Conditions: Contraception
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 750
Healthy volunteers: yes

Brief summary:
This is a randomized clinical trial designed to evaluate the effectiveness, safety and acceptability of Sayana® Press when injected every 4 months (17-18 weeks) for 3 treatment cycles (12 months) of use.

Detailed description:
This is a randomized, partially-blinded, multi-center, parallel-group study to evaluate the effectiveness, PK, safety, and acceptability of Sayana® Press when injected every 4 months (17-18 weeks) rather than the currently prescribed 3-month (12-14 weeks) regimen.

A total of 750 healthy, sexually active women aged 18 to 35 years with regular menstrual cycles and no DMPA use in the previous 12 months will be enrolled and followed for pregnancy. Among all enrolled, 710 will be randomized to receive injections in the abdomen or upper thigh in accordance with the PATH Sayana® injection instructions, which are consistent with prescribing information, for the primary effectiveness analysis. An additional 40 women will be randomized to receive injections subcutaneously in the back of the upper arm to assess whether differences in PK may exist which could impact the grace period for reinjections for that injection site.

A single MPA serum sample will be collected from all participants at baseline. All participants will receive re-injections at month 4 and month 8, and complete their scheduled follow-up at month 12. There will be a plus 7-day grace period for re-injections, but women who are up to 28 days late may continue treatment if they have a negative urine pregnancy test. Urine pregnancy testing will be performed at month 4, at study exit and at any other time during the study if clinically indicated. Participants will be evaluated for injection site reactions and asked to provide information on adverse events, prohibited concomitant medication and other contraceptive use, vaginal bleeding, and method acceptability at all regular follow-up visits (i.e., not including the PK visits at Months 2 and 3). Serious adverse events and adverse events leading to product withdrawal, will be recorded throughout the study.

Arms:
arm 1: Sayana® Press (MPA injectable suspension, 104 mg/0.65 mL, pre-filled in the UnijectTM delivery injection system) injected subcutaneously every 4 months (17-18 weeks) for 3 treatment cycles (12 months). arm 2: Sayana® Press (MPA injectable suspension, 104 mg/0.65 mL, pre-filled in the UnijectTM delivery injection system) injected subcutaneously every 4 months (17-18 weeks) for 3 treatment cycles (12 months). arm 3: Sayana® Press (MPA injectable suspension, 104 mg/0.65 mL, pre-filled in the UnijectTM delivery injection system) injected subcutaneously every 4 months (17-18 weeks) for 3 treatment cycles (12 months).

Interventions: intervention 1: Sayana® Press
Intervention descriptions: intervention 1: The active ingredient in Sayana® Press is Medroxyprogesterone acetate (MPA). Sayana® Press (MPA injectable suspension, 104 mg/0.65 mL, pre-filled in the UnijectTM delivery injection system) for subcutaneous injection.

Protocol document:
ICF_000.pdf: 
A Study to Evaluate the Effectiveness, Pharmacokinetics, Safety, and Acceptability of Sayana® Press 
when Injected Every Four Months 
 
 
FHI 360 Study Number 926400 
 
Informed Consent Form Version 4.0, last revised 19 September 2018 
 
NCT03154125 
 


Sayana Press | FHI 360 Study 926400 
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INFORMED CONSENT FORM 
 
A Study to Evaluate the Effectiveness, Pharmacokinetics, Safety, and Acceptability of Sayana® Press 
when Injected Every Four Months 
 
FHI 360 Study Number 926400 
 
 
Study Investigator: [Site to insert] 
Study Sponsor:  FHI 360, 359 Blackwell St, Suite 200, Durham, NC USA 27701 
Funded by: [Site to insert appropriate funder: USAID or The Bill & Melinda Gates Foundation] 
Introduction 
The purpose of this consent form is to give you information to help you decide if you want to participate 
in the research study named above. This consent form may contain some words that are not familiar to 
you. Please ask us to explain anything you do not understand. You will also have a chance to ask 
questions at the end. If you decide to participate, we will ask you to sign this form and give you a signed 
copy of this form.   
Why are we doing this study?  
We are doing this study to find out if Sayana® Press will prevent women from becoming pregnant when 
injected every 4 months instead of every 3 months as currently prescribed. 
General information about the study 
Sayana Press is a new, lower-dose form of the birth control shot Depo-Provera® (also known as DMPA).  
DMPA has been used for over 40 years by millions of women to prevent pregnancy in many countries, 
including Brazil, Chile and the Dominican Republic, where this study is being conducted.  
 
DMPA is injected into the muscle with a long needle. Sayana Press is injected with a short needle under 
the skin (subcutaneously). Both DMPA and Sayana Press are injected every 3 months.  
 
Both Sayana Press and DMPA release medroxyprogesterone acetate (MPA) into the bloodstream. When 
MPA is above a certain level, it prevents ovulation (i.e., when your ovaries produce an egg). We know 
from past studies that Sayana Press is safe and effective at preventing pregnancy when injected every 3 
months. The same studies also showed that MPA may prevent ovulation for 4 months or longer.  
 
Sayana Press is approved for use in many European and African countries.  However, Sayana Press is not 
approved for use in the United States (U.S.), Brazil, Chile or the Dominican Republic (DR). Because 
Sayana Press is not approved for use in your country, it can only be given as part of research. 
  
Approximately 750 healthy, sexually active women between the age of 18 and 35 years old will take part 
in this study. Women in this study will receive Sayana Press injections every 4 months and will stay in 
the study for 12 months. If you decide to participate in this study, you will be assigned by chance (like a 
lottery [or other equivalent local term, for example, throwing dice]), to receive the injection at either 
the abdomen, upper thigh, or upper arm. A computer will pick the injection site. This means neither you 
nor the study staff can choose where you receive the injection.  


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What will happen if you take part in this study? 
If you decide to participate, you will be in the study for about 12 months after you receive your first 
injection.  After today’s visit, you will come to the clinic for the following visits: 
• 
1 enrollment visit  
• 
3 follow-up visits  
 
Screening Visit 
If you agree to be in the study today, we will:  
• 
Explain study procedures  
• 
Ask you to sign this informed consent form 
• 
Ask questions to see if you can be in the study 
• 
Get your contact information 
• 
Schedule your enrollment visit. The visit will be scheduled during the first 5 days of your next 
menstrual period. If you are in the first 5 days of your menstrual period today, the enrollment 
visit may happen today (this does not apply if you also consent to participate in the Vaginal 
Immunity Study).  
 
During today’s visit, you may also be tested for infections passed through sex; given a breast exam, 
pelvic exam, and/or Pap smear, if the study doctor thinks you need it. The visit may last about [site to 
insert]. 
 
Enrollment Visit (Day 0)  
At the enrollment visit, we will:  
• 
Ask you to provide a urine sample for a pregnancy test  
• 
Measure your blood pressure, height and weight  
• 
Ask you about any medical problems or new drugs you are taking 
• 
Ask you about your sexual activity and condom use 
• 
Ask you about your vaginal bleeding pattern 
• 
Draw blood from your arm (about 1 teaspoon), which may be tested to find out if you already 
have MPA in your blood 
• 
Assign you by chance to receive the Sayana Press injection in the abdomen, upper thigh, or 
upper arm 
• 
Give you the injection where assigned 
• 
Tell you when to return to the clinic for your next follow-up visit  
 
The enrollment visit may last about [site to insert]. 
 
Follow-Up Visits (Month 4, Month 8 and Month 12) 
You will have 3 follow-up visits at 4 months, 8 months and 12 months after the enrollment visit, that will 
last about [site to insert].  At these visits, we will:  
• 
Measure your blood pressure and weight  
• 
Ask you about any medical problems or new drugs you are taking 
• 
Ask you about your bleeding patterns and if you like the study method 
• 
Ask you about your sexual activity and condom use since your last visit 
• 
Give you the Sayana Press injection (Months 4 and 8 only) 
• 
Tell you when to return to the clinic for your next follow-up visit  


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• 
Months 4 and 12 only: Ask you to provide a urine sample for a pregnancy test. We will only ask 
you to provide a urine sample for a pregnancy test at month 8 if you are more than 7 days late 
for the visit or if you think you may be pregnant    
It may be necessary for you to make additional visit(s) if you think you may be pregnant, have any 
medical problems or if you are worried about your study participation. 
Are there any possible risks to me? 
Risks of Sayana Press 
Sayana Press can cause side effects, although not everyone gets them.  There is no way to stop the 
action of the drug once it is given to you. Possible side effects may include irregular bleeding or no 
bleeding, headache, dizziness, breast swelling, bloating, mood changes, decreased sexual desire, weight 
gain or vaginal discharge. Serious health problems related to Sayana Press are very rare.  
 
Pregnancy 
When Sayana Press is injected every three months, less than 1 out of 300 women get pregnant. We do 
not know how well Sayana Press will prevent pregnancy when injected every four months, that is why 
we are doing this study. You may become pregnant during the course of the study. We will test you for 
pregnancy during the study at the 4 and 12-month visit, if you have signs of pregnancy, or think you 
might be pregnant.  If you become pregnant, we will draw blood from your arm (about 1 teaspoon) to 
test for MPA, the active drug in Sayana Press.  You will continue as a participant in the study, however, 
you will no longer receive the injections and you will not need to come for follow-up visits. Instead we 
will call you to ask about your pregnancy outcome. Due to the long-acting nature of the drug, the drug 
may remain in your body for some time after you get pregnant. Importantly, if you become pregnant it 
is very unlikely that your baby will have any health problems. Many studies have found that babies who 
are exposed to DMPA while in the womb do not have a higher risk of birth defects or health problems.   
 
You may not join this study if you are currently pregnant or wish to become pregnant in the next 18 
months. 
 
Injection Site Reactions 
About 1 out of every 10 women who receive Sayana Press has a mild skin reaction at the place of the 
injection. This reaction may include pain or tenderness, lump or dimpling. Most of these reactions go 
away quickly. Some women may have a permanent thickening of the skin at the place of injection but 
this is very rare (less than 1 out of every 1000 women). If you have any problems, we will look carefully 
at the place of injection for possible reactions. If necessary, a photograph of the injection site will be 
taken to document the changes in the skin.    
 
Menstrual Changes 
Most women have some changes in their menstrual bleeding while using Sayana Press. These changes 
may include irregular bleeding, spotting or no bleeding at all (which is not dangerous to your health). 
Some women might also experience heavy bleeding during the first few months after the injection.  If 
your bleeding was disrupted while using Sayana Press, it should be back to normal within 12 months 
after the last injection. 
 
Weight Gain 
Some women gain weight while using Sayana Press (about 1.6 kg in a year).  It is possible that you will 
gain a small amount of weight from participating in this study.   


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Risk of HIV 
Some studies have shown that risk of getting HIV may be higher among women using DMPA, but others 
did not show this link. We don’t know for sure if the risk of getting HIV is increased among DMPA users. 
Recently, the World Health Organization (WHO) – a global group that coordinates international health 
information - stated that women who are at high risk of HIV can use DMPA but should be informed of the 
possible increased risk of HIV with DMPA use.  Women who are not at high risk of HIV can use DMPA 
without restriction. No studies have assessed the relationship between Sayana Press and HIV, but we are 
providing you this information because DMPA and Sayana Press contain the same active ingredient.  
  
Neither DMPA nor the Sayana Press injection directly cause HIV infection. The main ways that a person 
can reduce the risk of HIV and other sexually transmitted infections (STIs) are: to not have sex; to use 
condoms during sex; to not share IV drug needles; or to only have one sexual partner who does not have 
HIV.  
 
Sayana Press does not protect you against STIs, including HIV. If you think you are at risk of HIV or you or 
your partner have HIV, you cannot join the study. During the study, if you feel you may be at risk of STIs 
and/or HIV, you should use condoms every time you have sex.  
 
Return to fertility 
Your usual level of fertility will return when the last injection has worn off. This time varies in different 
women.  In most women, the effect will have worn off 5 to 6 months after the last injection.  Although 
you may be able to get pregnant quickly, it is more likely to take a year or longer after your last injection 
before you get pregnant.”. This is why you can only join the study if you do not want to get pregnant in 
the next 18 months.  
 
Bone Mineral Density 
Women who use Sayana Press tend to have lower bone mineral density than women of the same age 
who have never used it. The effects of Sayana Press are greatest in the first 2-3 years of use. Bone 
mineral density generally improves after Sayana Press is stopped. It is unlikely that 3 injections of Sayana 
Press you will receive as a part of this study will have any effect on your bones.  
 
Other Risks  
 
Potential Drug Interactions 
There are some medicines (prescription and non-prescription) that may cause problems when taken 
with Sayana Press.  We will carefully review all of the medicines you are taking before giving you Sayana 
Press. Please tell us before you take any new medicines while you are in the study.  You may tell your 
other health care providers that you are participating in this study if you wish.  
 
Risk from Blood Draw 
You may feel slight discomfort or feel dizzy when blood is drawn from your arm. You may have a bruise 
or swelling at the site of the blood draw. You may get an infection at the site of blood draw, but this is 
very rare.  
 


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Are there any possible benefits to me? 
There are no direct study benefits to you. If Sayana Press prevents pregnancy well when injected every 4 
months, this information will be helpful to women who need long-acting birth control methods.  
Confidentiality 
We will do our best to prevent anyone outside the study from knowing about you and your part in this 
study, but there is always a chance that others may learn something about you during participation. All 
study files that list your name will be kept in a locked file. The information you give us will be sent to FHI 
360 in North Carolina, USA. When it is sent, only a number will identify you, not your name. Your name 
will not appear on any study report.  
 
FHI 360 staff working on the study may look at your records to monitor the study quality and progress. 
The study funder (USAID), ethics review committees and/or [site to insert Regulatory Authority, if 
applicable] may also review your records.  
 
The study data will be shared with USAID and might be used for future research.  However, the shared 
data will not contain any identifying information about you. 
 
We may also request to review your medical records relating to any care you receive during the study, 
even if you receive this care at another clinic. We will keep all the information about you confidential, to 
the best of our ability. 
 
If you agree to be in the study, we will ask you how you want us to contact you during the study. If you 
miss a scheduled visit, we may contact you by using only the methods you approved. 
 
The study is registered on clinicaltrials.gov, a U.S. website listing clinical studies with human participants 
conducted around the world. Identifying information about you will not be included on this website.   
Are there any costs to you if you join the study? 
There will be no costs for you to participate in this study.  
Will I receive compensation during the study? 
We will pay to compensate for your time and travel as follows: [site to insert visit specific amounts]. We 
will pay you at the end of each visit. We will not pay you for visits that you do not attend.  Participation 
in the study will not affect fees, payment, billing, or reimbursement for any other services at the clinic.  
What will happen if you do not join the study? 
Participation in this study is voluntary, you can decide if you want to be in this study or not. If you 
choose to join the study, you can change your mind at any time and leave the study. Your choices will 
not affect any care you receive now or in the future. We will tell you if we find any new information that 
could affect your choice to stay in the study.  
Alternatives to Participation  
You do not have to participate in the study in order to receive contraception. Other contraceptive 
options are available outside of the study.   


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What if you have a problem or have questions? 
If you have any questions about this study, you can contact: [site to insert] 
What if you get sick or have a health problem? 
If you experience a health problem or think you may be pregnant at any time during the study, you 
should come to the clinic right away. You can also contact us by phone: [site to insert contact 
information]. 
 
If you are sick or have a health problem because of being in this research study, medical care will be 
available to you. This medical care that is required as a result of a health problem caused by your 
participation in the study, will be covered by [site to insert], at no cost to you.  
What if you become pregnant? 
If you become pregnant during the study you will no longer receive the injection and you will not need 
to come for regular follow-up visits. However, you will remain in the study because we want to obtain 
information about your pregnancy and baby. Study staff will refer you to available medical care and 
other services you may need. The study does not pay for this care. 
What are your rights as a participant? 
This research was reviewed and approved by [site to insert IRB information] and the Protection of 
Human Subjects Committee at FHI 360. These committees review research studies in order to help 
protect participants. If you have any questions about how you are being treated by the research staff, or 
your rights as a research participant, you may contact: [site to insert IRB contact information] 
New information about the study 
We will tell you about any new information we learn during the study that may affect whether you want 
to continue to be in the study. 
 
 
 
 


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                                                                PARTICIPANT AGREEMENT                   Participant ID # ___________ 
 
I have been told what will happen if I take part in the study titled, “A Study to Evaluate the Effectiveness, 
Pharmacokinetics, Safety, and Acceptability of Sayana® Press when Injected Every Four Months,” 
including the risks and benefits.  
 
I have had a chance to ask questions, and my questions were answered to my satisfaction. I have been 
told that the people listed in this form will answer any questions I have in the future. Study staff will give 
me a copy of this consent form. By signing below, I voluntarily agree to be in this research study. 
 
 
____________________________________________ 
__________________ 
Printed Name of participant 
 
 
Date (dd/MON/yyyy) 
 
____________________________________________              
Signature of participant 
               
                              
  
I have carefully explained to the volunteer the nature and purpose of this study. The participant has 
been given enough time to decide whether to participate or not. The volunteer has had a chance to ask 
questions and receive answers about this study. The participant has demonstrated appropriate 
understanding of the information provided. 
 
____________________________________________ 
Printed Name of Person Who Obtained Consent 
 
____________________________________________           __________________ 
Signature of Person Who Obtained Consent 
 Date (dd/MON/yyyy) 
 


 
Sayana Press Extension | FHI 360 Study 926400 
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ICF | Version 3.0 
 
Approved by PHSC: 8 September 2017 
ADDENDUM INFORMED CONSENT FOR PARTICIPATION IN OPTIONAL VISITS AND PROCEDURES 
 
A Study to Evaluate the Effectiveness, Pharmacokinetics, Safety, and Acceptability of Sayana® Press 
when Injected Every Four Months 
 
FHI 360 Study Number 926400 
 
 
We are asking 120 women participating in this study to provide a sample of blood (no more than 1 
teaspoon) at each of their study follow-up visits to test for MPA, the active drug in Sayana Press. These 
women will also be asked to come to the clinic for 2 extra follow-up visits. This testing will help us 
understand how long MPA remains in the blood.  
 
The extra visits and blood draws are optional procedures. You do not have to agree to the optional 
procedures to join this study.  
 
Additional procedures 
If you agree to participate in this part of the study, at the enrollment visit, we will:  
• 
Test the blood that we draw from your arm to make sure that you don’t already have MPA in 
your blood 
• 
Randomly (like flipping a coin) assign you to receive the Sayana Press injection in the abdomen, 
upper thigh or in the upper arm.  
 
During your Months 4, 8, and 12 follow-up visits, in addition to the other study procedures, we will:  
• 
Draw blood from your arm for MPA testing 
 
Additional Visits 
You will come to the clinic for 2 additional follow-up visits at Months 2 and 3. At these visits, we will: 
• 
Draw blood from your arm for MPA testing 
 
Risk from Blood Draw 
You may feel slight discomfort or feel dizzy when blood is drawn from your arm. No more than 5 cc of 
blood (approximately 1 teaspoon), will be drawn at each visit. You may have a bruise or swelling at the 
site of the blood draw. You may get an infection at the site of blood draw, but this is very rare.  
  
Will I receive compensation for the optional visits and procedures? 
We will pay to compensate for your time and travel as follows: [site to insert visit specific amounts]. 
 
 
 
 


 
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PARTICIPANT AGREEMENT FOR OPTIONAL VISITS AND PROCEDURES 
Participant ID # ___________ 
 
I have been told that I do not have to agree to the optional procedures to join this study.  I have had a 
chance to ask questions, and my questions were answered to my satisfaction. Study staff will give me a 
copy of this consent form. By signing below, I voluntarily agree to take part in the optional study visits and 
procedures.  
 
____________________________________________ 
__________________ 
Printed Name of participant 
 
 
Date (dd/MON/yyyy) 
 
____________________________________________              
Signature of participant 
               
                              
  
 
I have carefully explained to the volunteer the nature and purpose the optional study visits and 
procedures. The participant has been given enough time to decide if she wants to participate. The 
volunteer has had a chance to ask questions and receive answers about the optional procedures. The 
participant has demonstrated appropriate understanding of the information provided. 
 
____________________________________________ 
__________________ 
Printed Name of Person Who Obtained Consent  
Date (dd/MON/yyyy) 
 
____________________________________________            
Signature of Person Who Obtained Consent 
  
 
 
 

SAP_002.pdf: 
 
Statistical Analysis Plan (Version 3.0) 
 
Page 1 of 18 
Study 926400: Sayana Press Extension 
 
Last revised: 28 May 2020 
A Study to Evaluate the Effectiveness, Pharmacokinetics, Safety, and 
Acceptability of Sayana® Press when Injected Every Four Months 
FHI 360 Study Number 926400 
Statistical Analysis Plan, Version 3.0 
 
 


Statistical Analysis Plan (Version 3.0)
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STATISTICAL ANALYSIS PLAN APPROVAL
Study No.:
926400
Study Title:
A Study to Evaluate the Effectiveness, Pharmacokinetics, Safety, and Acceptability 
of Sayana® Press when Injected Every Four Months
Author:
Rachael Fuchs, MS
Lead Biostatistician, Global Health and Population Research, FHI 360
______________________________________________________________________________
Approver:
Jen Deese, PhD, MPH, CCRP
Date
Study Director, Contraceptive Technology Innovation Department
FHI 360
______________________________________________________________________________
Approver:
Laneta Dorflinger, PhD
Date
Director, Contraceptive Technology Innovation Department
FHI 360
______________________________________________________________________________
Approver:
Douglas Taylor, PhD
Date
Senior Advisor, Quantitative Sciences, Product Development and Introduction
On behalf of Mario Chen, Director of Biostatistics
FHI 360


 
Statistical Analysis Plan (Version 3.0) 
 
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Study 926400: Sayana Press Extension 
 
Last revised: 28 May 2020 
STUDY SUMMARY 
Title:  
A Study to Evaluate the Effectiveness, Pharmacokinetics, Safety, and Acceptability 
of Sayana® Press when Injected Every Four Months 
FHI 360 Study #:  
926400 
Design:  
 
Randomized, multi-center, parallel-group study 
Investigational Drug:  Sayana® Press (medroxyprogesterone acetate injectable suspension, 104 
mg/0.65 mL) 
Active Ingredient: 
Medroxyprogesterone acetate (MPA) 
Phase of Study:  
3 
Number of Centers1:  3 
Countries Planned: 
Brazil, Chile, and Dominican Republic  
Study Duration:  
Recruitment is expected to take 9 months and each participant will be followed 
for 12 months of product use. The total study duration is anticipated to be 33 
months, including initiation activities, analysis, and reporting. 
Study Population: 
A total of 750 healthy, sexually active women between 18 and 35 years of age 
who are willing to use Sayana® Press injected every 4 months as their only 
means of contraception for 12 months.  
Primary Objective: 
To evaluate the effectiveness of Sayana® Press injected subcutaneously every 4 
months in the abdomen or upper thigh for 12 months (3 treatment cycles) of 
use. 
Primary Endpoint:
Pregnancy 
Secondary Objectives:  1) To assess trough concentrations, accumulation and apparent terminal half-
life of MPA, and the impact of subcutaneous injection site (abdomen, upper 
thigh, or back of the upper arm) on these parameters, when Sayana® Press is 
injected every 4 months for 12 months of use; 
2) To evaluate the safety of Sayana® Press when injected every 4 months for 12 
months of use;  
3) To evaluate the acceptability of Sayana® Press when injected every 4 months 
for 12 months of use. 
Secondary Endpoints:  Serum MPA concentrations on day 0 (baseline), months 2, 3, 4, 8, and 12 after 
treatment initiation (subset of 120 participants, only); serious adverse events 
and adverse events leading to product withdrawal; injection site reactions (ISR), 
bleeding patterns, blood pressure, and body weight; and responses to 
acceptability questions. 
 
1 The protocol refers to the three locations where the study will take place as study sites. This document will refer 
to them as centers to avoid confusion with the randomized injection sites. 


 
Statistical Analysis Plan (Version 3.0) 
 
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Study 926400: Sayana Press Extension 
 
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Exploratory Objective: To evaluate return to ovulation among a subset of study participants who 
received month 4 and month 8 injections and plan to use non-hormonal 
methods of contraception, or no contraception, for up to a maximum of 12 
months from the last study injection.  
Exploratory Endpoint: Return to ovulation, where ovulation is defined as a single elevated serum 
 or a confirmed pregnancy test. 
 
 


 
Statistical Analysis Plan (Version 3.0) 
 
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TABLE OF CONTENTS 
 
I. 
Introduction ...................................................................................................................... 7 
II. 
Study Design and Procedures............................................................................................... 7 
III. 
General Analytic Considerations....................................................................................... 7 
A. Study Size and Power ...................................................................................................... 7 
B. 
Data Source.................................................................................................................... 8 
C. 
Missing Data .................................................................................................................. 8 
D. Covariate Adjustment...................................................................................................... 8 
E. 
Test Size and Confidence Levels ........................................................................................ 8 
IV. 
Randomization, Allocation Concealment, and Blinding ........................................................ 8 
A. Randomization ............................................................................................................... 8 
B. 
Allocation Concealment ................................................................................................... 9 
C. 
Blinding ......................................................................................................................... 9 
V. 
Analysis Populations and Analysis Sets ................................................................................10 
A. Treated Population ........................................................................................................10 
i. 
Safety Analysis Set .......................................................................................................10 
ii. 
Treated Analysis Set.....................................................................................................10 
iii. Perfect use Analysis Set ................................................................................................10 
B. 
Pharmacokinetics Population and Analysis Set..................................................................11 
VI. 
Blind Review of Data ......................................................................................................11 
VII. 
Analysis of Baseline Data ................................................................................................11 
VIII. 
Analysis of Participant Disposition Data............................................................................12 
IX. 
Analysis of Primary Study Objective .................................................................................12 
A. Primary Objective and Endpoint ......................................................................................12 
B. 
Primary Efficacy Analysis ................................................................................................12 
C. 
Secondary Efficacy Analysis .............................................................................................13 
X. 
Analysis of Secondary Study Objectives ...............................................................................14 
A. Pharmacokinetics of MPA ...............................................................................................14 
B. 
Safety ...........................................................................................................................15 
C. 
Acceptability .................................................................................................................15 
XI. 
Analysis of Exploratory Study Objective ............................................................................16 
XII. 
Additional Data Summaries .............................................................................................16 
XIII. 
Sensitivity Analyses ........................................................................................................16 
XIV. 
Planned Interim Analyses................................................................................................17 


 
Statistical Analysis Plan (Version 3.0) 
 
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XV. 
MPA Testing of Baseline Serum Specimens .......................................................................17 
XVI. 
Appendices ...................................................................................................................18 
A. Visit Windows for MPA Measurements (PK Cohort Only) ....................................................18 
B. 
Changes to the Analysis Plan after Approval of Version 1.0 .................................................18 
i. 
Changes implemented in SAP version 2.0 ......................................................................18 
ii. 
Changes implemented in SAP version 3.0 ......................................................................18 
 
 
 


 
Statistical Analysis Plan (Version 3.0) 
 
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I. 
Introduction 
This statistical analysis plan (SAP) is an expanded version of the summary analysis plan included 
in the protocol (v8.0-B) approved by the FHI 360 PHSC on 4 February 2020. Any significant 
changes made to this plan after study initiation (including those made to address revisions to 
the protocol) will be documented in an Appendix and using footnotes. Mock tables, figures and 
listings (TFLs) designed to capture the results of analyses will be approved by the Study Director 
prior to any un-blinding. 
II. 
Study Design and Procedures
This is a three-arm, randomized, partially blinded, multi-center, parallel-group study to evaluate 
the effectiveness, pharmacokinetics (PK), safety, and acceptability of Sayana® Press when 
injected every 4 months (17-18 weeks) for 3 treatment cycles (12 months) of use. A total of 750 
healthy, sexually active women aged 18 to 35 years with regular menstrual cycles and no DMPA 
use in the previous 12 months will be enrolled and followed for pregnancy. Among all enrolled, 
710 will be randomized to receive subcutaneous (SC) injections in the abdomen or upper thigh 
in accordance with the PATH Sayana injection instructions, which are consistent with 
prescribing information, for the primary effectiveness analysis. An additional 40 women will be 
randomized to receive SC injections in the back of the upper arm to assess whether differences 
in PK may exist which could impact the grace period for reinjections for that injection site. 
Treatment will begin in the first 5 days of menses. A single MPA serum sample will be collected 
from all participants at baseline. All participants will be scheduled to receive re-injections at 
month 4 (approximately 17 weeks after treatment initiation) and month 8 (approximately 35 
weeks after treatment initiation) and complete their planned follow-up at month 12 
(approximately 53 weeks after treatment initiation). There will be a plus 7-day grace period for 
re-injections, but women who are up to 28 days late may continue treatment if they have a 
negative urine pregnancy test. Urine pregnancy testing will be performed at month 4, at study 
exit, at month 8 if the participant is more than 7 days late for her visit, and at any time during 
the study if clinically indicated. Participants will be evaluated for injection site reactions and 
asked to provide information on adverse events, prohibited concomitant medications and other 
contraceptive use, vaginal bleeding, and method acceptability at months 4, 8 and 12. 
Information on adverse events and use of any prohibited concomitant medications will be 
recorded if reported by participants at month 2 and 3 PK visits and at any unscheduled visits.  
III. 
General Analytic Considerations 
A. Study Size and Power 
The sample size of 710 women receiving injections in the abdomen or upper thigh is expected 
to be sufficient to ensure that the difference between the estimated Pearl Index (pregnancies 
per 100 woman-years of use) and the corresponding upper 95% confidence bound does not 
exceed 1.0, so long as the observed Pearl Index is less than 0.75 and at least 80% of participants 
complete 12 months of follow-up. (The study has a 90% chance of achieving this precision 
target if the true (unobserved) pregnancy rate is no more than 0.5 per 100 women-years). In 


 
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addition, a cohort of 120 women (40 receiving injections in each the abdomen, upper thigh, and 
back of the upper arm) is sufficient to provide 85% power to detect 30% relative differences in 
PK parameters between injection sites, assuming the coefficient of variation is no more than 
40% and using two-sided 0.05 level significance tests. 
B. Data Source 
Data management (DM) plans are detailed in a separate study-specific document. Briefly, study 
center data are recorded on paper case report forms (CRFs) which are scanned by the study 
centers and entered into a clinical database management system at FHI 360. Data will be 
verified by study monitors and appraised for consistency by FHI 360 DM staff using both 
automated logical checks and manual review. A trained medical coder at FHI 360 will code all 
SAEs, AEs leading to product withdrawal, and AEs that are Grade 1 or higher ISRs using the 
Medical Dictionary for Regulatory Activities (MedDRA). Any adjudication of estimated dates of 
fertilization or other endpoint data will be performed following FHI 360 Standard Operating 
Procedures (SOPs). A central laboratory (PPD Development) will perform serum MPA testing, 
with results transferred to FHI 360 DM via password-protected Excel files. FHI 360 DM will 
create SAS datasets (version 9.4 or higher) containing lab and CRF data for use by 
biostatisticians conducting interim and final analyses. 
C. Missing Data  
It is anticipated that some event dates required for safety analyses may be incomplete. Decision 
rules for how and when to impute such incomplete date fields will be developed and 
documented by the medical monitor when reviewing study data and be documented in any 
study report produced. All other missing data will be ignored (i.e., treated as missing at 
random) unless patterns are identified through exploratory analysis which suggest the potential 
for biased assessments of efficacy, safety, PK, or acceptability. In the event such patterns are 
identified, rules for imputing data will be clearly described and justified in the study report. 
D. Covariate Adjustment 
The primary efficacy analysis will adjust for study center through stratification. Any other 
adjustments for covariates are addressed in the relevant sections below. 
E. Test Size and Confidence Levels 
Unless otherwise noted, all confidence intervals reported for the primary, secondary, and 
subgroup analyses will be computed at the 95% coverage level, and all p-values will be assessed 
at the two-sided 0.05 significance level, with no adjustment for multiple testing. 
IV. 
Randomization, Allocation Concealment, and Blinding 
A. Randomization 
All participants will receive the same study drug, Sayana® Press, and will be randomized to 
receive their injections in one of three subcutaneous injection sites: abdomen, upper thigh, or 
back of the upper arm. One cohort of N=630 will be randomized 1:1 to receive their 
subcutaneous injections of Sayana® Press in the abdomen or upper thigh, and a second PK 
cohort of N=120 women who agree to serum MPA testing at 6 time points (baseline and 


 
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months 2, 3, 4, 8, and 12) will be randomized 1:1:1 to receive their injections in the abdomen, 
upper thigh, or back of the upper arm. Using this randomization scheme, 355 women will 
receive their injections in the abdomen, 355 in the upper thigh, and 40 in the back of the upper 
arm. Randomization in each cohort will use randomly-permuted blocks, stratified by study 
center and cohort with the following planned enrollment totals at each site: 250 at the center 
in Brazil (UNICAMP), 150 at the center in Chile (ICMER), and 350 at the center in the Dominican 
Republic (Profamilia). Within these totals, 42 at Profamilia, 36 at ICMER, and 42 at UNICAMP 
will be randomized in the PK cohort and the remainder of the enrollment total at each center 
will be randomized in the primary cohort. Randomization sequences will be created for each 
combination of study center and cohort by an FHI 360 Randomization Statistician using a 
validated program written in SAS® version 9.4 or higher. Recognizing that actual numbers of 
participants enrolled at each site may change during the enrollment period due to center 
performance or other issues, additional randomization numbers will be generated for the 
primary cohort within each center to allow one or two centers to expand enrollment to 
compensate for reduced enrollment at the remaining center(s)2. 
B. Allocation Concealment 
Treatment assignments will be concealed within sealed, opaque, sequentially numbered 
randomization envelopes provided to each study center. Each envelope will have the 
randomization number printed on the outside, with the corresponding SC injection site 
assignment concealed within. The randomization envelopes will be maintained in a secure 
location at each study center, with access limited to authorized personnel per center-specific 
study procedures. Trained center staff will open the next available envelope (from the 
appropriate sequence of envelopes based on which cohort the participant consented to), and 
allocate the next treatment assignment, only after a participant has been confirmed to be 
eligible, consented to participate, and undergone all other enrollment procedures, including 
having a blood sample collected for MPA testing among women agreeing to participate in the 
PK cohort.  
C. Blinding 
Since this study is not randomizing study drug but rather site of SC injection, neither 
participants nor center staff will be blinded. However, laboratory staff analyzing serum MPA 
specimens and staff at FHI 360 responsible for adjudicating pregnancy outcomes and coding 
adverse events will be blinded to individual participant injection site assignments for the 
 Other FHI 360 staff may review interim PK data, 
including MPA concentrations of any women who become pregnant, to inform other FHI 360 
MPA projects (see DSMB Operational Plan for details on timing of any un-blinded review of PK 
data). 
 
2 In September 2018, 100 of the planned enrollment total for UNICAMP, Brazil were shifted to Profamilia, DR due 
to study timelines and slower than expected enrollment at the UNICAMP center. 


 
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V. 
Analysis Populations and Analysis Sets 
In the below definitions, an Analysis Population refers to a particular set of participants and an 
Analysis Set defines the time contributed to analyses by participants in a given Population. 
Additional censoring rules for analyses based on these sets are described in relevant sections. 
A. Treated Population  
The Treated Population consists of all enrolled participants who receive a dose of study drug. 
Unless noted otherwise, all analyses based on this population will be performed per intention-
to-treat principles, ignoring any randomization errors, allocation errors, or the receipt of 
injections during follow-up that differ from the baseline injection site. 
i. 
Safety Analysis Set
The Safety Analysis Set includes all follow up time contributed by each participant in the 
Treated Population, including time in the 8-
.  
ii. 
Treated Analysis Set 
The Treated Analysis Set includes follow up time contributed by each participant in the Treated 
Population and censors time in analysis for each woman at the earlier of the following: her 
estimated date of fertilization (EDF) (for women becoming pregnant), her last negative urine 
pregnancy test (for women who do not become pregnant), and the date that is 7 days after her 
last target visit date. In addition, The Treated Analysis Set excludes any follow-up time 
contributed by a woman when she was 8 to 28 days late for a re-injection. 
For example, a woman who returns on week 20 rather than week 17 for her month 4 re-
injection (i.e., 2 weeks past her 7-day grace period) but who returns precisely at 18-week 
intervals for her month 8 and final visit without becoming pregnant, would contribute 56 
(20 + 18 +18) weeks to the Safety Analysis Set but only 54 (18 + 18 +18) weeks to the 
Treated Analysis Set.    
iii. 
Perfect use Analysis Set 
The Perfect Use Analysis Set is a subset of the Treated Analysis Set, excluding any time 
during which a participant reported using another contraceptive method (including 
condoms) or drugs known to impact ovarian function or PK of MPA, unless she became 
pregnant in that period and the drug being used is known to only increase the risk of 
pregnancy among women using injectable DMPA. Exclusionary periods for prohibited drugs 
or contraceptive methods other than condoms will be determined based on the start and 
end dates provided on the corresponding concomitant medication form. If the end date is 
missing or indicated as ongoing, then all follow-up time after the reported start date will be 
excluded. Periods of exclusion for condom use will be determined based on a question with 
three options recorded on the FU CRF at each visit. If a participant reports using condoms in 
the last 4 weeks and at any other time since the last injection, then all time since the 
previous injection date will be excluded; if a participant reports using condoms since last 
injection but not in the last 4 weeks, then only the time between the previous injection date 
and the date which is 4 weeks prior to the report visit will be excluded; and if a participant 


 
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reports using condoms in the last 4 weeks but not at any other time since last injection, 
then only the last 4 weeks prior to the report visit will be excluded.
B. Pharmacokinetics Population and Analysis Set 
The Pharmacokinetics (PK) Population is a subset of the Treated Population. The PK Population 
includes participants who agreed to serum MPA testing at 6 timepoints and were randomized 
into the PK cohort but excludes participants who did not contribute blood specimens for PK 
assessments, who had a baseline serum MPA concentration exceeding 0.05 ng/mL, or who 
required the use of more than one Sayana Press unit for their baseline injection (based on 
information provided on the injection CRF)3. The corresponding Pharmacokinetics Analysis Set 
will censor data collected after a participant receives an injection in an anatomical site which 
differs from the site used at enrollment and will exclude any MPA specimens collected during a 
time when a participant reports using a concomitant medication that may impact the PK of 
MPA as defined in the protocol. During the coding process, the medical monitor will define the 
length of the period 
s on a 
medication-specific basis. The Analysis Set will also exclude MPA results from any blood 
samples collected after an injection where more than one Sayana Press unit was inserted into 
it inserted at her month 4 
injection, then blood samples collected at months 8 and 12 would be excluded from the 
analysis set for that participant). PK analyses based on this analysis population will be 
performed according to the site of injection at enrollment, even if it was assigned or was 
received in error. 
VI. 
Blind Review of Data
As indicated above, neither participants nor center staff will be blinded to injection sites. 
However, to the extent possible, decisions regarding additions or modifications to planned 
analyses, determination of exclusion from analysis populations or analysis sets, and rules for 
handling missing or incomplete data will be made by statisticians, clinicians, or other study staff 
who do not have access to individual treatment data. The actual level of blinding maintained 
when performing these activities will be described in the clinical study report.
VII. 
Analysis of Baseline Data 
Baseline data will be presented for the Treated and PK Analysis Populations by injection site, 
study center, and pooled across injection sites and study center. Demographic and baseline 
characteristics, including medical history and concomitant medication use, will be provided in 
participant-specific listings and summarized using appropriate measures (frequencies and 
percentages for categorical data; means, standard deviations, standard errors, medians, 
minima, and maxima for continuous data). Differences in distributions of these characteristics 
 
3 At the time of injection, some Uniject devices were discovered to have malfunctioned after the needle had 
guarantee that no product was injected from the first device, we chose to exclude affected results.  


 
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between study centers will be assessed using exploratory analysis of variance for continuous 
 
VIII. 
Analysis of Participant Disposition Data 
Participant disposition data will be presented for the Treated and PK Analysis Populations, by 
injection site, study center, and pooled across injection sites and study centers. The numbers of 
participants screened, screened but not enrolled (including reason(s) not enrolled), 
randomized, treated (including reason(s) not treated, if any), and final status (e.g., early 
withdrawal (and reason), completed the study, etc.) will be summarized using frequencies and 
percentages. A diagram showing the flow of participants through the trial will be provided, as 
will a listing including study center, inclusion in the PK cohort, randomized injection site, actual 
injection site, final study status, and any other information that the study team determines to 
be relevant. Protocol violations will be provided in a listing and may also be summarized in a 
table using frequencies and percentages of violations falling into each of the categories given by 
violation category may be 
divided into additional categories if consistent themes appear. 
IX. 
Analysis of Primary Study Objective 
A. Primary Objective and Endpoint 
The primary study objective is to evaluate the effectiveness of Sayana® Press when injected 
subcutaneously every 4 months in the abdomen or upper thigh for 12 months (3 treatment 
cycles) of use. The primary endpoint is the occurrence of pregnancy, as defined by a positive 
urine pregnancy test. Positive urine tests will be confirmed by ultrasound and/or serum hCG 
testing whenever possible. The EDF for each pregnancy will be calculated by a qualified study 
clinician based on ultrasound and last menstrual period (LMP) in accordance with the study 
Medical Monitoring Plan. In the absence of ultrasound or LMP, best clinical judgment will be 
used to estimate the EDF based on all available related information including but not limited to 
vaginal bleeding, patterns of coitus, and the timing of previous negative pregnancy test results.  
Information on any pregnancies, miscarriages or abortions diagnosed outside the study center 
will be collected during follow-up interviews. Any such pregnancies with EDF determined to be 
within the treatment period will be included in the primary efficacy analysis unless the site 
investigator and study clinician unambiguously determine that the pregnancy diagnosis was 
incorrect and/or the self-reported data was unreliable.  
B. Primary Efficacy Analysis 
The primary efficacy analysis will be performed using the Treated Population4 and the Treated 
Analysis Set. Recognizing the plus 7-day grace period for re-injections, pregnancies with an EDF 
 
4 Exclusion of participants from the primary efficacy analysis based on protocol violations occurring at enrollment 
(such as participant being enrolled while ineligible) will be considered on a case-by-case basis. A decision regarding 
inclusion of the participant will be made by the principle investigator in consult with the medical monitor and lead 
biostatistician. If possible, the decision will be made while these staff remain blinded to injection site and before 
 


 
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up to 18 weeks (126 days) after the first (enrollment) injection or up to 19 weeks (133 days) 
after subsequent re-injections will be included in the primary efficacy analysis. 
The primary analysis of efficacy will be based on the pregnancy Pearl Index, defined as the 
number of pregnancies that occur during the treatment period per 100 women-years of time 
contributed to the Treated Analysis Set among women randomized to receive injections in the 
abdomen or thigh. Participants who do not become pregnant or who have EDFs that fall outside 
the windows used to define primary outcomes will be censored on the date of last negative 
urine pregnancy test or the end of the plus 7-day grace period since last injection, whichever is 
earlier. An exact 95% confidence interval for the Pearl Index will be computed based on an 
assumption that the number of pregnancies occurring in the treatment period follows a Poisson 
distribution. A listing of all participants who become pregnant during the study will include at 
least study center, randomized injection site, days on treatment until EDF, inclusion in the 
primary efficacy analysis, and pregnancy outcome. 
C. Secondary Efficacy Analysis 
Secondary efficacy analyses will include:  
 Typical use life-table estimates of the cumulative probability of pregnancy through 3 
treatment cycles, based on the Treated Population and Safety Analysis Set (excluding 
women randomized to receive injections in the upper arm). Point-wise 95% confidence 
intervals will be computed using the log-log transformation. For this analysis, the first, 
second and third treatment cycle can be up to 21, 22, and 22 weeks long, respectively (after 
accounting for up to a 28-day late period for re-injections or final study visit).
 An estimate of the Pearl Index computed based on the Perfect Use Analysis Set (excluding 
participants randomized to receive injections in the upper arm).  
 An estimate of the Pearl Index based on the Treated Population and Safety Analysis Set 
(excluding participants randomized to receive injections in the upper arm). This estimate 
will include all follow-up time contributed (regardless of pregnancy status) and any 
pregnancies detected while participants are up to 28 days late for their visits.  
 An estimate of the Pearl Index computed per the primary analysis, but including women 
randomized to receive injections in the upper arm. 
In addition to the non-comparative analyses listed above, a Pearl Index based on the Treated 
Analysis Set will be computed separately for participants randomized to receive injections in 
the abdomen, thigh, and upper arm. Difference in pregnancy risk between groups will be 
assessed using a log-rank test stratified on study center. If pregnancy events are sufficiently 
rare so as to make this test inappropriate, this difference will be assessed using 95% confidence 
intervals for incident rate ratios based on Poisson distribution assumptions instead. If at least 5 
pregnancies occur in one or more of the injection site groups, then the cumulative risk of 
pregnancy in each group will also be estimated using life-tables methods.  
 
results of any pregnancy tests are known for the participant in question. The actual level of blinding when 
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X. 
Analysis of Secondary Study Objectives 
The secondary study objectives are to assess the following when Sayana® Press is injected every 
4 months for 12 months of use: 1) trough concentrations, accumulation, and apparent terminal 
half-life of MPA, and the impact of subcutaneous injection site (abdomen, upper thigh, or back 
of the upper arm) on these parameters, 2) the safety of Sayana® Press, and 3) the acceptability 
of Sayana® Press.
A. 
Pharmacokinetics of MPA 
PK endpoints include serum MPA concentrations at baseline and months 2, 3, 4, 8, and 12. 
Post-baseline MPA concentrations that fall below the limit of quantification (LOQ) will be 
replaced by half the applicable LOQ. PK analyses will be performed using the PK Analysis 
Population and Set. 
Serum MPA concentrations that fall within defined sampling windows (see Appendix A) will be 
summarized by timepoint and injection site in the following ways: 1) graphically using box plots 
with whiskers extending to 5th and 95th percentiles, and 2) in tables using means, geometric 
means, quartiles, minima, maxima, standard deviations, and percent coefficients of variation. A 
listing of all MPA concentrations for each participant will be provided along with an indication 
of any that fall outside of defined sampling windows, or any excluded from the PK Analysis Set 
due to concomitant medication use, injection in an anatomical site different from the site used 
at enrollment, or insertion of multiple Sayana Press units at the time of injection. The listing will 
also include subject age and BMI at time of sampling.  
Month 2, 3, and 4 data will be used to estimate the apparent half-life for each injection site 
based on mixed-effects log-linear models with random intercept and slope terms, under the 
assumption that the terminal phase of absorption begins by month 2.5 Unique variance 
components will be used for each injection site, and observations falling outside sampling 
windows will not be excluded. The estimated slope (m) for each injection site will be used to 
calculate the apparent half-life according to the following formula: half-life = ln(2)/(-m). 
Pharmacokinetics in the terminal phase will be compared across injection sites based on overall 
and, if significant at the 0.05 level, pairwise Wald-type tests of differences in fixed-effects 
intercepts and slopes. Differences in variance components (both within-and between-subject 
effects) will similarly be assessed using likelihood ratio-tests. 
Accumulation of MPA concentrations at months 8 and 12 will be estimated for each injection 
site by calculating the geometric mean ratio (GMR) of trough concentrations at 8 or 12 months 
to the trough concentration at 4 months, using mixed-effects models to compute 95% CIs of 
each GMR (with unspecified covariance of log-transformed repeated measures). Any MPA 
date (along with any future measurements) will be excluded from the above accumulation 
 
5 This assumption will be formally assessed using appropriate log-linear random-effects model diagnostics, and by 
comparing predicted month 8 and month 12 concentrations (based on the half-life estimates and 4-month data) 
with the observed month 8 and 12 concentrations. 


 
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analysis. Steady-state accumulation ratios will be estimated as R = [1-(0.5) dosing interval/half-life]-1, 
where the dosing interval is assumed to be 126 days and the half-life is estimated in the 
method described above.  
The effects of study center, BMI, and age on trough concentrations will be explored graphically 
and by incorporating covariates in mixed-effects models based on month 4, 8, and 12 data.
Intra-subject variability across injection cycles may also be explored using MPA trough levels at 
months 4, 8, and 12. 
B. 
Safety 
Safety endpoints will include serious adverse events (SAEs), adverse events (AEs) leading to 
product withdrawal, injection site reactions, bleeding patterns, blood pressure, and body 
weight recorded at months 4, 8, and final visits. All SAEs, AEs leading to product withdrawal, 
and AEs which are Grade 1 or higher ISRs will be coded by a trained medical coder at FHI 360 
using the Medical Dictionary for Regulatory Activities (MedDRA) to classify them according to 
preferred term and system organ class (SOC). Safety analyses will be performed using the 
Treated Population and Safety Analysis Set and will be based on treatment group actually 
received. 
All relevant information on any SAEs will be discussed in the subject narrative included in any 
clinical study report and in a listing. Numbers and percentages of participants experiencing AEs 
(specifically AEs leading to product withdrawal and ISRs which are Grade 1 or higher) will be 
presented by severity, study center, and injection site. Percentages of participants experiencing 
specified AEs will be compared across injection sites (pooled over severity and study center) 
 Listings of any AEs will include actual injection site, a 
description of AE, type of AE, days to onset, relatedness to Sayana Press, seriousness, severity, 
outcome, and duration. Numbers and percentages of participants experiencing ISRs of any 
grade will be summarized by injection site, and ISRs will also be presented in a listing. 
Answers to questions about bleeding pattern (such as type of bleeding, average cycle length, 
duration of flow, and amount of flow) will be summarized by study center, injection site, and 
overall at enrollment, months 4 and 8, and final visit using appropriate measures (i.e., means, 
standard deviations, medians, minima, and maxima for continuous variables, and numbers and 
percentages for categorical ones). Blood pressure and body weight will also be summarized by 
study center, injection site, and overall at enrollment, months 4 and 8, and final visit using 
means, standard deviations, medians, minima, and maxima. Changes from baseline in bleeding 
patterns, blood pressure, and body weight at month 4, month 8, and final visit will also be 
summarized using shift-tables. 
C. 
Acceptability 
Acceptability endpoints include responses to questions about perception of bleeding patterns 
(recorded at enrollment, months 4 and 8, and final visit) and other side effects, likes, and 
dislikes about the regimen (recorded only at final visit). Acceptability will be assessed using the 
Treated Population and Safety Analysis Set. These will be summarized for each relevant visit by 


 
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study center, injection site, and overall using frequencies and percentages. Changes in 
perception of bleeding patterns over time will be summarized using shift-tables.  
XI. 
Analysis of Exploratory Study Objective 
Plans for analysis of the exploratory objective will be described in an appendix to this 
document. 
XII. 
Additional Data Summaries 
Any concomitant medications recorded at enrollment or during the study will be provided in a 
listing including at least the following information: participant number, actual injection site, 
generic name and dosage of medication, administration route, indication, days from enrollment 
to start date, and duration of use. 
XIII. 
Sensitivity Analyses 
Two sensitivity analyses will be performed for the efficacy objective. A Pearl Index and exact 
95% confidence interval will be computed per the primary analysis (section IX.B) but excluding 
any women who had protocol violations occurring at enrollment that warrant exclusion based 
on blind review. Another Pearl Index and exact 95% confidence interval will be computed per 
the primary analysis but excluding results from pregnancy tests taken at home and any time 
-clinic pregnancy test and her exit from the study. This will assess 
the impact of final pregnancy tests completed at home in response to the COVID-19 pandemic. 
Two sensitivity analyses will be performed for the PK objective. The first will assess the impact 
of baseline MPA on PK profiles and will include all participants (except for those who required 
the use of more than one Sayana Press unit) in the PK cohort who provide samples for MPA 
testing. This will be done in the following way: calculate the half-life ( ) for each injection site 
using the same method described in the secondary objective above but using the revised 
population; use that half-life to calculate the concentration at time t (CBt) due to the baseline 
amount (C0) using the following formula 
 
then subtract that amount from the corresponding monthly concentrations for each 
participant. Summaries of trough concentrations will be provided using these modified values 
and population.  
Secondly, a table summarizing trough concentrations and half-life will be provided for a 
population comprised of the PK Population plus any participants or samples excluded from the 
PK Population or Analysis Set based on injection issues (i.e., more than one unit inserted into 
skin). 


 
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XIV. 
Planned Interim Analyses 
An independent DSMB will review interim data when approximately 250 participants have 
completed 18 weeks of follow-up. This single, pre-planned interim analysis is intended to 
inform a decision whether to stop or modify the study if the estimated probability of pregnancy 
pooled across all injection sites is greater than 2% in the first injection interval. Details are 
provided in a separate DSMB Operational Plan.  
XV. 
MPA Testing of Baseline Serum Specimens
In preparation for the interim analysis, all available serum specimens from the PK cohort will be 
shipped for MPA testing at PPD approximately 8-10 weeks prior to the scheduled interim DSMB 
meeting. Once MPA results are received at FHI 360, baseline specimens will be analyzed to 
inform the following decision. If more than 10% of tested baseline specimens from the PK 
cohort have MPA concentrations greater than or equal to 0.1 ng/mL, or if more than 20% of 
tested baseline specimens from the PK cohort have MPA concentrations greater than or equal 
to 0.05 ng/mL, then the study team will proceed with MPA testing of all baseline specimens 
from the main cohort.  
As soon as the decision is made to test baseline specimens from the main cohort (if applicable), 
all available baseline specimens from participants in the main cohort will be shipped to PPD for 
MPA testing. Once serum MPA results from this enrolled subset of the main cohort are received 
at FHI 360, baseline specimens will be analyzed to inform the following second decision. If more 
than 10% of tested baseline specimens from the main cohort have MPA concentrations greater 
than or equal to 0.1 ng/mL, or if more than 20% of tested baseline specimens from the main 
cohort have MPA concentrations greater than or equal to 0.05 ng/mL, then the study team will 
make a determination as to whether subjects with baseline levels exceeding a threshold should 
be excluded from the primary analysis, and initiate a discussion with the study funder 
surrounding the potential for expansion of enrollment to account for such exclusions. 
Specimens from the remainder of the main study cohort (enrolled after the first batch are 
shipped) will be sent to PPD for testing at a later time in order to inform any analysis decisions. 
Any analysis decisions made based on results of MPA testing of baseline specimens from main 
cohort participants will be made blind to pregnancy outcome results and will be recorded in 
future versions of the analysis plan or in the final report as appropriate.  


 
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XVI. 
Appendices 
A. Visit Windows for MPA Measurements (PK Cohort Only)
Visit
Target Day (Window)
In-Window Range (inclusive)
Month 2
61 (+/-7)
54-68
Month 3
91 (+/-7)
84-98
Month 4
119 (+7)
119-126
Month 8*
245 (+7)
245-252
Month 12*
371 (+7)
371-378
*The target days for these visits will be shifted if a participant is more than 7 days (but less than 29 days) 
late for reinjection at the previous visit. If so, the target day(s) for the remaining visit(s) will be 
calculated in 126-day intervals after date of delayed reinjection (with the corresponding 7-day window). 
For example, if a participant comes in for her Month 4 visit on day 130, then her Month 8 target day (in-
window range) becomes 256 (256-263) and her Month 12 target day (in-window range) becomes 382 
(382-389). 
B. Changes to the Analysis Plan after Approval of Version 1.0 
 
 
i. 
Changes implemented in SAP version 2.0 
 
Updated randomization section to reference re-allocation of 100 participants to 
DR from Brazil due to slow recruitment at Brazil 
 
Added footnote clarifying how protocol violations at enrollment will be 
addressed within the primary efficacy analysis in section IX.B 
 
Added sensitivity analysis to assess efficacy after excluding women with 
protocol violations surrounding enrollment 
 
Added criteria for testing baseline specimens of MPA in the main study cohort 
based on results of baseline testing in the PK cohort 
 
Added possible exploratory analysis to look at intra-subject variability in trough 
levels across injection cycles 
ii.  
Changes implemented in SAP version 3.0 
 
Added exploratory objective and endpoint per version 8.0-B of the protocol; 
added statement that analysis of this objective will be described separately 
 
Revised baseline and disposition tables to change summaries by injection site 
within study center to simply by study center  
 
Revised definition of PK Population and Analysis Set to exclude any time after 
relevant injections for participants whose provider was required to use more 
than one device to deliver the drug 
 
Moved previously defined sensitivity analysis in section IX.B to new section 
specifically for sensitivity analyses (XII) 
 
Defined one new sensitivity analysis for the efficacy objective around home 
pregnancy tests 
 
Defined two sensitivity analyses for the PK objective, based on baseline MPA 
concentrations and injection issues 
 


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Prot_001.pdf: 
FHI 360 IRBNet # 926400, Extended Duration of Sayana® Press Study 
Last revised: 23 January 2020 
Protocol, Version 8.0-B 
Page 1 of 56 
Approved by PHSC: 4 February 2020 
CLINICAL STUDY PROTOCOL 
Title: 
A Study to Evaluate the Effectiveness, Pharmacokinetics, Safety, and 
Acceptability of Sayana® Press when Injected Every Four Months 
FHI 360 Study #:  
926400 
Version: 
8.0-B (for Brazil site participating in optional specimen collection for the 
Vaginal Immunity Study, optional DXA scan for the Body Composition 
and Bone Mineral Density Study, and Extended Follow-up Subset) 
Funded by:  
USAID  
The Bill & Melinda Gates Foundation 
Investigational Drug: 
Sayana® Press (medroxyprogesterone acetate injectable suspension, 
104 mg/0.65 mL)   
Study Sponsor:  
FHI 360 
359 Blackwell Street, Suite 200 
Durham, NC 27701 
Study Director:  
Jennifer Deese, PhD, MPH, CCRP 
Scientist 
FHI 360 
359 Blackwell Street, Suite 200 
Durham, NC 27701 
Tel: 1-919-544-7040 x 11292 
jdeese@fhi360.org  
Site investigators and Sites: 
Lic. Vivian Brache 
Asociación Dominicana Pro Bienestar de la Familia, Inc. (PROFAMILIA) 
Nicolas de Ovando esq. Calle 16 
Ens. Luperon 
Santo Domingo, Dominican Republic 
Tel: 1-809-681-8357 
vbrache@gmail.com 
Luis Bahamondes, MD 
Family Planning Clinic 
Department of Obstetrics and Gynecology 
Faculty of Medical Sciences 
Universidade Estadual de Campinas (UNICAMP)  
Caixa Postal 6181 
13084-971 Campinas, SP, Brazil  
Tel: 55-19-3289-2856 
drluisbahamondes@hotmail.com   


FHI 360 IRBNet # 926400, Extended Duration of Sayana® Press Study 
Last revised: 23 January 2020 
Protocol, Version 8.0-B 
Page 2 of 56 
Approved by PHSC: 4 February 2020 
 
Abril Salinas Quero, MD 
Instituto Chileno De Medicina Reproductiva (ICMER) 
Jose Victorino Lastarria 29, ap 101 
Santiago, Chile 
Tel: 56- 968423737 
abrilsalinasq@gmail.com 
 
Medical Monitor: 
 
Vera Halpern, MD 
 
 
 
 
 
Director, Medical Research  
FHI 360 
 
 
 
 
Tel: 1-919-544-7040 x 11390 
vhalpern@fhi360.org 
 
Central Laboratory: 
 
PPD Development 
2244 Dabney Road 
Richmond, VA 23230 
Tel: 1-804-359-1900 
This protocol is the confidential information of FHI 360 and is intended solely for the guidance of the 
clinical investigation. This protocol may not be disclosed to parties not associated with the clinical 
investigation or used for any purpose without the prior written consent of FHI 360. 
 
 
 
 


FHI 360 IRBNet # 926400, Extended Duration of Sayana® Press Study 
Last revised: 23 January 2020 
Protocol, Version 8.0-B 
Page 3 of 56 
Approved by PHSC: 4 February 2020 
INVESTIGATOR SIGNATURE FORM 
A Study to Evaluate the Effectiveness, Pharmacokinetics, Safety, and Acceptability of Sayana® Press 
when Injected Every Four Months 
Version: 8.0-B 
Date: 23 January 2020 
Funded by: USAID and The Bill & Melinda Gates Foundation 
 
I, the site investigator, agree to conduct this study in full accordance with the provisions of this protocol 
and in accordance with the International Conference on Harmonization (Section E6 (R1) Good Clinical 
Practice), US Department of Health and Human Services 45 Code of Federal Regulations Part 46, local 
regulatory requirements, and the Statement of Investigator, which I have also signed. I agree to 
maintain all study documentation until FHI 360 advises that it is no longer necessary.   
I read and understood the information in this protocol and the Prescribing Information for the clinical 
product used in this study, including the potential risks and side effects and will ensure that all 
associates, colleagues, and employees assisting in the conduct of the study are informed about the 
obligations incurred by their contribution to the study. 
 
 
____________________________ 
Printed name of Site Investigator 
 
 
____________________________ 
______________________________ 
Signature of Site Investigator  
 
Date 
 
 
 


FHI 360 IRBNet # 926400, Extended Duration of Sayana® Press Study 
Last revised: 23 January 2020 
Protocol, Version 8.0-B 
Page 4 of 56 
Approved by PHSC: 4 February 2020 
CLINICAL STUDY SYNOPSIS 
Title of Protocol:  
A Study to Evaluate the Effectiveness, Pharmacokinetics, Safety, and Acceptability 
of Sayana® Press when Injected Every Four Months 
Study Sponsor:  
FHI 360 
Funded by:  
 
USAID 
The Bill & Melinda Gates Foundation 
Study Number:  
926400 
Investigational Drug:  Sayana® Press (medroxyprogesterone acetate injectable suspension, 104 
mg/0.65 mL) 
Active Ingredient:  
Medroxyprogesterone acetate (MPA) 
Phase of Study:  
3 
Number of Sites:  
3 
Countries Planned:  
Brazil, Chile, and Dominican Republic  
Study Duration:  
Recruitment is expected to take 9 months and each participant will be followed 
for 12 months of product use. A subset of participants will be followed until 
resumption of ovulation or up to a maximum of 12 months from the last study 
injection. The total study duration is anticipated to be 41 months, including 
initiation activities, analysis, and reporting. 
Study Population: 
A total of 750 healthy, sexually active women between 18 and 35 years of age 
who are willing to use Sayana® Press injected every 4 months as their only 
means of contraception for 12 months.  
Primary Objective: 
To evaluate the effectiveness of Sayana® Press injected subcutaneously every 4 
months in the abdomen or upper thigh for 12 months (3 treatment cycles) of 
use. 
Primary Endpoint: 
Pregnancy 
Secondary Objectives:  1) To assess trough concentrations, accumulation and apparent terminal half-
life of MPA, and the impact of subcutaneous injection site (abdomen, upper 
thigh, or upper arm) on these parameters, when Sayana® Press is injected every 
4 months for 12 months of use; 
2) To evaluate the safety of Sayana® Press when injected every 4 months for 12 
months of use;  
3) To evaluate the acceptability of Sayana® Press when injected every 4 months 
for 12 months of use. 
 


FHI 360 IRBNet # 926400, Extended Duration of Sayana® Press Study 
Last revised: 23 January 2020 
Protocol, Version 8.0-B 
Page 5 of 56 
Approved by PHSC: 4 February 2020 
Secondary Endpoints:  Serum MPA concentrations on day 0 (baseline), months 2, 3, 4, 8, and 12 after 
treatment initiation (subset of 120 participants, only); serious adverse events 
and adverse events leading to product withdrawal; injection site reactions, 
bleeding patterns, blood pressure, and body weight; and responses to 
acceptability questions. 
Exploratory Objective:  To evaluate return to ovulation among a subset of study participants who 
received month 4 and month 8 injections and plan to use non-hormonal 
methods of contraception, or no contraception, for up to a maximum of 12 
months from the last study injection.  
Exploratory Endpoint:  Return to ovulation, where ovulation is defined as a single elevated serum 
progesterone (P ≥4.7 ng/mL) or a confirmed pregnancy test. 
General Design and Methodology:  
This study will evaluate the effectiveness, pharmacokinetics (PK), safety, and acceptability of Sayana® 
Press when injected every 4 months (17-18 weeks) for 3 treatment cycles (12 months) of use. A total of 
750 healthy, sexually active women aged 18 to 35 years with regular menstrual cycles and no DMPA use 
in the previous 12 months will be enrolled and followed for pregnancy. Among all enrolled, 710 will be 
randomized to receive injections in the abdomen or upper thigh in accordance with the PATH Sayana® 
injection instructions (Appendix 1), which are consistent with prescribing information, for the primary 
effectiveness analysis.  An additional 40 women will be randomized to receive injections subcutaneously 
in the back of the upper arm to assess whether differences in PK may exist which could impact the grace 
period for reinjections for that injection site. 
Treatment will begin in the first 5 days of menses. A single MPA serum sample will be collected from all 
participants at baseline. All participants will receive re-injections at month 4 (17 weeks after treatment 
initiation) and month 8 (35 weeks after treatment initiation), and complete their scheduled follow-up at 
approximately month 12 (53 weeks after treatment initiation). There will be a plus 7-day grace period 
for re-injections, but women who are up to 28 days late may continue treatment if they have a negative 
urine pregnancy test. Urine pregnancy testing will be performed for all women at enrollment, at month 
4, at month 12/study exit and at any other time during the study if clinically indicated. An additional 
urine pregnancy test will be completed at month 8 for Brazilian women enrolled in the Body 
Composition and Bone Mineral Density (BC-BMD) sub-study. Participants will be evaluated for injection 
site reactions and asked to provide information on adverse events, prohibited concomitant medication 
and other contraceptive use, vaginal bleeding, and method acceptability at months 4, 8 and 12; 
information on adverse events and prohibited concomitant medications will be recorded if self-reported 
by participants at the month 2 and 3 PK visits, and at unscheduled visits.   
Method of Randomization:  
One cohort of N=630 will be randomized 1:1 to receive their subcutaneous injections of Sayana® Press in 
the abdomen or upper thigh, and a second PK cohort of N=120 women who agree to serum MPA testing 
at 6 time points (baseline and months 2, 3, 4, 8, and 12) will be randomized 1:1:1 to receive their 
injections in the abdomen, upper thigh, or back of the upper arm. Using this randomization scheme, 355 
women will receive their injections in the abdomen, 355 in the upper thigh, and 40 in the back of the 


FHI 360 IRBNet # 926400, Extended Duration of Sayana® Press Study 
Last revised: 23 January 2020 
Protocol, Version 8.0-B 
Page 6 of 56 
Approved by PHSC: 4 February 2020 
upper arm. Randomization in each cohort will use randomly-permuted blocks, stratified by research 
center. Neither participants nor site staff will be blinded. 
Study Drug Dose and Mode of Administration: 
Sayana® Press (MPA injectable suspension, 104 mg/0.65 mL), injected subcutaneously in the abdomen, 
upper thigh, or back of the upper arm using the pre-filled UnijectTM delivery device. 
Criteria for Inclusion:  
Women may be included in the study if, at enrollment, they meet all of the following criteria:  
• 
not pregnant and no desire to become pregnant in the next 18 months 
• 
regular menstrual cycles (25 to 35 days in length when not using hormonal contraception, 
pregnant, or lactating)  
• 
at risk of pregnancy (no diagnosis of infertility, no history of tubal ligation or hysterectomy, and 
an average of 1 or more unprotected acts of vaginal intercourse per month) 
• 
in good general health as determined by a medical history  
• 
18 to 35 years of age, inclusive 
• 
willing to provide informed consent, follow all study requirements, and rely on Sayana® Press 
injected every 4 months as the only means of contraception for 12 months 
• 
has only one sexual partner and expects to have that same sexual partner for the next 12 
months 
Criteria for Exclusion:  
Women will be excluded from this study if they meet any of the following criteria at enrollment:  
• 
has a primary partner who has received a vasectomy or is otherwise sterile 
• 
medical contraindications to depot medroxyprogesterone acetate (DMPA) per World Health 
Organization medical eligibility criteria for contraceptive use 
• 
known HIV-infection (for her or her partner) 
• 
diagnosis or treatment for a sexually transmitted infection in the past month (for her or a 
partner), excluding recurrent herpes or condyloma 
• 
received an injection of a progestin-only containing contraceptive (DMPA or norethisterone 
enanthate) in the past 12 months 
• 
received an injection of a combined injectable contraceptive in the past 6 months 
• 
known or suspected allergic reaction to DMPA 
• 
used a levonorgestrel-releasing intrauterine system, NuvaRing, contraceptive patch, oral 
contraceptives or a contraceptive implant in the 7 days prior to enrollment (PK cohort only) 
• 
previous (within 1 month prior to enrollment), current or planned (in the next 12 months) use of 
an investigational drug, prohibited drug per protocol or other drug which in the opinion of the 
site investigator could complicate study findings  
• 
has been pregnant in the past month 
• 
is lactating 
• 
plans to move to another location in the next 12 months 
• 
has a social or medical condition which in the opinion of the site investigator would make study 
participation unsafe, or interfere with adherence to protocol requirements.  


FHI 360 IRBNet # 926400, Extended Duration of Sayana® Press Study 
Last revised: 23 January 2020 
Protocol, Version 8.0-B 
Page 7 of 56 
Approved by PHSC: 4 February 2020 
Study size and Statistical Analysis: 
The 710 women receiving injections in the abdomen or upper thigh will constitute the primary efficacy 
population. This study size is sufficient to ensure that the difference between the estimated Pearl Index 
(pregnancies per 100 woman-years of use) and the corresponding upper 95% confidence bound does 
not exceed 1.0, so long as the observed index is less than 0.75 and at least 80% of participants complete 
12 months of follow-up. The PK cohort of 120 women (40 receiving injections in each the abdomen, 
upper thigh, and back of the upper arm) is sufficient to provide 85% power to detect 30% relative 
differences in PK parameters between injection sites, assuming the coefficient of variation is no more 
than 40% and using two-sided 0.05 significance tests.  
Interim analysis:  
An independent Data and Safety Monitoring Board (DSMB) will review interim data when 250 
participants have completed 4 months of follow-up. This single, pre-planned interim analysis is intended 
to inform a decision whether to stop or modify the study (e.g., drop an injection site) if the estimated 
probability of pregnancy is greater than 2% in the first injection interval. Additional interim analyses may 
be requested by the DSMB based on periodic reviews of study indicators (pregnancy, adverse event, 
recruitment and continuation rates) if deemed necessary to protect participant safety or to make 
recommendations to modify the study.  
 
 


FHI 360 IRBNet # 926400, Extended Duration of Sayana® Press Study 
Last revised: 23 January 2020 
Protocol, Version 8.0-B 
Page 8 of 56 
Approved by PHSC: 4 February 2020 
TABLE OF CONTENTS 
INVESTIGATOR SIGNATURE FORM ......................................................................................................3 
CLINICAL STUDY SYNOPSIS .................................................................................................................4 
LIST OF ABBREVIATIONS ...................................................................................................................... 13 
1 
BACKGROUND INFORMATION .................................................................................................. 14 
1.1 
Introduction ................................................................................................................................ 14 
1.2 
Name and Description of Product .............................................................................................. 15 
1.3 
Findings from Nonclinical and Clinical Studies ........................................................................... 15 
1.3.1 
Nonclinical Studies .............................................................................................................. 15 
1.3.2 
Clinical Studies .................................................................................................................... 16 
1.4 
Known and Potential Risks and Benefits to Human Participants ............................................... 19 
1.4.1 
Known and Potential Health Risks of the Study Drug ......................................................... 19 
1.4.2 
Benefits to Participants ....................................................................................................... 21 
1.5 
Selection of Drugs and Dosages ................................................................................................. 21 
1.6 
Compliance Statement ............................................................................................................... 21 
1.7 
Population to Be Studied ............................................................................................................ 22 
2 
PURPOSE OF THE STUDY AND STUDY OBJECTIVES...................................................................... 22 
2.1 
Purpose of the Study .................................................................................................................. 22 
2.2 
Study Objectives ......................................................................................................................... 22 
2.2.1 
Primary Objective ................................................................................................................ 22 
2.2.2 
Secondary Objectives .......................................................................................................... 22 
2.2.3 
Exploratory Objective.......................................................................................................... 22 
2.3 
Study Endpoints .......................................................................................................................... 23 
2.3.1 
Primary Endpoint ................................................................................................................ 23 
2.3.2 
Secondary Endpoint ............................................................................................................ 23 
2.3.3 
Exploratory Endpoint .......................................................................................................... 23 
3 
STUDY DESIGN .......................................................................................................................... 23 
3.1 
General Design and Study Schema ............................................................................................. 23 
3.2 
Justification for the Study Design ............................................................................................... 25 
3.3 
Efficacy Measure......................................................................................................................... 25 
3.4 
Pharmacokinetic Measures ........................................................................................................ 26 
3.5 
Safety Measures ......................................................................................................................... 26 
3.6 
Acceptability Measures .............................................................................................................. 26 


FHI 360 IRBNet # 926400, Extended Duration of Sayana® Press Study 
Last revised: 23 January 2020 
Protocol, Version 8.0-B 
Page 9 of 56 
Approved by PHSC: 4 February 2020 
3.7 
Randomization, Allocation Concealment and Blinding .............................................................. 26 
3.7.1 
Randomization .................................................................................................................... 26 
3.7.2 
Allocation Concealment ...................................................................................................... 26 
3.7.3 
Blinding ............................................................................................................................... 26 
3.8 
Data and Safety Monitoring Board ............................................................................................. 27 
3.9 
Study Drug and Dosage .............................................................................................................. 27 
3.10 
Drug Supply and Accountability.................................................................................................. 27 
3.10.1 
Drug Accountability ............................................................................................................. 27 
3.11 
Duration of Study Participation .................................................................................................. 28 
3.12 
Discontinuation Criteria .............................................................................................................. 28 
3.12.1 
Study Termination ............................................................................................................... 28 
3.12.2 
Participant Discontinuation ................................................................................................ 28 
3.12.3 
Drug Supply, Storage and Security ...................................................................................... 28 
3.13 
Source Data Recorded on Case Report Forms ............................................................................ 28 
3.14 
Study Procedures ........................................................................................................................ 29 
3.14.1 
Screening Visit ..................................................................................................................... 30 
3.14.2 
Enrollment Visit (Day 0) ...................................................................................................... 31 
3.14.3 
Regularly Scheduled Follow-up Visits ................................................................................. 32 
3.14.4 
Additional Blood Draw Visits (Months 2 and 3) .................................................................. 33 
3.14.5 
Additional Vaginal, Endocervical and Blood Samples ......................................................... 34 
3.14.6 
Additional BC and BMD Measurements ............................................................................. 34 
3.14.7 
Extended Follow-Up Subset Procedures ............................................................................. 34 
3.14.8 
Missed and Unscheduled Visits........................................................................................... 34 
3.14.9 
Post-Discontinuation Visits ................................................................................................. 35 
3.14.10 Loss to Follow Up ................................................................................................................ 35 
4 
SELECTION AND WITHDRAWAL OF PARTICIPANTS ..................................................................... 35 
4.1 
Inclusion Criteria ......................................................................................................................... 35 
4.2 
Exclusion Criteria ........................................................................................................................ 35 
4.3 
Justification for Key Inclusion and Exclusion Criteria ................................................................. 36 
4.4 
Withdrawal Criteria and Procedures .......................................................................................... 36 
5 
TREATMENT OF PARTICIPANTS ................................................................................................. 37 
5.1 
Study Drugs Administered During the Study .............................................................................. 37 
5.2 
Restrictions ................................................................................................................................. 37 


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5.3 
Prior and Concomitant Therapy or Medication .......................................................................... 37 
5.4 
Procedures for Monitoring Participant Treatment Compliance................................................. 37 
6 
ASSESSMENT OF EFFICACY ........................................................................................................ 37 
7 
ASSESSMENT OF PHARMACOKINETICS ...................................................................................... 38 
7.1 
Pharmacokinetic Measures ........................................................................................................ 38 
7.2 
Blood Sampling, Handling, and Laboratory Analysis .................................................................. 38 
8 
ASSESSMENT OF SAFETY ........................................................................................................... 38 
8.1 
Adverse Events ........................................................................................................................... 39 
8.2 
Serious Adverse Events ............................................................................................................... 39 
8.2.1 
Definition of a Serious Adverse Event ................................................................................. 39 
8.2.2 
Reporting SAEs .................................................................................................................... 40 
8.3 
Injection site reactions ............................................................................................................... 40 
8.4 
Return to ovulation (extended follow-up subset only) .............................................................. 40 
8.4.1 
Blood Sampling, Handling, and Laboratory Analysis ........................................................... 41 
8.5 
Pregnancy outcomes .................................................................................................................. 41 
8.6 
Bleeding Assessment .................................................................................................................. 42 
8.7 
Measurement of Body weight and BP ........................................................................................ 42 
8.8 
Concomitant Medication ............................................................................................................ 42 
8.9 
Social Harm Events ..................................................................................................................... 42 
8.10 
Methods and Timing of Assessing, Recording, and Analyzing Safety Data ................................ 42 
9 
ASSESSMENT OF ACCEPTABILITY ............................................................................................... 42 
10 
STATISTICS ............................................................................................................................ 42 
10.1 
Sample Size and Power Considerations ...................................................................................... 42 
10.2 
Analysis Populations and Analysis Sets ...................................................................................... 43 
10.2.1 
Treated Population and Analysis Set .................................................................................. 43 
10.2.2 
Pharmacokinetics Population and Analysis Set .................................................................. 43 
10.2.3 
Extended Follow-up Population .......................................................................................... 43 
10.3 
Data Handling Conventions ........................................................................................................ 43 
10.4 
Multiple Comparisons and Multiplicity ...................................................................................... 44 
10.5 
Assessment of Study Populations ............................................................................................... 44 
10.5.1 
Participant Disposition ........................................................................................................ 44 
10.5.2 
Demographic and other Baseline Characteristics ............................................................... 44 
10.6 
Efficacy Analysis .......................................................................................................................... 44 


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10.6.1 
Primary Endpoint ................................................................................................................ 44 
10.6.2 
Planned Methods of Analysis .............................................................................................. 45 
10.7 
Pharmacokinetic Analysis ........................................................................................................... 45 
10.7.1 
Pharmacokinetic Endpoints ................................................................................................ 45 
10.7.2 
Planned Method of Analysis ............................................................................................... 45 
10.8 
Safety Endpoints and Analysis .................................................................................................... 46 
10.8.1 
Safety Endpoints ................................................................................................................. 46 
10.8.2 
Safety Analysis .................................................................................................................... 46 
10.9 
Acceptability Variables and Analysis .......................................................................................... 46 
10.10 Exploratory Variables and Analysis ............................................................................................. 46 
10.11 BC and BMD Variables and Analysis ........................................................................................... 46 
10.12 Planned Interim Analysis ............................................................................................................ 47 
10.13 Reporting Deviations from the Statistical Plan ........................................................................... 47 
11 
DIRECT ACCESS TO SOURCE DATA/DOCUMENTS .................................................................... 47 
12 
QUALITY CONTROL AND QUALITY ASSURANCE ...................................................................... 47 
12.1 
Protocol Amendments ................................................................................................................ 47 
12.2 
Protocol Violations ..................................................................................................................... 48 
12.3 
Information to Study Personnel ................................................................................................. 48 
12.4 
Study Monitoring ........................................................................................................................ 48 
12.5 
Audit and Inspection ................................................................................................................... 49 
13 
ETHICS .................................................................................................................................. 49 
13.1 
Informed Consent ....................................................................................................................... 49 
13.2 
Compensation ............................................................................................................................. 49 
13.3 
Health Authorities and IRBs ........................................................................................................ 50 
13.4 
Study Participant Confidentiality ................................................................................................ 50 
13.5 
Registration of the Clinical Study ................................................................................................ 50 
14 
DATA HANDLING, DATA QUALITY CONTROL, AND RECORD KEEPING ...................................... 50 
14.1 
Data Collection ........................................................................................................................... 50 
14.2 
Data Quality Control ................................................................................................................... 51 
14.3 
Archiving of Case Report Forms and Source Documents ........................................................... 51 
14.3.1 
Investigator Responsibilities ............................................................................................... 51 
14.3.2 
FHI 360 Responsibilities ...................................................................................................... 52 
15 
FINANCING AND INSURANCE ................................................................................................. 52 


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16 
REPORTING AND PUBLICATION OF RESULTS .......................................................................... 52 
17 
REFERENCES ......................................................................................................................... 53 
18 
APPENDICES ......................................................................................................................... 55 
18.1 
Appendix 1: Sayana® Press Injection Job Aid.............................................................................. 55 
 
 
 


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LIST OF ABBREVIATIONS  
AE 
 
Adverse Event 
BC 
 
Body Composition 
BC-BMD 
Body Composition and Bone Mineral Density Study 
BP 
 
Blood pressure 
BMD 
 
Bone Mineral Density 
Cxmo 
 
Serum MPA Concentration at Month ‘x’ following Injection 
CDMS  
Clinical Data Management System 
CRF 
 
Case Report Form 
DSMB  
Data and Safety Monitoring Board 
DMPA  
Depot Medroxyprogesterone Acetate 
DXA 
 
Dual Energy X-ray absorptiometry (DXA) 
EDF 
 
Estimated Date of Fertilization 
FN 
 
Femoral neck 
FSH 
 
Follicle Stimulating Hormone 
GCP 
 
Good Clinical Practice 
hCG 
 
Human Chorionic Gonadotropin 
HIV 
 
Human Immunodeficiency Virus 
ICH 
 
International Council for Harmonization 
IM 
 
Intramuscular 
IRB 
 
Institutional Review Board 
ISR 
 
Injection Site Reaction 
LMP 
 
Last Menstrual Period  
LS 
 
Lumbar spine 
LH 
 
Luteinizing Hormone 
MPA 
 
Medroxyprogesterone Acetate 
NDA 
 
New Drug Application 
PD 
 
Pharmacodynamics 
PK 
 
Pharmacokinetics 
PHSC 
 
Protection of Human Subjects Committee 
SAE 
 
Serious Adverse Event 
SAP 
 
Statistical Analysis Plan 
SC 
 
Subcutaneous 
SOP 
 
Standard Operating Procedure 
STI 
 
Sexually Transmitted Infection 
T1/2 
 
Apparent Terminal Half-Life  
USAID   
United States Agency for International Development 
USFDA  
United States Food and Drug Administration 
WHO 
 
World Health Organization 
WY 
 
Woman-Years 
 
 


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1 BACKGROUND INFORMATION 
1.1 Introduction 
Globally, over 40 million women use injectable contraceptives for pregnancy prevention [1]. Depo-
Provera® CI (150 mg/mL medroxyprogesterone acetate [MPA] injectable suspension) (Pfizer, New York, 
NY) and generic versions of the same are the most commonly used injectable method. Also known as 
depot medroxyprogesterone acetate (DMPA) for intramuscular (IM) administration (DMPA-IM), it has a 
decades-long history as a highly efficacious contraceptive, with a pregnancy rate of approximately 0.3 
per 100 woman-years (WY) when injected as prescribed at a dose of 150 mg every 3 months [2]. The 
World Health Organization’s (WHO) evidence-based family planning guidance further specifies that 
repeat injections can be given up to 4 weeks late without requiring additional contraceptive protection 
[3]. Although widely used, DMPA-IM carries a burden of side effects including weight gain, bleeding 
disturbances, metabolic effects, reduced bone mineral density (BMD) [4-6] and delayed return to 
fertility [7]. The use of DMPA-IM has also been associated with an increased risk of Human 
Immunodeficiency Virus (HIV) acquisition [8, 9], but a causal relationship has not been established. 
More recently, Pfizer developed an alternative MPA formulation for subcutaneous (SC) injection in the 
abdomen or upper thigh (Depo-SubQ Provera 104®). Due in part to a slower rate of absorption following 
SC administration [10], Depo-SubQ Provera 104® achieves the same degree of efficacy as DMPA-IM but 
at a 31% lower dose (104 mg/0.65 mL every 3 months) [11, 12]. Because of the ease of SC 
administration, Depo-SubQ Provera 104® and in particular Sayana® Press (0.65 mL of Depo-SubQ 
Provera 104® pre-filled in the UnijectTM delivery system) have the potential to increase access in 
settings where resource constraints can be a barrier to provision and consistent use of injectable 
contraception. Studies have demonstrated that it can be safely provided outside the clinic setting (e.g., 
using community health workers) and that self-injection is acceptable and feasible [13, 14]. Study 
findings have motivated donors such as the U.S. Agency for International Development (USAID) to try to 
expand access to Sayana® Press in developing countries, but price remains a barrier.   
Despite its 31% lower dose, side effects of Depo-SubQ Provera 104® remain similar to DMPA-IM [11]. 
This could be related to the slower release rate for the SC product, resulting in a similar steady-state 
trough MPA concentration as DMPA-IM; in a randomized study, average serum concentrations 1 and 2 
years after initiating Depo-SubQ Provera 104® were 100% and 85% of the corresponding DMPA-IM 
values [12]. The potential dose-dependent nature of some side effects has motivated interest in 
lowering the MPA exposure still further [15]. Indeed, the lack of any pregnancies in phase 3 trials of 
Depo-SubQ Provera 104® [16] is consistent with the hypothesis that the injected dose is higher than 
necessary.  
We hypothesize that a high degree of contraceptive efficacy will be maintained when extending the 
injection interval of Sayana® Press from 3 to 4 months. Extending the interval would reduce long-term 
MPA exposure by 25% and lower steady state trough MPA concentrations, thus shortening the delay in 
return to fertility and possibly reducing the severity of other dose-dependent side effects. This would 
also decrease programmatic costs, thereby facilitating access to Sayana® Press in resource-constrained 


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settings. We base our hypothesis on a review of available pharmacokinetics (PK) and pharmacodynamics 
(PD) data for Depo-SubQ Provera 104®. This review suggests that the risk of ovulation following 
initiation of Sayana® Press might be minimal, and that the accumulation of MPA (and hence the 
duration of action following multiple doses) is likely greater than was reported in the main PK study that 
informed the regulatory approval of Depo-SubQ Provera 104®[10]. In order to test our hypothesis, we 
will conduct a clinical study to estimate the effectiveness of Sayana® Press when injected every 4 
months for 12 months (3 injection cycles) of use. We will also estimate trough MPA concentrations and 
apparent terminal half-life to determine whether the anatomical site of injection meaningfully affects 
the PK of MPA, and to inform an appropriate grace period for re-injections outside the clinical trial 
setting where the dosing interval is tightly controlled. 
One of the important dose-dependent side effects of the existing 3-month DMPA is delayed return to 
ovulation. The 4-month re-injection interval may improve the side effect profile, specifically shortening 
time to return to ovulation, by lowering the overall drug exposure. We will collect limited clinical data 
from a subset of women participating in this study on return to ovulation. This analysis can help to 
inform how much sooner women may expect to return to ovulation (and therefore, to fertility) when 
shifting from a 3-month to a 4-month DMPA dosing regimen.   
1.2 Name and Description of Product 
The investigational product is Sayana® Press, consisting of 104 mg/0.65 mL MPA injectable suspension 
pre-filled in the UnijectTM delivery device. The drug component of Sayana® Press, Depo-subQ Provera 
104®, is approved by the US Food and Drug Administration (USFDA) as a contraceptive when delivered 
at a SC dose of 104 mg every 3 months (New Drug Application [NDA] # 21-583). The predominant 
method of action of the drug is the inhibition of gonadotropin-releasing hormone secretion, which 
suppresses levels of follicle stimulating hormone (FSH) and luteinizing hormone (LH), and in turn 
prevents follicular maturation and ovulation. Pfizer has not sought USFDA approval for the combination 
of drug and device which constitutes Sayana® Press, but it is registered in more than 36 countries and 
approved for self-injection in the United Kingdom [17].  
1.3 Findings from Nonclinical and Clinical Studies 
1.3.1 Nonclinical Studies  
The active pharmaceutical ingredient of Sayana® Press, MPA, has been marketed in various doses and 
formulations for decades. These include but are not limited to: 2.5, 5.0 and 10.0 mg oral tablets for the 
treatment of amenorrhea and uterine bleeding (NDA # 011839); a 150 mg/mL IM formulation for 
contraception (NDA # 20-246); and the 104 mg/0.65 mL SC formulation under study here, approved for 
contraception (NDA # 21-583) and the management of endometriosis-associated pain (NDA # 21-584).  
The toxicology of MPA has been reviewed by the USFDA as part of recent marketing applications. 
Accordingly, a complete battery of toxicology studies has been conducted in compliance with the 
International Council for Harmonization (ICH) guidance for non-clinical safety studies. A thorough 
toxicology review was also performed by Jordan [18]. Depo-Provera® CI did not show signs of chronic or 


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reproductive toxicity, nor was there mutagenic or carcinogenic potential in animals. Multiple studies in 
different species have shown that DMPA has limited toxicity following administration by SC, IM or 
intravenous injection. The median lethal dose for intravenous administration was 376 mg/kg and 100 
mg/kg in mice and rats, respectively. When given SC, the median lethal dose was increased to more than 
4000 mg/kg and 8000 mg/kg in mice and rats, respectively [18].  
1.3.2 Clinical Studies 
1.3.2.1 
Pharmacokinetics 
The clinical pharmacology section of the Sayana® Press label was primarily informed by the study of  Jain 
et al. which evaluated the PK profile of Depo-subQ Provera 104® and reported an average maximum 
serum concentration (Cmax), 3-month trough (C3mo), apparent terminal half-life (t1/2), and area under the 
serum concentration-time curve (AUC) extrapolated to infinity of 1.56ng/mL, 0.40 ng/mL, 43 days, and 
92.8 ng•day/mL, respectively [10]. Neither the manuscript nor the product label reports the site of 
injection used in the Jain study. Toh et al. evaluated the impact of injection site on PK of Depo-subQ 
Provera 104® among Asian women, and found a significantly lower Cmax for injections in the abdomen 
than in the thigh (0.94 ng/mL versus 1.65 ng/mL). Mean t1/2 and C3mo were larger for the abdomen (104 
days and 0.47 ng/mL, respectively) than the thigh (81 days and 0.41 ng/mL), but the differences were 
not statistically significant [19]. A PK/PD study comparing Sayana® Press to Depo-subQ Provera 104® in 
pre-filled glass syringe also failed to report the site of injection, but the average Cmax for each device 
group (0.95 ng/mL and 0.79 ng/mL, respectively [17]) was consistent with the abdominal data in Toh et 
al. [19]. The mean MPA profile observed in a study of Depo-subQ Provera 104® injected in the upper 
arm was also more similar to the Toh et al. abdomen data [20], although the variability of t1/2 and trough 
concentrations appeared higher with the upper arm injection site. Finally, the accumulation of MPA 
reported in an efficacy study of Depo-subQ Provera 104® [12] was consistent with a noticeably longer 
t1/2 than reported by Jain et al. (Figure 1, inset). Overall, these data support the conclusion that, on 
average, the apparent terminal half-life of MPA may be longer than indicated by the Depo-subQ Provera 
104® label, and that the PK of MPA may differ by injection site.    


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1.3.2.2 
Pharmacodynamics 
The study by Jain et al. [10] is the only randomized trial comparing return to ovulation between Depo-
subQ Provera 104® and DMPA-IM, and it was limited to 39 and 19 participants in the SC and IM groups, 
respectively. Other contemporaneous PD data for Depo-subQ Provera 104® include the study by Toh et 
al. [19] and the Sayana® Press Public Assessment Report [17]. Time to ovulation in these studies was 
based on a single elevated serum progesterone (P) concentration of 4.7 ng/mL or higher, supported with 
data on estradiol, LH, and FSH levels. The estimated cumulative probability of return to ovulation based 
on a meta-analysis of all the Depo-subQ Provera 104® data is presented in Figure 2. The timing of each 
ovulation was obtained by digitalizing data in the manuscript or using the event and censoring times 
specified in the reports (one event time that was only stated to have occurred before day 92 in the 
Sayana® Press study was imputed as day 46). Four participants with known dosing errors in the Sayana® 
Press study are excluded. All other PD outcomes are included, even if supportive data raised doubts in 


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the minds of investigators as to whether they were true ovulations. Caution is required when making 
comparisons between groups due to the lack of randomization and the small number of DMPA-IM users. 
Nonetheless, the data are consistent with a significantly longer time to ovulation following initiation of 
Depo-subQ Provera 104® than DMPA-IM (p=0.02 based on a Wilcoxon log-rank statistic). Furthermore, 
only 1 of 96 women (1.0%) using Depo-subQ Provera 104® were observed to ovulate between days 90 
and 120, compared to 2.4% who ovulated in the first 90 days using DMPA-IM. 
 
Overall, the combination of PK data which suggests an apparent longer terminal half-life of MPA than 
reported on the Depo-subQ Provera 104® label, and the PD data demonstrating longer return to 
ovulation among Depo-subQ Provera 104® users as compared to DMPA-IM users, suggests that the 
overall risk of pregnancy between months 3-4 post-dose may be low.  
1.3.2.3 
Clinical Efficacy Studies 
There are no available data on the pregnancy rate for Depo-subQ Provera 104® when it is injected at 
intervals longer than three months (every 12-14 weeks). However, no pregnancies were detected 
among 2,042 women who used the product in the abdomen or thigh every 3 months for up to 3 years in 
three contraceptive studies that supported the NDA. When restricted to women aged 36 years or less at 


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the time of treatment initiation, the 95% confidence interval for the Pearl Index (pregnancies per 100 
WY of use) was 0.00-0.25 in the first year of use [16].  
1.4 Known and Potential Risks and Benefits to Human Participants 
1.4.1 Known and Potential Health Risks of the Study Drug 
1.4.1.1 
Pregnancy 
All women will be tested for pregnancy and the injection will be given during the first 5 days of the 
menstrual cycle to rule out pregnancy prior to enrollment. During the study, each woman will have a 
urine pregnancy test prior to receiving her second injection at month 4 and at month 12/study exit. A 
woman will also have a urine pregnancy test at month 8 if she is more than 7 days late for her third 
injection or enrolled in the BC-BMD sub-study, or any time during the study if she is experiencing any 
symptoms or signs of pregnancy or if she suspects she may be pregnant. Women participating in the 
extended follow-up subset will be tested for pregnancy at time points specified in Table 3. Based on the 
existing data the risk of pregnancy while using Sayana® Press injected every 4 months is assumed to be 
low (see Section 1.3.2). However, pregnancy rates will be monitored and if necessary, the pregnancy 
testing schedule may be modified and/or study participants informed if the actual pregnancy rate is 
higher than anticipated. Although no DMPA product should be used during pregnancy, there is little or 
no increased risk of birth defects in women who have inadvertently been exposed to MPA injections in 
early pregnancy [7]. Neonates exposed to MPA in-utero and followed to adolescence showed no 
evidence of any adverse effects on their health including their physical, intellectual, sexual or social 
development [21]. 
1.4.1.2 
Injection Site Reactions 
Clinical trials have demonstrated that there is a small risk of injection site reactions (ISRs) for Depo-subQ 
Provera 104®. In 5 clinical studies involving 2,325 women (282 treated for up to two injection intervals; 
1,780 treated for up to four injection intervals; and 263 women treated for up to 8 injection intervals), 
5% reported ISRs and 1% had persistent skin changes, typically described as small areas of induration or 
atrophy [12, 16]. A retrospective study based on individual case safety reports of women receiving 
Depo-subQ Provera 104® identified 398 injection site reactions reported to the WHO VigiBase through 
January 2016. Notably, the rate of ISRs in the retrospective study could not be quantified due to the 
unknown total number of women and injections [22]. 
1.4.1.3 
Menstrual Changes 
Most women using Depo-subQ Provera 104® experience disruption of menstrual bleeding patterns. 
Altered menstrual bleeding patterns include amenorrhea, irregular or unpredictable bleeding or 
spotting, prolonged spotting or bleeding, and heavy bleeding. As women continue using Depo-subQ 
Provera 104®, fewer experience irregular bleeding and more experience amenorrhea. In three efficacy 
trials, the rates of amenorrhea were 39% at month 6 and 56.5% at month 12 [16]. It is unknown whether 
extending the dosing interval to 4 months will alter these patterns.  


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1.4.1.4 
Weight Gain 
Women tend to gain weight when using Depo-subQ Provera 104® every 3 months, with an average 
increase of 1.6 kg observed after 1 year. Longer term effects of Depo-subQ Provera 104® are unknown; 
however, women using DMPA-IM gain an average of 6.6 kg after 10 years of uninterrupted use [16, 23]. 
We will assess the weight of participants during the study to characterize the pattern of weight change 
when dosing every 4 months. In addition, the Brazil site will measure changes in body composition (BC) 
– including but not limited to total body mass, lean and fat mass, percentage of total fat mass, and 
central-peripheral fat ratio – in a subset of Brazilian users of Sayana® Press at baseline, month 8 and 
month 12.  
1.4.1.5 
Risk of HIV 
Depo-subQ Provera 104® provides no protection against sexually transmitted infections (STIs), including 
HIV.  While some observational data have suggested an association between the use of DMPA-IM and 
an increased risk of HIV acquisition [8, 9], the data are inconsistent [9, 24, 25]. In light of the inconclusive 
evidence, the WHO recently revised their Medical Eligibility Criteria for contraceptive use [26]. Per the 
revised criteria, women at low risk of HIV can continue using all hormonal methods of contraception 
including DMPA without restriction. Women who are at high risk of HIV, however, can use DMPA if they 
are informed of the possible increased risk of HIV acquisition among DMPA users, the uncertainty over a 
causal relationship, and how to minimize their risk of acquiring HIV. Notably, no studies have assessed 
the relationship between the lower-dose Depo-subQ Provera 104® product and HIV. The WHO and US 
Centers for Disease Control recommend that women at high risk of HIV who choose to use DMPA or any 
other hormonal product should be counseled to use condoms consistently and correctly [25]. This study 
will not recruit women at known risk of HIV, including women with partners who are known to be HIV-
positive at baseline. However, women will be provided the information required by WHO in the 
informed consent and will be counseled to use condoms for protection against HIV/STI if their risk status 
changes during the study. 
1.4.1.6 
Return to fertility 
Return to fertility is delayed after stopping the use of Depo-subQ Provera 104® when injected every 3 
months. Among 28 women in clinical studies who stopped treatment to become pregnant, only 1 
became pregnant within 1 year of her last injection. Similarly, among 15 women who received multiple 
doses of Depo-subQ Provera 104®, the median time to ovulation was 10 months after the last injection, 
and only 12 women (80%) ovulated within 1 year [16]. Extending the injection interval from 3 to 4 
months is anticipated to reduce the accumulation of MPA concentrations and hence the delay in return 
to ovulation and fertility. Nevertheless, only women who do not desire pregnancy for a minimum of 18 
months (10 months from last study injection) will be enrolled in the study. 
1.4.1.7 
Bone Mineral Density  
A boxed warning regarding skeletal health was added to the label of Depo-subQ Provera 104® in 2004 
indicating that long-term use (more than 2 years) may reduce peak bone mass and place women at 
increased risk for osteoporotic fractures [16]. Changes in BMD are reversible and comparable to the 
changes associated with pregnancy and lactation. Also, no clinical evidence exists that long-term use of 
DMPA is associated with increased risk of fracture [27]. After reviewing the evidence, WHO concluded 


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that there should be no restriction on the use of the drug among women aged 18 to 45, including no 
restriction on duration of use [28]. The Brazil site will assess BMD at the lumbar spine (LS) (L1-L4) and 
femoral neck (FN) in a subset of Brazilian users of Sayana® Press at baseline, month 8 and month 12. 
1.4.1.8 
Other Medical Risks 
Additional information regarding possible risks of Depo-subQ Provera 104® use may be found in the 
package insert [16] and the Sayana® Press package leaflet [29]. 
1.4.1.9 
Loss of Confidentiality 
All study staff will protect the confidentiality of participants to the fullest extent possible, except as 
required by law. No participant personal identifiers will appear on any data or documentation sent to 
FHI 360. Participants will not be identified by name in any report or publication resulting from study 
data. Loss of confidentiality may present a risk to study participants if these procedures are 
inadvertently breached.  
1.4.2 Benefits to Participants  
There will be no direct benefits of study participation. 
1.5 Selection of Drugs and Dosages  
Sayana® Press (104 mg MPA in 0.65 mL injectable suspension) is the only drug that will be used in this 
study. Injections will be given subcutaneously in the abdomen, upper thigh or back of the upper arm 
every 4 months for a 12-month treatment period (3 doses). The drug, dosage and regimen were chosen 
based on the objectives of the trial: to assess the effectiveness, PK, safety, and acceptability of Sayana® 
Press when injected every 4 months.  
1.6 Compliance Statement 
Before implementation, the protocol and relevant study documents including recruitment materials will 
be approved by the study sites’ local institutional review boards (IRBs) and FHI 360’s Protection of 
Human Subjects Committee (PHSC). The study will be conducted in compliance with FHI 360 Standard 
Operating Procedures (SOPs), and in accordance with ICH Good Clinical Practice (GCP) Consolidated 
Guideline (E6) and any other applicable national and local laws and regulations. Any episode of 
noncompliance with these guidelines and regulations will be documented in the Trial Master File and 
reported to national regulatory authorities and governing IRBs as required. 
Site investigators are responsible for performing the study at his or her site in accordance with the 
protocol, applicable GCP guidelines, and IRB and local regulatory authority requirements. Agreement of 
each site investigator to conduct the study in accordance with the protocol will be documented on the 
Investigator Signature form, in separate study agreements with FHI 360, and other applicable forms as 
required by national authorities. The site investigators will permit trial-related monitoring, audits, 
ethical review and regulatory inspections by providing direct access to source data and other study-
related documents. 


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Site investigators are also responsible for ensuring the privacy, health, and welfare of participants during 
the study, and will ensure that trained personnel are immediately available in the event of a medical 
emergency. Site investigators and applicable study staff will be trained in research ethics prior to 
working on the study and must be familiar with the properties and side effects of Depo-subQ Provera 
104® and Sayana® Press as described in the prescribing information.  
1.7 Population to Be Studied 
Healthy, sexually active female participants between 18 and 35 years of age at the time of enrollment 
who are willing to use Sayana® Press injected every 4 months as the only means of contraception for 12 
months. 
2 PURPOSE OF THE STUDY AND STUDY OBJECTIVES 
2.1 Purpose of the Study 
The purpose of the study is to evaluate the effectiveness, PK, safety, and acceptability of Sayana® Press 
when injected every 4 months (17-18 weeks) rather than the currently prescribed 3-month (12-14 
weeks) regimen. 
2.2 Study Objectives 
2.2.1 Primary Objective 
To evaluate the effectiveness of Sayana® Press when injected subcutaneously every 4 months in the 
abdomen or upper thigh for 12 months (3 treatment cycles) of use. 
2.2.2 Secondary Objectives 
The secondary objectives of the study are to: 
• 
Assess trough concentrations, accumulation, and apparent terminal half-life of MPA, and the 
impact of subcutaneous injection site (abdomen, upper thigh, or back of the upper arm) on 
these parameters, when Sayana® Press is injected every 4 months for 12 months of use 
• 
Evaluate the safety of Sayana® Press when injected every 4 months for 12 months of use 
• 
Evaluate the acceptability of Sayana® Press when injected every 4 months for 12 months of 
use 
2.2.3 Exploratory Objective 
To evaluate return to ovulation among a subset of study participants who have received both month 4 
and month 8 injections and plan to use non-hormonal methods of contraception, or no contraception, 
for up to 12 months from the last study injection.  


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2.3 Study Endpoints 
2.3.1 Primary Endpoint 
The primary study endpoint is the occurrence of pregnancy, as defined by a positive urine pregnancy 
test. Positive urine tests will be confirmed by ultrasound and/or serum hCG testing whenever possible.  
2.3.2 Secondary Endpoint 
Secondary endpoints include serum MPA concentrations on day 0 (baseline) and months 2, 3, 4, 8, and 
12 in a subset of 120 participants; serious adverse events (SAEs) and adverse events (AEs) leading to 
product withdrawal; ISRs, bleeding patterns, blood pressure (BP) and body weight; and responses to 
acceptability questions. 
2.3.3 Exploratory Endpoint 
Return to ovulation, where ovulation is defined as a single elevated serum progesterone (P ≥4.7 ng/mL). 
Given that ovulation must precede conception, for the purpose of this analysis, a confirmed pregnancy 
test (regardless of progesterone results) will be considered an ovulation. 
3 STUDY DESIGN 
3.1 General Design and Study Schema 
This study will evaluate the effectiveness, PK, safety, and acceptability of Sayana® Press when injected 
every 4 months (17-18 weeks) for 12 months (3 treatment cycles), rather than every 3 months (12-14 
weeks) per current prescribing information. A total of 750 healthy, sexually active women aged 18 to 35 
years with regular menstrual cycles and at risk of pregnancy will be enrolled at 3 sites: Biomedical 
Research Department at Profamilia in the Dominican Republic (Profamilia); Universidade Estadual de 
Campinas in Brazil (UNICAMP), and Instituto Chileno de Medicina Reproductiva in Chile (ICMER). One 
cohort of N=630 women will be randomized 1:1 to receive injections of Sayana® Press in the abdomen 
or upper thigh, and a second PK cohort of N=120 women who, in addition to pregnancy testing, agree to 
blood draws for MPA testing at 6 time points during their study participation, will be randomized 1:1:1 
to receive injections in the abdomen, upper thigh, or back of the upper arm. The N=710 women 
receiving injections in the abdomen or thigh, per Sayana® Press package insert instructions, will 
constitute the primary population for assessing contraceptive efficacy.  However, because upper arm 
injections are supported by PATH instructional materials, and have been reported as the preferred 
injection site in prior studies, analyses will be done to compare PK across the three injection sites [14]. 
Treatment will begin in the first 5 days of menses. All participants will have a single serum sample 
collected at enrollment for possible MPA testing. Participants will receive re-injections in their randomly 
assigned SC injection site at month 4 (17 weeks after treatment initiation) and at month 8 (35 weeks 
after treatment initiation), and complete their scheduled follow-up at month 12 (53 weeks after 
treatment initiation). There will be a plus 7-day grace period for re-injections, but women who are up to 
28 days late may continue treatment if they have a negative urine pregnancy test (participants who are 
more than 28 days late for re-injection will be discontinued from the study). Participants will be asked to 


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provide information on adverse events, prohibited concomitant medication and other contraceptive 
use, vaginal bleeding, and method acceptability at months 4, 8, and 12; information on adverse events 
and concomitant medications will be recorded if self-reported by participants at the month 2 and 3 PK 
visits, and any unscheduled visits. Urine pregnancy testing will be performed for all women at month 4 
and month 12/study exit, if a participant is more than 7 days late for her month 8 visit and at any other 
time it is clinically indicated. An additional pregnancy test will be completed at month 8 for women 
enrolled in BC-BMD sub-study in Brazil. Participants will be advised to return to the clinic for 
unscheduled visits any time they think they may be pregnant or have a medical problem that may be 
related to their study participation. In addition to pregnancy testing, participants in the PK cohort will 
provide blood specimens for serum MPA testing on day 0 (baseline) and months 2, 3, 4, 8, and 12. 
A subset of approximately 20 participants at select study sites who received both month 4 and month 8 
injections and plan to use a non-hormonal contraceptive method, or no contraception, after study 
discontinuation will be invited to be in the extended follow-up subset and monitored until resumption 
of ovulation or up to a maximum of 12 months after the last study injection, whichever comes first. At 
predetermined time points (specified in Table 2 and Table 3), blood will be collected for progesterone, 
estradiol, MPA and other synthetic steroids (e.g., levonorgestrel, etonorgestrel and ethinyl estradiol); 
urine pregnancy testing will be performed; and blood pressure and weight will be measured. 
DMPA-IM has been associated with a possible increased risk of HIV acquisition and an ongoing 
randomized controlled trial (ECHO) will provide the first prospective data comparing risk with DMPA-IM 
compared to other contraceptive methods. There are no data available to assess the relationship 
between the lower subcutaneous administered dose of Depo-SubQ Provera 104® (104 mg MPA) and HIV 
acquisition [24]. The putative biologic mechanisms that might underlie a potential association between 
DMPA and HIV are poorly understood, but are believed to be related to the effects of DMPA on the 
immune environment in the female genital tract. One of the hypotheses concerning the mechanism of 
this potential association is the hypoestrogenic effects of DMPA.  Another is a direct effect of MPA on 
the glucocorticoid receptor, leading to immunosuppression. In in vitro studies, the effects of MPA have 
been shown to vary with concentration, with some markers showing dose-response effects [30]. 
However, no clinical studies have evaluated the effects of different DMPA dosages and serum hormone 
concentrations on female genital tract immunity in vivo. FHI 360 is planning a study to evaluate the 
effect of different dosages of DMPA on soluble and cellular markers of genital tract immunity and on the 
genital microbiome (referred to here and thereafter as the Vaginal Immunity Study). The outcomes of 
that study should provide comparative information on markers of vaginal immunity and assess whether 
the lower doses of DMPA are potentially safer for women in terms of acquisition of HIV and other 
sexually transmitted infections (STIs). At select sites, we will ask participants in this study if they are 
willing to provide a blood sample and vaginal and cervical swabs for the Vaginal Immunity Study. 
Participants who agree to collection of additional specimens for the Vaginal Immunity Study will provide 
blood and vaginal specimens at the following visits: screening and follow-up months 1, 3, 4, 8 and 
12/final. 
There is scarce information about BC and BMD among users of Depo-subQ Provera 104®. The Brazil site 
plans to conduct the BC-BMD sub-study to assess BC and bone health in Brazilian users of Sayana® Press 
when injected every 4 months for 12 months of use. At that site only, we will ask participants in this 
study if they are willing to provide additional BC and BMD measurements. A sub-study cohort of N=139 


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will be achieved by enrolling the first 139 women agreeing to participate. Participants who consent will 
undergo Dual Energy X-ray absorptiometry (DXA) imaging (GE Healthcare, Lunar Corporation, Madison, 
Wisconsin, USA) at day 0 (baseline), month 8 and month 12 after treatment initiation. At month 8, urine 
pregnancy testing will be performed for BC-BMD participants prior to radiation exposure. The site will be 
responsible for all activities related to this sub-study, with the exception of CRF entry.   
3.2 Justification for the Study Design 
The study is designed to meet criteria for assessing the efficacy of hormonal contraceptive products 
specified in the European Medicines Agency Guideline on Clinical Investigation of Steroid Contraceptives 
in Women[31]. Specifically, at least 400 women completing one year of use and sufficient total months 
of use to obtain a 95% confidence interval for the Pearl Index (pregnancies per 100 WY of follow-up) 
with a half-width of no more than 1%. A study size of 710 women receiving injections in the abdomen or 
thigh is expected to achieve these criteria, while also allowing us to assess whether pregnancy risk may 
differ between these two injection sites.  
The PK cohort will allow us to inform an appropriate grace period for re-injections based on estimated 
trough concentrations and apparent terminal half-life. Although the Product Leaflet for Sayana® Press 
specifies that injections are to be administered in the abdomen or thigh [29], back of the upper arm 
injection instructions are provided by PATH and the back of the upper arm is used by some providers 
([32], Appendix 1). By randomizing an additional N=40 women to receive injections in the back of the 
upper arm we will be able to confirm findings from a previous non-comparative PK study which 
indicated MPA concentrations are more variable when drug is administered in this anatomical site [20], 
and inform the potential impact of any excess variability on efficacy. 
To inform how much sooner women may expect to return to ovulation (and therefore, to fertility) when 
shifting from a 3-month to a 4-month dosing regimen, we will evaluate return to ovulation among a 
subset of study participants who received both month 4 and month 8 injections and plan to use a non-
hormonal method of contraception, or no contraception, after study discontinuation, until resumption 
of ovulation or up to a maximum of 12 months from the last study injection, whichever comes first. We 
will also test for pregnancy, and measure levels of MPA and other synthetic steroids (e.g., 
levonorgestrel, etonogestrel and ethinyl estradiol) to rule out concurrent use of other hormonal 
contraceptives that may suppress ovarian activity. 
  
3.3 Efficacy Measure  
The primary efficacy measure is the pregnancy Pearl Index, computed as the number of pregnancies 
occurring during the treatment per 100 WY of follow-up. Time to pregnancy will be based on the 
difference between the date of treatment initiation and the estimated date of fertilization (EDF), where 
the latter is determined by ultrasound, the first day of last menstrual period (LMP) prior to the positive 
pregnancy test, or using best clinical judgment in the absence of these results. Participants who do not 
become pregnant will be censored on the date of their last negative urine pregnancy test or the end of 
their treatment use period, whichever is earlier (see Section 10.6 for definition of treatment use period).  


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3.4 Pharmacokinetic Measures 
The PK of MPA will be evaluated among participants in the PK cohort based on estimated trough 
concentrations at month 4 (C4mo), month 8 (C8mo), and month 12 (C12mo); apparent half-life (t1/2); and 
accumulation of MPA over 3 cycles of use. 
3.5 Safety Measures 
Safety measures will include the occurrence of SAEs, AEs leading to product withdrawal, ISRs, change in 
bleeding pattern, change from baseline in BP and body weight at the month 4, 8, and final visits. 
3.6 Acceptability Measures 
Method acceptability will be assessed based on responses to questions about vaginal bleeding (at 
baseline) and other side effects, likes, and dislikes about the regimen at month 4, 8, and final visits. 
3.7 Randomization, Allocation Concealment and Blinding 
3.7.1 Randomization 
All participants will receive the same study drug, Sayana® Press. However, women will be randomized to 
receive their injections in the abdomen, back of the upper arm, or upper thigh to control for potential 
confounding when assessing relationships between SC injection site, efficacy, and PK. One cohort of 
N=630 women will be randomized 1:1 to receive their injections in the abdomen or thigh, and a 
separate PK cohort of N=120 women agreeing to MPA testing will be randomized 1:1:1 to receive their 
injections in the abdomen, upper thigh, or back of the upper arm. Randomization will be stratified by 
cohort and site using appropriate randomly permuted block sizes. Randomization sequences will be 
created for each combination of site and cohort by an FHI 360 randomization statistician using a 
validated program written in SAS® version 9.4 or higher.  
3.7.2 Allocation Concealment 
Sequentially numbered, opaque randomization envelopes matching the randomization sequences will 
be provided to each clinic site. Each envelope will have the randomization number printed on the 
outside, with the corresponding SC injection site assignment concealed within. The randomization 
envelopes will be maintained in a secure office, with access limited to designated study staff. The next 
available randomization number will be assigned to the next study participant only after she has been 
confirmed to be eligible, consented to participate, and undergone all other enrollment procedures, 
including having a blood sample collected for MPA testing among women agreeing to participate in the 
PK cohort.  
3.7.3 Blinding 
Neither participants nor site staff will be blinded to SC injection sites. However, laboratory staff 
analyzing serum MPA specimens and staff at FHI 360 responsible for adjudicating pregnancy outcomes 
and coding adverse events will be blinded to individual participant injection site assignments for the 


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duration of each participant’s follow up. In addition, the FHI 360 may review interim PK data, including 
MPA concentrations of any women who become pregnant, to inform other FHI 360 MPA projects. 
3.8 Data and Safety Monitoring Board  
An independent Data and Safety Monitoring Board (DSMB) will review interim data when 250 
participants have completed 4 months of follow-up. This single, pre-planned interim analysis is intended 
to inform a decision whether to stop or modify the study if the estimated probability of pregnancy is 
greater than 2% in the first injection interval. Additional interim analyses may be requested by FHI 360 
or the DSMB based on periodic reviews of study indicators (pregnancy, AE, recruitment and 
continuation rates) if deemed necessary to protect participant safety or to make recommendations to 
modify the study. 
3.9 Study Drug and Dosage 
Sayana® Press (MPA injectable suspension, 104 mg/0.65 mL, pre-filled in the UnijectTM delivery injection 
system) is indicated for the prevention of pregnancy. The composition of each 0.65 mL dose of drug is 
shown in Table 1. Sayana® Press will be administered as a SC injection every 4 months, rather than every 
3 months per current prescribing information. Instructional materials developed by PATH, which are 
consistent with the prescribing information, will be followed when providing injections [32]; Appendix 
1).  
Table 1. Composition of Depo-subQ Provera 104® 
Ingredients 
Amount per 
0.65mL 
Active: 
 
  MPA  
104 mg 
Inactive: 
 
  Polysorbate 80  
1.95 mg 
  Sodium chloride  
5.2 mg 
  Methionine-Phosphate buffer  
17.47 mM 
  Povidone 
3.25 mg 
  Methylparaben  
1.04 mg 
  Propylparaben  
0.098 mg 
  Water for injection  
qs to 0.65 mL 
3.10 Drug Supply and Accountability 
3.10.1 Drug Accountability 
The site investigator or designee will acknowledge receipt of study product indicating shipment content 
and condition, and follow drug accountability procedures throughout the study. Drug accountability 
includes maintaining accurate records on the quantity of product received, date of receipt, condition at 
receipt, lot number of products received and dispensed, description of damaged units, dispensation, and 
product disposition or destruction. Storage temperature continuity tracking will occur during storage. 


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Site personnel are responsible for routine temperature monitoring and safe storage of the study 
products after they are received on-site. Study drug product will only be administered to participants 
enrolled in the trial; unused units will be disposed of per FHI 360 written instructions. 
3.11 Duration of Study Participation 
This study will consist of a screening period (up to 1 month prior to enrollment) and a 12-month 
treatment period, for approximately 13 months of study participation per subject. A subset of 
approximately 20 participants will be followed until the resumption of ovulation or a maximum of 12 
months from the last study injection, whichever comes first.  
3.12 Discontinuation Criteria 
3.12.1 Study Termination  
This study may be discontinued at any time by FHI 360, FHI 360’s PHSC, applicable government or 
regulatory authorities, or site IRBs. If the study is closed early for any reason, site investigators and IRBs 
will be promptly notified. Site investigators will inform study participants and assure that final visit 
procedures are completed whenever possible.  
3.12.2 Participant Discontinuation  
A participant may discontinue participation at any time for any reason without loss of other benefits or 
services to which she may be entitled. A participant may also be discontinued early from the study if the 
site investigator considers it to be in the participant's best interest. Final visit procedures should be 
completed for all participants who discontinue early, if possible. Reasons for discontinuation from the 
study will be recorded on the appropriate Case Report Form (CRF).   
3.12.3 Drug Supply, Storage and Security 
Sayana® Press is manufactured and distributed by Pfizer, Inc. Drug supply will be procured by USAID for 
this study. If applicable, prior to initiation, the product will be labeled per local regulatory agency 
requirements. Drug product will be stored in a secure, dry place at controlled room temperature of 15 
to 30°C according to the manufacturer’s stipulations. 
3.13 Source Data Recorded on Case Report Forms 
Some CRF fields will have data directly recorded into them and will be considered source. Other source 
documents will include, but will not be limited to, clinical notes, laboratory results, dispensing records 
and consent forms. Source for all study data will be defined and documented in site-specific source 
documentation guides.  
MPA testing will be conducted by PPD Development (Richmond, VA, USA), which will maintain source 
documentation for MPA data. MPA results will not be entered into CRFs but transferred electronically to 
the FHI 360 in accordance with written study-specific procedures. 


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3.14 Study Procedures 
All participants will come to the study clinic for a screening visit, an enrollment visit (when treatment 
initiation occurs), re-injection visits at month 4 and month 8 post-treatment initiation, and a final visit at 
month 12. Participants in the PK cohort will attend additional visits at months 2 and 3 to provide blood 
specimens for MPA testing. Participants in the extended follow-up subset will return at predetermined 
time points (specified in Table 3) until return to ovulation or up to a maximum of 12 months from the 
last study injection, whichever comes first. See Table 2 and Table 3 for timing of study procedures.  
Table 2: Study Procedures and Assessments 
Procedures 
Screening a 
Enrollment 
(Day 0) 
Month 1 
Months  
2 and 3 b 
Months 4 
and 8 
Final/ 
Month 12 k 
Informed consent 
X 
 
 
 
 
X l 
Inclusion/exclusion 
criteria 
X 
X 
 
 
 
 
Baseline characteristics 
X 
X 
 
 
 
 
Height 
 
X 
 
 
 
 
Body weight 
 
X 
 
X 
X 
X 
Blood pressure 
 
X 
 
X 
X 
X 
Urine pregnancy test 
X c 
X 
 
 
  X d 
X 
Randomization 
 
X 
 
 
 
 
Drug administration 
 
X 
 
 
X 
 
Serum MPA  
 
X 
 
Xe 
Xe 
Xe,l 
AE documentation f 
 
 
 
X 
X 
X 
ISR documentation 
 
X 
 
 
X 
X 
Concomitant medication 
documentation g 
 
 
 
X 
X 
X 
Vaginal bleeding 
 
X 
 
 
X 
X 
Acceptability 
 
 
 
 
X 
X 
Coital frequency and 
condom use 
 
X 
 
 
X 
X 
Specimens for vaginal 
immunity study h 
X 
 
X 
X 
X 
X 
DXA for BC and BMD sub-
study i 
 
X 
 
 
X j 
X 
a May coincide with enrollment visit if participant is in the first 5 days of her menses (this does not apply to women 
also participating in the Vaginal Immunity Study) 
b Only for the PK cohort 
c If clinically indicated 
d Participants will only be tested at month 8 if they are more than 7 days late for their visit or are enrolled in the 
BC-BMD sub-study 


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e For all participants at enrollment. At follow-up visits only for the PK cohort and for any participant in the full 
cohort who has a positive pregnancy test during follow-up 
f Serious adverse events, adverse events leading to product withdrawal, and injection site reactions that are Grade 
1 or higher will be recorded on the AE CRF 
g Use of prohibited concomitant medications and other contraceptives, will be recorded on CRFs 
h Participants who consent to the collection of genital and blood specimens for the Vaginal Immunity Study will 
also be asked to come to the clinic approximately 1 and 3 months after enrollment for specimen collection only. 
i Only for Brazilian participants who consent to measurement of BC and BMD by DXA scan. Does not need to be 
done in the case of early discontinuation.  
j Only at month 8 for BC-BMD participants.  
k Procedures to be done at the Month 12 visit, or at any visit of early discontinuation. 
l Only for the extended follow-up subset; may occur after the Final/Month 12 visit so long as the participant meets 
the eligibility criteria for the extended cohort and the timetable for extended follow-up procedures.  
 
Table 3: Study Procedures and Assessments (Extended Follow-Up Subset) 
Procedures a 
Week 
38 d 
Week 
39 d 
Week 
40 d 
Week 
41 d 
Week 
42 d 
Week 
46 d 
Week 
47 d 
Week 
48 d 
Week 
49 d 
Week 
50 d 
Body weight 
X 
 
 
 
 
X 
 
 
 
 
Blood pressure 
X 
 
 
 
 
X 
 
 
 
 
Urine pregnancy test b  
X  
X c 
X c 
X c 
X  
X  
X c 
X c 
X c 
X  
Serum MPA  
X 
 
 
 
 
X 
 
 
 
 
Serum Estradiol 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Serum Progesterone 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Plasma levonorgestrel, 
etonogestrel, ethinyl 
estradiol 
X 
 
 
 
 
X 
 
 
 
 
AE documentation e 
 
 
 
 
 
 
 
 
 
 
Concomitant 
medication 
documentation f 
 
 
 
 
 
 
 
 
 
 
a Participants will be discontinued from the study at the visit in which ovulation is confirmed (defined as a single 
elevated serum progesterone [P ≥4.7 ng/mL] or confirmed pregnancy test) or she does not ovulate by week 50 
(from last injection), whichever occurs first 
b If positive at any time, discontinue 
c If clinically indicated  
d Weeks from last injection 
e Only SAEs will be recorded on study CRFs and reported to FHI 360 
f Use of prohibited concomitant medications and other contraceptives, will be recorded on CRFs 
3.14.1 Screening Visit  
Women will be recruited through various channels which may include, but not be limited to, searches of 
internal participant databases, informing women seeking contraception at the study sites about the 
study, referrals from local clinics and use of advertisements. Women expressing interest in participating 
in the study will be given the informed consent form to review and trained site personnel will review the 


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consent information including the study objectives, design and procedures, and potential risks of 
participation. Potentially eligible women will be asked if they are willing to be in the PK cohort, and 
provide blood specimens for MPA testing, until enrollment into the PK cohort is complete. Those that 
sign the informed consent form will be assigned a participant number and have a screening interview, 
including collection of medical history and demographic information. Each site may also conduct clinical 
procedures per site-specific standard of care that are not required per the study protocol (e.g., STI 
testing, Pap smear, and breast exam).  
Each potentially eligible woman will be scheduled to return to clinic for enrollment procedures during 
the first 5 days of her next menses, but if she is currently in the first 5 days of menses then enrollment 
procedures can begin immediately (this does not apply to women who also consent to participate in the 
Vaginal Immunity Study). In summary, the following will be done during the screening visit: 
• 
Study purpose and procedures explained 
• 
Written informed consent obtained 
• 
Participant number assigned 
• 
Assess study eligibility and collect baseline data 
• 
Enrollment visit scheduled for first 5 days of next menses 
• 
Appropriate CRFs completed 
3.14.2 Enrollment Visit (Day 0) 
The enrollment visit will take place during the first 5 days of menses. During this visit a urine pregnancy 
test will be performed and other eligibility criteria verified. Height, weight and BP measurements will be 
recorded.  Vaginal bleeding information will be collected. Approximately 5 mL of blood for MPA testing 
will be collected before randomization. 
After a participant is confirmed eligible and had all other enrollment procedures completed, the study 
site’s randomization manager will open the next sequentially numbered randomization envelope from 
the appropriate stream of envelopes (PK cohort or non-PK cohort). Each participant will receive an 
injection of Sayana® Press in her assigned SC injection site, be monitored for at least 15 minutes for 
possible anaphylactic reactions and/or ISRs, and be scheduled to return to the clinic 4 months later for 
re-injection on study day 119 (17 weeks after enrollment) (participants who are unable to return 
precisely on study day 119 may have their re-injection scheduled to take place up to 7-days late, on or 
before study day 126). Participants in the PK cohort will be scheduled to return for additional blood 
draw visits at month 2 (study day 61) and month 3 (study day 91), allowing for a plus/minus 7-day grace 
period.  
In summary, the following will be done during the enrollment visit:  
• 
Urine pregnancy test performed 
• 
Study eligibility confirmed and baseline data collected 
• 
Coital frequency and condom use assessed 
• 
Vaginal bleeding assessed 
• 
BP, height, and weight measured 


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• 
Blood drawn for MPA assessment (MPA testing will only be done on specimens from participants 
in the main cohort if MPA is detected above the threshold defined in the Statistical Analysis Plan 
among baseline specimens from the PK cohort) 
• 
Randomization completed  
• 
Study drug administered and site of injection evaluated for possible ISRs  
• 
Study visit schedule provided 
• 
Appropriate CRFs completed 
3.14.3 Regularly Scheduled Follow-up Visits 
3.14.3.1 Month 4 re-injection 
The first re-injection visit is scheduled to occur on study day 119, 4 months (17 weeks) after treatment 
initiation. Participants will be asked if they have experienced any medical problems or have taken any 
medications since the previous visit (serious adverse events, adverse events leading to product 
withdrawal, ISRs and use of any study prohibited concomitant medications and other contraceptives , 
will be recorded on CRFs); asked to report on coital frequency and condom use since the last injection of 
study drug; have vaginal bleeding and product use acceptability evaluated; have BP and weight 
measured; and complete a urine pregnancy test. Any participants who are determined to be pregnant 
will have a blood specimen collected for MPA testing. Participants in the PK cohort will also provide 
approximately 5 mL of blood for MPA testing. Otherwise, participants who have a negative urine 
pregnancy test will receive a re-injection of Sayana® Press and be reminded to return for the next 
scheduled visit on study day 245, 8 months (35 weeks) after treatment initiation. 
Participants who are up to 28 days late for the month 4 visit may continue treatment if they have a 
negative urine pregnancy test result. If a participant is more than 7 days late, however, then her month 
8 and final study visits will be re-scheduled to occur at 18-week (126 day) intervals over the next 36 
weeks in order to avoid shortening the effective lengths of subsequent treatment intervals. Participants 
who are more than 28 days late will undergo final visit procedures (see Section 3.14.3.3) and be 
discontinued from the study. 
3.14.3.2 Month 8 re-injection 
The second re-injection visit is schedule to occur on study day 245, 8 months (35 weeks) after treatment 
initiation. Participants will be asked if they have experienced any medical problems or have taken any 
medications since the previous visit (serious adverse events and adverse events leading to product 
withdrawal, ISRs, and use of any study prohibited concomitant medications and other contraceptives , 
will be recorded on CRFs); asked to report on coital frequency and condom use since the last injection of 
study drug; have vaginal bleeding and product use acceptability evaluated; and have BP and weight 
measured. A urine pregnancy test will not be performed unless the participant is more than 7 days late 
for her month 8 visit, she is enrolled in the BC-BMD sub-study, or if testing is clinically indicated. Any 
participants who are determined to be pregnant will have a blood specimen collected for MPA testing. 
Participants in the PK cohort will also provide approximately 5 mL of blood for MPA testing. Otherwise, 
participants who are not pregnant will receive a re-injection of Sayana® Press and be reminded to return 
for a final visit on study day 371, 12 months (53 weeks) after treatment initiation. 


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Participants who are 8 to 28 days late for the month 8 visit may continue treatment if the urine 
pregnancy test result is negative. If a participant is more than 7 days late, however, then the final study 
visit will be re-scheduled to occur 18 weeks (126 days) later. Participants who are more than 28 days 
late will undergo final visit procedures (see Section 3.14.3.3) and be discontinued from the study. 
3.14.3.3 Final visit 
The final visit is scheduled to occur on study day 371, 12 months (53 weeks) after treatment initiation. 
Participants will be asked if they have experienced any medical problems or have taken any medications 
since the previous visit; asked to report on coital frequency and any condom use since the last injection 
of study drug; have final vaginal bleeding and product use acceptability evaluated; have BP and weight 
measured; and complete a urine pregnancy test. Any participants who are determined to be pregnant 
will have a blood specimen collected for MPA testing. Interested participants who meet qualifications 
will be consented to the extended follow-up subset. Participants in the PK cohort and extended follow-
up subset will also provide approximately 5 mL of a blood for MPA testing. Participants will be offered 
contraception of their choice from methods available at the study clinic and will be provided referrals as 
need for ongoing services.  Final visit procedures should be done at the time of any early 
discontinuation. 
In summary, the following will be done during regularly scheduled re-injection and final study visits: 
• 
Participant asked about adverse events and concomitant medication use (serious adverse events, 
adverse events leading to product withdrawal, ISRs, and use of any study prohibited concomitant 
medications and other contraceptives, will be recorded on CRFs) 
• 
Coital frequency and condom use assessed 
• 
Vaginal bleeding and product use acceptability assessed 
• 
BP and weight measured 
• 
Consented to the extended follow-up subset* 
• 
Blood drawn for MPA assessment (PK cohort, extended follow-up subset*, or if pregnant, only) 
• 
Urine pregnancy test performed (at month 8 visit, only if more than 7 days late, or enrolled in the 
BC-BMD sub-study)  
• 
Study drug administered (month 4 and month 8, only; contraception [locally available] offered at 
final visit) 
• 
Site of the previous and new injection(s) evaluated for possible ISRs, as appropriate  
• 
Appointment reminders provided (month 4, month 8, and extended follow-up subset only) 
• 
Appropriate CRFs completed 
 
*May occur after the Final/Month 12 visit so long as the participant meets the eligibility criteria for the 
extended cohort and the timetable for extended follow-up procedures. 
3.14.4 Additional Blood Draw Visits (Months 2 and 3)  
Participants in the PK cohort will complete additional clinic visits to provide blood specimens for MPA 
testing at month 2 (study day 61) and month 3 (day 91). Blood pressure and weight will be measured; 
information on AEs and concomitant medication use will not be solicited; however, if reported by the 


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participant, serious adverse events and adverse events leading to product withdrawal, and use of any 
study prohibited concomitant medications and other contraceptives, will be recorded on CRFs. 
Additional blood draw visits will be scheduled to allow for a plus or minus 7-day grace period, but 
women returning outside the window will still have blood drawn for MPA testing. 
3.14.5 Additional Vaginal, Endocervical and Blood Samples 
At select study sites, consenting participants will provide additional vaginal, endocervical and blood 
specimens for the Vaginal Immunity Study at the following timepoints: screening and follow-up months 
1, 3, 4, 8 and 12/final.  Commercially available swabs and cytobrushes will be procured by the study 
sites, or if needed, provided by FHI 360.  The collected specimens will be stored at -80°C until further 
shipment instructions from FHI 360.  Additional instructions for the collection, processing and storage of 
specimens will be standardized in the study manual. 
3.14.6 Additional BC and BMD Measurements  
At the Brazil site only, consenting participants will undergo DXA imaging for the BC-BMD sub-study at 
enrollment, month 8 and month 12. BC measurements will include, but are not limited to, total body 
mass, lean and fat mass, percentage of total fat mass, central-peripheral fat ratio, and Fat Mass Index 
(kg/m2). BMD will be measured at the LS (L1-L4) and FN. Additional instructions for DXA imaging will be 
standardized in a site-specific SOP.  
3.14.7 Extended Follow-Up Subset Procedures 
At select sites, consenting participants will be scheduled to return for two 5-week intervals at 10 and 12 
months from the last study injection to monitor for return to ovulation. The first 5-week interval will be 
scheduled to occur 38 weeks from the date of the last injection (i.e., month 8 re-injection date + 38 
weeks) with subsequent weekly visits occurring up to 42 weeks or return to ovulation, whichever comes 
first. If ovulation does not return within the 42 weeks from last injection, participants will be scheduled 
to return for a second 5-week interval scheduled to occur 46 weeks from the date of their last injection 
(i.e., month 8 re-injection date + 46 weeks) with subsequent weekly visits occurring up to 50 weeks (12 
months from last injection). At predetermined time points (specified in Table 3), blood will be collected 
for progesterone, estradiol, MPA and other synthetic steroids (e.g., levonorgestrel, etonogestrel and 
ethinyl estradiol); urine pregnancy testing will be performed; and blood pressure and weight will be 
measured. Participants will be discontinued when ovulation is confirmed (i.e., defined as a single 
elevated serum progesterone [P ≥4.7 ng/mL] or confirmed pregnancy test) or at 50 weeks from last 
injection, whichever comes first.   
3.14.8 Missed and Unscheduled Visits 
Re-injection and final visits will be scheduled to occur based on specific days since treatment initiation, 
allowing for up to a plus 7-day grace period. If a participant cannot return to the clinic within this visit 
window, the study staff will attempt to have the participant return as soon as possible. However, 
treatment will be stopped and the participant discontinued from the study if she is more than 28 days 
late for a re-injection visit. Sites will also ask participants to return to clinic for unscheduled visits if they 
suspect that they may be pregnant or if they have any other problems or concerns with study 
participation.  


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3.14.9 Post-Discontinuation Visits 
Post-discontinuation visits may be conducted if necessary to ensure or monitor participant safety or to 
assess the EDF of women who report being pregnant within 3 months of having exited the study. 
3.14.10 
Loss to Follow Up  
If a participant does not appear for a scheduled visit, at least three attempts to contact her will be made. 
If she does not return to clinic while the study is ongoing then she will be considered potentially lost to 
follow up, but her file will remain open until study closeout. If the participant does not return before the 
study is closed, she will be classified as lost to follow up. The lost to follow up designation cannot be 
made for any participant until the closing date of the study. 
4 SELECTION AND WITHDRAWAL OF PARTICIPANTS 
The target population is sexually active women between 18 and 35 years of age who are willing to use 
Sayana® Press injected every 4 months as their only means of contraception for 12 months. 
4.1 Inclusion Criteria 
Women may be included in the study if they meet all of the following criteria at enrollment:  
• 
not pregnant and no desire to become pregnant in the next 18 months 
• 
regular menstrual cycles (25 to 35 days in length when not using hormonal contraception, 
pregnant, or lactating)  
• 
at risk of pregnancy (no diagnosis of infertility, no history of tubal ligation or hysterectomy, and 
an average of 1 or more unprotected acts of vaginal intercourse per month) 
• 
in good general health as determined by a medical history 
• 
18 to 35 years of age, inclusive 
• 
willing to provide informed consent, follow all study requirements, and rely on Sayana® Press 
injected every 4 months as her sole means of contraception for 12 months 
• 
has only one sexual partner and expects to have that same sexual partner for the next 12 
months 
4.2 Exclusion Criteria 
Women will be excluded from this study if they meet any of the following criteria at enrollment:  
• 
has a primary partner who has received a vasectomy or is otherwise sterile 
• 
medical contraindications to depot medroxyprogesterone acetate (DMPA) per WHO medical 
eligibility criteria for contraceptive use [33] 
• 
known HIV-infection (for her or a partner) 
• 
diagnosis or treatment for an STI in the past month (for her or a partner), excluding recurrent 
herpes or condyloma 
• 
received an injection of a progestin-only containing contraceptive (DMPA or norethisterone 
enanthate) in the past 12 months 


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• 
received an injection of a combined injectable contraceptive in the past 6 months 
• 
known or suspected allergic reaction to DMPA 
• 
used a levonorgestrel intrauterine system, NuvaRing, contraceptive patch, oral contraceptives or 
a contraceptive implant in the past 7 days (PK cohort only) 
• 
Previous (within 1 month prior to enrollment), current or planned (in the next 12 months) use of 
an investigational drug, prohibited drug per protocol (see Section 5.3) or other drug which in the 
opinion of the investigator could complicate study findings  
• 
has been pregnant in the past month 
• 
is lactating 
• 
plans to move to another location in the next 12 months 
• 
has a social or medical condition which in the opinion of the investigator would make study 
participation unsafe, or interfere with adherence to protocol requirements.  
4.3 Justification for Key Inclusion and Exclusion Criteria 
Only women reasonably expected to be at risk of pregnancy in the absence of using the study product 
will be enrolled so as to estimate the contraceptive efficacy of the regimen. Women at high risk of HIV 
and/or STIs will be excluded to limit condom use during the treatment period. Since DMPA is associated 
with an extended delay in return to fertility, women who have used DMPA-IM or Depo-SubQ Provera 
104® in the previous 12 months will be excluded. The study will also not enroll women who have a 
medical or social condition that may make study participation unsafe or complicate data interpretation 
according to the site investigator’s assessment. 
4.4 Withdrawal Criteria and Procedures 
Participants may withdraw from study participation at any time without loss of other benefits or 
services to which they would otherwise receive as part of standard clinical care. The site investigator can 
also withdraw a participant from the study for the safety of the participant. Participants who return to 
the clinic more than 28 days late for a re-injection visit will be discontinued from the study. Participants 
will also be withdrawn if the study is terminated early. Reasons for withdrawal from the study will be 
recorded on CRFs. When early discontinuation from the study occurs, the final visit procedures will be 
followed and every reasonable effort will be made to assess information relevant to the primary and 
secondary endpoints at the time of discontinuation. Post-discontinuation visits may be conducted if 
necessary to ensure participant safety or to assess the EDF of women who report being pregnant within 
3 months of having exited the study 
Participants who withdraw early will not be replaced. However, consideration will be given to expanding 
enrollment if deemed necessary to ensure that the study objectives regarding the number of evaluable 
participants completing 12 months of treatment and precision of the Pearl Index are achieved. 


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5 TREATMENT OF PARTICIPANTS 
5.1 Study Drugs Administered During the Study 
Each participant will receive an injection of Sayana® Press at enrollment, month 4, and month 8, with SC 
injection site determined by randomization. Instructional materials developed by PATH, which are 
consistent with prescribing information, will be followed when providing injections [32]; Appendix 1). 
5.2 Restrictions 
Medications prohibited before and during the study are described in Section 5.3. Participants will 
remain at the study clinic for at least 15 minutes after study drug injection for observation for possible 
allergic reaction and/or injection site reaction. The study site will have an EpiPen® (or generic 
epinephrine injection) available and access to emergency care in the unlikely event of an anaphylaxis or 
anaphylactoid reaction. 
5.3 Prior and Concomitant Therapy or Medication 
Study staff must record on the corresponding CRF use of any study prohibited concomitant medications 
and other contraceptives the participant takes during the study. Indication, dosage, and start and end 
dates will be entered on the corresponding CRF. Use of the following medications is an exclusion 
criterion at enrollment, and participants should not initiate their use during study participation unless 
prescribed by a physician:  
• 
Rifampicin 
• 
Griseofulvin 
• 
Anticonvulsants 
• 
Barbiturates 
• 
Non-nucleoside reverse transcriptase inhibitors (efavirenz, nevirapine) and ritonavir-boosted 
protease inhibitors  
• 
Aminoglutethimide 
• 
St. John’s wort 
• 
Steroids (synthetic estrogens, progestins, androgens) 
• 
Use of selective COX-2 inhibitors (e.g., meloxicam, celecoxib) for 5 or more consecutive days  
5.4 Procedures for Monitoring Participant Treatment Compliance 
Participant compliance with treatment will be monitored by tracking attendance at scheduled re-
injection visits and documenting the dates and anatomical site of re-injection.   
6 ASSESSMENT OF EFFICACY 
Contraceptive efficacy of Sayana® Press administered at 4-month intervals will primarily be evaluated 
based on the pregnancy Pearl Index over the 12-month treatment period. Any pregnancy outcome 
which does not undergo confirmatory testing, including self-reports, will be included in the primary 


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assessment of efficacy unless the site investigator and study clinician unambiguously determine that the 
diagnosis was incorrect or that self-report was not reliable. Women who suspect pregnancy in the first 3 
months after study participation has ended will be asked to return to the clinic to determine if 
fertilization may have occurred while still in the study; any such pregnancies with EDF that fall in the 
treatment period (as defined in Section 10.6) will be included in the primary efficacy assessment.  
7 ASSESSMENT OF PHARMACOKINETICS 
7.1 Pharmacokinetic Measures 
The PK of MPA when Sayana® Press is injected every 4 months will be evaluated based on serum MPA 
concentrations collected at baseline (day 0) and months 2, 3, 4, 8, and 12 among the subset of N=120 
women in the PK cohort. PK measures, including 4-month trough concentrations, accumulation ratio, 
and apparent half-life will be summarized by SC injection site. Any participant with more than 0.05 
ng/mL MPA in her baseline specimen will be excluded from the primary PK analysis. 
7.2 Blood Sampling, Handling, and Laboratory Analysis  
Blood samples from all participants at enrollment, participants in the PK cohort, and participants who 
become pregnant, will be collected via venipuncture for serum MPA concentration measurements. The 
dates and times of each sample will be recorded on appropriate study CRFs and tracking tools. Detailed 
instructions for preparation of serum samples for MPA testing will be provided in the Study Manual.   
One aliquot will remain frozen on site, and another will be sent on dry ice in batches with other samples 
to PPD Development (Richmond, VA, USA) where MPA concentrations will be measured via a 
proprietary method utilizing sensitive and selective high-performance liquid chromatography coupled 
with mass spectrometry. This validated method is applicable to the quantitation of MPA within a 
nominal range of 0.02 to 5.00 ng/mL, and requires a 250-μL aliquot of human serum.  
PPD will maintain source documentation for MPA data. MPA results will be transferred to FHI 360 as 
password-protected Excel files for analysis. MPA results will not be documented on study CRFs or 
communicated to the study participants. No further testing of any remaining blood samples is planned; 
however, any remaining serum will be stored by PPD at least until the end of the study in the event of 
needed repeat testing or analysis of long-term stored sample stability. The PPD lab will discard 
remaining blood samples per PPD’s SOPs upon receiving written approval from FHI 360. Aliquots stored 
on site will also be maintained until the end of the study, and only discarded after receiving written FHI 
360 approval. 
8 ASSESSMENT OF SAFETY  
Safety will be assessed by qualified study staff by evaluating the following: serious AEs, AEs leading to 
product withdrawal, changes in BP, changes in bleeding and changes in body weight.  


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8.1 Adverse Events  
Participants will be provided instructions for contacting the study site to report any untoward medical 
occurrences they may experience (whether they think it is related or not related to the study product), 
except for events which they perceive to be emergencies, for which they will be instructed to seek 
immediate emergency care. Participants will be able to seek evaluation at the study site, where feasible 
and medically appropriate. The site investigator should provide or refer for medical care, and monitor 
any clinically significant AE until it has resolved or stabilized. With permission of the participant, and 
whenever possible, records from all non-study medical providers related to untoward medical 
occurrences may be obtained by study staff for review.  
Any participant who experiences an AE may be withdrawn from study treatment at any time at her will 
or at the discretion of the site investigator. When early discontinuation from the study occurs, every 
reasonable effort will be made to assess information relevant to the endpoints at the time of 
discontinuation and recorded on the Final CRF. Discontinued participants will be monitored at the 
discretion of the site investigator (e.g., until any clinically significant AE has resolved or stabilized, until 
the participant is referred to the care of a health care professional, or until a determination of a cause 
unrelated to the study drug or study procedure is made). 
SAEs and AEs resulting in product discontinuation will be recorded on study CRFs and reported to FHI 
360. For these AEs the severity will be graded per the Division of AIDS Table for Grading Adult and 
Pediatric Adverse Events Version 2.0, November 2014. The relationship to the study drug will be 
characterized as follows: 
• 
Definitely related: AEs for which, after careful medical consideration at the time they are 
evaluated, a connection with the study drug administration is determined with certainty. 
• 
Possibly related: AEs for which, after careful medical consideration at the time they are evaluated, 
a connection with the study drug administration cannot be ruled out with certainty. 
• 
Not related: AEs that, after careful consideration, are clearly due to extraneous causes (disease, 
environment, etc.) or to AEs that, after careful medical consideration at the time they are 
evaluated, are judged to be unrelated to the study drug. 
Departures from the protocol may be allowed on a case by case basis if a participant experiences an AE 
or medical emergency. After stabilization and/or treatment has been administered to ensure participant 
safety, the site investigator or other physician in attendance must contact the FHI 360 Study Director as 
soon as possible to discuss the situation. The site investigator, in consultation with FHI 360, will decide 
whether the participant should continue to participate in the study despite the protocol deviation. Any 
departures from the protocol because of AEs will be noted on a Protocol Violation CRF. 
8.2 Serious Adverse Events 
8.2.1 Definition of a Serious Adverse Event 
An AE is considered an SAE if, in the view of either the site investigator or FHI 360, it results in any of the 
following outcomes: 


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• 
Death 
• 
A life-threatening adverse event (an AE that in the view of the site investigator or FHI 360, places 
the participant at immediate risk of death) 
• 
Inpatient hospitalization (excluding hospitalization for elective surgery of pre-existing condition) or 
prolongation of existing hospitalization 
• 
A persistent or significant incapacity or substantial disruption of the ability to conduct normal life 
functions 
• 
A congenital anomaly/birth defect 
• 
Important medical events that may not result in death, be life-threatening, or require 
hospitalization may be considered serious when, based upon appropriate medical judgment, they 
may jeopardize the patient or subject and may require medical or surgical intervention to prevent 
one of the outcomes listed in this definition 
8.2.2 Reporting SAEs 
8.2.2.1 
Investigator Responsibilities 
SAEs that occur during the study, regardless of judged relationship to treatment with the study drug, 
must be reported to FHI 360 by the site investigator. All contact information and detailed instructions 
for SAE reporting will be provided in the Study Manual. The event must be reported within 24 hours of 
the site learning of the event. Additional information about any SAE unavailable at the initial reporting 
should be sent to FHI 360 by the site investigator when it becomes known. The SAE will be documented 
on the appropriate forms, and, in addition to FHI 360, communicated to the local regulatory authorities 
(if applicable) and local IRBs by the site investigator according to the local requirements.  
8.2.2.2 
FHI 360 Responsibilities 
FHI 360 will report all SAEs in this study to FHI 360’s PHSC per applicable SOPs. If an SAE is believed to be 
both related to the study drug and unexpected (i.e., not listed in the Prescribing Information for Depo-
SubQ Provera 104® or not listed at the specificity or severity that has been previously observed), then 
FHI 360 will take appropriate steps to notify all site investigators. Details on the SAE reporting will be 
included in a Safety Management Plan.  
8.3 Injection site reactions 
The site of new and previous injection(s) will be observed for possible injection site reactions at the 
enrollment, re-injection and final visits. Following administration of Sayana® Press all participants will 
stay in the clinic for 15 minutes for observation.  All injection site reactions will be graded according to 
the DAIDS AE severity table.  All ISRs that are classified as Grade 1 or higher will be reported as AEs. 
When feasible and with written consent from the study participant, photographs may be taken of the 
injection site to supplement documentation of ISRs. 
8.4 Return to ovulation (extended follow-up subset only)  
The exploratory pharmacodynamics endpoint for this study is ovulation defined as a single elevated 
serum progesterone (P≥4.7 ng/mL) or a confirmed pregnancy test. Progesterone will be measured 


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weekly during the two 5-weeks intervals for return to ovulation. Pregnancy test will be performed at 
weeks 38, 42, 46 and 50. Estradiol, an additional pharmacodynamics indicator, will be measured every 
time progesterone is measured. We will also measure MPA and other hormones (e.g., levonorgestrel, 
etonogestrel and ethinyl estradiol) at weeks 38 and 46 post last injection to rule out concurrent use of 
other hormonal contraceptives that may suppress ovarian function. See Table 3 for timing of study 
procedures.  
8.4.1 Blood Sampling, Handling, and Laboratory Analysis  
Blood samples will be collected via venipuncture. The dates and times of each sample will be recorded 
on appropriate study CRFs and tracking tools. Detailed instructions for preparation of serum samples for 
MPA testing and plasma for levonorgestrel, etonogestrel and ethinyl estradiol will be provided in the 
Study Manual.   
One aliquot will remain frozen on site, and another will be sent on dry ice in batches with other samples 
to PPD Development (Richmond, VA, USA) where MPA concentrations will be measured via a 
proprietary method utilizing sensitive and selective high-performance liquid chromatography coupled 
with mass spectrometry. This validated method is applicable to the quantitation of MPA within a 
nominal range of 0.02 to 5.00 ng/mL, and requires a 250-μL aliquot of human serum. Levonorgestrel, 
etonogestrel and ethinyl estradiol will be measured as well.  
PPD will maintain source documentation for all data. Results will be transferred to FHI 360 as password-
protected Excel files for analysis. Results will not be documented on study CRFs or communicated to the 
study participants. No further testing of any remaining blood samples is planned; however, any 
remaining serum will be stored by PPD at least until the end of the study in the event of needed repeat 
testing or analysis of long-term stored sample stability. The PPD lab will discard remaining blood 
samples per PPD’s SOPs upon receiving written approval from FHI 360. Aliquots stored on site will also 
be maintained until the end of the study, and only discarded after receiving written FHI 360 approval. 
8.5 Pregnancy outcomes 
A urine pregnancy test will be performed at enrollment, month 4, the final visit, if a woman is more than 
7 days late for her month 8 visit, or if she is experiencing any symptoms or signs of pregnancy. A blood 
specimen for MPA testing will be collected at any time of a clinic-based positive pregnancy test during 
follow-up. Any participant who becomes pregnant during the study will be discontinued from regular 
follow-up and pregnancy recorded as reason for study completion on appropriate study CRFs. 
Participants who become pregnant will be monitored to the completion or termination of the pregnancy 
or longer if required by local regulations or IRBs.  Participants who become pregnant will be asked to 
contact the study site at the time of pregnancy resolution to provide information on the pregnancy 
outcome including spontaneous or voluntary termination, details of birth and presence or absence of 
any birth defect, congenital abnormalities, or maternal and newborn complications.  Approximately one 
month after the estimated date of delivery, women who have not contacted the study site will be 
contacted to attempt collection of pregnancy outcome information.   


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8.6 Bleeding Assessment 
Bleeding patterns will be assessed and recorded on the appropriate CRF at baseline, months 4, 8, and 
final visit.   
8.7 Measurement of Body weight and BP  
Measurement of body weight and BP, will be performed at baseline and at regularly scheduled visits 
(months 4, 8, and final) (See Table 2), and documented on appropriate CRFs. Measurement of body 
weight and BP will also be performed at weeks 38 and 42 (extended follow-up subset only [see Table 3]). 
8.8 Concomitant Medication 
Use of study prohibited concomitant medication and other contraceptives will be monitored and 
recorded on appropriate study CRFs throughout the study. Details of prohibited medications are found 
in Section 5.3. 
8.9 Social Harm Events 
A social harm event is an adverse social consequence or outcome due to study participation. If a site 
investigator learns of a social harm event that is serious, unexpected and judged to be related or 
possibly related to the study protocol he/she will report the event to FHI 360 within 24 hours of 
becoming aware of the event. FHI 360 will report the event to FHI 360’s PHSC. 
8.10 Methods and Timing of Assessing, Recording, and Analyzing Safety Data 
Methods and timing of assessing safety data are discussed in Section 3.14. Procedures for recording 
safety data are discussed in Section 8, above, and methods of analysis are discussed in Section 10. 
9 ASSESSMENT OF ACCEPTABILITY 
The acceptability of a Sayana® Press injected every 4 months will be assessed and recorded on 
appropriate study CRFs at regularly scheduled visits (months 4, 8, and final). Acceptability questions will 
include questions such as acceptability of bleeding pattern and whether the participant would use the 
method in the future.   
10 STATISTICS 
Details of the planned statistical analyses to address the study objectives will be provided in a separate 
statistical analysis plan (SAP) developed prior to implementation of the trial. The following is a summary 
of the planned analyses of the study.  
10.1 Sample Size and Power Considerations 
The sample size of 710 women receiving injections in the abdomen or thigh is expected to be sufficient 
to ensure that the difference between the estimated Pearl Index and the corresponding upper 95% 


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confidence bound does not exceed 1.0, so long as the observed index is less than 0.75 and at least 80% 
of participants complete 12 months of follow-up. In addition, a cohort of 120 women (40 per SC 
injection site) is sufficient to provide 85% power to detect 30% relative differences in PK parameters 
between injection sites, assuming the corresponding coefficient of variation is no more than 40% and 
using two-sided 0.05 significance tests. 
10.2 Analysis Populations and Analysis Sets  
In the below definitions, an Analysis Population refers to a particular set of participants and an Analysis 
Set defines the time contributed to analyses by participants in a given Population. Additional censoring 
rules for analyses based on these sets are described in relevant sections of the SAP. 
10.2.1 Treated Population and Analysis Set 
The Treated Population consists of all screened participants who are enrolled and receive a dose of 
study drug. For the primary efficacy analysis, the corresponding Treated Analysis Set includes all follow 
up time contributed by each participant in the Treated Population until their EDF, the end of their 
treatment period, or the date of their last negative urine pregnancy test (for participants who do not 
become pregnant), whichever is earlier. Comparative efficacy analyses based on SC injection site will be 
performed according to intention-to-treat principles, ignoring any randomization or allocation errors.  
10.2.2 Pharmacokinetics Population and Analysis Set 
The Pharmacokinetics Population is a subset of the Treated Population, excluding participants who did 
not contribute blood specimens for PK assessments or who had a baseline serum MPA concentration 
exceeding 0.05 ng/mL. The corresponding Pharmacokinetics Analysis Set will censor data collected after 
a participant receives an injection in an anatomical site which differs from the site used at enrollment 
and will exclude any MPA specimens collected during a time when a participant reports use of a 
concomitant medication that may impact the PK of MPA. PK analyses based on this analysis 
populationconmed will be performed according to the SC site of injection at enrollment, even if received 
in error. 
10.2.3 Extended Follow-up Population  
The Extended Follow-up Population is a subset of the Treated Population, including participants who 
meet criteria for the extended follow-up subset and consent to remain in follow-up past their month 12 
visit in order to provide information on return to ovulation.  
10.3 Data Handling Conventions  
Estimated dates of fertilization will be adjudicated following FHI 360 SOPs based on ultrasound reports, 
LMP, or best clinical judgment (if ultrasound results are not available). It is anticipated that some event 
dates required for safety analyses may be incomplete. For example, participants may not recall the exact 
day of onset for a self-reported AE. Decision rules for how and when to impute such incomplete date 
fields will be developed by the medical monitor when reviewing study data and be documented in the 
study report. Other missing outcome or predictor variables will be ignored unless patterns are identified 


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which suggest the potential for biased assessments of efficacy, safety, PK or acceptability. In that event, 
rules for imputing data will be clearly described and justified in the study report. 
10.4 Multiple Comparisons and Multiplicity 
There is a single primary assessment in this study: the pregnancy Pearl Index among women randomized 
to receive injections in the abdomen or thigh. All confidence intervals reported for the primary, 
secondary, and subgroup analyses will be computed at the 95% coverage level, and all p-values will be 
assessed at the two-sided 0.05 significance level, with no adjustment for multiple testing. 
10.5 Assessment of Study Populations 
Participant disposition, demographic, and other baseline characteristics of the Treated and 
Pharmacokinetics Analysis Populations will be provided. Summaries will be presented by SC injection 
site, injection site within study clinic, and pooled across injection sites and study clinics. 
10.5.1 Participant Disposition 
The numbers of participants screened, participants screened but not enrolled (including reason(s) not 
enrolled), participants who withdraw early (and reason), and participants who complete the study will 
be summarized using descriptive statistics. 
10.5.2 Demographic and other Baseline Characteristics  
Demographic and baseline characteristics, including medical history and concomitant medication use, 
will be summarized using frequencies and percentages for categorical data and means, standard 
deviations, standard errors, medians, minima, and maxima for continuous variables. Differences in 
distributions of these characteristics between clinic sites will be assessed using exploratory analysis of 
variance for continuous variables and Chi-squared or Fisher’s Exact tests for categorical variables. 
10.6 Efficacy Analysis 
10.6.1 Primary Endpoint 
Pregnancies will be detected by urine pregnancy tests conducted at site visits and confirmed by 
ultrasound and/or serum hCG testing. The EDF for each pregnancy will be calculated by a qualified study 
clinician based on ultrasound and LMP. In the absence of ultrasound or LMP, best clinical judgment will 
be used to estimate the EDF based on all available related information including but not limited to 
vaginal bleeding, patterns of coitus, and the timing of previous negative pregnancy test results. Time to 
pregnancy will be computed as the number of days between study enrollment and EDF. Recognizing the 
plus 7-day grace period for re-injections, pregnancies with an EDF up to 18 weeks (126 days) after the 
first (enrollment) injection or up to 19 weeks (133 days) after subsequent re-injections will be included 
in the primary efficacy analysis.   
Information on any pregnancies, miscarriages or abortions diagnosed outside the study clinic will be 
collected during follow-up interviews. Any such pregnancies with EDF determined to be within the 
treatment period defined above will be included in the primary efficacy analysis unless the site 


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investigator and study clinician unambiguously determine that the pregnancy diagnosis was incorrect 
and/or self-reported data was unreliable.  
10.6.2 Planned Methods of Analysis 
10.6.2.1 Primary Efficacy Analysis 
The primary efficacy analysis will be based on the pregnancy Pearl Index, computed as the number of 
pregnancies that occur during the treatment period multiplied by 100 and divided by the number of WY 
of treatment contributed to the Treated Analysis Set among women receiving injections in the abdomen 
or thigh. Participants who do not become pregnant or who have EDFs that fall outside the windows used 
to define primary outcomes will be censored on the date of last negative urine pregnancy test or the last 
day of the treatment period of last injection (126 days after first injection or 133 days after injections at 
months 4 or 8), whichever is earlier. An exact 95% confidence interval for the Pearl Index will be 
computed based on a Poisson distribution assumption.  
10.6.2.2 Secondary Efficacy Analyses 
Secondary efficacy analyses will include:  
• 
Typical use Life-Table estimate of the cumulative probability of pregnancy through 3 
treatment cycles in the Treated Population (excluding women randomized to the upper arm) 
• 
Pearl Index that excludes follow-up periods during which participants report using other 
contraceptives (including condoms), drugs known to impact ovarian function, or drugs known 
to impact the PK of MPA, unless she became pregnant in that period  
• 
Pearl Index that includes any pregnancies with EDF that fall in an 8-28 day ‘late’ period for 
reinjections or final visits, as well as all person-time (regardless of pregnancy status) 
contributed to these periods 
• 
Pearl Index computed per the primary analysis, but including women randomized to receive 
injections in the upper arm 
In addition to the non-comparative analyses listed above, a Pearl Index will be computed separately by 
anatomical site of injection (abdomen or thigh), and the difference in pregnancy risk between site of 
injection will be assessed using a log-rank test, stratified on clinic site.  
10.7 Pharmacokinetic Analysis 
10.7.1 Pharmacokinetic Endpoints 
Pharmacokinetic endpoints include serum MPA concentrations at month 2, 3, 4, 8, and 12. 
10.7.2 Planned Method of Analysis 
Serum MPA concentration data falling within defined sampling windows will be summarized graphically 
using box plots, by SC injection site and overall. Trough concentrations at months 4, 8, and 12 will also 
be summarized using geometric means, standard deviations, and percent coefficient of variation. Month 
2, 3, and 4 data will be used to estimate t1/2 based on random effects log-linear models (under the 
assumption that the terminal phase of absorption begins by month 2), including random intercept and 


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slope terms. Accumulation of MPA concentrations at months 8 and 12 will be estimated according to the 
ratio of trough concentrations and using the formula R=[1-(0.5) dosing interval/half-life]-1, where the dosing 
interval is 126 days. Anatomical sites of injection will be compared by computing 95% confidence 
intervals for geometric mean ratios of t1/2 and trough concentrations. The effects of site, body mass 
index, and age on PK of MPA will be explored graphically and using analysis of covariance.  
10.8 Safety Endpoints and Analysis 
10.8.1 Safety Endpoints 
The overall safety of study drug will be assessed throughout the study by evaluating the following 
endpoints and variables in the Treated Analysis Set: 
• 
occurrence of SAEs and AEs leading to product discontinuation  
• 
occurrence of ISRs 
• 
BP and weight at regularly scheduled visits  
• 
changes in bleeding pattern  
10.8.2 Safety Analysis 
All SAEs, AEs leading to product withdrawal, and AEs that are Grade 1 or higher ISRs will be coded by a 
trained medical coder at FHI 360 using the Medical Dictionary for Regulatory Activities (MedDRA) by 
preferred term and system organ class. The numbers and percentages of participants experiencing AEs 
leading to product withdrawal and AEs that are Grade 1 or higher ISRs will be presented by severity. All 
relevant information on any deaths or other SAEs will be discussed in the subject narrative included in 
the clinical study report. Numbers and percentages of participants experiencing any ISR will be 
summarized by SC injection site, and ISRs will also be presented in a listing. Body weight, BP, and 
bleeding patterns will be summarized graphically or using shift-tables (i.e., change from baseline). 
10.9 Acceptability Variables and Analysis 
Perception of bleeding patterns and other responses to acceptability questions will be summarized using 
descriptive statistics based on routine questions asked at regularly scheduled visits (enrollment, months 
4 and 8, and final). 
10.10 Exploratory Variables and Analysis 
To evaluate the exploratory objective of return to ovulation, the proportion of participants in the 
Extended Follow-up Population who have returned to ovulation will be summarized at 10 months (42 
weeks) and 12 months (50 weeks) after final injection.  
10.11 BC and BMD Variables and Analysis 
Brazil site investigators will develop an analysis plan for the BC-BMD Study. FHI 360 will review and 
approve the analysis plan prior to data transfer to the site.  


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10.12 Planned Interim Analysis 
An independent DSMB will review interim data when 250 participants have completed 4 months of 
follow-up. This single, pre-planned interim analysis is intended to inform a decision to stop or modify the 
study if the estimated probability of pregnancy is greater than 2% in the first injection interval. 
Consideration may also be given to expanding enrollment if it is deemed necessary to ensure that study 
objectives regarding the number of evaluable participants completing 12 months of treatment and the 
desired precision of the Pearl Index are achieved. The interim 4-month PK data, including serum MPA 
concentrations of any women who become pregnant, may be reviewed by FHI 360 (after the DSMB has 
deliberated) to inform other FHI 360 MPA projects. 
Additional interim analyses may be requested by FHI 360 or the DSMB based on periodic reviews of 
study indicators (pregnancy, AE, recruitment and continuation rates) if deemed necessary to protect 
participant safety or to make recommendations to modify the study. Further details of interim 
monitoring procedures will be provided in a separate DSMB Operational Plan. 
10.13 Reporting Deviations from the Statistical Plan 
Deviations from analyses described here, along with their reasons, will be provided in protocol 
amendments, the separate SAP, the clinical study report, or a combination of these, as appropriate. 
11 DIRECT ACCESS TO SOURCE DATA/DOCUMENTS 
Study monitors, auditors, IRBs, and health authority inspectors will be given direct access to source data 
and documentation (e.g., medical records, laboratory test results) for source data verification, provided 
that participant confidentiality is maintained in accordance with local requirements. 
The site investigator must maintain the original records (i.e., source documents) of each participants’ 
data at all times. Examples of source documents are signed informed consent forms, clinical notes, 
laboratory reports and CRFs that are used as the source. Source documents for each participant and 
original CRFs will be retained by the site investigator per guidelines specified in Section 14.3 of this 
protocol. No records may be destroyed without written permission from FHI 360. 
12 QUALITY CONTROL AND QUALITY ASSURANCE 
12.1 Protocol Amendments 
No changes from the final approved protocol will be initiated without the prior written approval by the 
governing IRBs, except when necessary to address immediate safety concerns to the participants or 
when the change involves only logistics or administration. The site investigator will sign the protocol 
amendment investigator signature page prior to implementation.  


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12.2 Protocol Violations 
Protocol violations which may significantly impact the accuracy and/or reliability of study data or that 
may significantly affect a participant's rights, safety, or well-being will be recorded on study CRFs and 
reported to IRBs and regulatory authorities per requirements.  
Emergency departures from protocol that eliminate an apparent immediate hazard to participants and 
are deemed crucial for the safety and well-being of a participant may be instituted for that participant 
only by the site investigator. In those cases, the site investigator will notify the local IRB and FHI 360 in 
writing as soon as possible and document the reasons for the violation. 
12.3 Information to Study Personnel 
The site investigator is responsible for giving information about the study to all staff members involved 
in the implementation of the study or in any element of participant management, both before starting 
the study and during the course of the study (e.g., when new staff become involved). The site 
investigator must assure that all study staff members are qualified by education, experience, and 
training to perform their specific responsibilities. All study staff will have training in research ethics and 
Good Clinical Practice. These study staff members must be listed on the staff responsibility log, which 
includes a clear description of each staff member’s responsibilities. FHI 360 is responsible for explaining 
the protocol to all study staff, including the site investigator, and for ensuring they comply with the 
protocol. 
12.4 Study Monitoring 
Qualified clinical monitors will conduct periodic study monitoring in accordance with FHI 360 policies. 
Details of timing and duration of monitoring visits will be described in a clinical monitoring plan. Briefly, 
clinical monitors will: 
• 
Review informed consent forms and documentation 
• 
Assess compliance with the study protocol, GCP, and applicable regulatory requirements  
• 
Verify that all SAEs have been recorded and reported properly and in accordance with applicable 
regulatory guidelines 
• 
Perform source document verification to ensure the accuracy and completeness of study data 
• 
Verify proper storage of biological specimens 
• 
Verify proper storage, dispensing, and accountability of study products 
• 
Verify that current credentials are available on site for study staff listed on the current Statement 
of Investigator Form and Delegation of Responsibilities Log 
Site investigators and study staff will allow the clinical monitors to inspect study facilities and 
documentation including the regulatory file, consent forms, CRFs, and other source documents for 
verification of the study data. The site investigator and assisting staff must agree to cooperate with the 
study monitor to resolve any problems, errors, or possible misunderstandings concerning the findings 
detected in the course of these monitoring visits and/or provided in follow up written communication. 


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As part of the supervision of study progress, other FHI 360 staff or representatives may accompany the 
study monitor on visits to the study site. Sites will maintain a site visit log to document all visits.   
12.5 Audit and Inspection 
FHI 360 or regulatory authorities may audit the study sites to evaluate study conduct and compliance 
with the protocol, SOPs, GCP, and applicable IRB and regulatory requirements. 
13 ETHICS 
13.1 Informed Consent 
A participant will not be enrolled into this research study until the site investigator has obtained her 
signed informed consent (including consent to additional visits if in the PK cohort). The site investigator 
shall seek such consent under circumstances that provide the prospective participant with sufficient 
opportunity to learn about the study and consider whether or not to participate. Informed consent will 
be obtained without coercion, undue influence or misrepresentation of the potential benefits and risks 
that might be associated with participation in the research study. Informed consent encompasses all 
oral or written information given to the participant about the study and the study materials. This 
includes the consent form(s) signed by the participant and any other information provided to the 
participant. All such information that is given to the participant will be in a language that is 
understandable to her. The participant must agree that she understands the investigational nature of 
the study, its inherent risks and benefits, other treatment alternatives, her rights to terminate 
participation in the study without affecting her health care at the site, whom to contact with questions 
regarding the study, and that she has freely given informed consent to participate in the study and to 
have her medical records reviewed as part of the study.  
Informed consent will be documented by the use of a written consent form (or forms) signed by the 
participant. Copies of signed informed consent forms will be given to her. The original signed consent 
form(s) for each participant will be stored in a secure location separately from the study data forms. The 
consent form(s) must include each of the basic and additional elements of informed consent described 
in 45 CFR Part 46.116. The informed consent form will include a statement that personal identifying 
information will be removed from participant data and the non-identified study data will be shared with 
the donor, USAID, and might be used for future research. The information will not include any language 
in which the participant is made to waive any of her rights or which releases or appears to release the 
site investigator, the site investigator’s institution, or FHI 360 from liability for negligence.  
13.2 Compensation 
Participants will be compensated for time and effort for participation in this study. Reimbursement will 
cover transportation costs and time away from work, and may vary by site depending on local ethical 
review requirements. Reimbursement amounts will be specified in the site-specific informed consent 
forms and reviewed with participants upon study enrollment. 


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13.3 Health Authorities and IRBs 
This protocol, the informed consent forms, and other appropriate documentation will be reviewed and 
approved as required by the PHSC at FHI 360 and the site IRBs. The site investigator is responsible for 
ensuring that all requirements of the local IRB are met. Before implementing any changes to the 
protocol, informed consent, or participant written materials, the site investigator must have the changes 
approved by FHI 360’s PHSC and the local IRB, and applicable health regulatory agencies, except where 
necessary to eliminate immediate hazards to study participants. If the local IRB withdraws its approval of 
this research at any time before its completion, the site investigator must notify FHI 360 as soon 
possible, but no later than within 48 hours.  
The site investigator is responsible for providing progress reports to the local IRB and to FHI 360 
annually and within 3 months after study termination or completion. The reports should include at a 
minimum the total number of participants enrolled, the numbers and reason(s) for discontinuation, a 
description of all SAEs, the number of participants completing the study, all changes in the research 
activity, and all unanticipated problems involving risks to study participants or others. Copies of all 
study-related correspondence with the local IRB must be sent to FHI 360. 
13.4 Study Participant Confidentiality  
The site investigator must assure that the privacy of the participants, including their identity and 
confidentiality of all personal medical information, will be maintained at all times. In CRFs and other 
documents or image material submitted to FHI 360, participants will be identified not by their names, 
but by a participant ID number only. 
Personal medical information may be reviewed for the purpose of participant safety and/or verifying 
data in the source and transcribed onto the CRF. This review may be conducted by the study monitor, 
properly authorized persons on behalf of the sponsor, the quality assurance unit, and/or regulatory 
authorities. Personal medical information will always be treated as private and confidentiality will be 
maintained. 
13.5 Registration of the Clinical Study 
FHI 360 will register this trial on clinicaltrials.gov, a registry and results database of clinical studies of 
human participants conducted globally. 
14 DATA HANDLING, DATA QUALITY CONTROL, AND RECORD KEEPING 
A detailed data management plan will be written prior to study initiation. The following is a brief 
summary of the plan.  
14.1 Data Collection 
Data will be collected using CRFs that are specifically designed for this study. The data collected on the 
CRFs will be captured in a clinical data management system (CDMS) that meets the technical 


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requirements described in 21CFR Part 11. The CDMS has been validated to ensure that it meets the 
scientific, regulatory, and logistical requirements of the study before it is used to capture data from this 
study. Before using the CDMS, all users will receive training on the system and study specific training. 
After they are trained, users will be provided with individual system access rights. 
Data will be collected at the study site by appropriately designated and trained personnel, and CRFs 
must be completed for each screened participant. For participants who enter the study but do not meet 
screening criteria, at a minimum, data for screen failure reason will be entered onto a CRF.  
Participant identity should not be discernible from the data provided on the CRFs. Data will be verified 
by the monitor and reviewed for consistency by Data Management using both automated logical checks 
and manual review. All data collected will be approved by the site investigator or designee at the study 
site. This approval acknowledges the review and acceptance of the data as being complete and accurate.  
Data processed from PPD will be sent electronically to FHI 360 for direct import into the clinical 
database, but not entered onto the CRF unless otherwise specified in the protocol.  
14.2 Data Quality Control  
Data Management is responsible for the accuracy, quality, completeness, and internal consistency of the 
data from this study. Data handling, including data quality control, will comply with international 
regulatory guidelines, including ICH GCP guidelines. Data management and control processes specific to 
this study, along with all steps and actions taken regarding data management and data quality control, 
will be described in a data management plan. 
Case report forms received will be processed and reviewed for completeness, consistency, and the 
presence of mandatory values. Applicable terms will be coded according to the coding conventions for 
this study. Logical checks will be implemented to ensure data quality and accuracy. Any necessary data 
changes will be made in the clinical database, and data review and validation procedures will be 
repeated as needed. Discrepancies found will be queried. 
Data corrections will be made using the CDMS Discrepancy module. The system audit trail captures the 
reason for each change, the previous and new data values, date and time, and the username of the staff 
person making the change. 
At the conclusion of the study, the CDMS and all other study data will be locked to prevent further 
changes. Locking the study data represents the acknowledgement that all data have been captured and 
confirmed as accurate. 
14.3 Archiving of Case Report Forms and Source Documents  
14.3.1 Investigator Responsibilities 
All records related to the study (i.e., source data, source documents, CRFs, copies of protocols and 
protocol amendments, drug accountability forms, correspondence, signed informed consent forms, and 
other essential documents) must be retained by the site investigator. Per GCP, essential documents 
should be retained until at least 2 years after the last approval of a marketing application in an ICH 


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region and until there are no pending or contemplated marketing applications in an ICH region or at 
least 2 years have elapsed since the formal discontinuation of clinical development of the investigational 
product.  FHI 360 will inform the site investigator as to when these documents no longer need to be 
retained. No records may be destroyed without written permission from FHI 360. Should the site 
investigator wish to assign the study records to another party or move them to another location, 
advance written notice will be given to FHI 360. 
14.3.2 FHI 360 Responsibilities 
FHI 360 will be responsible for the processing and quality control of the data. Data management will be 
carried out as described in FHI 360 SOPs and the data management plan. 
15 FINANCING AND INSURANCE 
A separate financial agreement will be made between FHI 360 and the clinical sites before the study 
drug is delivered. 
The study will comply with requirements of US and the countries where the study is conducted 
regarding liability insurance coverage, as applicable. 
16 REPORTING AND PUBLICATION OF RESULTS 
There will be a primary publication of the study led by FHI 360 reporting the results of the primary and 
secondary objectives stated in the study protocol, which must precede any secondary publications or 
presentations of the results by the participating site investigators. Collaborators will discuss and agree 
upon any planned publication before submission. The study sites may not publish data collected in this 
study, or any sub-studies, without prior written approval from FHI 360. 
All publications, reports and official presentations will include the following statement "This 
(study/report/visual/other information/media product) is made possible by the generous support of the 
American people through the U.S. Agency for International Development (USAID). The contents are the 
responsibility of FHI 360 and do not necessarily reflect the views of USAID or the United States 
Government.” 
Authorship roles will be assigned primarily according to the contributions of individual members. Other 
key contributors to the research will be acknowledged as part of the research team. Results will be 
presented at relevant conferences and published in peer-reviewed journals as open access articles 
unless a waiver is granted by USAID.  
 


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17 REFERENCES 
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Hatcher, R.A., et al., Contraceptive Efficacy. Eighteenth Revised Edition ed. Contraceptive 
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Heffron, R., et al., Use of hormonal contraceptives and risk of HIV-1 transmission: a prospective 
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Morrison, C.S., et al., Hormonal contraception and the risk of HIV acquisition: an individual 
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Medicines and Healthcare Products Regulatory Agency (MHRA), Public Assessment Report, 
Mutual Recognition Procedure, Sayana 104mg/0.65mL suspension for injection. Revised August 
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Toh, Y.C., et al., Suppression of ovulation by a new subcutaneous depot medroxyprogesterone 
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21. 
Center for Disease Control and Prevention (CDC), Update to CDC's U.S. Medical Eligibility Criteria 
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Modesto, W., et al., Weight variation in users of depot-medroxyprogesterone acetate, the 
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18 APPENDICES 
18.1 Appendix 1: Sayana® Press Injection Job Aid 
  
 
 


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