Conditions: HIV Infections
Allocation: RANDOMIZED | Intervention model: SEQUENTIAL
Enrollment: 1104
Healthy volunteers: yes

Brief summary:
The purpose of this study is to evaluate the maternal and infant safety of the dapivirine (DPV) vaginal ring (VR) and daily oral Truvada in HIV-uninfected pregnant women and their infants.

Detailed description:
The purpose of this study is to evaluate the maternal and infant safety of the dapivirine (DPV) vaginal ring (VR) and daily oral Truvada in HIV-uninfected pregnant women and their infants.

Participants will be assigned to one of three cohorts based on gestational age:

* Cohort 1: 36 0/7 weeks - 37 6/7 weeks
* Cohort 2: 30 0/7 weeks - 35 6/7 weeks
* Cohort 3: 12 0/7 weeks - 29 6/7 weeks

Within each cohort, participants will be randomized to receive either DPV VR or oral Truvada. Participants randomized to the DPV VR will use the VR continuously for approximately one month, replacing the VR each month. Participants taking the Truvada tablet will take one tablet orally per day. Participants will use their assigned study product until their pregnancy outcome, but no later than 41 6/7 weeks of gestation.

Participants will attend several study visits throughout the study and study staff will also contact participants by phone at different timepoints throughout the study.

The total duration of study participation will vary depending on gestational age at time of enrollment and length of pregnancy prior to pregnancy outcome and will range from approximately 12 weeks or less for Cohort 1 to approximately 36 weeks or less for Cohort 3. Infants born to study participants will be followed for approximately 52 weeks.

Arms:
arm 1: Participants in Cohort 1 (36 0/7 weeks - 37 6/7 weeks) will use one DPV VR continuously for approximately one month, replacing the DPV VR each month. Participants will use the DPV VR until their pregnancy outcome but no later than 41 6/7 weeks of gestation. arm 2: Participants in Cohort 1 (36 0/7 weeks - 37 6/7 weeks) will take one Truvada oral tablet daily. Participants will take Truvada until their pregnancy outcome but no later than 41 6/7 weeks of gestation. arm 3: Participants in Cohort 2 (30 0/7 weeks - 35 6/7 weeks) will use one DPV VR continuously for approximately one month, replacing the DPV VR each month. Participants will use the DPV VR until their pregnancy outcome but no later than 41 6/7 weeks of gestation. arm 4: Participants in Cohort 2 (30 0/7 weeks - 35 6/7 weeks) will take one Truvada oral tablet daily. Participants will take Truvada until their pregnancy outcome but no later than 41 6/7 weeks of gestation. arm 5: Participants in Cohort 3 (12 0/7 weeks - 29 6/7 weeks) will use one DPV VR continuously for approximately one month, replacing the DPV VR each month. Participants will use the DPV VR until their pregnancy outcome but no later than 41 6/7 weeks of gestation. arm 6: Participants in Cohort 3 (12 0/7 weeks - 29 6/7 weeks) will take one Truvada oral tablet daily. Participants will take Truvada until their pregnancy outcome but no later than 41 6/7 weeks of gestation. arm 7: Infants born to maternal participants in the Cohort 1 (36 0/7 weeks - 37 6/7 weeks) DPV VR arm. arm 8: Infants born to maternal participants in the Cohort 1 (36 0/7 weeks - 37 6/7 weeks) Truvada oral tablet daily arm. arm 9: Infants born to maternal participants in the Cohort 2 (30 0/7 weeks - 35 6/7 weeks) DPV VR arm. arm 10: Infants born to maternal participants in the Cohort 2 (30 0/7 weeks - 35 6/7 weeks) Truvada oral tablet daily arm. arm 11: Infants born to maternal participants in the Cohort 3 (12 0/7 weeks - 29 6/7 weeks) DPV VR arm. arm 12: Infants born to maternal participants in the Cohort 3 (12 0/7 weeks - 29 6/7 weeks) Truvada oral tablet daily arm.

Interventions: intervention 1: Dapivirine (DPV) Vaginal Ring (VR) intervention 2: Truvada Tablet
Intervention descriptions: intervention 1: Vaginal ring containing 25 mg of DPV intervention 2: Tablet taken orally

Protocol document:
SAP_002.pdf: 
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STATISTICAL ANALYSIS PLAN 
 
Phase 3b, Randomized, Open Label Safety Trial of 
Dapivirine Vaginal Ring and Oral TRUVADA® Use in 
Pregnancy 
 
MTN-042 
 
Effective Date: Date of last signature 
Version: 1.0 


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Author(s): 
STATISTICAL ANALYSIS PLAN 
 
Protocol Name: 
Phase 3b, Randomized, Open Label Safety Trial of Dapivirine 
Vaginal Ring and Oral TRUVADA® Use in Pregnancy 
Protocol Number: 
MTN-042 
Author(s): 
Barbra Richardson, PhD 
Daniel Szydlo, MS 
Version: 
1.0 
 
 
 
Research Professor 
Legal Name 
Barbra Richardson 
Job Title 
Research Professor 
Signature & Date 
Digitally signed by Barbra 
Barbra Richardson Richardson 
Date: 2024.07.03 08:04:35 -07'00' 
 
 
Statistical Manager 
Legal Name 
Daniel Szydlo 
Job Title 
Statistical Manager 
Signature & Date 
Electronically signed by: Daniel Szydlo 
Daniel Szydlo 
Reason: I am an author of the 
document. 
Date: Jul 3, 2024 09:30 PDT 


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DAIDS Representative 
Legal Name 
Dean Follman 
Job Title 
DAIDS Representative 
Signature & Date 
 
 
The effective date of this document is the date of the latest signature. 
Approvals: 


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TABLE OF CONTENTS 
1. 
LIST OF ABBREVIATIONS AND ACRONYMS .......................................................................... 6 
2. 
INTRODUCTION ..................................................................................................................... 7 
2.1 
GENERAL DESIGN CONSIDERATIONS ................................................................................................................ 7 
2.2 
STUDY OBJECTIVES AND ENDPOINTS ............................................................................................................... 8 
2.3 
RANDOMIZATION ........................................................................................................................................... 10 
2.4 
BLINDING ........................................................................................................................................................ 10 
2.5 
PRIMARY STUDY HYPOTHESES ...................................................................................................................... 10 
2.6 
SAMPLE SIZE AND POWER ............................................................................................................................. 10 
3. 
GENERAL DATA ANALYSIS CONSIDERATIONS .................................................................... 12 
3.1 
ANALYSIS SET(S) ................................................................................................................ 12 
3.2 
STATISTICAL ANALYSIS ISSUES ....................................................................................................................... 12 
4. 
INTERIM ANALYSIS AND DATA MONITORING COMMITTEE ............................................. 13 
5. 
GENERAL ANALYSIS METHODS .......................................................................................... 14 
6. 
TRIAL PARTICIPANT DISPOSITION ...................................................................................... 14 
6.1 
DISPOSITION OF PARTICIPANTS ..................................................................................................................... 14 
6.2 
TREATMENT EXPOSURE ................................................................................................................................. 16 
6.3 
PROTOCOL DEVIATIONS ................................................................................................................................. 16 
6.4 
PRODUCT DISCONTINUATION .........................................................................................................................17 
6.5 
RETENTION ..................................................................................................................................................... 17 
7. 
BASELINE DATA ................................................................................................................... 18 
7.1 
MOTHER DEMOGRAPHICS ............................................................................................................................. 18 
7.2 
PREGNANCY HISTORY .....................................................................................................................................18 
7.3 
GESTATIONAL AGE ..........................................................................................................................................18 
7.4 
BASELINE MEDICAL HISTORY ........................................................................................................................ 18 
7.5 
PRIOR MEDICATION ........................................................................................................................................19 
7.6 
PELVIC EXAM .................................................................................................................................................. 19 
8. 
PRIMARY ENDPOINTS ......................................................................................................... 19 
8.1 
PRIMARY MATERNAL SAFETY ........................................................................................................................ 20 
8.2 
PRIMARY INFANT SAFETY .............................................................................................................................. 20 
8.3 
PREGNANCY OUTCOMES ................................................................................................................................21 
9. 
SECONDARY ENDPOINTS .................................................................................................... 21 
9.1 
PREGNANCY COMPLICATIONS ........................................................................................................................21 
9.2 
INFANT DRUG LEVELS .................................................................................................................................... 22 
9.3 
ADHERENCE .................................................................................................................................................... 22 
9.4 
ACCEPTABILITY ............................................................................................................................................... 23 


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10. 
SAFETY ANALYSES ............................................................................................................... 24 
10.1 
MATERNAL ADVERSE EVENTS ....................................................................................................................... 24 
10.2 
INFANT ADVERSE EVENTS .............................................................................................................................. 24 
10.3 
PRODUCT HOLDS ............................................................................................................................................25 
10.4 
MOTHER LABORATORY EVALUATIONS .......................................................................................................... 25 
10.5 
INFANT LABORATORY EVALUATIONS ............................................................................................................. 26 
10.6 
MOTHER HIV-1 ................................................................................................................ 26 
10.7 
INFANT HIV-1................................................................................................................... 26 
10.8 
SEXUALLY TRANSMITTED INFECTIONS ........................................................................................................... 26 
10.9 
CONCOMITANT MEDICATIONS ...................................................................................................................... 27 
10.10 
INFANT CONCOMITANT MEDICATIONS ......................................................................................................... 27 
10.11 
PHYSICAL EXAMINATION ............................................................................................................................... 28 
10.12 
INFANT PHYSICAL EXAM ................................................................................................................................ 28 
10.13 
INFANT AGES AND STAGES ASSESSMENT ..................................................................................................... 28 
10.14 
EDINBURGH POSTNATAL DEPRESSION SCALE ............................................................................................... 29 
10.15 
INFANT DEMOGRAPHICS ................................................................................................................................ 30 
10.16 
SOCIAL BENEFITS ............................................................................................................................................ 30 
10.17 
SOCIAL IMPACTS ............................................................................................................................................ 30 
11. 
CHANGE HISTORY ............................................................................................................... 31 
12. 
APPENDIX I MOTHER EXPECTED VISITS FROM WEEK 5 UNTIL PREGNANCY OUTCOME. 31 
13. 
APPENDIX II VISIT TIMING REQUIREMENTS ...................................................................... 35 
14. 
APPENDIX III RESIDUAL DRUG LEVELS CALCULATION ....................................................... 39 


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1. LIST OF ABBREVIATIONS AND ACRONYMS 
 
Term/Abbreviation 
Definition 
AE 
adverse event 
AIDS 
acquired immune deficiency syndrome 
ASPIRE 
A Study to Prevent Infection with a Ring for Extended Use 
CRF 
case report form 
CSR 
Clinical Study Report 
CV 
coefficient of variation 
DAIDS 
Division of Acquired Immunodeficiency Syndrome 
DPV 
dapivirine 
FTC 
emtricitabine 
GA 
gestational age 
IQR 
interquartile range 
IRP 
Interim Review Panel 
LLOQ 
lower limit of quantification 
MTN 
Microbicide Trials Network 
NIAID 
National Institute of Allergy and Infectious Diseases 
NICHD 
National Institute of Child Health and Human Development 
NIH 
National Institutes of Health 
NIMH 
National Institute of Mental Health 
PO 
pregnancy outcome 
PPO 
post-pregnancy outcome 
PrEP 
pre-exposure prophylaxis 
PROM 
premature rupture of membranes 
PUEV 
product use end/early termination visit 
SAE 
serious adverse event 
SAP 
statistical analysis plan 
SD 
standard deviation 
SEV 
study exit visit 
TFV 
tenofovir 
TLFs 
tables, listings, and figures 
VOICE 
Vaginal and Oral Interventions to Control the Epidemic 


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VR 
vaginal ring 
 
2. INTRODUCTION 
The purpose of this statistical analysis plan (SAP) is to define the analyses that will be conducted to 
describe mother and infant safety, pregnancy outcomes, pregnancy complications, infant drug levels, 
adherence, and acceptability for the MTN-042 final protocol analysis. 
 
2.1 General Design Considerations 
 
The following is a summary of Protocol Version 2.0 
Short Title: 
DELIVER: A Phase 3b Safety Study of the Dapivirine Ring and PrEP in 
Pregnant Women 
 
IND Sponsor: 
DAIDS 
 
Funders: 
Division of AIDS, NIAID, NIMH, NICHD, US NIH 
Protocol Chair: 
Katherine Bunge, MD, MPH 
Felix Mhlanga, MBChB, MMed 
 
Protocol Co-Chair: 
Lee Fairlie, MBChB, FCPaeds 
Sample Size: 
Approximately 550 women and their infants 
 
Study Population:  Healthy, HIV-uninfected pregnant females, 18-40 (inclusive) years old, with an 
uncomplicated singleton pregnancy who are willing to be randomized to study 
product, and their infants 
 
Study Sites: 
MTN-042 site(s) selected by the MTN Executive Committee 
 
Study Hypotheses:  
Daily use of Truvada oral tablet and dapivirine (DPV) vaginal matrix ring 
(25 mg) inserted once every 4 weeks will both be generally safe and well- 
tolerated by the participants and their fetuses/infants. 
Participants who use Truvada oral tablet daily and insert the DPV vaginal 
matrix ring (25 mg) once every 4 weeks will experience similar distributions 
of pregnancy outcomes to the general population. 
Study Design: 
Phase 3b, two-arm, open label, multi-site, randomized (2:1) trial (DPV vaginal 
ring [VR], Truvada oral tablet), with onset of dosing period to occur within the 
following gestational age (GA) ranges: 
Cohort 1: 36 0/7 weeks – 37 6/7 weeks 150 women 
Cohort 2: 30 0/7 weeks – 35 6/7 weeks 150 women 
Cohort 3: 12 0/7 weeks – 29 6/7 weeks 150 women 
Study Duration: 
The total duration of study participation for each participant will vary depending 
on gestational age at time of enrollment and length of pregnancy prior to 
pregnancy outcome, and will range from approximately 12 weeks or less for 
Cohort 1 to approximately 36 weeks or less for Cohort 3. Participants who 


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become infected with HIV will continue in study follow-up with a modified study 
visit/procedure schedule for a minimum of twelve months. Also, infants born to 
MTN-042 participants will be followed for approximately 52 weeks (i.e., one 
year) 
 
Study Products: 
Silicone elastomer matrix VR containing 25 mg of DPV 
Oral tablets (Truvada) containing 200 mg emtricitabine/300 mg tenofovir 
disoproxil fumarate (FTC/TDF) 
Study Regimen: 
Within Cohorts 1 and 2, participants will be randomized to the above study 
products in a 2:1 ratio (VR:tablet). Cohort 3 participants will be randomized to 
the above study products in a 4:1 ratio (200 VR:50 tablet). Participants 
randomized to the DPV VR will use one VR continuously for approximately 
one month, replacing the VR each month. Participants using Truvada tablet 
will take one tablet orally per day. Participants will use their assigned study 
product until their pregnancy outcome but no later than 41 6/7 weeks of 
gestation. 
 
Figure 1: Study Visit Schedule – Cohort 2 
 
 
 
The primary objective of the IRP is to monitor the safety of the products being evaluated and make 
recommendations about the continuation, modification, or termination of either or both arms of the study in 
the next gestational age cohort. 
 
2.2 Study Objectives and Endpoints 
Primary Objectives: 
Maternal and Infant Safety: To describe the maternal and infant safety profile associated with 


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study product exposure during pregnancy 
 
Pregnancy Outcomes: To describe the pregnancy outcomes associated with study product 
exposure during pregnancy 
Primary Endpoints: 
 
Maternal Safety (composite) 
All serious adverse events, including maternal deaths 
All Grade 3 or higher adverse events (AE) as defined by the Division of AIDS (DAIDS) 
Table for Grading the Severity of Adult and Pediatric Adverse Events, Corrected Version 
2.1, July 2017 and/or Addendum 1 (Female Genital Grading Table for Use in Microbicide 
Studies [Dated November 2007]) 
Infant Safety (composite) 
 
All serious adverse events, including infant deaths and congenital anomalies 
 
All Grade 3 or higher AEs as defined by the Division of AIDS (DAIDS) Table for Grading 
the Severity of Adult and Pediatric Adverse Events, Corrected Version 2.1, July 2017 
Pregnancy Outcomes 
 
Frequency of the following pregnancy outcomes: 
o 
 
 
o 
Premature live birth (<37 0/7 weeks) 
o 
 
o 
Pregnancy loss (<20 0/7 weeks) 
Secondary Objectives: 
 
Pregnancy Complications: To describe pregnancy complications associated with study product 
exposure during pregnancy 
Infant Drug Levels: To describe infant levels of study drugs associated with study product 
exposure during pregnancy 
 
Adherence: To characterize adherence to open label use of the DPV VR (25 mg) and oral 
Truvada in pregnant women 
Acceptability: To characterize acceptability of open label use of the DPV VR (25 mg) and oral 
Truvada in pregnant women 
Secondary Endpoints: 
Pregnancy Complications 
 
Frequency of the following pregnancy complications: 
o 
Hypertensive disorders of pregnancy 
o 
Chorioamnionitis 
o 
Puerperal sepsis and endometritis 
o 
Antepartum, intrapartum and postpartum hemorrhage 
o 
Preterm premature rupture of membranes (PROM) 
o 
Fever of unclear etiology 
Infant Drug Levels 


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Infant blood tenofovir diphosphate (TFV-DP) and emtricitabine triphosphate (FTCTP) 
concentrations 
Infant plasma DPV concentrations 
Adherence 
Maternal blood TFV-DP and FTC-TP concentrations 
Maternal plasma DPV concentrations 
Participant report of frequency of study product use (e.g., missed doses for oral Truvada 
and VR removal/expulsions [voluntary and involuntary] and duration without VR in 
vagina) 
Residual drug levels in returned VRs 
Acceptability 
 
 Self-reported attitudes about study product attributes and willingness to use study 
products during pregnancy 
 
Proportion of participants who find the study products to be at least as acceptable as 
other HIV prevention methods 
 
2.3 Randomization 
 
Participants in Cohorts 1 and 2 were randomized in a 2:1 ratio to the two arms of the study, two DPV VR 
to one FTC/TDF, stratified by study site. Participants in Cohort 3 were randomized in a 4:1 ratio, four DPV 
VR to one FTC/TDF, also stratified by study site. 
 
2.4 Blinding 
 
This was an open label study. Study staff and participants were blinded to the sequence prior to 
randomization of the participant. 
 
2.5 Primary Study Hypotheses 
 
 
It is hypothesized that daily use of Truvada oral tablet or DPV vaginal matrix ring (25 mg) inserted 
once every 4 weeks will be generally safe and well-tolerated by the participants and their 
fetuses/infants. 
 
It is hypothesized that participants who use Truvada oral tablet daily or insert the DPV vaginal 
matrix ring (25 mg) once every 4 weeks will experience similar distributions of pregnancy 
outcomes to the general population. 
 
2.6 Sample Size and Power 
 
For primary analyses of outcomes there will be no direct statistical testing between study arms or 
between study arms and the data presented in MTN-042B. Instead, the frequency of primary and 
secondary outcomes from MTN-042 will be viewed in the context of local background pregnancy outcome 
data compiled in the MTN-042B study, a multi-site, cross-sectional chart review of pregnancy outcome 
data from the same four African sites. It is hypothesized that participants who use Truvada oral tablet 
daily and insert the DPV vaginal matrix ring (25 mg) once every 4 weeks will experience distributions of 
pregnancy outcomes that are qualitatively similar to the general population (i.e. the data compiled in 
MTN-042B). Comparisons to MTN-042B will not be included in the Clinical Study Report (CSR). 
To characterize the statistical properties of this study, the below presents the probability of observing 
zero, at least one, ten or more, and fifty or more safety endpoints in each group by cohort size and among 
the total study population for various “true” event rates, ranging from low to high: 


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Table 1. Probability (%) of observing an event given different “true” event rates by cohort size 
“True” 
event 
rate 
P (0 events) 
 
  
 
 
 
 
 
 
 
 
 
Cohorts 
1-2a 
n=100 
n=50 
n=100 
n=50 
n=100 
n=50 
n=100 
n=50 
1% 
36.6 
60.50 
63.40 
39.50 
0.00 
0.00 
0.00 
0.00 
5% 
0.59 
7.69 
99.41 
92.31 
1.15 
0.00 
0.00 
0.00 
10% 
0.00 
0.52 
100.00 
99.48 
41.68 
0.94 
0.00 
0.00 
15% 
0.00 
0.03 
100.00 
99.97 
90.06 
11.99 
0.00 
0.00 
25% 
0.00 
0.00 
100.00 
100.00 
99.99 
73.78 
0.07 
0.00 
Cohort 
3a 
n=200 
n=50 
n=200 
n=50 
n=200 
n=50 
n=200 
n=50 
1% 
13.4 
60.50 
86.6 
39.50 
0.00 
0.00 
0.00 
0.00 
5% 
0.00 
7.69 
100.00 
92.31 
41.69 
0.00 
0.00 
0.00 
10% 
0.00 
0.52 
100.00 
99.48 
99.19 
0.94 
0.00 
0.00 
15% 
0.00 
0.03 
100.00 
99.97 
100.00 
11.99 
0.01 
0.00 
25% 
0.00 
0.00 
100.00 
100.00 
100.00 
73.78 
46.21 
0.00 
Overalla 
n=400 
n=150 
n=400 
n=150 
n=400 
n=150 
n=400 
n=150 
1% 
1.80 
22.15 
90.95 
44.30 
0.27 
0.00 
0.00 
0.00 
5% 
0.00 
0.05 
100.00 
99.59 
99.06 
13.22 
0.00 
0.00 
10% 
0.00 
0.00 
100.00 
100.00 
100.00 
89.40 
4.36 
0.00 
15% 
0.00 
0.03 
100.00 
100.00 
100.00 
99.86 
91.06 
0.00 
25% 
0.00 
0.00 
100.00 
100.00 
100.00 
100.00 
100.00 
0.85 
a Sample sizes in the table based on the proposed cohort sizes and study design. For example, Cohort 1 will include 
approximately 150 participants, with 2:1 randomization, there will be 100 participants in the VR arm and 50 participants 
in the Truvada arm. 
 
An alternative way of describing the statistical properties of the study design is in terms of the 95% 
confidence interval for the “true” rate based on the observed data. The table below shows the exact 2- 
sided 95% confidence intervals for the probability of an event based on a particular observed rate. For 
example, if none of the 400 participants receiving the VR regimen experience a safety event, the 95% 
exact 2-sided upper confidence bound for the true rate of such events in a particular arm of the study is 
0.92%. 
 
Table 2. Confidence intervals for endpoint rate (proportion of participants with endpoint) given 
number of endpoints (rows) in with number of participants (columns) 
Number 
of events 
Number of participantsa 
n=50 
n=100 
n=150 
n=200 
n=400 
0 
0.00, 7.11 
0.00, 3.62 
0.00, 2.43 
0.00, 1.83 
0.00, 0.92 
1 
0.05, 10.65 
0.03, 5.45 
0.00, 3.66 
0.01, 2.75 
0.00, 1.38 
2 
0.49, 13.71 
0.24, 7.04 
0.16, 4.73 
0.12, 3.57 
0.06, 1.79 
3 
1.25, 16.55 
0.62, 8.52 
0.41, 5.73 
0.31, 4.32 
0.15, 2.18 
4 
2.22, 19.23 
1.10, 9.93 
0.73, 6.69 
0.55, 5.04 
0.27, 2.54 
5 
3.33, 21.81 
1.64, 11.28 
1.09, 7.61 
0.82, 5.74 
0.41, 2.89 


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Number 
of events 
Number of participantsa 
n=50 
n=100 
n=150 
n=200 
n=400 
6 
4.53, 24.31 
2.23, 12.60 
1.48, 8.50 
1.11, 6.42 
0.55, 3.24 
8 
7.17, 29.11 
3.52, 15.16 
2.33, 10.24 
1.74, 7.73 
0.87, 3.90 
10 
10.03, 33.72 
4.90, 17.62 
3.24, 11.92 
2.42, 9.00 
1.21, 4.55 
12 
13.06, 38.17 
6.36, 20.02 
4.20, 13.56 
3.14, 10.25 
1.56, 5.18 
15 
17.86, 44.61 
8.65, 23.53 
5.71, 15.96 
4.26, 12.07 
2.11, 6.11 
20 
26.41, 54.82 
12.67, 29.18 
8.34, 19.84 
6.22, 15.02 
3.08, 7.62 
30 
45.18, 73.59 
21.24, 39.98 
13.92, 27.30 
10.35, 20.72 
5.12, 10.53 
a Sample sizes in the table based on the proposed cohort size and study design. 
Based on pregnancy outcome data from previous studies, we expect certain pregnancy outcomes such 
 
-3%, 
respectively). Among all women who became pregnant in MTN-003 (VOICE) and MTN-020 (ASPIRE), 
pregnancy loss < 20 weeks was between 19-22%. Given the enrollment criteria for this study, it is 
expected that the frequency of pregnancy loss < 20 weeks will be lower in enrolled MTN-042 participants. 
As such, the probability and confidence interval estimates presented in Table 1 and Table 2 also apply to 
estimates of the frequency of pregnancy outcomes. For example, if there was one stillbirth among the 100 
participants in Cohort 1 receiving the VR regimen, the stillbirth frequency would be 1.00% and the 95% 
exact 2-sided confidence interval would be (0.03, 5.45). 
 
 
3. GENERAL DATA ANALYSIS CONSIDERATIONS 
3.1 Analysis Set(s) 
 
The ITT Analysis Set will consist of all enrolled and randomized women, and all enrolled infants. 
Participant treatment for mothers will be determined according to their randomization arm assignment. 
Participant treatment for infants will be determined according to their mother’s randomization arm 
assignment. 
 
A secondary Product Exposure Set will be used for some analyses and will differ from the ITT Analysis 
Set in that participants who never received any study product (per the Pharmacy Dispensation CRF) and 
endpoints that occur > 7 days after study product discontinuation (per the Discontinuation of Study 
Product CRF) will be excluded. 
A secondary Infant Exposure Set will be used for some analyses and will be the same as the ITT Analysis 
Set except that infants whose mothers never received study product will be excluded. If all enrolled and 
randomized mothers in a cohort received study product then the Infant Exposure Set and Infant ITT 
Analysis Set will be identical, and analyses using the Infant Exposure Set will not be performed. 
 
3.2 Statistical Analysis Issues 
 
All analyses will be descriptive unless otherwise noted. 
 
Background rates of select pregnancy outcomes and complications are available through MTN-042B but 
are not appropriate for direct comparison as the study populations differed significantly. MTN-042B 
included all women who presented to the local delivery facility over an eight week period. By design, 
women who experienced an early loss would not be captured in this cohort. MTN-042 excluded women 
with complciated pregnancies and as a consequence rates of pregnancy complications and poor obstetric 
outcomes are likely to be lower in MTN-042 than in MTN-042B. 


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Study visit numbers for pre-pregnancy outcome visits were defined in relation to enrollment (e.g., visit 
10/Week 8 visit occurred 8 weeks after enrollment). Summaries by visit are by study visit unless 
otherwise noted. Some study procedures were completed at visits corresponding to certain weeks of 
gestation, and since mothers were enrolled at different gestational ages this means that these procedures 
were not completed at the same study visit for all participants. Some analyses will be performed by 
grouping these gestational-week-dependent visits together, instead of summarizing by study visit. 
Gestational age at enrollment is recorded on the Pregnancy Assessment CRF. 
 
Relevant gestational-week-dependent visits correspond to the following study visits: 
4-week visit corresponding to, or immediately before, 36th week of gestation: 
Visit 10 if gestational age 25-28 weeks 
Visit 14 if gestational age 21-24 weeks 
Visit 18 if gestational age 17-20 weeks 
Visit 22 if gestational age 13-16 weeks 
Visit 26 if gestational age 12 weeks 
4-week visit corresponding to, or immediately following, the 30th week of gestation: 
Visit 6 if gestational age 26-29 weeks 
Visit 10 if gestational age 22-25 weeks 
Visit 14 if gestational age 18-21 weeks 
Visit 18 if gestational age 14-17 weeks 
Visit 22 if gestational age 12-13 weeks 
Visit corresponding to, or immediately following, the 28th week of gestation: 
Visit 10 if gestational age 20-23 weeks 
Visit 14 if gestational age 16-19 weeks 
Visit 18 if gestational age 12-15 weeks 
Participants were instructed to use study product until they went into labor. This complicates analyses of 
laboratory adherence measures (see Section 9.3) taken at the Visit 101 – PPO Visit, since this visit could 
occur up to 14 days after the pregnancy outcome, i.e., this visit will include time when the participant was 
expected to not be using study product and drug levels are expected to drop quickly following product 
discontinuation. This applies to all three laboratory adherence measures, including residual drug levels in 
VRs since the residual drug measure adjusts for how long the participant had the ring. 
 
Some laboratory adherence measures were tested for a subset of the study population. TFV-DP and 
FTC-TP were tested for a subset of Cohort 1 mothers (30% of the mothers with a collected sample) (all 
collected samples were tested for infants, and for mothers in Cohorts 2 and 3). Plasma DPV was tested 
for a subset of mothers in all three cohorts (50% of the mothers with a collected sample) (all collected 
samples were tested for infants). 
 
 
4. INTERIM ANALYSIS AND DATA MONITORING COMMITTEE 
No DSMB oversight was planned for this study. The MTN SMC conducted interim reviews of study 
progress, including rates of participant accrual, retention, completion of primary and secondary endpoint 
assessments, and study or laboratory issues. These reviews took place after all pregnancy outcomes had 
occurred for Cohort 1, after all pregnancy outcomes had occurred for Cohort 2, and after all mothers had 
been enrolled for Cohort 3. 
An interim review of the safety data by the Interim Review Panel (IRP) was planned and conducted after 
each cohort completed scheduled participation and prior to beginning accrual in the next scheduled 
cohort. Planned IRP analyses are documented in the IRP SAP for MTN-042 Cohort 1 and the IRP SAP 
for MTN-042 Cohort 2. 


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5. GENERAL ANALYSIS METHODS 
When the use of descriptive statistics to assess group characteristics or differences is described, the 
following methods will be used: for categorical variables, the number and percent in each category; for 
continuous variables, the mean, median, standard deviation, quartiles, and range (minimum, maximum). 
 
Descriptions of tabular summaries that are “by study arm and overall” indicate that the table should have 
columns summarizing each arm as well as a column summarizing the combined arms. 
Tabular summaries by visit do not include interim visits, unless otherwise noted. Results from all visits 
(including interim visits) will be included in listings. 
 
In addition to separate analyses/summaries for each of the three cohorts, an exploratory analysis will split 
Cohort 3 participants into two groups based on gestational age (20 0/7 weeks through 29 6/7 weeks and 
12 0/7 weeks through 19 6/7 weeks) as collected on the Pregnancy Assessment CRF. These ages were 
originally going to be two separate cohorts in Protocol Version 1.0 before being combined into one cohort 
in Protocol Version 2.0. These exploratory analyses splitting Cohort 3 will be done only for certain 
analyses, as specified in this document. 
 
 
6. TRIAL PARTICIPANT DISPOSITION 
6.1 Disposition of Participants 
 
The number of pregnant women screened, screened out (with reasons for not enrolling), randomized to 
each study arm (with reasons for not receiving assigned intervention), with obtainable pregnancy 
outcomes (with reasons outcome was not obtainable), completing study follow-up (with reasons study 
follow-up was not completed), the number of infants enrolled (with reasons not enrolled), and number of 
infants completing study follow-up (with reasons infant follow-up was not completed) will be presented in 
a CONSORT flow diagram. Separate diagrams will be used for each cohort. 


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n Not enrolled 
n [reasons not enrolled] 
n Assessed for eligibility 
n Received DPV 
n Did not receive DPV 
n [reasons not received] 
n Randomized to Truvada 
n Randomized to DPV 
<same boxes as in the DPV 
column> 
n Infants did not enroll 
n [reasons did not enroll] 
n Completed study follow-up 
n Did not complete study follow-up 
n [reasons did not complete] 
n Had obtainable pregnancy outcome 
n Randomized 
n Infants completed study follow-up 
n Infants did not complete study follow-up 
n Infants enrolled 
n Did not have obtainable 
pregnancy outcome 
n [reasons not obtainable] 
Figure 1. Mock CONSORT Diagram 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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6.2 Treatment Exposure 
 
As described in Section 3.1 Analysis Set(s), the Product Exposure analysis set will exclude endpoint data 
that occurs > 7 days after study production discontinuation, and will exclude participants who never 
received study product. 
Study duration, infant study duration, on product duration, on study pregnancy duration, and estimated 
gestational age at pregnancy outcome will be summarized as continuous variable in tables, by study arm 
and overall for each of the three cohorts, and for the three cohorts combined. 
 
Study duration will be calculated as the date of study exit (Study Termination CRF) minus the participant’s 
randomization date + 1 day, unless the participant had a termination reason of “Lost to follow-up”. If a 
participant was lost to follow-up then their study duration will be calculated as the date of their last 
attended visit minus their randomization date + 1 day. The last attended visit is either the last visit with a 
completed Follow-up Visit Summary CRF, or the last Interim Visit Summary CRF where at least one study 
procedure was completed (per Interim Visit Summary CRF, “What study procedures were completed at 
this visit? Select all that apply” item), whichever occurred last. 
Infant study duration will be calculated as the date of study exit (Study Termination CRF) minus the 
infant’s birth date + 1 day, unless the infant had a termination reason of “Lost to follow-up”. If an infant 
was lost to follow-up then their study duration will be calculated as the date of their last attended visit 
minus their birth date + 1 day. The last attended visit is either the last visit with a completed Infant Follow- 
up Visit Summary CRF, or the last Infant Interim Visit Summary CRF where at least one study procedure 
was completed (per Interim Visit Summary CRF, “What study procedures were completed at this visit? 
Select all that apply” item), whichever occurred last. 
 
On product duration will be calculated as the date of product discontinuation (Discontinuation of Study 
Product CRF) minus the participant’s randomization date + 1 day. Only participants who ever received 
study product will be included in this summary. 
On study pregnancy duration will be calculated as the date of the pregnancy outcome (outcome date on 
Pregnancy Outcome CRF) minus the participant’s randomization date + 1 day. Only participants with an 
obtainable pregnancy outcome will be included in this summary. 
 
Estimated gestational age at pregnancy outcome will be calculated as the date of the pregnancy outcome 
minus the date of the participant’s pregnancy assessment (Pregnancy Assessment CRF) + 1 day, plus 
the participant’s estimated gestational age (in days) at their pregnancy assessment (Pregnancy 
Assessment CRF), and will be reported in weeks (e.g., an estimated gestational age of 38 weeks 6/7 
days would be treated as 38.86 weeks for this summary). Note that this derivation will be used even if the 
participant had an available gestational age by best estimation at delivery on the Pregnancy Outcome 
CRF. 
 
6.3 Protocol Deviations 
 
Protocol deviations will be summarized in tables, overall for each of the three cohorts, and for the three 
cohorts combined. These tables will summarize the number of protocol deviations, the number and 
percentage of individuals with at least one protocol deviation (denominator is the number of individuals 
screened for the study), the number and percentage of deviations reported to local IRB/EC (denominator 
is number of events), and the number and percentage of each type of deviation (denominator is the 
number of events). All screened participants will be included. 


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6.4 Product Discontinuation 
 
Product discontinuation will be summarized in tables, overall and by arm for each of the three cohorts, 
and overall and by arm for the three cohorts combined. These tables will summarize the number and 
percentage of responses to the ”Primary reason for completion/discontinuation” item on the Product 
Discontinuation CRF. The denominator will be the number of participants in the ITT Analysis Set. 
 
6.5 Retention 
 
Study retention will be summarized by type of visit (mothers) or visit (infants) in tables, overall and by arm 
for each of the three cohorts, and overall and by arm for the three cohorts combined. Separate tables will 
be prepared for mother participants and infants. These tables will include the number and percentage of 
visits that were completed, missed, or that occurred after early termination at each visit/type of visit. 
 
For mothers, visit expectation depended on the cohort and gestational age at enrollment of the 
participant, as well as the timing of their pregnancy outcome. Assuming that their pregnancy outcome had 
not yet occurred, all mothers were expected to complete the Week 1 phone contact (visit 3), Week 2 bi- 
weekly visit (visit 4), Week 3 phone contact (visit 5), and Week 4 visit (visit 6). Once the pregnancy 
outcome occurred, they were also expected to complete the PPO visit (visit 101) and 6-week PPO visit 
(visit 103). In between these visits the expected visits depended on cohort and gestational age at 
enrollment, and these expectations are provided in Appendix I. 
 
Infants were expected to complete their PPO visit (visit 201), 1-week PPO visit (visit 202), 6-week PPO 
visit (visit 203), 6-month PPO visit (visit 204), and 12-month PPO visit (visit 205). 
A completed visit is defined as an expected visit where the participant had a Follow-up Visit Summary 
CRF (or Infant Follow-up Visit Summary CRF for infants) with a non-missing visit date. A visit where the 
participant had already terminated early is an expected visit where the last date of the visit window was 
on or after the date of study termination. A missed visit is defined as a visit that was expected but not 
completed and which occurred prior to study termination. For the purposes of these calculations, a visit 
will only be included if the last date of the visit window occurred on or prior to the date of the participant’s 
pregnancy outcome (e.g., a visit will be not counted as missed or expected if it was not attended and the 
pregnancy outcome occurred while the visit window was still open, and similarly a visit will not be counted 
as completed or expected if the visit occurred and then the pregnancy outcome occurred during the visit 
window). 
 
Each study visit had a visit window in which it was to be completed; these windows are provided in 
Appendix II. 
 
Summaries of mother retention will summarize the number and percentage of visits that were completed, 
missed, or that occurred after early termination at each visit/type of visit for the following types of visits: 
 
Phone contact visits (visit 3, visit 5, and others depending on gestational age at enrollment, see 
Appendix I) 
 
In-person visits (visit 4, visit 6, and others depending on gestational age at enrollment, see 
Appendix I 
 
PPO visits (visit 101) 
 
6-week PPO visit (visit 103) 
The denominator for the percentages will be the number of expected visits. 
 
Summaries of infant retention will summarize the number and percentage of visits that were completed, 
missed, or that occurred after early termination at each visit/type of visit for the PPO visit (visit 201), 1- 
week PPO visit (visit 202), 6-week PPO visit (visit 203), 6-month PPO visit (visit 204), and 12-month PPO 
visit (visit 205). 


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7. BASELINE DATA 
Unless otherwise noted, all baseline data summaries are restricted to mothers in the analysis set. 
 
7.1 Mother Demographics 
 
Baseline demographic characteristics will include participant age (both as a continuous variable and as 
the following categories: 18-19 years, 20-24, 25-29, 30-34, and 35-40), enrollment site, ethnic group or 
tribe, whether or not the participant has a primary partner, number of lifetime sex partners (both as a 
continuous variable and as the following categories: 1 partner, 2, 3, 4, and 5+), whether or not the 
participant had a sexual relationship in order to get money, and the HIV status of their primary sex 
partner. These tables will be presented by study arm and overall for each of the three cohorts, and by 
study arm and overall for the three cohorts combined. These items are collected on the Demographics 
CRF. 
 
7.2 Pregnancy History 
 
Pregnancy history, as collected on the Pregnancy History CRF, will be summarized in tables, by study 
arm and overall for each of the three cohorts, and by study arm and overall for the three cohorts 
combined. These tables will summarize the number and percentage of participants who had any prior 
pregnancies. Among the participants with a prior pregnancy, the following will be summarized (as 
continuous variables): 
• premature live births (<37 weeks) 
 
• spontaneous abortions (<20 weeks) 
• therapeutic/elective abortions 
• ectopic pregnancies 
 
7.3 Gestational Age 
 
Participant gestational age at enrollment, as collected on the Pregnancy Assessment CRF, will be 
summarized in tables, by study arm and overall for each of the three cohorts, and by study arm and 
overall for the three cohorts combined. These tables will summarize the estimated gestational age at 
enrollment (as a continuous variable). Gestational age will be described in weeks, not in weeks and days 
as it is captured on the CRF (e.g., a gestational age on the CRF of 37 weeks 4 days will be defined as 
37.6 weeks for the table summaries). 
 
7.4 Baseline Medical History 
 
Baseline medical history will be summarized in tables, by study arm and overall for each of the three 
cohorts, and by study arm and overall for the three cohorts combined. These tables will summarize the 
following (as categorical variables): 
 
Number and percentage of randomized participants who had any medical history event (yes or 
no, from Baseline Medical History Y/N CRF), and the number of events (from the Baseline 
Medical History Log). 
 
Number and percentage of participants who had a gradeable event (at least one gradeable event 
vs. no gradeable events, from “Is condition/event gradable” on the Baseline Medical History Log), 
with the denominator being the number of participants with a medical history event. The total 
number of gradeable events will also be summarized. 
 
Number and percentage of participants with a maximum severity event (Grade 4 is highest 
severity, Grade 1 is lowest, from “Severity grade” item on the Baseline Medical History Log), with 


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the denominator being the number of participants who had a gradeable event. The total number 
of events in each severity will also be summarized. 
 
Number and percentage of participants with an ongoing event (at least one ongoing event vs. no 
ongoing events, from “Is the condition ongoing?” item on the Baseline Medical History Log). 
 
7.5 Prior Medication 
 
Prior medication will be summarized in tables, by study arm and overall for each of the three cohorts, and 
by study arm and overall for the three cohorts combined. These tables will summarize: 
 
Number and percentage of randomized participants who had any prior medication (yes or no), 
and the number of medications. 
 
Number and percentage of randomized participants with at least one prior medication in each 
observed ATC Level 3 category, and the total number of prior medications in each ATC Level 3 
category. 
 
Within each ATC Level 3 category, the number and percentage of randomized participants with 
at least one prior medication in each observed ATC Level 1 category, and the total number of 
prior medications in each ATC Level 1 category. The denominator for these percentages is the 
number of participants in the ITT Analysis Set. 
Prior medications are defined as medications recorded on the Concomitant Medications Log CRF that 
had a “Date stopped” prior to the participant’s randomization date. 
 
7.6 Pelvic Exam 
 
Baseline pelvic examination findings will be summarized in tables, by study arm and overall for each of 
the three cohorts, and by study arm and overall for the three cohorts combined. These tables will use 
data collected on the Pelvic Exam CRF at the enrollment visit and will include: 
 
Number and percentage of participants with a pelvic exam assessment (non-missing value on the 
“Pelvic exam assessment” item), with the denominator being the number of participants in the ITT 
Analysis Set. 
 
Number and percentage of participants with each pelvic exam assessment result (not done, 
abnormal findings, or no abnormal findings), with the denominator being the number with a non- 
missing pelvic exam assessment result. Note that a result being missing entirely is treated as 
different from a result being marked as “not done”. 
 
Number and percentage of participants with each type of abnormal pelvic exam finding (from 
vulvar edema through other abnormal findings), with the denominator being the number with a 
non-missing pelvic exam assessment result. 
o 
For the abnormal vaginal discharge finding, the number and percentage of participants 
who had each type of abnormal vaginal discharge (slight, moderate, or pooling) will also 
be summarized, with the denominator being the number of participants with an abnormal 
vaginal discharge finding. 
 
 
8. PRIMARY ENDPOINTS 
An intent to treat analysis will be performed to summarize the frequency of primary endpoints (maternal 
safety, infant safety and pregnancy outcome) by study arm (ITT Analysis Set). An additional analysis will 
be conducted including only visits in which a participant has been exposed to the study product (Product 
Exposure Set). Analyses will be conducted separately for each of the three cohorts (including an 
exploratory analysis that splits Cohort 3 based on gestational age as described in Section 5), with a final 
aggregate analysis that will include all enrolled participants from each of the three cohorts. The number 
and the percentages of participants experiencing each primary endpoint will be tabulated by study arm. 
Each participant will contribute once in each category (i.e., only for highest severity AE for each 


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participant) for the calculation of event rates. Exact binomial confidence intervals will be calculated for 
each primary endpoint. Primary endpoint event rates will be compared to baseline estimates from MTN- 
042B by checking whether the baseline estimates are included in the exact binomial confidence intervals 
(this will not be included as part of the CSR). A secondary analysis will be performed to summarize the 
total number of primary and secondary safety endpoints reported per participant by study arm. 
 
8.1 Primary Maternal Safety 
 
The primary maternal safety endpoint is all maternal adverse events that were either serious adverse 
events (SAEs) or were Grade 3 or higher. These are referred to in this document as “composite AEs”. 
 
The number and percentage of participants experiencing at least one composite AE and the exact 
binomial confidence intervals for those proportions will be summarized by study arm and overall for each 
of the three cohorts (including an exploratory analysis that splits Cohort 3 based on gestational age as 
described in Section 5), and by study arm and overall for the three cohorts combined. This analysis will 
include all participants in the ITT Analysis Set. 
 
Secondary analyses will be conducted to further explore maternal safety. These analyses include: 
1. The analyses in the preceding paragraph will be repeated using the Product Exposure Set 
2. Summaries of the total number of primary maternal safety endpoints reported per participant, by 
study arm and overall for each of the three cohorts (including a summary of the two Cohort 3 
subgroups defined in Section 5), and by study arm and overall for the three cohorts combined. 
This will use the ITT Analysis Set. 
3. A Poisson regression model will be fitted comparing the number of primary maternal safety 
endpoints per participant by arm, adjusted for site, with an offset of the number of days from 
randomization to study product discontinuation (see “on product duration” definition in Section 
6.2). This model will be fitted for all cohorts combined only, and will use the ITT Analysis Set. 
 
8.2 Primary Infant Safety 
 
The primary infant safety endpoint is all infant adverse events that were either SAEs or were Grade 3 or 
higher. These are referred to in this document as “composite AEs”. 
The number and percentage of infants experiencing at least one composite AE and the exact binomial 
confidence intervals for those proportions will be summarized by study arm and overall for each of the 
three cohorts (including an exploratory analysis that splits Cohort 3 based on gestational age as 
described in Section 5), and by study arm and overall for the three cohorts combined. This analysis will 
include all infants in the ITT Analysis Set (as appropriate given the cohort/study arm being summarized). 
 
Secondary analyses will be conducted to further explore infant safety. These analyses include: 
1. The analyses in the preceding paragraph will be repeated using the Infant Exposure Analysis Set. 
2. Summaries of the total number of primary infant safety endpoints reported per infant, by study 
arm and overall for each of the three cohorts (including a summary of the two Cohort 3 subgroups 
defined in Section 5), and by study arm and overall for the three cohorts combined. This will use 
the ITT Analysis Set. 
3. A Poisson regression model will be fitted comparing the number of primary infant safety 
endpoints per participant by arm, adjusted for site, with an offset of the number of days from birth 
to study termination (see "infant study duration” definition in Section 6.2). This model will be fitted 
for all cohorts combined only, and will use the ITT Analysis Set. 


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8.3 Pregnancy Outcomes 
 
The number and percentage of pregnancy outcomes (full term live birth [
 0/7 weeks], premature live 
birth [<37 0/7 weeks], stillbirth/intrauterine fetal demise [
 
], and spontaneous abortion [<20 
0/7 weeks]) and the exact binomial confidence intervals for those proportions will be summarized by study 
arm and overall for each of the three cohorts, and by study arm and overall for the three cohorts 
combined. This analysis will include all participants in the analysis set who had an obtainable pregnancy 
outcome. If a participant was found to have a non-singleton pregnancy after enrollment then each 
outcome from that pregnancy will be included in this analysis. 
A secondary analysis will be conducted by repeating the pregnancy outcome summaries for only 
participants who received study product (i.e., the participants in the Product Exposure Set). 
 
 
9. SECONDARY ENDPOINTS 
9.1 Pregnancy Complications 
 
Pregnancy complications will be summarized in tables by study arm and overall for each of the three 
cohorts, and by study arm and overall for the three cohorts combined. This analysis will include all 
participants in the analysis set who had an obtainable pregnancy outcome. 
The summaries of complications will include the following complications, gathered on the Pregnancy 
Outcome CRF: 
 
any hypertensive disorders of pregnancy, and the different individual types of hypertensive 
disorders: 
o 
chronic 
o 
gestational 
o 
pre-eclampsia without severe features 
o 
pre-eclampsia with severe features 
o 
eclampsia 
o 
not specified 
 
chorioamnionitis 
 
either of puerperal sepsis or endometritis (combination of the puerperal sepsis and endometritis 
items), and summaries of both individually: 
o 
puerperal sepsis 
o 
endometritis 
 
either of peripartum and postpartum hemorrhage (Cohort 1 only) 
 
either of antepartum, intrapartum, or postpartum hemorrhage (Cohorts 2 and 3 only), and 
summaries of each type of hemorrhage individually: 
o 
peripartum hemorrhage (Cohort 1 only) 
o 
antepartum hemorrhage (Cohorts 2 and 3 only) 
o 
intrapartum hemorrhage (Cohorts 2 and 3 only) 
o 
postpartum hemorrhage 
 
preterm premature rupture of membranes (PROM) (the preterm premature rupture of membranes 
(PPROM) item) 
 
fever of unclear etiology 
 
other 
The table will include a footnote listing the responses to “If ‘Other’, specify” for complications categorized 
as other. The number and percentage of participants, and the exact binomial confidence intervals for 
those proportions, with these complications will be summarized. The denominator will be the number of 
participants in the analysis set with a pregnancy outcome. 


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9.2 Infant Drug Levels 
 
The number and percentage of infants with detectable drug levels in each study arm for each sample type 
will be summarized using descriptive statistics in tables overall for each of the three cohorts, and overall 
for the three cohorts combined. Participants with a drug level for the assay corresponding to their 
mother’s randomization arm (i.e., plasma DPV concentration for the DPV VR arm, blood TFV-DP and 
FTC-TP concentration for the FTC/TDF arm) above the lower limit of quantification (LLOQ) at the PPO 
visit (including interim PPO visits) will be considered to have a detectable drug level for that sample type; 
otherwise, the participant will be considered to have an undetectable drug level for that sample type. If a 
participant has multiple concentrations at a visit, they will be considered to have a detectable drug level 
for that sample type if any of the concentrations are above the LLOQ. The denominator will be the 
number of infants in the analysis set with at least one valid drug result for the assay corresponding to their 
mother’s randomization arm. Valid drug results are defined as any result that does not have any of the 
following censor codes: A, D, O, P, X, Z. 
 
Additionally, drug concentration levels at the PPO visit (including interim PPO visits) will be summarized 
using geometric mean, geometric coefficient of variation (CV), arithmetic mean, standard deviation (SD), 
median, interquartile range (IQR), and range (minimum, maximum). The CV will be calculated as 100 x 
standard deviation / Mean of the concentration values. Drug concentrations below the LLOQ will be 
treated as having a value of half the LLOQ for these summaries. Drug concentrations from assays that do 
not correspond to the mother’s randomization arm, or which have any of the censor code A, D, O, P, X, 
and/or Z, will be excluded from these summaries. 
 
9.3 Adherence 
 
Laboratory adherence measures (maternal blood TFV-DP and FTC-TP, maternal plasma DPV, and 
residual drug levels in VRs) will be summarized by visit for each of the three cohorts, and for the three 
cohorts combined. Residual drug levels in VRs will be reported in terms of the estimated residual drug 
release rate (see Appendix III for definition). Summaries will include the number of valid results, arithmetic 
mean, SD, median, IQR, and range. 
 
Laboratory measures that do not correspond to the participant’s randomization arm (i.e., maternal blood 
TFV-DP and/or FTC-TP for a participant randomized to receive the DPV VR, maternal plasma DPV 
and/or residual drug level in VRs for participants randomized to receive Truvada) will be excluded from all 
analyses described in this section. TFV-DP, FTC-TP, and plasma DPV measures that have any of the 
following censor codes will be excluded from all analyses described in this section: A, D, O, P, X, Z. 
Residual drug level measures that have the censor codes X or Z or for which residual drug release rate is 
unable to be calculated (see Appendix III) will also be excluded from all analyses described in this 
section. 
 
By visit summaries will include the visits where the assessment was expected to be collected (e.g., 
mother blood TFV-DP and FTC-TP will include summaries for the time points where DBS for TFV-DP and 
FTC-TP drug levels were expected to be collected per protocol). Blood TFV-DP and plasma DPV 
samples that were collected at other visits will be treated as having been collected at the immediately 
preceding visit where collection was expected (e.g., a sample collected at an interim visit 4.1 will be 
treated as having been collected at visit 4). VRs that were returned at other visits will be treated as having 
been collected at the immediately following visit (see details below). 
Residual drug levels in VRs visits 
Visit 6 – Week 4: includes all rings returned on or prior to visit 6.0 
Visit 10 – Week 8: includes all rings returned after visit 6.0 (i.e., visit 6.1 and later) and on or prior to visit 
10.0 
Visit 14 – Week 12, Visit 18 – Week 16, etc. are handled similarly. 
Visit 101 – PPO Visit: includes all rings returned after last attended bi-weekly visit. 


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Laboratory adherence will also be categorized as follows: 
Residual drug levels: 
Red (rate  0.9 mg/month) 
Yellow (0.9 mg/month < rate 
 
 
Green (rate > 4.0 mg/month) 
Blood TFV-DP: 
 
If sample was collected within 6 weeks (i.e., specimen collection date - randomization date + 1 
day <= 42 days): 
Red (<150 fmol/punch) 
Yellow (150 fmol/punch – 599 fmol/punch) 
Green (
 
 
If sample was collected more than 6 weeks (i.e., specimen collection date – randomization date + 
1 day > 42 days) after randomization date: 
Red (<200 fmol/punch) 
Yellow (200 fmol/punch – 649 fmol/punch) 
Green 
 
 
Plasma DPV: 
Red (<LLOQ (i.e., < 20 pg/mL)) 
Yellow (LLOQ – 95 pg/mL, inclusive) 
Green (> 95 pg/mL) 
These categories will be summarized in terms of the number and percentage of participant visits, by visit 
(including all visits combined) and study arm for each of the three cohorts, and by visit and study arm for 
the three cohorts combined. The denominator will be the number of valid samples at the visit. 
Adherence will also be summarized at a participant level for all three measures, with participants 
categorized as either “ever exposed” (if they have at least one measure in the Yellow or Green category) 
or “never exposed” (if they have no measures in the Yellow or Green categories). These categories will 
be summarized by number and percentage of participants by study arm for each of the three cohorts, and 
by study arm for the three cohorts combined. The denominator will be the number of participants with at 
least one valid sample. 
 
Additional exploratory analyses of Blood TFV-DP categories may be done if additional information 
regarding adherence cutoffs becomes available. These exploratory analyses would not be part of the 
CSR. 
Participant report of frequency of study product use will be summarized by visit for each of the three 
cohorts, and for the three cohorts combined. For participants randomized to the FTC/TDF arm this will be 
the responses to the “In the past 4 weeks, how often did you miss taking the pills” item on the Tablet 
Adherence CRF (possible responses are “never”, “rarely”, or “often”). For participants randomized to the 
DPV VR arm this will be the responses to the “in the past 4 weeks, how often was the ring out of your 
vagina for any extended period of time, that is more than 12 hours in a row?”, “in the past 4 weeks, how 
often was the ring out of your vagina, even for just a minute excluding expected instances when a ring 
was briefly removed and replaced with a new ring?”, and “was the ring ever removed (in the past 4 
weeks)?” items on the Ring Adherence CRF. 
 
9.4 Acceptability 
 
Acceptability questions were asked of participants in Cohorts 2 and 3. 


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Self-reported attitude about study product and willingness to use study products during pregnancy will be 
assessed by summarizing the “would you be willing to use the [pills/ring] for HIV prevention when 
pregnant in the future?” item from the Follow-up Behavioral Assessment and Post-PO Behavioral 
Assessment CRFs. The responses from these two CRFs will be summarized separately for each of the 
visits where responses were expected to be collected (including interim visits for those expected visits): 
Visit 6 Follow-up Behavioral Assessment (both cohorts), Follow-up Behavioral Assessment from the 4- 
week Visit corresponding to, or immediately before, 36th week gestation (Cohort 3 only, see Section 3.2 
Statistical Analysis Issues), and the Visit 103 6-week PPO Post-PO Behavioral Assessment, by study arm 
and overall for each of Cohorts 2 and 3. Responses at Visit 6 and Visit 103 will also be summarized by 
study arm and overall for these cohorts combined. 
The proportion of participants who find the study products to be at least as acceptable as other HIV 
prevention methods will be assessed by summarizing the “overall, how much do you like or dislike male 
condoms for HIV prevention?”, “overall, how much do you like or dislike the [pills/ring] for HIV 
prevention?”, and “overall, how satisfied have you been with the [pills/ring] for preventing HIV?” items on 
the Follow-up Behavioral Assessment CRF. The responses from Visit 6 will be summarized by study arm 
and overall for each of Cohorts 2 and 3, and by study arm and overall for these cohorts combined. 
Responses from the 4-week Visit corresponding to, or immediately before, 36th week gestation (see 
Section 3.2 Statistical Analysis Issues) will be summarized by study arm and overall for Cohort 3. The 
denominator for each proportion will be the participants in the analysis set who responded to the item. 
 
 
10. SAFETY ANALYSES 
10.1 
Maternal Adverse Events 
 
In addition to the summaries of the primary maternal safety endpoint detailed in Section 8.1, maternal 
adverse event summaries will include: 
 
the total number and percentage of participants with an SAE 
 
the total number of SAEs by severity grade and relationship to study product 
 
the total number of composite AEs by severity grade and relationship to study product 
 
the number and percentages of composite AEs for each level of relationship to study product (not 
related, related) for the most causal relationship per participant overall and by system organ class 
and preferred term. 
 
the number and percentage of participants with any AE, and number and percentage of AEs by 
body system, preferred term, and severity 
 
the number and percentage of participants with any AE, and number and percentage of AEs by 
body system, preferred term, and relationship to study product 
 
listing of all AEs, including participant ID, cohort, randomization arm, site, whether or not the AE 
was an SAE, whether or not the AE was a composite AE, preferred term, severity, relationship to 
study product, visit of AE report, AE onset date, AE outcome date, AE duration, AE outcome, and 
associated comments. 
 
the above summaries will be repeated using the Product Exposure Set 
The denominator for all percentages described above is the number of participants in the analysis set. All 
summaries will be presented by arm across all cohorts, and by arm within each cohort. No statistical 
comparisons are planned. 
 
10.2 
Infant Adverse Events 
 
In addition to the summaries of the primary infant safety endpoint detailed in Section 8.2, infant adverse 
event summaries will include: 


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the total number and percentage of infants with an SAE 
 
the total number of infant SAEs by severity grade and relationship to study product 
 
the total number of infant composite AEs by severity grade and relationship to study product 
 
the number and percentages of infant composite AEs for each level of relationship to study 
product (not related, related) for the most causal relationship per participant overall and by 
system organ class and preferred term. 
 
the number and percentage of participants with any AE, and number and percentage of AEs by 
body system, preferred term, and severity 
 
the number and percentage of participants with any AE, and number and percentage of AEs by 
body system, preferred term, and relationship to study product 
 
listing of all infant composite AEs, including participant ID, cohort, mother’s randomization arm, 
site, whether or not the AE was an SAE, preferred term, severity, relationship to study product, 
visit of AE report, AE onset date, AE outcome date, AE duration, AE outcome, and associated 
comments. 
 
the above summaries will be repeated using the Infant Exposure Analysis Set 
 
The denominator for all percentages described above is the number of infants in the analysis set. All 
summaries will be presented by arm across all cohorts, and by arm within each cohort. No statistical 
comparisons are planned. 
 
10.3 
Product Holds 
 
The number and percentage of participants who had at least one product hold, the total number of 
product holds, the number and percentage of reasons for product hold, the number and percentage of the 
instructions whether to resume study product use, and the duration of product hold (for those holds where 
the participant was instructed to resume use) will be summarized in tables. These tables will be presented 
by arm and overall for each of the three cohorts, and by arm and overall for the three cohorts combined. 
Product holds are collected on the Product Hold CRF. 
 
The denominator for the percentage of participants with at least one product hold will be the number of 
mothers in the analysis set. The denominator for the other percentages will be the total number of product 
holds. The duration of product hold will be summarized as a continuous variable (see Section 5 General 
Analysis Methods). 
 
10.4 
Mother Laboratory Evaluations 
 
Results of mother laboratory evaluations will be summarized for the following tests: hemogram 
(hemoglobin, hematocrit, MCV, platelets, WBC, neutrophils, lymphocytes, 
monocytes, eosinophiles, and basophils) test results as collected on the Hematology CRF, 
chemistries (AST, ALT, creatinine, and creatinine clearance) test results as collected on the Chemistry 
Panel CRF, and dipstick urinalysis (leukocyte esterase, nitrites, protein, and glucose) test results as 
collected on the Urine Test Results CRF. Boxplots (for continuous variables, i.e., hemogram and 
chemistries) and tables with summary statistics (for all) will be reported for laboratory evaluations 
performed at expected visits. These summaries will be by visit, by arm and overall for each of the three 
cohorts, and by visit, by arm and overall for the three cohorts combined. Results from non-expected visits, 
including interim visits, will not be summarized in the boxplots or summary tables. 
 
Expected visits for hemogram, chemistries (AST and ALT), and dipstick urinalysis are the following: 
 
Screening (visit 1) 
 
Enrollment (visit 2) 
 
first 4-week visit (visit 6; this visit only for Cohorts 2 and 3) 


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the visit corresponding to, or immediately following, the 28th week of gestation (only for Cohort 3; 
this is visit 10 if the participant had a gestational age of 20-23 weeks at enrollment, visit 14 if the 
gestational age was 16-19 weeks, or visit 18 if the gestational age was 12-15 weeks, all 
according to the Pregnancy Assesment CRF, see Section 3.2 Statistical Analysis Issues) 
 
6-week PPO visit/SEV/early SEV (visit 103) 
The results for the 28th week of gestation visit will be reported as one visit (i.e., not reported separately for 
visit 10, visit 14, and visit 18). 
 
Expected visits for creatinine and creatinine clearance are the following: 
 
Screening (visit 1) 
 
Enrollment (visit 2) 
 
second bi-weekly visit/first 4-week visit (visit 6) 
 
4-week visit 12 weeks after first 4-week visit (Cohorts 2 and 3 only; visit 18) 
 
6-week PPO visit/SEV/early SEV (visit 103) 
10.5 
Infant Laboratory Evaluations 
 
Boxplots and tables with summary statistics will be reported for infant creatinine results at expected visits. 
These summaries will be by visit, by mother randomization arm and overall for each of the three cohorts, 
and by visit, by arm and overall for the three cohorts combined. Results from non-expected visits, 
including interim visits, will not be summarized in the boxplots or summary tables. Creatine test results 
were expected at the PPO visit (visit 201) and at the 6-week PPO visit (visit 203). 
 
10.6 
Mother HIV-1 
 
Tables summarizing the number and percentage of participants with post-enrollment HIV-1 diagnosis will 
be prepared. A participant will be considered to have been diagnosed with HIV-1 if they have an HIV 
Confirmatory Results CRF with a “Final HIV Status” of HIV infected at any visit after Enrollment. The 
denominator will be the number of participants in the analysis set with at least one post-Enrollment visit 
HIV Test Results CRF indicating that a rapid HIV test sample collected for testing. These tables will be 
presented by study arm and overall for each of the three cohorts, and by arm and overall for the three 
cohorts combined. 
 
10.7 
Infant HIV-1 
 
Tables summarizing the number and percentage of infants with an HIV-1 diagnosis will be prepared. An 
infant will be considered to have been diagnosed with HIV-1 if they have an Infant HIV Confirmatory 
Results CRF with a “Final HIV Status” of HIV infected. The denominator will be the number of infants in 
the analysis set. These tables will be presented by study arm and overall for each of the three cohorts, 
and by study arm and overall for the three cohorts combined. 
 
10.8 
Sexually Transmitted Infections 
 
The number and percentage of participants diagnosed with syphilis, trichomonas, gonorrhea, or 
chlamydia, as well as the number and percentage diagnosed with any of those four STIs during follow-up 
will be summarized in tables, by arm and overall for each of the three cohorts, and by arm and overall for 
the three cohorts combined. These will be summarized using the STI Test Results CRF from follow-up 
visits (e.g., Week 1 Phone Contact/Visit 3 or later). 
 
A positive result for trichomonas, gonorrhea, or chlamydia is defined as having a value of “Positive” for 
“Trichomonas test”, “N. gonorrhea”, or “C. trachomatis” respectively, and a negative result as having a 
value of “Negative”. A positive result for syphilis is defined as having a value of “Reactive” for “Syphilis 


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screening test” and a value of “Positive” for “Syphilis confirmatory test”, and a negative result if the 
syphilis test was done but did not meet the above definition for positivity. If “Was a vaginal sample 
collected for NAAT for GC/CT/Trich testing?” is “No” or the response to “Trichomonas test” is “Not done” 
or missing the participant will not be counted in the denominator for trichomonas. If “Was a vaginal 
sample collected for NAAT for GC/CT/Trich testing?” is “No” or the response to “N. gonorrhea” is “Not 
done” or missing the participant will not be counted in the denominator for gonorrhea, and if “Was a 
vaginal sample collected for NAAT for GC/CT/Trich testing?” is “No” or the response to “C. trachomatis” is 
“Not done” or missing the participant will not be counted in the denominator for chlamydia. 
 
Participants will be categorized as a positive result if they ever had a positive result during follow-up (e.g., 
participants will only be counted once per STI). Participants will be categorized as a negative result for 
each if they had at least one test result during follow-up and no positive results. 
 
10.9 
Concomitant Medications 
 
Concomitant medications will be summarized in tables, by study arm and overall for each of the three 
cohorts, and by study arm and overall for the three cohorts combined. These tables will summarize: 
 
Number and percentage of randomized participants who had any concomitant medications (yes 
or no), and the number of medications. 
 
Number and percentage of randomized participants with at least one concomitant medication in 
each observed ATC Level 3 category, and the total number of concomitant medications in each 
ATC Level 3 category. 
 
Within each ATC Level 3 category, the number and percentage of randomized participants with 
at least one concomitant medication in each observed ATC Level 1 category, and the total 
number of concomitant medications in each ATC Level 1 category. The denominator for these 
percentages is the number of participants in the ITT Analysis Set. 
 
Concomitant medications are defined as medications recorded on the Concomitant Medications Log CRF 
that overlapped with a participants’ time on study; i.e., that had a “Date stopped” on or after the 
participant’s randomization date, or that were marked “Ongoing”. 
 
10.10 
Infant Concomitant Medications 
 
Infant concomitant medications will be summarized in tables, by study arm and overall for each of the 
three cohorts, and by study arm and overall for the three cohorts combined. 
 
Number and percentage of enrolled infants who had any concomitant medications (yes or no), 
and the number of medications. 
 
Number and percentage of enrolled infants with at least one concomitant medication in each 
observed ATC Level 3 category, and the total number of concomitant medications in each ATC 
Level 3 category. 
 
Within each ATC Level 3 category, the number and percentage of enrolled infants with at least 
one concomitant medication in each observed ATC Level 1 category, and the total number of 
concomitant medications in each ATC Level 1 category. The denominator for these percentages 
is the number of infants in the ITT Analysis Set. 
 
 
Infant concomitant medications are defined as medications recorded on the Concomitant Medications Log 
CRF that overlapped with an infant’s time on study; i.e., that had a “Date stopped” on or after the infant’s 
birth date, or that were marked “Ongoing”. 


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10.11 
Physical Examination 
 
Tables summarizing physical examination findings will be prepared. These summaries will be by visit, by 
arm and overall for each of the three cohorts, and by visit, by arm and overall for the three cohorts 
combined. These will be summarized for visits where the physical examination was expected to be 
performed. 
Expected visits for physical examinations are the following: 
Screening (visit 1) 
4-week visits (e.g., visit 6, visit 10, visit 14, etc.; these visits only for Cohorts 2 and 3) (targeted 
exam only, i.e., only general appearance) 
PPO visit (visit 101) (targeted exam only, i.e., only general appearance) 
These tables will use data collected on the Physical Examination CRF and will include: 
 
Number and percentage of participants with a physical exam (non-missing value on the “Physical 
exam” item), with the denominator being the number of participants in the ITT Analysis Set who 
completed the visit. 
 
Number and percentage of participants with each physical exam result (not done, normal, or 
abnormal findings), with the denominator being the number with a physical exam. Note that a 
result being missing entirely is treated as different from a result being marked as “not done” 
o 
The "General appearance” item will be summarized for all expected visits. The remaining 
items will only be summarized for Screening. 
 
10.12 
Infant Physical Exam 
 
Tables summarizing infant physical examination findings will be prepared. These summaries will be by 
visit, by arm and overall for each of the three cohorts, and by visit, by arm and overall for the three 
cohorts combined. These will be summarized for visits where the infant physical examination was 
expected to be performed. 
 
Expected visits for physical examinations are the following: 
 
PPO visit (visit 201) 
 
6-week PPO visit (visit 203) 
 
6-month PPO visit (visit 204) 
 
12-month PPO visit/early SEV (visit 205) 
These tables will use data collected on the Physical Examination CRF and will include: 
 
Number and percentage of infants with a physical exam (non-missing value on the “Physical 
exam” item), with the denominator being the number of infants in the ITT Analysis Set who 
completed the visit. 
 
Number and percentage of infants with each physical exam result (not done, normal, or abnormal 
findings), with the denominator being the number with a physical exam. Note that a result being 
missing entirely is treated as different from a result being marked as “not done” 
o 
The “Heart/Cardiovascular”, “Lung/Respiratory”, and "General appearance” items will be 
summarized for all expected visits. The remaining items will only be summarized for the 
PPO visit. 
 
10.13 
Infant Ages and Stages Assessment 
 
Tables summarizing infant ages and stages will be prepared. These summaries will be by visit, by arm 
and overall for each of the three cohorts, and by visit, by arm and overall for the three cohorts combined. 
These will be summarized for visits where the infant ages and stages assessment was expected to be 
collected, which are the 6-month PPO visit (visit 204) and the 12-month PPO visit/early SEV (visit 205). 


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These tables will use data collected on the Infant Ages and Stages Assessment CRF and will include: 
Number and percentage of infants with an Ages and Stages Assessment completed (non-missing 
value on the “Was the Ages and Stages Assessment Completed?” item), with the denominator 
being the number of infants in the ITT Analysis Set who completed the visit. 
Summaries of the “Communication total”, “Gross Motor total”, “Fine Motor total”, “Problem solving 
total”, and “Personal-Social total” items as continuous variables. 
Number and percentage of infants with abnormalities observed for communication, gross motor, 
fine motor, problem solving, personal-social, and other abnormalities, with the denominator being 
the number of infants with the Ages and Stages Assessment completed. 
 
Summary of the sum of the communication, gross motor, fine motor, problem solving, and 
person-social totals, as a continuous variable. 
 
Number and percentage of infants with any abnormality observed (across communication, gross 
motor, fine motor, problem solving, personal-social, and other), and the total number of 
abnormalities. 
 
10.14 
Edinburgh Postnatal Depression Scale 
 
Tables summarizing results from the Edinburgh Postnatal Depression Scale will be prepared. These 
summaries will be by visit, by arm and overall for each of the three cohorts, and by visit, by arm and 
overall for the three cohorts combined. These will be summarized for visits where the questionnaire was 
expected to be administered. 
Expected visits for the Edinburgh Postnatal Depression Scale are the following: 
 
Enrollment visit (visit 2) 
 
4-week visit corresponding to, or immediately following, the 30th week of gestation (only for 
Cohort 3; this is visit 6 if the gestational age at enrollment was 26-29 weeks, visit 10 if the GA 
was 22-25 weeks, visit 14 if the GA was 18-21 weeks, visit 18 if the GA was 14-17 weeks, or visit 
22 if the GA was 12-13 weeks) 
 
6-week PPO visit (visit 103) 
These tables will use data collected on the Edinburgh Postnatal Depression Score CRF and will include: 
 
Number and percentage of participants with an assessment performed (“Was this assessment 
performed?” was “Yes”), with the denominator being the number of participants in the ITT 
Analysis Set who completed the visit. 
 
Number and percentage of participants with each response to the 10 items on the questionnaire 
(“I have been able to laugh and see the funny side of things”, “I have looked forward with 
enjoyment to things”, “I have blamed myself unnecessarily when things went wrong”, “I have been 
anxious or worried for no good reason”, “I have felt scared or panicky for no very good reason”, 
“Things have been getting on top of me”, “I have been so unhappy that I have had difficulty 
sleeping”, “I have felt sad or miserable”, “I have been so unhappy that I have been crying”, “The 
thought of harming myself has occurred to me”), with the denominator being the number of 
participants in the ITT Analysis Set with an assessment performed. 
 
Number and percentage of participants who were subsequently referred for further evaluation 
and/or management (“Following completion of this questionnaire, was the mother subsequently 
referred for further evaluation and/or management”), with the denominator being the number of 
participants in the ITT Analysis Set with an assessment performed. 
 
Summary of the EPDS Score as a continuous variable. 


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10.15 
Infant Demographics 
 
Tables summarizing infant sex at birth will be prepared and will be by arm and overall for each of the 
three cohorts, and by arm and overall for the three cohorts combined. These will be summarized using 
the “sex at birth” item on the Infant Demographics CRF. 
 
 
10.16 
Social Benefits 
 
Tables summarizing social benefits will be prepared and will be by arm and overall for each of the three 
cohorts, and by arm and overall for the three cohorts combined. These summaries will include responses 
from the Social Benefits CRF collected at the 6-week PPO visit (visit 103), including interim 6-week PPO 
visits for participants who did not have the Social Benefits CRF collected at their scheduled 6-week PPO 
visit. 
 
These tables will include: 
 
Numbers and percentages of participants with each possible response to items under “From your 
perspective, what are all the benefits of participating in this study?” (i.e., from “The financial 
reimbursement”, “Free health care from the study”,…, “To help my relationship with my partner 
and/or family”, and “Other”), with the denominators being the number of participants in the ITT 
Analysis Set. 
 
Number and percentage of participants with each response to “What is the most important benefit 
or reason for your participation in this study?”, with the denominator being the number of 
participants in the ITT Analysis Set. 
 
10.17 
Social Impacts 
 
Tables summarizing social impacts will be prepared and will be by arm and overall for each of the three 
cohorts, and by arm and overall for the three cohorts combined. These tables will include: 
 
Number and percentage of participants who reported a social impact during the study (any Social 
Impact Y/N CRF with a “Has the participant reported a social impact during the study?” of “Yes”), 
with the denominator being the number of participants in the ITT Analysis Set. 
 
Number and percentage of participants with each type of social impact (“Social impact type” from 
the Social Impact Log CRF) and the total number of each type of impact. The denominator will be 
the number of participants who reported a social impact. 
 
Number and percentage of participants who reported an impact involving physical harm (“Did this 
involve physical harm to the participant?”) and the total number of impacts involving physical 
harm. The denominator will be the number of participants who reported a social impact. 
 
Number and percentage of participants who reported an impact involving harm to children (“Did 
this involve physical or other harm to participant’s child(ren)?”) and the total number of impacts 
involving harm to children. The denominator will be the number of participants who reported a 
social impact. 
 
The total number of impacts with each level of impact (“What impact did this situation have on the 
participant’s quality of life?”, responses of “minimal disturbance”, “moderate disturbance; no 
significant impact”, and “major disturbance with significant impact”). 
 
The total number of impacts with each current status (“Current status”, responses of “unresolved”, 
“unresolved at end of study”, “unable to resolve; no further action taken”, “resolved). 


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11. CHANGE HISTORY 
 
Version 
Affected 
Section(s) 
Activity Description 
Number 
Effective 
Date 
1.0 
Date of 
last 
signature 
All 
New document 
 
12. APPENDIX I Mother Expected Visits from Week 5 until Pregnancy Outcome 
Table 3: Cohort 1 Mother Expected Visits from Week 5 until Pregnancy Outcome 
GA (wks) 
at 
Enrollment 
Week 5 
(phone 
contact) 
37 
36 
Visit (GA 41) 
Cells shaded blue represent expected phone contact visits. The parenthetical “GA x” displays the 
gestational age in weeks of the participant at that visit. Visits in this table are only considered expected up 
until the participant’s pregnancy outcome. 
Note that the 37 weeks gestational age at enrollment group did not have any expected visits between 
Visit 6 – Week 4 and their pregnancy outcome. 
 
Table 4: Cohort 2 Mother Expected Visits from Week 5 until Pregnancy Outcome 
GA (wks) 
at 
Enrollment 
Week 5 
(phone 
contact) 
Week 6 
(in- 
person 
Week 7 
(phone 
contact) 
Week 8 
(in- 
person) 
Week 9 
(phone 
contact) 
Week 10 
(in- 
person) 
Week 11 
(phone 
contact 
35 
Visit 7 
(GA 40) 
Visit 8 
(GA 41) 
34 
Visit 7 
(GA 39) 
Visit 8 
(GA 40) 
Visit 9 
(GA 41) 
33 
Visit 7 
(GA 38) 
Visit 8 
(GA 39) 
Visit 9 
(GA 40) 
Visit 10 
(GA 41) 
32 
Visit 7 
(GA 37) 
Visit 8 
(GA 38) 
Visit 9 
(GA 39) 
Visit 10 
(GA 40) 
Visit 11 
(GA 41) 
31 
Visit 7 
(GA 36) 
Visit 8 
(GA 37) 
Visit 9 
(GA 38) 
Visit 10 
(GA 39) 
Visit 11 
(GA 40) 
Visit 12 
(GA 41) 
30 
Visit 8 
(GA 36) 
Visit 9 
(GA 37) 
Visit 10 
(GA 38) 
Visit 11 
(GA 39) 
Visit 12 
(GA 40) 
Visit 13 
(GA 41) 


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Cells shaded blue represent expected phone contact visits. Cells shaded yellow represent expected in- 
person visits. The parenthetical “GA x” displays the gestational age in weeks of the participant at that 
visit. Visits in this table are only considered expected up until the participant’s pregnancy outcome. 
 
 
 
Table 5: Cohort 3 GA 24-29 weeks Mother Expected Visits from Week 5 until Pregnancy Outcome 
Cells shaded blue represent expected phone contact visits. Cells shaded yellow represent expected in- 
person visits. The parenthetical “GA x” displays the gestational age in weeks of the participant at that 
visit. Visits in this table are only considered expected up until the participant’s pregnancy outcome. 
GA 
(wks) 
at 
Enroll 
Week 7 
(phone 
contact) 
Week 8 
(in- 
person) 
Week 9 
(phone 
contact) 
Week 
10 (in- 
person) 
Week 
11 
(phone 
contact 
Week 
12 (in- 
person) 
Week 
13 
(phone 
contact) 
Week 
14 (in- 
person) 
Week 
15 
(phone 
contact) 
Week 
16 (in- 
person) 
Week 
17 
(phone 
contact) 
29 
Visit 9 
(GA 36) 
Visit 10 
(GA 37) 
Visit 11 
(GA 38) 
Visit 12 
(GA 39) 
Visit 13 
(GA 40) 
Visit 14 
(GA 41) 
28 
Visit 10 
(GA 36) 
Visit 11 
(GA 37) 
Visit 12 
(GA 38) 
Visit 13 
(GA 39) 
Visit 14 
(GA 40) 
Visit 15 
(GA 41) 
27 
Visit 10 
(GA 35) 
Visit 11 
(GA 36) 
Visit 12 
(GA 37) 
Visit 13 
(GA 38) 
Visit 14 
(GA 39) 
Visit 15 
(GA 40) 
Visit 16 
(GA 41) 
26 
Visit 10 
(GA 34) 
Visit 12 
(GA 36) 
Visit 13 
(GA 37) 
Visit 14 
(GA 38) 
Visit 15 
(GA 39) 
Visit 16 
(GA 40) 
Visit 17 
(GA 41) 
25 
Visit 10 
(GA 33) 
Visit 13 
(GA 36) 
Visit 14 
(GA 37) 
Visit 15 
(GA 38) 
Visit 16 
(GA 39) 
Visit 17 
(GA 40) 
Visit 18 
(GA 41) 
24 
Visit 10 
(GA 32) 
Visit 14 
(GA 36) 
Visit 15 
(GA 37) 
Visit 16 
(GA 38) 
Visit 17 
(GA 39) 
Visit 18 
(GA 40) 
Visit 19 
(GA 41) 
 
Note that these gestational ages at enrollment groups did not have any expected visits after Visit 6 and 
prior to Visit 9 and these visits are omitted from Table 5. 


Table 6: Cohort 3 GA 18-23 weeks Mother Expected Visits from Week 5 until Pregnancy Outcome 
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GA 
(wks) 
at 
Enroll 
Wk 
8 
Wk 
12 
Wk 
13 
Wk 
14 
Wk 
15 
Wk 
16 
Wk 
17 
Wk 
18 
Wk 
19 
Wk 
20 
Wk 
21 
Wk 
22 
Wk 
23 
23 
V10 
(GA 
31) 
V14 
(GA 
35) 
V15 
(GA 
36) 
V16 
(GA 
37) 
V17 
(GA 
38) 
V18 
(GA 
39) 
V19 
(GA 
40) 
V20 
(GA 
41) 
22 
V10 
(GA 
30) 
V14 
(GA 
34) 
V16 
(GA 
36) 
V17 
(GA 
37) 
V18 
(GA 
38) 
V19 
(GA 
39) 
V20 
(GA 
40) 
V21 
(GA 
41) 
21 
V10 
(GA 
29) 
V14 
V17( 
GA 
36) 
V18 
(GA 
37) 
V19 
(GA 
38) 
V20 
(GA 
39) 
V21 
(GA 
40) 
V22 
(GA 
41) 
20 
V10 
(GA 
28) 
V14 
(GA 
32) 
V18 
(GA 
36) 
V19 
(GA 
37) 
V20 
(GA 
38) 
V21 
(GA 
39) 
V22 
V23 
(GA 
41) 
(GA 
40) 
19 
V10 
(GA 
27) 
V14 
(GA 
31) 
V18 
(GA 
35) 
V19 
(GA 
36) 
V20 
(GA 
37) 
V21 
(GA 
38) 
V22 
V23 
(GA 
40) 
V24 
(GA 
(GA 
39) 
41) 
18 
V10 
(GA 
26) 
V14 
(GA 
30) 
V18 
(GA 
34) 
V20 
(GA 
36) 
V21 
(GA 
37) 
V22 
V23 
(GA 
39) 
V24 
V25 
(GA 
41) 
(GA 
(GA 
38) 
40) 
Cells shaded blue represent expected phone contact visits. Cells shaded yellow represent expected in- 
person visits. The parenthetical “GA x” displays the gestational age in weeks of the participant at that 
visit. Visits in this table are only considered expected up until the participant’s pregnancy outcome. 
 
Note that these gestational age at enrollment groups did not have any expected visits after Visit 6 and 
prior to Visit 10, and after Visit 10 and prior to Visit 14, and these visits are omitted from Table 6. 


Table 7: Cohort 3 GA 12-17 weeks Mother Expected Visits from Week 5 until Pregnancy Outcome 
Confidential 
All proprietary rights reserved 
TMP-0041 Statistical Analysis Plan Template rev. 9 eff: 02/01/2023 
Page 34 of 40 
 
 
GA 
(wks) 
at 
Enroll 
Wk 
8 
Wk 
12 
Wk 
16 
Wk 
19 
Wk 
20 
Wk 
21 
Wk 
22 
Wk 
23 
Wk 
24 
Wk 
25 
Wk 
26 
Wk 
27 
Wk 
28 
Wk 
29 
17 
V10 
(GA 
25) 
V14 
(GA 
29) 
V18 
(GA 
33) 
V21 
(GA 
36) 
V22 
(GA 
37) 
V23 
(GA 
38) 
V24 
(GA 
39) 
V25 
(GA 
40) 
V26 
(GA 
41) 
16 
V10 
(GA 
24) 
V14 
(GA 
28) 
V18 
(GA 
32) 
V22 
(GA 
36) 
V23 
(GA 
37) 
V24 
(GA 
38) 
V25 
(GA 
39) 
V26 
(GA 
40) 
V27 
(GA 
41) 
15 
V10 
(GA 
23) 
V14 
(GA 
27) 
V18 
(GA 
31) 
V22 
(GA 
35) 
V23 
(GA 
36) 
V24 
(GA 
37) 
V25 
(GA 
38) 
V26 
(GA 
39) 
V27 
(GA 
40) 
V28 
(GA 
41) 
14 
V10 
(GA 
22) 
V14 
(GA 
26) 
V18 
(GA 
30) 
V22 
(GA 
34) 
V24 
(GA 
36) 
V25 
(GA 
37) 
V26 
(GA 
38) 
V27 
(GA 
39) 
V28 
V29 
(GA 
41) 
(GA 
40) 
13 
V10 
(GA 
21) 
V14 
(GA 
25) 
V18 
(GA 
29) 
V22 
(GA 
33) 
V25 
(GA 
36) 
V26 
(GA 
37) 
V27 
(GA 
38) 
V28 
V29 
(GA 
40) 
V30 
(GA 
(GA 
39) 
41) 
12 
V10 
(GA 
20) 
V14 
(GA 
24) 
V18 
(GA 
28) 
V22 
(GA 
32) 
V26 
(GA 
36) 
V27 
(GA 
37) 
V28 
V29 
(GA 
39) 
V30 
V31 
(GA 
41) 
(GA 
(GA 
38) 
40) 
Cells shaded blue represent expected phone contact visits. Cells shaded yellow represent expected in- 
person visits. The parenthetical “GA x” displays the gestational age in weeks of the participant at that 
visit. Visits in this table are only considered expected up until the participant’s pregnancy outcome. 
 
Note that these gestational ages at enrollment groups did not have any expected visits after Visit 6 and 
prior to Visit 10, after Visit 10 and prior to Visit 14, after Visit 14 and prior to Visit 18, and after V18 and 
prior to Visit 21, and these visits are omitted from Table 7. 


Confidential 
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TMP-0041 Statistical Analysis Plan Template rev. 9 eff: 02/01/2023 
Page 35 of 40 
 
 
13. APPENDIX II Visit Timing Requirements 
Table 8: Visit Timing Requirements for Mothers in Cohort 1 
Visit 
Target Day 
Window Opens 
Window Closes 
Visit 1 - Screening 
N/A 
N/A 
Visit 2 - Day 0 Enrollment 
0 
Up to 35 days after screening informed 
consent date 
Visit 3 - Week 1 Phone Contact 
7 
6 days prior to target 
2 days after target 
Visit 4 - Week 2 Bi-weekly Visit 
14 
4 days prior to target 
4 days after target 
Visit 5 - Week 3 Phone Contact 
21 
2 days prior to target 
2 days after target 
Visit 6 - Week 4 Bi-weekly Visit 
28 
4 days prior to target 
4 days after target 
Visit 7 - Week 5 Phone Contact 
(women who enroll at 36 
weeks 
GA only) 
35 
2 days prior to target 
2 days after target 
PPO Visit 
as soon after the 
PO as possible 
Pregnancy Outcome 
14 days after target 
1-Week PPO Phone Contact* 
7 days after PO 
6 days prior to target 
7 days after target 
6-Week PPO Visit/SEV 
42 days after PO 
13 days prior to 
target 
13 days after target 
*The 1-Week PPO Phone Contact may be skipped if the PPO Visit occurs within the 
visit window for this phone contact 


Table 9: Visit Timing Requirements for Mothers in Cohort 2 
Visit 
Target Day 
Window Opens 
Window Closes 
Confidential 
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TMP-0041 Statistical Analysis Plan Template rev. 9 eff: 02/01/2023 
Page 36 of 40 
 
 
Visit 1 - Screening 
N/A 
N/A 
Visit 2 - Day 0 Enrollment 
0 
Up to 35 days after screening informed 
consent date 
Visit 3 - Week 1 Phone Contact 
7 
6 days prior to target 
2 days after target 
Visit 4 - Week 2 2w Visit 
14 
4 days prior to target 
4 days after target 
Visit 5 - Week 3 Phone Contact 
21 
2 days prior to target 
2 days after target 
Visit 6 - Week 4 4w Visit 
28 
4 days prior to target 
4 days after target 
Visit 7 - Week 5 Phone Contact 
35 
2 days prior to target 
2 days after target 
Visit 8 - Week 6 Bi-weekly Visit 
42 
4 days prior to target 
4 days after target 
Visit 9 - Week 7 Phone Contact 
49 
2 days prior to target 
2 days after target 
Visit 10 - Week 8 Bi-weekly Visit 
56 
4 days prior to target 
4 days after target 
Visit 11 - Week 9 Phone Contact 
63 
2 days prior to target 
2 days after target 
Visit 12 - Week 10 Bi-weekly Visit 
70 
4 days prior to target 
4 days after target 
Visit 13 - Week 11 Phone Contact 
77 
2 days prior to target 
2 days after target 
Visit 101 - PPO Visit 
as soon after the 
PO as possible 
Pregnancy Outcome 
14 days after target 
Visit 102 - 1-Week PPO Phone 
Contact* 
7 days after PO 
7 days prior to target 
7 days after target 
Visit 103 - 6-Week PPO Visit/SEV 
42 days after PO 
13 days prior to target 
13 days after target 
*The 1-Week PPO Phone Contact may be skipped if the PPO Visit occurs within the 
visit window for this phone contact 


Table 10: Visit Timing Requirements for Mothers in Cohort 3 
Visit 
Target Day 
Window Opens 
Window Closes 
Confidential 
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TMP-0041 Statistical Analysis Plan Template rev. 9 eff: 02/01/2023 
Page 37 of 40 
 
 
Visit 1 - Screening 
N/A 
N/A 
Visit 2 - Day 0 Enrollment 
0 
Up to 35 days after screening informed 
consent date 
Visit 3 - Week 1 Phone Contact 
7 
6 days prior to target 
2 days after target 
Visit 4 - Week 2 2w Visit 
14 
4 days prior to target 
4 days after target 
Visit 5 - Week 3 Phone Contact 
21 
2 days prior to target 
2 days after target 
Visit 6 - Week 4 4w Visit 
28 
4 days prior to target 
4 days after target 
Visit 7 
N/A 
N/A 
49 
56 
56 
63 
70 
77 
N/A 
Visit 8 
N/A 
Visit 9 - Week 7 Phone Contact 
2 days prior to target 
2 days after target 
Visit 10 - Week 8 Bi-weekly Visit 
(participants enrolled at 29 weeks 
gestation) 
4 days prior to target 
4 days after target 
Visit 10 - Week 8 4w Visit 
(participants enrolled at 12-28 
weeks gestation) 
4 days prior to target 
4 days after target 
Visit 11 - Week 9 Phone Contact 
2 days prior to target 
2 days after target 
Visit 12 - Week 10 Bi-weekly 
Visit 
4 days prior to target 
4 days after target 
Visit 13 - Week 11 Phone 
Contact 
2 days prior to target 
2 days after target 
Visit 14 - Week 12 Bi-weekly 
Visit (participants enrolled at 25- 
29 weeks gestation) 
84 
4 days prior to target 
4 days after target 
Visit 14 - Week 12 4w Visit 
(participants enrolled at 12-24 
weeks gestation) 
84 
4 days prior to target 
4 days after target 
Visit 15 - Week 13 Phone 
Contact 
91 
2 days prior to target 
2 days after target 
Visit 16 - Week 14 Bi-weekly 
Visit 
98 
4 days prior to target 
4 days after target 


Confidential 
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TMP-0041 Statistical Analysis Plan Template rev. 9 eff: 02/01/2023 
Page 38 of 40 
 
 
 
Visit 17 - Week 15 Phone 
Contact 
105 
2 days prior to target 
2 days after target 
Visit 18 - Week 16 Bi-weekly 
Visit (participants enrolled at 21- 
25 weeks gestation) 
112 
4 days prior to target 
4 days after target 
Visit 18 - Week 16 4w Visit 
(participants enrolled at 12-20 
weeks gestation) 
112 
4 days prior to target 
4 days after target 
Visit 19 - Week 17 Phone 
Contact 
119 
2 days prior to target 
2 days after target 
Visit 20 - Week 18 Bi-weekly 
Visit 
126 
4 days prior to target 
4 days after target 
Visit 21 - Week 19 Phone 
Contact 
133 
2 days prior to target 
2 days after target 
Visit 22 - Week 20 Bi-weekly 
Visit (participants enrolled at 17- 
21 weeks gestation) 
140 
4 days prior to target 
4 days after target 
Visit 22 - Week 20 4w Visit 
(participants enrolled at 12-16 
weeks gestation) 
140 
4 days prior to target 
4 days after target 
Visit 23 - Week 21 Phone 
Contact 
147 
2 days prior to target 
2 days after target 
Visit 24 - Week 22 Bi-weekly 
Visit 
154 
4 days prior to target 
4 days after target 
Visit 25 - Week 23 Phone 
Contact 
161 
2 days prior to target 
2 days after target 
Visit 26 - Week 24 Bi-weekly 
Visit (participants enrolled at 
13- 17 weeks 
gestation) 
168 
4 days prior to target 
4 days after target 
Visit 26 - Week 24 4w Visit 
(participants enrolled at 12 
weeks gestation) 
168 
4 days prior to target 
4 days after target 
Visit 27 - Week 25 Phone 
Contact 
175 
2 days prior to target 
2 days after target 
Visit 28 - Week 26 Bi-weekly 
Visit 
182 
4 days prior to target 
4 days after target 
Visit 29 - Week 27 Phone 
Contact 
189 
2 days prior to target 
2 days after target 


Confidential 
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TMP-0041 Statistical Analysis Plan Template rev. 9 eff: 02/01/2023 
Page 39 of 40 
 
 
 
Visit 30 - Week 28 Bi-weekly 
Visit 
196 
4 days prior to target 
4 days after target 
Visit 31 - Week 29 Phone 
Contact 
203 
2 days prior to target 
2 days after target 
Visit 101 - PPO Visit 
as soon after the 
PO as possible 
Pregnancy Outcome 
14 days after target 
Visit 102 - 1-Week PPO Phone 
Contact* 
7 days after PO 
7 days prior to target 
7 days after target 
Visit 103 - 6-Week PPO 
Visit/SEV 
42 days after PO 
13 days prior to target 
13 days after target 
*The 1-Week PPO Phone Contact may be skipped if the PPO Visit occurs within the 
visit window for this phone contact 
 
Table 11: Visit Timing Requirements for Infants 
Visit 
Target Day 
Window Opens 
Window Closes 
V201 - PPO Visit 
as soon after the 
PO as possible 
Pregnancy Outcome 
14 days after target 
V202 - 1-Week PPO Phone 
Contact 
7 days after PO 
6 days prior to target 
7 days after target 
V203 - 6-Week PPO Visit 
42 days after PO 
13 days prior to 
target 
13 days after target 
V204 - 6-Month PPO Visit 
183 days after 
PO 
28 days prior to 
target 
28 days after target 
V205 - 12-Month PPO Visit 
365 days after 
PO 
28 days prior to 
target 
28 days after target 
*The 1-Week PPO Phone Contact may be skipped if the PPO Visit occurs within the 
visit window for this phone contact 
 
 
14. APPENDIX III Residual Drug Levels Calculation 
 
The DPV release rate per 28 days of use is calculated as: 
 = 
 
× 28 
With concm being the amount of residual drug in the manufacturer lot, concr being the amount of residual 
drug in the returned ring, and days being the number of days the participant should have been using the 
ring. 
 
An individual ring is identified in the lab residual DPV data using the guspec identifier, with each 
individual ring having it’s own unique identifier. Some rings were tested multiple times and will have 
multiple observations with the same guspec value. Observations with censor values of “(A)X”, “(A) X”, 
“(B)X”, “(B) X”, “(B)Z”, “(B) Z”, or “Z” should not be analyzed. The amount of residual dapivirine in the ring 
(concr above) is indicated by the value of conc. 
( 
) 


Confidential 
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TMP-0041 Statistical Analysis Plan Template rev. 9 eff: 02/01/2023 
Page 40 of 40 
 
 
 
Rings from the lab residual DPV data are linked to the clinical data through the Ring Insertion and 
Removal CRF, using the participant ID (ptid) and specimen collection date (spcdt) from the lab data 
and participant ID and the “Date ring returned” from the CRF data. For participants with multiple rings 
collected on the same date (i.e., two observations with same ptid and spcdt and different guspec), 
one ring needs to be assigned to correspond to “ring #1” in the Ring Return section of the CRF, and one 
to “ring #2”. In this case, the lab observation with the smaller value of recnum will be linked to the earlier 
ring return date on the CRF, and the larger value of recnum will be linked to the later ring return date. 
The number of days (days in the above equation) is calculated by taking the specimen collection date – 
“date returned ring #1 was provided” + 1 day (or “date returned ring #2 was provided”), unless the 
specimen collection date is after the participant’s pregnancy outcome date, in which the duration is 
calculated as the pregnancy outcome date – “date returned ring #1 was provided” + 1 day. 
 
Ring lot number is determined by linking the “date returned ring #1/#2 was provided” to the Pharmacy 
Dispensation CRF “date study product dispensed” and taking the “vaginal ring #1 lot number” or “vaginal 
ring #2 lot number”, as appropriate. That lot number is linked to the manufacturer record of the 
concentration for that lot (concm above). 

Prot_000.pdf: 
MTN-042 
 
 
Phase 3b, Randomized, Open Label Safety Trial of Dapivirine Vaginal Ring and Oral 
TRUVADA® Use in Pregnancy  
 
Microbicide Trials Network 
 
Funding Agencies: 
Division of AIDS, US National Institute of Allergy and Infectious Diseases 
US Eunice Kennedy Shriver National Institute of  
Child Health and Human Development 
US National Institute of Mental Health 
US National Institutes of Health 
 
 
Grant Numbers: 
UM1AI068633, UM1AI068615, UM1AI106707 
 
 
DAIDS Protocol ID: 38544 
 
 
IND Sponsor: 
DAIDS 
 
IND #: 139,598 
 
 
Pharmaceutical Company Collaborators: 
Gilead Sciences, Inc. 
International Partnership for Microbicides 
 
 
Protocol Chairs: 
Katherine Bunge, MD, MPH 
Bonus Makanani, MBBS, FCOG(SA) 
 
Protocol Co-Chair: 
Lee Fairlie, MBChB, FCPaeds 
 
 
Version 2.0 
 
May 20, 2021 
 
 


MTN-042, Version 2.0 
2 
 May 20, 2021 
 
MTN-042 
 
Phase 3b, Randomized, Open Label Safety Trial of Dapivirine Vaginal Ring and Oral 
TRUVADA® Use in Pregnancy  
 
TABLE OF CONTENTS 
 
TABLE OF CONTENTS .................................................................................................. 2 
LIST OF ABBREVIATIONS AND ACRONYMS ............................................................... 6 
PROTOCOL TEAM ROSTER ....................................................................................... 10 
INVESTIGATOR SIGNATURE FORM .......................................................................... 19 
PROTOCOL SUMMARY ............................................................................................... 20 
1 
KEY ROLES .................................................................................................... 24 
1.1 
Protocol Identification ....................................................................................... 24 
1.2 
Sponsor and Monitor Identification ................................................................... 24 
1.3 
Medical Officer ................................................................................................. 25 
1.4 
Clinical Laboratories ......................................................................................... 25 
1.5 
Data Centers .................................................................................................... 26 
1.6 
Study Operations ............................................................................................. 26 
2 
INTRODUCTION ............................................................................................. 27 
2.1 
Pregnancy and HIV in Sub-Saharan Africa ...................................................... 27 
2.2 
Description of DPV VR and Truvada Tablet ..................................................... 28 
2.3 
Nonclinical Studies – DPV................................................................................ 30 
2.4 
Nonclinical Studies – Truvada .......................................................................... 32 
2.5 
Clinical Studies – DPV ..................................................................................... 33 
2.6 
Clinical Studies – Truvada................................................................................ 37 
2.7 
Cross-resistance to ART .................................................................................. 40 
2.8 
Acceptability and Adherence ............................................................................ 41 
2.9 
Rationale for Study Design............................................................................... 43 
3 
OBJECTIVES .................................................................................................. 46 
3.1 
Primary Objectives ........................................................................................... 46 
3.2 
Secondary Objectives ...................................................................................... 46 
3.3 
Exploratory Objectives ..................................................................................... 47 
4 
STUDY DESIGN .............................................................................................. 47 
4.1 
Identification of Study Design ........................................................................... 47 
4.2 
Summary of Major Endpoints ........................................................................... 47 
4.3 
Description of Study Population ....................................................................... 48 
4.4 
Time to Complete Accrual ................................................................................ 48 
4.5 
Expected Duration of Participation ................................................................... 49 
4.6 
Sites ................................................................................................................. 49 
5 
STUDY POPULATION ..................................................................................... 49 
5.1 
Selection of the Study Population .................................................................... 49 
5.2 
Inclusion Criteria .............................................................................................. 50 
5.3 
Exclusion Criteria ............................................................................................. 51 
5.4 
Infant Enrollment .............................................................................................. 52 
5.5 
Co-enrollment Guidelines ................................................................................. 53 


MTN-042, Version 2.0 
3 
 May 20, 2021 
 
6 
STUDY PRODUCT .......................................................................................... 53 
6.1 
Regimen ........................................................................................................... 53 
6.2 
Administration .................................................................................................. 54 
6.3 
Study Product Formulation ............................................................................... 54 
6.4 
Supply and Accountability ................................................................................ 55 
6.5 
Retrieval of Study Product................................................................................ 56 
6.6 
Concomitant Medications and Practices .......................................................... 56 
6.7 
Prohibited Medications ..................................................................................... 56 
6.8 
Condoms .......................................................................................................... 57 
7 
STUDY PROCEDURES .................................................................................. 57 
7.1 
Pre-Screening .................................................................................................. 58 
7.2 
Visit 1:  Screening Visit .................................................................................... 59 
7.3 
Visit 2:  Enrollment Visit (Day 0) ....................................................................... 60 
7.4 
Follow-up Visits/Contacts Prior to Pregnancy Outcome ................................... 61 
7.5 
Follow-up Visits After Pregnancy Outcome ...................................................... 66 
7.6 
Semi-annual PPO Visits/Early SEV for Infants ................................................. 70 
7.7 
Follow-up Procedures for Participants Who Temporarily Hold or Permanently 
Discontinue Study Product ............................................................................... 71 
7.8 
Final Contact .................................................................................................... 74 
7.9 
Behavioral Evaluations ..................................................................................... 74 
7.10 Counseling ....................................................................................................... 75 
7.11 Clinical Evaluations and Procedures ................................................................ 75 
7.12 Laboratory Evaluations .................................................................................... 77 
7.13 Calculation of Gestational Age ......................................................................... 78 
7.14 Specimen Management ................................................................................... 79 
7.15 DAIDS Laboratory Oversight ............................................................................ 79 
7.16 Biohazard Containment .................................................................................... 79 
8 
ASSESSMENT OF SAFETY ........................................................................... 80 
8.1 
Safety Monitoring ............................................................................................. 80 
8.2 
Clinical Data Safety Review ............................................................................. 80 
8.3 
Adverse Events Definitions and Reporting Requirements ................................ 80 
8.4 
Expedited Adverse Event Reporting Requirements ......................................... 84 
8.5 
Social Harms Reporting ................................................................................... 85 
8.6 
Regulatory Requirements ................................................................................ 85 
9 
CLINICAL MANAGEMENT .............................................................................. 86 
9.1 
Grading System ............................................................................................... 86 
9.2 
Dose Modification Instructions ......................................................................... 86 
9.3 
General Criteria for Temporary/Permanent Discontinuation of Study Product . 86 
9.4 
Temporary Product Hold/Permanent Discontinuation in Response to Observed 
Adverse Events ................................................................................................ 87 
9.5 
Other Clinical Findings ..................................................................................... 87 
9.6 
HIV Infection ..................................................................................................... 90 
9.7 
Criteria for Early Termination of Study Participation ......................................... 90 
10 
ANALYTICAL CONSIDERATIONS .................................................................. 91 
10.1 Overview and Summary of Design ................................................................... 91 
10.2 Study Endpoints ............................................................................................... 91 


MTN-042, Version 2.0 
4 
 May 20, 2021 
 
10.3 Primary Study Hypotheses ............................................................................... 92 
10.4 Sample Size and Power Calculations .............................................................. 93 
10.5 Participant Accrual, Follow-up and Retention ................................................... 94 
10.6 Randomization ................................................................................................. 95 
10.7 Data and Safety Monitoring Procedures .......................................................... 95 
10.8 Analyses........................................................................................................... 96 
11 
DATA HANDLING AND RECORDKEEPING ................................................... 97 
11.1 Data Management Responsibilities .................................................................. 97 
11.2 Source Documents and Access to Source Data/Documents ........................... 98 
11.3 Quality Control and Quality Assurance ............................................................ 98 
12 
CLINICAL SITE MONITORING ....................................................................... 98 
13 
HUMAN SUBJECTS PROTECTIONS ............................................................. 99 
13.1 Institutional Review Boards/Ethics Committees ............................................... 99 
13.2 Protocol Registration ........................................................................................ 99 
13.3 Study Coordination ......................................................................................... 100 
13.4 Risk Benefit Statement ................................................................................... 100 
13.5 Informed Consent Process ............................................................................. 103 
13.6 Participant Confidentiality ............................................................................... 104 
13.7 Special Populations ........................................................................................ 104 
13.8 Compensation ................................................................................................ 108 
13.9 Communicable Disease Reporting ................................................................. 108 
13.10 Access to HIV-related Care ............................................................................ 108 
13.11 Study Discontinuation .................................................................................... 108 
14 
PUBLICATION POLICY ................................................................................. 109 
15 
APPENDICES ................................................................................................ 109 
APPENDIX I:  Table of Visits and Study Procedures – Mothers ................................. 110 
APPENDIX II:  Table of Visits and Study Procedures – Infants ................................... 113 
APPENDIX III:  Algorithm For HIV Testing – SCREENING/ENROLLMENT ............... 114 
APPENDIX IV:  Algorithm For HIV Testing – FOLLOW-UP ........................................ 115 
APPENDIX V: Sample Informed Consent Form  (Screening, Enrollment, Long-Term 
Storage and Off-Site Visit), MOTHER – COHORT 1 ................................................... 116 
APPENDIX VI: Sample Informed Consent Form  (Screening, Enrollment, Long-Term 
Storage and Off-Site Visit), MOTHER – COHORT 2 ................................................... 130 
APPENDIX VII: Sample Informed Consent Form  (Screening, Enrollment, Long-Term 
Storage and Off-Site Visit), MOTHER – COHORT 3 ................................................... 144 
APPENDIX VIII: Sample Informed Consent Form  (Screening, Enrollment, Long-Term 
Storage, Off-Site Visit, and Photography) – INFANT................................................... 158 
REFERENCES ............................................................................................................ 169 
 
List of Figures and Tables 
 
Figure 1: Study Visit Schedule – Cohort 1 .................................................................................. 21 
Figure 2: Study Visit Schedule – Cohort 2 .................................................................................. 22 
Figure 3: Study Visit Schedule – Cohort 3 .................................................................................. 22 
Figure 4: Expected Maximum Duration of Product Use by Study Cohort ................................... 54 
Figure 5: Study Visit Schedule – Cohort 1 .................................................................................. 57 
Figure 6: Study Visit Schedule – Cohort 2 .................................................................................. 58 


MTN-042, Version 2.0 
5 
 May 20, 2021 
 
Figure 7: Study Visit Schedule – Cohort 3 .................................................................................. 58 
 
Table 1: Retrieval of Study Product ............................................................................................ 56 
Table 2: Visit 1 – Screening Visit ................................................................................................ 59 
Table 3: Visit 2 – Enrollment Visit ............................................................................................... 60 
Table 4: Phone Contacts Prior to Pregnancy Outcome .............................................................. 62 
Table 5: Bi-weekly Visits After 36th Week of Gestation ............................................................... 62 
Table 6: 2-week Visit (Cohorts 2-3) ............................................................................................ 64 
Table 7: 4-week Visit(s) (Cohorts 2-3) ........................................................................................ 65 
Table 8: PPO Visit – Mothers ...................................................................................................... 66 
Table 9: PPO Visit – Infants ........................................................................................................ 67 
Table 10: 1-week PPO Phone Contact – Mothers ...................................................................... 68 
Table 11: 1-week PPO Phone Contact – Infants ........................................................................ 68 
Table 12: 6-week PPO/SEV/Early SEV – Mothers ..................................................................... 68 
Table 13: 6-week PPO Visit – Infants ......................................................................................... 70 
Table 14: Semi-annual PPO Visits/Early SEV ............................................................................ 70 
Table 15. Protocol-required Infant Blood Draw Volumes by Study Arm and by Clinic Visit ........ 78 
Table 16. Guidelines for Redating based on Ultrasonography ................................................... 79 
Table 17. Probability (%) of observing an event given different “true” event rates by cohort size
 .................................................................................................................................................... 93 
Table 18. Confidence intervals for endpoint rate (proportion of participants with endpoint) given 
number of endpoints (rows) in with number of participants (columns) ........................................ 94 
 
 
 


 
MTN-042, Version 2.0 
6 
 May 20, 2021 
 
MTN-042 
 
Phase 3b, Randomized, Open Label Safety Trial of Dapivirine Vaginal Ring and Oral 
TRUVADA® Use in Pregnancy  
LIST OF ABBREVIATIONS AND ACRONYMS 
 
ADAPT 
Alternative Dosing to Augment PrEP Pill Taking 
AE   
adverse event  
AIDS  
acquired immune deficiency syndrome  
ALT 
alanine transaminase 
ANC 
antenatal clinic 
ART 
antiretroviral therapy 
ARV 
antiretroviral 
ASCP 
American Society of Clinical Pathology 
ASPIRE 
A Study to Prevent Infection with a Ring for Extended Use 
AST 
aspartate aminotransferase 
AUC 
area under the curve 
AVAC 
Global Advocacy for HIV Prevention 
BMC 
bone mineral content 
BPM 
beats per minute 
BRWG 
Behavioral Research Working Group 
BSWG 
Biomedical Science Working Group 
BUN 
blood urea nitrogen 
BV 
CAB 
bacterial vaginosis 
Community Advisory Board 
CAPRISA 
Centre for the AIDS Programme of Research in South Africa 
CBC 
complete blood count 
CDC  
U.S. Centers for Disease Control and Prevention 
CFR 
Code of Federal Regulations 
Cmax 
maximum concentrations 
Cmin 
minimum concentrations 
CMRB 
Clinical Microbicide Research Branch 
CONRAD 
Contraception Research and Development 
CRF  
case report form 
CRMS 
Clinical Research Management System 
CROI 
Conference on Retroviruses and Opportunistic Infections 
CRL 
crown-rump length 
CRS 
clinical research site 
CT 
Chlamydia trachomatis 
CTA 
clinical trial agreement 
CTU 
clinical trials unit 
CVF 
cervicovaginal fluid 
CWG 
Community Working Group 
DAERS 
DAIDS Adverse Experience Reporting System 
DAIDS  
Division of Acquired Immunodeficiency Syndrome 
DAPY 
di-aminopyrimidine 
DBS 
dried blood spot 
DLV 
delavirdine 
DNA 
deoxyribonucleic acid 


 
MTN-042, Version 2.0 
7 
 May 20, 2021 
 
DOD 
directly observed dosing 
DPV 
dapivirine 
DREAM 
Dapivirine Ring Extended Access and Monitoring 
DSMB 
Data and Safety Monitoring Board 
EAE 
expedited adverse event 
EBL 
estimated blood loss 
EC 
Ethics Committee 
EC50 
50% effective concentration 
EDD 
estimated delivery date 
EFV 
efavirenz 
EMA 
European Medicines Agency 
FDA  
Food & Drug Administration (U.S.) 
FHCRC 
Fred Hutchinson Cancer Research Center 
FHR 
fetal heart rate 
FTC 
FTC-TP 
emtricitabine 
emtricitabine triphosphate 
FTP 
File Transfer Protocol 
g 
grams 
GA 
gestational age 
GC 
Neisseria gonorrhoeae 
GCP 
Good Clinical Practice 
GEE 
generalized estimating equations 
GMP 
good manufacturing practices 
HBsAg 
hepatitis B surface antigen 
HBV 
hepatitis B virus 
HCP 
health care provider 
HEENT 
Head, Eye, Ear, Nose and Throat 
HHS 
Department of Health and Human Services (U.S.) 
HIV-1  
human immunodeficiency virus-1 
HOPE 
HIV Open-label Prevention Extension 
HPTN 
HIV Prevention Trials Network 
HSV 
herpes simplex virus 
IAS 
International AIDS Society 
IATA 
International Association of Air Transport 
IB 
Investigator’s Brochure 
ICF 
ICH 
Informed Consent Form 
International Council on Harmonization 
ICRC 
International Clinical Research Center 
IDI 
in-depth interview 
IMPAACT 
International Maternal, Pediatric, Adolescent AIDS Clinical Trials Group 
IND 
Investigational New Drug 
IoR 
Investigator of Record 
IPM 
International Partnership for Microbicides 
iPrEX 
Iniciativa Profilaxis Pre-Exposición 
IPV 
intimate partner violence 
IQR 
interquartile range 
IRB  
Institutional Review Board 
IRP 
Interim Review Panel 
KOH 
potassium hydroxide 
3TC 
lamivudine 
LC 
Laboratory Center 


 
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LDMS 
LMP 
Laboratory Data Management System 
last menstrual period 
LOC 
Leadership and Operations Center 
μg 
microgram 
μM 
micromolar (10−3 mol/m3) 
mg 
milligram 
mL 
milliliter 
MO 
Medical Officer 
MSC 
Mail Stop Code 
MSM 
men who have sex with men 
MTCT 
MTD 
mother-to-child transmission 
maximum tolerated dose 
MTN 
Microbicide Trials Network 
MU-JHU 
Makerere University – John Hopkins University Research Collaboration 
NAAT 
nucleic acid amplification test 
ng 
nanogram  
NGO 
non-governmental organization 
NIAID 
National Institute of Allergy and Infectious Diseases 
NICHD 
National Institute of Child Health and Human Development 
NIH 
National Institutes of Health 
NIMH 
National Institute of Mental Health 
nM 
nanomolar (10−6 mol/m3) 
NNRTI  
non-nucleoside reverse transcriptase inhibitor 
NOAEL 
no observed adverse effect level 
NRTI  
nucleoside reverse transcriptase inhibitor 
NVP 
nevirapine 
OHRP 
Office for Human Research Protections 
PCR  
polymerase chain reaction 
PEP 
post-exposure prophylaxis 
pg 
picogram 
PI 
Principal Investigator 
PID  
pelvic inflammatory disease 
PK  
pharmacokinetic 
PMTCT 
PoR 
prevention of mother-to-child transmission 
Pharmacist of Record 
PPD 
Pharmaceutical Product Development, Inc. 
PPO 
post-pregnancy outcome 
PrEP 
pre-exposure prophylaxis 
PRO 
Protocol Registration Office 
PROM 
premature rupture of membranes 
PSP 
Prevention Sciences Program 
PSRT 
Protocol Safety Review Team 
PTID 
participant identification 
PUEV 
Product Use End/Early Termination Visit 
RE 
regulatory entity 
RHI 
Reproductive Health and HIV Institute 
RNA 
ribonucleic acid 
RSC 
Regulatory Support Center 
RT 
reverse transcriptase 
RTI 
reproductive tract infection 
SAE  
serious adverse event 


 
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SAHPRA 
South African Health Products Regulatory Authority 
SCHARP 
Statistical Center for HIV/AIDS Research & Prevention 
SCORE 
Site Clinical Operations and Research Essentials 
SDMC 
Statistical Data Management Center 
SEV 
study exit visit 
SMC 
Study Monitoring Committee 
SOP 
standard operating procedure 
SSA 
sub-Saharan Africa 
SSP 
study specific procedure(s) 
STI  
sexually transmitted infection 
SUSAR 
suspected, unexpected serious adverse reaction 
TDF 
tenofovir disoproxil fumarate 
TEAE  
treatment emergent adverse event  
TFV 
TFV-DP 
tenofovir 
tenofovir diphosphate 
TMC-120 
dapivirine 
TV 
trichomonas vaginalis 
UA 
urinalysis  
UNAIDS 
Joint United Nations Programme on HIV/AIDS 
UNICEF 
United Nations Children’s Fund 
UPMC 
University of Pittsburgh Medical Center 
URAI 
unprotected receptive anal intercourse 
USA 
United States of America 
UTI 
urinary tract infection 
VOICE 
Vaginal and Oral Interventions to Control the Epidemic 
VR 
vaginal ring 
WHO 
World Health Organization 
ZDV 
zidovudine 


 
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MTN-042 
 
Phase 3b, Randomized, Open Label Safety Trial of Dapivirine Vaginal Ring and Oral 
TRUVADA® Use in Pregnancy  
 
PROTOCOL TEAM ROSTER 
 
 
 
Protocol Chairs 
 
Katherine Bunge, MD, MPH 
Protocol Chair 
Magee-Womens Hospital of UPMC 
300 Halket Street 
Pittsburgh, PA 15213 USA 
Phone: 412-641-6967 
Fax: 412-641-1133 
Email: kbunge@mail.magee.edu 
 
Bonus Makanani, MBBS, FCOG(SA)  
Protocol Chair/Site Investigator 
Johns Hopkins University Research Project  
Chipatala Avenue, P.O. Box 1131  
Blantyre, Malawi  
Phone: 265-1875-129  
Fax: 265-1870-132  
Email: bmakanani@jhu.medcol.mw 
 
 
Protocol Co-Chair 
 
Lee Fairlie, MBChB, FCPaeds 
Protocol Co-Chair/Site Investigator of Record 
Wits Reproductive Health & HIV Institute (Wits RHI)  
22 Esselen Street, Hillbrow 
Johannesburg, South Africa  2001  
Phone: 27-11-358-5317 
Fax: 27-86-554-1093 
Email: LFairlie@wrhi.ac.za 
 
 


 
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Site Investigators 
 
Blantyre Clinical Research Site (CRS) 
 
Taha E. Taha, PhD 
Clinical Trials Unit (CTU) Principal Investigator (PI) 
Johns Hopkins University Bloomberg School of Public Health  
615 N. Wolfe Street 
Baltimore, MD 21205 
Phone: 410-614-5255 
Fax: 410-502-0688 
Email: ttaha@jhsph.edu 
 
Bonus Makanani, MBBS, FCOG(SA)  
Protocol Chair/Site Investigator of Record 
Johns Hopkins University Research Project  
Chipatala Avenue, P.O. Box 1131  
Blantyre, Malawi  
Phone: 265-1875-129  
Fax: 265-1870-132  
Email: bmakanani@jhu.medcol.mw 
 
 
The University of Zimbabwe Clinical Trials Research Centre (UZ-CTRC) Clinical Trials 
Unit (CTU) – Zengeza CRS 
 
Z. Mike Chirenje, MD, FRCOG 
CTU PI 
UZ-CTRC CTU 
15 Phillips Avenue, Belgravia 
Harare, Zimbabwe 
Phone: +263-24-2704-966 
Fax: + 263-24-2704-897 
Email: mchirenje@uz-ctrc.org 
 
Nyaradzo M. Mgodi, MBChB, MMed  
Site Investigator of Record 
UZ-CTRC CTU 
15 Phillips Avenue, Belgravia 
Harare, Zimbabwe 
Phone: +263-24-2704-920 
Fax: + 263-24-2704-897 
Email: nmmgodi@uz-ctrc.org   
 
 
 


 
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Makerere University - Johns Hopkins University (MU-JHU) Research Collaboration CRS 
 
Mary Glenn Fowler, MD, MPH 
CTU Co-PI 
Johns Hopkins University School of Medicine  
600 N. Wolfe Street 
Baltimore, MD 21287 
Phone: 410 502 0683 
Fax: 410 502 0688 
Email: mfowler5@jhmi.edu 
 
Clemensia Nakabiito, MBChB, MMed  
Site Principal Investigator MTN MU-JHU Research Collaboration 
Site Investigator of Record 
P.O. Box 23491  
Kampala, Uganda  
Phone: 256-41-541044/256-772-405332  
Fax: 256-41-541044/256-41-532091  
Email: cnakabiito@mujhu.org  
 
 
Wits RHI Shandukani Research Centre CRS 
 
Lee Fairlie, MBChB, FCPaeds 
Protocol Co-Chair/Site Investigator of Record 
Wits Reproductive Health & HIV Institute (Wits RHI)  
22 Esselen Street, Hillbrow 
Johannesburg, South Africa  2001  
Phone: 27-11-358-5317 
Fax: 27-86-554-1093 
Email: LFairlie@wrhi.ac.za 
 
 
 
 


 
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US National Institutes of Health (NIH) 
 
Roberta Black, PhD 
Chief, Clinical Microbicide Research 
Branch 
National Institute of Allergy and Infectious 
Diseases (NIAID), Division of AIDS (DAIDS) 
5601 Fishers Lane, Room 8B62, MSC 9831 
Rockville, MD 20852 USA 
Phone: 301-496-8199 
Email: rblack@niaid.nih.gov 
 
Nahida Chakhtoura, MD, MsGH 
Maternal and Pediatric Infectious Disease 
Branch, Eunice Kennedy Shriver National 
Institute of Child Health and Human 
Development (NICHD) 
National Institutes of Health (NIH) 
6710B Rockledge Drive, Room 2140 
Bethesda, MD 20817 
Phone: 301-435-6872 
Fax: 301-480-3882 
Email: nahida.chakhtoura@nih.gov 
 
Naana Cleland, MHCA 
Health Specialist, Clinical Microbicide 
Research Branch (CMRB) 
Therapeutics Research Program (TRP) 
DAIDS, NIAID, NIH – U.S. Department of 
Health and Human Services (HHS) 
5601 Fishers Lane, Room 8B27 
Rockville, MD 20852 USA 
Phone: 240-292-4779 
Email: naana.cleland@nih.gov 
 
Jeanna M. Piper, MD 
DAIDS Senior Medical Officer 
DAIDS/NIAID/NIH/HHS 
5601 Fishers Lane, Room 8B68, MSC 9831 
Rockville, MD 20852 USA 
Phone: 240-292-4798 
Email: piperj@niaid.nih.gov  
 
 
 
 
Dianne M. Rausch, PhD 
Director, Division of AIDS Research, National 
Institutes of Mental Health (NIMH) 
5601 Fishers Lane Room 8D20, MSC 9831 
Rockville, MD 20852 USA 
Phone: 240-627-3874 
Fax: 240-627-3467 
Email: dianne.rausch@nih.gov 
 
Teri Senn, PhD 
Program Chief, Psychosocial Co-morbidities 
of HIV Prevention and Treatment 
Division of AIDS Research, NIMH 
5601 Fishers Lane Room 9G29 
Rockville, MD 20852 USA 
Phone: 301-761-7852 
Email: teri.senn@nih.gov 
 


 
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MTN Leadership and Operations Center (LOC) – Pitt 
 
Richard Beigi, MD, MSc 
Protocol Physician 
Magee-Womens Hospital of UPMC 
300 Halket Street 
Pittsburgh, PA  15213 USA 
Phone: 412-641-3313 
Fax: 412-641-1133 
Email: rbeigi@mail.magee.edu 
Catherine Chappell, MD 
Protocol Safety Physician 
Magee-Womens Hospital of UPMC 
300 Halket Street 
Pittsburgh, PA 15213 USA 
Phone: 412-641-1804 
Fax: 412-641-1109 
Email: chappellca@upmc.edu 
Cindy Jacobson, PharmD 
Director of Pharmacy Affairs 
Microbicide Trials Network 
204 Craft Avenue 
Pittsburgh, PA 15213 USA 
Phone: 412-641-8913 
Fax: 412-641-6170 
Email: cjacobson@mail.magee.edu  
Lisa Noguchi, PhD, CNM 
Director, Pregnancy Research 
Johns Hopkins Bloomberg School of Public Health 
Department of Epidemiology 
615 N. Wolfe Street 
Baltimore, MD 21205 USA 
Phone: 202-664-2721 
Email: lnoguch1@jhu.edu 
 
Luis Duran, DrPH, MPIA 
Project Manager 
Microbicide Trials Network 
204 Craft Avenue 
Pittsburgh, PA 15213 USA 
Phone: 412-641-8539 
Email: duranl2@mwri.magee.edu 
Sharon A. Riddler, MD, MPH 
Protocol Physician 
UPMC, Keystone Building, Suite 510 
3520 Fifth Avenue 
Pittsburgh, PA 15213 USA 
Phone:  412-383-1741 or 412-383-1675 
Fax: 412-383-2900 
Email: riddler@dom.pitt.edu  
Sharon Hillier, PhD 
MTN Principal Investigator 
Microbicide Trials Network 
204 Craft Avenue 
Pittsburgh, PA 15213 USA 
Phone: 412-641-6435 
Fax: 412-641-6170 
Email: shillier@mail.magee.edu 
Devika Singh, MD, MPH 
Protocol Safety Physician 
19 Randall Drive 
Jericho, VT  05465 USA 
Phone: 206-920-0975 
Email: devika@mtnstopshiv.org  
Mei Song, PhD 
Project Manager 
Microbicide Trials Network 
204 Craft Avenue 
Pittsburgh, PA 15213 USA 
Phone: 412-641-2282 
Email: songm4@mail.magee.edu 
 
 
 
 
 
 
 
 


 
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MTN Laboratory Center (LC) 
 
Peter Anderson, PharmD 
LC Pharmacology Core 
University of Colorado School of Pharmacy 
Mail Stop C238 
12850 E. Montview Blvd. V20-4101 
Aurora, CO 80045 USA 
Phone: 303-724-6128 
Email: Peter.Anderson@ucdenver.edu 
 
 
Edward Livant, BSMT (ASCP), MPH 
MTN LC Research Manager 
Microbicide Trials Network 
204 Craft Avenue 
Pittsburgh, PA 15213 USA 
Phone: 412-641-3772 
Fax: 412-641-5290 
Email: livantew@upmc.edu 
 
Mark Marzinke, PhD, DABCC 
LC Pharmacology Core Investigator 
Johns Hopkins at Bayview 
Clinical Pharmacology Analytical Laboratory (CPAL)/Marzinke Lab 
4940 Eastern Avenue 
Mason F. Lord (MFL) Center Tower Suite 6000, Room 621 
Baltimore, Maryland 21224 
Office: 443-287-7516 
CPAL Office: 410-550-9703 
Fax: 410-955-0767 
Email: mmarzin1@jhmi.edu 
Jenny Robinson, MD, MPH, FACOG 
LC Pharmacology Core Investigator 
Johns Hopkins University 
600 North Wolfe Street, Harvey 502 
Baltimore, MD 21287 USA 
Phone: 410-550-7202 
Fax: 410-550-0196 
Email: jrobin87@jhmi.edu 
 
 
 
 
 
 
 
 
 
 
 
 


 
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MTN LOC – FHI 360 
 
Cheryl Blanchette 
Community Program Manager  
FHI 360 
359 Blackwell St., Suite 200 
Durham, NC 27701 USA  
Phone: 919-544-7040 ext 11359 
Fax: 919 544-0207 
Email: ccokley@fhi360.org 
 
Jontraye Davis, MHA 
Community Program Manager 
FHI 360 
359 Blackwell St., Suite 200 
Durham, NC  27701 USA  
Phone: 919-544-7040, Ext. 11715 
Fax: 919-544-0904 
Email: jodavis@fhi360.org 
 
Ashley Mayo, MPH  
Sr. Clinical Research Manager  
FHI 360 
359 Blackwell St., Suite 200 
Durham, NC  27701 USA  
Phone: 919-544-7040 Ext. 11164  
Fax: 919-544-0904 
Email: amayo@fhi360.org  
Tara McClure, MPH 
Sr. Clinical Research Manager 
FHI 360 
359 Blackwell St., Suite 200 
PO Box 21059 
Durham, NC 27701 USA 
Phone: 919-544-7040 Ext. 11012 
Fax: 919-544-7261 
Email: TMcClure@fhi360.org 
 
Rachel Scheckter, MPH 
Sr. Clinical Research Manager 
FHI 360 
359 Blackwell St., Suite 200 
Durham, NC  27701 USA  
Phone: 919-544-7040, Ext. 11392 
Fax: 919-544-7261 
Email: rscheckter@fhi360.org 
 
 
 
 
 
 
 
 
 
 
 
  
 
 


 
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MTN Statistical Data Management Center (SDMC) 
 
Jennifer Balkus, PhD, MPH 
SDMC Protocol Epidemiologist 
Fred Hutchinson Cancer Research Center (FHCRC) – Statistical Center for HIV/AIDS Research 
and Prevention (SCHARP) 
1100 Fairview Ave N, M2-C200 
Seattle, WA 98109-1024  
Phone: 206-667-7149 
Fax: 206-667-4812 
Email: jbalkus@fredhutch.org  
 
Tanya Harrell 
Clinical Data Manager 
FHCRC-SCHARP 
1100 Fairview Ave. North, E3-455P 
PO Box 19024 
Seattle, WA 98109-1024 USA 
Phone: 206-667-6568  
Email: tharrell@scharp.org 
 
Barbra Richardson, PhD 
Faculty Statistician 
FHCRC-SCHARP 
1100 Fairview Ave. North, M2-C200 
PO Box 19024 
Seattle, WA 98109-1024 USA 
Phone: 206-667-7788 
Fax: 206-667-4812 
Email: barbrar@uw.edu 
 
Daniel Szydlo, MS 
Statistical Research Associate 
FHCRC - SCHARP 
1100 Fairview Avenue North, M2-C200 
PO Box 19024 
Seattle, WA 98109-1024 USA 
Phone: 206-667-7451 
Fax: 206-667-4378 
Email: dszydlo@scharp.org 
 


 
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MTN Working Group Representatives 
 
Ariane van der Straten, PhD, MPH  
Behavioral Research Working Group (BRWG) Representative 
Microbicide Trials Network 
256 Stanford Avenue 
Kensington, CA 94708 
Phone: 510-374-9187 
Email: arianevds@gmail.com 
 
Elizabeth Montgomery, PhD  
BRWG Representative 
RTI International 
2150 Shattuck Avenue, Suite 800 
Berkeley, CA 94704 USA  
Phone: 310-694-2772 
Email: emontgomery@rti.org  
 
Ringson Ngozo 
Community Working Group (CWG) Representative 
Wits RHI Shandukani Research Centre 
22 Esselen Street, Hillbrow 
Johannesburg, South Africa  2001  
Email: RNgozo@wrhi.ac.za  
 
Craig Hendrix, MD 
Biomedical Science Working Group (BSWG) Representative 
Johns Hopkins University 
600 North Wolfe Street, Harvey 502 
Baltimore, MD 21287 USA 
Phone: 410-955-9707 
Fax: 410-955-9708 
Email: cwhendrix@jhmi.edu 
 
 
 


 
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MTN-042 
 
Phase 3b, Randomized, Open Label Safety Trial of Dapivirine Vaginal Ring and Oral 
TRUVADA® Use in Pregnancy 
INVESTIGATOR SIGNATURE FORM 
Version 2.0; May 20, 2021 
A Study of the Microbicide Trials Network 
 
Funded by: 
Division of AIDS (DAIDS), US National Institute of Allergy and Infectious Diseases 
US Eunice Kennedy Shriver National Institute of Child Health and Human Development 
US National Institute of Mental Health 
US National Institutes of Health (NIH) 
 
IND Sponsor: 
DAIDS (DAIDS Protocol ID: 38544) 
 
I, the Investigator of Record, agree to conduct this study in full accordance with the provisions of 
this protocol and all applicable protocol-related documents. I agree to conduct this study in 
compliance with United States (US) Health and Human Service regulations (45 CFR 46); 
applicable U.S. Food and Drug Administration regulations; standards of the International 
Conference for Harmonization Guideline for Good Clinical Practice (E6); Institutional Review 
Board/Ethics Committee determinations; all applicable in-country, state, and local laws and 
regulations; and other applicable requirements (e.g., NIH, DAIDS) and institutional policies.   
 
I agree to maintain all study documentation for at least two years after the last approval of a 
marketing application in an ICH region and until there are no pending or contemplated 
marketing applications in an ICH region or at least two years have elapsed since the formal 
discontinuation of clinical development of the investigational product. These documents should 
be retained for a longer period, however, if required by the applicable regulatory requirements or 
by an agreement with the sponsor. DAIDS will inform the investigator/institution as to when 
these documents no longer need to be retained. 
 
I have read and understand the information in the Investigator's Brochure(s), including the 
potential risks and side effects of the products under investigation, 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. 
  
 
 
______________________________ 
Name of Investigator of Record (print) 
 
 
 
____________________________  
 
______________________________ 
Signature of Investigator of Record   
 
Date 


 
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MTN-042 
 
Phase 3b, Randomized, Open Label Safety Trial of Dapivirine Vaginal Ring and Oral 
TRUVADA® Use in Pregnancy 
PROTOCOL SUMMARY 
 
Short Title: 
DELIVER: A Phase 3b Safety Study of the Dapivirine Ring and PrEP  
 
 
in Pregnant  Women 
 
IND Sponsor: 
DAIDS 
 
Funders:  
Division of AIDS, NIAID, NIMH, NICHD, US NIH 
 
Protocol Chair: 
Katherine Bunge, MD, MPH 
 
 
Bonus Makanani, MBBS, FCOG(SA) 
 
 
 
Protocol Co-Chair: 
Lee Fairlie, MBChB, FCPaeds 
 
Sample Size: 
Approximately 550 women and their infants 
 
Study Population: 
Healthy, HIV-uninfected pregnant females, 18-40 (inclusive) years old, 
with an uncomplicated singleton pregnancy who are willing to be 
randomized to study product, and their infants 
 
 
 
Study Sites: 
MTN-042 site(s) selected by the MTN Executive Committee 
 
Study Hypotheses: 
 
• 
Daily use of Truvada oral tablet or dapivirine (DPV) vaginal matrix 
ring (25 mg) inserted once every 4 weeks will be generally safe 
and well-tolerated by the participants and their fetuses/infants.  
• 
Participants who use Truvada oral tablet daily or insert the DPV 
vaginal matrix ring (25 mg) once every 4 weeks will experience 
similar distributions of pregnancy outcomes to the general 
population. 
 
 
Study Design: 
Phase 3b, two-arm, open label, multi-site, randomized (2:1 in Cohorts 
1-2 and 4:1 in Cohort 3) trial (DPV vaginal ring [VR], Truvada oral 
tablet), with onset of dosing period to occur within the following 
gestational age (GA) ranges: 
 
 
Cohort 1: 36 0/7 weeks – 37 6/7 weeks  150 women 
 
Cohort 2: 30 0/7 weeks – 35 6/7 weeks  150 women 
 
Cohort 3: 12 0/7 weeks – 29 6/7 weeks 250 women 
 
 
Study Duration: 
The total duration of study participation for each participant will vary 
depending on gestational age at time of enrollment and length of 
pregnancy prior to pregnancy outcome, and will range from 
approximately 12 weeks or less for Cohort 1 to approximately 36 
weeks or less for Cohort 3. Participants who become infected with 


 
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HIV will continue in study follow-up with a modified study 
visit/procedure schedule for a minimum of twelve months. Also, 
infants 
born 
to 
MTN-042 
participants 
will 
be 
followed 
for 
approximately 52 weeks (i.e., one year). 
 
Study Products: 
 
• 
Silicone elastomer matrix VR containing 25 mg of DPV 
• 
Oral tablets (Truvada) containing 200 mg emtricitabine/300 mg 
tenofovir disoproxil fumarate (FTC/TDF) 
 
Study Regimen: 
Within Cohorts 1 and 2, participants will be randomized to the above 
study products in a 2:1 ratio (100 VR: 50 tablet). Cohort 3 participants 
will be randomized to the above study products in a 4:1 ratio (200 VR: 
50 tablet). Participants randomized to the DPV VR will use one VR 
continuously for approximately one month, replacing the VR each 
month. Participants using Truvada tablet will take one tablet orally per 
day. Participants will use their assigned study product until their 
pregnancy outcome but no later than 41 6/7 weeks of gestation. 
 
Figure 1: Study Visit Schedule – Cohort 1 
 
 
Cohort 1
Enrollment Window
36 0/7 weeks of 
gestation– 37 6/7 
weeks of gestation
Infants enroll    
Mothers exit     
Screening
Enrollment
Every odd-numbered week after Enrollment (e.g., follow-up weeks 1, 3, 5) until pregnancy 
outcome (phone, home or clinic as needed per local standard of care)
Every even-numbered week after Enrollment (e.g., follow-up weeks 2, 4, 6) until pregnancy 
outcome
Post-pregnancy outcome (delivery hospital/facility or clinic)
1-week post-pregnancy outcome (phone, home or clinic as needed per local standard of care)
Approximately 6 weeks post-pregnancy outcome
Approximately 6 months post-delivery
Approximately 12 months post-delivery


 
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Figure 2: Study Visit Schedule – Cohort 2 
 
 
Figure 3: Study Visit Schedule – Cohort 3 
 
 
 
 
Primary Objectives: 
 
Maternal and Infant Safety:  To describe the maternal and infant safety profile 
associated with study product exposure during pregnancy  
 
Cohort 2
Enrollment Window
30 0/7 weeks of 
gestation – 35 6/7 
weeks of gestation
Infants enroll    
Mothers exit     
Screening
Enrollment
1-week (phone, home or clinic as needed per local standard of care)
2-week
3-week (phone, home or clinic as needed per local standard of care) 
4-week
Every odd-numbered week after 36th week of gestation (e.g., follow-up weeks 5, 7, 9) until 
pregnancy outcome (phone, home or clinic as needed per local standard of care)
Every even-numbered week including and after 36th week of gestation (e.g., follow-up weeks 
6, 8, 10) until pregnancy outcome
Post-pregnancy outcome visit (delivery hospital/facility or clinic)
1-week post-pregnancy outcome (phone, home or clinic as needed per local standard of 
care)
Approximately 6 weeks post-pregnancy outcome
Approximately 6 months post-delivery
Approximately 12 months post-delivery
Cohort 3
Enrollment Window
12 0/7 weeks of 
gestation – 29 6/7 
weeks of gestation
Infants enroll    
Mothers exit     
Screening
Enrollment
1-week (phone, home or clinic as needed per local standard of care) 
2-week
3-week (phone, home or clinic as needed per local standard of care)
4-week and every 4 weeks until 36th week of gestation 
Every odd-numbered week after 36th week of gestation (e.g., follow-up weeks 19, 21, 23) until 
pregnancy outcome (phone, home or clinic as needed per local standard of care)
Every even-numbered week including and after 36th week of gestation (e.g., follow-up weeks 
20, 22, 24) until pregnancy outcome
Post-pregnancy outcome visit (delivery hospital/facility or clinic)
1-week post-pregnancy outcome (phone, home or clinic as needed per local standard of care)
Approximately 6 weeks post-pregnancy outcome
Approximately 6 months post-delivery
Approximately 12 months post-delivery


 
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Pregnancy Outcomes:  To describe the pregnancy outcomes associated with study 
product exposure during pregnancy 
 
Primary Endpoints: 
 
Maternal Safety (composite) 
• 
All serious adverse events, including maternal deaths  
• 
All Grade 3 or higher adverse events (AE) as defined by the Division of AIDS 
(DAIDS) Table for Grading the Severity of Adult and Pediatric Adverse Events, 
Corrected Version 2.1, July 2017 and/or Addendum 1 (Female Genital Grading Table 
for Use in Microbicide Studies [Dated November 2007]) 
 
Infant Safety (composite) 
• 
All serious adverse events, including infant deaths and congenital anomalies 
• 
All Grade 3 or higher AEs as defined by the Division of AIDS (DAIDS) Table for 
Grading the Severity of Adult and Pediatric Adverse Events, Corrected Version 2.1, 
July 2017 
 
Pregnancy Outcomes  
• 
Frequency of the following pregnancy outcomes: 
o Full term live birth (≥37 0/7 weeks) 
o Premature live birth (<37 0/7 weeks) 
o Pregnancy loss (≥20 0/7 weeks) 
o Pregnancy loss (<20 0/7 weeks) 
 
Secondary Objectives: 
 
Pregnancy Complications: To describe pregnancy complications associated with study 
product exposure during pregnancy  
 
Infant Drug Levels: To describe infant levels of study drugs associated with study 
product exposure during pregnancy 
 
Adherence: To characterize adherence to open label use of the DPV VR (25 mg) and 
oral Truvada in pregnant women  
 
Acceptability: To characterize acceptability of open label use of the DPV VR (25 mg) 
and oral Truvada in pregnant women  
 
Secondary Endpoints: 
 
Pregnancy Complications 
• 
Frequency of the following pregnancy complications: 
o Hypertensive disorders of pregnancy 
o Chorioamnionitis 
o Puerperal sepsis and endometritis 
o Antepartum, intrapartum and postpartum hemorrhage 
o Preterm premature rupture of membranes (PROM) 
o Fever of unclear etiology 
 


 
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Infant Drug Levels 
• 
Infant blood tenofovir diphosphate (TFV-DP) and emtricitabine triphosphate (FTC-
TP) concentrations 
• 
Infant plasma DPV concentrations  
 
Adherence 
• 
Maternal blood TFV-DP and FTC-TP concentrations 
• 
Maternal plasma DPV concentrations  
• 
Participant report of frequency of study product use (e.g., missed doses for oral 
Truvada and VR removal/expulsions [voluntary and involuntary] and duration without 
VR in vagina) 
• 
Residual drug levels in returned VRs 
 
Acceptability  
• 
Self-reported attitudes about study product attributes and willingness to use study 
products during pregnancy 
• 
Proportion of participants who find the study products to be at least as acceptable as 
other HIV prevention methods 
 
Exploratory Objectives: 
 
Genital Microenvironment: To describe changes in the genital microenvironment 
associated with study product exposure during pregnancy 
 
Exploratory Endpoints: 
 
Genital Microenvironment 
• 
Genital microflora characteristics in Gram stain and quantitative polymerase chain 
reaction (PCR) 
• 
Biomarker expression in vaginal secretions 
 
 
 
1 
KEY ROLES 
 
1.1 
Protocol Identification 
 
Protocol Title:   
Phase 3b, Randomized, Open Label Safety Trial of Dapivirine 
Vaginal Ring and Oral TRUVADA® Use in Pregnancy 
 
Protocol Number: 
 
MTN-042 
 
Date:  
 
May 20, 2021 
 
1.2 
Sponsor and Monitor Identification 
 
Funding Agencies:  
US Division of AIDS (DAIDS)/National Institute of Allergy and 
Infectious Diseases (NIAID) 
National Institutes of Health (NIH) 


MTN-042, Version 2.0 
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5601 Fishers Lane 
Rockville, MD 20852 USA 
 
 
 
 
 
US National Institute of Mental Health (NIMH) 
6001 Executive Boulevard 
Rockville, MD 20852 USA 
 
 
US Eunice Kennedy Shriver National Institute of Child Health and 
Human Development (NICHD)  
6100 Executive Boulevard 
Bethesda, MD 20892 USA 
 
Pharmaceutical Company  
 
 
 
Collaborators:  
 
Gilead Sciences, Inc. 
 
 
 
 
333 Lakeside Drive 
 
 
 
 
Foster City, CA 94404 USA 
 
 
 
 
 
International Partnership for Microbicides (IPM) 
 
 
 
8401 Colesville Road, Suite 200 
 
 
 
Silver Spring, MD 20910 USA 
 
IND Sponsor: 
DAIDS/NIAID/NIH 
 
5601 Fishers Lane 
 
Rockville, MD 20852 USA 
 
Monitor: 
Pharmaceutical Product Development, Inc. (PPD) 
929 North Front Street 
Wilmington, NC  28401-3331 USA 
 
1.3 
Medical Officer 
 
Medical Officer: 
Jeanna M. Piper, MD 
 
 
5601 Fishers Lane  
 
 
Rockville, MD 20852 USA 
 
1.4 
Clinical Laboratories 
 
Laboratory Center: 
 
MTN Laboratory Center (LC) 
 
 
 
204 Craft Avenue 
 
 
 
Pittsburgh, PA 15213 USA 
 
Pharmacology: 
 
MTN Pharmacology Core 
 
 
 
Johns Hopkins University; 600 N. Wolfe Street, Osler 527 
 
 
 
Baltimore, MD 21287 USA 
 
MTN Pharmacology Core 
Clinical Pharmacology Analytical Laboratory (CPAL)/Marzinke Lab 
4940 Eastern Avenue 
Mason F. Lord (MFL) Center Tower Suite 6000, Room 621 
Baltimore, Maryland 21224 USA 
 


MTN-042, Version 2.0 
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MTN Pharmacology Core 
University of Colorado School of Pharmacy 
12850 E. Montview Blvd. V20-4101; Mail Stop C238 
Aurora, CO 80045 USA 
 
1.5 
Data Centers 
 
Data Center: 
MTN Statistical Data and Management Center (SDMC) Statistical 
Center for HIV/AIDS Research & Prevention (SCHARP)/Fred 
Hutchinson Cancer Research Center (FHCRC) 
 
 
 
 
1100 Fairview Avenue N., LE-400 
 
 
 
 
PO Box 19024 
 
 
 
 
Seattle, WA 98109-1024 USA 
 
Qualitative Data Center: 
Women’s Global Health Imperative, RTI International 
2150 Shattuck Avenue, Suite 800 
Berkeley, CA 94704 USA 
 
1.6 
Study Operations 
 
Study Operations:  
 
MTN LOC - FHI 360  
 
 
 
359 Blackwell Street, Suite 200  
 
 
 
PO Box 21059 
 
 
 
Durham, NC 27701 USA 
 


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2 
INTRODUCTION 
 
2.1 
Pregnancy and HIV in Sub-Saharan Africa 
 
Reproductive-age women are disproportionately affected by HIV-1, accounting for 56% of adults 
living with HIV-1 in sub-Saharan Africa.1 In eastern and southern Africa, for example, young 
women (aged 15–24 years) accounted for 26% of new HIV infections in 2016 despite making up 
just 10% of the population.2 AIDS-related illnesses remain the second leading cause of death 
for young women aged 15–24 years in Africa.2 These data clearly show reproductive women in 
sub-Saharan Africa are at high risk of HIV acquisition.  
 
Furthermore, findings suggest that biological and behavioural changes during and after 
pregnancy may further increase a woman’s HIV risk. Gray et al have shown that pregnancy 
produces a two-fold increase in susceptibility to HIV acquisition3, and a recent analysis found 
that the per-sexual act probability of HIV acquisition increased steadily throughout pregnancy 
and into the postpartum period.4,5 Potentially relevant biological changes/factors include 
elevated hormone levels and changes in the vaginal microbiome associated with genital or 
cervical inflammation, as well as nutritional deficiency and lowered immunity. Social and 
behavioral factors during pregnancy and breastfeeding may also increase exposure and 
susceptibility to HIV infection; for example, untreated sexually transmitted infections (STIs), 
reduced condom use, changes in extra-primary partnerships, and increased intimate partner 
violence (IPV).  In addition, incident HIV infection during pregnancy has been demonstrated to 
increase the odds of mother-to-child transmission (MTCT) by 15-fold.5 A woman’s 
seroconversion during pregnancy imparts a significant risk of transmitting HIV to her infant due 
to high levels of HIV viremia during acute infection. In one study representing nearly 10,000 
mother and infant pairs, the 3% of women infected with HIV during pregnancy accounted for 
over 25% of all MTCT cases of HIV.6 
 
In sub-Saharan African countries, the estimated fertility rates are high – 5.1 births per woman.7 
Also, the prevalence of breastfeeding in many of these countries is relatively high and of long 
duration. In 2017, in Eastern and Southern Africa, 55% of children were exclusively breastfed 
the first six months of life, compared with 43% of children globally; 87% of children continued 
breastfeeding at one year, compared with 74% of children globally; and 53% of children 
continued breastfeeding at two years, compared with 45% of children globally.8 These data, plus 
the fact that pregnant women remain sexually active, strongly suggest that these women 
represent a key target group for HIV prevention efforts.9 
 
Prior clinical trials of antiretroviral (ARV) drug use during pregnancy have primarily been in the 
context of treatment and/or prevention of mother-to-child transmission (PMTCT) in women 
known to have acquired HIV. However, unintended pregnancy is common, as high as 40% 
globally, thereby highlighting the need to characterize the consequences of HIV prevention 
agents during pregnancy.10 Although medication use (and fetal exposure) during pregnancy is 
common, the standard regulatory approach has in the past limited research efforts during 
pregnancy.11 The ethical imperative to investigate medication during pregnancy is a well-
recognized concept with documented justification. Informed use of medical therapies during 
pregnancy is necessary to optimize care (principle of beneficence) and there is a large societal 
cost from the lack of safety data and the resulting reticence to use indicated therapies during 
pregnancy.11 Studies of HIV prevention agents in pregnancy and lactation are ethically 
justifiable based on the concept of “prospect of direct benefit” to the mother, without a 
requirement for statistical power solely in studies of pregnant and lactating women to detect this 
benefit.11 With the increased risk of HIV acquisition during pregnancy and increased 


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transmission risk to the infant with new infection during pregnancy and lactation, careful 
investigation into identifying safe and effective ARV-based prevention interventions during 
pregnancy is warranted. 
 
While pregnant women are among those most in need of safe and effective HIV prevention and 
treatment, research during pregnancy has been limited. Pregnancy and HIV/AIDS: Seeking 
Equitable Study (PHASES) was a seven-year project funded by the National Institute of Allergy 
and Infectious Diseases (NIAID) with the primary aim of developing concrete guidance to 
address these evidence gaps, delays and inequities. The project’s extensive research, much of 
it conducted in sub-Saharan Africa, was published in July 202012. The study team together with 
a multidisciplinary working group of 26 international experts recommended the advancement of 
timely, needed and responsible research with pregnant women because without fair 
representation and inclusion in research, women are bound to face decisions about the use of 
medications during pregnancy with little or no scientific evidence on which to base those 
decisions. Of note, the PHASES report mentions the MTN-042/DELIVER study as an example 
of a study that will provide critically needed evidence about the safety of the dapivirine (DPV) 
vaginal ring (VR) and oral pre-exposure prophylaxis (PrEP) during pregnancy. 
 
Two ARV-based prevention interventions, the DPV VR (25 mg) and once-daily Truvada (200 mg 
emtricitabine [FTC]/300 mg tenofovir disoproxil fumarate [TDF]), have been evaluated in 
individuals at high risk for HIV infection and have shown in vitro and in vivo efficacy and 
favorable safety profiles.13,14  
 
2.2 
Description of DPV VR and Truvada Tablet 
 
2.2.1 
DPV VR 
 
The Dapivirine Vaginal Ring-004 is an off-white matrix ring, containing 25 mg of DPV dispersed 
in a platinum-catalyzed silicone elastomer. The DPV molecule was originally developed as an 
oral ARV agent by Janssen Sciences Ireland UC, which conducted the early, non-clinical and 
clinical development. DPV, also known as TMC-120, a substituted di-aminopyrimidine derivative 
(DAPY), is a tight binding non-nucleoside reverse transcriptase inhibitor (NNRTI) with potent 
antiviral 
activity 
against 
HIV-1. 
DPV 
is 
chemically 
described 
as 
4-[[4-[(2,4,6-
trimethylphenyl)amino]-2-pyrimidinyl]amino]benzonitrile. DPV’s ARV profile is superior to that of 
several other NNRTI drugs, including nevirapine (NVP), delavirdine (DLV), and efavirenz (EFV). 
Like other NNRTIs, in vitro tests have also shown that DPV is not active against HIV-2 and has 
little or no activity against common sexually transmitted infections (STIs), therefore, it is not 
intended for use against HIV-2 or other STIs. DPV does not have any contraceptive properties. 
DPV has potent activity against wild-type HIV-1 strains and strains harboring different 
resistance-inducing mutations. Detailed information on DPV is available in the DPV VR 
Investigator’s Brochure (IB).13 
 
Based on its proven in vitro and in vivo efficacy and favorable safety profile, as well as its 
physical and chemical properties, DPV has proven to be a promising microbicide candidate.  
Under a license agreement with Janssen Sciences Ireland UC, the International Partnership for 
Microbicides (IPM) has developed different non-oral pharmaceutical forms (either as a gel or VR 
delivery system) of DPV for prevention of infection with human immunodeficiency virus type 1 
(HIV-1) through male-to-female vaginal intercourse. The Dapivirine Vaginal Ring-004 was 
designed to provide sustained release of DPV for a minimum of one month to provide for a 
convenient dosing schedule. The in vitro release from the DPV VR (25 mg) in isopropyl alcohol 
(IPA):water (1:1) over 28 days was approximately 12 mg. Data from post-use analysis of DPV 


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residual levels in used rings indicate that approximately 4 mg of DPV is released over a one 
month period of VR use. When delivered in this manner, DPV has demonstrated favorable 
safety and pharmacokinetic (PK) profiles.13  
 
On July 23, 2020, the DPV VR received a positive scientific opinion from the European 
Medicines Agency (EMA) under Article 58 for its use in HIV prevention by cisgender women 
ages 18 and older in low- and middle-income countries.15 The World Health Organization 
(WHO) has since included the DPV VR on its prequalification list of medicines.16 The WHO has 
also formulated a conditional recommendation which states the DPV VR “may be offered as an 
additional prevention choice for women at substantial risk of HIV infection (defined as HIV 
incidence >3 per 100 person-years in the absence of PrEP) as part of combination prevention 
approaches”.17 The recommendation comes after a recent Guideline Development Group 
meeting assessed the benefits of the DPV VR outweighed the harms based on a systematic 
review and meta-analysis of the scientific evidence presented to them, including the DPV VR’s 
cost–effectiveness, acceptability, demonstrated feasibility, and its potential to increase 
equity.16,17 The Group noted some variability in DPV VR effectiveness in younger age groups 
and limited data regarding DPV VR use among pregnant and breastfeeding women. IPM is 
currently seeking regulatory approval of the ring’s use in several African countries through a 
collaborative process led by the WHO that accelerates country regulatory reviews for products 
that have received a positive opinion from the EMA or other stringent regulatory authority. The 
first of these decisions could occur by mid-2021. The ring is also under review by the US Food 
and Drug Administration. 
 
2.2.2 
Truvada Tablet  
 
Truvada (200 mg FTC/300 mg TDF) is a fixed-dose combination of the antiviral drugs 
emtricitabine (FTC) and tenofovir disoproxil fumarate (TDF). The chemical name of FTC is 5-
fluoro-1-(2R,5S)-[2(hydroxymethyl)-1,3-oxathiolan-5-yl]cytosine. TDF is a fumaric acid salt of 
the bis-isopropoxycarbonyloxymethyl ester derivative of tenofovir (TFV). The chemical name of 
TDF is 9-[(R)-2 [[bis[[(isopropoxycarbonyl)oxy]methoxy] phosphinyl]methoxy]propyl]adenine 
fumarate (1:1).14 
 
Truvada was originally approved by the US Food and Drug Administration (FDA) in 2004 in 
combination with other ARV agents as a treatment for HIV-1 infection in adults. Gilead 
Sciences, Inc. received US FDA approval in 2012 for once-daily Truvada (FTC and TDF), in 
combination with safer sex practices, to reduce the risk of sexually acquired HIV-1 infection in 
adults at high risk. Truvada, known as PrEP, is the first agent to be approved for HIV prevention 
in uninfected adults.18 Truvada for oral PrEP has also been approved for use by adults at high 
risk of sexually acquiring HIV-1 infection in a number of other countries, including South Africa, 
Malawi, Kenya and Zimbabwe.19 Furthermore, a Technical Working Group convened in April 
2017 at the Ugandan Ministry of Health following the release of WHO’s 2016 guidance. Due to 
the high cost of Truvada, they recommended use of the TDF/lamivudine (3TC) 300/300mg 
tablet for PrEP instead, although private health care providers (HCPs) or non-governmental 
organizations (NGOs) would be allowed to give Truvada or other TFV-containing drugs for PrEP 
if available and affordable. The World Health Organization recommends use of Truvada in 
pregnant and lactating women at risk of HIV; guidelines regarding use in pregnancy and 
lactation differ by country. 
 
Truvada  does not protect against common STIs such as gonorrhea, syphilis or chlamydia; 
therefore, it is recommended that it be used in conjunction with condoms.20 However, a 
secondary analysis21 within the Partners PrEP study for HIV-1 prevention among 4,747 highly-


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adherent serodiscordant couples found that daily oral TDF-based PrEP reduced herpes simplex 
virus (HSV)-2 acquisition by 30% compared to placebo among initially HSV-2-seronegative 
participants. Truvada does not have any contraceptive properties, and animal studies have not 
found evidence that Truvada alters female fertility.14 Detailed information on Truvada is 
available in the package insert.14 
 
2.2.3 
Mechanism of Action 
 
DPV VR 
DPV is an NNRTI; NNRTIs bind to the HIV reverse transcriptase (RT) enzyme thereby 
preventing viral replication and therefore the production of an infectious virus.13    
 
Truvada Tablet 
Truvada is a fixed-dose combination of antiviral drugs FTC and TDF. FTC and TDF are 
nucleoside reverse transcriptase inhibitors (NRTIs), which act by blocking RT enzyme, 
preventing HIV replication and therefore the production of an infectious virus.14   
 
2.2.4 
Strength of Study Products 
 
DPV VR 
The Dapivirine Vaginal Ring-004 contains 25 mg of DPV as active ingredient.  It is a matrix VR 
in which the drug substance is dispersed in a platinum-catalyzed cured silicone.13    
 
Truvada Tablet 
The once-daily film-coated Truvada oral tablet contains 200 mg of FTC and 300 mg of TDF, 
equivalent to 245 mg of tenofovir disoproxil, as active ingredients. Dosages used in MTN-042 
are the same as licensed doses, and the safety profile has been assessed as part of FDA 
licensure.14  
 
2.3 
Nonclinical Studies – DPV 
 
2.3.1 
In vitro and In vivo Studies of DPV 
 
Anti-HIV-1 Activity 
The activity of DPV against wild-type HIV-1, African isolates of HIV-1 (including subtype C 
virus), and a panel of NNRTI-resistant viruses has been established using in vitro models. The 
50% effective concentration (EC50) values ranged from 0.3 ng/mL (0.9 nM) against laboratory 
isolates to <33 ng/mL (<100 nM) against HIV-1 isolates encoding one or more known NNRTI 
resistance mutations.22,23 The anti-HIV activity of DPV was also confirmed in an ex vivo model of 
human cervical explant cultures.22,23 Pre-treatment of tissue with DPV for 2 or 24 hours inhibited 
HIV-1 infection when challenged with virus on Days 0, 2, 4 and 6 post drug removal.  DPV was 
also able to inhibit virus dissemination by migratory cells up to 6 days post drug removal at 
concentrations as low as 10 μM (3.3 μg/mL) following treatment for 2 or 24 hours. In addition, 
DPV (32.9 ng/mL) was able to block transfer of free virus by migratory dendritic cells to indicator 
T-cells (IC50= 0.1 nM [0.03 ng/mL]).  More information regarding HIV-1 activity can be found in 
the Dapivirine Investigator’s Brochure (IB).13  
 
Resistance to DPV  
In wild-type HIV-1 laboratory strains (at a high multiplicity of infection and in the presence of 
increasing concentrations of DPV), at DPV [40 nM], [200 nM] and [1 μM], virus breakthrough 
occurred between 4 and 7 days; between 7 and 10 days; and up to 30 days, respectively. In all 


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cases, mutations were present. Virus with the Y181C mutation was resistant to DPV. More 
information regarding resistance activity can be found in the Dapivirine IB.13  
 
In vitro, DPV has demonstrated reduced antiviral activity against subtype B virus with certain 
single NNRTI mutations. Low-level resistance to DPV occurred with virus containing K101E, 
K103N, or Y181C, 3 commonly transmitted NNRTI resistance mutations. Additionally, low-level 
resistance was seen with the E138K, F227C, and K103S mutations. Intermediate- or high-level 
DPV resistance was conferred by the L100V, L100I, M230L, Y188L, K101P, Y181I, and Y181V 
mutations.24 
 
Cross-resistance of DPV 
In comparison with NVP, DLV, EFV and emivirine, DPV showed significantly better in vitro 
activity against laboratory and recombinant HIV strains resistant to one or more drugs of the 
same class. The EC50 was below 32.9 ng/mL (100 nM) for 80% of the strains compared with 
only 56% of the strains for EFV.13 When tested against 433 clinical isolates with phenotypic 
resistance to at least one of the NNRTIs (NVP, DLV, EFV, or DPV), DPV was able to inhibit 
46% (202/433) of the samples, including 41% (142/350) of the strains resistant to EFV. In 
contrast, only 10% (24/231) of the DPV-resistant strains were inhibited by EFV.13  
 
DPV cross-resistance was also evaluated using plasma samples derived from HIV-1 subtype C-
infected individuals failing first-line neviripine- or efavirenz-containing antiretroviral therapy 
(ART) regimens in South Africa. The majority of virus samples demonstrated cross-resistance to 
DPV. Although resistance levels (based on required inhibitory concentrations of DPV) were 
found to be greater than the expected plasma concentrations of DPV during VR use, 
researchers concluded that both wild type and resistant virus may be inhibited by high genital 
tract DPV concentrations.25 More information regarding cross-resistance activity can be found in 
the Dapivirine IB.13  
 
Carcinogenicity, reproductive toxicity and mutagenicity of DPV 
The DPV VR was investigated in a comprehensive nonclinical safety assessment program that 
included safety pharmacology studies, single dose and repeat dose toxicity studies of up to 39 
weeks’ duration, reproductive toxicity and mutagenicity studies, and a 2-year carcinogenicity 
study. Data from in vitro and in vivo mutagenicity studies indicate that DPV is non-genotoxic. 
The vaginal reproductive toxicity studies in rats and rabbits using gels containing DPV at 
concentrations up to 2.0 mg/mL (0.2%; 25 times higher than the maximum concentration 
measured in the vaginal fluid of women using the DPV VR) showed that there were no adverse 
effects on the maternal animals or the developing embryo/fetus. No treatment-related neoplastic 
or non-neoplastic findings were seen in a vaginal carcinogenicity study in rates at 
concentrations up to  5 mg/mL. In rat and dog, the NOAEL was considered to be 20 mg/kg/day, 
based on prior nonclinical toxicity studies using the oral route of administration. Results show 
there were no effects in rats at the maternally non-toxic dose of 20 mg/kg/day, or in rabbits at up 
to 90 mg/kg. These data suggest that the risk of any adverse effects in pregnant women 
exposed to DPV, when used as a microbicide, is low. These data fulfill one of the major 
recommendations of conducting research within a pregnant population – reliable non-clinical 
data, especially with respect to mutagenic and teratogenic effects.26-29 
 
2.3.2 
Condom Compatibility Studies (DPV Gel and Placebo VR) 
 
Chemical compatibility studies with different DPV-containing gel formulations have been 
conducted on the following types of condoms13: Non-lubricated latex condoms (male condom); 
Silicone lubricated latex condoms (male and female condoms); Aqueous lubricated latex 


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condoms (male condom); Silicone lubricated polyurethane condoms (male and female 
condoms); and Silicone lubricated nitrile condoms (female condom). 
 
The results of condom compatibility testing indicate that DPV-containing vaginal gel 
formulations (0.05%) have no deleterious effects on the integrity of male or female condoms, as 
indicated by tensile condom properties tested pre- and post-treatment.  Two clinical condom 
functionality studies (one with male condoms [IPM 029] and one with female condoms [IPM 
033]) were conducted with a placebo VR (silicone elastomer VR containing no active 
ingredient). Results from both studies showed that the difference between the total clinical 
failure rate between condom use while using a VR and condom use while not using a VR was 
less than the pre-defined non-inferiority margins in both studies (3% for the male condom study 
and 8% for the female condom study). Condom use was safe and well tolerated during placebo 
VR use.13   
 
2.4 
Nonclinical Studies – Truvada 
 
Anti-HIV-1 Activity  
No antagonism was observed in combination studies evaluating the in vitro antiviral activity of 
Truvada. More information regarding anti-HIV-1 activity can be found in the Truvada package 
insert.14  
 
Resistance 
HIV-1 isolates with reduced susceptibility to the combination of FTC and TDF have been 
selected in vitro. Genotypic analysis of these isolates identified the M184V/I and/or K65R amino 
acid substitutions in the viral RT. In addition, a K70E substitution in HIV-1 RT has been selected 
by TDF and results in reduced susceptibility to TDF. Individuals with K65R have increased 
susceptibility to other NRTIs such as zidovudine (ZDV). More information regarding resistance 
studies can be found in the Truvada package insert.14   
 
Cross-Resistance 
Cross-resistance among certain NRTIs has been recognized. The M184V/I and/or K65R 
substitutions selected in vitro by the combination of FTC and unformulated TDF are also 
observed in some HIV-1 isolates from subjects failing treatment with TDF in combination with 
either lamivudine (3TC) or FTC, and other ARVs. More information regarding cross-resistance 
studies can be found in the Truvada package insert.14   
 
Carcinogenicity, reproductive toxicity and mutagenicity of Truvada 
Both emtricitabine (FTC) and tenofovir disoproxil fumarate (TDF) were evaluated in nonclinical 
safety assessment programs inclusive of toxicity, pharmacology, reproductive toxicity, 
mutagenicity and long-term carcinogenicity studies. For FTC, the long-term oral carcinogenicity 
studies showed no drug-related increases in tumor incidence found in mice at doses up to 750 
mg/kg/day (26 times the human systemic exposure at the therapeutic dose of 200 mg/day) or in 
rats at doses up to 600 mg/kg/day (31 times the human systemic exposure at the therapeutic 
dose). Also, FTC was not found to be genotoxic in mutagenicity studies. Finally, FTC did not 
affect fertility in male rats at approximately 140-fold or in male and female mice at approximately 
60-fold higher exposures (AUC) than in humans given the recommended 200 mg daily dose. 
Fertility was normal in the offspring of mice exposed daily from before birth (in utero) through 
sexual maturity at daily exposures (AUC) of approximately 60-fold higher than human 
exposures at the recommended 200 mg daily dose in reproductive fertility testing.14 
 


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For TDF in long-term oral carcinogenicity studies in mice and rats, the results show that at the 
high dose in female mice, liver adenomas were increased at exposures 16 times that in 
humans. In rats, the study was negative for carcinogenic findings at exposures up to 5 times 
that observed in humans at the therapeutic dose. TDF was mutagenic in the in vitro mouse 
lymphoma assay and negative in an in vitro bacterial mutagenicity test (Ames test). In an in vivo 
mouse micronucleus assay, TDF was negative when administered to male mice. There were no 
effects on fertility, mating performance, or early embryonic development when TDF was 
administered to male rats at a dose equivalent to 10 times the human dose based on body 
surface area comparisons for 28 days prior to mating and to female rats for 15 days prior to 
mating through day 7 of gestation. There was, however, an alteration of the estrous cycle in 
female rats. In toxicology studies to rats, dogs, and monkeys, tenofovir exposure (based on 
AUCs) greater than or equal to 6-fold those observed in humans cause bone toxicity. In 
monkeys the bone toxicity was diagnosed as osteomalacia. Osteomalacia observed in monkeys 
appeared to be reversible upon dose reduction or discontinuation of tenofovir. In rats and dogs, 
the bone toxicity manifested as reduced bone mineral density. The mechanism(s) underlying 
bone toxicity is unknown. Evidence of renal toxicity was noted in four animal species. Increases 
in serum creatinine, BUN, glycosuria, proteinuria, phosphaturia, and/or calciuria and decreases 
in serum phosphate were observed to varying degrees in these animals. These toxicities were 
noted at exposures (based on AUCs) 2–20 times higher than those observed in humans. The 
relationship of the renal abnormalities, particularly the phosphaturia, to the bone toxicity is not 
known.14 These data fulfill the one of the major recommendations of conducting research within 
a pregnant population - reliable non-clinical data, especially with respect to mutagenic and 
teratogenic effects.26-29 
 
2.5 
Clinical Studies – DPV 
 
To date, a total of 31 Phase 1 and Phase 2 clinical research studies of DPV have been 
completed: ten studies of DPV VRs (containing 25 mg, 503 subjects received DPV VRs); eight 
studies of DPV vaginal gel (491 subjects received DPV vaginal gel); eleven studies of oral DPV 
(211 subjects received oral DPV); two studies of DPV vaginal film (25 women received DPV 
vaginal film).13  
 
Two Phase 3 studies, MTN-020 (ASPIRE) and IPM 027 (The Ring Study), evaluating the long-
term safety and efficacy of the monthly use of the DPV VR (25 mg) have been completed. A 
total of 4588 participants were enrolled between the two studies, with 2620 assigned to receive 
DPV VRs.30,31 Two Phase 3B open-label extension trials, IPM 032 (DREAM) and MTN-025 
(HOPE), offering the extended use of the DPV VR to former participants of The Ring Study and 
ASPIRE, respectively, have also been completed. A total of 2309 participants were enrolled 
between the two Phase 3B studies, including 978 assigned to the placebo rings in the Phase 3 
trials.13  
 
To date, approximately 5350 adult women between 18 and 65 years of age have been exposed 
to the DPV VR across the clinical development program’s completed Phase 1-3B studies.13  
 
2.5.1 
Clinical Pharmacokinetics (PK) of DPV 
 
In clinical trials evaluating the use of VRs and vaginal gels to date, DPV concentrations in 
plasma have been very low (less than 2 ng/mL) or undetectable up to 84 days after drug 
exposure. Maximum plasma levels of DPV after vaginal administration were 1000-fold lower 
than maximum plasma concentrations after oral administration of DPV (e.g., DPV Cmax after oral 
administration (300 mg b.i.d., for 14 days) was 2286 ng/mL).32  


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The clinical PK profile of the Dapivirine Vaginal Ring-004 formulation evaluated in IPM 013 
showed a rapid increase in plasma and vaginal fluid concentrations of DPV after VR insertion.13  
Maximal DPV plasma concentrations were achieved in plasma by Day 7 of VR use and maximal 
DPV concentrations in cervicovaginal fluids (CVF) were achieved between Day 1 and Day 14 of 
VR use. DPV concentrations decreased steadily over the remainder of a 28-day or 35-day VR 
use period. Plasma DPV concentrations did not exceed 1 ng/mL, and were therefore well below 
concentrations at the maximum tolerated dose (MTD) for multiple oral DPV doses. For DPV in 
CVF, the highest DPV concentration was observed in the area where the VR was placed, 
followed by the cervix, with the lowest concentrations near the introitus.  
 
Data from post-use analysis of residual DPV levels in the Dapivirine Vaginal Ring-004 (IPM 015, 
in which a VR containing DPV 25 mg was inserted once every 28 days over a 12-week period) 
indicate that, on average, 4 mg of DPV were released over approximately one month of VR 
use.13 The mean remaining amounts of DPV in the used VRs returned at Weeks 4, 8 and 12 
were 21.09 mg, 21.54 mg and 21.84 mg, respectively. No clear relationship (neither linear nor 
exponential) was observed between the residual amount of DPV and corresponding plasma 
concentrations (i.e., at scheduled VR removal). DPV plasma concentrations below 
approximately 200 pg/mL were generally associated with above-average VR residual amounts, 
while plasma concentrations above 200 pg/mL were generally associated with relatively 
constant residual levels (between approximately 20 and 22 mg).13  
 
2.5.2 
Phase 1 and 2 Studies of DPV 
 
Across all clinical trials conducted in healthy participants evaluating multiple VR formulations, 
the DPV VR was generally well-tolerated.13   
 
The Dapivirine Vaginal Ring-004 has been evaluated in ten completed Phase 1 and Phase 2 
clinical research studies, each demonstrating the relative safety of this VR.13  
 
MTN-029/IPM 039 was a Phase 1, open-label clinical study designed to assess the presence of 
DPV in blood, breast milk, and CVF when delivered via a VR containing 25mg of DPV used 
continuously for 14 days by lactating women.33 The study also evaluated the safety and 
tolerability of the DPV VR as well as adherence to the DPV VR during lactation. MTN-029/IPM 
039 enrolled 16 healthy, HIV-negative women, aged 18 years or older, at least 6 weeks 
postpartum, who were lactating but not breastfeeding, at two U.S. sites. All participants had 
detectable DPV in milk and plasma, with median (interquartile range) peak concentration for 
milk and plasma at 676 pg/mL (443, 924.5) and 327 pg/mL (274.5, 378), respectively. Estimated 
daily infant exposure was 68.0 ng/kg/day (53.0, 85.1). Estimated terminal concentration half-life 
after VR removal was 39.0 hours (27.1, 53.4) and 35.2 hours (29.8, 46.4) for milk and plasma, 
respectively. Six of 16 (38%) participants experienced eight total AEs, most of which were mild 
and unrelated to study product.  
 
2.5.3 
Phase 3 Studies of DPV 
 
IPM 027 (The Ring Study) 
IPM 027 (also known as The Ring Study), initiated in March 2012, was a randomized, double-
blind, placebo-controlled efficacy and long-term safety study that enrolled 1959 healthy, HIV-
uninfected women, ages 18-45. Participants were randomized in a 2:1 ratio to receive either a 
DPV VR or a placebo VR to be used every four weeks over approximately two years.32,36  
 


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The median age at enrollment was 25 years, and 91% were unmarried. At the data cut-off point, 
there were 2806 person-years of follow-up, and 761 women had completed the two-year follow-
up period. A total of 139 post-randomization HIV-1 infections occurred: 80 among women 
assigned to DPV VR (incidence 4.23 per 100 person-years) and 59 among women assigned to 
placebo (incidence 6.43 per 100 person-years). The DPV VR reduced the risk of HIV-1 infection 
by 35.1% (95% CI: 9.05-53.64%; p=0.0114) relative to placebo. A 38.6% (95% CI: 7.48-
59.26%) reduction in HIV-1 infection was observed in a subgroup analysis of women older than 
21 years at baseline and a 27.51% (95% CI: -31.30% to 59.98%) reduction was observed in the 
subgroup of women who were 18 to 21 years of age at baseline.30,34 There is no apparent 
biological rationale for this difference between age groups, however the trial was not designed 
to explore efficacy by age group. The overall level of DPV VR efficacy observed in IPM 027 has 
been updated to 35% as a result of EMA review of the application submitted under Article 58.35 
 
No clinically significant differences in the frequency of TEAEs were detected between the DPV 
and placebo treatment groups, and the majority (>80%) were assessed as moderate (Grade 2) 
or mild (Grade 1) in severity. Product-related AEs in both treatment groups included 
metrorrhagia, menometrorrhagia, pelvic discomfort/pain, suprapubic pain and application site 
pain, and all were assessed as mild (Grade 1) in severity by the Investigator. There were no 
statistically significant differences in the frequency of the primary safety endpoints between the 
study arms. Further, there was no overall difference between NNRTI resistance profiles.13  
 
MTN-020 (ASPIRE) 
MTN-020, A Study to Prevent Infection with a Ring for Extended Use (ASPIRE), was a Phase 3 
clinical study designed to assess the efficacy and safety of the 25 mg DPV VR for the 
prevention of HIV-1 acquisition in women. The double-blind, randomized controlled study was 
conducted in HIV-uninfected women, ages 18-45. A total of 2629 women from Malawi, South 
Africa, Uganda, and Zimbabwe enrolled in the study. Participants replaced the VR monthly for a 
minimum of one year. Results were presented at the February 2016 CROI36 and published that 
same month in the New England Journal of Medicine.31 
 
A total of 168 HIV-1 infections occurred: 71 among those assigned the DPV VR and 97 among 
those assigned the placebo VR (incidence 3.3 and 4.5 per 100 person-years, respectively). DPV 
VR resulted in a 27% (95% CI: 1-46%, p=0.046) relative reduction in HIV-1 incidence overall 
and a 37% (95% CI: 12-56%, p=0.007) reduction in an analysis defined early in the study 
excluding data from two study sites with lower retention and adherence. In pre-defined as-
randomized subgroup analyses, HIV protection differed significantly by age, with a 61% reduced 
risk of HIV for women ≥ 25 years (95% CI: 32-77%, p<0.001), and 10% reduced risk for women 
< 25 years (95% CI: -41-43%, p=0.64). A post-hoc analysis was conducted to further explore 
this result, which indicated a 56% (95% CI: 31-71%, p<0.001) reduction among women older 
than 21 years of age, and no HIV-1 protection for women aged 18-21; importantly, objective 
markers of adherence were lower in the 18-21 year-old subgroup compared to women older 
than 21.31  
 
There were no statistically significant differences in the frequency of the primary safety 
endpoints between the study arms or in other AEs commonly detected in the study population. 
Incident STIs occurred at a similar rate in the two study arms. Product-related AEs included 
pelvic pain, application site pain, pelvic inflammatory disease (PID), cervix erythema, cervix 
edema, cervicitis, urinary tract infection (UTI), urinary incontinence, dyspareunia, headache, 
decreased neutrophil count, abnormal weight loss, and dysmenorrhea, and all were assessed 
as moderate (Grade 2) in severity. Finally, among those acquiring HIV-1, detection of NNRTI 


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mutations did not differ by study arm (8/68 assigned DPV and 10/96 assigned placebo, 
p=0.80).13   
 
MTN-025 (HOPE) 
MTN-025, the HIV Open-label Prevention Extension (HOPE) study, was a multi-site, open-label, 
randomized, Phase 3b study implemented in the ASPIRE clinical research sites.37 Eligible HIV-
uninfected ASPIRE participants received the same VR used in MTN-020, a silicone elastomer 
VR containing 25 mg of DPV, to be replaced monthly, for a total period of 12 months of use. 
Study follow-up visits occurred monthly for the first 3 months and quarterly thereafter, reflecting 
a transition to a more real-world type of follow-up (versus a clinical trial approach). The HOPE 
study enrolled 1456 former ASPIRE participants who were HIV­ negative and otherwise eligible 
to enroll. As with ASPIRE, the HOPE study found no significant safety concerns with the ring, 
while ring use adherence was higher in HOPE. Furthermore, though the HOPE study lacked a 
comparison placebo group, HIV-1 incidence was lower than expected by weighted bootstrap 
sampling of the placebo arm of ASPIRE (matched by site, age, and presence of a curable STI at 
baseline).  
 
Product-related AEs were minimal and similar in frequency and severity as those observed in 
ASPIRE, with no serious adverse events (SAE) related to ring use. At baseline, 1342 
participants (92%) accepted the VR, and ring uptake remained high throughout the study: 90%, 
89%, 87%, 83%, and 79% at Months 1, 2, 3, 6, and 9. Most (86%) returned rings had residual 
DPV levels consistent with some use during the prior month (>0.9 mg released). A total of 35 
HIV‐1 infections were observed among enrolled participants between July 2016 and August 
2018 for an observed incidence of 2.7 per 100 person‐years (95% CI: 1.9-3.8) among all women 
in HOPE, regardless of ring acceptance or use. Expected HIV‐1 incidence was 4.4 per 100 
person‐years (95% CI: 3.2-5.8) in the absence of access to the ring; an incidence of ≤ 2.7 would 
be expected to occur in fewer than 33 in 10,000 (0.33%) samplings. Lastly, no clear resistance 
pathway for resistance-associated mutations potentially selected by DPV was identified based 
on the pattern of NNRTI mutations observed among the 35 HOPE participants who acquired an 
HIV infection during the study. 
 
IPM 032 (DREAM) 
IPM 032, the Dapivirine Ring Extended Access and Monitoring (DREAM) study, was a multi-
site, open-label follow-on study to The Ring Study implemented in six of the IPM 027 sites.38 In 
total, 941 eligible HIV-uninfected former Ring Study participants received the same DPV VR 
used in The Ring Study. Like the HOPE study, DREAM study participants were asked to use the 
DPV VR for a total period of 12 months, replacing it monthly, and to attend monthly study follow-
up visits for the first 3 months and quarterly thereafter.  
 
The ring was found to be well-tolerated in DREAM with a safety profile similar to The Ring 
Study. Most (95%) DREAM participants’ returned rings had residual DPV levels which showed 
they had used the ring at least some of the time (ranging from intermittent to consistent use), up 
from 83% in The Ring Study. From July 2016 to November 2018, an HIV-1 incidence of 1.6 
percent was observed, compared to an incidence rate of 4.3% in a simulated placebo group 
based on data from participants with similar characteristics in the placebo arm of The Ring 
Study, suggesting an estimated 63% reduction in HIV-1 risk for women who used the ring. 
 
Studies of the DPV VR in Pregnancy 
The use of DPV VR has been shown to be well-tolerated for HIV-1 prevention in nonpregnant 
reproductive-aged women. Clinical data in pregnant women are limited, as pregnant women 
were excluded from participation in clinical trials. Participants who became pregnant 


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discontinued use of the DPV VR, and since pregnancy testing was conducted at monthly visits 
for MTN-020 and IPM 027, overall exposure of the developing embryo to DPV was limited.39 
However, limited data of DPV on pregnancy outcomes and infants are available. Of the 2629 
women enrolled in ASPIRE, 169 became pregnant during follow-up, resulting in 179 incident 
pregnancies and 181 pregnancy outcomes. No difference in pregnancy incidence by study arm 
was observed (HR=0.93; 95% CI 0.68 – 1.26). The distribution of pregnancy outcomes was 
similar by study arm, and no difference was noted in the frequency or pattern of congenital 
anomalies or infant growth parameters by study arm.40 In IPM 027, 53 pregnancies occurred 
among the 1959 participants with 38 known outcomes; the proportion of participants who 
reported adverse pregnancy outcomes was similar between the DPV and placebo groups.13 In 
both IPM 027 and MTN-020, the rare congenital abnormalities reported were reported with 
similar frequencies between the DPV VR group and the placebo ring group.39 No safety signals 
were found and no congenital anomalies or birth defects were observed in any of the 70 
pregnancies that occurred among HOPE participants who may have used the ring early on in 
their pregnancy prior to discovery of the pregnancy and subsequent product use 
discontinuation.41 Similarly, no safety signals were found in respect of pregnancy outcomes 
among DREAM participants who may have used the ring early on in their pregnancy prior to 
discovery of the pregnancy, and subsequent product use discontinuation. One congenital 
umbilical hernia was reported in the infant of a participant who became pregnant during the 
clinical trial. The congenital umbilical hernia was considered resolved after a duration of 102 
days during follow up of the infant.38 
 
2.6 
Clinical Studies – Truvada 
 
2.6.1 
Clinical Pharmacokinetics of Truvada 
 
Truvada may be administered with or without food.14 In vitro and clinical PK drug-drug 
interaction studies have shown that the potential for CYP450 mediated interactions involving 
FTC and TFV with other medicinal products is low. FTC and TFV are primarily excreted renally 
by a combination of glomerular filtration and active tubular secretion. No drug-drug interactions 
due to competition for renal excretion have been observed; however, coadministration of 
Truvada with drugs eliminated by active tubular secretion may increase concentrations of FTC, 
TFV, and/or the co-administered drug. Drugs that decrease renal function may increase 
concentrations of FTC and/or TFV.14 
 
2.6.2 
Phase 3 Studies of FTC with TDF 
 
Clinical studies of FTC with TDF in HIV prevention 
A review42 of seven completed PrEP randomized clinical trials with a combined 18,747 female 
and male participants, including the iPrEX (Iniciativa Profilaxis Pre-Exposición), Partners PrEP, 
the Bangkok Tenofovir Study, FEM-PrEP, VOICE (Vaginal and Oral Interventions to Control the 
Epidemic) and CAPRISA (Centre for the AIDS Programme of Research in South Africa) studies, 
evaluated safety, efficacy, adherence and potential barriers to ‘real-world’ uptake. Across all 
studies, reduction in HIV risk provided by oral TDF alone or in combination with FTC ranged 
from 0%–75%.  While adherence to daily pill-taking assessed by pill counts and self-report was 
high at 84%–95%, the proportion of participants in the PrEP arms with detectable serum drug 
levels was lower, ranging from 24%–82%. Regarding safety, TDF-based oral PrEP did not 
increase rates of serious (grade 3 or 4) AEs in any studies. In some studies, the risk of nausea, 
vomiting, diarrhea, unexplained weight loss, fatigue, and dizziness was higher than with 
placebo. Side effects were generally mild, infrequent (affecting 1%–10% of participants), and 
disappeared after 1 to 2 months of use. Drug resistance was rare among participants who 


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acquired an HIV infection after starting PrEP (0%–12% of incident cases during follow-up), but 
was common among participants who were recently infected with HIV before starting PrEP (up 
to 100% of such cases). 
 
iPrEx study 
The iPrEx trial was a randomized, double-blind, placebo-controlled multinational study 
evaluating Truvada in 2,499 HIV-seronegative men or transgender women who have sex with 
men and with evidence of high-risk behavior for HIV-1 infection.43 All subjects received monthly 
HIV-1 testing, risk-reduction counseling, condoms, and management of sexually transmitted 
infections. Of the 2,499 enrolled subjects, 1,251 received Truvada and 1,248 received placebo. 
The mean age of subjects was 27 years; 5% were Asian, 9% Black, 18% White, and 72% 
Hispanic/Latino. Subjects were followed for 4,237 person-years. The primary outcome measure 
was the incidence of documented HIV seroconversion. At the end of treatment, emergent HIV-1 
seroconversion was observed in 131 subjects, of which 48 occurred in the Truvada group and 
83 occurred in the placebo group, indicating a 42% (95% CI: 18–60%) reduction in risk. Risk 
reduction was found to be higher (53%; 95% CI: 34–72%) among subjects who reported 
previous unprotected receptive anal intercourse (URAI) at screening (732 and 753 subjects 
reported URAI within the last 12 weeks at screening in the Truvada and placebo groups, 
respectively). In a post-hoc case control study of plasma and intracellular drug levels in about 
10% of study subjects, risk reduction appeared to be greatest in subjects with detectable 
intracellular tenofovir diphosphate concentrations. Efficacy was therefore strongly correlated 
with adherence. 
 
TDF treatment is known to cause decreases in renal function, and there were trends toward 
more creatinine elevations in the Truvada group than in the placebo group. In testing for 
elevations in serum creatinine levels, there were 41 instances of elevations that were at least 
1.1 times the upper limit of the normal range or more than 1.5 times the baseline level. Of these 
elevations, 26 (2%) were in the FTC–TDF group and 15 (1%) were in the placebo group 
(P=0.08). Two of these elevations increased in grade, accounting for a total of 43 creatinine 
adverse events. Overall, 18 creatinine elevations (44%) remained in the normal range, and 36 
(88%) were not confirmed on the next test. A total of 10 elevations led to discontinuation of a 
study drug (7 in the Truvada group and 3 in the placebo group); study drugs were restarted in 9 
subjects. Serum creatinine levels were elevated at more than one consecutive test in 5 subjects 
in the FTC–TDF group (<1%) and in none of the subjects in the placebo group. All elevations in 
the serum creatinine level resolved after the discontinuation of a study drug, within 4 weeks in 3 
subjects, within 12 weeks in 1 subject, and within 20 weeks in 1 subject. Four of the subjects 
resumed taking FTC–TDF without recurrence of the elevation. Moderate nausea (grade 2 and 
above) was reported more frequently in the Truvada group than in the placebo group (22 vs. 10 
events, P=0.04), as was unintentional weight loss of 5% or more (34 vs. 19 events, P=0.04). 
 
Partners PrEP study 
The Partners PrEP study was a Phase 3 trial of TDF or Truvada in serodiscordant heterosexual 
couples in Kenya and Uganda; it found high efficacy against HIV acquisition, and the DSMB 
overseeing the study recommended stopping the placebo arm early.44 The team enrolled a total 
of 4,758 HIV serodiscordant couples.  Participants were randomized in a 1:1:1 ratio, to TDF, 
Truvada, and a matched placebo.  Following 7,827 person-years of follow-up, 82 emergent HIV-
1 seroconversions were reported, with an overall observed seroincidence rate of 1.05 per 100 
person-years. Of the 82 seroconversions, 13 and 52 occurred in partner subjects randomized to 
Truvada and placebo, respectively. Two of the 13 seroconversions in the Truvada arm and 3 of 
the 52 seroconversions in the placebo arm occurred in women during treatment interruptions for 
pregnancy. Findings from this study revealed 67% (95% CI 44 to 81%, p<0.0001) and 75% 


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(95% CI 55 to 87%, p < 0.0001) reductions in HIV acquisition compared to those who received 
placebo in the TDF and Truvada arms, respectively. Efficacy of daily oral PrEP was high in all 
women; among subgroups of higher-risk women (those with placebo-arm HIV-1 incidence >5.0 
per 100 person years), daily oral TDF and Truvada PrEP efficacy estimates ranged from 64% to 
84%.45 In a post-hoc case control study of plasma drug levels in about 10% of study subjects, 
risk reduction appeared to be greatest in subjects with detectable plasma tenofovir 
concentrations.  
 
Additional analyses from the Partners PrEP data relevant to MTN-042 were findings for: the 
efficacy of TFV-containing PrEP in reducing HSV-2 incidence,21 safety in early pregnancy,46 the 
low incidence of drug resistance in PrEP users detected by sensitive assays,47 and the low 
incidence and reversibility of renal glomerular changes.48  
 
Other studies of Truvada in pregnancy and lactation 
Although there have been no adequate and well-controlled trials conducted in pregnant and/or 
lactating women, limited exposure data for Truvada in pregnant and postpartum women are 
available.49,50 Results from the Antiretroviral Pregnancy Registry (APR) Interim Report, 
1January1989 through 31July2017, showed exposures for pregnant women to emtricitabine- 
and tenofovir-containing regimens were: 1148 and 3777 in the first trimester; 120 and 984 
exposures, respectively, in second trimester; and 61 and 488 exposures, respectively, in the 
third trimester. Birth defects occurred in 60 of 2614 (2.3%) live births for emtricitabine-containing 
regimens and 76 of 3342 (2.3%) live births for tenofovir-containing regimens among first 
trimester exposures. Compared to the background birth defect rate of 2.7% for pregnant women 
in the U.S. (reference population), there was no association between emtricitabine or tenofovir 
and overall birth defects.51 
 
A recent systematic review52 noted multiple research gaps, including limited data on: (1) 
accurately measured PrEP exposure within maternal and infant populations including drug 
levels needed for maternal protection; (2) uncommon perinatal outcomes (e.g., congenital 
anomalies); (3) infant outcomes such as bone growth beyond one year following PrEP 
exposure; and (4) outcomes in HIV-uninfected women who use PrEP during pregnancy and/or 
lactation. The authors concluded that early safety studies of PrEP among pregnant women 
without HIV infection are reassuring and ongoing/planned studies will contribute extensive new 
data to bolster the safety profile of PrEP use in pregnancy. 
 
PROMISE trial 
The P1084s sub-study of the Promoting Maternal-Infant Survival Everywhere, or PROMISE, trial 
compared newborn bone mineral content (BMC), measured using dual-energy X-ray 
absorptiometry scans of whole body and lumbar spine obtained within 28 days of birth, in 425 
infants by exposure to maternal antiretroviral regimens at gestational ages older than 14 weeks 
at 8 sites in 4 African countries. The women were randomly assigned to initiate 1 of 3 
antiretroviral regimens during pregnancy: arm 1 (zidovudine with single-dose nevirapine plus 
one dose of TDF and emtricitabine); arm 2 (zidovudine, lamivudine, and ritonavir-boosted 
lopinavir); or arm 3 (TDF, emtricitabine, and ritonavir-boosted lopinavir). No adverse 
associations were found between infant whole-body and lumbar spine BMC measurements and 
maternal TDF use when arms 2 and 3 were directly compared.53 This is in contrast to an earlier 
finding from a smaller cohort study that compared 74 tenofovir-exposed infants to 69 unexposed 
infants and found a statistically significant lower mean of 12% newborn BMC level following 
maternal TDF use.54 
 


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IMPAACT 2009 
IMPAACT (International Maternal, Pediatric, Adolescent AIDS Clinical Trials Group) 2009: 
Feasibility, Acceptability and Safety of Oral PrEP for Primary HIV Prevention During Pregnancy 
and Breast Feeding in Adolescents and Young Women is a parallel, observational cohort study 
of HIV-uninfected pregnant adolescents and young women (aged 16-24). The study is designed 
to characterize adherence over time among women who initiate once-daily oral PrEP during 
pregnancy and continue in the first 6 months following delivery, and to compare pregnancy 
outcomes among participants who take PrEP and participants who decline PrEP during the 
antenatal period. Prior to initiation of the main study component, a PK study component was 
implemented to establish adherence benchmarks for tenofovir diphosphate (TFV-DP) in dried 
blood spots (DBS) for pregnant (14-24 weeks gestation at Enrollment) and postpartum (6-12 
weeks postpartum at Enrollment) adolescents and young women who took PrEP daily under 
direct observation, and to compare these benchmarks in the pregnant and postpartum groups. 
Twenty pregnant and twenty postpartum women enrolled in the PK study component and took 
PrEP daily for twelve weeks, with >99% of oral PrEP doses taken under direct observation. 
Consistent with other studies, TFV-DP in DBS was 31-37% lower in pregnant women compared 
with postpartum women.55 As of Q1 2021, the study is pending initiation of accrual into the main 
study in Zimbabwe, Malawi, Uganda, and South Africa. No safety data will be available from this 
study prior to initiation of the last two MTN-042 Cohorts. 
 
2.7 
Cross-resistance to ART 
 
ART resistance is a serious emerging threat to HIV treatment access – particularly in sub-
Saharan Africa where weak health systems and poor access to monitoring and diagnostics 
make managing HIV even more challenging considering the high incidence of HIV infections in 
the region. 
 
2.7.1 
DPV VR 
 
Virologic failure and ART resistance following initiation of ART was assessed among women 
who acquired HIV infection during participation in ASPIRE. All ASPIRE participants with incident 
HIV during product use and with at least one CD4 cell count and HIV RNA (viral load) 
measurement were included in the analysis. Virologic failure was defined as either lack of 
suppression of plasma HIV RNA to <200 copies/ml after 6 months of ART, or plasma HIV RNA 
rebound to ≥200 copies/ml at any time after suppression. Of 168 participants with incident HIV 
infection observed in ASPIRE, 158 had at least one HIV RNA measurement and were included 
in the analysis. Virologic failure occurred in 14 participants with no significant difference 
between DPV and placebo recipients (17% vs 23%; Fisher’s exact P=0.76). Among the 14 
virologic failure events, 8 were viral rebound and 6 never suppressed. 18/158 women with 
incident HIV infection on study product had one or more NNRTI resistance mutations, of which 
10/18 initiated ART and had ≥6 months post-ART follow-up: 2/10 (20%) with NNRTI mutations 
vs. 12/57 (21%) with no NNRTI mutations had virologic failure. Genotypic resistance test results 
were available for 9/14 participants with virologic failure. NNRTI drug resistance mutations 
occurred in 7/9 overall; 6/7 were treatment-emergent. The most common mutation was K103N, 
occurring in 4/9 participants. The use of the DPV VR in women acquiring HIV during the 
ASPIRE trial was thus not associated with significant differences in the virologic outcomes 
following initiation of NNRTI-containing ART. There was no significant difference in virologic 
response time or frequency of virologic failure among DPV recipients compared to placebo, and 
no evidence to suggest that the presence of NNRTI mutations at seroconversion impacted the 
rate of virologic failure.56 
 


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2.7.2 
Truvada Tablet 
 
Resistance in individuals seroconverting while taking Truvada has been assessed from 5 
placebo-controlled, Phase 3 studies. All studies included an active arm in which participants 
were assigned a once daily regimen of oral TDF/FTC, and all participants underwent monthly 
rapid testing for HIV seroconversion.57-61 Resistance to TFV and FTC was found to be infrequent 
(3%) from use of TDF/FTC tablet for oral PrEP if HIV-1 infection is not present at the time oral 
PrEP is started (5 cases in 160 seroconverters assigned to TDF/FTC in 5 PrEP studies).  
Resistance to TFV and FTC is much more common (41%) if TDF/FTC PrEP is started during 
undiagnosed acute HIV-1 infection (7 cases in 17 participants).47,62-66 The risk of resistance with 
Truvada is low if acute HIV-1 infection is excluded before starting oral PrEP.67 
 
2.8 
Acceptability and Adherence 
 
2.8.1 
DPV VR  
 
Multiple clinical trials have also evaluated adherence to the DPV VR among reproductive-aged 
women in Africa and the US.68-72 Adherence was assessed either by self-report or by objective 
measures such as residual DPV concentrations in used VRs or blood plasma DPV levels. Self-
reported adherence to VR use was very high overall, with >80% of participants across studies 
saying they used the VR every day. Blood plasma drug levels supported these findings, 
although adherence was likely overestimated in the ASPIRE study given that participants who 
used the VR for only a portion of the month would have been categorized as adherent as per 
the study definition of adherence.  
 
The most commonly stated activities that led to voluntary removal of the VR were cleaning, 
menses and sexual intercourse, while the most commonly stated activities that led to involuntary 
expulsions of the VR were urination/defecation and sexual activity. Reasons for removing the 
VR included: male partner’s wishes, menses, and perceived side effects. In ASPIRE, drug 
detection appeared to increase after the first months of VR use and become stable after the first 
year, which may indicate that some time was needed for participants to become comfortable 
with the VR. 
 
Subgroup analyses of residual VR data suggest that the majority of women inconsistently used 
the VR throughout their participation in ASPIRE and that consistent VR use led to greater 
reductions in HIV-1 acquisition risk.73 Residual dapivirine levels indicating at least some use 
(>0.9 mg released over a month) were associated with a 48% relative reduction in HIV‐1 
acquisition risk (95% CI: 21% to 66%; p = 0.002) compared to placebo. Exploratory analyses 
accounting for potential misclassification in timing of HIV‐1 acquisition estimated 75% to 91% 
HIV‐1 risk reduction with >4 mg released when compared to placebo. Results for the subgroup 
of women <25 years of age, who tended to have lower adherence, were generally consistent 
with those overall. 
 
Adherence was higher in the HOPE open-label study than in ASPIRE.37 89.3% of returned rings 
(12,530 of 14,034) had residual dapivirine amounts consistent with some use during the 
previous month (>0.9 mg released) and the mean dapivirine amount released was greater than 
in the ASPIRE trial (by 0.21 mg; p<0.0001). Similarly, adherence was higher in the DREAM 
open-label study than in IPM 027.38 At all timepoints, most participants had dapivirine residual 
amounts in used rings of 23.5 mg or less, indicating at least some VR use, and mean dapivirine 
residual amounts in used rings were lower than in the IPM 027 trial (by 0.25 mg; p=0.027). 
 


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The VR was highly acceptable overall to participants in ASPIRE. Acceptability increased over 
time and varied by country, with participants in Uganda and Zimbabwe reporting higher 
likelihood of future use.74 Participants with low overall acceptability were less likely to use the 
VR consistently based on objective adherence measurements. Some attributes of acceptability, 
including effects on sex, perceived negative change to the vaginal environment, and minding 
VR use during menses influenced adherence more strongly, whereas others like comfort and 
ease of insertion had no effect. 
 
2.8.2 
Truvada Tablet 
 
Multiple clinical trials have evaluated the acceptability of and adherence to the Truvada oral 
tablet among reproductive-aged women in Africa.57,60,68,75-81 One study conducted with female 
sex workers in Kenya found the Truvada tablet a feasible and highly acceptable product 
regardless of dosing schedule (daily, twice weekly, or within two hours after sex); however, 
another study conducted with South African women found the pericoital dosing schedule to be a 
poor fit with their usual post-sex routines. The latter study, HPTN 067, found acceptability could 
be enhanced by interpersonal support, personal belief in PrEP’s efficacy, cellphone and other 
reminders, and keeping pills at hand, and that a daily dosing regimen may lead to better habit 
formation and more forgiveness for missed doses. 
 
Adherence was assessed by self-report, returned pill count, and/or blood plasma drug levels. 
Overall, Truvada tablet adherence tended to be high by self-report (>88% across studies) and 
returned pill counts (>75% across studies), but less consistently so by blood plasma drug levels 
(from <30% in VOICE to 86% in the Partners Demonstration Project). Most VOICE participants 
did not use the study products daily, a finding that is not consistent with pre-study assessments 
of the willingness of the target populations to use such products, adherence assessments based 
on clinic-based product counts and self-reporting, and the high rates of retention. Lower 
adherence in VOICE was associated with characteristics that predicted a higher risk of HIV 
acquisition. Results were consistent with those of the FEM-PrEP study, in which daily Truvada 
use did not reduce HIV-1 acquisition among women and in which study drug adherence was 
also low. However, VOICE results markedly differed from those of Partners PrEP, which 
displayed a significant reduction in risk of HIV-1 acquisition. Of note was that VOICE 
participants who were most likely to adhere were similar in terms of age and marital status to 
women in the Partners PrEP study. The VOICE study highlights the need for biomarker 
measures of adherence that do not rely solely on self-reporting and that are not easily 
manipulated by participants, such as real-time biologic monitoring of drug levels. 
 
Barriers and facilitators to adherence were assessed in the HPTN 067 and FEM-PrEP studies. 
Facilitators included: participant’s support for the research, HIV risk reduction, personal 
experiences with persons living with HIV/AIDS, strategies and tools such as adherence 
counseling and reminder alerts, social and emotional support (e.g., from partners and clinic 
staff), material support (e.g., financial reimbursement and clinical care). Barriers included: 
concerns about side effects, community stigma and distrust, privacy concerns (e.g., disclosure 
to partner, being identified as an HIV positive person), negative clinic or research participation 
experiences, and Truvada tablet characteristics (e.g., odor, size). Lastly, data from Partners 
PrEP and other Phase 3 PrEP studies like iPrEx and VOICE indicate that adherence at early 
time points predict adherence over the next one to two years, suggesting that adherence-
focused interventions should occur as soon as possible after initiation of PrEP. 
 


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2.9 
Rationale for Study Design 
 
The purpose of MTN-042, a multicenter, prospective, open-label, randomized phase 3b is to 
characterize the safety, adherence, and acceptability of the DPV VR (25 mg), inserted every 4-
weeks, and once-daily, Truvada (200 mg FTC/300 mg TDF) tablet used by African women 
during pregnancy. This study will further elucidate safety during pregnancy by testing the 
hypothesis that the administration of either study product will be safe and well-tolerated by 
women and their fetuses/infants so that women will experience similar rates of adverse 
pregnancy outcomes with either the DPV VR or Truvada compared to the general population. 
  
Prior clinical trials of ARV drugs during pregnancy have primarily been in the context of 
treatment and/or PMTCT in women known to have acquired HIV. However, unintended 
pregnancy is common, as high as 40% globally, thereby highlighting the need to characterize 
the consequences of HIV prevention agents during pregnancy. Although there have not been 
adequate and well-controlled trials of DPV VR and Truvada conducted in pregnant and/or 
postpartum women, to date, limited exposure data suggests these agents could be safe for 
women and their fetuses/infants. The availability of these agents further supports the need for 
controlled studies during pregnancy to inform national programs as well as country regulators 
on conditions of licensure.  
 
Ethical justification 
The FDA28, EMA26, and SAHPRA27, among other organizations, consider inclusion of pregnant 
women in clinical trials ethically justifiable when the trial holds the prospect of direct benefit to 
the mother and/or fetus, and adequate nonclinical studies have been completed on the 
investigational products. Development of accessible HIV prevention options for pregnant women 
in the study countries is a significant public health issue. MTN-042 affords the prospect of direct 
benefit to pregnant women and their infants in sub-Saharan Africa – a region where young 
women of reproductive age have high HIV acquisition rates2 and limited access to HIV 
prevention options - with two products that have been shown to be well-tolerated and to reduce 
risk of HIV-1 infection in non-pregnant populations13,14,31,82.  For the fetuses and infants of the 
participants, this study provides access to two products that have shown no significant risk of 
causing congenital abnormalities according to non-clinical data13,14 and available clinical data 
from exposure during pregnancy39,51, and provides direct benefit by reducing the maternal risk of 
HIV infection during pregnancy which dramatically increases the odds of MTCT.5 
 
As noted by the PHASES study team12, however, more research with pregnant women is 
needed to provide the necessary evidence for women to make informed choices about HIV 
prevention methods during pregnancy. Use of the DPV VR during pregnancy is currently 
considered missing information by the EMA due to limited available data. Acknowleding that 
some women may be at high risk of HIV-1 infecton during pregnancy, allowance is made in the 
currently approved Summary of Product Characteristics35 for clinical judgment on the part of 
healthcare professionals in deciding on its use during pregnancy. Given that health care 
providers will be allowed to use their best judgement when deciding whether to prescribe the 
DPV VR to pregnant women, it is inevitable that some pregnant women will use it, and it is in 
their best interest for the data to be available as early as responsibly possible. 
 
Safeguards to mitigate risk 
Several safeguards have been implemented in the design and execution of the study to mitigate 
potential risks from exposure to the DPV VR and Truvada during pregnancy. Eligibility criteria 
for the study restricts enrollment to only healthy, HIV-uninfected pregnant females, 18-40 


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(inclusive) years of age, with an uncomplicated singleton pregnancy who are willing to be 
randomized to study product, and their newborn infants.  
 
Additionally, a step-wise approach with pauses in accrual for interim safety reviews will be used 
to enroll subjects. Enrollment will begin with later gestational ages – i.e., later in pregnancy –  
then progress to earlier gestational ages once safety is confirmed. Participant accrual will be 
paused at all sites once accrual goals are met for the currently enrolling cohort. This will be 
done to allow all enrolled participants to give birth and to conduct interim safety analyses to 
determine if accrual into the next cohort can commence or if the study needs to be stopped 
early.  
 
Criteria for MTN-042 site selection included provision of prenatal care at the site or a related 
clinic, and a relationship with local inpatient maternity units that participants would be 
anticipated to utilize for delivery. Study sites will have established relationships with hospitals 
and other facilities serving the study participants, and these facilities will represent the highest 
standard of care available in the study countries. This will mean faster and more comprehensive 
communication with study staff of any adverse events or complications observed during 
participants’ prenatal care and delivery, and any subsequent response measures taken to 
address them, that may occur outside the study site clinics. In order to ensure that participants 
are receiving appropriate prenatal care during the course of the study, sites will collect 
documentation (certified copies of maternal records where possible) of antenatal visits from the 
participant herself and from her care provider once she has provided written permission during 
the screening process. In the event a problem with a pregnancy is suspected, an ultrasound can 
be ordered at the site or a referral will be provided. 
 
Finally, subjects may voluntarily withdraw from the study for any reason and/or the investigator 
may withdraw the participant to protect their safety and/or for their unwillingness to comply with 
required study procedures.  
 
Understanding cultural beliefs, societal norms and roles within the community is critically 
important for the success of a study involving pregnant women. In order to do so, MTN 
conducted a qualitative study, MTN-041 - Qualitative Assessment of Acceptability of Vaginal 
Ring and Oral Pre-exposure Prophylaxis Use during Pregnancy and Breastfeeding, in order to 
identify specific factors, belief systems and attitudes that may affect pregnant women’s 
perceptions of the MTN-042 study and potential interest in using a monthly vaginal ring or daily 
PrEP during pregnancy and/or breastfeeding, and who within a woman’s sphere of influence is 
most likely to support or discourage the use of either or both products. This study took place at 
the planned trial sites for MTN-042, and involved focus group discussions with women currently 
or recently pregnant and breastfeeding; men whose partners are or were recently pregnant or 
breastfeeding; and mothers and mothers-in-law of pregnant and breastfeeding women. In-depth 
interviews were conducted with community and traditional leaders, health providers, midwives 
and traditional birth attendants. Findings were utilized to inform recruitment, retention, 
community activities, data collection instruments, and study tools. The information gained from 
MTN-041 is helping the MTN-042 team to better understand the socio-cultural context of the 
participants’ communities and be attentive to sensitivities and contextual considerations that 
may be important to understand for participant comfort and confidence in the study team. 
Increased trust may mitigate risk through improved communication between pregnant 
participants and the study team, bringing potential issues of concern to attention sooner than 
later. 
 


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Young women and adherence 
In the VOICE study, which examined use of daily Truvada and 1% tenofovir gel, women 
younger than 25 were least likely to use their assigned products.59 ASPIRE31 and The Ring 
Study13 both found lower levels of HIV protection in young women aged 18-21; the rationale 
behind these data was that poor adherence observed in this age group resulted in decreased 
effectiveness of the DPV VR. In a study of a subset of ASPIRE participants, the non-adherence 
of young women was attributed to their tendency to be less serious about the future and about 
HIV prevention in general.83  
 
Young women in sub-Saharan Africa represent one of the populations most vulnerable to HIV 
1,2, and in this region that has one of the highest birth rates in the world 7, biological, social, and 
behavioral factors related to pregnancy increase the susceptibility of young, pregnant women in 
sub-Saharan Africa to HIV acquisition.3,4,5   However, pregnancy is not only a time of increased 
risk in a woman’s life, but it can also be a time of significant change. Altruistic motivations 
toward the unborn infant has been shown in expectant mothers84,85, and this can drive health-
seeking behaviors that last beyond pregnancy. The data from prior DPV VR and Truvada trials 
suggest that HIV risk reduction is correlated with adherence to product use; MTN-042 seeks to 
investigate whether changing motivations in pregnant women may mean greater adherence to 
HIV prophylaxis. Pregnant HIV-infected women, for example, have been found to have greater 
adherence to ARVs than non-pregnant women.86 
 
Investigation of microbiota as biomarkers for HIV risk 
With bacterial targets serving as biomarkers of HIV risk or protection, data on the description of 
the possible impact of product use on participants’ vaginal microenvironment, will be an 
important contribution to this area of HIV research. 
 
Community support 
At the MTN-042 Stakeholders’ Consultation held April 2018 in Johannesburg, South Africa, 
organized by MTN and AVAC, regional and international experts joined stakeholders with 
expertise in bioethics, maternal and fetal health, HIV prevention clinical trial design, regulatory 
affairs and health policy, as well as civil society and community representatives to share views 
about the study’s design and objectives and opinions about specific aspects of the study.87 
Stakeholders were very supportive of the study; there was consensus that pregnant women 
deserve safe, effective and equitable access to prevention.87 Stakeholders supported further 
study of the DPV VR and were unanimous in their view that the time is right to move forward 
with this agenda.87 And though IMPAACT 2009 (which recently completed its initial PK 
component) will be evaluating the safety of PrEP in adolescent and young women during 
pregnancy, stakeholders felt that, together, both studies would contribute much needed data 
about the safety of PrEP in pregnant women.87 Consideration was given to the challenges in 
and ethical and regulatory framework for conducting research among pregnant women, and the 
socio-cultural barriers and belief structures within communities.87 The stakeholders’ input and 
enthusiastic support has shaped the development of MTN-042. 
 
Justification for design change: Merging Cohorts 3 and 4 and 4:1 randomization in 
merged Cohort 3 
The HIV prevention landscape has changed substantially since the MTN-042 study protocol was 
approved. Recent years have seen an increased call for better drug safety data during 
pregnancy and for ethical inclusion of pregnant women in clinical research.88 Furthermore, the 
DPV VR has received a positive scientific opinion from the EMA under Article 58 for use as an 
HIV prevention method by cisgender women ages 18 and older in low- and middle-income 
countries,15 and the WHO has included the DPV VR on its prequalification list of medicines as 


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well as formulated a conditional recommendation supporting offering of the DPV VR as an HIV 
prevention option.16 IPM is seeking regulatory approval of the ring in several African countries 
through WHO’s Stringent Regulatory Authorities Collaborative Review process, and the first in-
country decisions are likely to be issued as early as mid-2021. Prescribing information for the 
DPV VR will likely indicate a preference to avoid the use of the DPV VR during pregnancy, but 
still allow the healthcare provider to exercise their discretion if they consider that the woman 
and/or her unborn child are at high risk of HIV-1 infection. 
 
Should the ring be approved, there will likely be women exposed to the DPV VR during 
pregnancy due to not yet realizing they are pregnant or because they are at high risk of HIV 
acquisition and they and their providers agree the benefits of ring use outweigh the potential 
risks. Providing safety data on DPV VR use by pregnant women is therefore more urgent, and 
the long pause between Cohorts 3 and 4 is a concern. While the 4-step design was optimal 
when the protocol was first developed, it is now unnecessarily complex, and if the DPV VR is 
approved, the delay between Cohorts 3 and 4 will needlessly postpone the availability of data 
during DPV VR rollout in African countries. Recently published results from the DPV VR open-
label studies37,38 and MTN-02389 have added to the existing literature on its use for HIV 
prevention, providing further evidence of its favorable safety profile. 
 
This protocol modification will collapse Cohorts 3 and 4 into a new combined Cohort 3, with 200 
participants randomized to the DPV VR and 50 participants randomized to oral Truvada. This 
combined Cohort 3 would encompass the gestational ages at enrollment (12-29 6/7 weeks) 
originally included in both Cohorts 3 and 4 so would provide safety data covering all of the 
initially planned gestational ages. Efforts will be made to ensure that entire gestational age 
range is represented among the enrollments. There are no changes to safety monitoring 
included in this modification. The proposed changes should allow the study to enroll and 
complete follow-up for all participants through delivery by early 2023. This will expedite the 
availability of safety data for DPV VR use by pregnant women, which will be critical to inform 
product rollout should the DPV VR be approved for HIV prevention. To further that goal, the 
team also proposes publishing safety data from each of the two earlier Cohorts as soon as they 
are available. 
 
 
3 
OBJECTIVES 
 
3.1 
Primary Objectives 
 
Maternal and Infant Safety:  To describe the maternal and infant safety profile 
associated with study product exposure during pregnancy  
 
Pregnancy Outcomes:  To describe the pregnancy outcomes associated with study 
product exposure during pregnancy  
 
3.2 
Secondary Objectives 
 
Pregnancy Complications: To describe pregnancy complications associated with study 
product exposure during pregnancy  
 
Infant Drug Levels: To describe infant levels of study drugs associated with study 
product exposure during pregnancy 


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Adherence: To characterize adherence to open label use of the DPV VR (25 mg) and 
oral Truvada in pregnant women  
 
Acceptability: To characterize acceptability of open label use of the DPV VR (25 mg) 
and oral Truvada in pregnant women  
 
3.3 
Exploratory Objectives 
 
Genital Microenvironment: To describe changes in the genital microenvironment 
associated with study product exposure during pregnancy 
 
 
4 
STUDY DESIGN 
 
4.1 
Identification of Study Design 
 
MTN-042 is a multi-site, two-arm, randomized (2:1 in Cohorts 1-2 and 4:1 in Cohort 3), open-
label Phase 3b study evaluating the safety, adherence and acceptability profiles of the monthly 
DPV VR and daily oral Truvada tablet when used by HIV-uninfected pregnant women in Africa. 
The MTN-042 study will take a step-wise approach to dosing starting at later gestational ages, 
then progressing to earlier gestational ages. The following gestational age ranges will determine 
eligibility for each study cohort: 
 
 
Cohort 1: 36 0/7 weeks – 37 6/7 weeks 
 
Cohort 2: 30 0/7 weeks – 35 6/7 weeks 
 
Cohort 3: 12 0/7 weeks – 29 6/7 weeks 
 
 
4.2 
Summary of Major Endpoints 
 
Primary Endpoints: 
 
Maternal Safety (composite) 
• 
All serious adverse events, including maternal deaths  
• 
All Grade 3 or higher AEs as defined by the Division of AIDS (DAIDS) Table for 
Grading the Severity of Adult and Pediatric Adverse Events, Corrected Version 2.1, 
July 2017 and/or Addendum 1 (Female Genital Grading Table for Use in Microbicide 
Studies [Dated November 2007]) 
 
Infant Safety (composite) 
• 
All serious adverse events, including infant deaths and congenital anomalies 
• 
All Grade 3 or higher AEs as defined by the Division of AIDS (DAIDS) Table for 
Grading the Severity of Adult and Pediatric Adverse Events, Corrected Version 2.1, 
July 2017 
 
Pregnancy Outcomes 
• 
Frequency of the following pregnancy outcomes: 
o Full term live birth (≥37 0/7 weeks) 
o Premature live birth (<37 0/7 weeks) 
o Pregnancy loss (≥20 0/7 weeks) 


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o Pregnancy loss (<20 0/7 weeks) 
 
Secondary Endpoints: 
 
Pregnancy Complications 
• 
Frequency of the following pregnancy complications: 
o Hypertensive disorders of pregnancy 
o Chorioamnionitis 
o Puerperal sepsis and endometritis 
o Antepartum, intrapartum and postpartum hemorrhage 
o Preterm premature rupture of membranes (PROM) 
o Fever of unclear etiology 
 
Infant Drug Levels 
• 
Infant blood TFV-DP and FTC-TP concentrations 
• 
Infant plasma DPV concentrations  
 
Adherence 
• 
Maternal blood TFV-DP and FTC-TP concentrations 
• 
Maternal plasma DPV concentrations  
• 
Participant report of frequency of study product use (e.g., missed doses for oral 
Truvada and VR removal/expulsions [voluntary and involuntary] and duration without 
VR in vagina) 
• 
Residual drug levels in returned VRs 
 
Acceptability  
• 
Self-reported attitudes about study product attributes and willingness to use study 
products during pregnancy 
• 
Proportion of participants who find the study products to be at least as acceptable as 
other HIV prevention methods 
 
Exploratory Endpoints: 
 
Genital Microenvironment 
• 
Genital microflora characteristics in Gram stain and quantitative PCR 
• 
Biomarker expression in vaginal secretions 
 
4.3 
Description of Study Population 
 
The MTN-042 study population will consist of approximately 550 healthy, HIV-uninfected, 
pregnant females 18-40 (inclusive) years of age who have an uncomplicated singleton 
pregnancy and are willing to be randomized to study product, and their infants, who meet 
eligibility criteria as described in Sections 5.2 to 5.4. Cohorts 1-2 will each consist of 
approximately 150 women and their infants, and Cohort 3 will consist of approximately 250 
women and their infants. 
 
4.4 
Time to Complete Accrual 
 
Time to complete accrual will be approximately 4 to 9 months for recruitment and enrollment of 
each Cohort, with accrual pauses of approximately 3 to 8 months between Cohorts to allow all 


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enrolled participants to give birth and for interim safety analyses to be conducted before 
continuing to the next Cohort, for a study duration of approximately 37-45 months.* Also, infants 
born to MTN-042 participants will be followed for approximately one year, for a total study 
duration of approximately 48-56 months including the one year of infant follow-up for the last 
study Cohort. See Section 10.5 for additional details. 
 
* Overall study duration – from first enrollment through closure of all follow-up – may be longer 
than planned if temporary site closures due to the COVID-19 pandemic cause delays or pauses 
in enrolling participants at one or more research sites. 
 
4.5 
Expected Duration of Participation 
 
The total duration of study participation for each participant will vary depending on gestational 
age at time of enrollment and length of pregnancy prior to pregnancy outcome, and will range 
from approximately 12 weeks or less for Cohort 1 to approximately 36 weeks or less for Cohort 
3.  Participants who become infected with HIV will continue in study follow-up with a modified 
study visit/procedure schedule for a minimum of twelve months. In addition, infants born to 
MTN-042 participants will be followed for approximately one year. 
 
4.6 
Sites 
 
MTN-042 participants will be recruited from clinical research sites (CRS) selected by the MTN 
Executive Committee. 
 
 
5 
STUDY POPULATION 
 
 
5.1 
Selection of the Study Population 
 
Approximately 550 women and their infants will be enrolled in this study.  Inclusion and 
Exclusion Criteria, Sections 5.2 and 5.3, respectively, are used to ensure the appropriate 
selection of study participants for MTN-042.   
 
5.1.1 
Recruitment 
 
Participants will be recruited from a variety of sources across sites including, but not limited to, 
antenatal clinics, primary care health clinics, HIV testing facilities, gynecology clinics, and 
community-based organizations. It is anticipated that all participating MTN-042 sites will have 
established relationships with hospitals and other facilities serving pregnant women. 
Participants may also be referred to the study from other local research projects and other 
health and social service providers serving the target study population. Recruitment materials 
will be approved by site Institutional Review Boards/Ethics Committees (IRBs/ECs) prior to use. 
Site community representatives should advise on these materials before they are submitted to 
the IRB/EC for review. Community education strategies, including group sessions, may be 
employed as part of participant and significant other (e.g., partner) outreach. 
 


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5.1.2 
Retention 
 
Once a participant is enrolled into the study, the study site will make every effort to retain the 
participant in follow-up to minimize possible bias associated with loss-to-follow-up. An average 
retention rate of 95% will be targeted across sites. 
 
5.2 
Inclusion Criteria 
 
Potential participants must meet all of the following criteria to be eligible for inclusion in the 
study: 
 
1. Age 18 through 40 years (inclusive) at Enrollment, verified per site standard operating 
procedures (SOPs). 
 
2. At Enrollment, evidence of a viable, intrauterine, singleton pregnancy with sonographic 
confirmation, including for gestational age assessment. 
 
Note: If adequate (per judgment of Investigator of Record [IoR]/designee) sonographic 
results are not available from medical records at Screening, an ultrasound must be 
performed and results be available for review at Enrollment for all Cohorts. The 
ultrasound should be performed no later than the 36th week of gestation for Cohort 1 or 
the 28th week of gestation for Cohort 2. 
 
3. At Enrollment, pregnancy within gestational age limits of the currently enrolling cohort 
(per Section 7.13). 
 
4. HIV-uninfected based on testing performed at Screening and Enrollment (per protocol 
algorithm in Appendix III). 
 
5. At Screening and Enrollment, intending to continue her pregnancy until delivery. 
 
6. At Screening and Enrollment, intending to deliver at a health center or hospital where 
adequate records may be obtained, as defined in site SOPs. 
 
Note: Plans to deliver at a health center or hospital where adequate records may be 
obtained is inclusionary due to logistical challenges related to collection of VRs, 
specimens and delivery outcome data outside of those settings. 
 
7. At Screening and Enrollment, willing to be randomized at time of enrollment to either of 
the two study arms, and to continue study product use until delivery. 
 
8. Able and willing to comply with all study requirements and complete all study 
procedures. 
 
9. Able and willing to provide the following: 
a. Informed consent for her and her infant to be screened for and to enroll in MTN-042, 
as defined in site SOPs. 
b. Adequate locator information, as defined in site SOPs. 
c. Adequate documentation of registration for antenatal care, as defined in site SOPs. 
d. Permission to contact participant’s antenatal and postpartum care provider(s) and to 
obtain copies of antenatal and postpartum care records. 


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10. At Screening and Enrollment, agrees not to participate in other research studies 
involving drugs, medical devices, vaginal products, or vaccines for the duration of study 
participation, unless approved by the PSRT. 
 
5.3 
Exclusion Criteria 
 
Potential participants who meet any of the following criteria will be excluded from the study: 
 
1. Per participant report at Screening and/or Enrollment, intends to do any of the following 
during the study participation period: 
a. Use oral PrEP outside the context of study participation. 
b. Relocate away from the study site. 
c. Travel away from the study site for a time period that would interfere with study 
participation. 
 
2. At Screening or Enrollment, has a positive HIV test. 
 
3. At Screening or Enrollment, diagnosed with urinary tract infection (UTI), cervicitis, STI or 
reproductive tract infection (RTI) requiring treatment per WHO guidelines. 
 
Note: Detection of BV or candida in the absence of symptoms is not exclusionary. 
Otherwise eligible participants diagnosed during screening with a UTI, cervicitis, or 
STI/RTI requiring treatment per WHO guidelines are offered treatment consistent with 
WHO recommendations.  If treatment is completed and symptoms have resolved within 
35 days of obtaining informed consent for screening, the participant may be enrolled. 
 
4. At Enrollment, has a clinically apparent Grade 2 or higher pelvic exam finding.* 
 
Note: Cervical friability bleeding associated with speculum insertion and/or specimen 
collection judged to be within the range of normal according to the clinical judgment of 
the Investigator of Record (IoR)/designee is considered expected bleeding and is not 
exclusionary.   
 
5. Participant report, clinical evidence and/or antenatal/medical care record of any of the 
following: 
a. Currently breastfeeding at Enrollment. 
b. Known adverse reaction to any of the study products (ever). 
c. Known adverse reaction to latex and polyurethane (ever). 
d. Symptoms suggestive of acute HIV infection at Screening or Enrollment. 
e. Non-therapeutic injection drug use in the 12 months prior to Enrollment. 
f. 
Use of HIV post-exposure prophylaxis (PEP) and/or PrEP during the current 
pregnancy. 
g. Participation in any other research study involving drugs, medical devices, vaginal 
products, or vaccines during the current pregnancy. 
h. At Screening or Enrollment, known to have any of the following during the current 
pregnancy: 
• 
Multiple gestation 
• 
Placenta previa 
• 
Cervical cerclage 


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• 
Abnormal fetal anatomy (in the opinion of the IoR or designee) 
• 
Intrauterine growth restriction 
• 
Pre-existing or gestational diabetes 
• 
Hypertensive disorder of pregnancy 
• 
Severe malaria 
• 
Treatment for preterm labor 
• 
Abnormal quantity of amniotic fluid (oligohydramnios or polyhydramnios) 
i. 
At Screening, known to have had any of the following in a previous pregnancy: 
• 
Intrauterine growth restriction 
• 
Gestational diabetes 
• 
Hypertensive disorder of pregnancy 
• 
Intrauterine fetal demise (estimated gestational age ≥20 weeks) 
• 
Delivery prior to 37 0/7 weeks 
j. 
At Enrollment, as determined by the IoR/designee, has any significant obstetrical 
complication (e.g., premature rupture of membranes, any abnormal placentation) or 
uncontrolled active or chronic cardiovascular, renal, liver, hematologic, neurologic, 
gastrointestinal, psychiatric, endocrine, respiratory, immunologic disorder or 
infectious disease that would make study participation unsafe.  
 
6. At Screening, has any of the following laboratory abnormalities: 
a. Positive for hepatitis B surface antigen (HBsAg). 
b. Aspartate aminotransferase (AST) or alanine transaminase (ALT) ≥ Grade 1.** 
c. Hemoglobin ≥ Grade 2.**  
d. Platelet count ≥ Grade 1.** 
e. Creatinine ≥ Grade 1.** 
f. 
Estimated creatinine clearance ≥ Grade 2 (Cockcroft Gault formula).** 
g. Glycosuria ≥ Grade 2.** 
h. Proteinuria ≥ Grade 2.** 
 
Note: Otherwise eligible participants with an exclusionary test (other than HBsAg) may 
be re-tested during the screening process; re-testing procedure details can be found in 
the MTN-042 Study Specific Procedures (SSP) Manual. If improvement to a non-
exclusionary grade or resolution is documented within 35 days of providing informed 
consent for screening, the participant may be enrolled. 
 
7. Has any condition that, in the opinion of the IoR/designee, would preclude informed 
consent, make study participation unsafe, complicate interpretation of study outcome 
data, or otherwise interfere with achieving the study objectives. 
 
*Female Genital Grading Table for Use in Microbicide Studies Addendum 1 (Dated November 
2007) to the DAIDS Table for Grading the Severity of Adult and Pediatric Adverse Events, 
Corrected Version 2.1, July 2017.  
**DAIDS Table for Grading the Severity of Adult and Pediatric Adverse Events Corrected Version 
2.1, July 2017. 
 
5.4 
Infant Enrollment 
 
Infants are prospectively selected for inclusion in MTN-042 when their mothers enroll in the 
study. Infants enter the study when they are born, without set inclusion or exclusion criteria. If 
an infant is deemed too ill to undergo study procedures, the IoR/designee may opt to omit 


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specific study procedures. Participant mothers will be strongly encouraged to complete one year 
of follow-up for their infants, but can decline further participation at any time.  
 
5.5 
Co-enrollment Guidelines 
 
As indicated in Sections 5.2 and 5.3, participants should not take part in other research studies 
involving drugs, medical devices, vaginal products or vaccines after the Screening Visit and 
while taking part in this study. Each site will be responsible for defining procedures for 
management and prevention of co-enrollment prior to initiation.  
 
Exceptions to this guideline may be made for participants to co-enroll in the following types of 
studies at the discretion of the IoR/designee: 
• 
Participants may take part in ancillary studies approved by the MTN-042 Protocol 
Chair.  
• 
Participants who acquire HIV may take part in observational and/or interventional 
studies for HIV-positive persons. 
• 
Participants may take part in observational studies, including pregnancy registries if 
available. 
 
Should any participant report or should study staff discover concurrent participation in any other 
study after enrolling in MTN-042, the IoR/designee will consult the PSRT regarding ongoing 
product use and other potential safety considerations associated with co-enrollment.  
 
 
6 
STUDY PRODUCT 
 
6.1 
Regimen 
 
Each participant will be randomized (2:1 in Cohorts 1 and 2 and 4:1 in Cohort 3) to one of two 
study products: a VR containing 25 mg of DPV to be inserted monthly or a Truvada oral tablet 
containing 200 mg FTC/300 mg TDF taken daily. Participants will use one of the two study 
products up to 41 6/7 weeks of gestation, i.e., for a maximum of approximately six (6) to thirty 
(30) weeks depending on their gestational age cohort and time to pregnancy outcome. Figure 4 
illustrates the increasing duration of study product exposure for later enrolled groups.  
 


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Figure 4: Expected Maximum Duration of Product Use by Study Cohort 
 
 
6.2 
Administration 
 
6.2.1 
DPV VR (25 mg)  
 
The participant will insert the study VR at the clinic monthly, and if needed, a study 
clinician/designee will check that the VR is properly placed. Study participants will be given 
detailed instructions in the clinic on proper VR insertion and removal procedures. Hands should 
be thoroughly washed before and after study VR insertion and/or removal. Additional details on 
the use of the DPV VR (VR insertion, removal, procedures in the event of expulsion or loss) will 
be provided in the MTN-042 SSP. 
 
6.2.2 
Truvada Tablet 
 
Study participants will be instructed to take one Truvada oral tablet daily for their assigned study 
period, and will take the first tablet at the clinic under direct observation. Truvada should be 
taken close to the same time each day. If a participant misses a dose, the missed dose should 
be taken as soon as possible, unless the next dose is estimated to be due within 6 hours. If the 
next dose is estimated to be due within 6 hours, the missed dose must be skipped. The next 
dose must be taken as originally scheduled. 
 
6.3 
Study Product Formulation 
 
6.3.1 
DPV VR (25 mg) 
 
The study VR is an off-white, flexible ring containing 25 mg of DPV dispersed in a platinum-
catalyzed-cured silicone matrix. The VR dimensions are as follows: 56 mm and 7.7 mm, outer 
diameter and cross-sectional diameter, respectively. The VR is designed to provide sustained 
release of drug over a minimum period of one month. DPV 0.3125% (w/w) is dispersed in a 
flexible, opaque, cured silicone VR delivery device. The DPV VR optimally should be stored in 
Expected Maximum Duration of Product Use
Cohort 1
36 0/7 - 41 6/7 weeks or pregnancy outcome
Cohort 2
30 0/7 - 41 6/7 weeks or pregnancy outcome
Cohort 3
12 0/7 - 41 6/7 weeks or pregnancy outcome


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the site pharmacy at 25°C (77°F). Excursions are permitted between 15°C and 30°C (59°F and 
86°F). 
   
6.3.2 
Truvada Tablet 
 
Truvada is a fixed dose combination oral tablet containing FTC and TDF. One Truvada tablet 
contains 200 mg FTC plus 300 mg of TDF. Truvada should be stored at 25°C (77°F). 
Excursions are permitted between 15°C and 30°C (59°F and 86°F). 
 
6.4 
Supply and Accountability 
 
6.4.1 
Supply 
 
DPV VR (25 mg) 
IPM (Silver Spring, MD, USA) will supply and oversee the manufacture of the study VRs and 
analyze/release the rings under Good Manufacturing Practices (GMP). 
 
Truvada Tablet 
Truvada tablets are supplied by Gilead Sciences, Inc. (Foster City, CA, USA). 
 
6.4.2 
Accountability 
 
Each CRS Pharmacist of Record (PoR) is required to maintain a complete record of all study 
products received and subsequently dispensed. All study products not dispensed must be 
returned to the MTN Pharmacist after the study is completed or terminated unless otherwise 
instructed by the MTN Pharmacist. The procedures to be followed are provided in the MTN-042 
Pharmacy Study Product Management Procedures Manual.   
 
All study product dispensed to a participant must be documented by the clinic staff when it is 
returned. This includes VR(s) brought back to the clinic by the participant and any VR removed 
at the clinic visit as well as any unused tablets. Any study products not returned must also be 
documented by the clinic. 
 
6.4.3 
Study Product Dispensing 
 
Study VRs and tablets are dispensed only to enrolled study participants or clinic staff on behalf 
of the participant, upon receipt of a written prescription from an authorized prescriber. An 
authorized prescriber includes the IoR or a licensed clinician directly responsible to the IoR as 
noted on the FDA Form 1572.  
 
Dispensing takes place on the day of enrollment and at each scheduled monthly follow-up visit 
until the participant’s pregnancy outcome is ascertained. The pharmacist will dispense one VR 
per month or one bottle of 30 tablets per month. 
 
During study product use, participants will receive a new VR or a supply of tablets monthly.  
Product will be dispensed in quantities sufficient to last until the next scheduled monthly study 
visit. In the event that additional study products between visits are needed, participants will be 
instructed to contact the study site. If the participant is unable to attend their next scheduled 
visit, it is up to the discretion of the IoR/designee to allow the provision of additional study 
product. The IoR/designee will document approval of this additional dispensation. 
 


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6.5 
Retrieval of Study Product 
 
Study participants will be instructed to return all study products (unused Truvada oral tablets or 
unused/used VR) to the clinic at each scheduled monthly study visit. Clinic staff should forward 
all unused study products to the site pharmacy. In the event that study products are not returned 
at the end of each study visit, site staff members will make every effort to encourage 
participants to return study product as soon as possible. If study product is not returned within 
the time frames outlined below for permanent discontinuations or temporary holds, the MTN-042 
PSRT must be notified. 
 
Table 1: Retrieval of Study Product 
Condition 
Timeframe for Retrieval 
Permanent discontinuation due to potential HIV infection 
or Grade 3 or higher renal or hepatic toxicity 
Within 24 hours 
Permanent discontinuation for any other reason or IoR 
discretion 
Within 5 working days 
Temporary hold for reasons with expected duration of at 
least 7 days 
 Within 7 working days  
 
Pregnancy outcome (e.g., delivery) 
Within 10 working days 
 
Participants will be instructed to return all study product (used or unused) prior to exiting the 
study. Specifically, for each participant, all VRs or oral tablets remaining in the participant’s 
possession should be retrieved at the Post-Pregnancy Outcome (PPO) visit. If the participant 
does not bring her study product to this visit, or if the participant delivers outside of a hospital or 
health center, study staff must arrange to retrieve the VR or oral tablets within 10 business days 
of her pregnancy outcome. 
 
6.6 
Concomitant Medications and Practices 
 
With the exception of those listed below as prohibited, enrolled participants may use 
concomitant medications during study participation. Throughout the course of the study, 
prescription medications, over-the-counter preparations, vitamins and nutritional supplements, 
and herbal preparations will be recorded as concomitant medications on a case report form 
(CRF) designated for that purpose. Intravaginal product use and practices will also be recorded. 
 
The use of vaginal products, including, spermicides, lubricants, contraceptive VRs, douches, 
vaginal medications, etc., is prohibited. Receptive sexual activity (including penile-vaginal 
intercourse, anal intercourse, receptive oral intercourse, finger stimulation) and inserting any 
non-study objects into the vagina (including tampons, pessaries, sex toys, female condoms, 
diaphragms, menstrual cups, cervical caps or any other vaginal barrier method, etc.), is 
permitted, except for 24 hours prior to clinic visits. 
 
6.7 
Prohibited Medications  
 
Concomitant use of medications for PEP and PrEP outside the context of study participation is 
prohibited (see Section 9.3 for product hold details). 
 


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6.8 
Condoms 
 
All participants will be offered condoms. The condoms will be made available in the clinic and 
will be dispensed by the clinic staff. 
 
 
7 
STUDY PROCEDURES 
 
An overview of the study visit and evaluations schedules are provided in Appendices I and II. 
Presented below is additional information on visit-specific study procedures. With approved 
SOPs and participant permission, appropriate components of some study visits may be 
completed off-site. Detailed instructions to guide and standardize operating procedures across 
sites as well as information regarding the study visit windows are provided in the MTN-042 SSP 
Manual available at http://www.mtnstopshiv.org/research/studies. 
 
Figure 5: Study Visit Schedule – Cohort 1 
 
 
Cohort 1
Enrollment Window
36 0/7 weeks of 
gestation – 37 6/7 
weeks of gestation
Infants enroll    
Mothers exit     
Screening
Enrollment
Every odd-numbered week after Enrollment (e.g., follow-up weeks 1, 3, 5) until pregnancy 
outcome (phone, home or clinic as needed per local standard of care)
Every even-numbered week after Enrollment (e.g., follow-up weeks 2, 4, 6) until pregnancy 
outcome
Post-pregnancy outcome (delivery hospital/facility or clinic)
1-week post-pregnancy outcome (phone, home or clinic as needed per local standard of care)
Approximately 6 weeks post-pregnancy outcome
Approximately 6 months post-delivery
Approximately 12 months post-delivery


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Figure 6: Study Visit Schedule – Cohort 2 
 
 
Figure 7: Study Visit Schedule – Cohort 3 
 
 
 
 
7.1 
Pre-Screening 
 
As part of participant outreach and recruitment strategies, study staff may pre-screen potential 
study participants either on-site or at off-site locations. Study staff will consult with their local 
IRBs/ECs regarding pre-screening potential pregnant participants. If deemed acceptable, during 
pre-screening interactions study staff may explain the study to potential participants and 
ascertain elements of presumptive eligibility, to be confirmed at clinic screening visits. A key 
Cohort 2
Enrollment Window
30 0/7 weeks of 
gestation – 35 6/7 
weeks of gestation
Infants enroll    
Mothers exit     
Screening
Enrollment
1-week (phone, home or clinic as needed per local standard of care)
2-week
3-week (phone, home or clinic as needed per local standard of care) 
4-week
Every odd-numbered week after 36th week of gestation (e.g., follow-up weeks 5, 7, 9) until 
pregnancy outcome (phone, home or clinic as needed per local standard of care)
Every even-numbered week including and after 36th week of gestation (e.g., follow-up weeks 
6, 8, 10) until pregnancy outcome
Post-pregnancy outcome visit (delivery hospital/facility or clinic)
1-week post-pregnancy outcome (phone, home or clinic as needed per local standard of care)
Approximately 6 weeks post-pregnancy outcome
Approximately 6 months post-delivery
Approximately 12 months post-delivery
Cohort 3
Enrollment Window
12 0/7 weeks of 
gestation – 29 6/7 
weeks of gestation
Infants enroll    
Mothers exit     
Screening
Enrollment
1-week (phone, home or clinic as needed per local standard of care)
2-week
3-week (phone, home or clinic as needed per local standard of care)
4-week and every 4 weeks until 36th week of gestation 
Every odd-numbered week after 36th week of gestation (e.g., follow-up weeks 19, 21, 23) 
until pregnancy outcome (phone, home or clinic as needed per local standard of care)
Every even-numbered week including and after 36th week of gestation (e.g., follow-up weeks 
20, 22, 24) until pregnancy outcome
Post-pregnancy outcome visit (delivery hospital/facility or clinic)
1-week post-pregnancy outcome (phone, home or clinic as needed per local standard of care)
Approximately 6 weeks post-pregnancy outcome
Approximately 6 months post-delivery
Approximately 12 months post-delivery


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element of presumptive eligibility, gestational age, will be confirmed by ultrasound conducted 
prior to enrollment for all Cohorts but no later than the potential participant’s 36th week of 
gestation for Cohort 1 or 28th week of gestation for Cohort 2. This may occur during pre-
screening as part of standard of care, especially for Cohorts 1 and 2. Process information (e.g., 
number of potential participants contacted, number presumptively eligible) may be recorded in 
the absence of written informed consent from potential participants, provided the information is 
collected in such a manner that it cannot be linked to potential participant identifiers. Whenever 
de-identified process information is recorded, it will be stored at the study site. At each site, 
procedures and documentation will comply with local IRB/EC requirements. Potential 
participants may be pre-screened for the currently enrolling group or for the subsequent group 
not yet open for enrollment, with attention to the participant’s gestational age and the screening 
window. Any participant who at any time expresses an interest in involving her current sexual 
partner and/or family members in discussions about study participation will be encouraged to 
bring them to the clinic, where a staff member can explain the study and answer any questions 
they may have. 
 
7.2 
Visit 1:  Screening Visit 
 
A Screening Visit may take place up to 35 days prior to the Enrollment Visit (Day 0). Multiple 
visits may be conducted to complete all required screening procedures, if necessary, including 
sonographic confirmation of gestational age. Potential participants will be instructed to bring 
antenatal records (e.g., antenatal care card) with them to the Screening Visit, if possible, to 
expedite the screening process. Participants will also provide permission for the study site to 
obtain copies of their antenatal records, including laboratory and ultrasound results, for review 
prior to final confirmation of eligibility. If required per local laws and regulations, signed record 
release forms will be obtained. For participants who do not meet the eligibility criteria, screening 
will be discontinued once ineligibility is determined.   
 
NOTE: Participants who fail their first screening attempt may be re-screened once.    
 
Table 2: Visit 1 – Screening Visit 
Visit 1 – Screening Visit 
Component 
Procedures 
Administrative and 
Regulatory 
• 
Obtain informed consent for screening and enrollment 
• 
Obtain signed medical records release and antenatal care 
provider information (if required per local laws/regulations)  
• 
Obtain planned location for delivery 
• 
Schedule ultrasound (if adequate records not available at 
Screening) 
• 
Assign a unique Participant Identification (PTID) Number 
• 
Assess eligibility 
• 
Collect demographic information 
• 
Collect locator information 
• 
Provide reimbursement  
• 
Schedule next visit* 
Behavioral/Counseling 
• 
HIV pre- and post-test counseling 
• 
HIV/STI risk reduction counseling 


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Visit 1 – Screening Visit 
Component 
Procedures 
Clinical 
• 
Review medical history and obstetric symptoms 
• 
Review available ultrasound results and antenatal care records 
• 
Review concomitant medications and vaginal products 
• 
Physical exam 
• 
Pelvic exam* 
• 
Obstetric abdominal exam 
• 
Calculate gestational age 
• 
Treat RTI/UTI/STIs* 
• 
Disclose available test results 
Laboratory 
Urine 
• 
Dipstick urinalysis (UA) (and/or culture**)  
Blood 
• 
HIV-1 testing 
• 
HBsAg  
• 
AST/ALT 
• 
Creatinine  
• 
Complete blood count (CBC) with platelets 
• 
Syphilis serology 
Pelvic 
• 
Nucleic acid amplification test (NAAT) for Neisseria 
gonorrhoeae (GC)/Chlamydia trachomatis (CT)/Trichomonas 
vaginalis (Trich) 
• 
Wet prep/potassium hydroxide (KOH) wet mount for 
candidiasis and/or BV* 
• 
Vaginal pH* 
Study Product/Supplies 
• 
Offer condoms 
* if indicated and/or per local standard of care 
 
** Per local standard of care 
 
7.3 
Visit 2:  Enrollment Visit (Day 0) 
 
The Enrollment Visit must be completed within 35 days of the Screening Visit.   
 
Table 3: Visit 2 – Enrollment Visit 
Visit 2 – Enrollment Visit 
Component 
Procedures 
Administrative and 
Regulatory 
• 
Re-assess and confirm eligibility 
• 
Review/confirm informed consent 
• 
Randomization 
• 
Review/update locator information 
• 
Provide reimbursement  
• 
Schedule next visit/contact* 
Behavioral/Counseling 
• 
Baseline behavioral assessment 
• 
Baseline product acceptability assessment (Cohorts 2-3 only) 
• 
HIV pre- and post-test counseling 
• 
HIV/STI risk reduction counseling 
• 
Protocol adherence counseling 


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Visit 2 – Enrollment Visit 
Component 
Procedures 
Clinical 
• 
Review/update medical history and obstetric symptoms 
• 
Review/update available ultrasound results and antenatal 
care records 
• 
Review/update concomitant medications and vaginal 
products 
• 
Targeted physical exam* 
• 
Pelvic exam 
• 
Obstetric abdominal exam 
• 
Confirm calculation of gestational age 
• 
Treat RTI/UTI/STIs* 
• 
Disclose available test results 
Laboratory 
 
Urine 
• 
Dipstick UA (and/or culture**)  
Blood 
• 
HIV-1 testing 
• 
Creatinine 
• 
AST/ALT 
• 
CBC with platelets 
• 
Syphilis serology* 
• 
Plasma archive 
• 
Dried blood spot (DBS) for baseline TFV-DP and FTC-TP 
drug levels 
Pelvic 
• 
NAAT for GC/CT/Trich* 
• 
Wet prep/KOH wet mount for candidiasis and/or BV* 
• 
Vaginal pH 
• 
Vaginal swab(s) for microbiota 
• 
Vaginal Gram stain 
• 
Vaginal swab(s) for biomarkers 
Study Product/Supplies 
• 
Provide study VR or study tablets 
• 
Insertion of study VR at the clinic (clinician to check VR 
placement if inserted by participant) (for DPV group) or DOD 
of first study tablet (for Truvada group) 
• 
Provide product use instructions 
• 
Offer condoms 
* if indicated and/or per local standard of care 
 
** Per local standard of care 
 
7.4 
Follow-up Visits/Contacts Prior to Pregnancy Outcome 
 
7.4.1 
Phone Contacts Prior to Pregnancy Outcome 
 
This phone contact (or visit, if needed per local standard of care) will occur 1 week (i.e., 
approximately 7 days) and 3 weeks (i.e., approximately 21 days) following enrollment for all 
participants. The 1-week phone contact can occur no earlier than 6 days before the target date 
and no later than 2 days following the target date. The 3-week phone contact can occur no 
earlier than 2 days before the target date and no later than 2 days following the target date. 
Beginning on their 36th week of gestation until pregnancy outcome, this phone contact (or visit, if 
needed) will also occur every odd-numbered week of study participation. These contacts can 
occur no earlier than 2 days before the target date and no later than 2 days following the target 


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date. This phone contact may not occur for Cohort 1 participants due to proximity of delivery. 
Participants contacted over the phone who show a need for counseling  and/or treatment for 
RTI/UTI/STIs can have these procedures conducted as part of an interim visit if scheduling 
allows. 
 
Table 4: Phone Contacts Prior to Pregnancy Outcome 
Phone Contacts Prior to Pregnancy Outcome 
Component 
Procedures 
Administrative and 
Regulatory 
• 
Review/update locator information 
• 
Review/update planned location for delivery 
• 
Provide reimbursement (sites to reference SOPs) 
• 
Schedule next visit/contact 
Behavioral/Counseling 
• 
Protocol adherence counseling* 
• 
HIV/STI risk reduction counseling* 
Clinical 
• 
Review/update medical history and obstetric symptoms 
• 
Review/update concomitant medications and vaginal products 
• 
Collect AEs 
• 
Treat RTI/UTI/STIs* 
• 
Disclose available test results 
* if indicated and/or per local standard of care 
 
7.4.2 
Bi-weekly Visits After 36th Week of Gestation 
 
This visit will occur for all participants every two weeks (i.e., approximately 14 days) following 
their 36th week (inclusive – the visit should occur in the 36th week) of gestation until pregnancy 
outcome This means that participants in Cohort 1 will have bi-weekly follow-up visits every two 
weeks (i.e., approximately 14 days) following their Enrollment Visit until pregnancy outcome. 
Beginning on their 36th week of gestation until pregnancy outcome, participants in Cohorts 2-3 
will have bi-weekly follow-up visits every even-numbered week of study participation. 
Participants in Cohorts 2-3 will also have a follow-up visit two and four weeks following their 
Enrollment Visit, but those will be called the 2-week and 4-week Visits (see Sections 7.4.3 and 
7.4.4). These visits can occur no earlier than 4 days before the target date and no later than 4 
days following the target date. Participants in the DPV VR group will be instructed to remove the 
VR if they believe they are going into labor and bring it with them to the PPO Visit. This follow-
up visit may not occur for all participants due to proximity of delivery (especially Cohort 1).  
 
Table 5: Bi-weekly Visits After 36th Week of Gestation 
Bi-weekly Visits After 36th Week (inclusive) of Gestation 
Component 
Procedures 
Administrative and 
Regulatory 
• 
Review/update locator information 
• 
Review/update planned location for delivery 
• 
Provide reimbursement  
• 
Schedule next visit/contact 
Behavioral/Counseling 
• 
HIV pre- and post-test counseling▲ 
• 
HIV/STI risk reduction counseling▲ 
• 
Protocol adherence counseling 
• 
Contraceptive counseling▲ 
• 
In-depth interview (subset) ♦ 


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Bi-weekly Visits After 36th Week (inclusive) of Gestation 
Component 
Procedures 
Clinical 
• 
Review/update medical history and obstetric symptoms 
• 
Review/update available ultrasound results and antenatal 
care records 
• 
Review/update concomitant medications and vaginal 
products 
• 
Targeted physical exam* 
• 
Pelvic exam* 
• 
Obstetric abdominal exam 
• 
Collect AEs 
• 
Treat RTI/UTI/STIs* 
• 
Disclose available test results 
Laboratory 
Urine 
• 
Dipstick UA (and/or culture**) *  
Blood 
• 
HIV-1 testing▲ 
• 
Creatinine (Cohort 1 only)▲ 
• 
Creatinine (Cohorts 2-3)* 
• 
AST/ALT* 
• 
CBC with platelets* 
• 
Syphilis serology* 
• 
DBS for TFV-DP and FTC-TP drug levels (Truvada group) 
• 
Plasma for DPV drug levels (DPV group) 
Pelvic 
• 
NAAT for GC/CT/Trich* 
• 
Wet prep/KOH wet mount for candidiasis and/or BV* 
• 
Vaginal pH*  
• 
Vaginal swab(s) for microbiota  
• 
Vaginal Gram stain  
• 
Vaginal swab(s) for biomarkers  
Study 
Product 
• 
Adherence assessment: Returned study VR * 
Study Product/Supplies 
• 
Remove and/or collect study VR or study tablets * 
• 
Provide study VR or study tablets * 
• 
Provide product use instructions * 
• 
Insertion of study VR at the clinic (clinician to check VR 
placement, as needed) (for DPV group) or DOD of first study 
tablet (for Truvada group)ⱽ 
• 
Offer condoms 
* if indicated and/or per local standard of care, ** Per local standard of care, ▲ Required at second Bi-weekly 
Visit and if indicated at all others, ⱽ Required if product resupply occurs during visit, ♦ May be scheduled any time 
between 1st Bi-weekly Visit and study exit to accommodate participant availability 
 


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7.4.3 
2-week Visit (Cohorts 2-3) 
 
This visit will occur 2 weeks (i.e., approximately 14 days) following enrollment for participants in 
Cohorts 2-3. This visit can occur no earlier than 4 days before the target date and no later than 
4 days following the target date. Participants in Cohort 1 will also have follow-up visits two 
weeks following their Enrollment Visit if they are still pregnant at that time, but those are called 
the Bi-weekly Visits After 36th Week of Gestation (see Section 7.4.2). 
 
Table 6: 2-week Visit (Cohorts 2-3) 
2-week Visit (Cohorts 2-3) 
Component 
Procedures 
Administrative and 
Regulatory 
• 
Review/update locator information 
• 
Provide reimbursement  
• 
Schedule next visit/contact 
Behavioral/Counseling 
• 
HIV pre- and post-test counseling* 
• 
HIV/STI risk reduction counseling* 
• 
Protocol adherence counseling 
Clinical 
• 
Review/update medical history and obstetric symptoms 
• 
Review/update concomitant medications and vaginal products 
• 
Targeted physical exam* 
• 
Pelvic exam* 
• 
Obstetric abdominal exam 
• 
Collect AEs 
• 
Treat RTI/UTI/STIs* 
• 
Disclose available test results 
Laboratory 
 
Urine 
• 
Dipstick UA (and/or culture**) *  
Blood 
• 
HIV-1 testing* 
• 
Creatinine* 
• 
AST/ALT* 
• 
CBC with platelets* 
• 
Syphilis serology* 
• 
DBS for TFV-DP and FTC-TP drug levels (for Truvada group) 
• 
Plasma for DPV drug levels (for DPV group) 
Pelvic 
• 
NAAT for GC/CT/Trich* 
• 
Wet prep/KOH wet mount for candidiasis and/or BV* 
• 
Vaginal pH* 
• 
Vaginal swab(s) for microbiota 
• 
Vaginal Gram stain 
• 
Vaginal swab(s) for biomarkers 
Study Product/Supplies 
• 
Offer condoms 
* if indicated and/or per local standard of care 
 
** Per local standard of care 
 
7.4.4 
4-week Visit(s) (Cohorts 2-3) 
 
This visit will occur 4 weeks (i.e., approximately 28 days) following enrollment for participant 
Cohorts 2-3. For Cohort 3, this visit will also occur every 4 weeks after their first 4-week Visit 
until their 36th week (inclusive – this visit should occur in the 36th week) of gestation. These visits 


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can occur no earlier than 4 days before the target date and no later than 4 days following the 
target date. Participants in Cohort 1 will also have follow-up visits four weeks following their 
Enrollment Visit if they are still pregnant at that time, but those are called the Bi-weekly Visits 
After 36th Week of Gestation (see Section 7.4.2). 
 
Table 7: 4-week Visit(s) (Cohorts 2-3) 
4-week Visit(s) (Cohorts 2-3) 
Component 
Procedures 
Administrative and 
Regulatory 
• 
Review/update locator information 
• 
Provide reimbursement  
• 
Schedule next visit/contact 
Behavioral/Counseling 
• 
Behavioral assessment ɸ  
• 
Product acceptability assessment ɸ  
• 
Social harms assessment ɸ  
• 
In-depth interview (IDI) (subset) ♦ 
• 
HIV pre- and post-test counseling 
• 
HIV/STI risk reduction counseling 
• 
Protocol adherence counseling 
Clinical 
• 
Review/update medical history and obstetric symptoms 
• 
Review/update available ultrasound results and antenatal 
care records 
• 
Review/update concomitant medications and vaginal 
products 
• 
Targeted physical exam 
• 
Pelvic exam* 
• 
Obstetric abdominal exam 
• 
Collect AEs 
• 
Treat RTI/UTI/STIs* 
• 
Disclose available test results 
Laboratory 
Urine 
• 
Dipstick UA (and/or culture**) ∇   
Blood 
• 
HIV-1 testing (or confirmation of testing) 
• 
Creatinine π 
• 
AST/ALT ∇ 
• 
CBC with platelets ∇ 
• 
Syphilis serology* 
• 
DBS for TFV-DP and FTC-TP drug levels (for Truvada group) 
• 
Plasma for DPV drug levels (for DPV group) 
Pelvic 
• 
NAAT for GC/CT/Trich* 
• 
Wet prep/KOH wet mount for candidiasis and/or BV* 
• 
Vaginal pH* 
• 
Vaginal swab(s) for microbiota 
• 
Vaginal Gram stain 
• 
Vaginal swab(s) for biomarkers 
Study 
Product 
• 
Adherence assessment: Returned study VR 


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4-week Visit(s) (Cohorts 2-3) 
Component 
Procedures 
Study Product/Supplies 
• 
Remove and/or collect study VR or study tablets  
• 
Provide study VR or study tablets 
• 
Provide product use instructions 
• 
Insertion of study VR at the clinic (clinician to check VR 
placement, as needed) (for DPV group) or DOD of first study 
tablet (for Truvada group) 
• 
Offer condoms 
* if indicated and/or per local standard of care, ** Per local standard of care, ♦ May be scheduled any time 
between 1st 4-week Visit and study exit to accommodate participant availability, ɸ Required at 1st 4-week Visit 
for Cohorts 2-3, and also at the 4-week visit corresponding to, or immediately before, the 36th week of gestation 
for Cohort 3, ∇ Required at 1st 4-week Visit for Cohorts 2-3, and also for Cohort 3 at the visit corresponding to, 
or immediately following, the 28th week of gestation, π Required at 1st 4-week Visit and every 12 weeks 
thereafter 
 
7.5 
Follow-up Visits After Pregnancy Outcome 
 
7.5.1 
Post-Pregnancy Outcome (PPO) Visit 
 
All participants will have a follow-up visit as soon after their pregnancy outcome as possible but 
no later than two weeks (i.e., 14 days) of their pregnancy outcome. If the PPO Visit is missed, a 
subset of these procedures will be made up as part of an interim visit as outlined in the MTN-
042 SSP Manual. 
 
Table 8: PPO Visit – Mothers 
PPO Visit – Mothers 
Component 
Procedures 
Administrative and 
Regulatory 
• 
Review/update locator information 
• 
Review/update signed medical records release and delivery 
care provider information (if required per local 
laws/regulations) 
• 
Obtain actual location of delivery 
• 
Provide reimbursement 
• 
Schedule next visit/contact* 
Behavioral/Counseling 
• 
Contraceptive counseling* 
• 
HIV pre- and post-test counseling* 
• 
HIV/STI risk reduction counseling* 
• 
Protocol adherence counseling 
• 
Behavioral assessment (Cohorts 2-3 only) 
Clinical 
• 
Review/update medical history and obstetric symptoms 
• 
Review/update available delivery and antenatal care records 
• 
Review/update concomitant medications and vaginal 
products 
• 
Targeted physical exam 
• 
Collect AEs 
• 
Treat RTI/UTI/STIs* 
• 
Disclose available test results 
Laboratory 
Urine 
• 
Dipstick UA (and/or culture**) *  


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PPO Visit – Mothers 
Component 
Procedures 
Blood 
• 
HIV-1 testing* 
• 
Creatinine* 
• 
AST/ALT*  
• 
CBC with platelets*  
• 
Syphilis serology* 
• 
DBS for TFV-DP and FTC-TP drug levels (for Truvada 
group) 
• 
Plasma for DPV drug levels (for DPV group) 
Pelvic 
• 
NAAT for GC/CT/Trich* 
• 
Wet prep/KOH wet mount for candidiasis and/or BV* 
Study 
Product 
• 
Adherence assessment: Returned study VR 
Study Product/Supplies 
• 
Remove and/or collect study VR or study tablets (if final VR 
or tablets not already collected) 
• 
Offer condoms 
* if indicated and/or per local standard of care 
 
** Per local standard of care 
 
Table 9: PPO Visit – Infants 
PPO Visit – Infants 
Component 
Procedures 
Administrative and 
Regulatory 
• 
Obtain consent for infant if not already obtained 
• 
Collect/review/update locator information 
• 
Provide reimbursement  
• 
Schedule next visit/contact* 
Clinical 
• 
Review infant health, anthropometry, feeding history 
• 
Review/update delivery records 
• 
Review/update infant health records 
• 
Review/update concomitant medications  
• 
Physical exam 
• 
Collect AEs 
• 
Disclose available test results 
Laboratory 
Blood 
• 
HIV-1 testing* 
• 
Creatinine 
• 
AST/ALT*  
• 
CBC with platelets*  
• 
DBS for TFV-DP and FTC-TP drug levels (for infants born to 
mothers in the Truvada group) 
• 
Plasma for DPV drug levels (for infants born to mothers in 
the DPV group) 
* if indicated and/or per local standard of care 
 
7.5.2 
1-week PPO Phone Contact 
 
This phone contact (or visit, if needed) will occur 1 week (i.e., approximately 7 days) following 
pregnancy outcome for all participants, and may be skipped if the PPO Visit occurs within the 
visit window for this phone contact. This visit can occur no earlier than 7 days before the target 


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date and no later than 7 days following the target date. All participants will be asked about the 
outcome of their pregnancy, including the status of their infant at the time of delivery. No infant 
procedures will occur during the phone contact unless the infant has already been enrolled. 
Participants who show a need for counseling and/or treatment for RTI/UTI/STIs can have these 
procedures conducted as part of an interim visit if scheduling allows. 
 
Table 10: 1-week PPO Phone Contact – Mothers 
1-week PPO Phone Contact – Mothers 
Component 
Procedures 
Administrative and 
Regulatory 
• 
Review/update locator information 
• 
Provide reimbursement (sites to reference SOPs) 
• 
Schedule next visit/contact 
Behavioral/Counseling 
• 
Protocol adherence counseling* 
• 
HIV/STI risk reduction counseling* 
Clinical 
• 
Review/update medical history and obstetric symptoms 
• 
Review/update concomitant medications and vaginal products 
• 
Collect AEs 
• 
Treat RTI/UTI/STIs* 
• 
Disclose available test results 
* if indicated and/or per local standard of care 
 
Table 11: 1-week PPO Phone Contact – Infants 
1-week PPO Phone Contact – Infants 
Component 
Procedures 
Administrative and 
Regulatory 
• 
Collect/review/update locator information 
• 
Provide reimbursement  
• 
Schedule next visit/contact 
Clinical 
• 
Review/update infant health, anthropometry, feeding history 
• 
Review/update concomitant medications 
• 
Collect AEs 
• 
Disclose available test results 
 
7.5.3 
6-week PPO/Study Exit Visit (SEV)/Early SEV 
 
All participants, including infants, will have follow-up visits six weeks (i.e., approximately 42 
days) following pregnancy outcome. This visit can occur no earlier than 13 days before the 
target date and no later than 13 days following the target date. This will be the Study Exit Visit 
(SEV) for all participant mothers. This set of visit procedures will also be performed as the Early 
SEV for participants who are withdrawn from the study for any reason, if they are willing to 
complete a final study visit. 
 
Table 12: 6-week PPO/SEV/Early SEV – Mothers 
6-week PPO/SEV/Early SEV – Mothers 
Component 
Procedures 
Administrative and 
Regulatory 
• 
Review/update locator information 
• 
Provide reimbursement 
• 
Schedule next visit/contact* 


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6-week PPO/SEV/Early SEV – Mothers 
Component 
Procedures 
Behavioral/Counseling 
• 
Behavioral assessment 
• 
Social harms assessment 
• 
Social benefits assessment 
• 
Contraceptive counseling 
• 
Protocol adherence counseling 
• 
HIV pre- and post-test counseling 
• 
HIV/STI risk reduction counseling 
Clinical 
• 
Review/update medical history and obstetric symptoms 
• 
Review/update available delivery and postpartum care 
records 
• 
Review/update concomitant medications and vaginal 
products 
• 
Targeted maternal physical exam* 
• 
Pelvic exam* 
• 
Collect AEs 
• 
Treat RTI/UTI/STIs* 
• 
Disclose available test results 
Laboratory  
Urine 
• 
Dipstick UA (and/or culture**) 
• 
Offer pregnancy testing 
Blood 
• 
HIV-1 testing 
• 
Creatinine 
• 
AST/ALT 
• 
CBC with platelets 
• 
Syphilis serology 
Pelvic 
• 
NAAT for GC/CT/Trich 
• 
Wet prep/KOH wet mount for candidiasis and/or BV* 
• 
Vaginal pH 
• 
Vaginal swab(s) for microbiota 
• 
Vaginal Gram stain 
• 
Vaginal swab(s) for biomarkers 
Study Product/Supplies 
• 
Offer condoms 
* if indicated and/or per local standard of care 
 
** Per local standard of care 
 


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Table 13: 6-week PPO Visit – Infants 
6-week PPO Visit – Infants 
Component 
Procedures 
Administrative and 
Regulatory 
• 
Collect/review/update locator information 
• 
Provide reimbursement  
• 
Schedule next visit/contact 
Clinical 
• 
Review/update infant health, anthropometry, feeding history 
• 
Review/update infant health records 
• 
Review/update concomitant medications 
• 
Targeted infant physical exam 
• 
Collect AEs 
• 
Disclose available test results 
Laboratory 
Blood 
• 
HIV-1 testing* 
• 
Creatinine 
• 
AST/ALT* 
• 
CBC with platelets* 
* if indicated and/or per local standard of care 
 
7.6 
Semi-annual PPO Visits/Early SEV for Infants 
 
All participants who deliver live births will bring their infant for a follow-up visit 6 months (i.e., 
approximately 26 weeks) and 12 months (i.e., approximately 52 weeks) following delivery. 
These visits can occur no earlier than 28 days before the target date and no later than 28 days 
following the target date. This set of visit procedures will also be performed as the Early SEV for 
infants who are withdrawn from the study for any reason, if their mothers are willing to bring 
them in for a final study visit. 
 
Table 14: Semi-annual PPO Visits/Early SEV 
Semi-annual PPO Visits/Early SEV for Infants 
Component 
Procedures 
Administrative and 
Regulatory 
• 
Review/update locator information 
• 
Provide reimbursement 
• 
Schedule next visit/contact (if indicated at Month 12) 
Clinical 
• 
Review/update infant health, anthropometry, feeding history 
• 
Review/update infant health records 
• 
Review/update concomitant medications 
• 
Targeted infant physical exam 
• 
Collect AEs 
• 
Disclose available test results 
Laboratory 
Blood 
• 
HIV-1 testing* 
• 
Creatinine* 
• 
AST/ALT* 
• 
CBC with platelets* 
Study Product/Supplies 
• 
Offer condoms to mother 
* if indicated and/or per local standard of care 
 


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7.7 
Follow-up Procedures for Participants Who Temporarily Hold or Permanently 
Discontinue Study Product 
 
Participants who permanently discontinue study product use due to an AE must continue to be 
followed until resolution or stabilization of the AE is documented.   
 
Guidance related to permanent discontinuation of study product, including additional information 
regarding consultation with the PSRT, is included in Section 9.   
 
7.7.1 
Participants Who Become Infected with HIV 
 
If a participant acquires HIV-1 after the Enrollment Visit, she will be referred to local care and 
treatment services that have capacity to provide ART services. Participants who acquire an HIV 
infection will continue in study follow-up with a modified study visit/procedure schedule for a 
minimum of twelve months. Protocol-specified procedures for MTN-042 will continue except the 
following: 
 
• 
HIV-1 testing 
• 
Provision of study VR or study tablets, provision of product use instructions, and 
retrieval and collection of study VR or study tablets 
• 
Collection of drug level and biomarker specimens  
• 
Behavioral and product acceptability assessments 
• 
Provision of HIV pre- and post-test, and product adherence counseling 
 
Upon documentation of the first positive rapid HIV test, the following procedures must be 
performed regardless of whether or not they are scheduled to be completed: 
 
• 
Plasma collection, CD4+ T cell count and HIV-1 RNA PCR  
• 
CBC with platelets 
• 
AST/ALT 
• 
Blood creatinine and calculation of creatinine clearance 
• 
Collection of drug level and biomarker specimens 
 
Upon confirmation of HIV infection per the algorithm in Appendix IV, the following procedures 
are performed on the mother at the following time points:  
 
• 
Plasma collection, CD4+ T cell count and HIV-1 RNA PCR will be performed at the 
clinic visit immediately following confirmation of an HIV-infection and every three 
months thereafter for a minimum of twelve months. (See MTN-042 SSP for other 
procedures to be completed during these quarterly visits.)  
• 
HIV-1 genotyping will be performed on the stored plasma closest to the time of HIV-1 
infection.   
• 
HIV-1 RNA PCR or HIV-1 genotyping may be performed at additional/alternate time 
points as requested by site IOR or at the discretion of the Laboratory Center (LC). 
 
Upon delivery of a live infant by an HIV-infected participant, or upon HIV seroconversion of a 
participant between the birth of her infant and her infant’s first birthday (whether found via study 
testing or report from external testing), the following procedures are performed on the infant if 
consented to by the participant: 
 


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• 
Infant HIV-1 testing will be performed at the PPO Visit or as soon as possible after 
delivery for infants born to HIV-positive participants. For infants whose mothers 
seroconverted after they were born, HIV-1 testing will be performed as soon as 
possible after discovery of the mother’s HIV-positive status. Infant HIV-1 testing 
(including confirmation of HIV infection) will be done per local standard of care and 
may occur at a scheduled visit or an interim visit. 
 
The following procedures are performed on HIV-positive infants if consented to by the 
participant: 
 
• 
Immediately following confirmation of HIV infection, perform plasma collection, CD4+ 
T cell count, HIV-1 RNA PCR test, and HIV-1 genotyping.   
• 
Facilitate rapid referral of the infant for appropriate further management including 
necessary blood tests, urgent ART initiation, and adherence counselling and follow 
up for the mother/guardian. 
• 
At all subsequent scheduled clinic visits until the infant is one year old, perform 
plasma collection, CD4+ T cell count and HIV-1 RNA PCR. HIV-1 RNA PCR or HIV-
1 genotyping may be performed at additional/alternate time points as requested by 
site IoR or at the discretion of the Laboratory Center (LC). 
 
HIV/STI risk reduction counseling will be modified to address primary and secondary prevention. 
 
7.7.2 
Participants Who Experience a Pregnancy Loss 
 
If a participant experiences a pregnancy loss after the Enrollment Visit, she will discontinue 
product use (as a scheduled end of use due to pregnancy outcome) and attend routine post-
pregnancy outcome visits with the following procedures performed at her next clinic visit: 
 
• 
CBC with platelets 
• 
AST/ALT 
• 
Blood creatinine and calculation of creatinine clearance 
• 
Collection of drug level and biomarker specimens 
7.7.3 
Participants Who Permanently Discontinue Study Product Use for Reasons 
other than Seroconversion or Loss of Pregnancy 
 
Participants who permanently discontinue study product use for any reason (clinician-initiated or 
self-initiated) other than seroconversion or loss of pregnancy will continue follow-up visits with a 
modified study visit/procedure schedule until their originally scheduled study exit date. Infants 
born to participants who are permanently discontinued from study product use will continue 
follow-up visits with their original study visit/procedure schedule until their originally scheduled 
study exit date. 
 
Upon documentation of the product discontinuation, the following procedures must be 
performed regardless of whether or not they are scheduled to be completed: 
 
• 
CBC with platelets 
• 
AST/ALT 
• 
Blood creatinine and calculation of creatinine clearance 
• 
Collection of drug level and biomarker specimens 


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For those participants who permanently discontinue study product use for reasons other than 
seroconversion or loss of pregnancy and who remain in MTN-042 follow-up, protocol-specified 
procedures for MTN-042 will continue except the following: 
 
• 
Provision of study VR or study tablets, provision of product use instructions, and 
retrieval and collection of study VR or study tablets 
• 
Collection of drug level and biomarker specimens  
• 
Behavioral and product acceptability assessments 
• 
Provision of product adherence counseling 
 
7.7.4 
Participants Who Temporarily Hold Study Product Use  
 
All protocol-specified study procedures will continue except the following: 
 
• 
Provision of study VR or tablet, product use instructions, and protocol adherence 
counseling.  
 
Drug level and biomarker specimens must be collected at the visit in which the study product is 
temporarily held, regardless of whether or not they were scheduled; however, they are to be 
discontinued at subsequent visits.   
 
The aforementioned protocol procedures are to be resumed at follow-up visits once study 
product use has been resumed. 
 
7.7.5 
Interim Visits 
 
Interim visits and telephone contacts may be performed at any time during the study, for the 
following or other reasons: 
 
• 
For administrative reasons, e.g., a participant may have questions for study staff, or 
may need to re-schedule a follow-up visit or to perform missed procedures. 
• 
For product-related reasons, including to provide participants with a replacement or 
additional VR or tablets. 
• 
In response to AEs and/or SAEs.  When interim contacts or visits are completed in 
response to participant reports of AEs and/or SAEs, study staff will assess the 
reported event clinically and provide or refer the participant to appropriate medical 
care (see Sections 8 and 9). 
• 
For interim STI counseling and testing in response to STI symptoms.  
• 
For interim HIV counseling and testing in response to participant report of symptoms 
consistent with acute infection or presumed exposure to HIV. 
• 
To provide participants with the results of confirmatory HIV test results, per the 
algorithm in Appendix IV. 
• 
To capture pregnancy outcome and/or infant health information (e.g., if a participant 
misses her PPO Visit). 
• 
For other reasons at participant request, e.g., to report a social harm. 
 
Given the specification of visit windows for this study, interim contacts and visits will occur when 
more than one visit takes place within an allowable visit window. All interim contacts and visits 
will be documented in participants’ study records and on CRFs, if applicable.  


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7.8 
Final Contact 
 
Since participant mothers’ final study visit includes laboratory testing for HIV and other 
conditions, additional contacts after this visit may be required to provide her additional study test 
results and post-test counseling, if needed. Since participant infants’ final study visit includes 
medical exams and may include laboratory testing, additional contacts after this visit may be 
required to provide these test results and for AE follow-up. Study sites may complete these 
contacts at the study clinic or at community-based locations, depending on site capacities and 
site and participant preferences. All final contacts will be documented in participant study 
records.   
 
7.9 
Behavioral Evaluations 
 
Behavioral endpoints will be assessed via CRFs.* A Baseline Behavioral Questionnaire will be 
administered in the clinic at the Enrollment Visit to all participants in Cohorts 1-3. All participants 
will be asked about the context of HIV prevention and study product use, while participants in 
Cohorts 2-3 will be asked more detailed questions about sexual behavior, HIV prevention 
method use and intravaginal practice history, and about their attitudes towards the attributes of 
the study product, their attitudes and perceptions about using the study product during 
pregnancy, and other preliminary acceptability measures of the study product. At their first 4-
week Visit, participants in Cohorts 2-3 will be asked to complete the Follow-up Behavioral 
Questionnaire which will include participant reports of their use of study product, coital 
frequency, HIV prevention method use and intravaginal practices, acceptability questions similar 
to those from the Enrollment Visit, and additional questions about their experiences using the 
study product, including reasons for non-use, if applicable, willingness to use in the future, 
beliefs around use of vaginal products and/or oral medications during pregnancy, and any 
perceived effect on the fetus/infant. Participants in Cohort 3 will also complete the Follow-up 
Behavioral Questionnaire at the 4-week Visit corresponding with their 36th week of gestation. 
Participants in Cohorts 2-3 will complete a brief Post-PPO Behavioral Questionnaire at their 
PPO Visit and all participants will complete a Behavioral Questionnaire at their SEV, which may 
include follow-up questions about the context of study product use. 
 
IDIs will also be conducted with a subset of all participants in Cohort 1 at the Bi-weekly Visit(s) 
after the 36th week of gestation (these may be scheduled any time between the first bi-weekly 
visit and study exit to accommodate participant availability), and with a subset of all participants 
in Cohorts 2-3 at the 4-week Visit (these may be scheduled any time between the first 4-week 
Visit and study exit to accommodate participant availability). All IDIs will be conducted by trained 
and experienced facilitators to gain further insight on the social and behavioral issues described 
above.* Additional IDIs may be conducted at undetermined time points during study follow-up 
with a subset of participants representing unexpected and/or interesting examples of 
experiences and behaviors relevant to the study endpoints. Interviews will be audio-recorded. 
Depending on participant availability and visit length, it may be necessary to conduct these IDIs 
as a separate visit. 
 
* At Enrollment (for new participants) or at their next scheduled study visit (for already enrolled 
participants) and at one or more timepoints during the study, additional questions may be asked 
related to COVID-19’s potential influence on the context of participants’ HIV prevention and 
study product use, in order to explore the impact of the pandemic on study product adherence 
and acceptability. 
 


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7.10 
Counseling 
 
HIV testing and risk reduction counseling will be provided to all participants upon study 
screening. Protocol adherence counseling, including product use adherence counseling during 
the product use period, will be provided to all participants upon enrollment into the study. 
Contraception counseling will be provided to all participants at specific study visits prior to and 
after their pregnancy outcome. Counseling will be provided in accordance with standard 
methods using a participant-centered approach to frame discussions around their experiences 
with the study and the prevention products. Counseling sessions may be audio-recorded to 
ensure the quality and consistency of the counseling across study sites, and to allow the 
counseling session content to be analyzed to understand participant experiences and concerns 
about study participation. Cognitive behavioral and motivational strategies will be incorporated 
into the counseling sessions as desired by participants to address adherence barriers. Lastly, 
sites may offer additional support strategies (e.g., text messages, phone calls, peer support 
groups) for participants to complement their protocol adherence counseling. 
 
Participants will be monitored for symptoms of depression throughout their participation in the 
study. A validated depression scale designed for use with pregnant and postpartum women will 
be administered in the antenatal period and in the postpartum period. Participants will be 
referred to additional counseling and/or mental health services if clinically indicated. 
 
7.11 
Clinical Evaluations and Procedures 
 
Physical exams will include the following assessments: 
• 
Vital signs 
o Temperature 
o Pulse  
o Blood pressure 
o Respirations 
• 
General appearance 
• 
Weight  
• 
Abdomen* 
• 
Head, eye, ear, nose and throat (HEENT)*  
• 
Height* 
• 
Lymph nodes*  
• 
Neck*  
• 
Heart* 
• 
Lungs*  
• 
Extremities* 
• 
Skin*  
• 
Neurological* 
 
*May be omitted after the Screening Visit. 
 
Obstetric abdominal exams will include the following assessments: 
• 
Appearance 
• 
Palpation of abdomen 
• 
Fundal height 


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• 
Auscultation of fetal heart tones (by Doppler, fetoscope or ultrasound), including rate 
per minute (not measured if fetus already known to be deceased but has not yet 
been delivered) 
 
If a problem with the pregnancy is suspected, an ultrasound can be ordered, or a referral will be 
provided. 
 
Once born, clinical evaluation of infants will include the following assessments (including 
assessment for and documentation of any anomalies, and photograph[s] of the infant if 
permitted by the mother/guardian): 
• 
Vital signs 
o Temperature 
o Pulse  
o Blood pressure (if indicated) 
o Respirations 
o Oxygen saturation (if indicated at sites with capacity) 
• 
General appearance 
• 
Weight 
• 
Length 
• 
Head circumference 
• 
Anterior fontanel closure/posterior fontanel closure 
• 
Heart 
• 
Lungs 
• 
Abdomen* 
• 
Head, eye, ear, nose and throat (HEENT)*  
• 
Lymph nodes*  
• 
Neck*  
• 
Extremities* 
• 
Skin*  
• 
Neurological* 
• 
Ages and stages assessment (at 6- and 12-month visits only) 
 
*May be omitted after the PPO Visit. 
 
Pelvic examination and specimen collection 
Pelvic examinations will be conducted per guidelines for naked eye inspection described in the 
WHO/CONRAD Manual for Standardization of Colposcopy for the Evaluation of Vaginal 
Products, 
Update 
2004, 
available 
at 
https://apps.who.int/iris/bitstream/handle/10665/69748/WHO_RHR_04.02_eng.pdf. 
 
Additional clinical assessments may be performed at the discretion of the examining clinician in 
response to symptoms or illnesses present at the time of the exam. Speculum exams will be 
required at the Enrollment Visit; at all other visits they will be performed only as indicated (e.g., 
abnormal discharge, pain) per the local standard of care. 
 
The required sequence of procedures and specimen collection performed during pelvic exams 
will be specified in the MTN-042 SSP Manual. 
 


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7.12 
Laboratory Evaluations 
 
Local Laboratory 
• 
Urine 
o Dipstick UA and/or culture 
o Pregnancy testing 
• 
Blood 
o Plasma archive and storage (kept at site until notified by MTN LC) 
o Syphilis serology 
o HIV-1 testing 
o CD4+ T cell count 
o HIV-1 RNA PCR  
o CBC with platelets 
o AST/ALT 
o Creatinine and calculation of creatinine clearance 
 
Weight will be captured each time creatinine is measured in all 
participants in order to calculate creatinine clearance 
o HbsAg  
• 
Pelvic  
o NAAT for GC/CT/Trich* 
o Vaginal pH 
o Wet prep/KOH wet mount for candidiasis and/or BV 
 
*In the event of laboratory supply issues, the MTN Laboratory Center can approve an alternate 
methodology  to be used as backup. 
 
Laboratory Center 
• 
Blood 
o TFV-DP and FTC-TP concentrations in maternal and infant blood 
o DPV concentrations in maternal and infant plasma 
o HIV-1 confirmatory testing as needed (see Appendix IV) 
o HIV-1 drug resistance  
o COVID-19 infection testing 
 
Testing related to COVID-19 infection would only be performed 
retrospectively on stored plasma samples if such testing is available 
and deemed necessary to better understand the impact of COVID-19 
infection on the study safety endpoints. 
• 
Pelvic  
o Vaginal Gram stain 
o Vaginal swabs for microbiota 
o Vaginal swabs for biomarkers 
 
Designated Laboratory: 
• 
VR for residual DPV levels 
 
Infant blood draw volume amounts planned for this study fall within the limits recommended by 
the U.S. National Institutes of Health (NIH) Guidelines for Limits on Blood Drawn for Research 
Purposes for pediatric patients: ≤ 5 mL/kg in a single day and ≤ 9.5 mL/kg over any eight-week 
period.90 The maximum amount required to be drawn for research purposes from infants in the 
Truvada arm is 6 mL over 12 months of study participation (with ≤ 4 mL in a single day and ≤ 6 


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mL in any given eight-week period). The maximum amount required to be drawn for research 
purposes from infants in the DPV VR arm is 6 mL over 12 months of study participation (with ≤ 4 
mL in a single day and ≤ 6 mL in any given eight-week period). See Table 15 below for a 
summary of infant blood volumes to be drawn for research purposes by clinic visit and by study 
arm. Additional blood may be drawn if clinically indicated, including: HIV testing (3-4 mL); 
creatinine, AST and ALT (1-2 mL); and CBC (1 mL). In instances of clinical need, it is the 
responsibility of the infant’s attending physician to determine if phlebotomy in excess of the 
stated limits may be permitted, particularly for patients with significant anemia or compromised 
cardiac output. 
 
Table 15. Protocol-required Infant Blood Draw Volumes by Study Arm and by Clinic Visit 
Clinic Visit 
Truvada Group 
DPV VR Group 
PPO Visit 
4 mL 
4 mL 
6-week PPO Visit 
2 mL 
2 mL 
6-month PPO Visit 
0 mL 
0 mL 
12-month PPO Visit 
0 mL 
0 mL 
TOTAL 
6 mL 
6 mL 
 
Once all required study analyses of collected specimens are complete, any remaining samples 
may be shipped to the MTN LC for use in study-related quality assurance and quality control 
testing. If study samples will be used for assay validation or proficiency testing that is not study 
related, all participant identifiers will be removed from the samples prior to use. Specimens 
obtained from participants who do not consent to long term storage will not be used for assay 
validation or proficiency testing purposes. 
 
7.13 
Calculation of Gestational Age 
 
The best obstetric estimate should be used as the measure for gestational age, rather than 
estimates based on the LMP alone. Per site SOPs and as needed to confirm gestational age of 
potential participants, ultrasound measurement of the fetus will be conducted prior to enrollment 
but no later than the 36th week of gestation for Cohort 1 or the 28th week of gestation for Cohorts 
2 and 3. Gestational age confirmation by ultrasound may occur between the Screening and 
Enrollment Visits if available medical and/or antenatal care records do not contain this 
evaluation. 
 
Ultrasound measurement of the fetus in the first trimester (up to and including 13 6/7 weeks of 
gestation) is the most accurate method to establish or confirm gestational age. Gestational age 
assessment based on measurement of the crown–rump length (CRL) has an accuracy of ±5–7 
days in the first trimester. However, it may not be possible to ensure that participants have a 
first-trimester ultrasound, particularly for Cohorts 1 and 2, given these are not routinely 
performed in the study countries. The range of second-trimester gestational ages (14 0/7 weeks 
to 27 6/7 weeks of gestation) introduces greater variability and complexity, which can affect 
revision of LMP dating and assignment of a final estimated delivery date (EDD). Table 16 
includes guidelines for redating based on ultrasonography.  
 


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Table 16. Guidelines for Redating based on Ultrasonography 
Gestational Age Range 
Discrepancy between Ultrasound Dating and 
LMP that Supports Redating 
≤ 8 6/7 weeks 
More than 5 days 
9 0/7 weeks to 15 6/7 weeks 
More than 7 days 
16 0/7 weeks to 21 6/7 weeks 
More than 10 days 
22 0/7 weeks to 27 6/7 weeks 
More than 14 days 
28 0/7 weeks and beyond 
More than 21 days 
 
If the estimated gestational age by the participant’s LMP differs from the ultrasound estimate by 
more than these accepted variations, the ultrasound estimate of gestational age should be used 
instead of the participant's LMP estimate.  
 
7.14 
Specimen Management 
 
Each study site will adhere to the standards of good clinical laboratory practice in accordance 
with 
DAIDS 
Laboratory 
Policy 
(https://www.niaid.nih.gov/sites/default/files/laboratorypolicy1.pdf), 
MTN-042 
SSP 
Manual 
(http://www.mtnstopshiv.org/research/studies) and site SOPs for proper collection, processing, 
labeling, transport, and storage of specimens to standardize procedures. Specimen collection, 
testing, and storage at the site laboratories will be documented when applicable using the 
Laboratory Data Management System (LDMS). In cases where laboratory results are not 
available due to administrative or laboratory error, sites are permitted to re-draw specimens. 
Further, as part of quality control, researchers may need to look at short pieces of non-coding 
repetitive deoxyribonucleic acid (DNA) sequence (3-7 base pairs) from blood in the event of 
sample mix-up. This test will only let researchers know the number of times this short segment 
is repeated and not specific genes or specific sequences of base pairs. This sequence element 
does not contain any information about genes, therefore researchers will not be able to identify 
if participants are predisposed to specific diseases or any other genetic information based on 
this information. This test will be an important tool for distinguishing whether two samples 
collected at the same or different time points are likely from the same person. The test will only 
be used as part of a sample investigation with the knowledge of the site in situations where a 
known or suspected sample mix-up has occurred. No genetic testing (limited or genome-wide) 
is planned on leftover samples that are stored for the purposes of future research. 
 
7.15 
DAIDS Laboratory Oversight 
 
All laboratories participating in DAIDS Sponsored and/or Funded Laboratories in Clinical Trials 
will 
adhere 
to 
the 
DAIDS 
Laboratory 
Policy 
(https://www.niaid.nih.gov/sites/default/files/laboratorypolicy1.pdf). 
 
7.16 
Biohazard Containment 
 
As the transmission of HIV and other blood-borne pathogens can occur through contact with 
contaminated needles, blood, and blood products, appropriate blood and secretion precautions 
will be employed by all personnel in the drawing of blood and shipping and handling of all 
specimens for this study as recommended by the U.S. Centers for Disease Control and 
Prevention (CDC) and National Institutes of Health (NIH). All biological specimens will be 
transported using packaging mandated by US Code of Federal Regulations (CFR) 42 Part 72. 
All dangerous goods materials, including diagnostic specimens and infectious substances, must 
be transported according to instructions detailed in the International Air Transport Association 


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(IATA) Dangerous Goods Regulations. Biohazard waste will be contained according to 
institutional, transportation/carrier, and all other applicable regulations.   
 
 
8 
ASSESSMENT OF SAFETY 
 
8.1 
Safety Monitoring 
 
Site IoRs/designees are responsible for continuous close safety monitoring of all study 
participants, and for alerting the PSRT if unexpected concerns arise. A sub-group of the 
Protocol Team, including the Protocol Chair(s), DAIDS MO, NICHD MO, Protocol Safety 
Physician(s), IPM Representative, and Gilead Representative will serve as the PSRT. The MTN 
Statistical Data and Management Center (SDMC) prepares routine AE and clinical data reports 
for review by the PSRT, which meets via conference call approximately once per month or as 
needed throughout the period of study implementation to review safety data, discuss product 
use management, and address any potential safety concerns.  
 
8.2 
Clinical Data Safety Review 
 
A multi-tiered safety review process will be followed for the duration of this study. The study site 
investigators are the first layer of this tiered system and are responsible for the initial evaluation 
and reporting of safety information at the participant level, and for alerting the PSRT if 
unexpected concerns arise.   
 
Participant safety is also monitored at the Network level through a series of routine reviews 
conducted by the SDMC staff, the PSRT, and study sponsor.   
 
During the study, the PSRT will review safety reports and conduct calls to review the data once 
a month. The content and format of the monthly safety reports will be agreed upon by the PSRT 
and the SDMC in advance of study implementation. In addition to these routine safety data 
reviews, the PSRT will convene on an ad hoc basis to make decisions regarding the handling of 
any significant safety concerns. If necessary, experts external to the MTN with expertise in the 
fields of microbicides, biostatistics, or medical ethics may be invited to join the PSRT safety 
review.   
 
The PSRT and an Interim Review Panel (IRP) will be charged with reviewing participant safety 
data as no DSMB is planned for this study. See Section 10.7 for additional details.   
 
8.3 
Adverse Events Definitions and Reporting Requirements 
 
8.3.1 
Adverse Events  
 
An AE is defined as any untoward medical occurrence in a clinical research participant 
administered an investigational product and which does not necessarily have a causal 
relationship with the investigational product. As such, an AE can be an unfavorable or 
unintended sign (including an abnormal laboratory finding, for example), symptom or disease 
temporally associated with the use of an investigational product, whether or not considered 
related to the product. This definition is applied to all study participants at the time of enrollment. 
This definition is applied to all study groups, and is applied beginning at the time of enrollment 


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(i.e., once a participant is randomized). The term “investigational products” for this study refers 
to the DPV VR and Truvada oral tablet. 
 
Study participants will be provided instructions for contacting the study site to report any 
untoward medical occurrences they may experience. In cases of potentially life-threatening 
events, participants will be instructed to seek immediate emergency care. Where feasible and 
medically appropriate, participants will be encouraged to seek evaluation where a study clinician 
is based, and to request that the clinician be contacted upon their arrival. With appropriate 
permission of the participant, whenever possible, records from all non-study medical providers 
related to untoward medical occurrences will be obtained and required data elements will be 
recorded on study CRFs. All participants reporting an untoward medical occurrence will be 
followed clinically until the occurrence resolves (returns to baseline) or stabilizes. 
 
Study site staff will document in source documents and in the study database all AEs reported 
by or observed in enrolled study participants, regardless of severity and presumed relationship 
to study product. Study staff will also report on CRFs all SAEs for infants (first year of life) born 
from pregnancies followed during MTN-042 participation.  
 
AE severity and laboratory tests will be graded per the DAIDS Table for Grading the Severity of 
Adult and Pediatric Adverse Events, Corrected Version 2.1, July 2017 and Addendum 1, 
(Female Genital Grading Table for Use in Microbicide Studies; dated November 2007). In cases 
where a genital AE is covered in both tables, the Female Genital Grading Table for Use in 
Microbicide Studies will be the grading scale utilized.  
 
The following will not be reportable as AEs: 
• 
Asymptomatic BV and asymptomatic candida. 
• 
Bleeding at the time of speculum insertion/removal or cervicovaginal specimen collection 
that is judged by the clinician to be within the range normally anticipated for that 
procedure; however, bleeding of greater quantity or longer duration than typical will still 
be reported.  
• 
Uterine cramping that is judged by the clinician to be within the range normally 
anticipated post-delivery. 
• 
Perineal pain that is judged by the clinician to be within the range normally anticipated 
post-delivery. 
• 
Lower extremity edema that is judged by the clinician to be within the range normally 
anticipated during pregnancy. 
• 
Decreased fetal movement; however, AEs identified in the course of clinical evaluation 
of decreased fetal movement will be captured.  
• 
Findings on electronic fetal monitoring strips.  
• 
Fetal losses (e.g., spontaneous abortions, spontaneous fetal deaths, stillbirths).  
o However, untoward maternal conditions that either result in or result from fetal 
losses will be reported as AEs.  
o All fetal losses will be reported by sites on pregnancy outcome CRFs to the 
SDMC and will be considered during safety reviews conducted by the SDMC, the 
DAIDS MO, the NICHD MO, PSRT, and IRP. 
• 
Physiologic discharge associated with pregnancy. 
• 
Lochia during the postpartum period. 
• 
Vaginal bleeding that is judged by the clinician to be within the range normally 
anticipated in the postnatal period. 
• 
HIV acquisition 


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o All instances of HIV acquisition will be reported by sites on HIV Confirmatory 
Results CRFs to the SDMC and will be considered during safety reviews 
conducted by the SDMC, the DAIDS MO, the NICHD MO, PSRT, and IRP. 
 
Protocol-specific grading scales will be used for the following AEs: 
• 
Bleeding during pregnancy, prior to the onset of labor 
o Grade 0: None 
o Grade 1: Spotting or bleeding less than menses 
o Grade 2: Bleeding like menses or heavier, no intervention indicated 
o Grade 3: Profuse bleeding with dizziness or orthostatic hypotension, transfusion 
indicated 
o Grade 4: Potentially life-threatening profuse bleeding and/or shock 
 
• 
Hypertensive disorders of pregnancy 
o Grade 0: None 
o Grade 1: Pregnancy-induced hypertension 
o Grade 2: Mild preeclampsia 
o Grade 3: Severe preeclampsia 
o Grade 4: HELLP (hemolysis, elevated liver enzymes, low platelet count) 
syndrome, eclampsia, or life-threatening sequelae of preeclampsia (e.g., 
pulmonary edema) 
 
• 
Gestational diabetes 
o Grade 0: None 
o Grade 1: Diet-controlled, no or minimal interference with usual social and 
functional activities 
o Grade 2: Medication prescribed 
o Grade 3: Evidence of adverse effects on pregnancy secondary to diabetes 
o Grade 4: N/A 
 
• 
Chorioamnionitis 
o Grade 0: None 
o Grade 1: Fever of 100.4°F -100.9°F with more than one of the following: FHR > 
160 BPM, maternal HR > 120, uterine tenderness between contractions, purulent 
AF, or preterm labor 
o Grade 2: Grade 1 plus fever of 101°F -104°F 
o Grade 3: Grade 2 plus fetal distress or fever > 104°F 
o Grade 4: Grade 3 plus fetal demise or maternal symptoms of shock 
 
• 
Puerperal sepsis and endometritis 
o Grade 0: None 
o Grade 1: Low grade fever and uterine tenderness, resolved with oral antibiotics 
o Grade 2: Moderate symptoms, treated by ≤ 3 days of parenteral antibiotics 
o Grade 3: Severe symptoms treated with > 3 days of IV antibiotics or addition of 
heparin 
o Grade 4: Severe infection or infection for which operative intervention is indicated 
 
• 
Postpartum hemorrhage 
o Grade 0: Estimated blood loss (EBL) < 500 mL for vaginal delivery or < 1000 mL 
after caesarian section (CS) or reported as normal 


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o Grade 1: EBL 500-1000 mL for vaginal delivery or 1000-1500 mL for CS or 
reported as slightly increased 
o Grade 2: EBL > 1000 mL or vaginal delivery or > 1500 mL for CS, with or without 
mild dizziness, no transfusion required 
o Grade 3: Hemorrhage at a level for which transfusion of 1-2 units of packed cells, 
but no other blood products indicated 
o Grade 4: Hemorrhage with shock or coagulopathy, for which transfusion of > 2 
units of packed cells or any amount of other blood components is indicated 
 
• 
Preterm PROM 
o Grade 0: None 
o Grade 1: N/A 
o Grade 2: Preterm rupture with hospitalization but not resulting in delivery at less 
than 37 weeks’ gestation 
o Grade 3: Delivery at 33-36 weeks’ gestation or 1501-2500 grams birth weight 
o Grade 4: Delivery < 33 weeks’ gestation or ≤ 1500 grams birth weight 
 
• 
Axillary measured fever 
o Grade 0: None 
o Grade 1: 99.3°F to <100.4°F (37.4°C to <38°C) 
o Grade 2: 100.4°F to <101.7°F (38°C to <38.7°C) 
o Grade 3: 101.7°F to <102.9°F (38.7°C to <39.4°C) 
o Grade 4: ≥102.9°F (≥39.4°C) 
 
• 
Creatinine (neonates 0-28 days old) 
o Grade 0: None 
o Grade 1: 1.1 mg/dL to <1.6 mg/dL 
o Grade 2: 1.6 mg/dL to <2.1 mg/dL 
o Grade 3: 2.1 mg/dL to 3.0 mg/dL 
o Grade 4: >3.0 mg/dL 
 
• 
Creatinine (infants >28 days old) 
o Grade 0: None 
o Grade 1: 0.5 mg/dL to <0.7 mg/dL 
o Grade 2: 0.7 mg/dL to <0.9 mg/dL 
o Grade 3: 0.9 mg/dL to 1.2 mg/dL 
o Grade 4: >1.2 mg/dL 
 
For any serious or expedited adverse events (EAEs) that are continuing at a participant’s study 
exit visit, the IoR/designee must establish a clinically appropriate follow-up plan for the AE. At a 
minimum, the SAE or EAE must be re-assessed by study staff 30 days after the participant’s 
study exit visit; additional evaluations also may take place at the discretion of the IoR/designee. 
The same approach must be taken for any AEs that are found to have increased in severity at 
the study exit visit, or any new ≥ Grade 3 AEs uncovered at the last visit. For those AEs 
requiring re-assessment, if the AE has not resolved or stabilized at the time of re-assessment, 
study staff will continue to re-assess the participant at least once per month while the study is 
ongoing. After the study has ended, all AEs requiring re-assessment will be re-assessed at least 
once within the 30-60 days after the study end date. The PSRT may advise study staff as to 
whether any additional follow-up may be indicated on a case by case basis. For AEs that are re-
assessed after study exit, information on the status of the AE at the time of re-assessment will 


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be recorded in source documents only — no updates should be made to AE Log CRFs based 
on the re-assessments.  
 
8.3.2 
Serious Adverse Events  
 
SAEs will be defined by the Manual for Expedited Reporting of Adverse Events to DAIDS 
(Version 2.0, January 2010) as AEs occurring at any dose that:  
 
• 
Result in death 
• 
Are life-threatening  
• 
Require inpatient hospitalization or prolongation of existing hospitalization 
• 
Result in persistent or significant disability/incapacity  
• 
Are congenital anomalies/birth defects 
• 
Are important medical events that may not result in death, be immediately life-
threatening, or require hospitalization but may jeopardize the participant or require 
intervention to prevent one of the outcomes listed in the definition above 
 
8.3.3 
Adverse Event Relationship to Study Product 
 
Relatedness is an assessment made by a study clinician of whether or not the event is related 
to the study agent. Degrees of relatedness will be categorized according to current DAIDS-
approved guidelines. Per the Manual for Expedited Reporting of Adverse Events to DAIDS 
(Version 2.0, January 2010), the relationship categories that will be used for this study are: 
 
• 
Related: There is a reasonable possibility that the AE may be related to the study agent 
• 
Not Related: There is not a reasonable possibility that the AE is related to the study 
agent 
 
8.4 
Expedited Adverse Event Reporting Requirements 
 
8.4.1 
Adverse Event Reporting to DAIDS 
 
Requirements, definitions and methods for expedited reporting of AEs are outlined in Version 
2.0 of the DAIDS EAE Manual, which is available on the Regulatory Support Center (RSC) 
website at https://rsc.niaid.nih.gov/clinical-research-sites/manual-expedited-reporting-adverse-
events-daids. For each study participant, EAE reporting will be undertaken throughout the 
scheduled duration of follow-up, i.e., from the time of Enrollment through study termination.   
 
The DAIDS Adverse Experience Reporting System (DAERS), an internet-based reporting 
system, must be used for EAE reporting to DAIDS. In the event of system outages or technical 
difficulties, EAEs may be submitted via the DAIDS EAE Form. For questions about 
DAERS, please contact the National Institute of Allergy and Infectious Diseases (NIAID) Clinical 
Research Management System (CRMS) Support at CRMSSupport@niaid.nih.gov. Site queries 
may also be sent from within the DAERS application itself. 
 
The DAIDS EAE Form is available on the RSC website, https://rsc.niaid.nih.gov/clinical-
research-sites/paper-eae-reporting.  
 
For questions about EAE reporting, please contact the RSC (DAIDSRSCSafetyOffice@tech-
res.com). 


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8.4.2 
Reporting Requirements for this Study 
 
The SAE Reporting Category, as defined in Version 2.0 of the DAIDS EAE Manual, will be used 
for this study. The study agents requiring expedited reporting are the dapivirine vaginal ring 
(DPV VR) and Truvada oral tablet.  
 
8.4.3 
Grading Severity of Events 
 
The grading of severity of events and the reporting period will be the same as for all AEs, as 
described in Section 8.3.1. The DAIDS Table for Grading the Severity of Adult and Pediatric 
Adverse Events, Corrected Version 2.1, July 2017 and the Female Genital Grading Table for 
Use in Microbicide Studies (Addendum 1, dated November 2007), will be used and is available 
on the RSC website at https://rsc.niaid.nih.gov/clinical-research-sites/daids-adverse-event-
grading-tables. 
 
8.4.4 
Expedited AE Reporting Period 
 
The EAE reporting period for this study begins once the participant is enrolled and continues up 
through the participant’s final study visit. After the protocol-defined AE reporting period, unless 
otherwise noted, only suspected, unexpected serious adverse reactions (SUSARs) as defined in 
Version 2.0 of the EAE Manual will be reported to DAIDS if the study staff become aware of the 
events on a passive basis (from publicly available information). 
 
8.5 
Social Harms Reporting 
 
Although study sites will make every effort to protect participant privacy and confidentiality, it is 
possible that participants’ involvement in the study could become known to others and that 
social harms – non-medical adverse consequences – may result. For example, participants 
could be treated unfairly, or could have problems being accepted by their families, partners 
and/or communities. Social harms that are judged by the IoR/designee to be serious or 
unexpected will be reported to the PSRT and responsible site IRBs/ECs according to their 
individual requirements beginning at the time of enrollment (i.e., after a participant signs the 
informed consent and eligibility is confirmed) until study participation is complete. In the event 
that a participant reports social harm, every effort will be made by study staff to provide 
appropriate care and counseling to the participant, and/or referral to appropriate resources for 
the safety of the participant as needed. Each site will provide such care and counseling in 
accordance with standardized guidance provided in the MTN-042 SSP Manual. While 
maintaining participant confidentiality, study sites may engage their community advisory boards 
(CABs) in exploring the social context surrounding instances of social harm. 
 
8.6 
Regulatory Requirements 
 
Information on all reported CRFs will be included in reports to the FDA and other applicable US, 
local and international government and regulatory authorities. Site IoRs/designees will submit 
AE information in accordance with local regulatory agencies’ or other local authorities’ 
requirements. Site IoRs/designees also will submit AE information and any other relevant safety 
information to their IRBs/ECs in accordance with IRB/EC requirements. 
 
 


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9 
CLINICAL MANAGEMENT 
 
Guidelines for clinical management and temporary product hold/permanent discontinuation of 
study product are outlined in this section. In general, the IoR/designee has the discretion to hold 
study product temporarily at any time if s/he feels that continued product use would be harmful 
to the participant or interfere with treatment deemed clinically necessary. Unless otherwise 
specified below, the IoR/designee should immediately consult the PSRT for further guidance on 
resuming study product, continuing the hold temporarily, or progressing to permanent 
discontinuation of study product. The IoR/designee will document all temporary product holds 
and permanent discontinuations on applicable CRFs.  
 
9.1 
Grading System 
 
AE severity grading is described in Section 8.3.1. 
 
9.2 
Dose Modification Instructions 
 
No dose modifications will be undertaken in this study. 
 
9.3 
General Criteria for Temporary/Permanent Discontinuation of Study Product 
 
Participants will be permanently discontinued from study product by the IoR/designee for any of 
the following reasons: 
 
• 
Acquisition of HIV-1 infection. 
• 
Acquisition of hepatitis B infection (for Truvada group only). 
• 
Confirmation of ≥ Grade 2 creatinine clearance (for Truvada group only). 
• 
Confirmation of ≥ Grade 2 glycosuria or proteinuria (for Truvada group only).  
• 
Allergic reaction to the study product. 
• 
Reported use of PrEP for HIV prevention prior to pregnancy outcome. 
• 
Non-therapeutic injection drug use. 
 
NOTE: Pregnancy loss and admission to care for labor and delivery management, 
including induction of labor and cesarean delivery, are scheduled reasons for end of 
product use. 
 
A participant will be temporarily held from study product for any of the following reasons: 
 
• 
A reactive rapid HIV test. The study product must be held beginning immediately upon 
recognition of the first reactive rapid HIV test. If, via the algorithm in Appendix IV, the 
participant is determined to be HIV-uninfected, she may resume product use. The 
IoR/designee must permanently discontinue the study product if HIV-1 infection is 
confirmed. 
• 
Reported use of PEP for potential HIV exposure. 
• 
Suspected onset of labor or rupture of membranes. If labor and rupture of membranes 
are subsequently ruled out, study product should be resumed. The IoR/designee must 
permanently discontinue the study product if labor or rupture of membranes is 
confirmed. 
• 
Participant is unable or unwilling to comply with required study procedures, or otherwise 
might be put at undue risk to her/her infant’s safety and well-being by continuing product 


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use, according to the judgment of the IoR/designee. The IoR/designee must consult the 
PSRT on all temporary product holds instituted for this reason for further guidance on 
resuming product use, continuing the temporary hold, or progressing to permanent 
discontinuation. If product use is temporarily held/permanently discontinued for this 
reason, but the underlying reason for the temporary hold later resolves, the 
IoR/designee should consult the PSRT to resume product use at that time.   
 
9.4 
Temporary Product Hold/Permanent Discontinuation in Response to Observed 
Adverse Events 
 
Grade 1 or 2 
In general, a participant who develops a Grade 1 or 2 AE not specifically addressed in Section 
9.5 below, regardless of relatedness to study product, may continue product use.   
 
Grade 3 
Participants who develop a Grade 3 AE that is not specifically addressed in Section 9.5 below 
and is judged by the IoR/designee to be not related to study product may continue product use.   
 
In general, for participants who develop a Grade 3 AE not specifically addressed below, judged 
by the IoR/designee to be related to study product, and unless otherwise decided in consultation 
with the PSRT, the IoR/designee should: 
• 
Temporarily hold the study product. 
• 
Re-evaluate the participant at least weekly for up to 2 weeks. 
• 
Resume study product if improvement to ≤ Grade 2 is documented within 2 weeks. 
• 
Consult PSRT regarding further study product management if improvement to severity ≤ 
Grade 2 cannot be documented within 2 weeks.   
 
If product use is resumed and the same Grade 3 AE deemed related to study product recurs at 
any time, the IoR/designee must temporarily hold study product and consult the PSRT for 
further guidance on continuing the temporary hold or progressing to permanent discontinuation 
of the study product. 
 
Grade 4 
Participants who develop a Grade 4 AE (including a complication of pregnancy and regardless 
of relationship to study product) should have the study product held. The IoR/designee must 
consult the PSRT and continue the temporary product hold until a recommendation is obtained 
from the PSRT.   
 
9.5 
Other Clinical Findings 
 
A thorough evaluation of participant complaints is expected in the context of this study; 
however, management of the following side effects common with Truvada oral tablet use should 
be done according to the following guidelines if such practice is in line with the local standards 
of care:   
 
≥ Grade 2 creatinine clearance  
• 
Oral study product should be held. 
• 
The PSRT should be notified. 
• 
The test should be repeated within one week.  


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o If a level of ≥ Grade 2 is confirmed, study product will be permanently 
discontinued.  
o If retesting cannot occur within one week, the IoR/designee must consult the 
PSRT for further guidance on resuming product use. 
 
NOTE: Absolute values for creatinine and creatinine clearance will be used to grade 
these AEs instead of changes from baseline due to absence of a true pre-pregnancy 
baseline measurement in this study population and due to normal fluctuations in these 
measurements during pregnancy.   
 
≥ Grade 2 glycosuria or proteinuria  
• 
Oral study product should be held. 
• 
The PSRT should be notified. 
• 
The test should be repeated within one week.  
o If a level of ≥ Grade 2 is confirmed, study product will be permanently 
discontinued.  
o If either retesting cannot occur within one week or if retesting yields a result of 
Grade 1, the IoR/designee must consult the PSRT for further guidance on 
resuming product use. 
 
Syndromic management of genital symptoms is acceptable while awaiting laboratory results if 
such practice is in line with the local standards of care. Observed single dose treatment should 
be provided whenever possible, per clinician discretion. When clinically appropriate, 
investigators should use oral or parenteral (in the case of syphilis, for example) medications 
when at all possible.   
 
STI/RTI requiring treatment 
• 
Study VR or tablet need not be held unless other temporary product hold/permanent 
discontinuation guidelines apply.  
• 
Should the IoR/designee determine that a temporary hold is warranted, consultation with 
the PSRT is required.  
 
NOTE: The IoR/designee should manage STI/RTI per local guidelines or current WHO 
guidelines, available at http://www.who.int/en/.   
 
Management of vaginal bleeding and chorioamnionitis events observed at scheduled or interim 
visits for all participants will be in accordance with the following: 
 
≥ Grade 2 genital bleeding 
• 
Temporarily hold study product. 
• 
Perform naked eye evaluation. 
• 
If determined to be due to deep epithelial disruption, refer to guidelines below; otherwise 
study product will be permanently discontinued. 
 
≥ Grade 2 chorioamnionitis 
• 
Participants who develop Grade 2 or higher chorioamnionitis will be referred for delivery 
per local standard of care; therefore, study product will be permanently discontinued. 
 
Management of genital events observed at scheduled or interim visits for participants using the 
VR will be in accordance with the following: 


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Superficial epithelial disruption (abrasion/peeling)  
• 
Continue study product use. 
• 
Perform naked eye evaluation. 
 
• 
Re-evaluate by speculum examination in 3-5 days. 
• 
If condition worsens, temporarily hold study product use and consult the PSRT; 
otherwise continue study product use. 
 
Deep epithelial disruption (ulceration) 
 
• 
Temporarily hold study product for deep epithelial disruption confirmed by site 
investigator. 
• 
Re-evaluate in 3-5 days and resume study product use if resolved. 
• 
If unresolved at 3-5 days, re-evaluate within 2-3 days. If resolved at that time, may 
resume study product use. If unresolved at this second reevaluation, continue temporary 
product hold, consult with PSRT regarding permanent discontinuation, and provide care 
per local standard.  
• 
If there is reoccurrence with no identified etiology, continue temporary product hold and 
consult the PSRT regarding permanent discontinuation. 
 
Localized erythema or edema: area of less than 50% of vulvar surface or combined 
vaginal and cervical surface 
 
• 
Continue study product use.  
• 
Perform naked eye evaluation. 
• 
If asymptomatic, re-evaluate at next regularly scheduled visit. 
• 
If symptomatic, re-evaluate by speculum examination in 3-5 days. 
• 
If worsened significantly, temporarily hold study product use and consult the PSRT; 
otherwise continue study product use. 
 
Generalized erythema or severe edema: area of more than 50% of vulvar surface or 
combined vaginal and cervical surface affected by erythema  
• 
Temporarily hold study product. 
• 
Perform naked eye evaluation. 
 
• 
Re-evaluate in 3-5 days and resume study product use if resolved. 
• 
If unresolved at 3-5 days, re-evaluate within 2-3 days. If resolved at that time may 
resume study product use. If unresolved at this second reevaluation, continue temporary 
product hold, consult with PSRT regarding permanent discontinuation, and provide care 
per local standard. 
• 
If there is reoccurrence with no identified etiology, continue temporary product hold and 
consult the PSRT regarding permanent discontinuation. 
 
Unexpected Grade 1 genital bleeding 
• 
Continue study product use (at study clinician’s discretion).  
• 
Perform naked eye evaluation. 
 
• 
If determined to be due to deep epithelial disruption, refer to guidelines above; otherwise 
continue study product use. 
 
Cervicitis (including findings on exam such as inflammation and/or friability)  
• 
Temporarily hold study product. 
• 
Evaluate for GC/CT; consider syndromic management, pending results of testing and 
per clinician discretion. 


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• 
If GC/CT detected, provide or prescribe treatment. 
• 
Reevaluate in 3-5 days. If all symptoms and signs are resolved at that time, regardless 
of etiology, resume study product use. 
• 
If unresolved at 3-5 days, continue temporary product hold, consult with PSRT regarding 
permanent discontinuation, and provide care per local standard.  
 
Genital petechiae  
• 
Continue study product use. 
• 
Perform naked eye evaluation.  
• 
Further evaluation or treatment per clinician discretion. 
 
Genital ecchymosis  
• 
Continue study product use. 
• 
Perform naked eye evaluation.  
• 
Further evaluation or treatment per clinician discretion. 
 
9.6 
HIV Infection 
 
A participant who has a positive test for HIV must have study product held, but will not be 
withdrawn from the study. If the participant is subsequently determined to be HIV-uninfected 
according to the algorithm in Appendix IV, study product may be resumed. If HIV infection is 
confirmed, study product will be permanently discontinued by the IoR/designee. Participants 
identified as infected with HIV (and their infants once they are born, if also infected with HIV) are 
managed or referred for management according to the local standard of care. These 
participants will also be offered the option to continue in study follow-up with a modified study 
visit/procedure schedule, as per Section 7.7.1, for at least 12 months after seroconversion. 
 
The care provided at the referral sites is at a level that meets or exceeds the community 
standard for HIV care, and will include testing and prophylaxis for infants exposed to HIV 
infection. Written SOPs for referral for HIV care and treatment are in place at each study site. All 
study site investigators have identified facilities offering psychological and social services and 
medical care, including ART, to people infected with HIV-1 in the study countries. Some of the 
research sites are part of health care institutions that provide HIV care and support, and can 
refer pregnant women to those services. Other sites have established referral agreements with 
programs to expand access to ART.   
 
At every study visit, study staff will actively follow-up on prior referrals to HIV care and support 
services, to determine whether the participant sought the care to which she was referred, the 
outcome of the referral, and whether additional referrals are needed. All follow-up actions, 
outcomes, counseling, and plans for next steps are documented in participant study records.  
Results of study laboratory testing may be helpful in clinical management, and these results are 
provided to the participant and her medical provider (with her permission) as soon as they are 
available. 
 
9.7 
Criteria for Early Termination of Study Participation 
 
Participants may voluntarily withdraw from the study for any reason at any time. The IoR also 
may withdraw a participant from the study to protect her/her infant’s safety and/or if she is 
unwilling or unable to comply with required study procedures. The PSRT must be notified of all 
terminations conducted per IoR discretion. Participants also may be withdrawn if NIAID, IPM, 


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Gilead Sciences, Inc., government or regulatory authorities including the FDA and Office for 
Human Research Protections (OHRP), or site IRBs/ECs terminate the study prior to its planned 
end date. Every reasonable effort will be made to complete a final evaluation of participants who 
withdraw or are withdrawn from the study prior to completing follow-up. Participants will also be 
asked permission for study staff to contact them up to one year after their pregnancy outcome to 
obtain information about their pregnancy outcome and their infant’s health. Study staff members 
will record the reason(s) for all withdrawals in participants’ study records. In the event that 
participants who voluntarily withdraw from the study wish to re-join the study, they may resume 
product use (if applicable) and follow-up through their originally scheduled study exit date, 
pending consultation with the PSRT.  In the event that participants who voluntarily withdraw 
from the study wish to keep their infants in study follow-up for one year postpartum, they may 
resume follow-up after giving birth until their originally scheduled study exit date. 
 
  
10 ANALYTICAL CONSIDERATIONS 
 
10.1 
Overview and Summary of Design 
 
The MTN-042 study is a multi-site, two-arm, randomized, open-label Phase 3b study evaluating 
the safety, adherence and acceptability profiles of two HIV-1 prevention products, the monthly 
DPV VR and daily oral Truvada tablet, when used by pregnant African women. Participants 
(aged 18-40 years) will be randomized in a 2:1 ratio (100 VR: 50 tablet) for Cohorts 1-2 and in a 
4:1 ratio (200 VR: 50 tablet) for Cohort 3.  The total length of follow-up for participant mothers 
will vary depending on gestational age at time of enrollment and length of pregnancy prior to 
pregnancy outcome, and will range from approximately 12 weeks or less for Cohort 1 to 
approximately 36 weeks or less for Cohort 3. Also, infants born to MTN-042 participants will be 
followed for approximately 52 weeks (i.e., one year).   
 
Local background pregnancy outcome data will be an important component of analyses; these 
data will be compiled from the proposed MTN-042B study, a multi-site, cross-sectional chart 
review of pregnancy outcome data from four African sites. The objectives include determination 
of frequencies of full-term live birth and premature live birth (<37 weeks), important pregnancy 
and newborn complications, mean birth weight, and method of delivery. 
 
10.2 
Study Endpoints  
 
10.2.1 
Primary Endpoints 
 
Maternal Safety (composite) 
• 
All serious adverse events, including maternal deaths  
• 
All Grade 3 or higher AEs as defined by the Division of AIDS (DAIDS) Table for 
Grading the Severity of Adult and Pediatric Adverse Events, Corrected Version 2.1, 
July 2017 and/or Addendum 1 (Female Genital Grading Table for Use in Microbicide 
Studies [Dated November 2007]) 
 


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Infant Safety (composite) 
• 
All serious adverse events, including infant deaths and congenital anomalies 
• 
All Grade 3 or higher AEs as defined by the Division of AIDS (DAIDS) Table for 
Grading the Severity of Adult and Pediatric Adverse Events, Corrected Version 2.1, 
July 2017 
 
Pregnancy Outcomes 
• 
Frequency of the following pregnancy outcomes: 
o Full term live birth (≥37 weeks) 
o Premature live birth (<37 weeks) 
o Pregnancy loss (≥20 weeks) 
o Pregnancy loss (<20 weeks) 
 
10.2.2 
Secondary Endpoints 
 
Pregnancy Complications 
• 
Frequency of the following pregnancy complications: 
o Hypertensive disorders of pregnancy 
o Chorioamnionitis 
o Puerperal sepsis and endometritis 
o Antepartum, intrapartum and postpartum hemorrhage 
o Preterm premature rupture of membranes (PROM) 
o Fever of unclear etiology 
 
Infant Drug Levels 
• 
Infant blood TFV-DP and FTC-TP concentrations 
• 
Infant plasma DPV concentrations  
 
Adherence 
• 
Maternal blood TFV-DP and FTC-TP concentrations 
• 
Maternal plasma DPV concentrations  
• 
Participant report of frequency of study product use (e.g., missed doses for oral 
Truvada and VR removal/expulsions [voluntary and involuntary] and duration without 
VR in vagina) 
• 
Residual drug levels in returned VRs 
 
Acceptability  
• 
Self-reported attitudes about study product attributes and willingness to use study 
products during pregnancy 
• 
Proportion of participants who find the study products to be at least as acceptable as 
other HIV prevention methods 
 
10.3 
Primary Study Hypotheses 
 
• 
It is hypothesized that daily use of Truvada oral tablet or DPV vaginal matrix ring (25 
mg) inserted once every 4 weeks will be generally safe and well-tolerated by the 
participants and their fetuses/infants.  
• 
It is hypothesized that participants who use Truvada oral tablet daily or insert the 
DPV vaginal matrix ring (25 mg) once every 4 weeks will experience similar 
distributions of pregnancy outcomes to the general population. 


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10.4 
Sample Size and Power Calculations 
 
The proposed total sample size is N=550 pregnant women, which is comprised of 3 cohorts: 
 
• 
Cohort 1: 150 women between 36 0/7 weeks – 37 6/7 weeks gestation  
• 
Cohort 2: 150 women between 30 0/7 weeks – 35 6/7 weeks gestation 
• 
Cohort 3: 250 women between 12 0/7 weeks – 29 6/7 weeks gestation 
 
Eligible women enrolled in Cohorts 1-2 will be randomized into 2 arms in a 2:1 ratio (100 VR: 50 
tablet). Eligible women enrolled in Cohort 3 will be randomized into 2 arms in a 4:1 ratio (200 
VR: 50 tablet). 
 
10.4.1 
Primary Endpoints – Maternal and Infant Safety 
 
To characterize the statistical properties of this study, Table 17 below presents the probability of 
observing zero, at least one, ten or more, and fifty or more safety endpoints in each group by 
cohort size and among the total study population for various “true” event rates, ranging from low 
to high: 
 
Table 17. Probability (%) of observing an event given different “true” event rates by cohort size 
“True” 
event 
rate 
P (0 events) 
P ≥ 1 event 
P (≥ 10 events) 
P (≥ 50 events) 
Cohorts 
1-2a 
n=100 
n=50 
n=100 
n=50 
n=100 
n=50 
n=100 
n=50 
1% 
36.6 
60.50 
63.40 
39.50 
0.00 
0.00 
0.00 
0.00 
5% 
0.59 
7.69 
99.41 
92.31 
1.15 
0.00 
0.00 
0.00 
10% 
0.00 
0.52 
100.00 
99.48 
41.68 
0.94 
0.00 
0.00 
15% 
0.00 
0.03 
100.00 
99.97 
90.06 
11.99 
0.00 
0.00 
25% 
0.00 
0.00 
100.00 
100.00 
99.99 
73.78 
0.07 
0.00 
Cohort 
3a 
n=200 
n=50 
n=200 
n=50 
n=200 
n=50 
n=200 
n=50 
1% 
13.4 
60.50 
86.6 
39.50 
0.00 
0.00 
0.00 
0.00 
5% 
0.00 
7.69 
100.00 
92.31 
41.69 
0.00 
0.00 
0.00 
10% 
0.00 
0.52 
100.00 
99.48 
99.19 
0.94 
0.00 
0.00 
15% 
0.00 
0.03 
100.00 
99.97 
100.00 
11.99 
0.01 
0.00 
25% 
0.00 
0.00 
100.00 
100.00 
100.00 
73.78 
46.21 
0.00 
Overalla 
n=400 
n=150 
n=400 
n=150 
n=400 
n=150 
n=400 
n=150 
1% 
1.80 
22.15 
90.95 
44.30 
0.27 
0.00 
0.00 
0.00 
5% 
0.00 
0.05 
100.00 
99.59 
99.06 
13.22 
0.00 
0.00 
10% 
0.00 
0.00 
100.00 
100.00 
100.00 
89.40 
4.36 
0.00 
15% 
0.00 
0.00 
100.00 
100.00 
100.00 
99.86 
91.06 
0.00 
25% 
0.00 
0.00 
100.00 
100.00 
100.00 
100.00 
100.00 
0.85 
a Sample sizes in the table based on the proposed cohort sizes and study design. For example, Cohort 1 will include 
approximately 150 participants, with 2:1 randomization, there will be 100 participants in the VR arm and 50 


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participants in the Truvada arm.  
 
An alternative way of describing the statistical properties of the study design is in terms of the 
95% confidence interval for the “true” rate based on the observed data. Table 18 below shows 
the exact 2-sided 95% confidence intervals for the probability of an event based on a particular 
observed rate. For example, if none of the 400 participants receiving the VR regimen 
experience a safety event, the 95% exact 2-sided upper confidence bound for the true rate of 
such events in a particular arm of the study is 0.92%.  
 
Table 18. Confidence intervals for endpoint rate (proportion of participants with endpoint) given 
number of endpoints (rows) in with number of participants (columns) 
Number of 
events 
Number of participantsa 
n=50 
n=100 
n=150 
n=200 
n=400 
0 
0.00, 7.11 
0.00, 3.62 
0.00, 2.43 
0.00, 1.83 
0.00, 0.92 
1 
0.05, 10.65 
0.03, 5.45 
0.00, 3.66 
0.01, 2.75 
0.00, 1.38 
2 
0.49, 13.71 
0.24, 7.04 
0.16, 4.73 
0.12, 3.57 
0.06, 1.79 
3 
1.25, 16.55 
0.62, 8.52 
0.41, 5.73 
0.31, 4.32 
0.15, 2.18 
4 
2.22, 19.23 
1.10, 9.93 
0.73, 6.69 
0.55, 5.04 
0.27, 2.54 
5 
3.33, 21.81 
1.64, 11.28 
1.09, 7.61 
0.82, 5.74 
0.41, 2.89 
6 
4.53, 24.31 
2.23, 12.60 
1.48, 8.50 
1.11, 6.42 
0.55, 3.24 
8 
7.17, 29.11 
3.52, 15.16 
2.33, 10.24 
1.74, 7.73 
0.87, 3.90 
10 
10.03, 33.72 
4.90, 17.62 
3.24, 11.92 
2.42, 9.00 
1.21, 4.55 
12 
13.06, 38.17 
6.36, 20.02 
4.20, 13.56 
3.14, 10.25 
1.56, 5.18 
15 
17.86, 44.61 
8.65, 23.53 
5.71, 15.96 
4.26, 12.07 
2.11, 6.11 
20 
26.41, 54.82 
12.67, 29.18 
8.34, 19.84 
6.22, 15.02 
3.08, 7.62 
30 
45.18, 73.59 
21.24, 39.98 
13.92, 27.30 
10.35, 20.72 
5.12, 10.53 
a Sample sizes in the table based on the proposed cohort sizes and study design. 
 
10.4.2 
Primary Endpoints – Pregnancy Outcomes 
 
Based on pregnancy outcome data from VOICE91 and ASPIRE40, we expect certain pregnancy 
outcomes such as premature live birth and pregnancy loss ≥ 20 weeks to occur at a low 
frequency (5% and 2-3%, respectively). Among all women who became pregnant in VOICE and 
ASPIRE, pregnancy loss < 20 weeks was between 19-22%. Given the enrollment criteria for this 
study, it is expected that the frequency of pregnancy loss < 20 weeks will be lower in enrolled 
MTN-042 participants. As such, the probability and confidence interval estimates presented in 
Table 16 and Table 17 also apply to estimates of the frequency of pregnancy outcomes. For 
example, if there was one stillbirth among the 100 participants in Cohort 1 receiving the VR 
regimen, the stillbirth frequency would be 1.00% and the 95% exact 2-sided confidence interval 
would be (0.03, 5.45).  
 
10.5 
Participant Accrual, Follow-up and Retention 
 
Approximately 550 participants and their infants will be enrolled across three cohorts. The 
accrual period for Cohorts 1-2 will be approximately 4-5 months, while the accrual period for 
Cohort 3 will be approximately 7-9 months; Cohort 3 was designed to be larger in order to 
accumulate more person-years of observation and to better evaluate less frequent outcomes, 
such as pregnancy loss in the second trimester, after comprehensive evaluation of safety in the 
preceding Cohorts.* Participant accrual will be paused at all sites once accrual goals are met for 
the currently enrolling Cohort. This will be done to allow all enrolled participants to give birth 
and, for Cohorts 1-2, to conduct interim safety analyses to determine if accrual into the next 


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Cohort can commence. The duration of these accrual pauses will vary depending on the Cohort 
and on the quantity and quality of data collected, and likely will resemble the following: 
approximately 3-4 months after Cohort 1 and approximately 4-6 months after Cohort 2. Cohort 1 
accrual began in February 2020 and is expected to finish in May 2021. Therefore, it is expected 
that the Cohort 1 phase of the study will last approximately 16-17 months, Cohort 2 
approximately 8-11 months, and Cohort 3 approximately 13-17 months, for a study duration of 
approximately 37-45 months.* In addition, infants born to MTN-042 participants will be followed 
up for approximately one year, though this will not be part of the interim safety analyses after 
Cohorts 1-2. Therefore, total study duration including infant follow-up for all cohorts will be 
approximately 48-56 months. 
 
* Overall study duration – from first enrollment through closure of all follow-up – may be longer 
than planned if temporary site closures due to the COVID-19 pandemic cause delays or pauses 
in enrolling participants at one or more research sites. 
 
10.6 
Randomization 
 
Participants will be randomized in a 2:1 ratio (or a 4:1 ratio in Cohort 3) to the two arms of the 
study stratified by study site. The randomization scheme will be generated and maintained by 
the MTN SDMC. 
 
10.7 
Data and Safety Monitoring Procedures 
 
No DSMB oversight is planned for this study. The MTN SMC will conduct interim reviews of 
study progress, including rates of participant accrual, retention, completion of primary and 
secondary endpoint assessments, and study or laboratory issues. These reviews will take place 
approximately every 6 months, or as needed. At the time of these reviews, or at any other time, 
the SMC may recommend that the study proceed as designed, proceed with design 
modifications, or be discontinued. Safety monitoring will be done by the PSRT. 
 
It is not expected that MTN-042 will predispose pregnant women to higher frequencies of 
untoward pregnancy outcomes, given the favorable safety profile demonstrated for both study 
products among non-pregnant women and among pregnant women who enrolled in MTN-016. 
However, an interim review of the safety data by the IRP is planned after each cohort completes 
scheduled participation and prior to beginning accrual in the next scheduled cohort. 
 
The IRP will consist of a multidisciplinary group of subject matter experts from the US and SSA 
that will likely include one or more obstetricians, pediatricians, statisticians, ethicists and/or 
public health professionals, among others. The IRP will review safety data collected in each 
cohort to look for higher frequencies for the primary outcomes compared to baseline estimates 
or when comparing between study drugs. In addition, a full safety review of secondary 
outcomes related to pregnancy will be conducted. If this were noted at interim review, serious 
consideration would be given as to the prudence of enrolling women in subsequent cohorts. 
Interim review results will be relayed to site IRBs/IECs and to study participants as appropriate. 
 
The IRP will review frequencies of the following primary and secondary safety endpoints for 
each cohort: 
 
• 
SAEs, including maternal and infant deaths and congenital anomalies 
• 
Grade 3 and higher AEs for mother and infant 
• 
Pregnancy outcomes: 


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ο 
Full term live birth (≥37 0/7 weeks) 
ο 
Premature live birth (<37 0/7 weeks) 
ο 
Pregnancy loss (≥20 weeks) 
ο 
Pregnancy loss (<20 weeks) 
• 
Pregnancy complications: 
ο 
Hypertensive disorders of pregnancy 
ο 
Chorioamnionitis 
ο 
Puerperal sepsis and endometritis 
ο 
Antepartum, intrapartum and postpartum hemorrhage 
ο 
Preterm PROM 
ο 
Fever of unclear etiology 
 
10.8 
Analyses 
 
When the use of descriptive statistics to assess group characteristics or differences is required, 
the following methods will be used: for categorical variables, the number and percent in each 
category; for continuous variables, the mean, median, standard deviation, quartiles and range 
(minimum, maximum). Within-treatment group assessment of the change from the baseline 
measurement to a follow-up measurement will be analyzed using McNemar’s test (for 
categorical response variables) or the paired t-test or Wilcoxon signed-ranks test (for continuous 
variables). To assess the adequacy of the randomization, participants in each of the two arms 
will be compared using descriptive statistics for baseline characteristics including demographics 
and laboratory measurements. No formal statistical comparisons will be performed. 
 
10.8.1 
Primary Analyses 
 
An intent to treat analysis will be performed to summarize the frequency of primary endpoints 
(maternal safety, infant safety and pregnancy outcome) by study arm. A secondary analysis will 
be conducted including only visits in which a participant has been exposed to the study product. 
Analyses will be conducted separately for each of the three cohorts, with a final aggregate 
analysis that will include all enrolled participants from each of the three cohorts. The number 
and the percentages of participants experiencing each primary endpoint (see Section 10.2) will 
be tabulated by study arm. Each participant will contribute once in each category (i.e., only for 
highest severity AE for each participant) for the calculation of event rates. Exact binomial 
confidence intervals will be calculated for each primary endpoint. Primary endpoint event rates 
will be compared to baseline estimates as described in Section 10.7. A secondary analysis will 
be performed to summarize the total number of primary and secondary safety endpoints 
reported per participant by study arm. 
 
10.8.2 
Analysis of Secondary Endpoints 
 
Pregnancy Complications 
Pregnancy complications will be analyzed using the same approach as the primary endpoints 
(see Section 10.8.1).  
 
Infant Drug Levels 
The concentrations of study product and number and percentages of infants with detectable 
concentrations of study product will be summarized by study arm. 
 


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Adherence 
For women randomized to the VR arm, a combination of measures (maternal plasma DPV 
concentration and residual DPV levels in returned VRs) will be used to characterize use of study 
product. For women randomized to Truvada, maternal plasma concentrations will be used to 
quantify study product use. The number and proportion of participants with concentrations 
indicative of study product use will be compared by study arm. Trends over time in study 
product use will be explored using generalized estimating equations (GEE). Reasons for study 
product non-use (i.e. VR removal, missed pills) will be tabulated by arm.  
 
Acceptability 
To assess acceptability of the study products, information will be obtained from questionnaires 
in which the participants will rate acceptability on a combination of categorical and continuous 
scales. Continuous measures of acceptability will be compared across arms using a t-test while 
categorical measures will be compared using chi-squared tests or Fisher’s exact test, as 
appropriate. The number and percentages of participants who report the study products to be at 
least as acceptable as other HIV prevention methods will be summarized by study arm. These 
binomial proportions will be used to assess the acceptability of the study products along with the 
corresponding 95% confidence intervals and will be compared using chi-squared tests or 
Fisher’s exact test, as appropriate. 
 
10.8.3 
Missing Data 
 
We expect little to no missing data. Data will be considered missing (no data on outcome 
measures) if a participant does not return for a follow-up visit. However, if the probability of 
missing measurements depends on either covariates or on the measurement outcomes of 
participants, then the methods described above may give biased inferences and point 
estimates. If a substantial amount of endpoint data is missing (e.g., follow-up data missing in at 
least 10% of participants), then secondary analyses of the endpoints will be conducted using 
methods that relax the missing completely at random assumption to a missing at random 
assumption. For a univariate binary and quantitative outcome, respectively, a generalized linear 
model with a binomial or Normal error distribution will be used for estimation and testing. 
 
 
11 DATA HANDLING AND RECORDKEEPING 
 
11.1 
Data Management Responsibilities 
 
Study CRFs will be developed by the MTN SDMC in conjunction with the protocol team. Quality 
control reports and queries will be generated routinely and distributed by the SDMC to the study 
sites for verification and resolution. As part of the study activation process, each study site must 
identify all CRFs to be used as source documents. Study data is entered into the electronic 
CRFs in the MTN-042 Medidata Rave study database, a data management system compliant 
with International Council on Harmonization (ICH) Good Clinical Practices (GCP) and CFR 
guidelines, which is maintained by the MTN SDMC. 
 
Interview files generated in the field will be electronically transferred to RTI International using a 
secure File Transfer Protocol (FTP) site, where they will be uploaded and managed using a 
qualitative software package. RTI International will act as a hub, and manage all qualitative data 
for the study. A convention for file naming will be developed, and all data will be labeled 


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according to this process. Transcripts will be transferred to RTI International as they are 
completed. RTI International will save all versions of all files on a secure, password-protected 
server.  
 
11.2 
Source Documents and Access to Source Data/Documents 
 
All study sites will maintain source data/documents in accordance with the DAIDS Site Clinical 
Operations 
and 
Research 
Essentials 
(SCORE) 
Manual 
(https://www.niaid.nih.gov/research/daids-score-manual).   
 
Each IoR/designee will maintain, and store securely, complete, accurate and current study 
records throughout the study. In accordance with U.S. regulations, for the investigational 
products tested, the IoR/designee will maintain all study documentation for at least two years 
following the date of marketing approval for the indication in which they were studied. If no 
marketing application is filed, or if the application is not approved, the records will be retained 
for two years after the investigation is discontinued and the US FDA is notified.   
 
Study records must be maintained on site for the entire period of study implementation.  
Thereafter, instructions for record storage will be provided by DAIDS. No study records may be 
moved to an off-site location or destroyed prior to receiving approval from DAIDS.   
 
11.3 
Quality Control and Quality Assurance 
 
All study sites will conduct quality control and quality assurance procedures in accordance with 
the DAIDS SCORE Manual (https://www.niaid.nih.gov/research/daids-score-manual). 
 
 
12 CLINICAL SITE MONITORING 
 
Study monitoring will be carried out by Pharmaceutical Product Development, Inc. (PPD) 
(Wilmington, NC) in accordance with current DAIDS policies. Study monitors will: 
 
• 
Review informed consent forms (ICFs), procedures, and documentation. 
• 
Assess compliance with the study protocol, GCP guidelines, and applicable regulatory 
requirements (US and non-US), including CFR Title 45 Part 46 and Title 21 Parts 50, 56, 
and 312.  
• 
Perform source document verification to ensure the accuracy and completeness of study 
data. 
• 
Verify proper collection and storage of biological specimens. 
• 
Verify proper storage, dispensing, and accountability of investigational study products. 
• 
Assess implementation and documentation of internal site quality management 
procedures. 
• 
Verify that current license/certification is available on site for study staff listed on the 
current FDA Form 1572, DAIDS IoRs, and Delegation of Responsibilities Log/Form. 
 
Monitoring visits may be conducted on-site or remotely. Remote visits may include remote 
source document verification using methods specified for this purpose by NIAID. Remote 
monitoring visits may be performed in place of or in addition to onsite visits to ensure the safety 
of study participants and data integrity.92 The site will make available study documents for site 


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monitors to review utilizing a secure platform. Selected platforms must be confirmed with the 
DAIDS Office of Clinical Site Oversight (OCSO) in advance. 
 
For on-site visits, the IoR/designee will allow study monitors to inspect study facilities and 
documentation (e.g., ICFs, clinic and laboratory records, other source documents, CRFs), as 
well as observe the performance of certain study procedures. The IoR/designee will also allow 
inspection of all study-related documentation by authorized representatives of the MTN 
Leadership and Operations Center (LOC), SDMC, LC, NIAID, FDA, IPM, Gilead Sciences, Inc., 
OHRP and other local, US, and international regulatory entities. A site visit log will be 
maintained at the study site to document all visits. 
 
 
13 HUMAN SUBJECTS PROTECTIONS 
 
13.1 
Institutional Review Boards/Ethics Committees 
 
Site investigators will make every effort to minimize risks to participants.* Participants and study 
staff members will take part in a thorough informed consent process. Before beginning the 
study, the IoR will have obtained IRB/EC approval and the protocol will have been submitted to 
the FDA.  The IoR will permit audits by the NIH, IPM, Gilead Sciences, Inc., the FDA, OHRP, 
any of their appointed agents, and other local, US, and international regulatory entities. 
 
* Changes to this protocol may be implemented by investigators prior to IRB/IEC approval, if 
those changes are required to eliminate apparent immediate hazards to the study 
participant.  [See 45 CFR 46.108(a)(3)(iii) under the 2018 Requirements and 45 CFR 
46.103(b)(4)(iii) under the pre-2018 Requirements.]  These changes must be documented as 
Protocol Deviations and reported to the Protocol Team and IRB/IEC as soon as possible. [See 
ICH E6(R2), Good Clinical Practice, Section 4.5.4.]  In the event of a public health emergency, 
investigators should adhere to the recommendations of their local institutions, IRB/IEC and local 
health departments.  When conflicts exist between local directives, MTN, Protocol Team and/or 
DAIDS policies or guidance, sites should follow the requirement that is most protective of study 
participants and site staff. [See DAIDS Guidance, Coronavirus Disease (COVID-19) and DAIDS 
HIV/AIDS Network Clinical Research Studies, Page 3, dated March 13, 2020.] 
 
13.2 Protocol Registration 
 
Prior to implementation of this protocol, and any subsequent full version amendments, each site 
must have the protocol and the protocol ICFs approved, as appropriate, by their local IRB/EC 
and any other applicable regulatory entities (REs). Upon receiving final approval, sites will 
submit all required protocol registration documents to the DAIDS Protocol Registration Office 
(PRO) at the RSC. The DAIDS PRO will review the submitted protocol registration packet to 
ensure that all of the required documents have been received.   
 
Site-specific ICFs will be reviewed and approved by the DAIDS PRO, and sites will receive an 
Initial Registration Notification when the DAIDS PRO receives a complete registration packet.  
Receipt of an Initial Registration Notification indicates successful completion of the protocol 
registration process. A copy of the Initial Registration Notification should be retained in the site's 
regulatory files. 
 


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Upon receiving final IRB/EC and any other applicable RE approval(s) for an amendment, sites 
should implement the amendment immediately. Sites are required to submit an amendment 
registration packet to the DAIDS PRO at the RSC. The DAIDS PRO will review the submitted 
protocol registration packet to ensure that all the required documents have been received. Site-
specific ICF(s) will not be reviewed and approved by the DAIDS PRO and sites will receive an 
Amendment Registration Notification when the DAIDS PRO receives a complete registration 
packet. A copy of the Amendment Registration Notification should be retained in the site's 
regulatory files. 
 
For additional information on the protocol registration process and specific documents required 
for initial and amendment registrations, refer to the current version of the DAIDS Protocol 
Registration Manual. 
 
13.3 Study Coordination 
 
DAIDS holds the Investigational New Drug (IND) application for this study. Assignment of all 
sponsor responsibilities for this study will be specified in a Clinical Trial Agreement (CTA) 
executed by NIAID, IPM, and Gilead Sciences, Inc. 
 
Study implementation will also be guided by the MTN-042 SSP Manual that provides further 
instructions and operational guidance on: conducting study visits; data and forms processing; 
specimen collection, processing, and shipping; AE assessment, management and reporting; 
dispensing study product and documenting product accountability; and other study operations.  
Standardized study-specific training will be provided to all sites by the MTN LOC, SDMC, LC 
and other designated members of the Protocol Team.   
 
Close coordination between protocol team members is necessary to track study progress, 
respond to queries about proper study implementation, and address other issues in a timely 
manner. The PSRT will address issues related to study eligibility and AE management and 
reporting as needed to assure consistent case management, documentation, and information-
sharing across sites. Rates of accrual, adherence, follow-up, and AE incidence will be 
monitored closely by the team as well as the SMC. 
 
13.4 Risk Benefit Statement 
 
13.4.1 
Risks 
 
General 
 
It is not expected that this study will expose human subjects to unreasonable risk.  
 
Pelvic examination and procedures may cause mild discomfort, pressure and/or vaginal 
bleeding or spotting. Phlebotomy may lead to discomfort, feelings of dizziness or faintness, 
and/or bruising, swelling and/or infection. Disclosure of HIV and STI status may cause worry, 
sadness or depression. Disclosure of HIV-positive status has been associated with depression, 
suicidal ideation, and denial as well as social isolation. Trained counselors will be available to 
help participants deal with these feelings.  
 
Participation in clinical research includes the risks of loss of confidentiality and discomfort with 
the personal nature of questions when discussing sexual behaviors. Participation in this study 
also includes the disclosure of protected health information (e.g., medical and antenatal care 


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records) to study staff. Participants will be counseled regarding potential confidentiality issues, 
including keeping any study materials (e.g., study products, handouts) and communications 
(e.g., text messages, phone calls, health records) confidential. 
 
Participants at sites where local regulatory authorities require partner notification in response to 
diagnosed STI or HIV infection could have problems in their relationships with their sexual 
partners. Participants also could have problems in their partner relationships associated with 
use of study product. 
 
Participants will be asked questions about their study product use and vaginal and sexual 
practices. These questions may make some participants uncomfortable.  
 
Dapivirine 
 
Use of the study VR may lead to urinary tract infections, vaginal discharge, vulvovaginal 
pruritus, vulvovaginitis, and pelvic pain. Less common side effects include: cervicitis, cystitis, 
vaginal odor, cervix erythema, cervix ecchymosis, cervix edema, cervical discharge, 
vulvovaginal pain/discomfort, pelvic discomfort, vaginal/uterine cervical erosion, genital 
itching/discomfort, dysuria, pollakiuria, bladder pain, abdominal pain/discomfort, suprapubic 
pain, application site pain/discomfort, and vaginal laceration. It is possible that a participant may 
have an allergic reaction to the study product.  Symptoms of an allergic reaction include rash or 
other skin irritation, itching, joint pain, or difficulty in breathing. As with any vaginally retained 
product, the possibility of toxic shock syndrome, although rare, exists. 
 
Safety data were evaluated from two Phase 3 studies, MTN-020 (ASPIRE) and IPM 027 (The 
Ring Study), which enrolled a total of 4588 women, and results were reported in February 2016. 
No safety concerns were noted in DPV VR users as compared to placebo VR users. There were 
no new safety concerns noted in the two DPV VR open-label extension trials, MTN-025 (HOPE) 
and IPM 032 (DREAM), which enrolled a total of 2309 women, and results were reported in July 
2019 and June 2019, respectively. No prospective data is available for DPV VR use during 
pregnancy, and therefore there may be some risk to pregnant women from using a product 
whose full safety profile is unknown. However, the benefits of using this HIV prevention method 
are anticipated to outweigh the risks for the pregnant women targeted for this study, who live in 
regions with high HIV incidence. Furthermore, the study was designed to minimize risk from 
product exposure by taking a carefully monitored, step-wise approach to dosing starting at later 
gestational ages, then progressing to earlier gestational ages only once safety is confirmed via 
interim safety review. 
 
Based on in vitro data, HIV-infected participants who have prolonged exposure to low 
concentrations of DPV by continuing to use the VR after infection may have a risk of selecting 
viruses carrying NNRTI resistance-associated mutations. Clinical relevance has yet to be 
established, however, as no clear resistance pathway has emerged. All NNRTI mutations 
observed in women using DPV VRs have also been observed in women using placebo rings, 
and it is unclear if the observed mutations were transmitted or arose due to DPV selective 
pressure given the increasing prevalence of NNRTI resistance mutations in the study 
communities and the absence of data on the transmitting partner’s virologic profile. 
 
Truvada (FTC/TDF) 
 
Truvada may have side effects, some of which are listed below. This list includes the more 
serious or common side effects with known or possible relationship. Participants taking Truvada 


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will be monitored closely for any side effects, and are asked to report all side effects to the study 
clinician.  
 
The following side effects have been commonly associated with the use of Truvada: 
• 
Gastrointestinal intolerance (such as nausea, abdominal pain, diarrhea, or vomiting) 
• 
Flatulence (gas) 
• 
Headache, dizziness, tiredness, or inability to sleep 
 
However, these were relatively infrequent (10% of users) and did not lead to product 
discontinuation; furthermore, gastrointestinal intolerance and flatulence typically resolved after 
the first or second month of oral PrEP use.14 
 
Rare, but serious side effects include: 
• 
Rash  
• 
Worsening or new kidney damage  
• 
Bone pain and bone changes such as thinning and softening  
• 
Allergic reaction 
• 
Lactic acidosis (buildup of too much acid in the body). Lactic acidosis can cause 
shortness of breath, nausea and liver failure  
• 
Individuals with HBV who suddenly stop taking Truvada may get a “flare” or worsening of 
hepatitis symptoms 
 
Little prospective data is available for Truvada tablet use during pregnancy by HIV-negative 
women, and therefore there may be some risk to pregnant women from using a product whose 
full safety profile is unknown. However, the benefits of using this HIV prevention method are 
anticipated to outweigh the risks for the pregnant women targeted for this study, who live in 
regions with high HIV incidence. Furthermore, the study was designed to minimize risk from 
product exposure by taking a carefully monitored, step-wise approach to dosing starting at later 
gestational ages, then progressing to earlier gestational ages only once safety is confirmed via 
interim safety review. 
 
Site staff will make every effort to protect participant privacy while in the study. Although study 
sites make every effort to protect participant privacy and confidentiality, it is possible that 
participants' involvement in the study could become known to others, and that social harms may 
result (i.e., because participants could become known as HIV-positive or "high risk" for HIV 
infection). For example, participants could be treated unfairly or discriminated against, or could 
have problems being accepted by their families and/or communities. 
 
13.4.2 
Benefits 
 
Given that the DPV VR received a positive scientific opinion to reduce the risk of HIV infection in 
adult women from the EMA under Article 58 and has been included in the WHO 
recommendations for HIV prevention, participants in MTN-042 will experience the direct benefit 
of using an HIV-1 prevention product currently being considered for potential regulatory 
approval. Furthermore, Truvada is an FDA licensed product that is used to treat HIV infection as 
well as reduce the risk of HIV infection.  
 
Participants and others may benefit in the future from information learned from this study.  
Specifically, information learned in this study may help to understand issues important for 
broader implementation of the DPV VR and PrEP and/or for the development of other 


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interventions to prevent HIV acquisition in pregnant women. Participants may also appreciate 
the opportunity to contribute to the field of HIV prevention research.  
 
Participants will receive HIV/STI risk reduction counseling, HIV and STI testing, physical 
examination, pelvic examination, obstetric abdominal examination, and routine laboratory 
testing.  Participants will be provided with an obstetric ultrasound if not already performed as 
part of their routine antenatal care. Participants will be provided STI treatment in accordance 
with WHO guidelines free of charge. In addition, STI testing, counseling and treatment, as well 
as HIV testing and counseling will be available for participants’ partners. For other medical 
conditions identified as part of the study screening and/or follow-up procedures, participants will 
be referred to other sources of care available in their community. Some volunteers may have 
the opportunity to access expedient treatment and as a result may have decreased morbidity 
due to early diagnosis and treatment of abnormalities identified during tests, examinations and 
referrals. Antenatal care and delivery services will not be provided by the study and must be 
accessed in local care facilities as would have occurred in the absence of study participation. 
 
13.5 Informed Consent Process 
 
Written informed consent will be obtained from all participants as per US regulations and local 
authorities. Informed consent is required prior to initiation of MTN-042 procedures. Written 
informed consent will also be obtained for long-term specimen storage and possible future 
testing, although consent for specimen storage and future testing is not required for study 
participation. In obtaining and documenting informed consent, the IoR and their designees will 
comply with applicable local and US regulatory requirements and will adhere to GCP and to the 
ethical principles that have their origin in the Declaration of Helsinki. Study staff must document 
the 
informed 
consent 
process 
in 
accordance 
with 
the 
DAIDS 
SCORE 
Manual 
(https://www.niaid.nih.gov/research/daids-score-manual). Participants will be provided with 
copies of the ICFs if they are willing to receive them.   
 
In addition to ICFs, the Protocol Team will work with study staff and community representatives 
to develop appropriate materials about the study and a standardized approach to the informed 
consent process to be implemented at all study sites, which will be detailed in the MTN-042 
SSP manual.   
 
The informed consent process will cover all elements of informed consent as required by the 
OHRP and applicable local research regulations. In addition, the process will specifically 
address the following topics of importance to this study: 
• 
The importance of adherence to the study visit and procedures schedule  
• 
The importance of study product adherence to its effectiveness 
• 
The potential medical risks of study participation (and what to do if such risks are 
experienced) 
• 
The potential social harms associated with study participation (and what to do if such 
harms are experienced) 
• 
The real benefit of study participation  
• 
The distinction between research and clinical care 
• 
The right to withdraw from the study at any time 
• 
New information on either study product or about other effective HIV-prevention products 
will be provided to MTN-042 participants   
 


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13.6 Participant Confidentiality 
 
All study procedures will be conducted in private, and every effort will be made to protect 
participant privacy and confidentiality to the extent possible. Each study site will implement 
confidentiality protections that reflect the local study implementation plan and the input of study 
staff and community representatives to identify potential confidentiality issues and strategies to 
address them. For example, participants will be counseled about keeping all study materials 
(e.g., study products, handouts) and communications (e.g., text messages, phone calls, health 
records) confidential.  In addition to local considerations, the protections described below will be 
implemented at all sites. 
 
All study-related information will be stored securely at the study site. All participant information 
will be stored in locked areas with access limited to study staff. All laboratory specimens, study 
data collection, and administrative forms will be identified by coded number only to maintain 
participant confidentiality. All records that contain names or other personal identifiers, such as 
locator forms and ICFs, will be stored securely. All local databases will be secured with 
password protected access systems. Forms, lists, logbooks, appointment books, and any other 
listings that link participants’ identification numbers to identifying information will be stored in a 
locked file in an area with limited access. All digital audio files will be stored on password-
protected computers.  Audio files will be translated and transcribed in English and securely 
stored. Please see MTN-042 SSP Manual for guidance.  
 
Participants’ study information will not be released without their written permission, except as 
necessary for review, monitoring, and/or auditing by the following: 
• 
Representatives of the US Federal Government, including the US FDA, the US OHRP, 
NIH and/or contractors of the NIH, and other local, US, and international regulatory 
entities 
• 
Representatives of IPM 
• 
Representatives of Gilead Sciences, Inc. 
• 
PPD 
• 
Study staff  
• 
Site IRBs/ECs 
 
13.7 Special Populations 
 
13.7.1 
Pregnant Women 
 
Based on an assessment of potential risks and benefits associated with the MTN-042 study 
products and procedures, the MTN-042 study team provides the following rationale to support 
the assertion that this study may be conducted. Final determination rests with each site’s local 
IRB/EC. 
 
As specified in US 45 CFR 46.204, pregnant women or fetuses may be involved in research if 
all of the following conditions are met:  
 
1. Where scientifically appropriate, preclinical studies, including studies on pregnant 
animals, and clinical studies, including studies on non-pregnant women, have been 
conducted and provide data for assessing potential risks to pregnant women and 
fetuses.  


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• 
To date, studies of the DPV VR and Truvada oral tablet have not identified significant 
safety risks to pregnant women and fetuses. Product safety data is included in 
Section 2 of this protocol.  
 
2. The risk to the fetus is caused solely by interventions or procedures that hold out the 
prospect of direct benefit for the woman or the fetus; or, if there is no such prospect of 
benefit, the risk to the fetus is not greater than minimal and the purpose of the research 
is the development of important biomedical knowledge which cannot be obtained by any 
other means.  
• 
Due to projected low exposure to either DPV, FTC or TDF for the fetus, associated 
risks are expected to be minimal. In addition, evidence pointing to the protective 
effect of both the DPV VR and the Truvada oral tablet against HIV in women holds 
out the prospect of direct benefit to both the woman and the fetus, as primary 
maternal infection with HIV poses significant risk to the fetus. Product efficacy data is 
included in Section 2. 
 
3. Any risk is the least possible for achieving the objectives of the research.  
• 
The MTN-042 study team has minimized participant risk for this study by taking a 
carefully monitored, step-wise approach to dosing, starting at later gestational ages, 
then progressing earlier in pregnancy once safety is confirmed. The rationale for the 
study design is detailed in Section 2.9. 
 
4. If the research holds out the prospect of direct benefit to the pregnant woman, the 
prospect of a direct benefit both to the pregnant woman and the fetus, or no prospect of 
benefit for the woman nor the fetus when risk to the fetus is not greater than minimal and 
the purpose of the research is the development of important biomedical knowledge that 
cannot be obtained by any other means, her consent is obtained in accord with the 
informed consent provisions of subpart A of this part.  
• 
The MTN-042 study includes an informed consent process consistent with all 
applicable requirements in the CFR.  
 
5. If the research holds out the prospect of direct benefit solely to the fetus then the 
consent of the pregnant woman and the father is obtained in accord with the informed 
consent provisions of subpart A of this part, except that the father's consent need not be 
obtained if he is unable to consent because of unavailability, incompetence, or 
temporary incapacity or the pregnancy resulted from rape or incest.  
• 
This section is not applicable, as there is the prospect of direct benefit to the 
pregnant woman from participation in the MTN-042 study.  
 
6. Each individual providing consent under paragraph (d) I(e) of this section is fully 
informed regarding the reasonably foreseeable impact of the research on the fetus or 
neonate.   
• 
This information has been included in the MTN-042 Sample Informed Consent 
documents, will be included in site-specific informed consent documents, and will be 
covered thoroughly during the informed consent process, including throughout the 
pregnant woman’s study participation. In addition, the pregnant woman will be 
informed of any applicable new information learned throughout this or other studies.  
 
7. For children as defined in 46.402(a) who are pregnant, assent and permission are 
obtained in accord with the provisions of subpart D of this part.  


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• 
This section is not applicable to MTN-042, as children under 18 years old who are 
pregnant will not be enrolled.  
 
8. No inducements, monetary or otherwise, will be offered to terminate a pregnancy.  
• 
Inducements to terminate a pregnancy will not be offered by MTN-042 study site 
staff.   
 
9. Individuals engaged in the research will have no part in any decisions as to the timing, 
method, or procedures used to terminate a pregnancy.  
• 
Individuals engaged in MTN-042 will have no part in decisions as to the timing, 
method, or procedures used to terminate a pregnancy by participants.  
 
10. Individuals engaged in the research will have no part in determining the viability of a 
neonate.  
• 
Individuals engaged in MTN-042 will have no part in determining the viability of a 
neonate. 
 
13.7.2 
Children 
 
The NIH has mandated that children be included in research studies when appropriate. Based 
on an assessment of potential risks and benefits associated with the MTN-042 study products 
and procedures, the MTN-042 study team provides the following rationale to support the 
assertion that this study may be conducted. Final determination rests with each site’s local 
IRB/EC. 
 
As specified in US 45 CFR 46.205, viable neonates and neonates of uncertain viability may be 
involved in research if all of the following conditions are met:  
 
1. Where scientifically appropriate, preclinical and clinical studies have been conducted and 
provide data for assessing potential risks to neonates.  
• 
To date, studies of DPV VR and Truvada oral tablet exposure in pregnancy have not 
identified significant safety risks to neonates. Product safety data is included in 
Section 2 of this protocol.  
 
2. Each individual providing consent for the neonate is fully informed regarding the reasonably 
foreseeable impact of the research on the neonate.  
• 
Individuals providing consent for participation in MTN-042 will be fully informed 
regarding the reasonably foreseeable impact of the research on the neonate, using 
IRB-approved consent materials. 
 
3. Individuals engaged in the research will have no part in determining the viability of a 
neonate.  
• 
Individuals engaged in MTN-042 will have no part in determining the viability of a 
neonate.  
 
4. The research holds out the prospect of enhancing the probability of survival of the neonate 
to the point of viability, and any risk is the least possible for achieving that objective, or the 
purpose of the research is the development of important biomedical knowledge which 
cannot be obtained by other means and there will be no added risk to the neonate resulting 
from the research.  


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• 
MTN-042 will enroll pregnant female participants who are age 18-40 years old at the 
time of enrollment for this study, as verified per site SOPs, as well as their infants 
once they are born. MTN-042 will provide critical safety data related to study drug 
exposure for the fetuses of those female participants. The research holds out the 
prospect of preventing HIV infection in the mother of the neonate, which may 
decrease the risk of neonatal HIV infection, a condition known to have a negative 
impact on neonatal survival. Neonates may experience benefit from increased 
medical screening during study participation, beyond the standard of care, which 
may have a positive impact on survival. 
 
5. The legally effective informed consent of either parent of the neonate or, if neither parent is 
able to consent because of unavailability, incompetence, or temporary incapacity, the legally 
effective informed consent of either parent's legally authorized representative is obtained in 
accord with subpart A of this part, except that the consent of the father or his legally 
authorized representative need not be obtained if the pregnancy resulted from rape or 
incest. 
• 
The legally effective informed consent of either parent's legally authorized 
representative would be obtained in accordance with the referenced regulation. 
 
As specified in US 45 CFR 46.405, children may be involved in research of greater than minimal 
risk but presenting the prospect of direct benefit to the individual subjects if all of the following 
conditions are met:  
 
1. The risk is justified by the anticipated benefit to the subjects.  
• 
The risk involved in this research is considered greater than minimal risk but 
presents the prospect of direct benefit to both female and infant participants. Both 
products being used in this study have been shown to be well-tolerated and to 
provide a statistically significant reduction in the risk of HIV-1 infection for adult 
women when used as instructed, but DPV is still under consideration for potential 
regulatory approval as an HIV-1 prevention product, and Truvada for oral PrEP has 
not yet been made widely accessible in the countries where the implementation of 
this study is planned. Therefore, this research holds out the prospect of direct benefit 
to the health and well-being of both adult and infant MTN-042 participants. 
 
2. The relation of the anticipated benefit to the risk is at least as favorable to the subjects as 
that presented by available alternative approaches.  
• 
The anticipated benefit to risk ratio of MTN-042 participation is acceptable for a 
safety study of HIV chemoprevention products, which are not currently available to 
pregnant women as local standard of care in study site communities.  
 
3. Adequate provisions are made for soliciting the assent of the children and permission of 
their parents or guardians, as set forth in § 46.408.  
• 
MTN-042 will follow an IRB-approved informed consent process as part of enrollment 
procedures for pregnant female participants who are aged 18-40 years at the time of 
enrollment for this study, as verified per site SOPs, as well as their infants once they 
are born. 
 


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13.8 
Compensation 
 
Pending IRB/EC approval, participants will be compensated for time and effort in this study, 
and/or be reimbursed for travel to study visits and time away from work. Site-specific 
reimbursement amounts will be specified in the study informed consent forms.   
 
If a participant becomes ill or injured as a result of participation in this trial, medical treatment for 
the adverse reaction or injury will be provided appropriately. The site staff will refer the 
participant for ongoing treatment for the injury, if needed. The study sponsor will be responsible 
for ensuring that insurance to cover appropriate medical expenses for treatment of any such 
illness or injury is provided if required by law or regulation. An HIV infection that occurs during 
the course of the trial will not be considered an injury or illness caused by trial participation. 
 
13.9 
Communicable Disease Reporting 
 
Study staff will comply with local requirements to report communicable diseases identified 
among study participants to health authorities, including HIV-1. Participants will be made aware 
of reporting requirements during the informed consent process. 
 
13.10 Access to HIV-related Care 
 
13.10.1 
HIV Counseling and Testing 
 
HIV test-related counseling will be provided to all potential study participants who consent to 
undergo HIV-1 screening to determine their eligibility for this study, and to all enrolled 
participants at each follow-up HIV-1 testing time point. Testing will be performed in accordance 
with the algorithms in Appendices III and IV. Counseling will be provided in accordance with 
standard HIV counseling policies and methods at each site and additionally will provide 
information regarding the known efficacy of the study products in preventing HIV-1 infection. In 
accordance with the policies of the NIH, participants must receive their HIV-1 test results to take 
part in this study. Condoms will be offered to participants throughout the duration of their 
participation. 
 
13.10.2 
Care for Participants Identified as HIV-Infected 
 
Care for participants identified as HIV-infected is described in Section 9.6. 
 
13.11 Study Discontinuation 
 
This study may be discontinued at any time by NIH, the MTN, IPM, Gilead, the US FDA, the US 
OHRP, other government or regulatory authorities, or site IRBs/ECs. 
 
 


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14 PUBLICATION POLICY 
 
DAIDS/NIAID and MTN policies and a CTA between IPM, Gilead Sciences, Inc., and NIAID, will 
govern publication of the results of this study. Any presentation, abstract, or manuscript will be 
submitted by the investigator to the MTN Manuscript Review Committee, DAIDS/NIAID, NICHD, 
National Institute of Mental Health (NIMH), IPM, and Gilead for review prior to submission. 
 
 
15 APPENDICES 
 
 


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APPENDIX I:  Table of Visits and Study Procedures – Mothers 
 
 
Visit 
1 
SCR 
Visit 
2 
ENR 
Phone 
Contacts 
Prior to 
Pregnancy 
Outcome 
Cohorts 2-3 
only 
Bi-
weekly 
Visits 
After 
36th 
Week 
PPO Visit 
1-week 
PPO 
Phone 
Contact 
6-week 
PPO 
Visit/SEV/ 
Early 
SEV 
2-
week 
Visit 
4-
week 
Visit(s) 
ADMINISTRATIVE AND REGULATORY 
Obtain/confirm informed consent 
X 
X 
 
 
 
 
 
 
 
Obtain/review/update signed 
medical records release and 
antenatal/delivery care provider 
information (if required per local 
laws/regulations) 
X 
 
 
 
 
 
X 
 
 
Schedule ultrasound (if records 
not available at Screening) 
X 
 
 
 
 
 
 
 
 
Assign a unique Participant 
Identification (PTID) number 
X 
 
 
 
 
 
 
 
 
Assess and/or confirm eligibility 
X 
X 
 
 
 
 
 
 
 
Collect demographic information 
X 
 
 
 
 
 
 
 
 
Collect/review/update locator 
information 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Obtain/review/update 
planned/actual location of delivery 
X 
 
X 
 
 
X 
X 
 
 
Randomization 
 
X 
 
 
 
 
 
 
 
Provide reimbursement (sites to 
reference SOPs) 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Schedule next visit/contact 
* 
* 
X 
X 
X 
X 
* 
X 
* 
BEHAVIORAL 
HIV pre- and post-test counseling 
X 
X 
 
* 
X 
▲ 
* 
 
X 
HIV/STI risk reduction counseling 
X 
X 
* 
* 
X 
▲ 
* 
* 
X 
Contraceptive counseling 
 
 
 
 
 
▲ 
* 
 
X 
Protocol adherence counseling 
 
X 
* 
X 
X 
X 
X 
* 
X 
Behavioral assessment  
 
X 
 
 
ɸ  
 
X 
(Cohorts 
2-3 only) 
 
X 
Product acceptability assessment 
(Cohorts 2-3 only) 
 
X 
 
 
ɸ  
 
 
 
 
Social harms assessment 
 
 
 
 
ɸ  
 
 
 
X 
Social benefits assessment 
 
 
 
 
 
 
 
 
X 
In-depth interview (IDI) (subset) 
 
 
 
 
♦ 
♦ 
 
 
 
CLINICAL 
Review/update medical history 
and obstetric symptoms 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Review/update available ultrasound
results and antenatal/delivery/ 
postpartum care records 
X 
X 
 
 
X 
X 
X 
 
X 
Review/update concomitant 
medications and vaginal products 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Physical exam (Targeted after 
Screening Visit) 
X 
* 
 
* 
X 
* 
X 
 
* 
Pelvic exam 
* 
X 
 
* 
* 
* 
 
 
* 
Obstetric abdominal exam 
X 
X 
 
X 
X 
X 
 
 
 
Calculate/confirm gestational age 
X 
X 
 
 
 
 
 
 
 
Treat RTI/UTI/STIs 
* 
* 
* 
* 
* 
* 
* 
* 
* 


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Visit 
1 
SCR 
Visit 
2 
ENR 
Phone 
Contacts 
Prior to 
Pregnancy 
Outcome 
Cohorts 2-3 
only 
Bi-
weekly 
Visits 
After 
36th 
Week 
PPO Visit 
1-week 
PPO 
Phone 
Contact 
6-week 
PPO 
Visit/SEV/ 
Early 
SEV 
2-
week 
Visit 
4-
week 
Visit(s) 
Disclose available test results 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Collect AEs 
 
 
X 
X 
X 
X 
X 
X 
X 
LABORATORY 
URINE 
Dipstick UA (and/or 
culture)** 
X 
X 
 
* 
∇ 
* 
* 
 
X 
Offer pregnancy testing 
 
 
 
 
 
 
 
 
X 
BLOOD 
HIV-1 testing 
X 
X 
 
* 
X 
▲ 
* 
 
X 
HBsAG 
X 
 
 
 
 
 
 
 
 
AST/ALT 
X 
X 
 
* 
∇ 
* 
* 
 
X 
Creatinine (Cohort 1 only) 
X 
X 
 
 
 
▲ 
* 
 
X 
Creatinine (Cohorts 2-3) 
X 
X 
 
* 
π 
* 
* 
 
X 
CBC with platelets 
X 
X 
 
* 
∇ 
* 
* 
 
X 
Syphilis serology 
X 
* 
 
* 
* 
* 
* 
 
X 
DBS for TFV-DP and FTC-
TP drug levels (after Visit 2, 
for Truvada group only) 
 
X 
 
X 
X 
X 
X 
 
 
Plasma for DPV drug levels 
(for DPV group) 
 
 
 
X 
X 
X 
X 
 
 
Plasma archive 
 
X 
 
 
 
 
 
 
 
PELVIC 
NAAT for GC/CT/Trich 
X 
* 
 
* 
* 
* 
* 
 
X 
Wet prep/KOH wet mount 
for candidiasis and/or BV 
* 
* 
 
* 
* 
* 
* 
 
* 
Vaginal pH 
* 
X 
 
* 
* 
* 
 
 
X 
Vaginal swab(s) for 
microbiota 
 
X 
 
X 
X 
X 
 
 
X 
Vaginal Gram stain 
 
X 
 
X 
X 
X 
 
 
X 
Vaginal swab(s) for 
biomarkers 
 
X 
 
X 
X 
X 
 
 
X 
STUDY 
PRODUCT 
Adherence assessment(s):  
Returned Study VR(s) 
 
 
 
 
X 
* 
X 
 
 
STUDY PRODUCT / SUPPLIES 
Provide study VR or study tablets 
 
X 
 
 
X 
* 
 
 
 
Provide product use instructions 
 
X 
 
 
X 
* 
 
 
 
Insertion of study VR at the clinic 
(clinician check of VR placement 
done with initial insertion by 
participant; check done as 
needed for subsequent VRs) (for 
DPV group) or DOD of first study 
tablet (for Truvada group) 
 
X 
 
 
X 
ⱽ 
 
 
 
Remove and/or collect study VR 
or study tablets 
 
 
 
 
X 
* 
X 
(if final 
VR or 
tablets 
not 
already 
collected) 
 
 
Offer condoms 
X 
X 
 
X 
X 
X 
X 
 
X 


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X = Required           * = If indicated and/or per local standard of care 
 
          ** Per local standard of care 
▲ = Required at second Bi-weekly Visit and if indicated at all others 
ⱽ = Required if product resupply occurs during visit 
ɸ = Required at 1st 4-week Visit for Cohorts 2-3, and 4-week Visit corresponding to, or immediately before, 36th week 
gestation for Cohort 3 
∇ = Required at 1st 4-week Visit for Cohorts 2-3, and also for Cohort 3 at the visit corresponding to, or immediately 
following, the 28th week of gestation 
♦ = May be scheduled any time between the 1st Bi-weekly Visit and study exit for Cohort 1, or the 1st 4-week Visit and 
study exit for Cohorts 2-3, to accommodate participant availability 
π Required at 1st 4-week Visit and every 12 weeks thereafter 


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APPENDIX II:  Table of Visits and Study Procedures – Infants 
 
 
PPO 
Visit 
1-week PPO 
Phone 
Contact 
6-week 
PPO  
Visit 
6-month 
PPO  
Visit 
12-month  
PPO 
Visit/Early 
SEV 
ADMINISTRATIVE AND REGULATORY 
Obtain consent for infant if not already obtained 
X 
 
 
 
 
Collect/review/update locator information 
X 
X 
X 
X 
X 
Provide reimbursement (sites to reference SOPs) 
X 
X 
X 
X 
X 
Schedule next visit/contact  
* 
X 
X 
X 
* 
CLINICAL 
Review infant health, anthropometry, feeding history 
X 
X 
X 
X 
X 
Review/update delivery records 
X 
 
 
 
 
Review/update infant health records 
X 
 
X 
X 
X 
Review/update concomitant medications 
X 
X 
X 
X 
X 
Physical exam (Targeted after PPO Visit) 
X 
 
X 
X 
X 
Collect AEs 
X 
X 
X 
X 
X 
Disclose available test results 
X 
X 
X 
X 
X 
LABORATORY – BLOOD 
HIV-1 testing 
* 
 
* 
* 
* 
AST/ALT 
* 
 
* 
* 
* 
Creatinine 
X 
 
X 
* 
* 
CBC with platelets 
* 
 
* 
* 
* 
DBS for TFV-DP and FTC-TP drug levels (for infants born 
to mothers in the Truvada group) 
X 
 
 
 
 
Plasma for DPV drug levels (for infants born to mothers in 
the DPV group) 
X 
 
 
 
 
STUDY SUPPLIES 
Offer condoms to mother 
 
 
 
X 
X 
X = required 
* = if indicated and/or per local standard of care 
 
 
 
 
 


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APPENDIX III:  Algorithm For HIV Testing – SCREENING/ENROLLMENT 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Report as 
HIV uninfected 
Ineligible 
for the study
-/-
+/- 
+/+
START
2 different Rapid Tests
Notify the MTN Laboratory Center 
for follow-up.
 


 
 
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APPENDIX IV:  Algorithm For HIV Testing – FOLLOW-UP  
 
 
 
 
START
2 different Rapid Tests
Report as HIV 
Uninfected 
-/-
+/+
or
+/-
HIV RNA  
- or Ind 
Confirmation Test
Report as HIV 
Infected
+
+
- 
Notify  MTN LC  
Repeat Confirmation Test after 1 month
Ind: Indeterminate test results
LC: Laboratory Center 


 
 
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APPENDIX V: Sample Informed Consent Form  
(Screening, Enrollment, Long-Term Storage and Off-Site Visit), MOTHER – 
COHORT 1 
 
SAMPLE INFORMED CONSENT FORM 
DIVISION OF AIDS, NIAID, NIH 
 
MTN-042 
 
Phase 3b, Randomized, Open Label Safety Trial of Dapivirine Vaginal Ring and 
Oral TRUVADA® Use in Pregnancy 
 
Version 2.0 
 
 May 20, 2021 
 
PRINCIPAL INVESTIGATOR: [Site to insert] 
PHONE: [Site to insert] 
Short Title for the Study: DELIVER: A Phase 3b Safety Study of the Dapivirine Ring and PrEP  
        in Pregnant Women 
 
INFORMED CONSENT  
You are being invited to join a research study funded by the US government [US National 
Institutes of Health (NIH)] and conducted by the Microbicide Trials Network (MTN).  There is a 
separate consent document for your baby. There are two products being used in this study: a 
ring inserted in the vagina and a tablet taken by mouth. The ring is supplied by International 
Partnership for Microbicides (IPM) and the tablet is supplied by Gilead Sciences, Inc.  The 
person in charge of this study at this site is [INSERT NAME OF PRINCIPAL INVESTIGATOR].   
 
STUDY SUMMARY 
Important things you should know: 
• 
The study products in this research study each contain a different anti-HIV medication:  
o The vaginal ring (VR) contains 25 mg of dapivirine (DPV). It is inserted in the vagina 
and worn continuously for approximately one month, to be replaced every month. We 
will refer to it in this document as the ring. 
o The oral tablet, Truvada, contains two drugs-  200 mg of emtricitabine (FTC) and 300 
mg of tenofovir disoproxil fumarate (TDF). It is taken once a day by mouth. We will 
refer to it in this document as the tablet. 
• 
The purpose of this study is to find out if using the ring or the tablet during pregnancy is safe 
and well-tolerated by women and their babies. 
• 
If you qualify and choose to participate, you will be randomly assigned to use one of the two 
study products for the remainder of your pregnancy (you will not use study product after the 
end of your pregnancy). 
• 
You will be asked to complete up to eleven (11) study visits (not including unscheduled 
visits), including the visit today and including up to four (4) phone contacts. Study visits will 
take place either at this study clinic, at the hospital where you intend to deliver your baby, or 
at other locations with your permission. You must intend to deliver at a hospital or similar 
health facility to be eligible for this study, such as [SITES TO INSERT NAMES OF 
LOCATIONS AFFILIATED WITH THE SITE]. The approximate length of your participation in 


 
 
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this study will be about 10 weeks. This includes the time remaining in your pregnancy and 
six additional weeks of follow-up for you. You will only take the study product while you are 
pregnant. 
• 
At some of the clinic visits, you will be asked to complete the following: a physical exam 
(including abdominal exam and ultrasound) , blood draw, urine and vaginal fluid collection, 
several short interviews (and possibly a longer interview at one or more visits, if you are 
selected), and you will be asked permission to access your medical records and contact 
your health care provider. 
• 
Some common risks or discomforts from the ring include: vaginal irritation, discharge, and/or 
discomfort. One serious but rare side effect is toxic shock syndrome caused by poisons 
(toxins) released by some types of Staphylococcus aureus, a common bacteria. 
• 
Some common risks or discomforts from the tablet include: nausea, abdominal pain, 
diarrhea, vomiting, passing gas, headache, dizziness, tiredness, and inability to sleep. More 
serious but rare side effects include: rash, liver problems, kidney problems, allergic reaction, 
and lactic acidosis. 
• 
You will be using a study product that may prevent you from getting HIV if you use it 
consistently, but neither study product can guarantee protection from HIV. Information 
learned from this study may also help in the development of ways to prevent the spread of 
HIV in the future. You will receive testing for HIV and other sexually transmitted infections 
(STI), medical examinations, HIV and contraceptive counseling, and routine laboratory 
testing to check your overall health.  
• 
Taking part in this research study is voluntary. You do not have to participate and you can 
stop at any time. 
• 
If you decide not to join this study, there are currently available methods to prevent sexually 
transmitted HIV: condom use during sex and/or the use of daily oral Truvada for pre-
exposure prophylaxis (PrEP) or post-exposure prophylaxis (PEP). Study staff can provide 
you with additional information about PrEP and PEP if you are interested.  
 
Please take time to read this entire form and ask questions before deciding to join this study. If 
you are willing to take part in the study, you will sign your name on this form. A copy of this form 
will be offered to you. Signing this consent form does not mean you will be able to join the study. 
You must first complete the screening tests and exams to see if you are eligible. It is important 
to know that your and your infant’s participation in this research study is your decision and 
taking part in this study is completely voluntary (see Your Rights as a Research 
Participant/Volunteer for more information). 
 
STUDY DETAILS 
 
Study Products 
The ring was tested and found to be well-tolerated for use by adolescent (15-17 years old) and 
adult (18 years and older) women. DPV works by stopping HIV from making copies of itself. It 
was found to reduce HIV infection in women when used consistently. Researchers believe that 
younger women were not protected from getting HIV because they did not use the ring 
consistently. The ring received a positive opinion from the European Medicines Agency to 
reduce the risk of HIV infection in adult women and is now recommended by the World Health 
Organization as an HIV prevention option. It remains under review by the US Food and Drug 
Administration (FDA) and has yet to be approved for HIV prevention in any country. 
 
The tablet, called Truvada, is an HIV prevention method approved for adults called oral pre-
exposure prophylaxis (PrEP). The tablet works by stopping HIV from making copies of itself and 


 
 
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reduces risk of HIV infection when used consistently.  The tablet is also approved to treat HIV 
infection in people older than 12 years when combined with other drugs.  
 
Neither study product is effective against common sexually transmitted diseases other than HIV. 
Neither study product can guarantee protection from HIV. 
 
Who will be in this research study? 
Five hundred fifty (550) healthy, pregnant women who are 18 to 40 years old will be enrolled in the 
study across various sites in Malawi, South Africa, Uganda and Zimbabwe. Of these, 150 women 
who are between 36 and 38 weeks in their pregnancy will be enrolled at this time. 
 
What will I be asked to do if I join this research study?   
For the remainder of your pregnancy, you will either insert a ring and leave it in place for a 
month, replacing it every month, or take an oral tablet every day. Which of the two products you 
will use will be decided by chance [SITES TO INSERT PREFERRED DESCRIPTION OF 
‘RANDOMIZATION’] – for every 2 women who will receive the ring, there will be 1 woman who 
will receive the tablet. Neither you nor the study staff can decide which of the two products you 
will use.   
 
You will come to the clinic every two weeks for the remainder of your pregnancy. You will also 
have a phone contact with study staff a week from today and every two weeks after that until 
delivery, and then one call up to two weeks after delivery. You will allow study staff to access 
your medical records, and to conduct a study visit as soon as possible after you deliver your 
baby, no later than two weeks after you deliver.  This visit may occur at the study clinic, at the 
hospital where you deliver, or other location (with your permission). Your final visit will occur 6 
weeks after you deliver, for a total maximum of eleven (11) study visits including the visit today 
and the phone contacts (but not including any unscheduled visits). You will be in the study for 
approximately 10 weeks. Your baby will also have study visits, which are outlined in a separate 
consent form. Each visit will take about [SITES TO INSERT THE APPROXIMATE LENGTH OF 
TIME]. During your visit after delivery and the 6 week visit, your baby will also have study 
procedures completed.   
 
Do I have to be in this study? 
You do not have to be in this study. You can still get the care you need even if you do not join 
the study. If you join today but change your mind later, you can inform the study staff that you 
no longer wish to participate. If you do not join the study, your baby cannot join the study. 
 
What procedures will be done for this study? 
Your first visit will happen today after you read, discuss, understand and sign/mark this form. 
The procedures done at this visit will let us know if you can join this study, and will take about 
[SITES TO INSERT THE APPROXIMATE LENGTH OF TIME].  
 
If it seems like you can join, you will be asked to come back for an Enrollment visit no later than 
35 days from today. During the Enrollment Visit, you will begin using the ring or begin taking the 
tablet, depending on which study group you have been assigned to. 
 
The following things will happen during your study visits: 
• 
We will ask questions about your health, any medications you may be taking, and any 
vaginal products you may be using. We will ask questions about your thoughts and feelings 
and your mood. We will also ask questions about your living situation to see if it affects your 
use of the study products, and about your reasons for wanting to join this study and how 


 
 
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worried you are about getting HIV.  
• 
We will ask your permission to access your medical records, including your delivery records 
to gather information about your baby at the time of birth. We will also ask your permission 
to contact your care provider and to conduct a study visit as soon as possible after you have 
your baby. 
• 
We will talk with you about what you need to do to be in the study, how to use the study 
products, and how to protect yourself from getting an infection, including HIV. We may 
audio-record these conversations to assess how our study staff counsel you and work with 
them to improve the quality of the counseling you receive, and to learn about experiences 
and concerns participants may have. The recordings will be kept confidential. If you do not 
want to have your counseling session recorded, let study staff know. 
o It is important that you know if you do not intend to deliver your baby at a 
hospital or similar health facility [SITES TO INSERT NAMES OF LOCATIONS 
AFFILIATED WITH THE SITE], you will not be eligible to participate in this 
study.  
• 
After the birth of your infant, we will also talk with you about how to keep from getting 
pregnant. 
• 
We will schedule you for an ultrasound if you have not had one or do not have your 
ultrasound results with you today. 
o It is important that you know if you do not have an ultrasound, you will not be 
eligible to participate in this study. 
• 
At each study visit, we will draw up to 30 mL (about 2 tablespoons) of blood per visit [Sites 
to insert local amount] to make sure you are healthy and to test you for HIV and other STIs. 
We will also test your blood to see if you are using the study products. More blood may be 
collected if you become ill. 
• 
At some visits, we will collect a urine sample to test you for STIs.  
• 
At some visits, we will give you a physical exam to make sure you are healthy.  
• 
At all visits before the birth of your infant, we will give you an abdominal exam to make sure 
your pregnancy is going well. 
• 
At the Enrollment Visit, we will give you a pelvic exam to check for infections and to make 
sure you are healthy. We may give you a pelvic exam at other visits, if needed. The study 
doctor or nurse will use a speculum to do the pelvic exam. A speculum is a plastic or metal 
tool used to help open the vagina so that the doctor or nurse can examine your vagina and 
cervix and take some fluids.  
• 
At some visits, we will take fluids from your vagina using a swab (e.g., Q-Tip or earbud). 
Vaginal fluids will be collected to look for any changes that may occur during your 
participation in the study and to test for STIs. 
• 
At some visits, you will answer questions about using the study products and other 
behaviors, including sexual activity. Some of the questions may be sensitive. If you ever feel 
uncomfortable, you can choose not to answer questions at any time. Your answers will be 
kept confidential and no one other than the study team will have access to your responses. 
• 
We may also ask you to do one or more longer interviews with study staff. You may choose 
not to do these interviews. During the interview(s), we may ask you to discuss your use of 
the study products, your feelings about the study products and about being in the study, and 
other questions that can help researchers to better understand participants’ experiences 
while in the study. We may audio-record the interview(s). We will keep the audio recording 
and related materials confidential and no one other than the study team will have access to 
your responses. 
• 
For every month you are in the study until the end of your pregnancy, we will give you either 
another ring to use, or another month of tablets to take.   


 
 
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• 
We will give you the results of any blood or urine tests when available. 
• 
We will give you treatment for sexually transmitted and other kinds of infections, if you need 
them. 
• 
In the event a problem with a pregnancy is suspected, an ultrasound can be ordered at the 
site or a referral will be provided. 
• 
We will give you referrals for other services, if you need them.  
• 
These visits will take about [SITES TO INSERT AVERAGE VISIT DURATION] to complete.  
 
If you enroll in the study, only for 24 hours prior to your clinic visits you will be asked to abstain 
from sex, tampon use and other non-study products.  
 
Activity: 
Not Permitted For How Long? 
Receptive sexual practices, including: 
• 
Penile-vaginal intercourse 
• 
Penile-anal intercourse 
• 
Receptive oral intercourse 
• 
Finger stimulation 
For 24 hours before each clinic visit 
Tampon use 
For 24 hours before each clinic visit 
Inserting any non-study objects into your vagina, including: 
• 
Pessaries 
• 
Sex toys 
• 
Female condoms  
• 
Diaphragms 
• 
Menstrual cups  
• 
Cervical caps or any other vaginal barrier method 
For 24 hours before each clinic visit  
 
Using vaginal products like spermicides, lubricants, contraceptive vaginal rings, douches, 
vaginal medications, etc., is not allowed at any time during this study. 
 
It is important for you to come to every study visit. If you cannot come to the visit, please tell the 
study staff as soon as possible so that the visit can be rescheduled.  
 
You may be asked to make additional visits so we can do more laboratory tests or have study 
procedures repeated. We will do this if there are abnormal test results or a mistake during the 
collection or the processing of your samples. We will also do this if you experience any changes 
in your physical condition, including symptoms of infection (urinary or sexually transmitted). 
 
What if I become infected with HIV? 
Being in this study will not cause HIV infection for you or your infant. But, there is always a 
chance that you can get HIV through condomless sex or other activities. If you become HIV-
positive, you will stop using the study product. But, we will ask you to continue to come for your 
study visits and to complete some of the study procedures for a minimum of twelve months. 
This study does not provide medication for treatment of HIV. If you become infected with HIV, 
the study staff will refer you for medical care and other available services to prevent your infant 
from getting HIV. If you get HIV, it is possible that the virus is resistant to some drugs. This 
means that some drugs may not work well to treat your HIV. This is also possible if your infant 
becomes infected. We will do a blood test to find out if you have drug resistance. These results 
can help us know which drugs would be best to treat your HIV. 
 
Depending on local and national health requirements, the study staff may need to report certain 
diseases, including HIV. The reportable diseases at this site are [SITES TO INSERT]. We must 
inform the following [SITES TO INSERT MORE DETAILED INFORMATION REGARDING WHO 


 
 
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WILL BE INFORMED OF THE REPORTABLE DISEASES]. [SITES TO INCLUDE/AMEND THE 
FOLLOWING]: Outreach workers from the [LOCAL HEALTH AUTHORITY] may then contact 
you about informing your partner/s, since they also should be tested. If you do not want to 
inform your partner/s yourself, the outreach workers will contact them, according to the 
confidentiality guidelines of the [LOCAL HEALTH AUTHORITY]. 
 
RISKS AND/OR DISCOMFORTS 
 
Risks of Blood Draws  
You may feel discomfort or pain when your blood is drawn.  You may feel dizzy or faint.  You 
may have a bruise, swelling, or small clot where the needle is inserted. Rarely, drawing blood 
can cause an infection where the needle goes into your hand or arm. 
 
Risks of Pelvic Exams  
You may feel discomfort or pressure during the pelvic exam.  You may have a small amount of 
vaginal bleeding or spotting which should stop shortly after the exam. 
 
Risks of the DPV VR 
We do not yet know all the side effects of the ring. Most people who have used the ring did not 
have any side effects. Some women who used the ring in other studies have had: discharge 
from the vagina; pelvic pain; burning or itchiness in the vagina; and urinary tract infections. Less 
common side effects included: irritation, bruising, swelling, inflammation, wearing, and 
discharge from the cervix; bladder pain and inflammation; vaginal odor, itching, inflammation, 
tearing, and discomfort; pelvic discomfort; abdominal pain and discomfort; and problems 
urinating. 
 
Although rare, the ring may cause an allergic reaction.  Signs of an allergic reaction include, but 
are not limited to: rash or other skin irritation, itching, joint pain, or difficulty in breathing.  
 
There is the possibility of getting toxic shock syndrome, although this is very rare. Toxic shock 
syndrome is a serious but rare infection caused by bacteria. Any product placed inside the 
vagina can cause it. Getting toxic shock syndrome from using the ring is unlikely. But, it is 
important that you tell the study staff as soon as possible if you have any of the following 
symptoms: sudden high fever, a faint feeling, diarrhea, headache, rash, and muscle aches. 
 
It is possible that the side effects from ring use may be different in women who are pregnant, or 
that the side effects may resemble normal symptoms of pregnancy. Studies with pregnant 
animals showed that DPV did not cause side effects to the animals or their fetuses. Women who 
became pregnant while using the ring in clinical studies did not experience more side effects 
than non-pregnant women, and neither did their infants. However, there is not enough 
information to know for sure. One small study found that DPV can be detected in breastmilk 
from women who used the ring while lactating, but it is unknown whether the small amounts of 
drug detected could produce side effects in babies. 
 
Risks of the Truvada tablet   
Most people who take the tablet do not have any side effects. The side effects that some people 
taking the tablet may have are well known because the drugs have been used by many people. 
People with hepatitis B who suddenly stop taking the tablet may get a flare-up or worsening of 
their hepatitis symptoms. 
 
One in ten people who take the tablet may have mild side effects that usually go away after 


 
 
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stopping the drug. These occasional side effects include: mild kidney problems that are only 
detected by laboratory tests, inability to sleep, lack of energy or tiredness, headache, upset 
stomach, passing gas, vomiting, soft or liquid stools, and dizziness. Upset stomach, passing 
gas, vomiting and soft or liquid stools typically go away after the first or second month of use. 
 
Other side effects are more serious, but less than one in a hundred people who take the tablet 
may have them. These rare side effects include: rash, liver problems, serious kidney damage, 
and allergic reaction. People taking the tablet may also have bone pain and/or small changes in 
the thickness of their bones, but these changes have not caused problems for the people who 
had them.  
 
In rare cases, some people with HIV who take the tablet in combination with other drugs may 
get lactic acidosis. This is a serious side effect of some drugs used to treat HIV that can cause 
shortness of breath, nausea, and liver failure. This serious side effect has been seen more often 
in women taking the tablet in combination with other drugs. You should call or come to the clinic 
if you have unexplained changes in urination, weight loss, cramps, muscle pain, dizziness, 
tiredness, nausea, vomiting, or shortness of breath.  
 
The use of antiretroviral drug combinations may lead to changes in body fat, some of which 
include: increase in fat around the waist and stomach area; increase in fat on the back of the 
neck; thinning of the face, legs and arms; and breast enlargement. If you have these symptoms, 
or any other symptoms that concern you, the study staff will check you and see if you should 
stop taking the tablet.  
 
It is possible that the side effects from using the tablet may be different in women who are 
pregnant, or that the side effects may resemble normal symptoms of pregnancy. Studies with 
pregnant animals showed that FTC and TDF, the drugs in the tablet, did not cause any effects 
on the animals’ fertility or their fetuses, although TDF led to changes in the menstrual cycles of 
rats. HIV-infected pregnant women and women who became pregnant while taking the tablet in 
clinical studies did not experience more side effects than non-pregnant women, and their infants 
did not have more birth defects than the general infant population. However, there is not enough 
information to know for sure. 
 
A small number of people in this study may have these side effects or other side effects that we 
do not know about yet. But, we will screen your kidneys and overall health before you join the 
study and during the study. This will reduce your chances of having any side effects. 
 
Risks of HIV and Sexually Transmitted Infection (STI) Testing 
HIV and STI testing may make you feel anxious regardless of the test results. Finding out your 
HIV status may cause sadness, depression, and thoughts of suicide, and may also cause 
problems with your family, friends, or partner.   
 
Other Possible Risks 
You may feel embarrassed and/or worried when talking about sexual activities, your living 
situation, ways to protect against HIV and STIs, and your test results. You can choose not to 
answer questions at any time. Trained study counselors will help you with any feelings or 
questions. 
 
It is possible that others may learn of your participation in this study, and because of this, may 
treat you unfairly or discriminate against you. If you have any problems, study counselors will 
talk with you and try to help you. 


 
 
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The ring and the tablet can protect you from getting HIV, but based on what we know, the level 
of protection may be different between the two products. This difference may have an effect on 
your and your infant’s risk of getting HIV. Trained study counselors will help you with any 
feelings or questions. 
 
BENEFITS 
You will be using one of two study products that may prevent you from getting HIV if you use it 
consistently, but neither study product can guarantee protection from HIV. Information learned 
from this study may help us learn how to prevent pregnant women from getting HIV. You will 
receive medical exams, and you will receive counseling and testing for HIV and STIs. You will 
also have tests to check your overall health. 
 
This study cannot give you antenatal care or delivery services, and cannot give you general 
medical care. Study staff will refer you to another medical provider for care, if needed. You will 
get free condoms, if you need them. You will be offered a family planning method after delivery, 
if you need it. If you have an STI diagnosed, you will receive medicine or a referral, if you need 
it.   
 
NEW INFORMATION 
You will be told any new information learned during this study that may affect your willingness to 
stay in the study. For example, we will let you know if we learn that the study products may be 
causing bad side effects. We will tell you any new information about preventing HIV, regardless 
of the product, if we learn that it works during pregnancy. We will also tell you when study 
results may be available, and how to learn about them. 
 
A description of this research study will be available on http://www.ClinicalTrials.gov, as 
required by U.S. law. This Web site will not include information that can identify you. At most, 
the Web site will include a summary of the results. You can search this Web site at any time. 
 
WHY YOU MAY STOP TAKING THE STUDY DRUG EARLY OR BE ASKED TO LEAVE THE 
STUDY 
You may need to leave the study early without your permission if: 
• 
The study is cancelled by the US FDA, US NIH, IPM, Gilead Sciences, Inc., the US Office 
for Human Research Protections (OHRP), MTN, the local government or regulatory agency, 
or the Institutional Review Board (IRB)/Ethics Committee (EC). An IRB/EC is a committee 
that watches over the safety and rights of study participants. 
• 
The Study Monitoring Committee (SMC) recommends that the study be stopped early. The 
SMC reviews the progress of the study. 
• 
The Interim Review Panel (IRP) recommends that the study be stopped early. The IRP 
reviews results after each group of participants finishes the study and decides if the next 
group should begin the study.  
• 
You are not able to keep appointments. 
• 
Other reasons that may prevent you from completing the study successfully. 
 
The study doctor will ask you to stop using the study products if you: 
• 
Acquire an HIV infection. 
• 
Acquire a hepatitis B infection (Truvada users only). 
• 
Use drugs for HIV prevention beyond what the study gives you.  
• 
Use drugs to prevent infection after being exposed to HIV. 


 
 
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• 
Use injectable drugs for reasons other than treating disease. 
• 
Go into labor. 
• 
Experience the death or serious health issue with your unborn child. 
• 
Have a bad reaction to study product, or a study doctor decides that using study product 
would be bad for you. 
• 
Are unable or unwilling to follow the study rules. 
 
If a study doctor asks you to stop using study product, we will ask that you and your infant come 
in for all remaining study visits to have some of the procedures we talked about earlier. 
 
If you are removed from the study or choose to leave, we will ask you to return the study 
product and to come back for one final clinic visit. If you do not have the study product with you 
when you come to the clinic, staff members will make every effort to assist you in returning it as 
soon as possible. [SITES TO SPECIFY ALLOWANCES FOR SPECIAL CIRCUMSTANCES.] If 
you leave the study, we will ask you to check in with study staff until the end of your pregnancy 
and for one year after giving birth so we can follow your health and the health of your infant. If 
you choose to leave the study and later wish to rejoin, you may resume using study product (if 
applicable) and come in for all study visits remaining in your original visit schedule after 
consultation with the Protocol Safety Review Team. 
 
ALTERNATIVES TO BEING IN THE STUDY 
[SITES TO INCLUDE/AMEND THE FOLLOWING, IF APPLICABLE: You may be able to join 
other studies here or in the community. There may be other places where you can go for HIV 
counseling and testing and family planning. We will tell you about those studies and those 
places if you wish.] 
 
COSTS TO YOU 
[SITE TO COMPLETE ACCORDING TO SITE CAPACITY] There is no cost to you for study 
visits, study products, medical exams, laboratory tests or other procedures. We can give you 
treatments for STIs other than HIV free of charge while you are in the study, or we can refer you 
for available treatment. 
 
REIMBURSEMENT 
[SITES TO INSERT INFORMATION ABOUT LOCAL REIMBURSEMENT]: You will receive 
[SITES TO INSERT AMOUNT $xx] for your time, effort, and travel to and from the clinic for each 
study visit. You may receive [SITES TO INSERT AMOUNT $xx] for any extra study visits. If you 
are chosen to take part in the longer interview(s) with staff, you will receive [SITES TO INSERT 
AMOUNT $xx]. 
 
CONFIDENTIALITY 
We will make every effort to keep your and your infant’s information private and confidential. 
But, we cannot guarantee it.   
 
Study visits will take place in private. We will keep the information about your study visits in a 
secure place that only certain people can access for the purposes of this study. We will only 
enter your information into computers protected by passwords and will not include information 
that could identify you. We will only record your study ID number. If you are selected to do the 
longer interview(s), you can choose not to answer questions at any time. We will keep the audio 
recordings and materials from all interviews and discussions confidential and will only use study 
numbers or fake names. [Sites to modify with their site-specific source documentation storage 


 
 
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duration requirements if required by their IRBs/IECs: All original study documents that provide 
information about you for this study will be kept for at least two years after either the dapivirine 
vaginal ring is approved for use or the clinical research development program for the dapivirine 
vaginal ring is stopped.] 
 
Your personal information may be disclosed if required by law. For example, if we learn 
something that would immediately put you or others in danger, the study staff must take steps to 
keep you and others safe. This means that we have to share any information with the authorities 
(hospital, police, or social services) that tells us you may be in danger. For example, if you tell 
us that you plan to hurt or kill yourself, hurt or kill someone else, or if you tell us that someone is 
abusing or neglecting you. 
 
The study staff may use your personal information to verify that you are not in any other 
research studies. [SITES TO INSERT INFORMATION ABOUT SYSTEMS CURRENTLY IN 
PLACE TO ENSURE PARTICIPANTS ARE NOT PART OF OTHER CONFLICTING STUDIES, 
INCLUDING BIOMETRIC IDENTIFICATION SYSTEMS.] This study will not use your name or 
identify you personally in any publication. 
 
Your records may be reviewed by: 
• 
Representatives of the US Federal Government, including the US FDA, US OHRP, NIH 
and/or NIH contractors, and other US, local, and international regulatory entities 
• 
[SITES TO INSERT APPLICABLE LOCAL AUTHORITIES] 
• 
IPM, the organization that supplies the ring 
• 
Gilead Sciences, Inc., the company that supplies the tablets 
• 
Study monitors 
• 
Site IRB/EC 
• 
Study staff 
 
The study staff will do everything they can to protect your privacy.   
 
RESEARCH-RELATED INJURY 
It is unlikely that you or your infant will be injured by being in this study. The U.S. NIH does not 
have a mechanism to pay money or give other forms of financial compensation for research 
related injuries. You are not giving up any legal rights by signing this form. [Sites to replace with 
their site-specific research-related injury institutional policy if they already provide clinical trials 
insurance:] If you become ill or injured as a result of participation in this study, medical 
treatment for the adverse reaction or injury will be provided appropriately. The site staff will refer 
you for ongoing treatment for the injury, if needed. The study sponsor will be responsible for 
ensuring that insurance is provided to cover appropriate medical expenses for treatment of any 
such illness or injury if required by law or regulation. An HIV infection that occurs during the 
course of the trial will not be considered an injury or illness caused by trial participation. The 
research site or sponsor is not responsible for any loss, injuries and/or damages that are 
caused by any of the following things: 
• 
Any injury that happens because you used other medicine during the study that you did not 
tell us about. 
• 
Any injury that happens because you did not follow instructions given by the study doctor or 
nurse. 
• 
Any injury that happens because of negligence on your part. 
 


 
 
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YOUR RIGHTS AS A RESEARCH PARTICIPANT 
[SITES TO SPECIFY INSTITUTIONAL POLICY]: Being in this study is completely voluntary. 
You may choose not to join this study or leave this study at any time. If you choose not to join or 
to leave the study, you can still join other studies and access non-study services you would 
normally get at this clinic. If you want the results of the study after it is over, let the study staff 
members know. 
 
PROBLEMS OR QUESTIONS 
If you ever have any questions about the study, or if you have a research-related injury, you 
should contact [INSERT NAME OF THE INVESTIGATOR OR OTHER STUDY STAFF] at 
[INSERT TELEPHONE NUMBER AND/OR PHYSICAL ADDRESS]. 
 
If you have questions about your rights as a research participant, you should contact [INSERT 
NAME OR TITLE OF PERSON ON THE IRB/EC OR OTHER ORGANIZATION APPROPRIATE 
FOR THE SITE] at [INSERT PHYSICAL ADDRESS AND TELEPHONE NUMBER]. 
 
 


 
 
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[SITES TO OMIT THE FOLLOWING IF A SEPARATE CONSENT FOR STORAGE AND 
FUTURE TESTING OF SPECIMENS IS REQUIRED] 
CONSENT FOR STORAGE AND FUTURE TESTING OF SPECIMENS and RELATED 
HEALTH INFORMATION 
There may be a small amount of urine, blood, and vaginal  fluids left over after we have done all 
of the study related testing. We would like to store your leftover body fluids for future work that 
could include testing for study products, testing for HIV risk and testing related to COVID-19 
infection  (if such testing is available and needed to better understand the impact of COVID-19 
infection on the study data). If you agree, your samples and related health information will be 
stored safely and securely.   
 
Only approved researchers will be able to use these samples and health information. Some 
employees will need to have access to these samples to store them and keep track of where 
they are, but these people will not have information that directly identifies you.  The de-identified 
data and specimens could then be used for future research by our research team or other 
researchers without notifying you or asking your permission for this use.    
 
There is no time limit on how long your samples will be stored. Your samples may be shipped 
and/or stored outside of the country. We do not yet know the specific type of testing that will be 
done with these samples. But, they may be used to check that certain laboratory tests perform 
correctly. Any other testing beyond that will have to be approved by an IRB/EC. We do not plan 
to do genetic testing or sequencing (for example, the mapping of all of your genes, which is also 
known as whole genome sequencing) of any kind. Your specimens will never be used for 
commercial profit. 
 
You can still be in this study if you decide we cannot store your urine, blood, and vaginal fluids. 
You can change your mind about storing and using these samples for future tests at any time by 
writing to the person in charge of this study. We will then destroy the leftover samples. But, 
researchers will not be able to destroy samples or information from research that is already 
started. 
 
 
PARTICIPANT INITIALS OR MARK 
 
_____________________________ 
Initials/Mark                     Date   
 
I DO agree to allow my biological specimens and health 
data to be stored and used in future research studies. 
 
_____________________________ 
Initials/Mark                     Date 
 
I DO NOT agree to allow my biological specimens and 
health data to be stored and used in future research 
studies. 
 
 


 
 
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CONSENT FOR OFF-SITE VISITS 
 [Sites to modify as needed] 
Members of the research team at this clinic may be able to schedule off site visits with you at 
your home or at another location as part of the study.  With your permission, some of the 
scheduled study visits and some of the study procedures may take place at your home or other 
location outside of the research clinic, if you are unable to come into the clinic.  For example, if 
you need to receive a new ring or to have a urine or blood sample collected, study staff could 
come to you your home or meet you at another location, if you give your permission and if the 
study staff determine that it is appropriate.  The study personnel will explain in greater detail the 
requirements of these visits (like the conditions of the place, the type of visit and the time it will 
take) and the procedures in-place to maintain your information in a confidential manner.  
However, it is important that you know that off-site visits may eventually affect your 
confidentiality even if the study staff take precautions not to disclose the purpose of the visits. 
 
In order to conduct visits outside of the clinic, we will need you to give us permission to do so.  
Please read carefully the following statement and initial/mark and date one option.  Choosing 
not to have study visit procedures outside of the study clinic will not affect your participation in 
this study.  Even if you agree today, you can withdraw your consent for off-site visits at any time 
by providing your request in writing to the person in charge of this study.  In addition, before 
each off-site visit, we will confirm with you that you still agree and remember today’s discussion.  
 
 
PARTICIPANT INITIALS OR MARK 
 
_____________________________ 
Initials/Mark                     Date   
 
I DO agree to have study visit procedures at a location other 
than the study clinic by clinic staff, when necessary. 
 
_____________________________ 
Initials/Mark                     Date 
 
I DO NOT agree to have study visit procedures at a 
location other than the study clinic by clinic staff, when 
necessary. 
 
 


 
 
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SIGNATURE PAGE 
[INSERT SIGNATURE BLOCKS AS REQUIRED BY THE LOCAL IRB/EC:] 
All of the above has been explained to me and all of my current questions have been answered.  
I understand that I can ask questions about any aspect of this research study during the course 
of this study, and that future questions will be answered by the researchers listed on the first 
page of this form. 
 
Any questions I have about my rights or my infant’s rights as research participants will be 
answered by [INSERT LOCAL IRB/EC INFORMATION]. 
 
I voluntarily agree to be in this research study. A copy of this permission form will be given to 
me. 
 
 
 
________________________________ 
      
Participant’s Name (Print)   
 
 
  
 
 
________________________________  
______________  
Participant’s Signature  
 
 
 
Date  
 
 
________________________________ 
            
Study Staff’s Name Conducting  
Consent Discussion (Print) 
 
 
  
 
________________________________  
______________  
Study Staff Conducting  
 
 
 
Date 
Consent Discussion (Signature) 
 
 
________________________________ 
      
Witness Name (Print)   
 
 
  
 
 
________________________________  
______________  
Witness Signature  
 
 
 
 
Date  
 
 


 
 
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APPENDIX VI: Sample Informed Consent Form  
(Screening, Enrollment, Long-Term Storage and Off-Site Visit), MOTHER – 
COHORT 2 
 
SAMPLE INFORMED CONSENT FORM 
DIVISION OF AIDS, NIAID, NIH 
 
MTN-042 
 
Phase 3b, Randomized, Open Label Safety Trial of Dapivirine Vaginal Ring and 
Oral TRUVADA® Use in Pregnancy 
 
Version 2.0 
 
May 20, 2021 
 
PRINCIPAL INVESTIGATOR: [Site to insert] 
PHONE: [Site to insert] 
Short Title for the Study: DELIVER: A Phase 3b Safety Study of the Dapivirine Ring and PrEP  
        in Pregnant Women 
 
INFORMED CONSENT 
You are being invited to join a research study funded by the US government [US National 
Institutes of Health (NIH)] and conducted by the Microbicide Trials Network (MTN).  There is a 
separate consent document for your baby. There are two products being used in this study: a 
ring inserted in the vagina and a tablet taken by mouth. The ring is supplied by International 
Partnership for Microbicides (IPM) and the tablet is supplied by Gilead Sciences, Inc.  The 
person in charge of this study at this site is [INSERT NAME OF PRINCIPAL INVESTIGATOR].   
 
STUDY SUMMARY 
Important things you should know: 
• 
The study products in this research study each contain a different anti-HIV medication:  
o The vaginal ring (VR) contains 25 mg of dapivirine (DPV). It is inserted in the vagina 
and worn continuously for approximately one month, to be replaced every month. We 
will refer to it in this document as the ring. 
o The oral tablet, Truvada, contains two drugs-  200 mg of emtricitabine (FTC) and 300 
mg of tenofovir disoproxil fumarate (TDF). It is taken once a day by mouth. We will 
refer to it in this document as the tablet. 
• 
The purpose of this study is to find out if using the ring or the tablet during pregnancy is safe 
and well-tolerated by women and their babies. 
• 
If you qualify and choose to participate, you will be randomly assigned to use one of the two 
study products for the remainder of your pregnancy (you will not use study product after the 
end of your pregnancy) 
• 
You will be asked to complete up to sixteen (16) study visits (not including unscheduled 
visits), including the visit today and including up to six (6) phone contacts. Study visits will 
take place either at this study clinic, at the hospital where you intend to deliver your baby, or 
at other locations with your permission. You must intend to deliver at a hospital or similar 
health facility to be eligible for this study, such as [SITES TO INSERT NAMES OF 
LOCATIONS AFFILIATED WITH THE SITE]. The maximum length of your participation in 


 
 
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this study will be about 18 weeks. This includes the time remaining in your pregnancy and 
six additional weeks of follow-up for you. You will only take the study product while you are 
pregnant. 
• 
At some of the clinic visits, you will be asked to complete the following: a physical exam 
(including abdominal exam and ultrasound), blood draw, urine and vaginal fluid collection, 
several short interviews (and possibly a longer interview at one or more visits, if you are 
selected), and you will be asked permission to access your medical records and contact 
your health care provider. 
• 
Some common risks or discomforts from the ring include: vaginal irritation, discharge, and/or 
discomfort. One serious but rare side effect is toxic shock syndrome caused by poisons 
(toxins) released by some types of Staphylococcus aureus, a common bacteria. 
• 
Some common risks or discomforts from the tablet include: nausea, abdominal pain, 
diarrhea, vomiting, passing gas, headache, dizziness, tiredness, and inability to sleep. More 
serious but rare side effects include: rash, liver problems, kidney problems, allergic reaction, 
and lactic acidosis. 
• 
You will be using a study product that may prevent you from getting HIV if you use it 
consistently, but neither study product can guarantee protection from HIV. Information 
learned from this study may also help in the development of ways to prevent the spread of 
HIV in the future. You will receive testing for HIV and other sexually transmitted infections 
(STI), medical examinations, HIV and contraceptive counseling, and routine laboratory 
testing to check your overall health.  
• 
Taking part in this research study is voluntary. You do not have to participate and you can 
stop at any time. 
• 
If you decide not to join this study, there are currently available methods to prevent sexually 
transmitted HIV: condom use during sex and/or the use of daily oral Truvada for pre-
exposure prophylaxis (PrEP) or post-exposure prophylaxis (PEP). Study staff can provide 
you with additional information about PrEP and PEP if you are interested.  
 
Please take time to read this entire form and ask questions before deciding to join this study. If 
you are willing to take part in the study, you will sign your name on this form. A copy of this form 
will be offered to you. Signing this consent form does not mean you will be able to join the study. 
You must first complete the screening tests and exams to see if you are eligible. It is important 
to know that your and your infant’s participation in this research study is your decision and 
taking part in this study is completely voluntary (see Your Rights as a Research 
Participant/Volunteer for more information). 
 
STUDY DETAILS 
 
Study Products 
The ring was tested and found to be well-tolerated for use by adolescent (15-17 years old) and 
adult (18 years and older) women. DPV works by stopping HIV from making copies of itself. It 
was found to reduce HIV infection in women when used consistently. Researchers believe that 
younger women were not protected from getting HIV because they did not use the ring 
consistently. The ring received a positive opinion from the European Medicines Agency to 
reduce the risk of HIV infection in adult women and is now recommended by the World Health 
Organization as an HIV prevention option. It remains under review by the US Food and Drug 
Administration (FDA) and has yet to be approved for HIV prevention in any country. 
 
The tablet, called Truvada, is an HIV prevention method approved for adults called oral pre-
exposure prophylaxis (PrEP). The tablet works by stopping HIV from making copies of itself and 


 
 
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reduces risk of HIV infection when used consistently.  The tablet is also approved to treat HIV 
infection in people older than 12 years when combined with other drugs.  
 
Neither study product is effective against common sexually transmitted diseases other than HIV. 
Neither study product can guarantee protection from HIV. 
 
Who will be in this research study? 
Five hundred fifty (550) healthy, pregnant women who are 18 to 40 years old will be enrolled in the 
study across various sites in Malawi, South Africa, Uganda and Zimbabwe. Of these, 150 women 
who are between 30 and 36 weeks in their pregnancy will be enrolled at this time. 
 
What will I be asked to do if I join this research study?   
For the remainder of your pregnancy, you will either insert a ring and leave it in place for a 
month, replacing it every month, or take an oral tablet every day. Which of the two products you 
will use will be decided by chance [SITES TO INSERT PREFERRED DESCRIPTION OF 
‘RANDOMIZATION’] – for every 2 women who will receive the ring, there will be 1 woman who 
will receive the tablet. Neither you nor the study staff can decide which of the two products you 
will use.   
 
You will come to the clinic every two weeks for the first month you are in the study, and then 
after you are 36 weeks pregnant, every two weeks for the remainder of your pregnancy. You will 
also have a phone contact with study staff one and three weeks from today, and after you are 
35 weeks pregnant, every two weeks until delivery, and then one call up to two weeks after 
delivery. You will allow study staff to access your medical records, and to conduct a study visit 
as soon as possible after you deliver your baby, no later than two weeks after you deliver. This 
visit may occur at the study clinic, at the hospital where you deliver, or other location (with your 
permission). Your final visit will occur 6 weeks after you deliver, for a total maximum of sixteen 
(16) study visits including the visit today and the phone contacts (but not including any 
unscheduled visits). You will be in the study for up to 18 weeks. Your baby will also have study 
visits, which are outlined in a separate consent form. Each visit will take about [SITES TO 
INSERT THE APPROXIMATE LENGTH OF TIME]. During your visit after delivery and the 6 
week visit, your baby will also have study procedures completed.   
 
Do I have to be in this study? 
You do not have to be in this study. You can still get the care you need even if you do not join 
the study. If you join today but change your mind later, you can inform the study staff that you 
no longer wish to participate. If you do not join the study, your baby cannot join the study. 
 
What procedures will be done for this study? 
Your first visit will happen today after you read, discuss, understand and sign/mark this form. 
The procedures done at this visit will let us know if you can join this study, and will take about 
[SITES TO INSERT THE APPROXIMATE LENGTH OF TIME].  
 
If it seems like you can join, you will be asked to come back for an Enrollment visit no later than 
35 days from today. During the Enrollment Visit, you will begin using the ring or begin taking the 
tablet, depending on which study group you have been assigned to. 
 
The following things will happen during your study visits: 
• 
We will ask questions about your health, any medications you may be taking, and any 
vaginal products you may be using. We will ask questions about your thoughts and feelings 
and your mood. We will also ask questions about your living situation to see if it affects your 


 
 
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use of the study products, and about your reasons for wanting to join this study and how 
worried you are about getting HIV.  
• 
We will ask your permission to access your medical records, including your delivery records 
to gather information about your baby at the time of birth. We will also ask your permission 
to contact your care provider, and to conduct a study visit as soon as possible after you 
have your baby. 
• 
We will talk with you about what you need to do to be in the study, how to use the study 
products, and how to protect yourself from getting an infection, including HIV. We may 
audio-record these conversations to assess how our study staff counsel you and work with 
them to improve the quality of the counseling you receive, and to learn about experiences 
and concerns participants may have. The recordings will be kept confidential. If you do not 
want to have your counseling session recorded, let study staff know. 
o It is important that you know if you do not intend to deliver your baby at a 
hospital or similar health facility [SITES TO INSERT NAMES OF LOCATIONS 
AFFILIATED WITH THE SITE], you will not be eligible to participate in this 
study.  
• 
After the birth of your infant, we will also talk with you about how to keep from getting 
pregnant. 
• 
We will schedule you for an ultrasound if you have not had one or do not have your 
ultrasound results with you today. 
o It is important that you know if you do not have an ultrasound, you will not be 
eligible to participate in this study. 
• 
At each study visit, we will draw up to 30 mL (about 2 tablespoons) of blood per visit [Sites 
to insert local amount] to make sure you are healthy and to test you for HIV and other STIs. 
We will also test your blood to see if you are using the study products. More blood may be 
collected if you become ill. 
• 
At some visits, we will collect a urine sample to test you for STIs.  
• 
At some visits, we will give you a physical exam to make sure you are healthy.  
• 
At all visits before the birth of your infant, we will give you an abdominal exam to make sure 
your pregnancy is going well. 
• 
At the Enrollment Visit, we will give you a pelvic exam to check for infections and to make 
sure you are healthy. We may give you a pelvic exam at other visits, if needed. The study 
doctor or nurse will use a speculum to do the pelvic exam. A speculum is a plastic or metal 
tool used to help open the vagina so that the doctor or nurse can examine your vagina and 
cervix and take some fluids.  
• 
At some visits, we will take fluids from your vagina using a swab (e.g., Q-Tip or earbud). 
Vaginal fluids will be collected to look for any changes that may occur during your 
participation in the study and to test for STIs. 
• 
At some visits, you will answer questions about using the study products and other 
behaviors, including sexual activity. Some of the questions may be sensitive. If you ever feel 
uncomfortable, you can choose not to answer questions at any time. You will also answer 
questions about what you liked and did not like about this study and about the study 
products. Your answers will be kept confidential and no one other than the study team will 
have access to your responses.  
• 
We may also ask you to do one or more longer interviews with study staff. You may choose 
not to do these interviews. During the interview(s), we may ask you to discuss your use of 
the study products, your feelings about the study products and about being in the study, and 
other questions that can help researchers to better understand participants’ experiences 
while in the study. We may audio-record the interview(s). We will keep the audio recording 
and related materials confidential and no one other than the study team will have access to 


 
 
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your responses. 
• 
For every month you are in the study until the end of your pregnancy, we will give you either 
another ring to use, or another month of tablets to take.   
• 
We will give you the results of any blood or urine tests when available. 
• 
We will give you treatment for sexually transmitted and other kinds of infections, if you need 
them. 
• 
In the event a problem with a pregnancy is suspected, an ultrasound can be ordered at the 
site or a referral will be provided. 
• 
We will give you referrals for other services, if you need them.  
• 
These visits will take about [SITES TO INSERT AVERAGE VISIT DURATION] to complete.  
 
If you enroll in the study, only for 24 hours prior to your clinic visits you will be asked to abstain 
from sex, tampon use and other non-study products. 
 
Activity: 
Not Permitted For How Long? 
Receptive sexual practices, including: 
• 
Penile-vaginal intercourse 
• 
Penile-anal intercourse 
• 
Receptive oral intercourse 
• 
Finger stimulation 
For 24 hours before each clinic visit 
Tampon use 
For 24 hours before each clinic visit 
Inserting any non-study objects into your vagina, including: 
• 
Pessaries 
• 
Sex toys 
• 
Female condoms  
• 
Diaphragms 
• 
Menstrual cups  
• 
Cervical caps or any other vaginal barrier method 
For 24 hours before each clinic visit  
 
Using vaginal products like spermicides, lubricants, contraceptive vaginal rings, douches, 
vaginal medications, etc., is not allowed at any time during this study. 
 
It is important for you to come to every study visit. If you cannot come to the visit, please tell the 
study staff as soon as possible so that the visit can be rescheduled.  
 
You may be asked to make additional visits so we can do more laboratory tests or have study 
procedures repeated. We will do this if there are abnormal test results or a mistake during the 
collection or the processing of your samples. We will also do this if you experience any changes 
in your physical condition, including symptoms of infection (urinary or sexually transmitted). 
 
What if I become infected with HIV? 
Being in this study will not cause HIV infection for you or your infant. But, there is always a 
chance that you can get HIV through condomless sex or other activities. If you become HIV-
positive, you will stop using the study product. But, we will ask you to continue to come for your 
study visits and to complete some of the study procedures for a minimum of twelve months. 
This study does not provide medication for treatment of HIV. If you become infected with HIV, 
the study staff will refer you for medical care and other available services to prevent your infant 
from getting HIV. If you get HIV, it is possible that the virus is resistant to some drugs. This 
means that some drugs may not work well to treat your HIV. This is also possible if your infant 
becomes infected. We will do a blood test to find out if you have drug resistance. These results 
can help us know which drugs would be best to treat your HIV. 
 


 
 
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Depending on local and national health requirements, the study staff may need to report certain 
diseases, including HIV. The reportable diseases at this site are [SITES TO INSERT]. We must 
inform the following [SITES TO INSERT MORE DETAILED INFORMATION REGARDING WHO 
WILL BE INFORMED OF THE REPORTABLE DISEASES]. [SITES TO INCLUDE/AMEND THE 
FOLLOWING]: Outreach workers from the [LOCAL HEALTH AUTHORITY] may then contact 
you about informing your partner/s, since they also should be tested. If you do not want to 
inform your partner/s yourself, the outreach workers will contact them, according to the 
confidentiality guidelines of the [LOCAL HEALTH AUTHORITY]. 
 
RISKS AND/OR DISCOMFORTS 
 
Risks of Blood Draws  
You may feel discomfort or pain when your blood is drawn.  You may feel dizzy or faint.  You 
may have a bruise, swelling, or small clot where the needle is inserted. Rarely, drawing blood 
can cause an infection where the needle goes into your hand or arm. 
 
Risks of Pelvic Exams  
You may feel discomfort or pressure during the pelvic exam.  You may have a small amount of 
vaginal bleeding or spotting which should stop shortly after the exam. 
 
Risks of the DPV VR 
We do not yet know all the side effects of the ring. Most people who have used the ring did not 
have any side effects. Some women who used the ring in other studies have had: discharge 
from the vagina; pelvic pain; burning or itchiness in the vagina; and urinary tract infections. Less 
common side effects included: irritation, bruising, swelling, inflammation, wearing, and 
discharge from the cervix; bladder pain and inflammation; vaginal odor, itching, inflammation, 
tearing, and discomfort; pelvic discomfort; abdominal pain and discomfort; and problems 
urinating. 
 
Although rare, the ring may cause an allergic reaction.  Signs of an allergic reaction include, but 
are not limited to: rash or other skin irritation, itching, joint pain, or difficulty in breathing.  
 
There is the possibility of getting toxic shock syndrome, although this is very rare. Toxic shock 
syndrome is a serious but rare infection caused by bacteria. Any product placed inside the 
vagina can cause it. Getting toxic shock syndrome from using the ring is unlikely. But, it is 
important that you tell the study staff as soon as possible if you have any of the following 
symptoms: sudden high fever, a faint feeling, diarrhea, headache, rash, and muscle aches. 
 
It is possible that the side effects from ring use may be different in women who are pregnant, or 
that the side effects may resemble normal symptoms of pregnancy. Studies with pregnant 
animals showed that DPV did not cause side effects to the animals or their fetuses. Women who 
became pregnant while using the ring in clinical studies did not experience more side effects 
than non-pregnant women, and neither did their infants. However, there is not enough 
information to know for sure. One small study found that DPV can be detected in breastmilk 
from women who used the ring while lactating, but it is unknown whether the small amounts of 
drug detected could produce side effects in babies. 
 
Risks of the Truvada tablet   
Most people who take the tablet do not have any side effects. The side effects that some people 
taking the tablet may have are well known because the drugs have been used by many people. 
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their hepatitis symptoms. 
 
One in ten people who take the tablet may have mild side effects that usually go away after 
stopping the drug. These occasional side effects include: mild kidney problems that are only 
detected by laboratory tests, inability to sleep, lack of energy or tiredness, headache, upset 
stomach, passing gas, vomiting, soft or liquid stools, and dizziness. Upset stomach, passing 
gas, vomiting and soft or liquid stools typically go away after the first or second month of use.  
 
Other side effects are more serious, but less than one in a hundred people who take the tablet 
may have them. These rare side effects include: rash, liver problems, serious kidney damage, 
and allergic reaction. People taking the tablet may also have bone pain and/or small changes in 
the thickness of their bones, but these changes have not caused problems for the people who 
had them.  
 
In rare cases, some people with HIV who take the tablet in combination with other drugs may 
get lactic acidosis. This is a serious side effect of some drugs used to treat HIV that can cause 
shortness of breath, nausea, and liver failure. This serious side effect has been seen more often 
in women taking the tablet in combination with other drugs. You should call or come to the clinic 
if you have unexplained changes in urination, weight loss, cramps, muscle pain, dizziness, 
tiredness, nausea, vomiting, or shortness of breath.  
 
The use of antiretroviral drug combinations may lead to changes in body fat, some of which 
include: increase in fat around the waist and stomach area; increase in fat on the back of the 
neck; thinning of the face, legs and arms; and breast enlargement. If you have these symptoms, 
or any other symptoms that concern you, the study staff will check you and see if you should 
stop taking the tablet.  
 
It is possible that the side effects from using the tablet may be different in women who are 
pregnant, or that the side effects may resemble normal symptoms of pregnancy. Studies with 
pregnant animals showed that FTC and TDF, the drugs in the tablet, did not cause any effects 
on the animals’ fertility or their fetuses, although TDF led to changes in the menstrual cycles of 
rats. HIV-infected pregnant women and women who became pregnant while taking the tablet in 
clinical studies did not experience more side effects than non-pregnant women, and their infants 
did not have more birth defects than the general infant population. However, there is not enough 
information to know for sure. 
 
A small number of people in this study may have these side effects or other side effects that we 
do not know about yet. But, we will screen your kidneys and overall health before you join the 
study and during the study. This will reduce your chances of having any side effects. 
 
Risks of HIV and Sexually Transmitted Infection (STI) Testing 
HIV and STI testing may make you feel anxious regardless of the test results. Finding out your 
HIV status may cause sadness, depression, and thoughts of suicide, and may also cause 
problems with your family, friends, or partner.   
 
Other Possible Risks 
You may feel embarrassed and/or worried when talking about sexual activities, your living 
situation, ways to protect against HIV and STIs, and your test results. You can choose not to 
answer questions at any time. Trained study counselors will help you with any feelings or 
questions. 
 


 
 
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It is possible that others may learn of your participation in this study, and because of this, may 
treat you unfairly or discriminate against you. If you have any problems, study counselors will 
talk with you and try to help you. 
 
The ring and the tablet can protect you from getting HIV, but based on what we know, the level 
of protection may be different between the two products. This difference may have an effect on 
your and your infant’s risk of getting HIV. Trained study counselors will help you with any 
feelings or questions. 
 
BENEFITS 
You will be using one of two study products that may prevent you from getting HIV if you use it 
consistently, but neither study product can guarantee protection from HIV. Information learned 
from this study may help us learn how to prevent pregnant women from getting HIV. You will 
receive medical exams, and you will receive counseling and testing for HIV and STIs. You will 
also have tests to check your overall health. 
 
This study cannot give you antenatal care or delivery services, and cannot give you general 
medical care. Study staff will refer you to another medical provider for care, if needed. You will 
get free condoms, if you need them. You will be offered a family planning method after delivery, 
if you need it. If you have an STI diagnosed, you will receive medicine or a referral, if you need 
it.   
 
NEW INFORMATION 
You will be told any new information learned during this study that may affect your willingness to 
stay in the study. For example, we will let you know if we learn that the study products may be 
causing bad side effects. We will tell you any new information about preventing HIV, regardless 
of the product, if we learn that it works during pregnancy. We will also tell you when study 
results may be available, and how to learn about them. 
 
A description of this research study will be available on http://www.ClinicalTrials.gov, as 
required by U.S. law. This Web site will not include information that can identify you. At most, 
the Web site will include a summary of the results. You can search this Web site at any time. 
 
WHY YOU MAY STOP TAKING THE STUDY DRUG EARLY OR BE ASKED TO LEAVE THE 
STUDY 
You may need to leave the study early without your permission if: 
• 
The study is cancelled by the US FDA, US NIH, IPM, Gilead Sciences, Inc., the US Office 
for Human Research Protections (OHRP), MTN, the local government or regulatory agency, 
or the Institutional Review Board (IRB)/Ethics Committee (EC). An IRB/EC is a committee 
that watches over the safety and rights of study participants. 
• 
The Study Monitoring Committee (SMC) recommends that the study be stopped early. The 
SMC reviews the progress of the study. 
• 
The Interim Review Panel (IRP) recommends that the study be stopped early. The IRP 
reviews results after each group of participants finishes the study and decides if the next 
group should begin the study.  
• 
You are not able to keep appointments. 
• 
Other reasons that may prevent you from completing the study successfully. 
 
The study doctor will ask you to stop using the study products if you: 
• 
Acquire an HIV infection. 


 
 
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• 
Acquire a hepatitis B infection (Truvada users only). 
• 
Use drugs for HIV prevention beyond what the study gives you.  
• 
Use drugs to prevent infection after being exposed to HIV. 
• 
Use injectable drugs for reasons other than treating disease. 
• 
Go into labor. 
• 
Experience the death or serious health issue with your unborn child. 
• 
Have a bad reaction to study product, or a study doctor decides that using study product 
would be bad for you. 
• 
Are unable or unwilling to follow the study rules. 
 
If a study doctor asks you to stop using study product, we will ask that you and your infant come 
in for all remaining study visits to have some of the procedures we talked about earlier. 
 
If you are removed from the study or choose to leave, we will ask you to return the study 
product and to come back for one final clinic visit. If you do not have the study product with you 
when you come to the clinic, staff members will make every effort to assist you in returning it as 
soon as possible. [SITES TO SPECIFY ALLOWANCES FOR SPECIAL CIRCUMSTANCES.] If 
you leave the study, we will ask you to check in with study staff until the end of your pregnancy 
and for one year after giving birth so we can follow your health and the health of your infant. If 
you choose to leave the study and later wish to rejoin, you may resume using study product (if 
applicable) and come in for all study visits remaining in your original visit schedule after 
consultation with the Protocol Safety Review Team. 
 
ALTERNATIVES TO BEING IN THE STUDY 
[SITES TO INCLUDE/AMEND THE FOLLOWING, IF APPLICABLE: You may be able to join 
other studies here or in the community. There may be other places where you can go for HIV 
counseling and testing and family planning. We will tell you about those studies and those 
places if you wish.] 
 
COSTS TO YOU 
[SITE TO COMPLETE ACCORDING TO SITE CAPACITY] There is no cost to you for study 
visits, study products, medical exams, laboratory tests or other procedures. We can give you 
treatments for STIs other than HIV free of charge while you are in the study, or we can refer you 
for available treatment. 
 
REIMBURSEMENT 
[SITES TO INSERT INFORMATION ABOUT LOCAL REIMBURSEMENT]: You will receive 
[SITES TO INSERT AMOUNT $xx] for your time, effort, and travel to and from the clinic for each 
study visit. You may receive [SITES TO INSERT AMOUNT $xx] for any extra study visits. If you 
are chosen to take part in the longer interview(s) with staff, you will receive [SITES TO INSERT 
AMOUNT $xx]. 
 
CONFIDENTIALITY 
We will make every effort to keep your and your infant’s information private and confidential. 
But, we cannot guarantee it.   
 
Study visits will take place in private. We will keep the information about your study visits in a 
secure place that only certain people can access for the purposes of this study. We will only 
enter your information into computers protected by passwords and will not include information 
that could identify you. We will only record your study ID number. If you are selected to do the 


 
 
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longer interview(s), you can choose not to answer questions at any time. We will keep the audio 
recordings and materials from all interviews and discussions confidential and will only use study 
numbers or fake names. [Sites to modify with their site-specific source documentation storage 
duration requirements if required by their IRBs/IECs: All original study documents that provide 
information about you for this study will be kept for at least two years after either the dapivirine 
vaginal ring is approved for use or the clinical research development program for the dapirivine 
vaginal ring is stopped.] 
 
Your personal information may be disclosed if required by law. For example, if we learn 
something that would immediately put you or others in danger, the study staff must take steps to 
keep you and others safe. This means that we have to share any information with the authorities 
(hospital, police, or social services) that tells us you may be in danger. For example, if you tell 
us that you plan to hurt or kill yourself, hurt or kill someone else, or if you tell us that someone is 
abusing or neglecting you. 
 
The study staff may use your personal information to verify that you are not in any other 
research studies. [SITES TO INSERT INFORMATION ABOUT SYSTEMS CURRENTLY IN 
PLACE TO ENSURE PARTICIPANTS ARE NOT PART OF OTHER CONFLICTING STUDIES, 
INCLUDING BIOMETRIC IDENTIFICATION SYSTEMS.] This study will not use your name or 
identify you personally in any publication. 
 
Your records may be reviewed by: 
• 
Representatives of the US Federal Government, including the US FDA, US OHRP, NIH 
and/or NIH contractors, and other US, local, and international regulatory entities 
• 
[SITES TO INSERT APPLICABLE LOCAL AUTHORITIES] 
• 
IPM, the organization that supplies the ring 
• 
Gilead Sciences, Inc., the company that supplies the tablets 
• 
Study monitors 
• 
Site IRB/EC 
• 
Study staff 
 
The study staff will do everything they can to protect your privacy.   
 
RESEARCH-RELATED INJURY 
It is unlikely that you or your infant will be injured by being in this study. The U.S. NIH does not 
have a mechanism to pay money or give other forms of financial compensation for research 
related injuries. You are not giving up any legal rights by signing this form. [Sites to replace with 
their site-specific research-related injury institutional policy if they already provide clinical trials 
insurance:] If you become ill or injured as a result of participation in this study, medical 
treatment for the adverse reaction or injury will be provided appropriately. The site staff will refer 
you for ongoing treatment for the injury, if needed. The study sponsor will be responsible for 
ensuring that insurance is provided to cover appropriate medical expenses for treatment of any 
such illness or injury if required by law or regulation. An HIV infection that occurs during the 
course of the trial will not be considered an injury or illness caused by trial participation. The 
research site or sponsor is not responsible for any loss, injuries and/or damages that are 
caused by any of the following things: 
• 
Any injury that happens because you used other medicine during the study that you did not 
tell us about. 
• 
Any injury that happens because you did not follow instructions given by the study doctor or 
nurse. 


 
 
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• 
Any injury that happens because of negligence on your part. 
 
YOUR RIGHTS AS A RESEARCH PARTICIPANT 
[SITES TO SPECIFY INSTITUTIONAL POLICY]: Being in this study is completely voluntary. 
You may choose not to join this study or leave this study at any time. If you choose not to join or 
to leave the study, you can still join other studies and access non-study services you would 
normally get at this clinic. If you want the results of the study after it is over, let the study staff 
members know. 
 
PROBLEMS OR QUESTIONS 
If you ever have any questions about the study, or if you have a research-related injury, you 
should contact [INSERT NAME OF THE INVESTIGATOR OR OTHER STUDY STAFF] at 
[INSERT TELEPHONE NUMBER AND/OR PHYSICAL ADDRESS]. 
 
If you have questions about your rights as a research participant, you should contact [INSERT 
NAME OR TITLE OF PERSON ON THE IRB/EC OR OTHER ORGANIZATION APPROPRIATE 
FOR THE SITE] at [INSERT PHYSICAL ADDRESS AND TELEPHONE NUMBER]. 
 
 


 
 
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[SITES TO OMIT THE FOLLOWING IF A SEPARATE CONSENT FOR STORAGE AND 
FUTURE TESTING OF SPECIMENS IS REQUIRED] 
CONSENT FOR STORAGE AND FUTURE TESTING OF SPECIMENS and RELATED 
HEALTH INFORMATION 
There may be a small amount of urine, blood, and vaginal fluids left over after we have done all 
of the study related testing. We would like to store your leftover body fluids for future work that 
could include testing for study products, testing for HIV risk and testing related to COVID-19 
infection  (if such testing is available and needed to better understand the impact of COVID-19 
infection on the study data). If you agree, your samples and related health information will be 
stored safely and securely.   
 
Only approved researchers will be able to use these samples and health information. Some 
employees will need to have access to these samples to store them and keep track of where 
they are, but these people will not have information that directly identifies you.  The de-identified 
data and specimens could then be used for future research by our research team or other 
researchers without notifying you or asking your permission for this use. 
 
There is no time limit on how long your samples will be stored. Your samples may be shipped 
and/or stored outside of the country. We do not yet know the specific type of testing that will be 
done with these samples. But, they may be used to check that certain laboratory tests perform 
correctly. Any other testing beyond that will have to be approved by an IRB/EC. We do not plan 
to do genetic testing or sequencing (for example, the mapping of all of your genes, which is also 
known as whole genome sequencing) of any kind.  Your specimens will never be used for 
commercial profit. 
 
You can still be in this study if you decide we cannot store your urine, blood, and vaginal fluids. 
You can change your mind about storing and using these samples for future tests at any time by 
writing to the person in charge of this study. We will then destroy the leftover samples. But, 
researchers will not be able to destroy samples or information from research that is already 
started. 
 
 
PARTICIPANT INITIALS OR MARK 
 
_____________________________ 
Initials/Mark                     Date   
 
I DO agree to allow my biological specimens and health 
data to be stored and used in future research studies. 
 
_____________________________ 
Initials/Mark                     Date 
 
I DO NOT agree to allow my biological specimens and 
health data to be stored and used in future research 
studies. 
 
 


 
 
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CONSENT FOR OFF-SITE VISITS 
 [Sites to modify as needed] 
Members of the research team at this clinic may be able to schedule off site visits with you at 
your home or at another location as part of the study.  With your permission, some of the 
scheduled study visits and some of the study procedures may take place at your home or other 
location outside of the research clinic, if you are unable to come into the clinic.  For example, if 
you need to receive a new ring or to have a urine or blood sample collected, study staff could 
come to you your home or meet you at another location, if you give your permission and if the 
study staff determine that it is appropriate.  The study personnel will explain in greater detail the 
requirements of these visits (like the conditions of the place, the type of visit and the time it will 
take) and the procedures in-place to maintain your information in a confidential manner.  
However, it is important that you know that off-site visits may eventually affect your 
confidentiality even if the study staff take precautions not to disclose the purpose of the visits. 
 
In order to conduct visits outside of the clinic, we will need you to give us permission to do so.  
Please read carefully the following statement and initial/mark and date one option.  Choosing 
not to have study visit procedures outside of the study clinic will not affect your participation in 
this study.  Even if you agree today, you can withdraw your consent for off-site visits at any time 
by providing your request in writing to the person in charge of this study.  In addition, before 
each off-site visit, we will confirm with you that you still agree and remember today’s discussion.  
 
 
PARTICIPANT INITIALS OR MARK 
 
_____________________________ 
Initials/Mark                     Date   
 
I DO agree to have study visit procedures at a location other 
than the study clinic by clinic staff, when necessary. 
 
_____________________________ 
Initials/Mark                     Date 
 
I DO NOT agree to have study visit procedures at a 
location other than the study clinic by clinic staff, when 
necessary. 
 
 


 
 
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SIGNATURE PAGE 
[INSERT SIGNATURE BLOCKS AS REQUIRED BY THE LOCAL IRB/EC:] 
All of the above has been explained to me and all of my current questions have been answered.  
I understand that I can ask questions about any aspect of this research study during the course 
of this study, and that future questions will be answered by the researchers listed on the first 
page of this form. 
 
Any questions I have about my rights or my infant’s rights as research participants will be 
answered by [INSERT LOCAL IRB/EC INFORMATION]. 
 
I voluntarily agree to be in this research study. A copy of this permission form will be given to 
me. 
 
 
 
________________________________ 
      
Participant’s Name (Print)   
 
 
  
 
 
________________________________  
______________  
Participant’s Signature  
 
 
 
Date  
 
 
________________________________ 
            
Study Staff’s Name Conducting  
Consent Discussion (Print) 
 
 
  
 
________________________________  
______________  
Study Staff Conducting  
 
 
 
Date 
Consent Discussion (Signature) 
 
 
________________________________ 
      
Witness Name (Print)   
 
 
  
 
 
________________________________  
______________  
Witness Signature  
 
 
 
 
Date  
 
 


 
 
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APPENDIX VII: Sample Informed Consent Form  
(Screening, Enrollment, Long-Term Storage and Off-Site Visit), MOTHER – 
COHORT 3 
 
SAMPLE INFORMED CONSENT FORM 
DIVISION OF AIDS, NIAID, NIH 
 
MTN-042 
 
Phase 3b, Randomized, Open Label Safety Trial of Dapivirine Vaginal Ring and 
Oral TRUVADA® Use in Pregnancy 
 
Version 2.0 
 
 May 20, 2021 
 
PRINCIPAL INVESTIGATOR: [Site to insert] 
PHONE: [Site to insert] 
Short Title for the Study: DELIVER: A Phase 3b Safety Study of the Dapivirine Ring and PrEP 
        in Pregnant Women 
 
INFORMED CONSENT 
You are being invited to join a research study funded by the US government [US National 
Institutes of Health (NIH)] and conducted by the Microbicide Trials Network (MTN).  There is a 
separate consent document for your baby. There are two products being used in this study: a 
ring inserted in the vagina and a tablet taken by mouth. The ring is supplied by International 
Partnership for Microbicides (IPM) and the tablet is supplied by Gilead Sciences, Inc.  The 
person in charge of this study at this site is [INSERT NAME OF PRINCIPAL INVESTIGATOR].   
 
STUDY SUMMARY 
Important things you should know: 
• 
The study products in this research study each contain a different anti-HIV medication:  
o The vaginal ring (VR) contains 25 mg of dapivirine (DPV). It is inserted in the vagina 
and worn continuously for approximately one month, to be replaced every month. We 
will refer to it in this document as the ring. 
o The oral tablet, Truvada, contains two drugs-  200 mg of emtricitabine (FTC) and 300 
mg of tenofovir disoproxil fumarate (TDF). It is taken once a day by mouth. We will 
refer to it in this document as the tablet. 
• 
The purpose of this study is to find out if using the ring or the tablet during pregnancy is safe 
and well-tolerated by women and their babies. 
• 
If you qualify and choose to participate, you will be randomly assigned to use one of the two 
study products for the remainder of your pregnancy (you will not use study product after the 
end of your pregnancy) 
• 
You will be asked to complete up to twenty (20) study visits (not including unscheduled 
visits), including the visit today and including up to six (6) phone contacts. Study visits will 
take place either at this study clinic, at the hospital where you intend to deliver your baby, or 
at other locations with your permission. You must intend to deliver at a hospital or similar 
health facility to be eligible for this study, such as [SITES TO INSERT NAMES OF 
LOCATIONS AFFILIATED WITH THE SITE]. The maximum length of your participation in 


 
 
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this study will be about 36 weeks. This includes the time remaining in your pregnancy and 
six additional weeks of follow-up for you. You will only take the study product while you are 
pregnant. 
• 
At some of the clinic visits, you will be asked to complete the following: a physical exam 
(including abdominal exam and ultrasound), blood draw, urine and vaginal fluid collection, 
several short interviews (and possibly a longer interview at one or more visits, if you are 
selected), and you will be asked permission to access your medical records and contact 
your health care provider. 
• 
Some common risks or discomforts from the ring include: vaginal irritation, discharge, and/or 
discomfort. One serious but rare side effect is toxic shock syndrome caused by poisons 
(toxins) released by some types of Staphylococcus aureus, a common bacteria. 
• 
Some common risks or discomforts from the tablet include: nausea, abdominal pain, 
diarrhea, vomiting, passing gas, headache, dizziness, tiredness, and inability to sleep. More 
serious but rare side effects include: rash, liver problems, kidney problems, allergic reaction, 
and lactic acidosis. 
• 
You will be using a study product that may prevent you from getting HIV if you use it 
consistently, but neither study product can guarantee protection from HIV. Information 
learned from this study may also help in the development of ways to prevent the spread of 
HIV in the future. You will receive testing for HIV and other sexually transmitted infections 
(STI), medical examinations, HIV and contraceptive counseling, and routine laboratory 
testing to check your overall health.  
• 
Taking part in this research study is voluntary. You do not have to participate and you can 
stop at any time. 
• 
If you decide not to join this study, there are currently available methods to prevent sexually 
transmitted HIV: condom use during sex and/or the use of daily oral Truvada for pre-
exposure prophylaxis (PrEP) or post-exposure prophylaxis (PEP). Study staff can provide 
you with additional information about PrEP and PEP if you are interested.  
 
Please take time to read this entire form and ask questions before deciding to join this study. If 
you are willing to take part in the study, you will sign your name on this form. A copy of this form 
will be offered to you. Signing this consent form does not mean you will be able to join the study. 
You must first complete the screening tests and exams to see if you are eligible. It is important 
to know that your and your infant’s participation in this research study is your decision and 
taking part in this study is completely voluntary (see Your Rights as a Research 
Participant/Volunteer for more information). 
 
STUDY DETAILS 
 
Study Products 
The ring was tested and found to be well-tolerated for use by adolescent (15-17 years old) and 
adult (18 years and older) women. DPV works by stopping HIV from making copies of itself. It 
was found to reduce HIV infection in women when used consistently. Researchers believe that 
younger women were not protected from getting HIV because they did not use the ring 
consistently. The ring received a positive opinion from the European Medicines Agency to 
reduce the risk of HIV infection in adult women and is now recommended by the World Health 
Organization as an HIV prevention option. It remains under review by the US Food and Drug 
Administration (FDA) and has yet to be approved for HIV prevention in any country. 
 
The tablet, called Truvada, is an HIV prevention method approved for adults called oral pre-
exposure prophylaxis (PrEP). The tablet works by stopping HIV from making copies of itself and 


 
 
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reduces risk of HIV infection when used consistently.  The tablet is also approved to treat HIV 
infection in people older than 12 years when combined with other drugs.  
 
Neither study product is effective against common sexually transmitted diseases other than HIV. 
Neither study product can guarantee protection from HIV. 
 
Who will be in this research study? 
Five hundred fifty (550) healthy, pregnant women who are 18 to 40 years old will be enrolled in the 
study across various sites in Malawi, South Africa, Uganda and Zimbabwe. Of these, 250 women 
who are between 12 and 30 weeks in their pregnancy will be enrolled at this time. 
 
What will I be asked to do if I join this research study?   
For the remainder of your pregnancy, you will either insert a ring and leave it in place for a 
month, replacing it every month, or take an oral tablet every day. Which of the two products you 
will use will be decided by chance [SITES TO INSERT PREFERRED DESCRIPTION OF 
‘RANDOMIZATION’] – for every 4 women who will receive the ring, there will be 1 woman who 
will receive the tablet. Neither you nor the study staff can decide which of the two products you 
will use.   
 
You will come to the clinic every two weeks for the first month you are in the study, then every 
four weeks until you are about 36 weeks pregnant, and then every two weeks for the remainder 
of your pregnancy. You will also have a phone contact with study staff one and three weeks 
from today, and after you are 35 weeks pregnant, every two weeks until delivery, and then one 
call up to two weeks after delivery. You will allow study staff to access your medical records, 
and to conduct a study visit as soon as possible after you deliver your baby, no later than two 
weeks after you deliver. This visit may occur at the study clinic, at the hospital where you 
deliver, or other location (with your permission). Your final visit will occur 6 weeks after you 
deliver, for a total maximum of twenty (20) study visits including the visit today and the phone 
contacts (but not including any unscheduled visits). You will be in the study for up to 36 weeks. 
Your baby will also have study visits, which are outlined in a separate consent form. Each visit 
will take about [SITES TO INSERT THE APPROXIMATE LENGTH OF TIME]. During your visit 
after delivery and the 6 week visit, your baby will also have study procedures completed.   
 
Do I have to be in this study? 
You do not have to be in this study. You can still get the care you need even if you do not join 
the study. If you join today but change your mind later, you can inform the study staff that you 
no longer wish to participate. If you do not join the study, your baby cannot join the study. 
 
What procedures will be done for this study? 
Your first visit will happen today after you read, discuss, understand and sign/mark this form. 
The procedures done at this visit will let us know if you can join this study, and will take about 
[SITES TO INSERT THE APPROXIMATE LENGTH OF TIME].  
 
If it seems like you can join, you will be asked to come back for an Enrollment visit no later than 
35 days from today. During the Enrollment Visit, you will begin using the ring or begin taking the 
tablet, depending on which study group you have been assigned to. 
 
The following things will happen during your study visits: 
• 
We will ask questions about your health, any medications you may be taking, and any 
vaginal products you may be using. We will ask questions about your thoughts and feelings 
and your mood. We will also ask questions about your living situation to see if it affects your 


 
 
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use of the study products, and about your reasons for wanting to join this study and how 
worried you are about getting HIV.  
• 
We will ask your permission to access your medical records, including your delivery records 
to gather information about your baby at the time of birth. We will also ask your permission 
to contact your care provider, and to conduct a study visit as soon as possible after you 
have your baby. 
• 
We will talk with you about what you need to do to be in the study, how to use the study 
products, and how to protect yourself from getting an infection, including HIV. We may 
audio-record these conversations to assess how our study staff counsel you and work with 
them to improve the quality of the counseling you receive, and to learn about experiences 
and concerns participants may have. The recordings will be kept confidential. If you do not 
want to have your counseling session recorded, let study staff know. 
o It is important that you know if you do not intend to deliver your baby at a 
hospital or similar health facility [SITES TO INSERT NAMES OF LOCATIONS 
AFFILIATED WITH THE SITE], you will not be eligible to participate in this 
study.  
• 
After the birth of your infant, we will also talk with you about how to keep from getting 
pregnant. 
• 
We will schedule you for an ultrasound if you have not had one or do not have your 
ultrasound results with you today. 
o It is important that you know if you do not have an ultrasound, you will not be 
eligible to participate in this study. 
• 
At each study visit, we will draw up to 30 mL (about 2 tablespoons) of blood per visit [Sites 
to insert local amount] to make sure you are healthy and to test you for HIV and other STIs. 
We will also test your blood to see if you are using the study products. More blood may be 
collected if you become ill. 
• 
At some visits, we will collect a urine sample to test you for STIs.  
• 
At some visits, we will give you a physical exam to make sure you are healthy.  
• 
At all visits before the birth of your infant, we will give you an abdominal exam to make sure 
your pregnancy is going well. 
• 
At the Enrollment Visit, we will give you a pelvic exam to check for infections and to make 
sure you are healthy. We may give you a pelvic exam at other visits, if needed. The study 
doctor or nurse will use a speculum to do the pelvic exam. A speculum is a plastic or metal 
tool used to help open the vagina so that the doctor or nurse can examine your vagina and 
cervix and take some fluids.  
• 
At some visits, we will take fluids from your vagina using a swab (e.g., Q-Tip or earbud). 
Vaginal fluids will be collected to look for any changes that may occur during your 
participation in the study and to test for STIs. 
• 
At some visits, you will answer questions about using the study products and other 
behaviors, including sexual activity. Some of the questions may be sensitive. If you ever feel 
uncomfortable, you can choose not to answer questions at any time. You will also answer 
questions about what you liked and did not like about this study and about the study 
products. Your answers will be kept confidential and no one other than the study team will 
have access to your responses.  
• 
We may also ask you to do one or more longer interviews with study staff. You may choose 
not to do these interviews. During the interview(s), we may ask you to discuss your use of 
the study products, your feelings about the study products and about being in the study, and 
other questions that can help researchers to better understand participants’ experiences 
while in the study. We may audio-record the interview(s). We will keep the audio recording 
and related materials confidential and no one other than the study team will have access to 


 
 
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your responses. 
• 
For every month you are in the study until the end of your pregnancy, we will give you either 
another ring to use, or another month of tablets to take.   
• 
We will give you the results of any blood or urine tests when available. 
• 
We will give you treatment for sexually transmitted and other kinds of infections, if you need 
them. 
• 
In the event a problem with a pregnancy is suspected, an ultrasound can be ordered at the 
site or a referral will be provided. 
• 
We will give you referrals for other services, if you need them.  
• 
These visits will take about [SITES TO INSERT AVERAGE VISIT DURATION] to complete.  
 
If you enroll in the study, only for 24 hours prior to your clinic visits you will be asked to abstain 
from sex, tampon use and other non-study products. 
 
Activity: 
Not Permitted For How Long? 
Receptive sexual practices, including: 
• 
Penile-vaginal intercourse 
• 
Penile-anal intercourse 
• 
Receptive oral intercourse 
• 
Finger stimulation 
For 24 hours before each clinic visit 
Tampon use 
For 24 hours before each clinic visit 
Inserting any non-study objects into your vagina, including: 
• 
Pessaries 
• 
Sex toys 
• 
Female condoms  
• 
Diaphragms 
• 
Menstrual cups  
• 
Cervical caps or any other vaginal barrier method 
For 24 hours before each clinic visit  
 
Using vaginal products like spermicides, lubricants, contraceptive vaginal rings, douches, 
vaginal medications, etc., is not allowed at any time during this study. 
 
It is important for you to come to every study visit. If you cannot come to the visit, please tell the 
study staff as soon as possible so that the visit can be rescheduled.  
 
You may be asked to make additional visits so we can do more laboratory tests or have study 
procedures repeated. We will do this if there are abnormal test results or a mistake during the 
collection or the processing of your samples. We will also do this if you experience any changes 
in your physical condition, including symptoms of infection (urinary or sexually transmitted). 
 
What if I become infected with HIV? 
Being in this study will not cause HIV infection for you or your infant. But, there is always a 
chance that you can get HIV through condomless sex or other activities. If you become HIV-
positive, you will stop using the study product. But, we will ask you to continue to come for your 
study visits and to complete some of the study procedures for a minimum of twelve months. 
This study does not provide medication for treatment of HIV. If you become infected with HIV, 
the study staff will refer you for medical care and other available services to prevent your infant 
from getting HIV. If you get HIV, it is possible that the virus is resistant to some drugs. This 
means that some drugs may not work well to treat your HIV. This is also possible if your infant 
becomes infected. We will do a blood test to find out if you have drug resistance. These results 
can help us know which drugs would be best to treat your HIV. 
 


 
 
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Depending on local and national health requirements, the study staff may need to report certain 
diseases, including HIV. The reportable diseases at this site are [SITES TO INSERT]. We must 
inform the following [SITES TO INSERT MORE DETAILED INFORMATION REGARDING WHO 
WILL BE INFORMED OF THE REPORTABLE DISEASES]. [SITES TO INCLUDE/AMEND THE 
FOLLOWING]: Outreach workers from the [LOCAL HEALTH AUTHORITY] may then contact 
you about informing your partner/s, since they also should be tested. If you do not want to 
inform your partner/s yourself, the outreach workers will contact them, according to the 
confidentiality guidelines of the [LOCAL HEALTH AUTHORITY]. 
 
RISKS AND/OR DISCOMFORTS 
 
Risks of Blood Draws  
You may feel discomfort or pain when your blood is drawn.  You may feel dizzy or faint.  You 
may have a bruise, swelling, or small clot where the needle is inserted. Rarely, drawing blood 
can cause an infection where the needle goes into your hand or arm. 
 
Risks of Pelvic Exams  
You may feel discomfort or pressure during the pelvic exam.  You may have a small amount of 
vaginal bleeding or spotting which should stop shortly after the exam. 
 
Risks of the DPV VR 
We do not yet know all the side effects of the ring. Most people who have used the ring did not 
have any side effects. Some women who used the ring in other studies have had: discharge 
from the vagina; pelvic pain; burning or itchiness in the vagina; and urinary tract infections. Less 
common side effects included: irritation, bruising, swelling, inflammation, wearing, and 
discharge from the cervix; bladder pain and inflammation; vaginal odor, itching, inflammation, 
tearing, and discomfort; pelvic discomfort; abdominal pain and discomfort; and problems 
urinating. 
 
Although rare, the ring may cause an allergic reaction.  Signs of an allergic reaction include, but 
are not limited to: rash or other skin irritation, itching, joint pain, or difficulty in breathing.  
 
There is the possibility of getting toxic shock syndrome, although this is very rare. Toxic shock 
syndrome is a serious but rare infection caused by bacteria. Any product placed inside the 
vagina can cause it. Getting toxic shock syndrome from using the ring is unlikely. But, it is 
important that you tell the study staff as soon as possible if you have any of the following 
symptoms: sudden high fever, a faint feeling, diarrhea, headache, rash, and muscle aches.  
 
It is possible that the side effects from ring use may be different in women who are pregnant, or 
that the side effects may resemble normal symptoms of pregnancy. Studies with pregnant 
animals showed that DPV did not cause side effects to the animals or their fetuses. Women who 
became pregnant while using the ring in clinical studies did not experience more side effects 
than non-pregnant women, and neither did their infants. However, there is not enough 
information to know for sure. One small study found that DPV can be detected in breastmilk 
from women who used the ring while lactating, but it is unknown whether the small amounts of 
drug detected could produce side effects in babies. 
 
Risks of the Truvada tablet   
Most people who take the tablet do not have any side effects. The side effects that some people 
taking the tablet may have are well known because the drugs have been used by many people. 


 
 
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People with hepatitis B who suddenly stop taking the tablet may get a flare-up or worsening of 
their hepatitis symptoms. 
 
One in ten people who take the tablet may have mild side effects that usually go away after 
stopping the drug. These occasional side effects include: mild kidney problems that are only 
detected by laboratory tests, inability to sleep, lack of energy or tiredness, headache, upset 
stomach, passing gas, vomiting, soft or liquid stools, and dizziness. Upset stomach, passing 
gas, vomiting and soft or liquid stools typically go away after the first or second month of use.  
 
Other side effects are more serious, but less than one in a hundred people who take the tablet 
may have them. These rare side effects include: rash, liver problems, serious kidney damage, 
and allergic reaction. People taking the tablet may also have bone pain and/or small changes in 
the thickness of their bones, but these changes have not caused problems for the people who 
had them.  
 
In rare cases, some people with HIV who take the tablet in combination with other drugs may 
get lactic acidosis. This is a serious side effect of some drugs used to treat HIV that can cause 
shortness of breath, nausea, and liver failure. This serious side effect has been seen more often 
in women taking the tablet in combination with other drugs. You should call or come to the clinic 
if you have unexplained changes in urination, weight loss, cramps, muscle pain, dizziness, 
tiredness, nausea, vomiting, or shortness of breath.  
 
The use of antiretroviral drug combinations may lead to changes in body fat, some of which 
include: increase in fat around the waist and stomach area; increase in fat on the back of the 
neck; thinning of the face, legs and arms; and breast enlargement. If you have these symptoms, 
or any other symptoms that concern you, the study staff will check you and see if you should 
stop taking the tablet.  
 
It is possible that the side effects from using the tablet may be different in women who are 
pregnant, or that the side effects may resemble normal symptoms of pregnancy. Studies with 
pregnant animals showed that FTC and TDF, the drugs in the tablet, did not cause any effects 
on the animals’ fertility or their fetuses, although TDF led to changes in the menstrual cycles of 
rats. HIV-infected pregnant women and women who became pregnant while taking the tablet in 
clinical studies did not experience more side effects than non-pregnant women, and their infants 
did not have more birth defects than the general infant population. However, there is not enough 
information to know for sure. 
 
A small number of people in this study may have these side effects or other side effects that we 
do not know about yet. But, we will screen your kidneys and overall health before you join the 
study and during the study. This will reduce your chances of having any side effects. 
 
Risks of HIV and Sexually Transmitted Infection (STI) Testing 
HIV and STI testing may make you feel anxious regardless of the test results. Finding out your 
HIV status may cause sadness, depression, and thoughts of suicide, and may also cause 
problems with your family, friends, or partner.   
 
Other Possible Risks 
You may feel embarrassed and/or worried when talking about sexual activities, your living 
situation, ways to protect against HIV and STIs, and your test results. You can choose not to 
answer questions at any time. Trained study counselors will help you with any feelings or 
questions. 


 
 
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It is possible that others may learn of your participation in this study, and because of this, may 
treat you unfairly or discriminate against you. If you have any problems, study counselors will 
talk with you and try to help you. 
 
The ring and the tablet can protect you from getting HIV, but based on what we know, the level 
of protection may be different between the two products. This difference may have an effect on 
your and your infant’s risk of getting HIV. Trained study counselors will help you with any 
feelings or questions. 
 
BENEFITS 
You will be using one of two study products that may prevent you from getting HIV if you use it 
consistently, but neither study product can guarantee protection from HIV. Information learned 
from this study may help us learn how to prevent pregnant women from getting HIV. You will 
receive medical exams, and you will receive counseling and testing for HIV and STIs. You will 
also have tests to check your overall health. 
 
This study cannot give you antenatal care or delivery services, and cannot give you general 
medical care. Study staff will refer you to another medical provider for care, if needed. You will 
get free condoms, if you need them. You will be offered a family planning method after delivery, 
if you need it. If you have an STI diagnosed, you will receive medicine or a referral, if you need 
it.   
 
NEW INFORMATION 
You will be told any new information learned during this study that may affect your willingness to 
stay in the study. For example, we will let you know if we learn that the study products may be 
causing bad side effects. We will tell you any new information about preventing HIV, regardless 
of the product, if we learn that it works during pregnancy. We will also tell you when study 
results may be available, and how to learn about them. 
 
A description of this research study will be available on http://www.ClinicalTrials.gov, as 
required by U.S. law. This Web site will not include information that can identify you. At most, 
the Web site will include a summary of the results. You can search this Web site at any time. 
 
WHY YOU MAY STOP TAKING THE STUDY DRUG EARLY OR BE ASKED TO LEAVE THE 
STUDY 
You may need to leave the study early without your permission if: 
• 
The study is cancelled by the US FDA, US NIH, IPM, Gilead Sciences, Inc., the US Office 
for Human Research Protections (OHRP), MTN, the local government or regulatory agency, 
or the Institutional Review Board (IRB)/Ethics Committee (EC). An IRB/EC is a committee 
that watches over the safety and rights of study participants. 
• 
The Study Monitoring Committee (SMC) recommends that the study be stopped early. The 
SMC reviews the progress of the study. 
• 
The Interim Review Panel (IRP) recommends that the study be stopped early. The IRP 
reviews results after each group of participants finishes the study and decides if the next 
group should begin the study.  
• 
You are not able to keep appointments. 
• 
Other reasons that may prevent you from completing the study successfully. 
 


 
 
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The study doctor will ask you to stop using the study products if you: 
• 
Acquire an HIV infection. 
• 
Acquire a hepatitis B infection (Truvada users only). 
• 
Use drugs for HIV prevention beyond what the study gives you.  
• 
Use drugs to prevent infection after being exposed to HIV. 
• 
Use injectable drugs for reasons other than treating disease. 
• 
Go into labor. 
• 
Experience the death or serious health issue with your unborn child. 
• 
Have a bad reaction to study product, or a study doctor decides that using study product 
would be bad for you. 
• 
Are unable or unwilling to follow the study rules. 
 
If a study doctor asks you to stop using study product, we will ask that you and your infant come 
in for all remaining study visits to have some of the procedures we talked about earlier. 
 
If you are removed from the study or choose to leave, we will ask you to return the study 
product and to come back for one final clinic visit. If you do not have the study product with you 
when you come to the clinic, staff members will make every effort to assist you in returning it as 
soon as possible. [SITES TO SPECIFY ALLOWANCES FOR SPECIAL CIRCUMSTANCES.] If 
you leave the study, we will ask you to check in with study staff until the end of your pregnancy 
and for one year after giving birth so we can follow your health and the health of your infant. If 
you choose to leave the study and later wish to rejoin, you may resume using study product (if 
applicable) and come in for all study visits remaining in your original visit schedule after 
consultation with the Protocol Safety Review Team. 
 
ALTERNATIVES TO BEING IN THE STUDY 
[SITES TO INCLUDE/AMEND THE FOLLOWING, IF APPLICABLE: You may be able to join 
other studies here or in the community. There may be other places where you can go for HIV 
counseling and testing and family planning. We will tell you about those studies and those 
places if you wish.] 
 
COSTS TO YOU 
[SITE TO COMPLETE ACCORDING TO SITE CAPACITY] There is no cost to you for study 
visits, study products, medical exams, laboratory tests or other procedures. We can give you 
treatments for STIs other than HIV free of charge while you are in the study, or we can refer you 
for available treatment. 
 
REIMBURSEMENT 
[SITES TO INSERT INFORMATION ABOUT LOCAL REIMBURSEMENT]: You will receive 
[SITES TO INSERT AMOUNT $xx] for your time, effort, and travel to and from the clinic for each 
study visit. You may receive [SITES TO INSERT AMOUNT $xx] for any extra study visits. If you 
are chosen to take part in the longer interview(s) with staff, you will receive [SITES TO INSERT 
AMOUNT $xx]. 
 
CONFIDENTIALITY 
We will make every effort to keep your and your infant’s information private and confidential. 
But, we cannot guarantee it.   
 
Study visits will take place in private. We will keep the information about your study visits in a 
secure place that only certain people can access for the purposes of this study. We will only 


 
 
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enter your information into computers protected by passwords and will not include information 
that could identify you. We will only record your study ID number. If you are selected to do the 
longer interview(s), you can choose not to answer questions at any time. We will keep the audio 
recordings and materials from all interviews and discussions confidential and will only use study 
numbers or fake names. [Sites to modify with their site-specific source documentation storage 
duration requirements if required by their IRBs/IECs: All original study documents that provide 
information about you for this study will be kept for at least two years after either the dapivirine 
vaginal ring is approved for use or the clinical research development program for the dapivirine 
vaginal ring is stopped.] 
 
Your personal information may be disclosed if required by law. For example, if we learn 
something that would immediately put you or others in danger, the study staff must take steps to 
keep you and others safe. This means that we have to share any information with the authorities 
(hospital, police, or social services) that tells us you may be in danger. For example, if you tell 
us that you plan to hurt or kill yourself, hurt or kill someone else, or if you tell us that someone is 
abusing or neglecting you. 
 
The study staff may use your personal information to verify that you are not in any other 
research studies. [SITES TO INSERT INFORMATION ABOUT SYSTEMS CURRENTLY IN 
PLACE TO ENSURE PARTICIPANTS ARE NOT PART OF OTHER CONFLICTING STUDIES, 
INCLUDING BIOMETRIC IDENTIFICATION SYSTEMS.] This study will not use your name or 
identify you personally in any publication. 
 
Your records may be reviewed by: 
• 
Representatives of the US Federal Government, including the US FDA, US OHRP, NIH 
and/or NIH contractors, and other US, local, and international regulatory entities 
• 
[SITES TO INSERT APPLICABLE LOCAL AUTHORITIES] 
• 
IPM, the organization that supplies the ring 
• 
Gilead Sciences, Inc., the company that supplies the tablets 
• 
Study monitors 
• 
Site IRB/EC 
• 
Study staff 
 
The study staff will do everything they can to protect your privacy.   
 
RESEARCH-RELATED INJURY 
It is unlikely that you or your infant will be injured by being in this study. The U.S. NIH does not 
have a mechanism to pay money or give other forms of financial compensation for research 
related injuries. You are not giving up any legal rights by signing this form. [Sites to replace with 
their site-specific research-related injury institutional policy if they already provide clinical trials 
insurance:] If you become ill or injured as a result of participation in this study, medical 
treatment for the adverse reaction or injury will be provided appropriately. The site staff will refer 
you for ongoing treatment for the injury, if needed. The study sponsor will be responsible for 
ensuring that insurance is provided to cover appropriate medical expenses for treatment of any 
such illness or injury if required by law or regulation. An HIV infection that occurs during the 
course of the trial will not be considered an injury or illness caused by trial participation. The 
research site or sponsor is not responsible for any loss, injuries and/or damages that are 
caused by any of the following things: 
• 
Any injury that happens because you used other medicine during the study that you did not 
tell us about. 


 
 
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• 
Any injury that happens because you did not follow instructions given by the study doctor or 
nurse. 
• 
Any injury that happens because of negligence on your part. 
 
YOUR RIGHTS AS A RESEARCH PARTICIPANT 
[SITES TO SPECIFY INSTITUTIONAL POLICY]: Being in this study is completely voluntary. 
You may choose not to join this study or leave this study at any time. If you choose not to join or 
to leave the study, you can still join other studies and access non-study services you would 
normally get at this clinic. If you want the results of the study after it is over, let the study staff 
members know. 
 
PROBLEMS OR QUESTIONS 
If you ever have any questions about the study, or if you have a research-related injury, you 
should contact [INSERT NAME OF THE INVESTIGATOR OR OTHER STUDY STAFF] at 
[INSERT TELEPHONE NUMBER AND/OR PHYSICAL ADDRESS]. 
 
If you have questions about your rights as a research participant, you should contact [INSERT 
NAME OR TITLE OF PERSON ON THE IRB/EC OR OTHER ORGANIZATION APPROPRIATE 
FOR THE SITE] at [INSERT PHYSICAL ADDRESS AND TELEPHONE NUMBER]. 
 
 


 
 
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[SITES TO OMIT THE FOLLOWING IF A SEPARATE CONSENT FOR STORAGE AND 
FUTURE TESTING OF SPECIMENS IS REQUIRED] 
CONSENT FOR STORAGE AND FUTURE TESTING OF SPECIMENS and RELATED 
HEALTH INFORMATION 
There may be a small amount of urine, blood and vaginal fluids left over after we have done all 
of the study related testing. We would like to store your leftover body fluids for future work that 
could include testing for study products, testing for HIV risk and testing related to COVID-19 
infection  (if such testing is available and needed to better understand the impact of COVID-19 
infection on the study data). If you agree, your samples and related health information will be 
stored safely and securely.   
 
Only approved researchers will be able to use these samples and health information. Some 
employees will need to have access to these samples to store them and keep track of where 
they are, but these people will not have information that directly identifies you.  The de-identified 
data and specimens could then be used for future research by our research team or other 
researchers without notifying you or asking your permission for this use. 
 
There is no time limit on how long your samples will be stored. Your samples may be shipped 
and/or stored outside of the country. We do not yet know the specific type of testing that will be 
done with these samples. But, they may be used to check that certain laboratory tests perform 
correctly. Any other testing beyond that will have to be approved by an IRB/EC. We do not plan 
to do genetic testing or sequencing (for example, the mapping of all of your genes, which is also 
known as whole genome sequencing) of any kind.  Your specimens will never be used for 
commercial profit. 
 
You can still be in this study if you decide we cannot store your urine, blood, and vaginal fluids. 
You can change your mind about storing and using these samples for future tests at any time by 
writing to the person in charge of this study. We will then destroy the leftover samples. But, 
researchers will not be able to destroy samples or information from research that is already 
started. 
 
 
PARTICIPANT INITIALS OR MARK 
 
_____________________________ 
Initials/Mark                     Date   
 
I DO agree to allow my biological specimens and health 
data to be stored and used in future research studies. 
 
_____________________________ 
Initials/Mark                     Date 
 
I DO NOT agree to allow my biological specimens and 
health data to be stored and used in future research 
studies. 
 
 


 
 
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CONSENT FOR OFF-SITE VISITS 
 [Sites to modify as needed] 
Members of the research team at this clinic may be able to schedule off site visits with you at 
your home or at another location as part of the study.  With your permission, some of the 
scheduled study visits and some of the study procedures may take place at your home or other 
location outside of the research clinic, if you are unable to come into the clinic.  For example, if 
you need to receive a new ring or to have a urine or blood sample collected, study staff could 
come to you your home or meet you at another location, if you give your permission and if the 
study staff determine that it is appropriate.  The study personnel will explain in greater detail the 
requirements of these visits (like the conditions of the place, the type of visit and the time it will 
take) and the procedures in-place to maintain your information in a confidential manner.  
However, it is important that you know that off-site visits may eventually affect your 
confidentiality even if the study staff take precautions not to disclose the purpose of the visits. 
 
In order to conduct visits outside of the clinic, we will need you to give us permission to do so.  
Please read carefully the following statement and initial/mark and date one option.  Choosing 
not to have study visit procedures outside of the study clinic will not affect your participation in 
this study.  Even if you agree today, you can withdraw your consent for off-site visits at any time 
by providing your request in writing to the person in charge of this study.  In addition, before 
each off-site visit, we will confirm with you that you still agree and remember today’s discussion.  
 
 
PARTICIPANT INITIALS OR MARK 
 
_____________________________ 
Initials/Mark                     Date   
 
I DO agree to have study visit procedures at a location other 
than the study clinic by clinic staff, when necessary. 
 
_____________________________ 
Initials/Mark                     Date 
 
I DO NOT agree to have study visit procedures at a 
location other than the study clinic by clinic staff, when 
necessary. 
 
 


 
 
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SIGNATURE PAGE 
[INSERT SIGNATURE BLOCKS AS REQUIRED BY THE LOCAL IRB/EC:] 
All of the above has been explained to me and all of my current questions have been answered.  
I understand that I can ask questions about any aspect of this research study during the course 
of this study, and that future questions will be answered by the researchers listed on the first 
page of this form. 
 
Any questions I have about my rights or my infant’s rights as research participants will be 
answered by [INSERT LOCAL IRB/EC INFORMATION]. 
 
I voluntarily agree to be in this research study. A copy of this permission form will be given to 
me. 
 
 
________________________________ 
      
Participant’s Name (Print)   
 
 
  
 
 
________________________________  
______________  
Participant’s Signature  
 
 
 
Date  
 
 
________________________________ 
            
Study Staff’s Name Conducting  
Consent Discussion (Print) 
 
 
  
 
________________________________  
______________  
Study Staff Conducting  
 
 
 
Date 
Consent Discussion (Signature) 
 
 
________________________________ 
      
Witness Name (Print)   
 
 
  
 
 
________________________________  
______________  
Witness Signature  
 
 
 
 
Date  
 
 


 
 
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APPENDIX VIII: Sample Informed Consent Form  
(Screening, Enrollment, Long-Term Storage, Off-Site Visit, and Photography) – 
INFANT 
 
SAMPLE INFORMED CONSENT FORM 
DIVISION OF AIDS, NIAID, NIH 
 
MTN-042 
 
Phase 3b, Randomized, Open Label Safety Trial of Dapivirine Vaginal Ring and 
Oral TRUVADA® Use in Pregnancy 
 
Version 2.0 
 
 May 20, 2021 
 
PRINCIPAL INVESTIGATOR: [Site to insert] 
PHONE: [Site to insert] 
Short Title for the Study: DELIVER: A Phase 3b Safety Study of the Dapivirine Ring and PrEP  
        in Pregnant Women 
 
INFORMED CONSENT  
You are being invited to allow your baby to join a research study funded by the US government 
[US National Institutes of Health (NIH)] and conducted by the Microbicide Trials Network (MTN).  
You baby can join the study if you consent to your own participation in this study in the separate 
consent document, in which you will use one of two products: a ring inserted in the vagina and a 
tablet taken by mouth. The ring is supplied by International Partnership for Microbicides (IPM) 
and the tablet is supplied by Gilead Sciences, Inc.  The person in charge of this study at this site 
is [INSERT NAME OF PRINCIPAL INVESTIGATOR].   
 
STUDY SUMMARY 
Important things you should know for your baby’s participation in the study: 
• 
The study products to be used by the mother in this research study each contain a different 
anti-HIV medication:  
o The vaginal ring (VR) contains 25 mg of dapivirine (DPV). It is inserted in the vagina 
and worn continuously for approximately one month, to be replaced every month. We 
will refer to it in this document as the ring. 
o The oral tablet, Truvada, contains two drugs - 200 mg of emtricitabine (FTC) and 300 
mg of tenofovir disoproxil fumarate (TDF). It is taken once a day by mouth. We will 
refer to it in this document as the tablet. 
• 
The purpose of this study is to find out if using the ring or the tablet during pregnancy is safe 
and well-tolerated by women and their babies. 
• 
You will be asked to allow your baby to complete up to four (4) study visits (not including 
unscheduled visits), and one (1) phone contact. Study visits will take place either at this 
study clinic, at the hospital where you intend to deliver your baby, or at other locations with 
your permission. The approximate length of your baby’s participation in this study will be 
about 12 months.  
• 
Most procedures done in this study are routine medical procedures, with little risk to your 
baby. 


 
 
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• 
After the birth of your baby, your baby will receive: a physical exam, blood draws, testing for 
HIV if needed, and routine laboratory testing to check his/her overall health.  
• 
Some common risks or discomforts from the blood collection may include pain, swelling, 
bruising, or bleeding where the needle is inserted. Rarely, drawing blood can cause infection 
where the needle enters the skin. 
• 
Taking part in this research study is voluntary. Your baby does not have to participate, and 
you can stop his/her participation at any time. 
• 
If you decide not to allow your baby to join this study, there are currently available methods 
you can use to prevent acquiring HIV and passing it on to your baby: condom use during 
sex and/or the use of daily oral Truvada for pre-exposure prophylaxis (PrEP) or post-
exposure prophylaxis (PEP). Study staff can provide you with additional information about 
PrEP and PEP if you are interested.  
 
Please take time to read this entire form and ask questions before deciding to allow your baby 
to join this study. If you decide to allow your baby to take part in the study, you will sign your 
name on this form. A copy of this form will be offered to you. It is important to know that your 
and your baby’s participation in this research study is your decision and taking part in this study 
is completely voluntary (see Your Rights as a Research Participant/Volunteer for more 
information). 
 
STUDY DETAILS 
 
Study Products 
Your baby will not use these study products but may be exposed to the study drugs from your 
use of them. One of the study products you may use is the dapivirine ring, which was found to 
reduce HIV infection in women ages 22-45 when used consistently. The ring received a positive 
opinion from the European Medicines Agency to reduce the risk of HIV infection in adult women 
and is now recommended by the World Health Organization as an HIV prevention option. It 
remains under review by the US Food and Drug Administration (FDA) and has yet to be 
approved for HIV prevention in any country. 
 
The other study product you may use is the tablet, called Truvada - an HIV prevention method 
approved for adults called oral pre-exposure prophylaxis (PrEP). The tablet works by stopping 
HIV from making copies of itself and reduces risk of HIV infection when used consistently.  The 
tablet is also approved to treat HIV infection in people older than 12 years when combined with 
other drugs. 
 
Neither study product can guarantee protection from HIV. 
 
Who will be in this research study? 
Five hundred fifty (550) healthy, pregnant women who are 18 to 40 years old and their babies will 
be enrolled in the study across various sites in Malawi, South Africa, Uganda and Zimbabwe.  
 
What will I be asked to do if my baby joins this research study?   
You will have a study visit with your baby as soon as possible after delivery, then have 
additional study visits six weeks, six months and twelve months after delivery, for a total 
maximum of four (4) study visits and one (1) phone contact that will occur within two weeks of 
delivery (but not including any unscheduled visits). Your baby will be in the study for 
approximately 12 months. Each visit will take about [SITES TO INSERT THE APPROXIMATE 


 
 
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LENGTH OF TIME]. During your baby’s first visit after delivery and the 6 week visit, you will also 
be asked to complete study procedures.   
 
Does my baby have to be in this study? 
Your baby does not have to be in this study. You can still get the care you need for your baby 
even if your baby does not join the study. If your baby joins the study but you change your mind 
later about his/her participation, you can inform the study staff that you no longer wish for your 
baby to participate. Your baby cannot join the study if you are not in the study. If you decide you 
do not want your baby to be in the study, you cannot join the study. 
 
What procedures will be done for this study? 
The following things will happen for your baby when you bring him/her for study visits: 
• 
We will ask questions about your baby’s health and any medications he or she may be 
taking. 
• 
We will give your baby a physical exam to make sure he or she is healthy. 
• 
At some visits, we will draw up to 8 mL of blood (about half a tablespoon) per visit [Sites to 
insert local amount] from your baby to make sure he or she is healthy. We will also test your 
baby ’s blood to see if there is study drug in his or her system. More blood may be collected 
if your baby becomes ill; HIV testing may be done if needed.  
• 
If it looks like something might be wrong with your baby, the study doctor might take pictures 
of your baby and share the pictures with experts who may be able to see what the problem 
might be. If you agree to have pictures taken of your baby, you will be asked to mark your 
permission at the end of this consent. We can give you a copy of any of the photographs. If 
you do not wish to have photographs taken of your baby, you will be able to mark at the end 
of this consent that no photographs may be taken of your baby.  
• 
These visits will take about [SITES TO INSERT AVERAGE VISIT DURATION] to complete.  
 
It is important for you to come to every study visit. If you cannot come to the visit, please tell the 
study staff as soon as possible so that the visit can be rescheduled.  
 
You may be asked to bring your baby for additional visits so we can do more laboratory tests or 
have study procedures repeated. We will do this if there are abnormal test results or a mistake 
during the collection or the processing of your samples. We will also do this if your baby 
experiences any changes in his or her physical condition. 
 
What if I become infected with HIV and my baby becomes infected? 
Being in this study will not cause HIV infection for you or your baby. But, there is always a 
chance that you can get HIV through condomless sex or other activities and if you become 
infected, your baby could be exposed to HIV. If you become HIV positive, there is a possibility 
that your baby could become HIV-infected - we will refer you to medical care to prevent HIV 
transmission between you and your baby.  
 
If you become HIV-positive and agree to the procedures, your baby will be tested for HIV as 
soon as possible after delivery. If your baby becomes HIV-positive and you agree to the 
procedures, your baby will have additional tests during their regularly scheduled study visits.  
 
Depending on local and national health requirements, the study staff may need to report certain 
diseases, including HIV. The reportable diseases at this site are [SITES TO INSERT]. We must 
inform the following [SITES TO INSERT MORE DETAILED INFORMATION REGARDING WHO 
WILL BE INFORMED OF THE REPORTABLE DISEASES]. [SITES TO INCLUDE/AMEND THE 
FOLLOWING]: Outreach workers from the [LOCAL HEALTH AUTHORITY] may then contact 


 
 
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you about informing your partner/s, since they also should be tested. If you do not want to 
inform your partner/s yourself, the outreach workers will contact them, according to the 
confidentiality guidelines of the [LOCAL HEALTH AUTHORITY]. 
 
RISKS AND/OR DISCOMFORTS 
 
Risks of Blood Draws  
Your baby may feel discomfort or pain when your blood is drawn.  Your baby may have a 
bruise, swelling, or small clot where the needle is inserted. Rarely, drawing blood can cause 
infection where the needle enters the skin. 
 
Risks of the DPV VR 
Studies with pregnant animals showed that DPV did not cause side effects to the animals’ 
fetuses. Babies of women who became pregnant while using the DPV ring in clinical studies did 
not seem to experience more side effects than babies of women who used a ring without 
medication in it, but there’s not enough information to know for sure. One small study found that 
DPV can be detected in breastmilk from women who used the ring while lactating, but it is 
unknown whether the small amounts detected could produce side effects in babies. We 
anticipate very little exposure of the study drug DPV to your baby. 
 
Risks of the Truvada tablet   
Studies with pregnant animals showed that FTC and TDF, the drugs in the tablet, did not cause 
any effects on the animals’ fetuses. Babies of HIV-infected pregnant women and women who 
became pregnant while taking the tablet in clinical studies did not have more birth defects than 
the general infant population. However, there is not enough information to know for sure. 
 
Other Possible Risks 
It is possible that others may learn of your baby’s participation in this study, and because of this, 
may treat you and your baby unfairly or discriminate against you and your baby. If you have any 
problems, study counselors will talk with you and try to help you. 
 
The ring and the tablet can protect you and therefore your baby from getting HIV, but based on 
what we know, the level of protection may be different between the two products. Trained study 
counselors will help you with any feelings or questions. 
 
BENEFITS 
You will be using one of two study products that may prevent you, and therefore your baby, from 
getting HIV if you use it consistently, but neither study product can guarantee protection from 
HIV. Information learned from this study may help us learn how to prevent pregnant women 
from getting HIV and passing it on to their babies. Your baby will receive medical exams. Your 
baby will also have tests to check his/her overall health. 
 
As appropriate, study staff will refer you to other medical providers for care.  
 
NEW INFORMATION 
You will be told any new information learned during this study that may affect your willingness 
for you and your baby to stay in the study. For example, we will let you know if we learn that the 
study products may be causing bad side effects. We will tell you any new information about 
preventing HIV, regardless of the product, if we learn that it works during pregnancy. We will 
also tell you when study results may be available, and how to learn about them. 
 


 
 
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A description of this research study will be available on http://www.ClinicalTrials.gov, as 
required by U.S. law. This Web site will not include information that can identify you. At most, 
the Web site will include a summary of the results. You can search this Web site at any time. 
 
WHY YOUR BABY MAY BE ASKED TO LEAVE THE STUDY 
Your baby may need to leave the study early without your permission if: 
• 
The study is cancelled by the US FDA, US NIH, IPM, Gilead Sciences, Inc., the US Office 
for Human Research Protections (OHRP), MTN, the local government or regulatory agency, 
or the Institutional Review Board (IRB)/Ethics Committee (EC). An IRB/EC is a committee 
that watches over the safety and rights of study participants. 
• 
The Study Monitoring Committee (SMC) recommends that the study be stopped early. The 
SMC reviews the progress of the study. 
• 
The Interim Review Panel (IRP) recommends that the study be stopped early. The IRP 
reviews results after each group of participants finishes the study and decides if the next 
group should begin the study.  
• 
You leave the study. 
• 
You are not able to keep appointments. 
• 
Other reasons that may prevent your baby from completing the study successfully. 
 
If your baby is asked to leave the study or you choose to stop his/her participation, we will ask 
you to come back for one final clinic visit. [SITES TO SPECIFY ALLOWANCES FOR SPECIAL 
CIRCUMSTANCES.]  
 
ALTERNATIVES TO BEING IN THE STUDY 
[SITES TO INCLUDE/AMEND THE FOLLOWING, IF APPLICABLE: Your baby may be able to 
join other studies here or in the community. We will tell you about those studies if you wish.] 
 
COSTS TO YOU 
[SITE TO COMPLETE ACCORDING TO SITE CAPACITY] There is no cost to you for your 
baby’s study visits, medical exams, laboratory tests or other procedures. We can refer your 
baby for available treatment if needed. 
 
REIMBURSEMENT 
[SITES TO INSERT INFORMATION ABOUT LOCAL REIMBURSEMENT]: You will receive 
[SITES TO INSERT AMOUNT $xx] for you and your baby’s time, effort, and travel to and from 
the clinic for each study visit.  
 
CONFIDENTIALITY 
We will make every effort to keep your and your baby’s information private and confidential. We 
cannot guarantee it.   
 
Study visits will take place in private. We will keep the information about your baby’s study visits 
in a secure place that only certain people can access for the purposes of this study. We will only 
enter your baby’s information into computers protected by passwords and will not include 
information that could identify your baby. We will only record your baby’s study ID number.  
[Sites to modify with their site-specific source documentation storage duration requirements if 
required by their IRBs/IECs: All original study documents that provide information about your 
baby for this study will be kept for at least two years after either the dapivirine vaginal ring is 
approved for use or the clinical research development program for the dapivirine vaginal ring is 
stopped.] 


 
 
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Your baby’s personal information may be disclosed if required by law. For example, if we learn 
something that would immediately put your baby or others in danger, the study staff must take 
steps to keep your baby and others safe. This means that we have to share any information with 
the authorities (hospital, police, or social services) that tells us your baby may be in danger. For 
example, if you tell us that you plan to hurt or kill yourself or your baby, or if you tell us that 
someone is abusing or neglecting your baby. 
 
The study staff may use your baby’s personal information to verify that your baby is not in any 
other research studies. [SITES TO INSERT INFORMATION ABOUT SYSTEMS CURRENTLY 
IN PLACE TO ENSURE PARTICIPANTS ARE NOT PART OF OTHER CONFLICTING 
STUDIES, INCLUDING BIOMETRIC IDENTIFICATION SYSTEMS.] This study will not use your 
baby’s name or identify your baby personally in any publication. 
 
Your baby’s records may be reviewed by: 
• 
Representatives of the US Federal Government, including the US FDA, US OHRP, NIH 
and/or NIH contractors, and other US, local, and international regulatory entities 
• 
[SITES TO INSERT APPLICABLE LOCAL AUTHORITIES] 
• 
IPM, the organization that supplies the DPV VR 
• 
Gilead Sciences, Inc., the company that supplies the Truvada tablets 
• 
Study monitors 
• 
Site IRB/EC 
• 
Study staff 
 
The study staff will do everything they can to protect your baby’s privacy.   
 
RESEARCH-RELATED INJURY 
It is unlikely that you or your baby will be injured by being in this study. The U.S. NIH does not 
have a mechanism to pay money or give other forms of financial compensation for research 
related injuries. You are not giving up any legal rights by signing this form. [Sites to replace with 
their site-specific research-related injury institutional policy if they already provide clinical trials 
insurance:] If your baby becomes ill or injured as a result of participation in this study, medical 
treatment for the adverse reaction or injury will be provided appropriately. The site staff will refer 
your baby for ongoing treatment for the injury, if needed. The study sponsor will be responsible 
for ensuring that insurance Is provided to cover appropriate medical expenses for treatment of 
any such illness or injury if required by law or regulation. An HIV infection that occurs during the 
course of the trial will not be considered an injury or illness caused by trial participation. The 
research site or sponsor is not responsible for any loss, injuries and/or damages that are 
caused by any of the following things: 
• 
Any injury that happens because your baby used other medicine during the study that you 
did not tell us about. 
• 
Any injury that happens because you did not follow instructions given by the study doctor or 
nurse regarding your baby’s participation in the study. 
• 
Any injury that happens because of negligence on your part. 
 
YOUR BABY’S RIGHTS AS A RESEARCH PARTICIPANT 
[SITES TO SPECIFY INSTITUTIONAL POLICY]: Being in this study is completely voluntary. 
You may choose not to allow your baby to join this study or stop your baby’s participation in this 
study at any time. If you choose not to allow your baby to join or to stop your baby’s participation 
in the study, your baby can still join other studies and access non-study services you would 


 
 
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normally get at this clinic. If you want the results of the study after it is over, let the study staff 
members know. 
 
PROBLEMS OR QUESTIONS 
If you ever have any questions about the study, or if your baby has a research-related injury, 
you should contact [INSERT NAME OF THE INVESTIGATOR OR OTHER STUDY STAFF] at 
[INSERT TELEPHONE NUMBER AND/OR PHYSICAL ADDRESS]. 
 
If you have questions about your baby’s rights as a research participant, you should contact 
[INSERT NAME OR TITLE OF PERSON ON THE IRB/EC OR OTHER ORGANIZATION 
APPROPRIATE FOR THE SITE] at [INSERT PHYSICAL ADDRESS AND TELEPHONE 
NUMBER]. 
 
 
 


 
 
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[SITES TO OMIT THE FOLLOWING IF A SEPARATE CONSENT FOR STORAGE AND 
FUTURE TESTING OF SPECIMENS IS REQUIRED] 
CONSENT FOR STORAGE AND FUTURE TESTING OF SPECIMENS and RELATED 
HEALTH INFORMATION 
There may be a small amount of blood left over after we have done all of the study related 
testing on your baby. We would like to store your baby’s leftover blood for future work that could 
include testing for study products, testing for HIV risk and testing related to COVID-19 infection  
(if such testing is available and needed to better understand the impact of COVID-19 infection 
on the study data). If you agree, your baby’s samples and related health information will be 
stored safely and securely.   
 
Only approved researchers will be able to use these samples and health information. Some 
employees will need to have access to these samples to store them and keep track of where 
they are, but these people will not have information that directly identifies your baby.  The de-
identified data and specimens could then be used for future research by our research team or 
other researchers without notifying you or asking your permission for this use. 
 
There is no time limit on how long your baby’s samples will be stored. Your baby’s samples may 
be shipped and/or stored outside of the country. We do not yet know the specific type of testing 
that will be done with these samples. But, they may be used to check that certain laboratory 
tests perform correctly. Any other testing beyond that will have to be approved by an IRB/EC. 
We do not plan to do genetic testing or sequencing (for example, the mapping of all of your 
baby’s genes, which is also known as whole genome sequencing) of any kind.  Your baby’s 
specimens will never be used for commercial profit. 
 
Your baby can still be in this study if you decide that we cannot store your baby’s blood. You 
can change your mind about storing and using these samples for future tests at any time by 
writing to the person in charge of this study. We will then destroy the leftover samples. But, 
researchers will not be able to destroy samples or information from research that is already 
started. 
 
 
PARTICIPANT INITIALS OR MARK 
 
_____________________________ 
Initials                     Date   
 
I DO agree to allow my baby’s biological specimens and 
health data to be stored and used in future research studies. 
 
_____________________________ 
Initials                     Date 
 
I DO NOT agree to allow my baby’s biological specimens 
and health data to be stored and used in future research 
studies. 
 
 


 
 
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CONSENT FOR OFF-SITE VISITS 
 [Sites to modify as needed] 
Members of the research team at this clinic may be able to schedule off site visits with you at 
your home or at another location as part of the study.  With your permission, some of the 
scheduled study visits and some of the study procedures may take place at your home or other 
location outside of the research clinic, if you are unable to come into the clinic.  For example, if 
your baby needs blood sample collected, study staff could come to your home or meet you at 
another location, if you give your permission and if the study staff determine that it is 
appropriate.  The study personnel will explain in greater detail the requirements of these visits 
(like the conditions of the place, the type of visit and the time it will take) and the procedures in-
place to maintain your information in a confidential manner.  However it is important that you 
know that off-site visits may eventually affect your confidentiality even if the study staff take 
precautions not to disclose the purpose of the visits. 
 
In order to conduct visits outside of the clinic, we will need you to give us permission to do so.  
Please read carefully the following statement and initial/mark and date one option.  Choosing 
not to have study visit procedures outside of the study clinic will not affect your baby’s 
participation in this study.  Even if you agree today, you can withdraw your consent for off-site 
visits for your baby at any time by providing your request in writing to the person in charge of 
this study.  In addition, before each off-site visit, we will confirm with you that you still agree and 
remember today’s discussion.  
 
 
PARTICIPANT INITIALS OR MARK 
 
_____________________________ 
Initials/Mark                     Date   
 
I DO agree to have study visit procedures for my baby at a 
location other than the study clinic by clinic staff, when 
necessary. 
 
_____________________________ 
Initials/Mark                     Date 
 
I DO NOT agree to have study visit procedures for my baby 
at a location other than the study clinic by clinic staff, when 
necessary. 
 
 


 
 
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CONSENT FOR TAKING PHOTOGRAPHS OF BABY 
 
Please initial/mark one of the following to show whether you agree/do not agree to have 
photograph(s) of your baby taken as may be requested by study staff: 
 
 
PARTICIPANT INITIALS OR MARK 
 
_____________________________ 
Initials/Mark            Date   
 
I DO agree to allow study staff to take photograph(s) of my 
baby 
 
_____________________________ 
Initials/Mark            Date 
 
I DO NOT agree to allow study staff to take photograph(s) of 
my baby 
 
 


 
 
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SIGNATURE PAGE 
[INSERT SIGNATURE BLOCKS AS REQUIRED BY THE LOCAL IRB/EC:] 
All of the above has been explained to me and all of my current questions have been answered.  
I understand that I can ask questions about any aspect of this research study during the course 
of this study, and that future questions will be answered by the researchers listed on the first 
page of this form. 
 
Any questions I have about my baby’s rights as a research participant will be answered by 
[INSERT LOCAL IRB/EC INFORMATION]. 
 
I voluntarily agree to allow my baby to be in this research study. I understand that my baby is 
not allowed to participate in this research study without my permission. I voluntarily agree to 
allow my baby to be in this research study when he/she is born. A copy of this permission form 
will be given to me. 
 
 
________________________________ 
      
Participant’s Name (Print)   
 
 
  
 
 
________________________________  
______________  
Participant’s Signature  
 
 
 
Date  
 
 
________________________________ 
            
Study Staff’s Name Conducting  
Consent Discussion (Print) 
 
 
  
 
________________________________  
______________  
Study Staff Conducting  
 
 
 
Date 
Consent Discussion (Signature) 
 
 
________________________________ 
      
Witness Name (Print)   
 
 
  
 
 
________________________________  
______________  
Witness Signature  
 
 
 
 
Date  
 
 
 
 
 
 
 
 


 
 
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