of the ethical considerations involved and
should indicate that there is compliance with the principles enunciated in this Declaration.
15 Medical research involving human subjects should be conducted only by scientifically qualified persons
and under the supervision of a clinically competent medical person. The responsibility for the human
subject must always rest with a medically qualified person and never rest on the subject of the research,
even though the subject has given consent.
16 Every medical research project involving human subjects should be preceded by careful assessment of
predictable risks and burdens in comparison with foreseeable benefits to the subject or to others. This
does not preclude the participation of healthy volunteers in medical research. The design of all studies
should be publicly available.
17 Physicians should abstain from engaging in research projects involving human subjects unless they are
confident that the risks involved have been adequately assessed and can be satisfactorily managed.
Physicians should cease any investigation if the risks are found to outweigh the potential benefits or if
there is conclusive proof of positive and beneficial results.
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18 Medical research involving human subjects should only be conducted if the importance of the objective
outweighs the inherent risks and burdens to the subject. This is especially important when the human
subjects are healthy volunteers.
19 Medical research is only justified if there is a reasonable likelihood that the populations in which the
research is carried out stand to benefit from the results of the research.
20 The subjects must be volunteers and informed participants in the research project.
21 The right of research subjects to safeguard their integrity must always be respected. Every precaution
should be taken to respect the privacy of the subject, the confidentiality of the patient's information and
to minimize the impact of the study on the subject's physical and mental integrity and on the personality
of the subject.
22 In any research on human beings, each potential subject must be adequately informed of the aims,
methods, sources of funding, any possible conflicts of interest, institutional affiliations of the researcher,
the anticipated benefits and potential risks of the study and the discomfort it may entail. The subject
should be informed of the right to abstain from participation in the study or to withdraw consent to
participate at any time without reprisal. After ensuring that the subject has understood the information,
the physician should then obtain the subject's freely-given informed consent, preferably in writing. If the
consent cannot be obtained in writing, the non-written consent must be formally documented and
witnessed.
23 When obtaining informed consent for the research project the physician should be particularly cautious if
the subject is in a dependent relationship with the physician or may consent under duress. In that case
the informed consent should be obtained by a well-informed physician who is not engaged in the
investigation and who is completely independent of this relationship.
24 For a research subject who is legally incompetent, physically or mentally incapable of giving consent or
is a legally incompetent minor, the Investigator must obtain informed consent from the legally authorized
representative in accordance with applicable law. These groups should not be included in research
unless the research is necessary to promote the health of the population represented and this research
cannot instead be performed on legally competent persons.
25 When a subject deemed legally incompetent, such as a minor child, is able to give assent to decisions
about participation in research, the Investigator must obtain that assent in addition to the consent of the
legally authorized representative.
26 Research on individuals from whom it is not possible to obtain consent, including proxy or advance
consent, should be done only if the physical/mental condition that prevents obtaining informed consent is
a necessary characteristic of the research population. The specific reasons for involving research
subjects with a condition that renders them unable to give informed consent should be stated in the
experimental protocol for consideration and approval of the review committee. The protocol should state
CONFIDENTIAL
that consent to remain in the research should be obtained as soon as possible from the individual or a
legally authorized surrogate.
27 Both authors and publishers have ethical obligations. In publication of the results of research, the
Investigators are obliged to preserve the accuracy of the results. Negative as well as positive results
should be published or otherwise publicly available. Sources of funding, institutional affiliations and any
possible conflicts of interest should be declared in the publication. Reports of experimentation not in
accordance with the principles laid down in this Declaration should not be accepted for publication.
C ADDITIONAL PRINCIPLES FOR MEDICAL RESEARCH COMBINED WITH MEDICAL CARE
28 The physician may combine medical research with medical care, only to the extent that the research is
justified by its potential prophylactic, diagnostic or therapeutic value. When medical research is
combined with medical care, additional standards apply to protect the patients who are research
subjects.
29 The benefits, risks, burdens and effectiveness of a new method should be tested against those of the
best current prophylactic, diagnostic, and therapeutic methods. This does not exclude the use of
placebo, or no treatment, in studies where no proven prophylactic, diagnostic or therapeutic method
exists.
30 At the conclusion of the study, every patient entered into the study should be assured of access to the
best proven prophylactic, diagnostic and therapeutic methods identified by the study.
31 The physician should fully inform the patient which aspects of the care are related to the research. The
refusal of a patient to participate in a study must never interfere with the patient-physician relationship.
32 In the treatment of a patient, where proven prophylactic, diagnostic and therapeutic methods do not exist
or have been ineffective, the physician, with informed consent from the patient, must be free to use
unproven or new prophylactic, diagnostic and therapeutic measures, if in the physician's judgement it
offers hope of saving life, re-establishing health or alleviating suffering. Where possible, these measures
should be made the object of research, designed to evaluate their safety and efficacy. In all cases, new
information should be recorded and, where appropriate, published. The other relevant guidelines of this
Declaration should be followed.
CONFIDENTIAL

PR 138 - EQL - 2008 Research Protocol - MPA Injection - Triyasa - English Informed Consent

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BIOEQUIVALENCE STUDY OF 150 MG MEDROXYPROGESTERONE ACETATE

Compound : Medroxyprogesterone acetate

BIOEQUIVALENCE STUDY OF 150 MG MEDROXYPROGESTERONE

Equilab Project Code : PR. 138/EQL/2008

Sponsor : PT Triyasa Nagamas Farma

D. 062/EQL Final version 23/12/2008 Page 1 of 42

Study Personnel and Responsibilities

Sponsor PT Triyasa Nagamas Farma

Study Director Effi Setiawati, Pharm, MSc

Principal Investigator & Danang Agung Yunaidi, MD

Medical/Clinical Investigator Danang Agung Yunaidi, MD

Clinical Laboratory PT Equilab International

Analytical Laboratory Manager Lucia Rat Handayani, Chem

D. 062/EQL Final version 23/12/2008 Page 2 of 42

Study Personnel and Responsibilities (cont.)

Data Management, Atika Rimainar, BSc

Co-Investigators Asriningtyas P.S., Pharm, BSc

Study Monitor Dra. Sorta Saulina, MBA, MM

Quality Assurance Siti Hawa Deniati, Chem, MSc

D. 062/EQL Final version 23/12/2008 Page 3 of 42

Bioequivalence study of 150 mg Medroxyprogesterone acetate injection

Author: Atika Rimainar, BSc

Principal Danang Agung Yunaidi, MD

Location: PT EQUILAB INTERNATIONAL

Telephone No.: +62 21 85911820-22

I, the undersigned, have reviewed this protocol, including Appendices. I will

Principal Investigator Date

D. 062/EQL Final version 23/12/2008 Page 4 of 42

Bioequivalence study of 150 mg Medroxyprogesterone acetate injection

Dra. Sorta Saulina, MBA, MM Date

Danang Agung Yunaidi, MD Date

Lucia Rat Handayani, Chem Date

Siti Hawa Deniati, Chem, MSc Date

Effi Setiawati, Pharm, MSc Date

D. 062/EQL Final version 23/12/2008 Page 5 of 42

D. 062/EQL Final version 23/12/2008 Page 6 of 42

D. 062/EQL Final version 23/12/2008 Page 7 of 42

D. 062/EQL Final version 23/12/2008 Page 8 of 42

Study No : PR. 138/EQL/2008

Compound under investigation : Medroxyprogesterone acetate

Principal Investigator : Danang Agung Yunaidi, MD

D. 062/EQL Final version 23/12/2008 Page 9 of 42

Test Drug, Dose and Mode of Administration :

Duration of the Clinical Phase :

Bioavailability Parameters and Bioequivalence Criteria :

Bioequivalence is concluded if the 90% confidence interval of the Test/Reference geometric

D. 062/EQL Final version 23/12/2008 Page 10 of 42

STUDY TIMEFRAME (TENTATIVE) :

D. 062/EQL Final version 23/12/2008 Page 11 of 42

II. BACKGROUND INFORMATION

2.2 Physicochemical Properties

Medroxyprogesterone acetate is a synthetic progestin. It is a derivative of progesterone (17α-

The commercially medroxyprogesterone injection is available in a sterile aqueous

The chemical name for medroxyprogesterone acetate is 17-hydroxy-6α-methylpregn-4-ene-

Fig. 1. Molecular structure of Medroxyprogesterone acetate

2.3 Pharmacology and Toxicology

Indications and Usage

D. 062/EQL Final version 23/12/2008 Page 12 of 42

Investigator’s signature : __ Date : _

Investigator’s signature : __ Date : _