Clinical trial NCT04644029
Conditions: HIV-I Human Immunodeficiency Virus Type 1 Prophylaxis
Keywords: Preexposure prophylaxis (PrEP) Prevention
Sponsor: Merck Sharp & Dohme LLC
Start date: 2021-02-24; Completion date: 2024-06-11
Enrollment: 730 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This study will evaluate whether oral islatravir (ISL) is effective in preventing Human Immunodeficiency Virus Type 1 (HIV-1) infection in women at high-risk for HIV-1 infection. The study will compare oral ISL taken once a month with standard-of-care medication for prevention of HIV-1 infection, emtricitabine/tenofovir disoproxil (FTC/TDF), taken once per day. The primary hypothesis is that oral ISL is more effective than FTC/TDF at reducing the incidence rate per year of confirmed HIV-1 infections.

Detailed description:
Based on laboratory findings of decreased lymphocyte and CD4+ T-cell counts across the islatravir program, dosing of blinded study intervention was halted on 13-Dec-2021 and screening and randomization of new participants was ended. Blinded assessments conducted prior to this date are designated as Study Part 1. During Study Part 2, participants from Part 1 have the option to receive daily open-label FTC/TDF while continuing in the study for safety monitoring. Study Part 3 was added to unblind each participant's Part 1 study intervention assignment, continue participants on FTC/TDF, and monitor safety.

Arms: arm 1: ISL (islatravir) once monthly AND placebo to FTC/TDF (emtricitabine/tenofovir disoproxil) once daily. Following study-wide cessation of ISL administration, participants had the option to receive open-label FTC/TDF administered once daily. arm 2: FTC/TDF (TRUVADA™ or generic product emtricitabine/tenofovir disoproxil) administered once daily. Placebo to ISL (islatravir) administered once monthly. Following study-wide cessation of ISL administration, participants had the option to continue on open-label FTC/TDF. Placebo was no longer administered once open label treatment began.
Interventions: intervention 1: Islatravir intervention 2: Placebo to FTC/TDF intervention 3: FTC/TDF intervention 4: Placebo to ISL
Intervention descriptions: intervention 1: Oral 60 mg tablet administered once monthly during Part 1. intervention 2: 0 mg tablet administered once daily during Part 1. intervention 3: Each tablet contains 200 mg emtricitabine and 245 mg of tenofovir disoproxil (equivalent to 300 mg tenofovir disoproxil fumarate or 201.22 mg tenofovir disproxil phosphate), administered orally once daily in Parts 1, 2, and 3. intervention 4: 0 mg tablet administered orally once monthly in Part 1.

Protocol documents:
Prot_SAP_001.pdf: 
Official Protocol Title: 
NCT number: 
NCT04644029 
Document Date: 
02-AUG-2022
A Phase 3, Randomized, Active-Controlled, Double-blind Clinical 
Study to Evaluate the Efficacy and Safety of Oral Islatravir Once-
Monthly as Preexposure Prophylaxis in Cisgender Women at High 
Risk for HIV-1 Infection


PRODUCT: MK-8591  
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Title Page
THIS PROTOCOL AMENDMENT AND ALL OF THE INFORMATION RELATING 
TO IT ARE CONFIDENTIAL AND PROPRIETARY PROPERTY OF MERCK 
SHARP & DOHME LLC, RAHWAY, NJ, USA (MSD).
Protocol Title: A Phase 3, Randomized, Active-Controlled, Double-blind Clinical Study to 
Evaluate the Efficacy and Safety of Oral Islatravir Once-Monthly as Preexposure 
Prophylaxis in Cisgender Women at High Risk for HIV-1 Infection
Protocol Number: 022-04
Compound Number: MK-8591
Sponsor Name:
Merck Sharp & Dohme LLC
(hereafter called the Sponsor or MSD)
Legal Registered Address:
126 East Lincoln Avenue
P.O. Box 2000
Rahway, NJ 07065 USA
Regulatory Agency Identifying Number(s):
IND
128,595
EudraCT
2021-001289-39
Approval Date: 02 August 2022
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Sponsor Signatory
Typed Name:
Title:
Date
Protocol-specific Sponsor contact information can be found in the Investigator Study
File Binder (or equivalent).
Investigator Signatory
I agree to conduct this clinical study in accordance with the design outlined in this protocol 
and to abide by all provisions of this protocol.
Typed Name:
Title:
Date
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DOCUMENT HISTORY
Document
Date of Issue
Overall Rationale
Amendment 04
02-AUG-2022
The protocol was amended to add Part 3 to the study to unblind each participant’s Part 
1 study intervention assignment, continue participants on FTC/TDF, and monitor 
safety.
Amendment 03
24-FEB-2022
Based on the laboratory findings of decreases in lymphocyte and CD4+ T-cell counts 
observed in clinical studies across the islatravir (ISL, MK-8591) program, as of 13-
DEC-2021, sites were instructed to discontinue dosing of blinded study intervention 
and participants were given the option to receive daily FTC/TDF or for HIV 
prevention treatment while continuing the study. Screening and randomization of new 
participants have stopped.
The purpose of this amendment is to define changes in study design and conduct 
implemented due to stopping of blinded study intervention, and to describe continued 
monitoring of participants.
Amendment 02
07-DEC-2021
The protocol was amended to increase frequency of monitoring of lymphocytes, add 
monitoring of CD4+ T-cells, and add discontinuation criteria in response to findings 
of decreases in lymphocytes (in studies of participants with or without HIV) and 
CD4+ T-cell counts (in studies of participants with HIV) in ISL clinical studies.
Amendment 01
06-MAY-2021
The protocol was amended to modify the management of participants who become 
pregnant, to modify PK assessments for participants who become pregnant and remain 
on ISL, and to modify breastfeeding options for participants who become pregnant.
Original Protocol
20-OCT-2020
Not applicable
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PROTOCOL AMENDMENT SUMMARY OF CHANGES 
Amendment: 04
Overall Rationale for the Amendments:
The protocol was amended to add Part 3 to the study to unblind each participant’s Part 1 study intervention assignment, continue 
participants on FTC/TDF, and monitor safety.
Summary of Changes Table:
Section # and Name
Description of Change 
Brief Rationale 
1.1 Synopsis
1.2 Schema
1.3 Schedule of 
Activities
2.1 Study Rationale
2.3 Benefit/Risk 
Assessment
3 Hypotheses, 
Objectives, and 
Endpoints
4 Study Design
6.1 Study 
Intervention(s) 
Administered
Part 3 added to study design:
Participants, investigators, and 
all Sponsor personnel will be 
unblinded to the participants’ 
original randomized study 
intervention group.
Continued blinding is unnecessary since all participants will be receiving 
open-label daily PrEP therapy with FTC/TDF and undergoing the same 
study procedures regardless of original assignment.
Ongoing participants will 
continue to receive FTC/TDF.
The Sponsor will continue to offer ongoing participants FTC/TDF to 
fulfill its ethical duties toward study participants.
No new participants will be 
screened or randomized during 
Part 3.
Since ISL is no longer being offered as a study intervention, there is no 
reason to screen or randomize any new participants.
Ongoing participants will 
continue to be monitored for 
safety.
The Sponsor will continue to monitor safety to ensure the wellbeing of 
study participants and to provide greater clinical detail for monitoring
total lymphocyte counts.
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Section # and Name
Description of Change 
Brief Rationale 
6.3 Measures to 
Minimize Bias: 
Randomization and 
Blinding
6.4 Study Intervention 
Compliance
6.9 Standard Policies
8 Study Assessments 
and Procedures
9 Statistical Analysis 
Plan
10.2 Appendix 2: 
Clinical Laboratory 
Tests
PRO preference will not be 
performed during Part 3.
PK samples will not be 
collected in Part 3.
No further assessments will be 
made by the eDMC.
Since participants are no longer receiving study intervention with ISL, 
PRO preference, PK sampling, and eDMC oversight are no longer 
necessary.
1.1 Synopsis
3 Hypotheses, 
Objectives, and 
Endpoints
9 Statistical Analysis 
Plan
Note added to describe that 
evaluation of the percentage of 
participants with confirmed 
HIV-1 infections will no 
longer be considered a primary 
endpoint and that the only 
study objective is to evaluate 
the safety and tolerability of 
ISL QM based on review of 
the accumulated safety data.
Since ISL is no longer being offered as a study intervention, formal 
hypothesis tests and comparisons between study intervention groups will 
not be conducted.
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Section # and Name
Description of Change 
Brief Rationale 
8.4 Adverse Events, 
Serious Adverse Events, 
and Other Reportable 
Safety Events
10.3.1 Definitions of 
Medication Error, 
Misuse, and Abuse
Requirement for investigators 
to document if an SAE is 
associated with medication 
error, misuse, or abuse added.
Definitions of medication 
error, misuse, and abuse 
added.
Per Regulation (EU) No 536/2014 of the European Parliament and of the 
Council.
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Section # and Name
Description of Change 
Brief Rationale 
4.2.6 Rationale for 
Collecting Infant Safety 
Follow-up Data
8.1.1.5 Consent for 
Infant Safety Data 
Collection
8.4.1 Time Period and 
Frequency for 
Collecting AE, SAE, 
and Other Reportable 
Safety Event 
Information
8.4.5 Pregnancy and 
Exposure During 
Breastfeeding
8.11.3.2 Clinical 
Management of 
Participants Who 
Become Pregnant – Part 
2 and Part 3
8.11.4 Infant Safety 
Data Collection
Updated infant safety 
follow-up procedures for 
Part 3.
Participants will not receive ISL during Part 3. Therefore, additional 
infant safety follow-up through 1 year of age will not be required for 
participants who become pregnant during Part 3. Standard AE reporting 
requirements will apply.
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Section # and Name
Description of Change 
Brief Rationale 
1.1 Synopsis
6.1 Study 
Intervention(s) 
Administered
Study intervention ‘Use’ term
updated from ‘Experimental’
to “Test product’ and study 
intervention classification 
column heading updated to 
include ‘AxMP’.
To align with the EU CTR.
4.4 Beginning and End 
of Study Definition
Clarification of what 
constitutes the beginning and 
end of the study added.
To align with the EU CTR.
5 Study Population
Text related to the collection 
of demographic data added.
To clarify the collection, use, and confidentiality of demographic data 
provided by participants.
10.2 Appendix 2: 
Clinical Laboratory 
Tests
Genetic analysis and blood for 
FBR were removed from the 
table of protocol-required 
laboratory assessments
These samples are not clinical laboratory tests and were placed there in 
error.
Title Page
10.1.1 Code of Conduct 
for Clinical Trials
Sponsor entity name and 
address changed.
Merck Sharp & Dohme Corp. underwent an entity name and address 
change to Merck Sharp & Dohme LLC, Rahway, NJ, USA. This 
conversion resulted only in an entity name change and update to the 
address.
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Section # and Name
Description of Change 
Brief Rationale 
8.1.9.1 Withdrawal 
From Future Biomedical 
Research
10.6 Appendix 6: 
Collection and 
Management of 
Specimens for Future 
Biomedical Research
Sponsor email address updated
from @merck.com to 
@MSD.com.
To reflect the recent change in the Sponsor’s email address.
Throughout as 
applicable
Minor administrative, 
formatting, grammatical, and 
typographical changes were 
made throughout the 
document.
To ensure clarity and accurate interpretation of the intent of the protocol.
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Table of Contents
DOCUMENT HISTORY ........................................................................................................3
PROTOCOL AMENDMENT SUMMARY OF CHANGES...............................................4
1
PROTOCOL SUMMARY ............................................................................................18
1.1
Synopsis.................................................................................................................18
1.2
Schema ..................................................................................................................22
1.3
Schedule of Activities...........................................................................................24
1.3.1
Schedule of Activities for Part 1 and, Part 2, and Part 3 .............................24
1.3.2
Schedule of Activities – Participants Who Discontinue Study 
Intervention Early and/or Withdraw Consent/Assent..................................35
1.3.3
Schedule of Activities – Participants With a Positive HIV-1 Test Result...38
1.3.4
Schedule of Activities for Participants Who Become Pregnant and 
Remain on ISL .............................................................................................41
2
INTRODUCTION..........................................................................................................42
2.1
Study Rationale....................................................................................................42
2.2
Background ..........................................................................................................43
2.2.1
Pharmaceutical and Therapeutic Background .............................................43
2.2.2
Information on Other Study-related Therapy ..............................................44
2.3
Benefit/Risk Assessment......................................................................................44
3
HYPOTHESES, OBJECTIVES, AND ENDPOINTS................................................46
4
STUDY DESIGN............................................................................................................48
4.1
Overall Design......................................................................................................48
4.2
Scientific Rationale for Study Design.................................................................50
4.2.1
Rationale for Endpoints ...............................................................................51
4.2.1.1
Efficacy Endpoints.............................................................................51
4.2.1.2
Safety Endpoints................................................................................51
4.2.1.3
Participant-reported Outcomes ..........................................................51
4.2.1.4
Renal Biomarkers...............................................................................52
4.2.1.5
Pharmacokinetic Endpoints ...............................................................52
4.2.1.6
Planned Exploratory Biomarker Research.........................................52
4.2.1.6.1
Planned Genetic Analysis ........................................................52
4.2.1.7
Future Biomedical Research..............................................................53
4.2.2
Rationale for the Use of Comparator/Placebo .............................................53
4.2.3
Rationale for Estimating Background HIV Incidence Rate.........................54
4.2.4
Rationale for Collecting Specific Data ........................................................55
4.2.5
Rationale for Continuing Study Intervention During Pregnancy ................55
4.2.6
Rationale for Collecting Infant Safety Follow-up Data...............................56
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4.3
Justification for Dose...........................................................................................56
4.3.1
Rationale for ISL QM Efficacious Exposure...............................................56
4.3.2
Rationale for Dose Selection .......................................................................57
4.4
Beginning and End-of-Study Definition ............................................................58
4.4.1
Clinical Criteria for Early Study Termination .............................................59
5
STUDY POPULATION ................................................................................................59
5.1
Inclusion Criteria.................................................................................................59
5.2
Exclusion Criteria................................................................................................61
5.3
Lifestyle Considerations......................................................................................63
5.4
Screen Failures.....................................................................................................63
5.5
Participant Replacement Strategy......................................................................64
6
STUDY INTERVENTION............................................................................................64
6.1
Study Intervention(s) Administered...................................................................64
6.2
Preparation/Handling/Storage/Accountability .................................................66
6.2.1
Dose Preparation..........................................................................................66
6.2.2
Handling, Storage, and Accountability........................................................66
6.3
Measures to Minimize Bias: Randomization and Blinding..............................67
6.3.1
Intervention Assignment..............................................................................67
6.3.2
Stratification.................................................................................................67
6.3.3
Blinding........................................................................................................68
6.4
Study Intervention Compliance..........................................................................69
6.5
Concomitant Therapy..........................................................................................69
6.5.1
Rescue Medications and Supportive Care ...................................................70
6.6
Dose Modification ................................................................................................71
6.7
Intervention After the End of the Study............................................................71
6.8
Clinical Supplies Disclosure................................................................................71
6.9
Standard Policies..................................................................................................71
7
DISCONTINUATION OF STUDY INTERVENTION AND PARTICIPANT 
WITHDRAWAL............................................................................................................72
7.1
Discontinuation of Study Intervention...............................................................72
7.2
Participant Withdrawal From the Study...........................................................73
7.3
Lost to Follow-up .................................................................................................74
8
STUDY ASSESSMENTS AND PROCEDURES........................................................74
8.1
Administrative and General Procedures ...........................................................75
8.1.1
Informed Consent.........................................................................................75
8.1.1.1
General Informed Consent.................................................................75
8.1.1.2
Consent and Collection of Specimens for Future Biomedical 
Research.............................................................................................76
8.1.1.3
Consent in the Event of a Positive Pregnancy Test ...........................76
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8.1.1.3.1
Consent for Open-label FTC/TDF...........................................76
8.1.1.3.2
Consent for Continuation or Interruption of Study 
Intervention During Pregnancy- Part 1 Only...........................76
8.1.1.4
Consent for Continuing Study Participation for Participants Who 
Choose to Breastfeed .........................................................................77
8.1.1.5
Consent for Infant Safety Data Collection.........................................77
8.1.2
Inclusion/Exclusion Criteria ........................................................................78
8.1.2.1
HIV Recency Assay Testing..............................................................78
8.1.3
Participant Identification Card.....................................................................78
8.1.4
Medical History ...........................................................................................78
8.1.5
Prior and Concomitant Medications Review...............................................78
8.1.5.1
Prior Medications...............................................................................78
8.1.5.2
Concomitant Medications..................................................................78
8.1.6
Assignment of Screening Number...............................................................79
8.1.7
Assignment of Treatment/Randomization Number.....................................79
8.1.8
Study Intervention Administration ..............................................................79
8.1.8.1
Timing of Dose Administration.........................................................79
8.1.8.2
HIV Risk Reduction...........................................................................80
8.1.8.3
Participant-reported Outcomes ..........................................................80
8.1.8.4
Interruption of Study Intervention .....................................................80
8.1.9
Discontinuation and Withdrawal .................................................................81
8.1.9.1
Withdrawal From Future Biomedical Research ................................81
8.1.10
Participant Blinding/Unblinding..................................................................81
8.1.11
Calibration of Equipment.............................................................................82
8.2
Efficacy Assessments ...........................................................................................82
8.2.1
HIV-1 Testing..............................................................................................82
8.2.2
Whole Blood Collection for HIV-1 Resistance Testing ..............................83
8.3
Safety Assessments...............................................................................................83
8.3.1
Physical Examinations.................................................................................83
8.3.2
Vital Signs....................................................................................................84
8.3.3
Confirmation of Contraception and Pregnancy Testing ..............................84
8.3.4
Sexually Transmitted Infections ..................................................................84
8.3.5
Clinical Safety Laboratory Assessments .....................................................85
8.3.6
Review of Social Harm Events....................................................................85
8.4
Adverse Events, Serious Adverse Events, and Other Reportable Safety 
Events....................................................................................................................85
8.4.1
Time Period and Frequency for Collecting AE, SAE, and Other 
Reportable Safety Event Information ..........................................................86
8.4.2
Method of Detecting AEs, SAEs, and Other Reportable Safety Events......88
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8.4.3
Follow-up of AE, SAE, and Other Reportable Safety Event Information...88
8.4.4
Regulatory Reporting Requirements for SAE .............................................88
8.4.5
Pregnancy and Exposure During Breastfeeding ..........................................89
8.4.6
Disease-related Events and/or Disease-related Outcomes Not Qualifying 
as AEs or SAEs............................................................................................89
8.4.7
Events of Clinical Interest............................................................................89
8.5
Treatment of Overdose........................................................................................90
8.6
Pharmacokinetics.................................................................................................90
8.6.1
Blood (Plasma) Collection for PK...............................................................90
8.6.2
Blood (Plasma) for Investigational PK........................................................91
8.6.3
Dried Blood Collection for PK ....................................................................91
8.6.4
Collection of PK Samples in Participants Who Become Pregnant and 
Continue ISL (Only Applicable for Part 1)..................................................92
8.6.5
Collection of PK Samples in Participants Who Discontinue Study 
Intervention Early, Withdraw Consent/Assent, or Have a Positive HIV-
1 Test............................................................................................................93
8.7
Pharmacodynamics..............................................................................................93
8.8
Biomarkers ...........................................................................................................94
8.8.1
Planned Genetic Analysis Sample Collection..............................................94
8.8.2
Renal Biomarkers.........................................................................................94
8.9
Future Biomedical Research Sample Collection...............................................94
8.10
Medical Resource Utilization and Health Economics.......................................94
8.11
Visit Requirements...............................................................................................94
8.11.1
Screening/Rescreening.................................................................................94
8.11.2
Treatment Period..........................................................................................95
8.11.2.1
Off-site Visits.....................................................................................95
8.11.3
Clinical Management of Participants Who Become Pregnant.....................96
8.11.3.1
Clinical Management of Participants Who Become Pregnant -
Part 1..................................................................................................96
8.11.3.1.1
Clinical Management of Participants Who Choose to 
Breastfeed – Part 1...................................................................99
8.11.3.2
Clinical Management of Participants Who Become Pregnant –
Part 2 and Part 3...............................................................................100
8.11.3.2.1
Clinical Management of Participants Who Choose to 
Breastfeed – Part 2 and Part 3................................................102
8.11.4
Infant Safety Data Collection.....................................................................102
8.11.4.1
Schedule of Activities: Infant Safety Collection .............................103
8.11.5
Participants Who Discontinue Study Intervention.....................................103
8.11.6
Participants Who Withdraw Consent/Assent.............................................104
8.11.7
Follow-up Phone Calls...............................................................................104
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9
STATISTICAL ANALYSIS PLAN ...........................................................................104
9.1
Statistical Analysis Plan Summary...................................................................105
9.2
Responsibility for Analyses/In-house Blinding ...............................................106
9.3
Hypotheses/Estimation ......................................................................................107
9.4
Analysis Endpoints.............................................................................................107
9.4.1
Efficacy Endpoints.....................................................................................107
9.4.2
Safety Endpoints........................................................................................107
9.5
Analysis Populations..........................................................................................107
9.5.1
Efficacy Analysis Population.....................................................................107
9.5.2
Safety Analysis Population........................................................................108
9.6
Statistical Methods.............................................................................................108
9.6.1
Efficacy Analyses ......................................................................................108
9.6.2
Safety Analysis ..........................................................................................111
9.6.3
Demographic and Baseline Characteristics ...............................................113
9.7
Interim Analyses ................................................................................................113
9.8
Multiplicity .........................................................................................................115
9.9
Sample Size and Power Calculations ...............................................................115
9.9.1
Sample Size and Power for Efficacy Analyses..........................................116
9.9.2
Sample Size and Power for Safety Analyses .............................................116
9.10
Subgroup Analyses.............................................................................................118
9.11
Compliance (Medication Adherence)...............................................................118
9.12
Extent of Exposure.............................................................................................119
10
SUPPORTING DOCUMENTATION AND OPERATIONAL 
CONSIDERATIONS...................................................................................................120
10.1
Appendix 1: Regulatory, Ethical, and Study Oversight Considerations......120
10.1.1
Code of Conduct for Clinical Trials...........................................................120
10.1.2
Financial Disclosure...................................................................................122
10.1.3
Data Protection...........................................................................................122
10.1.3.1
Confidentiality of Data ....................................................................123
10.1.3.2
Confidentiality of Participant Records.............................................123
10.1.3.3
Confidentiality of IRB/IEC Information..........................................123
10.1.4
Committees Structure.................................................................................124
10.1.4.1
Scientific Advisory Committee (SAC)............................................124
10.1.4.2
External Data Monitoring Committee .............................................124
10.1.4.3
Clinical Adjudication Committee (CAC) ........................................124
10.1.4.4
Executive Oversight Committee......................................................124
10.1.4.5
Protocol Steering Committee...........................................................125
10.1.5
Publication Policy......................................................................................125
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10.1.6
Compliance with Study Registration and Results Posting Requirements .125
10.1.7
Compliance with Law, Audit, and Debarment ..........................................126
10.1.8
Data Quality Assurance .............................................................................126
10.1.9
Source Documents .....................................................................................127
10.1.10
Study and Site Closure...............................................................................128
10.2
Appendix 2: Clinical Laboratory Tests............................................................129
10.3
Appendix 3: Adverse Events: Definitions and Procedures for Recording, 
Evaluating, Follow-up, and Reporting.............................................................137
10.3.1
Definitions of Medication Error, Misuse, and Abuse................................137
10.3.2
Definition of AE ........................................................................................137
10.3.3
Definition of SAE ......................................................................................138
10.3.4
Additional Events Reported.......................................................................139
10.3.5
Recording AE and SAE .............................................................................140
10.3.6
Reporting of AEs, SAEs, and Other Reportable Safety Events to the 
Sponsor ......................................................................................................143
10.4
Appendix 4: Device Events, Adverse Device Events, and Medical Device 
Incidents: Definitions, Collection, and Documentation..................................145
10.5
Appendix 5: Contraceptive Guidance..............................................................146
10.5.1
Definitions..................................................................................................146
10.5.2
Contraception Requirements......................................................................148
10.6
Appendix 6: Collection and Management of Specimens for Future 
Biomedical Research..........................................................................................149
10.7
Appendix 7: Country-specific Requirements..................................................153
10.8
Appendix 8: Abbreviations ...............................................................................154
10.9
Appendix 9: Calculation of Creatinine Clearance..........................................157
10.10 Appendix 10: Document to Support Assessment of HIV-1 Infection 
Risk/CDC Criteria for PrEP.............................................................................158
10.10.1
Background................................................................................................158
10.10.2
VOICE Risk Score – Sites in Africa..........................................................158
10.10.2.1
VOICE Risk Score Tool ..................................................................159
10.10.3
CDC Criteria for PrEP – Sites in the US ...................................................159
10.11 Appendix 11: MK-8591 PrEP Program HIV Testing Algorithm..................161
11
REFERENCES.............................................................................................................162
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LIST OF TABLES
Table 1
Laboratory Exclusion Criteria....................................................................63
Table 2
Study Interventions....................................................................................65
Table 3
Reporting Time Periods and Time Frames for Adverse Events and 
Other Reportable Safety Events.................................................................87
Table 4
Collection of Plasma PK Samples .............................................................91
Table 5
Collection of Dried Blood PK Samples.....................................................92
Table 6
Collection of Population PK Samples in Participants Who Become 
Pregnant and Continue ISL........................................................................93
Table 7
Analysis Strategy for Safety Parameters..................................................113
Table 8
Decision Rule and Corresponding Type 1 Error and Power for Testing 
the Primary Efficacy Hypothesis .............................................................115
Table 9
Percentage of Participants With AEs and 95% Upper Confidence 
Bound Based on Hypothetical Numbers of Participants With AEs 
(2250 Participants per Group)..................................................................117
Table 10
Difference in Percentage of Participants With AEs (ISL QM Minus 
FTC/TDC QD) That can be Ruled Out With 2250 Participants in Each 
Group .......................................................................................................118
Table 11
Protocol-required Laboratory Assessments.............................................129
Table 12
PK Sample Collection Timepoints...........................................................132
Table 13
Blood Volumes ........................................................................................134
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LIST OF FIGURES
Figure 1
Study Schema – Part 1...............................................................................22
Figure 2
Study Schema – Part 2...............................................................................23
Figure 3
Study Schema – Part 3...............................................................................23
Figure 4
Pregnancy Confirmation Flow Chart (Only applicable for Part 1)............97
Figure 5
Clinical Management of Participants Who Become Pregnant (Only 
applicable for Part 1)..................................................................................98
Figure 6
Clinical Management of Participants Who Choose to Breastfeed – Part 
1..................................................................................................................99
Figure 7
Pregnancy Confirmation Flow Chart (Only applicable for Part 2)..........100
Figure 8
Pregnancy Confirmation Flow Chart (Only applicable for Part 3)..........101
Figure 9
Clinical Management of Participants Who Choose to Breastfeed – Part 
2 & Part 3.................................................................................................102
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1
PROTOCOL SUMMARY
1.1
Synopsis
Protocol Title: A Phase 3, Randomized, Active-Controlled, Double-blind Clinical Study to 
Evaluate the Efficacy and Safety of Oral Islatravir Once-Monthly as Preexposure 
Prophylaxis in Cisgender Women at High Risk for HIV-1 Infection
Short Title: Oral ISL QM as PrEP in Cisgender Women at High Risk for HIV-1 Infection
Acronym: Impower - 022
Hypotheses, Objectives, and Endpoints:
Hypotheses are aligned with objectives in the Objectives and Endpoints table.
Note: As of Amendment -04, formal hypothesis tests and comparisons between study 
intervention groups will no longer be conducted; therefore, evaluation of the percentage of 
participants with confirmed HIV-1 infections will no longer be considered a primary
endpoint. The only study objective is to evaluate the safety and tolerability of ISL QM based 
on review of the accumulated safety data. Updated analyses are described in Section 9.
The following objectives will be evaluated in female participants, 16 to 45 years of age 
inclusive, at high risk for HIV-1 infection.
Objectives
Endpoints
Primary
•
To evaluate the efficacy of oral ISL QM 
compared to FTC/TDF QD for the 
prevention of HIV-1 infection as 
assessed by the incidence rate per year 
of confirmed HIV-1 infections
•
Hypothesis: ISL QM is superior to 
FTC/TDF QD as assessed by the 
incidence rate per year of confirmed 
HIV-1 infections
•
Confirmed HIV-1 infection
•
To evaluate the safety and tolerability of 
oral ISL QM compared with oral 
FTC/TDF QD as assessed by review of 
the accumulated safety data
•
Adverse events
•
Adverse events leading to 
discontinuation of study intervention
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Objectives
Endpoints
Secondary
•
To evaluate the efficacy of oral ISL QM 
in reducing the incidence per year of 
HIV-1 infection relative to the 
background rate
•
Hypothesis: ISL QM reduces the 
incidence rate of confirmed HIV-1 
infections compared with the 
background incidence rate
•
Confirmed HIV-1 infection
Overall Design:
Study Phase
Phase 3
Primary Purpose
Prevention
Indication
HIV Preexposure prophylaxis
Population
Cisgender Women at high risk for HIV-1 infection
Study Type
Interventional
Intervention Model
Parallel
This is a multi-site study.
Type of Control
Active Control
Study Blinding
Double-blind
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Blinding Roles
Participants or Subjects
Investigator
Sponsor
In Part 2: Personnel not directly involved with blinded 
safety monitoring of participants’ ongoing in the study will 
be unblinded to the participants’ original randomized study 
intervention group.
In Part 3: Participants, investigators, and all Sponsor 
personnel will be unblinded to the participants’ original 
randomized study intervention group.
Estimated Duration of Study
The Sponsor estimates that the study will require 
approximately 3 years from the time the first participant 
(or their legally acceptable representative) provides 
documented informed consent/assent until the last 
participant’s last study-related contact.
Number of Participants:
Approximately 4500 participants will be randomized. No participants will be randomized in 
Parts 2 or 3.
Intervention Groups and Duration:
Intervention 
Groups
Intervention 
Group Name
Drug
Dose 
Strength
Dose 
Frequency
Route of 
Admin-
istration
Regimen/ 
Treatment 
Period/ 
Vaccination 
Regimen
Use
Part 1
ISL QM Group
ISL
60 mg
QM
Oral
Visit 2 to (up 
to) Visit 37
Test 
Product
Part 1
ISL QM Group
Placebo to 
FTC/TDF
0 mg
QD
Oral
Visit 2 to (up 
to) Visit 37
Placebo
Part 1
FTC/TDF QD 
Group
FTC/TDF
200/245 mg
QD
Oral
Visit 2 to (up 
to) Visit 37
Test 
Product
Part 1
FTC/TDF QD 
Group
Placebo to 
ISL
0 mg
QM
Oral
Visit 2 to (up 
to) Visit 37
Placebo
Part 2
All Participants
FTC/TDF
200/245 mg
QD
Oral
QD for Part 2
Test 
Product
Part 3
All Participants
FTC/TDF
200/245 mg
QD
Oral
QD for Part 3
Test 
Product
FTC/TDF=emtricitabine/tenofovir disoproxil (including TRUVADATM [Gilead] and all generic versions); 
ISL=islatravir also known as MK-8591; PrEP=preexposure prophylaxis; QD=once daily; QM=once-monthly.
Each FTC/TDF tablet contains 200 mg emtricitabine and 245 mg of tenofovir disoproxil (equivalent to 300 mg 
tenofovir disoproxil fumarate or 291.22 mg tenofovir disoproxil phosphate).
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Total 
Number of 
Intervention 
Groups/
Arms
2
Duration of 
Participation
After a screening phase of up to 45 days, each participant will be in the 
study for up to 3 years from the time the participant provides documented 
Informed Consent/assent through final contact.
Because this is an endpoint-driven study, participation times will vary 
depending on when the participant is enrolled. Participants will be enrolled 
over an approximately 12-month period with study intervention 
administered for approximately 1 year and up to 3 years, based on estimated 
accrual of primary endpoint cases.
Participants who discontinue study intervention, become pregnant, or 
decide to breastfeed will be followed as described in the protocol.
Study Governance Committees:
Executive Oversight Committee
Yes
Data Monitoring Committee
Yes
Clinical Adjudication Committee
Yes
Study governance considerations are outlined in Appendix 1.
Note: The Executive Oversight Committee and Data Monitoring Committee are not 
applicable in Part 3.
Study Accepts Healthy Volunteers: Yes
A list of abbreviations used in this document can be found in Appendix 8.
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1.2
Schema
The study design is depicted in Figure 1 (Part 1), Figure 2 (Part 2), and Figure 3 (Part 3).
Blinded study intervention administration has been stopped; study assessments conducted 
prior to stopping blinded study intervention are designated as Part 1 (Figure 1).
During Part 2 (Figure 2), all participants were switched to PrEP therapy with FTC/TDF. No 
new participants will be screened or randomized during Part 2.
During Part 3 (Figure 3), all ongoing participants will continue to receive open-label PrEP 
therapy with FTC/TDF. No new participants will be screened or randomized during Part 3.
Figure 1
Study Schema – Part 1
FTC/TDF=emtricitabine/tenofovir disoproxil (including TRUVADATM [Gilead] and all generic versions); ISL=islatravir; 
QD=once daily; QM=once-monthly
a
Sentinel Cohort Interim Analysis (N=400) will be conducted 3 months after the last participant in the Sentinel Cohort 
has initiated study intervention.
b
An efficacy Interim Analysis will be performed when 25 primary endpoint cases are observed.
c
End of study includes the safety follow-up period of 42 days after the last dose of study intervention. End of Study will 
be determined based on estimated accrual of 40 primary endpoint cases. Participants will be enrolled over an 
approximately 12-month period with study intervention administered for approximately 1 year and up to 3 years.
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Figure 2
Study Schema – Part 2
FTC/TDF=emtricitabine/tenofovir disoproxil (including TRUVADATM [Gilead] and all generic versions); QD=once daily.
Note: For Part 2, throughout the protocol, references to study intervention refer to FTC/TDF.
Figure 3
Study Schema – Part 3
FTC/TDF=emtricitabine/tenofovir disoproxil (including TRUVADATM [Gilead] and all generic versions); QD=once daily.
All participants will be unblinded to original study intervention assignments in Part 3.
No new participants will be screened or randomized during Part 3.
Note For Part 3, throughout the protocol, references to study intervention refer to FTC/TDF.
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1.3
Schedule of Activities
Note: Blinded study intervention administration (Part 1) was stopped. During Part 2, all participants were switched to PrEP therapy 
with FTC/TDF and will maintain the visit schedule in Section 1.3.1. No new participants will be screened or randomized during 
Part 2. For Part 2, throughout the protocol, references to study intervention refer to FTC/TDF.
Note: At the start of Part 3, all participants will be unblinded to their Part 1 study intervention assignments and ongoing participants 
will continue to receive open-label daily PrEP therapy with FTC/TDF. No new participants will be screened or randomized 
during Part 3. For Part 3, throughout the protocol, references to study intervention refer to FTC/TDF.
1.3.1
Schedule of Activities for Part 1 and, Part 2, and Part 3
Study Period
Double-blind Study Intervention Period (Part 1)
PrEP Therapy With FTC/TDF (Part 2 and Part 3)
Follow-up
Visit Number
1
2
3
4
5
6
7
8
Recurring Visits
38
39
40
Notes
Scheduled Day/Month
Screening
(N/A during Part 2)
Day 1
(N/A during Part 2
and Part 3)
Month 1
Month 2
Month 3
Month 4
Month 5
Month 6
Every Montha
(Additional 
Assessments)
Every 3 Monthsb
(Additional
Assessments)
Every 6 Monthsc
Month 36/ EOT
14-Day Phone 
Call
42-Day Phone 
Call
Each visit should be calculated 
from date of Day 1 and based on a 
28-day month. A participant may 
have up to 40 visits, but may have 
fewer visits (endpoint-driven 
study). 
Visit Window 
≤45 
daysd
N/A
±7 Days
Visit windows for Part 3 are extended 
to ±14 Days
Administrative Procedures
Informed Consent/Assent
X
Informed Consent/Assent 
for Future Biomedical 
Research
X
Consent/Assent for Open-
label FTC/TDF
For participants with a positive 
urine pregnancy test only. To occur 
at the time of the first positive urine 
pregnancy test.
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Study Period
Double-blind Study Intervention Period (Part 1)
PrEP Therapy With FTC/TDF (Part 2 and Part 3)
Follow-up
Visit Number
1
2
3
4
5
6
7
8
Recurring Visits
38
39
40
Notes
Scheduled Day/Month
Screening
(N/A during Part 2)
Day 1
(N/A during Part 2
and Part 3)
Month 1
Month 2
Month 3
Month 4
Month 5
Month 6
Every Montha
(Additional 
Assessments)
Every 3 Monthsb
(Additional
Assessments)
Every 6 Monthsc
Month 36/ EOT
14-Day Phone 
Call
42-Day Phone 
Call
Each visit should be calculated 
from date of Day 1 and based on a 
28-day month. A participant may 
have up to 40 visits, but may have 
fewer visits (endpoint-driven 
study). 
Visit Window 
≤45 
daysd
N/A
±7 Days
Visit windows for Part 3 are extended 
to ±14 Days
Consent/Assent to 
Continue Study 
Participation after a 
Confirmed Continuing 
Pregnancy
For Part 1 participants with a 
confirmed continuing pregnancy 
only. To occur at the time a 
continuing pregnancy is confirmed. 
See Section 8.11.3 for details.
Consent/Assent to 
Continue Study 
Participation for 
Participants Who Choose 
to Breastfeed
For participants who choose to 
breastfeed during the study only. 
To occur before delivery. See 
Sections 8.11.3.1.1 and 8.11.3.2.1
for details.
Consent/Assent for Infant 
Safety Data Collection
For Part 1 and Part 2 participants 
with a confirmed continuing 
pregnancy only. To occur at any 
time after confirmation of 
continuing pregnancy (see Section 
8.11.3).
Inclusion/Exclusion 
Criteria
X
X
Review prior to randomization on 
Day 1 to confirm no changes in 
eligibility.
Recency Assay
X
X
Samples will be analyzed in 
participants with confirmed HIV-1 
infection at Screening or Day 1
Participant Identification 
Card
X
X
Randomization number will be 
added once the participant is 
randomized on Day 1.
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Study Period
Double-blind Study Intervention Period (Part 1)
PrEP Therapy With FTC/TDF (Part 2 and Part 3)
Follow-up
Visit Number
1
2
3
4
5
6
7
8
Recurring Visits
38
39
40
Notes
Scheduled Day/Month
Screening
(N/A during Part 2)
Day 1
(N/A during Part 2
and Part 3)
Month 1
Month 2
Month 3
Month 4
Month 5
Month 6
Every Montha
(Additional 
Assessments)
Every 3 Monthsb
(Additional
Assessments)
Every 6 Monthsc
Month 36/ EOT
14-Day Phone 
Call
42-Day Phone 
Call
Each visit should be calculated 
from date of Day 1 and based on a 
28-day month. A participant may 
have up to 40 visits, but may have 
fewer visits (endpoint-driven 
study). 
Visit Window 
≤45 
daysd
N/A
±7 Days
Visit windows for Part 3 are extended 
to ±14 Days
Register study visit in 
IRT
X
X
X
X
X
X
X
X
X
X
X
X
Medical History 
X
Prior/Concomitant 
Medication Review
X
X
X
X
X
X
X
X
X
X
X
X
Intervention 
Randomization
X
Assessment of acute 
retroviral syndrome
X
See Section 8.11.1
Dispense Study 
Intervention
X
X
X
X
X
X
X
X
During Part 1, in-clinic dosing of 
study intervention. The remaining 
supply of FTC/TDF or matching 
placebo will be dispensed at each 
visit.
Do NOT dispense study 
intervention if the participant’s 
Point-of-Care HIV test or urine 
pregnancy test is positive.
During Part 2 and Part 3, 
participants will receive only 
FTC/TDF. Participants should stop 
FTC/TDF if Point-of-Care HIV test 
result is positive while further 
testing is conducted. No other study 
intervention is to be dosed.
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Study Period
Double-blind Study Intervention Period (Part 1)
PrEP Therapy With FTC/TDF (Part 2 and Part 3)
Follow-up
Visit Number
1
2
3
4
5
6
7
8
Recurring Visits
38
39
40
Notes
Scheduled Day/Month
Screening
(N/A during Part 2)
Day 1
(N/A during Part 2
and Part 3)
Month 1
Month 2
Month 3
Month 4
Month 5
Month 6
Every Montha
(Additional 
Assessments)
Every 3 Monthsb
(Additional
Assessments)
Every 6 Monthsc
Month 36/ EOT
14-Day Phone 
Call
42-Day Phone 
Call
Each visit should be calculated 
from date of Day 1 and based on a 
28-day month. A participant may 
have up to 40 visits, but may have 
fewer visits (endpoint-driven 
study). 
Visit Window 
≤45 
daysd
N/A
±7 Days
Visit windows for Part 3 are extended 
to ±14 Days
Evaluation to receive 
continued study 
intervention
X
Study Intervention 
Adherence Review
X
X
X
X
X
X
X
X
X
Reconcile doses, assess study 
intervention adherence, and offer 
adherence counseling.
Contraceptive use 
confirmation (WOCBP 
only)
X
X
X
X
X
X
X
X
X
X
Contraception to be provided to 
participants if needed.
HIV Risk Reduction
X
X
X
X
X
X
X
X
X
X
Completion of the sexual activity 
form, offer condoms, lubricants, 
and HIV risk reduction counseling.
PRO: HIV infection Risk 
X
X
X
X
X
PRO: Preference 
X
X
X
X
Not applicable for Part 3.
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Study Period
Double-blind Study Intervention Period (Part 1)
PrEP Therapy With FTC/TDF (Part 2 and Part 3)
Follow-up
Visit Number
1
2
3
4
5
6
7
8
Recurring Visits
38
39
40
Notes
Scheduled Day/Month
Screening
(N/A during Part 2)
Day 1
(N/A during Part 2
and Part 3)
Month 1
Month 2
Month 3
Month 4
Month 5
Month 6
Every Montha
(Additional 
Assessments)
Every 3 Monthsb
(Additional
Assessments)
Every 6 Monthsc
Month 36/ EOT
14-Day Phone 
Call
42-Day Phone 
Call
Each visit should be calculated 
from date of Day 1 and based on a 
28-day month. A participant may 
have up to 40 visits, but may have 
fewer visits (endpoint-driven 
study). 
Visit Window 
≤45 
daysd
N/A
±7 Days
Visit windows for Part 3 are extended 
to ±14 Days
Efficacy Procedures
Point-of-Care HIV 
Testing
X
X
X
X
X
X
X
X
X
X
Performed at the study site. On 
Day 1, this testing should be 
performed prior to randomization 
and if positive, the participant 
should not be randomized.
At all subsequent visits after Day 1, 
if this test result is positive, PK 
samples (both plasma and dried 
blood) should be collected, 
regardless of the PK sampling 
schedule.
During Part 1, do NOT dispense 
study intervention if the 
participant’s Point-of-Care HIV test 
is positive while further testing is 
conducted.
During Part 2 and Part 3, 
participants should stop taking 
FTC/TDF if Point-of-Care HIV 
Test result is positive.
HIV-1/HIV-2 
Antibody/Antigen Testing
X
X
X
X
X
X
X
X
X
X
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Study Period
Double-blind Study Intervention Period (Part 1)
PrEP Therapy With FTC/TDF (Part 2 and Part 3)
Follow-up
Visit Number
1
2
3
4
5
6
7
8
Recurring Visits
38
39
40
Notes
Scheduled Day/Month
Screening
(N/A during Part 2)
Day 1
(N/A during Part 2
and Part 3)
Month 1
Month 2
Month 3
Month 4
Month 5
Month 6
Every Montha
(Additional 
Assessments)
Every 3 Monthsb
(Additional
Assessments)
Every 6 Monthsc
Month 36/ EOT
14-Day Phone 
Call
42-Day Phone 
Call
Each visit should be calculated 
from date of Day 1 and based on a 
28-day month. A participant may 
have up to 40 visits, but may have 
fewer visits (endpoint-driven 
study). 
Visit Window 
≤45 
daysd
N/A
±7 Days
Visit windows for Part 3 are extended 
to ±14 Days
Plasma HIV-1 RNA 
Quantification (Real Time 
PCR)
X
X
X
X
X
X
X
X
X
X
Samples will be collected at every 
visit and analyzed if Point-of-Care 
HIV test or HIV-1/HIV-2 
antibody/antigen test is positive.
Whole Blood Collection 
for HIV-1 Resistance 
Testing
X
See Section 1.3.3 for additional 
requirements for participants who 
have an HIV Infection 
Confirmation Visit.
Safety Procedures
Full physical examination 
X
Height
X
X
X
Weight
X
X
X
X
X
X
X
X
X
X
Symptom-directed 
Physical Examination
X
X
X
X
X
X
X
X
X
Vital Signs 
X
X
X
X
X
X
X
X
X
X
Includes pulse, blood pressure, 
body temperature, and respiratory 
rate.
Antenatal care record 
review
X
X
X
X
X
X
X
X
Only for participants who become 
pregnant in Parts 1 and 2 (see 
Sections 8.4.5 and 8.11.3).
Review of adverse events
X
X
X
X
X
X
X
X
X
X
X
X
Review of social harm 
events
X
X
X
X
X
X
X
X
X
X
X
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Study Period
Double-blind Study Intervention Period (Part 1)
PrEP Therapy With FTC/TDF (Part 2 and Part 3)
Follow-up
Visit Number
1
2
3
4
5
6
7
8
Recurring Visits
38
39
40
Notes
Scheduled Day/Month
Screening
(N/A during Part 2)
Day 1
(N/A during Part 2
and Part 3)
Month 1
Month 2
Month 3
Month 4
Month 5
Month 6
Every Montha
(Additional 
Assessments)
Every 3 Monthsb
(Additional
Assessments)
Every 6 Monthsc
Month 36/ EOT
14-Day Phone 
Call
42-Day Phone 
Call
Each visit should be calculated 
from date of Day 1 and based on a 
28-day month. A participant may 
have up to 40 visits, but may have 
fewer visits (endpoint-driven 
study). 
Visit Window 
≤45 
daysd
N/A
±7 Days
Visit windows for Part 3 are extended 
to ±14 Days
Laboratory Procedures
Urine Pregnancy Test 
(WOCBP only)
X
X
X
X
X
X
X
X
X
X
Conduct per local regulations and 
prior to administering/dispensing 
study intervention. Do NOT 
dispense study intervention if the 
participant’s urine pregnancy test is 
positive. Confirm with serum test if 
urine test is positivee.
Serum Pregnancy Test 
(WOCBP only)
X
Hepatitis B Serology 
(HBsAb/HBcAb)
X
Participants who do not 
demonstrate immunity to HBV 
should be encouraged to be 
vaccinated against HBV.
HBsAg
X
Syphilis Serologic 
Testing
X
X
X
X
X
Vaginal swab for bacterial 
vaginosis testing
X
X
X
X
X
Urine for Trichomonas
X
X
X
X
X
Collect the sample according to the 
laboratory manual.
Urine for GC/CT
X
X
X
X
X
Collect the sample according to the 
laboratory manual.
HSV-2 serology testing
X
X
Hematology
X
X
X
X
X
X
X
X
X
X
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Study Period
Double-blind Study Intervention Period (Part 1)
PrEP Therapy With FTC/TDF (Part 2 and Part 3)
Follow-up
Visit Number
1
2
3
4
5
6
7
8
Recurring Visits
38
39
40
Notes
Scheduled Day/Month
Screening
(N/A during Part 2)
Day 1
(N/A during Part 2
and Part 3)
Month 1
Month 2
Month 3
Month 4
Month 5
Month 6
Every Montha
(Additional 
Assessments)
Every 3 Monthsb
(Additional
Assessments)
Every 6 Monthsc
Month 36/ EOT
14-Day Phone 
Call
42-Day Phone 
Call
Each visit should be calculated 
from date of Day 1 and based on a 
28-day month. A participant may 
have up to 40 visits, but may have 
fewer visits (endpoint-driven 
study). 
Visit Window 
≤45 
daysd
N/A
±7 Days
Visit windows for Part 3 are extended 
to ±14 Days
CD4+ T-cell 
count/Lymphocyte subset 
panel
X
X
X
X
X
X
X
X
X
X
Chemistry
X
X
X
X
X
X
Creatinine Clearance 
Calculation
X
X
X
X
X
X
See Appendix 9
Cystatin-C
X
X
X
X
X
Pharmacokinetics 
Blood (Plasma) for PKf
X
X
X
X
X
X
Not applicable for Part 3.
See Section 8.6.1 and Table 12.
The sample must be collected 
irrespective of the planned PK 
collection schedule, if a participant 
has a positive Point-of-Care HIV 
test result at a visit.
See Section 1.3.4 for participants 
who become pregnant and remain 
on ISL.
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Study Period
Double-blind Study Intervention Period (Part 1)
PrEP Therapy With FTC/TDF (Part 2 and Part 3)
Follow-up
Visit Number
1
2
3
4
5
6
7
8
Recurring Visits
38
39
40
Notes
Scheduled Day/Month
Screening
(N/A during Part 2)
Day 1
(N/A during Part 2
and Part 3)
Month 1
Month 2
Month 3
Month 4
Month 5
Month 6
Every Montha
(Additional 
Assessments)
Every 3 Monthsb
(Additional
Assessments)
Every 6 Monthsc
Month 36/ EOT
14-Day Phone 
Call
42-Day Phone 
Call
Each visit should be calculated 
from date of Day 1 and based on a 
28-day month. A participant may 
have up to 40 visits, but may have 
fewer visits (endpoint-driven 
study). 
Visit Window 
≤45 
daysd
N/A
±7 Days
Visit windows for Part 3 are extended 
to ±14 Days
Blood (Plasma) for 
Investigational PKg
X
X
Not applicable for Part 3.
During Part 1, investigational PK 
samples will be collected predose at 
Visit 4 (Month 2) and at any time 
during Visit 11 (Month 9) and 
every 6 months starting from Visit 
11 (Month 9).
During Part 2, investigational PK 
samples can be collected at any 
time during the visit.
See Table 12. Samples will be 
stored and triggered for analysis by 
Sponsor, if needed.
See Section 1.3.4 for participants 
who become pregnant and remain 
on ISL.
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Study Period
Double-blind Study Intervention Period (Part 1)
PrEP Therapy With FTC/TDF (Part 2 and Part 3)
Follow-up
Visit Number
1
2
3
4
5
6
7
8
Recurring Visits
38
39
40
Notes
Scheduled Day/Month
Screening
(N/A during Part 2)
Day 1
(N/A during Part 2
and Part 3)
Month 1
Month 2
Month 3
Month 4
Month 5
Month 6
Every Montha
(Additional 
Assessments)
Every 3 Monthsb
(Additional
Assessments)
Every 6 Monthsc
Month 36/ EOT
14-Day Phone 
Call
42-Day Phone 
Call
Each visit should be calculated 
from date of Day 1 and based on a 
28-day month. A participant may 
have up to 40 visits, but may have 
fewer visits (endpoint-driven 
study). 
Visit Window 
≤45 
daysd
N/A
±7 Days
Visit windows for Part 3 are extended 
to ±14 Days
Dried Blood for PKf
X
X
X
X
X
X
X
Not applicable for Part 3.
See Section 8.6.3, Table 12 and 
Table 13.
The sample must be collected 
irrespective of the planned PK 
collection schedule, if a participant 
has a positive Point-of-Care HIV 
test result at a visit.
See Section 1.3.4 for participants 
who become pregnant and remain 
on ISL.
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Study Period
Double-blind Study Intervention Period (Part 1)
PrEP Therapy With FTC/TDF (Part 2 and Part 3)
Follow-up
Visit Number
1
2
3
4
5
6
7
8
Recurring Visits
38
39
40
Notes
Scheduled Day/Month
Screening
(N/A during Part 2)
Day 1
(N/A during Part 2
and Part 3)
Month 1
Month 2
Month 3
Month 4
Month 5
Month 6
Every Montha
(Additional 
Assessments)
Every 3 Monthsb
(Additional
Assessments)
Every 6 Monthsc
Month 36/ EOT
14-Day Phone 
Call
42-Day Phone 
Call
Each visit should be calculated 
from date of Day 1 and based on a 
28-day month. A participant may 
have up to 40 visits, but may have 
fewer visits (endpoint-driven 
study). 
Visit Window 
≤45 
daysd
N/A
±7 Days
Visit windows for Part 3 are extended 
to ±14 Days
Biomarkers
Blood for Genetic 
Analysis
X
See Section 8.8
Whole Blood for FBR
X
Optional participation, requires 
FBR Consent/assent.
EOT=End of treatment (not all participants will complete 36 months because this is a case-driven study); FBR=Future Biomedical Research; 
FTC/TDF=emtricitabine/tenofovir disoproxil (including TRUVADATM [Gilead] and all generic versions); GC/CT=Neisseria gonorrhoeae/Chlamydia 
trachomatis; HBcAb=hepatitis B core antibody; HBsAb=hepatitis B surface antibody; HBsAg=hepatitis B surface antigen; HBV=hepatitis B virus; HIV=human 
immunodeficiency virus; HSV=herpes simplex virus; IRT=Interactive Response Technology; ISL=islatravir (also known as MK-8591); N/A=not applicable; 
PCR=polymerase chain reaction; PK=pharmacokinetic(s); PRO=participant-reported outcome; RNA=ribonucleic acid; WOCBP=women of childbearing 
potential
a Assessments noted in this column will be repeated every month from Month 7 through Month 35 (Visits 9 through 37).
b Additional assessments noted in this column will be repeated every 3 months until Month 35 – at the following visits:
Month 9 (Visit 11), Month 12 (Visit 14), Month 15 (Visit 17), Month 18 (Visit 20), Month 21 (Visit 23), Month 24 (Visit 26), Month 27 (Visit 29), Month 30 
(Visit 32), Month 33 (Visit 35)
c Additional assessments noted in this column will be repeated every 6 months until Month 35 – at the following visits:
Month 12 (Visit 14), Month 18 (Visit 20), Month 24 (Visit 26), Month 30 (Visit 32)
d A screening period of up to 45 days is allowed, but participants are expected to enroll as soon as possible after eligibility is confirmed.
e Once a continuing pregnancy has been confirmed, monthly urine pregnancy tests should be deferred until 1 month following the end of the pregnancy.
f Additional timepoints for Blood (plasma) and Dried blood PK collection: Month 12 (Visit 14), Month 18 (Visit 20), Month 24 (Visit 26), Month 30 (Visit 
32). PK samples will not be collected in Part 3.
g Additional timepoints for Blood (Plasma) for Investigational PK collection: Month 9 (Visit 11), Month 15 (Visit 17), Month 21 (Visit 23), Month 27 (Visit 
29), Month 33 (Visit 35). PK samples will not be collected in Part 3.
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1.3.2
Schedule of Activities – Participants Who Discontinue Study Intervention Early and/or Withdraw Consent/Assent
Study Period
Early Discontinuation from Study Intervention
Notes
Visit Number
Unscheduled Visits
Scheduled Day/Week
Early Discontinuation of Study 
Intervention
Early Withdrawal from Study
Visit Window
N/A
N/A
Administrative Procedures
Register study visit in IRT
X
X
No study intervention will be dispensed. 
Concomitant medication review
X
X
Contraceptive use confirmation (WOCBP 
only)
X
X
PRO: HIV infection Risk 
X
X
PRO: Preference 
X
X
Not applicable for Part 3
HIV Risk Reduction
X
X
Completion of the sexual activity form; 
offer condoms, lubricants, and HIV risk
reduction counseling.
Efficacy Procedures
Point-of-Care HIV-1 Testing
X
X
Performed at the study site.
HIV-1/HIV-2 Antibody/Antigen Testing
X
X
Plasma HIV-1 RNA Quantification (Real 
Time PCR)
X
X
Samples will be collected and analyzed if 
Point-of-Care HIV test or HIV-1/HIV-2 
antibody/antigen test is positive.
Plasma for HIV-1 Drug Resistance Testing
X
X
Samples will be collected and analyzed if 
needed.
Safety Procedures
Symptom-directed physical examination
X
X
Vital signs
X
X
Includes pulse, blood pressure, body 
temperature, and respiratory rate.
Weight
X
X
Review of adverse events
X
X
Review of social harm events
X
X
Laboratory Assessments
Chemistry
X
X
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Study Period
Early Discontinuation from Study Intervention
Notes
Visit Number
Unscheduled Visits
Scheduled Day/Week
Early Discontinuation of Study 
Intervention
Early Withdrawal from Study
Visit Window
N/A
N/A
Hematology
X
X
CD4+ T-Cell Count/Lymphocyte subset 
panel
X
X
Creatinine clearance calculation 
X
X
See Appendix 9
Urine pregnancy test (WOCBP only)
X
X
Conduct per local regulations. Positive 
results to be confirmed with serum 
pregnancy test.
Cystatin-C
X
X
HSV-2 Serology
X
X
Pharmacokinetics
Blood (Plasma) for PK
X
X
Not applicable for Part 3.
PK samples should be collected at the time 
of discontinuation or withdrawal. For 
participants who do not withdraw 
consent/assent (ie, continuing to have 
study visits), PK samples will also be 
collected monthly for the next 3 months, 
after which the participant should resume 
the PK schedule outlined in Section 1.3.1.
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Study Period
Early Discontinuation from Study Intervention
Notes
Visit Number
Unscheduled Visits
Scheduled Day/Week
Early Discontinuation of Study 
Intervention
Early Withdrawal from Study
Visit Window
N/A
N/A
Dried blood for PK
X
X
Not applicable for Part 3.
PK samples should be collected at the time 
of discontinuation or withdrawal. For 
participants who do not withdraw 
consent/assent (continuing to have study 
visits), PK samples will also be collected 
monthly for the next 3 months, after which 
the participant should resume the PK 
schedule outlined in Section 1.3.1.
HIV=human immunodeficiency virus; HSV=herpes simplex virus; IRT=Interactive Response Technology; ISL=islatravir (also known as MK-8591); 
PCR=polymerase chain reaction; PRO=participant-reported outcome; RNA=ribonucleic acid; WOCBP=women of childbearing potential
For details on the Early Discontinuation of Study Intervention visit, see Section 8.11.4.
For details on the Early Withdrawal from Study visit, see Section 8.11.5.
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1.3.3
Schedule of Activities – Participants With a Positive HIV-1 Test Result
Study Period
Follow-up after Seroconversion
Notes
Visit Number
Unscheduled
Variesa
Scheduled Day
HIV-1 Infection 
Confirmation 
Follow-up 
Monthly 
Visits
Poststudy Intervention Follow-up Phone Callb
Each monthly visit will be based on 
a 28-day month.
Visit Window
Within 14 days of 
positive HIV-1 test
± 7 days
14 (+7) days after the last 
dose of study intervention
42 (+7) days after the last 
dose of study intervention
Visit windows for Part 3 Follow-up 
Monthly Visits are extended to ±14 
Days.
Administrative 
Procedures
Register study visit in 
IRT
X
X
X
X
Part 1, no study intervention will be 
dispensed. Part 2 and Part 3 
participants should stop taking PrEP 
with FTC/TDF while further testing 
is conducted. 
Link to HIV Treatment 
Services
X
Upon confirmed HIV-1 infection
Concomitant medication 
review
X
X
X
X
Including ART regimens
Contraceptive use 
confirmation (WOCBP 
only)
X
Contraception will be offered at 
monthly visits and confirmation of 
use is not required unless indicated.
HIV Risk Reduction
X
X
Completion of the sexual activity 
form, offer condoms, lubricants, 
and HIV risk reduction counseling 
Efficacy Procedures
Plasma HIV-1 RNA 
quantification (Real 
Time PCR)
X
HIV-1/HIV-2 
antibody/Antigen test
X
Whole blood and plasma 
for HIV-1 drug 
resistance testing
X
X
Samples will be collected and 
analyzed every 3 months following 
HIV Infection Confirmation Visit
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Study Period
Follow-up after Seroconversion
Notes
Visit Number
Unscheduled
Variesa
Scheduled Day
HIV-1 Infection 
Confirmation 
Follow-up 
Monthly 
Visits
Poststudy Intervention Follow-up Phone Callb
Each monthly visit will be based on 
a 28-day month.
Visit Window
Within 14 days of 
positive HIV-1 test
± 7 days
14 (+7) days after the last 
dose of study intervention
42 (+7) days after the last 
dose of study intervention
Visit windows for Part 3 Follow-up 
Monthly Visits are extended to ±14 
Days.
Safety Procedures
Symptom-directed 
physical examination
X
Vital signs
X
Includes pulse, blood pressure, body 
temperature, and respiratory rate
Weight
X
Review of adverse events
X
X
X
Review of social harm 
events
X
X
X
Hematology
X
X
CD4+ T-cell count
X
X
Chemistry
X
HSV-2 Serology
X
Pharmacokinetics 
Blood (Plasma) for PK 
X
X
Not applicable for Part 3.
PK samples should be collected at 
the time of HIV-1 infection 
confirmation visit, the first 
3 monthly follow-up visits, and then 
every 3 months thereafter. 
Dried Blood for PK 
X
X
Not applicable for Part 3.
PK samples should be collected at 
the time of the HIV-1 infection 
confirmation visit, the first 
3 monthly follow-up visits, and then 
every 3 months thereafter.
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Study Period
Follow-up after Seroconversion
Notes
Visit Number
Unscheduled
Variesa
Scheduled Day
HIV-1 Infection 
Confirmation 
Follow-up 
Monthly 
Visits
Poststudy Intervention Follow-up Phone Callb
Each monthly visit will be based on 
a 28-day month.
Visit Window
Within 14 days of 
positive HIV-1 test
± 7 days
14 (+7) days after the last 
dose of study intervention
42 (+7) days after the last 
dose of study intervention
Visit windows for Part 3 Follow-up 
Monthly Visits are extended to ±14 
Days.
Biomarkers
Whole blood for FBR
X
Optional participation, requires 
FBR consent/assent
ART=antiretroviral therapy; FBR=Future Biomedical Research; HIV=human immunodeficiency virus; HSV=herpes simplex virus; IRT=Interactive Response 
Technology; ISL=islatravir (also known as MK-8591); PCR=polymerase chain reaction; PK=pharmacokinetic(s); RNA=ribonucleic acid; STI=sexually 
transmitted infection
a
After the last completed visit prior to HIV-1 infection, the participant would start Follow-up Month 1 visit and monthly visits will align with the participant’s 
date of randomization and will end at the Month 36 visit (ie, participants will not be in the study for >36 months).
b
The 14-day and 42-day follow-up phone calls only need to be performed for participants who will not be completing the follow-up monthly visits after HIV-1 
infection confirmation. During Part 2 and Part 3, phone calls should be performed based on the last dose of PrEP with FTC/TDF.
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1.3.4
Schedule of Activities for Participants Who Become Pregnant and Remain on ISL
Note: This schedule is not applicable for Part 2 or Part 3 of the study.
Gestational Age
≤12 Weeks
13-26 Weeks
≥27 Weeks
Postpartum
Notes
Visit
P1
P2
P3
P4
P5
P6
P7
Visits will begin when the pregnancy is 
confirmed and consent is obtained.
Visits P1, P3, P5, and P7 should coincide with 1 
planned monthly visit during the time period 
(see Section 1.3.1) and will include all planned 
procedures except urine pregnancy test. Visits 
P2, P4, and P6 should occur approximately 2 
weeks after P1, P3, and P5, respectively.
Visit Window
± 7 days
All procedures performed at 
recurring monthly visit
X
X
X
X
See Section 1.3.1
Administrative procedures
Register study visit in IRT
X
X
X
X
Concomitant medications
X
X
X
X
X
X
X
Pharmacokinetics
Blood (Plasma) for PK
X
X
X
X
X
X
X
See Section 8.6.4
Dried Blood for PK
X
X
X
X
X
X
X
See Section 8.6.4
Safety
Antenatal care record review
X
X
X
X
X
X
X
See Sections 8.4.5 and 8.11.3
Weight
X
X
X
X
X
X
X
Symptom-directed physical 
examination
X
X
X
X
X
X
X
Vital Signs
X
X
X
X
X
X
X
Review of adverse events
X
X
X
X
X
X
X
Review of social harm events
X
X
X
X
X
X
x
Collect blood sample for CrCl
X
X
X
X
X
X
X
Collect sample for CrCl if not collected as part 
of the planned monthly visit.
CrCl=creatinine clearance; IRT=Interactive Response Technology; PK=pharmacokinetic(s)
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2
INTRODUCTION
ISL (also known as MK-8591) is a novel and potent NRTTI being developed for HIV-1 PrEP 
administered as a monthly oral dose in individuals at high risk for HIV-1 infection.
2.1
Study Rationale
Part 1
HIV-1 infection remains a worldwide epidemic with an estimated 38 million individuals 
infected globally and 1.7 million new infections estimated to have occurred in 2019 [Joint 
United Nations Programme on HIV/AIDS 2020]. Novel strategies to prevent HIV acquisition 
are urgently needed.
One proven biomedical intervention for the prevention of HIV infection is PrEP. Although 
clinical study data have demonstrated that the effectiveness of TRUVADATM
(emtricitabine/tenofovir disoproxil [FTC/TDF], Gilead) QD for PrEP is strongly correlated 
with adherence to daily therapy [Grant, R. M., et al 2010] [Baeten, J. M., et al 2012], 
adherence to FTC/TDF QD is suboptimal in many individuals at risk for HIV-1 infection 
[Marrazzo, J. M., et al 2015] [Hojilla, J. C., et al 2018]. In particular, women in subSaharan 
Africa have an ongoing unmet medical need for alternatives to FTC/TDF QD for PrEP. This 
population continues to have a high HIV-1 incidence rate and clinical studies have shown 
great variability in the effectiveness of FTC/TDF QD for PrEP, related, in part, to challenges 
associated with adhering to this daily regimen [Van Damme, L., et al 2012] [Marrazzo, J. M., 
et al 2015].
Long-acting agents, such as a monthly pill, have the potential to reduce the risk of HIV-1 
acquisition without relying on adherence to a daily regimen. In the same way that long-acting 
reversible contraceptives have provided important options and increased acceptability and 
uptake of contraception among women [Ross, J. 2013], expanded choices for HIV-1 
prevention may increase utilization, adherence, and effectiveness.
ISL has the potential to be an effective agent for HIV-1 PrEP due to its potent antiviral 
activity, long half-life, and favorable safety profile as demonstrated in early phase clinical 
studies. The convenience and discretion of monthly oral administration of ISL may facilitate 
adherence and access to PrEP for women at high risk for HIV-1 infection, ultimately leading 
to greater effectiveness for HIV-1 prevention than what is currently observed with FTC/TDF 
QD.
Part 2 and Part 3
Decreases in total lymphocyte and CD4+ T-cell counts have been observed in studies with 
ISL alone or in combination (including ISL 60/120 mg QM in participants not infected with 
HIV, and DOR/ISL 100 mg/0.75 mg QD or ISL 20 mg + MK-8507 100/200/400 mg QW in 
participants with HIV-1). The decreases in lymphocytes and CD4+ T-cell counts appeared to 
be ISL-dose dependent. These laboratory changes were not associated with AEs in those 
receiving ISL or DOR/ISL. The long-term clinical impact of these laboratory changes is 
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unknown; however, the Sponsor is assessing the reversibility of the reductions in CD4+ T-
cell and total lymphocyte counts.
Across the ISL clinical program, study protocols were amended to increase monitoring for 
decreases in total lymphocyte and CD4+ T-cell counts and to implement stopping rules for 
individuals who experience significant decreases in total lymphocytes and/or CD4+ T-cell 
counts.
In Part 3, participants, investigators, and all Sponsor personnel will be unblinded to the 
participants’ original randomized study intervention group to provide greater clinical detail 
for monitoring total lymphocyte counts and continued safety monitoring of participants. 
Furthermore, since all participants will be receiving open-label daily PrEP (FTC/TDF) and 
undergoing the same study procedures regardless of original assignment, continued blinding 
unnecessary.
2.2
Background
Refer to the IB for detailed background information on ISL.
2.2.1
Pharmaceutical and Therapeutic Background
ISL is an antiretroviral agent, known as an NRTTI, which blocks HIV-1 reverse transcriptase 
by novel mechanisms of action. ISL is an inactive nucleoside analog that is converted to the 
pharmacologically active triphosphate (ISL-TP) form via endogenous intracellular kinases. It 
acts through multiple mechanisms, including immediate chain termination by blocking 
translocation and delayed chain termination by preventing nucleotide excision [Michailidis E 
2014].
ISL is potent at low doses and has a long intracellular half-life [Markowitz, M. 2018]. In a 
rhesus macaque SHIV rectal-challenge prophylaxis-efficacy model, ISL provided complete 
protection against infection with weekly doses of 1.3 and 0.43 mg/kg [Markowitz, M., et al 
2019]. Doses of 0.1 mg/kg afforded a 92% reduction of infection risk [Markowitz, M., et al 
2019]. Studies in a rhesus macaque model demonstrated that ISL-TP concentrations were 
comparable in rectal and vaginal tissue, at levels predictive of prophylactic activity of ISL 
against HIV-1 in both men and women [Grobler, J., et al 2017]. Similarly, results from 
MK-8591 Protocol 009 indicate that at steady state with daily dosing, concurrent ISL-TP 
concentrations in human PBMCs, rectal and vaginal tissues were generally comparable, and 
observed to be at levels projected to be efficacious for treatment and prevention of HIV-1 
infection. Based on intracellular concentrations of ISL-TP required to inhibit HIV-1 
replication, the efficacy of ISL in the rhesus macaque SHIV challenge PrEP model, and 
associated exposures in animal models and human PK simulations, a QM regimen of ISL 60 
mg QM has the potential to provide efficacious prophylaxis against HIV-1 infection 
(Sections 4.3.1 and 4.3.2).
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2.2.2
Information on Other Study-related Therapy
FTC/TDF is currently the standard of care for prevention among individuals at high risk of 
HIV-1 infection. FTC/TDF was approved for use as PrEP in the US by the FDA in 2012. The 
USPSTF [Owens, D. K., et al 2019] recommends that clinicians offer PrEP for all persons at 
risk for HIV-1 infection, which includes men who have sex with men, women and men at 
risk through heterosexual contact, and people who inject drugs. FTC/TDF was approved for 
use as PrEP in Kenya and South Africa in 2015 [National AIDS and STI Control Program 
2017] [AVAC: Global Advocacy for HIV Prevention 2015] making it available in some of 
the regions with the greatest burden of HIV worldwide. In 2015 the WHO [World Health 
Organization 2015] recommended that oral PrEP containing tenofovir disoproxil should be 
offered as an additional prevention choice for people at substantial risk of HIV infection as 
part of combination HIV prevention approaches, defining “substantial risk” as HIV incidence 
>3 per 100 person-years in the absence of PrEP. Furthermore, tenofovir disoproxil, along 
with 3TC (or FTC), is part of the WHO preferred first-line ART regimen recommended for 
adults, including pregnant women [World Health Organization 2017].
In this study, participants receiving FTC/TDF will be administered either TRUVADATM
(Gilead) or a generic product (emtricitabine/tenofovir disoproxil) at the approved marketed 
dose for prevention. The tenofovir disoproxil component of the generic product contains a 
different salt form (phosphate) compared with TRUVADATM (fumarate), and is considered 
bioequivalent and is approved by the EMA. For simplicity, both TRUVADATM and all 
generic versions are abbreviated as FTC/TDF throughout the protocol.
2.3
Benefit/Risk Assessment
High potency against wild-type and resistant variants of HIV-1 virus, and a long half-life 
make ISL a suitable candidate for further development as a novel, long-acting PrEP agent. 
The comprehensive preclinical safety evaluations of ISL, including developmental toxicity 
studies, have not revealed toxicities of concern. In a rhesus macaque SHIV intrarectal 
challenge model [Markowitz, M., et al 2019], ISL provided protection against infection at 
drug levels that are projected to be achieved with the dose regimen used in this study.
Decreases of total lymphocyte and CD4+ T-cell counts that appear dose dependent were 
observed in ongoing Phase 2 and Phase 3 studies with ISL alone or in combination with other 
antiviral agents.
In the Phase 2, randomized, double-blind, placebo-controlled study evaluating the safety, 
tolerability, and PK of 60 mg and 120 mg of ISL monthly for PrEP (conducted in participants 
at low risk of HIV-1 infection; MK-8591-016), after 6 monthly doses there was a 21% mean 
decrease in total lymphocytes observed in the 60-mg arm (the dose of ISL being evaluated in 
this study), a 36% decrease in total lymphocytes observed in the 120-mg arm, and a 4% 
increase in the placebo arm compared with baseline values. Approximately 35% of 
participants in the ISL 60-mg arm had a >30% reduction in total lymphocyte counts during 
the study, with 3 of 95 participants reporting Grade 2 lymphocyte reductions and 1 of 95 
participants reporting a Grade 3 lymphocyte reduction (transient). Two of 97 participants in 
the 120 mg arm had Grade 3 lymphocyte reductions. In this population of participants not 
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infected with HIV-1, the mean lymphocyte counts remained in the normal range, and there 
were no increases in clinical AEs related to infection. With regard to the Phase 3 efficacy 
studies for PrEP, as of 13-DEC-2021, dosing (of 60 mg oral monthly ISL) has been stopped 
in all PrEP clinical studies. 
In a Phase 2 study (MK-8591-013) for once-weekly HIV-1 treatment, decreases from 
baseline in lymphocyte and CD4+ T-cell counts were observed in the ISL 20 mg + MK-8507
treatment arms at Week 12 and Week 24. Decreases from baseline in total lymphocyte count 
were observed in all dosing arms of ISL + MK-8507 starting at Week 8, with further 
decreases continuing through Week 24, and the reduction appeared more pronounced in the 
2 higher MK-8507 dose arms. Dosing of ISL + MK-8507 in MK-8591-013 has been 
discontinued.
In an interim analysis for 2 Phase 3 studies (MK-8591A-017 and MK-8591A-018) evaluating 
a switch to daily DOR 100 mg/ISL 0.75 mg for treatment of HIV-1 in virologically 
suppressed participants, mean decreases from baseline in total lymphocyte counts at Week 48 
were 10.7% (MK-8591 A 017) and 8.5% (MK-8591 A 018) in the DOR/ISL groups, and 
mean decreases from baseline of CD4+ T-cell counts at Week 48 were approximately 60 
cells/mm3 relative to the comparator arms.
At this point, the long-term clinical impact of these laboratory changes is unknown, and the 
Sponsor is assessing not only the reversibility of the reductions in CD4+ T-cell and total 
lymphocyte counts, but also the potential impact on other immune cell types. 
It cannot be guaranteed that participants in clinical studies will directly benefit from study 
intervention during participation as clinical studies are designed to provide information about 
the safety and effectiveness of an investigational medicine. The efficacy of ISL for HIV PrEP 
has not yet been demonstrated in humans. Participants who are randomized to the ISL QM 
group may be at risk of developing HIV-1 infection. To mitigate this risk, a monthly visit is 
required for HIV-1 testing at which time prevention counseling with distribution of lubricants 
and condoms will take place.
As of Amendment-03, all participants in the ISL 60-mg arm were switched to daily PrEP 
with FTC/TDF. There was monthly monitoring of lymphocyte and CD4+ T-cell counts to 
assess the reversibility of these laboratory changes, as well as ascertainment of any 
infections. As of Amendment-04, all ongoing participants will continue to receive open-label 
daily PrEP therapy with FTC/TDF.
Women have an increased risk of contracting HIV-1 infection during pregnancy and 
breastfeeding. Current guidelines recommend providing PrEP to pregnant and breastfeeding 
women to reduce the risk of HIV-1 infection in the woman and also the risk of subsequent 
mother-to-child transmission [World Health Organization 2017]. Nonclinical reproductive 
toxicity studies of ISL did not identify any clinically relevant concerns that would preclude 
continued dosing of ISL in participants who become pregnant during the study. The dosing 
of 60 mg ISL in pregnant women has been stopped while the Sponsor’s investigation is 
ongoing. Currently, there are no clinical data available to support or recommend against 
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breastfeeding by participants who have received ISL. Thus, women will not be permitted to 
continue ISL, but they may receive open-label FTC/TDF while breastfeeding.
Additional details regarding specific benefits and risks for participants in this clinical study 
may be found in the accompanying IBs and informed consent/assent documents.
3
HYPOTHESES, OBJECTIVES, AND ENDPOINTS
Hypotheses are aligned with objectives in the Objectives and Endpoints table.
Note: As of Amendment -04, formal hypothesis tests and comparisons between study 
intervention groups will no longer be conducted; therefore, evaluation of the percentage of 
participants with confirmed HIV-1 infections will no longer be considered a primary 
endpoint. The only study objective is to evaluate the safety and tolerability of ISL QM based 
on review of the accumulated safety data. Updated analyses are described in Section 9.
The following objectives will be evaluated in female participants, 16 to 45 years of age 
inclusive, at high risk for HIV-1 infection.
Objectives
Endpoints
Primary
•
To evaluate the efficacy of oral ISL QM 
compared to FTC/TDF QD for the 
prevention of HIV-1 infection as 
assessed by the incidence rate per year 
of confirmed HIV-1 infections
•
Hypothesis: ISL QM is superior to 
FTC/TDF QD as assessed by the 
incidence rate per year of confirmed 
HIV-1 infections
•
Confirmed HIV-1 infection
•
To evaluate the safety and tolerability of 
oral ISL QM compared with oral 
FTC/TDF QD as assessed by review of 
the accumulated safety data
•
Adverse events
•
Adverse events leading to 
discontinuation of study intervention
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Objectives
Endpoints
Secondary
•
To evaluate the efficacy of oral ISL QM 
in reducing the incidence per year of 
HIV-1 infection relative to the 
background rate
•
Hypothesis: ISL QM reduces the 
incidence rate of confirmed HIV-1 
infections compared with the 
background incidence rate
•
Confirmed HIV-1 infection
Tertiary/Exploratory
•
To evaluate preferences for QM vs QD 
dosing
•
Response for dosing preference
•
To evaluate the pharmacokinetics of ISL 
QM
•
Pharmacokinetic parameters
•
To evaluate rates and patterns of 
adherence to FTC/TDF QD and ISL QM
•
Pharmacokinetic-adherence relationship
•
To evaluate the impact of ISL QM on 
renal function compared with FTC/TDF 
QD as measured by the change from 
baseline in renal biomarkers at Weeks 
24 and 48
•
Renal biomarkers
•
To evaluate viral drug resistance in 
participants who seroconvert to HIV-1
•
Viral resistance-associated substitutions
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Objectives
Endpoints
•
To explore the relationship between 
genetic variation and response to the 
treatment(s) administered, and 
mechanisms of disease. Variation across 
the human genome may be analyzed for 
association with clinical data collected in 
the study
•
Germline genetic variation and 
association to clinical data collected in 
this study
•
To evaluate the pharmacokinetics of ISL 
in pregnant participants
•
Pharmacokinetic parameters
4
STUDY DESIGN
Blinded study intervention administration (Part 1), including ISL or its placebo, has been 
stopped. During Part 2, all participants were switched to PrEP therapy with FTC/TDF.
Study assessments conducted before stopping blinded study intervention are designated as 
Part 1. During Part 2 of the study, no new participants will be screened or randomized; 
participants already in the study will continue daily PrEP therapy with FTC/TDF, and 
samples for assessments will be collected at all monthly visits (Section 1.3.1). During Part 3 
of the study, no new participants will be screened or randomized; ongoing participants will 
continue to receive open-label daily PrEP therapy with FTC/TDF and samples for 
assessments will be collected at all monthly visits (Section 1.3.1).
4.1
Overall Design
Part 1
This is a randomized, active-controlled, parallel-group, multisite, double-blind, double-
dummy study to evaluate the safety and efficacy of ISL administered orally QM as PrEP in 
cisgender women who are at high risk for HIV-1 infection. The active comparator for this 
study (FTC/TDF) will be administered orally QD.
Approximately 4500 participants will be randomized (stratified by site and age) in a 1:1 ratio 
to receive either ISL or FTC/TDF for the duration of the study. Approximately 50% of the 
global study population will be <25 years of age.
The first approximately 400 participants ≥18 years of age enrolled will be identified as the 
Sentinel Cohort. An IA (hereafter referred to as the Sentinel Cohort IA) will be conducted by 
an external statistician 3 months after the last participant in the Sentinel Cohort has initiated 
study intervention. All available data will be submitted to an eDMC for a safety evaluation. 
Meanwhile, overall study enrollment will continue, but will be capped at no more than 
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1000 participants until safety and tolerability have been assessed. Enrollment for 16- or 
17-year-old participants should begin upon completion of the Sentinel Cohort IA and review 
of IA results by the eDMC.
Samples for efficacy assessments will be collected at all monthly visits from participants 
receiving study intervention (Section 1.3.1). The primary efficacy analysis will be performed 
upon accrual of a total 40 primary endpoint cases of confirmed incident HIV-1 infections. An 
efficacy IA will be performed when 25 primary endpoint cases are observed. The study may 
be stopped early for demonstration of efficacy or futility in the efficacy IA. Consideration 
may also be given to stopping the study at approximately 3 years after the first participant has 
been randomized if 40 confirmed incident HIV-1 infections have not yet been accrued by this 
time (Section 9.6.1). Participants will be enrolled over an approximate 12-month period with 
study intervention administered for approximately 1 year and up to 3 years, based on 
estimated accrual of primary endpoint cases.
Any participants with confirmed HIV infection will be discontinued from study intervention, 
referred for and linked to treatment per local standard of care. Any participants with 
seroconversion will be followed as outlined in Section 1.3.3 and assessed for viral drug 
resistance.
If a participant becomes pregnant (has a positive serum pregnancy test) while receiving study 
intervention, the participant, investigator, and Sponsor will assess if the participant should 
continue study intervention (Section 8.11.3).
Safety assessments will include all accumulated safety data until the end of study, which 
includes the safety follow-up period of 42 days after the last dose of study intervention.
Participant safety and overall conduct of the study will be monitored by an independent 
eDMC through periodic review of safety and efficacy data throughout study duration.
Part 2
Blinded study intervention administration in Part 1, including ISL or its placebo, will be 
stopped, as noted above. During Part 2, all participants will be switched to PrEP therapy with 
FTC/TDF.
During Part 2 of the study, no new participants will be screened or randomized; participants 
already in the study will continue daily PrEP therapy and samples for assessments will be 
collected at all monthly visits (Section 1.3.1).
The participant, the investigator, and Sponsor personnel or delegate(s) directly involved in 
the clinical monitoring or evaluation of participants will remain blinded to the participants’ 
original randomized study intervention group. Sponsor personnel or delegate(s) not directly 
involved in clinical monitoring or evaluation of the participants will be unblinded to the 
participants’ original randomized study intervention group.
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Part 3
In Part 3 of the study, participants, investigators, and all Sponsor personnel will be unblinded 
to the participants’ original randomized study intervention group. No new participants will be 
screened or randomized; participants already in the study will continue to receive open-label 
daily PrEP therapy with FTC/TDF and samples for assessments will be collected at all 
monthly visits (Section 1.3.1). As of Part 3, no further evaluations will be conducted by the 
eDMC.
Specific procedures to be performed during the study, including prescribed times and 
associated visit windows, are outlined in Section 1.3 of the SoA. Details of each procedure 
are provided in Section 8.
4.2
Scientific Rationale for Study Design
Part 1
The randomized, double-blinded, active-controlled, superiority study design is consistent 
with FDA regulatory guidance [Food and Drug Administration 2019]. A superiority design is 
recommended for studies of PrEP in at risk cisgender women to mitigate risks associated 
with NI margin prespecification because of variable historical evidence of HIV prevention 
efficacy in this population [Food and Drug Administration 2019] [Van Damme, L., et al 
2012] [Marrazzo, J. M., et al 2015].
This study design is deemed appropriate to provide safety and efficacy data in cisgender 
women at high risk for HIV-1 infection to demonstrate whether oral ISL QM is an effective 
option for HIV-1 PrEP in this population. Because of the long intracellular half-life of the 
pharmacologically active triphosphate (ISL-TP) form of ISL, a QM dosing regimen is being 
investigated. This dosing schedule is anticipated to facilitate adherence and be effective in 
preventing infection with HIV-1.
Cisgender women 16 to 45 years of age, inclusive, at the time of screening, will be eligible to 
participate in the study. Global surveillance data demonstrate that cisgender women are at 
highest risk of infection between 16 to 45 years of age and therefore, this study will focus on 
this demographic where demonstrated protective benefit is most needed [Balkus, J. E., et al 
2016] [de Oliveira, T., et al 2017].
Part 2
Given the findings of downward trends of total lymphocyte counts and CD4+ T-cell counts 
in studies with ISL alone or in combination with other antiviral agents, ISL will be stopped in
this study, and all participants will be switched to PrEP therapy with FTC/TDF. Participants 
will have intensified monitoring of laboratory parameters, including lymphocyte subset 
panels, and will continue to be monitored on a monthly basis for AEs. This will allow for 
study continuity and blinded monitoring of AEs and laboratory parameters.
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Part 3
To allow for study continuity and monitoring of AEs and laboratory parameters.
4.2.1
Rationale for Endpoints
4.2.1.1
Efficacy Endpoints
The primary efficacy endpoint will be the rate of confirmed HIV-1 infection, as assessed per 
a predefined algorithm for HIV-1 testing and diagnosis in recipients of PrEP. The algorithm 
was developed based on WHO-recommended strategies for point-of-care testing and takes 
into account the challenges of accurate detection of acute HIV infection in participants 
receiving ART for PrEP [Elliott, T., et al 2019] [Peluso, M. J., et al 2020]. The study site 
guidance for assessment and confirmation of HIV-1 infection based on this algorithm can be 
found in Appendix 11.
This study will be conducted at study sites with evidence of access to high risk individuals. 
To provide context for interpreting the results of the study, 2 methods will be utilized to 
estimate the background incidence of HIV-1 infection from the same site areas/time period in 
the screened population, which will include all individuals who come in for a screening visit 
for this study at one of the sites. One method will use local data on new HIV diagnoses to 
estimate incidence, while the second method will calculate HIV incidence based on a recency 
assay (assessment of recent infection biomarkers) [Murphy, G., et al 2017]. Recency assays 
distinguish between recent and nonrecent infection, thus cross-sectional surveys in a single 
population can be used for incidence estimation. These data will be referenced as an external 
benchmark to contextualize the study data and characterize the natural history of HIV 
acquisition in the community at large versus the enrolled population.
Frequent testing for HIV-1 acquisition during the study period (at all scheduled study visits) 
will help prevent dosing with the study intervention in a participant who may have acquired 
HIV infection, minimizing the risk of viral resistance and facilitating linkage to care. In 
addition, if a participant has signs or symptoms consistent with acute retroviral syndrome, or 
expresses a concern about recent HIV acquisition, HIV testing may be performed using an 
RNA test to detect early HIV-1 infection.
4.2.1.2
Safety Endpoints
Safety evaluations will include physical examinations (including vital signs) and laboratory 
tests (hematology and chemistry) performed per the SoA in Section 1.3. AEs and Social 
Harm events will be evaluated at each visit and assessed according to the guidelines in 
Section 8.4 and Appendix 3. Participants may be asked to return for unscheduled visits to 
perform additional safety monitoring.
4.2.1.3
Participant-reported Outcomes
PROs provide a unique opportunity to acquire information on the impact of HIV PrEP in the 
lives of individuals who receive it. In conjunction with efficacy and safety, capturing data 
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from the participant’s perspective may help clinicians, policy-makers, and individuals at risk 
for HIV infection make informed decisions when selecting a PrEP regimen.
Participants in this study will be administered 2 unvalidated questionnaires that measure 
preference and HIV infection risk, respectively. Each item on each questionnaire will be 
assessed independently. A 1-item preference questionnaire will be used to assess preference 
for daily or monthly dosing or no preference for HIV PrEP medication (not applicable in Part 
3). The HIV infection risk questionnaire will be used to measure changes in participants’ or 
their intimate partners’ risks for HIV due to changes in behavior. HIV infection risk 
questionnaire will not be administered in participants with a positive HIV-1 test. All items 
will be analyzed descriptively.
4.2.1.4
Renal Biomarkers
Impaired kidney function (usually mild or moderate) may occur in a small proportion of 
individuals who take FTC/TDF for PrEP, especially in those with other risk factors for 
impairment of renal function [Tetteh, R. A., et al 2017]. This study provides an opportunity 
to compare the impact of ISL on renal functions to that of FTC/TDF as measured by 
creatinine, cystatin-C, and creatinine clearance.
4.2.1.5
Pharmacokinetic Endpoints
The PK samples collected from all participants as described in SoA and Section 8.6 will be 
used to evaluate PK concentrations of ISL, and as appropriate, exploratory PK-efficacy, PK-
AE, and PK-adherence relationships of ISL. Additionally, TFV concentrations will be 
measured and analyzed (in a subset of study participants), as needed and may be used for 
exploratory study intervention adherence assessments.
Additional sparse PK samples from participants who become pregnant during the study and 
continue ISL treatment, will be collected as described in Section 1.3.4 and Section 8.6.4. 
These sparse PK samples will be used to explore and quantify the PK of ISL in pregnant 
participants compared with nonpregnant participants.
4.2.1.6
Planned Exploratory Biomarker Research
4.2.1.6.1
Planned Genetic Analysis
Genetic variation may impact a participant’s response to therapy, susceptibility to, severity, 
and progression of disease. Variable response to therapy may be due to genetic determinants 
that impact drug absorption, distribution, metabolism, and excretion; mechanism of action of 
the drug; disease etiology; and/or molecular subtype of the disease being treated. Therefore, 
where local regulations and IRB/IEC allow, a sample will be collected for DNA analysis 
from consenting participants.
DNA samples may be used for research related to the study intervention(s), the disease under 
study, or related diseases. They may also be used to develop tests/assays including diagnostic 
tests related to the disease under study, related diseases, and study intervention(s). Genetic 
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research may consist of the analysis of 1 or more candidate genes, the analysis of genetic 
markers throughout the genome, or analysis of the entire genome. Analysis may be 
conducted if it is hypothesized that this may help further understand the clinical data.
The samples may be analyzed as part of a multi-study assessment of genetic factors involved 
in the response to understand study disease or related conditions.
4.2.1.7
Future Biomedical Research
The Sponsor will conduct future biomedical research on specimens for which consent/assent 
was provided during this study. This research may include genetic analyses (DNA), gene 
expression profiling (RNA), proteomics, metabolomics (serum, plasma), and/or the 
measurement of other analytes, depending on which specimens are consented for future 
biomedical research.
Such research is for biomarker testing to address emergent questions not described elsewhere 
in the protocol (as part of the main study) and will only be conducted on specimens from 
appropriately consented participants. The objective of collecting/retaining specimens for 
future biomedical research is to explore and identify biomarkers that inform the scientific 
understanding of diseases and/or their therapeutic treatments. The overarching goal is to use 
such information to develop safer, more effective drugs/vaccines, and/or to ensure that 
participants receive the correct dose of the correct drug/vaccine at the correct time. The 
details of future biomedical research are presented in Appendix 6.
4.2.2
Rationale for the Use of Comparator/Placebo
Part 1
The International Council for Harmonisation of Technical Requirements for Pharmaceuticals 
for Human Use guidance E10 on Choice of Control Group and Related Issues in Clinical 
Trials (ICH E10) states that in cases where an available treatment is known to prevent serious 
harm, such as death or irreversible morbidity in the study population, it is generally 
inappropriate to use a placebo control. HIV-1 infection can lead to serious harm in the study 
population and FTC/TDF has been demonstrated to reduce the risk of sexually acquired HIV-
1 infection; therefore, a placebo control would not be appropriate for this study. Thus, rather 
than comparing the efficacy of oral ISL QM to placebo, the primary objective of this study 
will be to evaluate the efficacy of oral ISL QM compared with FTC/TDF QD for the 
prevention of HIV-1 infection. The active comparator for this study (FTC/TDF) is approved 
in many countries as PrEP and is currently standard of care for individuals at high risk for 
HIV-1 infection.
Matching placebo will be used in both study arms to provide a robust evaluation of the safety 
and tolerability profile of ISL by maintaining double-blind, double-dummy study 
intervention.
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Part 2
Blinded study intervention administration in Part 1, including ISL, its placebo, or placebo to 
FTC/TDF, was stopped; all participants were switched to PrEP therapy with FTC/TDF.
Part 3
All participants will receive open-label FTC/TDF in Part 3. No comparator/placebo or 
ISL/placebo will be administered.
4.2.3
Rationale for Estimating Background HIV Incidence Rate
Because this study includes 2 active study intervention arms, it will not be possible to assess 
the relative reduction in HIV-1 infection risk compared with that in the corresponding 
communities where PrEP is generally available according to local standard of care. Thus, a 
key secondary objective of this study will be to evaluate the efficacy of oral ISL QM in 
reducing the incidence per year of HIV-1 infection relative to the background rate.
Several methods exist for estimating population-level HIV incidence: direct observation of 
HIV incidence through longitudinal follow-up of persons at risk for new HIV infection, 
indirect measurement of HIV incidence using data on HIV prevalence in a defined 
population (such as women attending antenatal clinics) and estimates of HIV incidence 
through the use of tests that can differentiate “recent” from “nonrecent” infections based on 
biomarkers from cross-sectional specimens [Mastro, T. D., et al 2010]. Directly observing 
new infections in cohorts of HIV-negative individuals followed up over time are costly and 
logistically challenging, and indirect measurements of incidence have significant limitations 
and may not provide data that are representative of the study population; therefore, in this 
study the background incidence of HIV-1 infections in the population will be estimated using 
tests based on biomarkers that can differentiate “recent” from “nonrecent” infections in the 
population screened for this study.
Cross-sectional incidence estimation uses biomarkers to identify individuals who are likely to 
have recent HIV infection. Most methods include serologic assays that measure the antibody 
response to HIV infection [Busch, M. P., et al 2010]. Use of a single assay approach to 
estimate HIV incidence has been problematic, since viral suppression, advanced HIV disease, 
uncontrolled viremia, immune-suppression, and immune-dysregulation can cause these tests 
to have values that are associated with recent infection when the person does not have a 
recent infection (“false-recency”) [Brookmeyer, R., et al 2013], which can lead to an over-
estimation of the HIV incidence rate [Gonese, E., et al 2020]. In contrast, Recent Infection 
Testing Algorithms that combine serologic and nonserologic assays, such as viral load 
[Kassanjee, R., et al 2016] [Sun, X., et al 2020], have been identified that provide accurate 
incidence estimates in several studies. Various algorithms have been used to estimate HIV 
incidence in clinical trials and cohort studies [Brookmeyer, R., et al 2013] [Eshleman, S. H., 
et al 2013] [Laeyendecker, O., et al 2013] [Gonese, E., et al 2019] [Shah, N. S., et al 2017]. 
A limiting antigen avidity assay (HIV-1 LAg) [Duong, Y. T., et al 2019] is now widely used 
for HIV incidence estimation in surveillance and research studies. The manufacturers of the 
LAg Avidity assay recommend using the assay in an algorithm where individuals with VL 
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<1000 copies/mL are classified as having nonrecent infection [Sedia Biosciences Corporation 
2016] [Maxim Biomedical, Inc. 2019]. This algorithm is widely used to estimate HIV 
incidence in cross-sectional surveys [Rehle, T., et al 2015] [Szwarcwald, C. L., et al 2016]
and is currently being used in large surveys conducted as part of the PEPFAR-supported 
Population-based HIV Impact Assessment.
Kassanjee, et al, have developed an estimator, based on these principles, that substantially 
increases the robustness of incidence estimation based on cross-sectional surveys using tests 
for recent infection. This methodology will be used to estimate the background HIV 
incidence rate in this study [Kassanjee, R., et al 2012].
4.2.4
Rationale for Collecting Specific Data
Rationale for Collecting Behavioral Assessment Data
Risk of HIV infection is correlated with behavior [Centers for Disease Control and 
Prevention 2020]. Adherence to PrEP is one type of behavior inversely associated with risk 
of acquiring HIV. There are many other behaviors that have been identified to be associated 
with the risk of HIV, such as substance use, number of sexual partners and consistent 
condom use. Understanding and quantifying ongoing risk behavior may identify segments of 
the population in which these behaviors are prevalent and may provide support for targeted 
risk reduction interventions, including prioritization of PrEP for certain groups. Furthermore, 
there has been concern that use of PrEP may result in behavioral disinhibition, that is, those 
who are taking PrEP may not take other protective measures because they believe that PrEP 
alone can protect against HIV [Golub, S. A., et al 2010]. Therefore, in support of broader 
HIV prevention efforts, behavioral data will be collected throughout this study.
4.2.5
Rationale for Continuing Study Intervention During Pregnancy
It is important for women to remain on PrEP during pregnancy because of an increased risk 
of HIV acquisition during pregnancy and in the peripartum period [Thomson, K. A., et al 
2018]. Per WHO guidelines, in women who desire pregnancy or become pregnant while 
taking PrEP, continuing PrEP during pregnancy and breastfeeding should be considered if 
they continue to be at substantial risk of HIV-1 infection [World Health Organization 2017]. 
Similarly, the CDC recommends PrEP as an option to help protect women and their infants 
from acquiring HIV infection while a woman tries to get pregnant, during pregnancy, or 
while breastfeeding [Centers for Disease Control and Prevention 2018].
Additionally, clinicians need timely information on the extent of drug exposure to mothers 
and infants during pregnancy [Eke, A. C., et al 2020] as well as the safety and tolerability of 
antiretrovirals used for PrEP in this population.
Note: During Part 2 or Part 3 of this study, dosing of ISL during pregnancy is not 
applicable. Any participant who becomes pregnant during Part 2 or Part 3 of the study has 
the option to remain on PrEP therapy with FTC/TDF (Section 8.11.3).
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Nonclinical developmental and reproductive toxicology studies have not demonstrated any 
teratogenicity or other clinically relevant concerns, supporting continued dosing of ISL in 
participants who become pregnant and provide consent/assent to continue study intervention 
(Sections 8.1.1.3 and 8.11.3). Study intervention will be unblinded for participants with a 
confirmed continuing pregnancy.
For Part 1, only participants who were randomized to ISL will have the option to remain on 
open-label ISL or to transition to open-label FTC/TDF. Participants who were randomized to 
FTC/TDF may remain on open-label FTC/TDF.
There are no clinical data currently available to support breastfeeding by participants who are 
receiving ISL. Therefore, women who choose to breastfeed will not be permitted to continue 
ISL, but may receive FTC/TDF while breastfeeding.
4.2.6
Rationale for Collecting Infant Safety Follow-up Data
It is important to collect information on infants born to participants who become pregnant 
while receiving ISL. Follow-up through 1-year of age for infants born to participants who 
become pregnant while receiving study intervention provides the ability to monitor growth 
and development as well as potential adverse effects that may be associated with prenatal 
drug exposure. Growth parameters (ie, length, weight, and head circumference) within 
normal range at approximately 1-year of age are key noninvasive indicators that a serious 
congenital malformation caused by in utero drug exposure is unlikely.
Participants will not receive ISL during Part 2 or Part 3. Therefore, additional infant safety 
follow-up through 1 year of age, as described above, will not be required for participants who 
become pregnant during Part 3. Standard AE reporting requirements per Section 8.4 will 
apply.
4.3
Justification for Dose
4.3.1
Rationale for ISL QM Efficacious Exposure
Part 1
The lower efficacious exposure threshold for ISL PrEP efficacy is set at 0.05 pmol/106 cells 
in PBMCs to prevent HIV-1 infection. This conservative threshold is approximately 5-fold 
above the in vitro IC50 (≈ 0.00974 pmol/106 cells) of ISL-TP against wild-type HIV-1 virus 
and 2-fold above the EC90 (≈0.024 pmol/106 cells) in rhesus macaques [Grobler, J., et al 
2019]. Please refer to the IB for additional details.
In the Phase 1 proof-of-concept clinical study (MK-8591 Protocol 003) with HIV-1-infected, 
treatment-naïve participants; a single dose of ISL as low as 0.5 mg resulted in plasma HIV-1 
RNA reduction of median 1.26 log10 copies/mL as measured 7 days after a single dose, 
which compared favorably to a similar monotherapy study of daily tenofovir disoproxil 
[Schurmann, D., et al 2020]. At this dose, the geometric mean ISL-TP C168hr was 0.116 
pmol/106 cells, with the lowest concentration associated with antiviral efficacy at 0.0513 
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pmol/106 cells. This lowest observed ISL-TP concentration was associated with >1 log viral 
load reduction from baseline. Thus, the geometric mean ISL-TP C168hr is approximately 12-
fold above the in vitro IC50 of ISL-TP against wild-type HIV-1.
In a rhesus macaque SHIV challenge study, weekly administration of ISL at very low doses 
(0.43 mg/kg and 0.1 mg/kg) resulted in statistically significant protection for male rhesus 
macaques against infection following repeated rectal challenges with SHIV109CP3 
[Markowitz, M., et al 2019]. In this model, ISL was completely protective at ≥ 0.43 mg/kg 
and highly protective (92%) at 0.1 mg/kg, a dose that corresponds to ISL-TP EC90 of ≈ 0.024 
pmol/106 cells. Thus, this EC90 ISL-TP concentration is approximately 2-fold above the in 
vitro ISL-TP IC50 against wild-type HIV-1.
In comparison, the prophylactic TFV-DP EC90 associated with 90% risk reduction in rhesus 
macaques is 0.023 pmol/106 cells in PBMCs [Anderson, P. L., et al 2014]. In an intravaginal 
challenge study in female rhesus macaques using FTC/TAF, the observed minimum 
protective TFV-DP concentration was 0.123 pmol/106 cells [Massud, I., et al 2018]. This 
efficacious exposure is approximately ~3 fold above the in vitro TFV-DP IC50 against wild-
type HIV-1 [Grobler, J., et al 2019]. Moreover, in the iPrEx efficacy study of FTC/TDF as 
PrEP, which was conducted among men who have sex with men, the estimated TFV-DP-
EC90 was 0.016 pmol/106 cells [Anderson, P. L., et al 2012]. Overall, these prophylactic 
TFV-DP concentrations are approximately ~1-3 fold above the in vitro TFV-DP IC50 of wild-
type HIV-1[Grobler, J., et al 2019].
In summary, integrating data from in vitro activity of ISL-TP against wild-type HIV-1, a 
rhesus macaque SHIV challenge study, a proof-of-concept study conducted in treatment-
naïve participants infected with HIV-1, and relevant data from the literature regarding the 
prophylactic concentrations of TFV-DP, 0.05 pmol/106 cells in PBMCs has been determined 
to be a conservative, efficacious PrEP PK threshold.
Part 2
No study participants will receive ISL in Part 2 of the study.
Part 3
No study participants will receive ISL in Part 3 of the study.
4.3.2
Rationale for Dose Selection
Part 1
A 60-mg oral ISL QM dose is selected for this study to provide efficacious exposures for 
protection against HIV-1 (Section 4.3.1). Simulations predict that ISL 60 mg QM will 
achieve ISL-TP concentrations in PBMCs exceeding the PrEP PK exposure threshold of 0.05 
pmol/106 cells within 24 hours of the first dose and will provide sustained, adequate 
exposures even in the event of a delayed or missed dose (ie, up to 8 weeks following a dose).
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An IA of PK data from an ongoing Phase 2 study (MK-8591 Protocol 016) revealed that the 
observed concentrations for plasma ISL and ISL-TP in PBMCs were consistent with those 
from earlier MK-8591 Phase 1 and other Phase 2 studies. In this Protocol 016 IA, the PrEP 
PK exposure threshold of 0.05 pmol/106 cells in PBMCs was exceeded among all 
participants who received the 60-mg QM dose. The mean trough level of ISL-TP in PBMCs 
4 weeks after a single 60-mg dose is 1.32 pmol/106 cells, which is ~136 fold above the in 
vitro ISL-TP IC50 against wild-type HIV-1and ~26 fold above the prespecified PK threshold 
of 0.05 pmol/106 cells in PBMCs, respectively. The ISL 60-mg QM simulations predict that
at steady state the lower 2.5th percentile of the 95% prediction interval is ~0.17 pmol/106
cells in PBMCs. Thus, observations from Protocol 016 IA, (data not yet incorporated into the 
population PK model) together with the population PK simulations, support the selection of 
60-mg QM oral dose for this Phase 3 efficacy study.
Additionally, limited cervical tissue concentration data from MK-8591 Protocol 016 show 
that the ratio of ISL plasma to ISL-TP in this tissue-type was comparable to the ratios of ISL 
plasma to ISL-TP in vaginal and rectal tissues observed in the Phase 1 study MK-8591 
Protocol 009 [Matthews, R. P., et al 2018]. The estimated mean trough concentration in 
cervical tissue at Week 4, following a single oral dose of 60 mg ISL, was approximately 8.5 
fmol/mg. These preliminary data suggest rapid, sustained and adequate tissue penetration of 
ISL-TP at sites of potential HIV acquisition.
From a safety perspective, oral ISL has been evaluated in 8 Phase 1 clinical studies that 
demonstrated good tolerability of ISL in healthy participants who were administered: a single 
oral dose of up to 400 mg; 3 once-weekly doses of up to 100 mg; or a daily dose of 5 mg for 
6 weeks. In an ongoing Phase 2 HIV-1 treatment study (MK-8591 Protocol 011), ISL 
administered daily at 0.25 mg, 0.75 mg and 2.25 mg, in combination with DOR and 3TC, has 
been generally well tolerated through 96 weeks of dosing. Interim analysis of blinded data 
from Protocol 016 indicated that ISL administered monthly at 60 mg and 120 mg have been 
generally well tolerated. Overall exposures that result from the selected 60-mg QM oral dose 
are not expected to exceed those observed in Phase 1 and Phase 2 studies.
In summary, the 60-mg QM oral dose is expected to achieve a sufficient and adequate 
systemic threshold that will be efficacious as HIV-1 prophylaxis.
Part 2
No study participants will receive ISL in Part 2 of the study.
Part 3
No study participants will receive ISL in Part 3 of the study.
4.4
Beginning and End-of-Study Definition
The overall study begins when the first participant (or their legally acceptable representative) 
provides documented informed consent/assent. The overall study ends when the last 
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participant completes the last study-related contact, withdraws consent/assent, or is lost to 
follow-up (ie, the participant is unable to be contacted by the investigator).
For purposes of analysis and reporting, the overall study ends when the Sponsor receives the 
last laboratory result or at the time of final contact with the last participant, whichever comes 
last.
If the study includes countries in the European Economic Area (EEA), the local start of the 
study in the EEA is defined as First Site Ready (FSR) in any Member State.
4.4.1
Clinical Criteria for Early Study Termination
The clinical study may be terminated early if the extent (incidence and/or severity) of 
emerging effects/clinical endpoints is such that the risk/benefit ratio to the study population 
as a whole is unacceptable. In addition, further recruitment in the study or at (a) particular 
study site(s) may be stopped due to insufficient compliance with the protocol, GCP, and/or 
other applicable regulatory requirements, procedure-related problems or the number of 
discontinuations for administrative reasons is too high.
Early study termination may also be considered based on interim analysis(es) or after review 
of accumulating efficacy and safety data by the eDMC (Section 9.7).
5
STUDY POPULATION
As stated in the Code of Conduct for Clinical Trials (Appendix 1.1) this study includes 
participants of varying age, race, ethnicity, and sex. The collection and use of these 
demographic data will follow all local laws and participant confidentiality guidelines while 
supporting the study of the disease, its related factors, and the IMP under investigation.
No new participants will be screened or randomized in Part 2 or Part 3.
Female participants who are at high risk of acquiring HIV-1 infection will be enrolled in this 
study.
Prospective approval of protocol deviations to recruitment and enrollment criteria, also 
known as protocol waivers or exemptions, is not permitted.
5.1
Inclusion Criteria
A participant will be eligible for inclusion in the study if the participant:
Type of Participant and Disease Characteristics
1. Is confirmed HIV-uninfected based on negative HIV-1/HIV-2 test results before 
randomization.
Note: If a positive result is obtained for any HIV test prior to randomization, the 
participant is not eligible for the study. Additional testing to confirm suspected HIV 
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infection during screening will be performed in accordance with local guidelines. If HIV 
infection is confirmed, participants will be referred for appropriate care, as necessary.
2. Has been sexually active (vaginal and/or anal sex) with a male sexual partner in the 30 
days prior to Screening.
3. Is at high risk for HIV-1 infection as defined by a risk score ≥5 using a VOICE risk score 
tool (sites in Africa) or meets criteria for PrEP eligibility in accordance with CDC 
guidance (sites in the US) (see Appendix 10).
Demographics
4. Was assigned female sex at birth, is cisgender, 16 years to 45 years of age, inclusive, at 
the time of providing informed consent/assent.
Note: Participants 16 or 17 years of age must weigh ≥35 kg. Enrollment of 16- to 17-
year-old participants will begin only after completion of the Sentinel Cohort IA and 
review of IA results by the eDMC.
Female Participants
5. A female participant is eligible to participate if she is not pregnant or breastfeeding, and 
at least one of the following conditions applies:

Is not a WOCBP
OR

Is a WOCBP and using an acceptable contraceptive method, as described in 
Appendix 5 during the intervention period and for at least 42 days after the last dose 
(corresponding to the time needed to eliminate any study intervention [approximately 
5 terminal half-lives]).

A WOCBP must have a negative highly sensitive pregnancy test ([urine or serum] as 
required by local regulations) within 24 hours before the first dose of study 
intervention.

If a urine test cannot be confirmed as negative (eg, an ambiguous result), a serum 
pregnancy test is required. In such cases, the participant must be excluded from 
participation if the serum pregnancy result is positive.

Additional requirements for pregnancy testing during and after study intervention are 
located in Appendix 2.

The investigator is responsible for review of medical history, menstrual history, and 
recent sexual activity to decrease the risk for inclusion of a woman with an early 
undetected pregnancy.
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
Contraceptive use by women should be consistent with local regulations regarding the 
methods of contraception for those participating in clinical studies.
Informed Consent
6. The participant (or legally acceptable representative) has provided documented informed 
consent/assent for the study. The participant may also provide consent/assent for future 
biomedical research. However, the participant may participate in the main study without 
participating in future biomedical research.
Additional Categories
7. Has no plans to relocate or travel away from the site for ≥4 consecutive weeks during 
study participation.
5.2
Exclusion Criteria
The participant must be excluded from the study if the participant:
Medical Conditions
1. Has hypersensitivity or other contraindication to any of the components of the study 
interventions as determined by the investigator.
2. Findings of chronic HBV (HBsAg-positive) or past HBV (HBsAg-negative and HBcAb-
positive) infection, which could indicate risk for hepatitis B reactivation.
Note: Participants who do not demonstrate immunity to HBV are encouraged to be 
vaccinated against HBV.
3. Current or chronic history of liver disease (eg, nonalcoholic or alcoholic steatohepatitis) 
or known hepatic or biliary abnormalities (with the exception of Gilbert’s syndrome, 
asymptomatic gallstones, or cholecystectomy), unless the participant has stable liver 
function tests and no significant hepatic synthetic dysfunction.
Note: Hepatic synthetic dysfunction is defined as a serum albumin <2.8 g/dL or an 
INR>1.7 in the absence of another explanation for the abnormal laboratory value.
4. Has a history of malignancy within 5 years of screening except for adequately treated 
basal cell or squamous cell skin cancer, or in situ cervical cancer.
5. Has a history or current evidence of any condition (including active tuberculosis 
infection), therapy, laboratory abnormality or other circumstance (including drug or 
alcohol use or dependence) that might, in the opinion of the investigator, confound the 
results of the study or interfere with the participant’s participation for the full duration of 
the study, such that it is not in the best interest of the participant to enroll.
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Prior/Concomitant Therapy
6. Has taken cabotegravir, lenacapavir, or any other long-acting HIV prevention product at 
any time (past or current use).
7. Is currently receiving or is anticipated to require any prohibited therapies outlined in 
Section 6.5 from 30 days prior to Day 1 through the duration of the study.
Note: Participants taking tenofovir-based PrEP at screening may continue their regimen 
until 1 day prior to Day 1. Also, any prior or current HIV PrEP medications taken by the 
participant, regardless of timing, are to be recorded as prior medications.
Prior/Concurrent Clinical Study Experience
8. Is currently participating in or has participated in an interventional clinical study with an 
investigational compound or device within 30 days prior to Day 1 through the duration of 
the study.
Note: Prior participation in a COVID-19 vaccine study is allowed provided the final 
vaccination occurred ≥30 days before Day 1 (ie, a participant still in a study for long-
term follow-up assessments is permitted).
Note: Concurrent participation in observational or noninterventional studies may be 
permitted and should be discussed with the Sponsor before enrollment and through study 
duration.
Diagnostic Assessments
9. Has exclusionary laboratory values within 45 days prior to Day 1 as listed in Table 1.
Note: A single repeat of a laboratory screening test will be allowed for test results that 
are unexpected, but the repeat test results must be available within the 45-day screening 
window.
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Table 1
Laboratory Exclusion Criteria
Laboratory Assessment
Exclusionary Values
Absolute neutrophil count
≤750 cells/mm3
Alkaline Phosphatase
>3 × ULN
AST
>3 × ULN
ALT
>3 × ULN
Bilirubin
≥2.5 × ULN
Calculated CrCl
<60 mL/mina based on the Cockcroft-Gault equation (Appendix 9)
CD4+ T-cell count
<400 cells/mm3
Hemoglobin
<10.0 g/dL
Lymphocyte count
<650 cells/mm3
Platelet count
<100,000/mm3
ALT=alanine aminotransferase; AST=aspartate aminotransferase; CrCl=creatinine clearance; ULN=upper limit of normal.
a Although not protocol exclusionary, sites should carefully consider the advisability of enrolling participants with 
calculated CrCl between 60 to 70 mL/min, as limited changes in CrCl during study conduct will lead to protocol-
mandated product holds and may alter the risk-benefit considerations of study participation.
Other Exclusions
10. Is expecting to conceive or donate eggs at any time during the study.
Note: Investigators should provide appropriate guidance to female participants 
regarding egg donation after completion of the study intervention. Consistent with the 
recommendations for contraceptive use, it is recommended that all female participants 
refrain from egg donation for 42 days following their last dose of study intervention. 
5.3
Lifestyle Considerations
All participants should be counseled on safer sex practices to prevent acquisition of HIV or 
other STIs.
5.4
Screen Failures
Screen failures are defined as participants who consent/assent to participate in the clinical 
study, but are not subsequently randomized in the study. A minimal set of screen failure 
information is required to ensure transparent reporting of screen failure participants to meet 
the CONSORT publishing requirements and to respond to queries from regulatory 
authorities. Minimal information includes demography, screen failure details, eligibility 
criteria, and any AEs or SAEs meeting reporting requirements as outlined in the data entry 
guidelines.
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Screen failures who are HIV-uninfected will be referred to locally available HIV prevention 
services.
Screen failures who are HIV-infected will be referred to and linked with locally available 
HIV treatment services.
5.5
Participant Replacement Strategy
A participant who discontinues from study intervention OR withdraws from the study will 
not be replaced.
6
STUDY INTERVENTION
Study intervention is defined as any investigational intervention(s), marketed product(s), 
placebo, or medical device(s) intended to be administered to a study participant according to 
the study protocol.
Clinical supplies of study interventions provided by the Sponsor will be packaged to support 
enrollment. Clinical supplies will be affixed with a clinical label in accordance with 
regulatory requirements.
6.1
Study Intervention(s) Administered
The study intervention(s) to be used in this study are outlined in Table 2.
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Table 2
Study Interventions
Arm Name
Arm Type
Inter-
vention 
Name
Inter-
vention 
Type
Dose 
Form-
ulation
Unit Dose 
Strength(s)
Dosage 
Level(s)
Route of 
Admin-
istration
Regimen/
Treatment Period
Use
IMP or
NIMP/
AxMP
Sourcing
Part 1
ISL QM
Group
Experimental
ISL
Drug
Tablet
60 mg
60 mg
Oral
QM from Visit 2 to 
(up to) Visit 37
Test Product
IMP
Central
Part 1
ISL QM 
Group
Experimental
Placebo to 
FTC/TDF
Drug
Tablet
0 mg
0 mg
Oral
QD from Visit 2 to 
(up to) Visit 37
Placebo
IMP
Central
Part 1
FTC/TDF 
QD Group
Active 
Comparator
FTC/TDF
Drug
Tablet
200/245 mg
200/245 mg
Oral
QD from Visit 2 to 
(up to) Visit 37
Test Product
IMP
Central/Local
Part 1
FTC/TDF 
QD Group
Active 
Comparator
Placebo to 
ISL
Drug
Tablet
0 mg
0 mg
Oral
QM from Visit 2 to 
(up to) Visit 37
Placebo
IMP
Central
Part 2 All 
Participants
Active 
Comparator
FTC/TDF
Drug
Tablet
200/245 mg
200/245 mg
Oral
QD in Part 2
Test Product
IMP
Provided centrally 
by Sponsor
Part 3 All 
Participants
Active 
Comparator
FTC/TDF
Drug
Tablet
200/245 mg
200/245 mg
Oral
QD in Part 3
Test Product
IMP
Provided centrally 
by Sponsor
EEA =European Economic Area; FTC/TDF=emtricitabine/tenofovir disoproxil (including TRUVADATM and all generic versions); IMP=Investigational Medicinal Product; ISL=islatravir (also 
known as MK-8591); NIMP/AxMP=noninvestigational/auxiliary medicinal product; QD=once daily; QM=once-monthly.
Each FTC/TDF tablet contains 200 mg emtricitabine and 245 mg of tenofovir disoproxil (equivalent to 300 mg tenofovir disoproxil fumarate or 291.22 mg tenofovir disoproxil phosphate).
FTC/TDF may also be locally sourced.
The classification of IMP and NIMP/AxMP in this table is based on guidance issued by the European Commission and applies to countries in the EEA. Country differences with respect to the 
definition/classification of IMP and NIMP/AxMP may exist. In these circumstances, local legislation is followed.
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All supplies indicated in Table 2 will be provided per the “Sourcing” column depending on 
local country operational requirements. If local sourcing, every attempt should be made to 
source these supplies from a single lot/batch number where possible (eg, not applicable in the 
case where multiple lots or batches may be required due to the length of the study, etc).
Refer to Section 8.1.8 for details regarding administration of the study intervention.
All placebos were created by the Sponsor to match the active product.
6.2
Preparation/Handling/Storage/Accountability
6.2.1
Dose Preparation
There are no specific calculations or evaluations required to be performed in order to 
administer the proper dose to each participant. The rationale for selection of doses to be used 
in this study is provided in Section 4.3.
6.2.2
Handling, Storage, and Accountability
The investigator or designee must confirm appropriate temperature conditions have been 
maintained during transit for all study intervention received, and any discrepancies are 
reported and resolved before use of the study intervention.
Only participants enrolled in the study may receive study intervention, and only authorized 
site staff may supply or administer study intervention. All study interventions must be stored 
in a secure, environmentally controlled, and monitored (manual or automated) area in 
accordance with the labeled storage conditions with access limited to the investigator and 
authorized site staff.
The investigator, institution, or the head of the medical institution (where applicable) is 
responsible for study intervention accountability, reconciliation, and record maintenance (ie, 
receipt, reconciliation, and final disposition records).
For all study sites, the local country Sponsor personnel or designee will provide appropriate 
documentation that must be completed for drug accountability and return, or local discard 
and destruction if appropriate. Where local discard and destruction is appropriate, the 
investigator is responsible for ensuring that a local discard/destruction procedure is 
documented.
The study site is responsible for recording the lot number, manufacturer, and expiry date for 
any locally purchased product (if applicable) as per local guidelines unless otherwise 
instructed by the Sponsor.
The investigator shall take responsibility for and shall take all steps to maintain appropriate 
records and ensure appropriate supply, storage, handling, distribution, and usage of study 
interventions in accordance with the protocol and any applicable laws and regulations.
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6.3
Measures to Minimize Bias: Randomization and Blinding
6.3.1
Intervention Assignment
Part 1
Intervention randomization will occur centrally using an IRT system. There are 2 study 
intervention arms. Participants will be assigned randomly in a 1:1 ratio to ISL QM and 
placebo to FTC/TDF QD, OR FTC/TDF QD and placebo to ISL QM.
Part 2
No new participants will be screened or randomized in Part 2. Blinded study intervention 
administration, including ISL or its placebo, was stopped, and all participants were switched 
to PrEP therapy with FTC/TDF.
Part 3
No new participants will be screened or randomized in Part 3. Ongoing participants will 
continue to receive open-label daily PrEP therapy with FTC/TDF.
6.3.2
Stratification
Part 1
Intervention randomization will be stratified according to the following factors:
Site
•
All US sites as 1 stratum
•
Ex-US sites as individual strata
Age (at Randomization)
•
<25 years
•
≥25 years
Site is included as a stratification factor due to regional differences in linkages to care, 
likelihood of sexual partners knowing HIV status (infection or viral suppression) and the 
burden of untreated HIV-1 infection in the community and thus among potential sexual 
partners. Age is included since risk may also vary by age (with higher risk among younger 
participants). Stratification at randomization ensures that the intervention groups are well-
balanced within each stratum level.
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Part 2
No new participants will be screened or randomized; therefore, there is no stratification for 
Part 2.
Part 3
No new participants will be screened or randomized; therefore, there is no stratification for 
Part 3.
6.3.3
Blinding
Part 1
A double-blinding technique with in-house blinding will be used. ISL and FTC/TDF will be 
packaged identically to their matching placebos so that blind is maintained. The participant, 
the investigator, and Sponsor personnel or delegate(s) who are involved in the study 
intervention administration or clinical evaluation of the participants are unaware of the 
intervention assignments.
To allow timely completion of population PK modeling, restricted early (before database 
lock) unblinding of PK and relevant clinical data may be requested. No personnel directly 
associated with study conduct will be unblinded before database lock. Before granting select 
personnel access to unblinded PK and relevant clinical data, an official memo detailing 
unblinding procedures will be generated per Sponsor SOP. This memo will list the names of 
the personnel who will have access to unblinded PK and relevant clinical data before 
database lock.
If a participant is confirmed HIV-infected, results from HIV-1 drug resistance testing will not 
be provided to site personnel who are directly involved in supporting the study, as there is the 
potential for the data to unblind the participant’s intervention group. HIV Resistance results 
will be blinded to the study team and site personnel.
Part 2
All participants have been switched to PrEP therapy with FTC/TDF. The participant, the
investigator, and Sponsor personnel or delegate(s) directly involved in the clinical monitoring 
or evaluation of participants will remain blinded to the participants’ original randomized 
study intervention group. Sponsor personnel or delegate(s) not directly involved in clinical 
monitoring or evaluation of the participants will be unblinded to the participants’ original 
randomized study intervention group.
Part 3
In Part 3, participants, investigators, and all Sponsor personnel will be unblinded to the 
participants’ original randomized study intervention group.
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6.4
Study Intervention Compliance
Part 1
In-clinic dosing of study intervention is required on the day of monthly study visits. 
Participants should be instructed to bring their bottle of FTC/TDF or matching placebo to 
their visits. At each visit, the site personnel will count the number of tablets of FTC/TDF or 
matching placebo remaining in the bottle. This information will be reviewed and recorded in 
source documentation. The results will be used to assess study intervention adherence. If a 
discrepancy is noted, the investigator/study coordinator must discuss the discrepancy with the 
participant and the explanation must be documented in the source documents. Participants 
should be reminded of the importance of taking their study intervention as instructed for the 
entire duration of the study.
Decisions to temporarily withhold study intervention dosing because of an AE will be 
reviewed on a case-by-case basis by the investigator. Interruptions from the protocol-
specified treatment of ≥1 monthly dose OR, for daily dosing, ≥7 consecutive days, require 
consultation between the investigator and the Sponsor and written documentation of the 
collaborative decision on participant management.
A record of the number of study intervention tablets dispensed to and taken by each 
participant must be maintained and reconciled with study intervention and adherence records. 
Intervention start and stop dates, including dates for intervention delays and/or any 
deviations from the prescribed dosage regimen will also be recorded in the CRF.
Part 2
All participants have been switched to PrEP therapy with FTC/TDF. At each visit, site 
personnel will review the participant’s FTC/TDF dosing adherence. The dosing record will 
also be recorded in the CRF as instructed by the Sponsor.
Part 3
Ongoing participants will continue to receive open-label daily PrEP therapy with FTC/TDF. 
At each visit, site personnel will review the participant’s FTC/TDF dosing adherence. The 
dosing record will also be recorded in the CRF as instructed by the Sponsor.
6.5
Concomitant Therapy
Medications specifically prohibited in the exclusion criteria are not allowed during the 
ongoing study and during time periods specified by this protocol for that medication. If there 
is a clinical indication for any medications specifically prohibited, discontinuation from study 
intervention may be required. The investigator should discuss any questions regarding this 
with the Sponsor Clinical Director. The final decision on any supportive therapy rests with 
the investigator and/or the participant’s primary physician. However, the decision to continue
the participant on study intervention requires the mutual agreement of the investigator, the 
Sponsor, and the participant.
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Use of cabotegravir, lenacapavir, or any other long-acting HIV prevention product at any 
time (prior or current) is prohibited.
The following are specific restrictions for prior and concomitant therapies not permitted from 
30 days before receiving study intervention through the study duration (ie, up to 42 days 
following last dose of study intervention) for all participants:
•
Pentostatin (an adenosine deaminase inhibitor that may increase ISL levels) – only 
applicable for Part 1.
•
Any nonstudy antiretrovirals.
Notes:
-
PEP is permitted if clinically indicated and should be managed according to local 
standard of care. Any potential interactions of PEP with study intervention will be 
managed by the investigator.
-
Part 1-Participants taking tenofovir-based PrEP at screening may continue their 
regimen until 1 day prior to Day 1.
-
Part 2- All participants were switched to PrEP therapy with FTC/TDF.
•
Any nonstudy investigational agents (including devices)
•
Any immune therapy agents, immune modulators, or other systemic immunosuppressive 
therapies
Note: Time-limited courses of corticosteroids (eg, for asthma exacerbation) are allowed.
•
Any prohibited (ie, contraindicated or not recommended) therapy(ies) as specified in the 
local product circular for FTC/TDF
Any medication (including over-the-counter or prescription medicines, vitamins, and/or 
herbal supplements or other specific categories of interest) that the participant is receiving at 
the time of enrollment or receives during the study must be recorded along with:
•
Reason for use
•
Dates of administration including start and end dates
•
Dosage information, including dose and frequency (if known)
Note: Vaccines for COVID-19 approved locally for Emergency Authorized Use, or 
equivalent, that do not have a known or anticipated DDI with ISL, are permitted.
The Medical Monitor should be contacted if there are any questions regarding concomitant or 
prior therapy.
6.5.1
Rescue Medications and Supportive Care
No rescue or supportive medications are specified for use in this study.
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6.6
Dose Modification
A participant’s dose will not be modified during the study.
6.7
Intervention After the End of the Study
At the end of the study, provided development of ISL as PrEP for HIV-1 continues, the 
Sponsor is planning for a mechanism for eligible participants to continue receiving ISL.
Providing ongoing study medication for a woman who is pregnant at the time of her last 
study visit will be handled the same as any other participant.
6.8
Clinical Supplies Disclosure
The emergency unblinding call center will use the intervention/randomization schedule for 
the study to unblind participants and to unmask study intervention identity. The emergency 
unblinding call center should only be used in cases of emergency (see Section 8.1.10). If the 
emergency unblinding call center is not available for a given site in this study, the central 
electronic intervention randomization system (IRT) should be used to unblind participants 
and to unmask study intervention identity. The Sponsor will not provide random 
code/disclosure envelopes or lists with the clinical supplies.
6.9
Standard Policies
Participants will be provided letter(s) specific to the placebo(s) in the image of the 
competitor’s product actually received per the following options, as appropriate:
TRUVADATM (US Source)
After unblinding, a letter is to be sent by the investigator to those participants who received 
placebos in the image of the competitor’s product to provide the following advice: “You have 
participated in a study conducted by the Sponsor. This letter is to advise you that you were 
among those who received a look-alike tablet created by the Sponsor to resemble the 
drug/vaccine TRUVADATM 200 mg/300 mg (emtricitabine/tenofovir disoproxil fumarate) as 
much as possible. You did not receive the active drug/vaccine TRUVADATM 200 mg/300 mg 
(emtricitabine/tenofovir disoproxil fumarate) as manufactured by Gilead Sciences, Inc.”
Emtricitabine/Tenofovir Disoproxil (EU Source)
After unblinding, a letter is to be sent by the investigator to those participants who received 
placebos in the image of the competitor’s product to provide the following advice: “You have 
participated in a study conducted by the Sponsor. This letter is to advise you that you were 
among those who received a look-alike tablet created by the Sponsor to resemble the 
drug/vaccine emtricitabine/tenofovir disoproxil 200 mg/245 mg as much as possible. You did 
not receive the active drug/vaccine emtricitabine/tenofovir disoproxil 200 mg/245 mg as 
manufactured by Ratiopharm GmbH.”
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TRUVADATM (EU Source)
After unblinding, a letter is to be sent by the investigator to those participants who received 
placebos in the image of the competitor’s product to provide the following advice: “You have 
participated in a study conducted by the Sponsor. This letter is to advise you that you were 
among those who received a look-alike tablet created by the Sponsor to resemble the 
drug/vaccine TRUVADATM 200 mg/245 mg (emtricitabine/tenofovir disoproxil) as much as 
possible. You did not receive the active drug/vaccine TRUVADATM 200 mg/245 mg 
(emtricitabine/tenofovir disoproxil) as manufactured by Gilead Sciences, Ireland UC.”
7
DISCONTINUATION OF STUDY INTERVENTION AND PARTICIPANT 
WITHDRAWAL
7.1
Discontinuation of Study Intervention
Discontinuation of study intervention does not represent withdrawal from the study.
As certain data on clinical events beyond study intervention discontinuation may be 
important to the study, they must be collected through the participant’s last scheduled follow-
up, even if the participant has discontinued study intervention. Therefore, all participants 
who discontinue study intervention before completion of the protocol-specified treatment 
period will still continue to participate in the study as specified in Section 8.11.4.
Participants may discontinue study intervention at any time for any reason or be discontinued 
from the study intervention at the discretion of the investigator should any untoward effect 
occur. In addition, a participant may be discontinued from study intervention by the 
investigator or the Sponsor if study intervention is inappropriate, the study plan is violated, or 
for administrative and/or other safety reasons. Specific details regarding procedures to be 
performed at study intervention discontinuation are provided in Section 8.1.9 and Section 
8.11.4.
A participant must be discontinued from study intervention, but continue to be monitored per
Section 8.11.4 in the study for any of the following reasons:
•
The participant or participant’s legally acceptable representative requests to discontinue 
study intervention, including in relation to dosing while pregnant.
•
The participant has confirmed HIV-1 or HIV-2 infection.
Note: Participants who become infected with HIV-1 or HIV-2 during the study will stop 
receiving study intervention and will be referred to and linked with a local medical 
provider for HIV care and treatment. No poststudy antiretroviral therapy will be 
provided by the study.
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•
The participant has a medical condition or personal circumstance, which in the opinion of
the investigator, in consultation with the Sponsor, placed the participant at unnecessary 
risk from continued administration of study intervention.
Note: In the case of certain new medical conditions, such as if the participant develops a 
malignancy (eg, lymphoma, or a condition requiring a contraindicated medication per 
the local label of FTC/TDF) after randomization, or if a participant requires treatment 
for active tuberculosis infection, consultation regarding management should take place 
with the Sponsor Clinical Director on a case-by-case basis.
•
The participant has an SAE or Grade 4 laboratory AE that is assessed by the investigator 
to be related to study intervention AND that is life-threatening or results in prolonged 
hospitalization.
•
The participant is breastfeeding (This is applicable for Part 1 only. For Part 2 and Part 3, 
see Section 8.11.3.2.1).
Note: Participants may take open-label FTC/TDF during breastfeeding (Section 
8.11.3.1.1). Participants who decide to not breastfeed their infants may continue on 
assigned study intervention (Part 1 Only).
Note: Participants may take FTC/TDF while breastfeeding during Part 2 or Part 3 of the 
study (Section 8.11.3.2.1).
•
The participant has 2 consecutive DAIDS Grade 3 (<500 cells/mm3) or higher grade of 
lymphocyte count and/or 2 consecutive DAIDS Grade 3 (<200 cells/mm3) or higher 
grade of CD4+ T-cell count (at least 3 weeks apart) while on study intervention at any 
time during the study, unless there is a clear alternative explanation for the result (eg, 
COVID-19). If a participant is discontinued from study intervention for this reason, 
discontinuation is considered “permanent,” and they will not be allowed to restart study 
intervention.
Note: If study intervention is discontinued for this reason, participants should stay in the 
study and may take open-label FTC/TDF, and continue to complete study assessments as 
outlined in the SoA (Section 1.3.1).
Unless otherwise noted above, participants may be allowed to begin study intervention again 
if deemed medically appropriate.
7.2
Participant Withdrawal From the Study
A participant must be withdrawn from the study if the participant or participant’s legally 
acceptable representative withdraws consent/assent from the study.
If a participant withdraws from the study, they will no longer receive study intervention or be 
followed at scheduled protocol visits.
Specific details regarding procedures to be performed at the time of withdrawal from the 
study, as well as specific details regarding withdrawal from future biomedical research, are 
outlined in Section 8.1.9. The procedures to be performed should a participant repeatedly fail 
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to return for scheduled visits and/or if the study site is unable to contact the participant are 
outlined in Section 7.3.
7.3
Lost to Follow-up
If a participant fails to return to the clinic for a required study visit and/or if the site is unable 
to contact the participant, the following procedures are to be performed:
•
The site must attempt to contact the participant and reschedule the missed visit. If the 
participant is contacted, the participant should be counseled on the importance of 
maintaining the protocol-specified visit schedule.
•
The investigator or designee must make every effort to regain contact with the participant 
at each missed visit (eg, telephone calls and/or a certified letter to the participant’s last 
known mailing address or locally equivalent methods). These contact attempts should be 
documented in the participant’s medical record.
8
STUDY ASSESSMENTS AND PROCEDURES
Note: Blinded study intervention administration (Part 1) has been stopped. During Part 2, all 
participants were switched to PrEP therapy with FTC/TDF and will maintain the visit 
schedule in Section 1.3.1. No new participants will be screened or randomized during Part 2; 
therefore, assessments performed as part of screening and randomization (Day 1) will not be 
performed during Part 2. 
Note: During Part 3, all ongoing participants will continue to receive open-label daily PrEP 
therapy with FTC/TDF and will maintain the visit schedule in Section 1.3.1. No new 
participants will be screened or randomized; therefore, assessments performed as part of 
screening and randomization (Day 1) will not be performed during Part 3.
•
Study procedures and their timing are summarized in the SoA.
•
Adherence to the study design requirements, including those specified in the SoA, is 
essential and required for study conduct.
•
The investigator is responsible for ensuring that procedures are conducted by 
appropriately qualified (by education, training, and experience) staff. Delegation of 
study-site personnel responsibilities will be documented in the Investigator Trial File 
Binder (or equivalent).
•
All study-related medicaldecisions must be made by an investigator who is a qualified 
physician
•
All screening evaluations must be completed and reviewed to confirm that potential 
participants meet all eligibility criteria. The investigator will maintain a screening log to 
record details of all participants screened and to confirm eligibility or record reasons for 
screening failure, as applicable.
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•
Additional evaluations/testing may be deemed necessary by the investigator and or the 
Sponsor for reasons related to participant safety. In some cases, such evaluation/testing 
may be potentially sensitive in nature (eg, HIV, hepatitis C), and thus local regulations 
may require that additional informed consent be obtained from the participant. In these 
cases, such evaluations/testing will be performed in accordance with those regulations.
The maximum amount of blood collected from each participant over the duration of the study 
will be approximately 1110 mL, with an additional approximately 49 mL each for any 
unscheduled visits required for HIV confirmation, early discontinuation of study 
intervention, or early withdrawal from study (Table 13). Participants who become pregnant 
and remain on ISL, will have additional assessments resulting in approximately 21 mL of 
blood collected.
Repeat or unscheduled samples may be taken for safety reasons or for technical issues with 
the samples.
8.1
Administrative and General Procedures
8.1.1
Informed Consent
The investigator or medically qualified designee (consistent with local requirements) must 
obtain documented informed consent/assent from each potential participant (or their legally 
acceptable representative) prior to participating in this clinical study or future biomedical 
research. If there are changes to the participant’s status during the study (eg, health or age of
majority requirements), the investigator or medically qualified designee must ensure the 
appropriate documented informed consent/assent is in place.
8.1.1.1
General Informed Consent
Informed consent/assent given by the participant or their legally acceptable representative 
must be documented on a consent/assent form. The form must include the trial protocol 
number, trial protocol title, dated signature, and agreement of the participant (or his/her 
legally acceptable representative) and of the person conducting the consent/assent discussion.
•
A copy of the signed and dated informed consent/assent form should be given to the 
participant (or their legally acceptable representative) before participation in the study.
•
The initial ICF, any subsequent revised ICF, and any information provided to the 
participant must receive the IRB/IEC’s approval/favorable opinion in advance of use. The 
participant or his/her legally acceptable representative should be informed in a timely 
manner if new information becomes available that may be relevant to the participant’s 
willingness to continue participation in the study. The communication of this information 
will be provided and documented via a revised consent/assent form or addendum to the 
original consent/assent form that captures the participant’s or the participant’s legally 
acceptable representative’s dated signature.
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•
Specifics about the study and the study population are to be included in the study 
informed consent/assent form.
•
Informed consent/assent will adhere to IRB/IEC requirements, applicable laws and 
regulations, and Sponsor requirements.
8.1.1.2
Consent and Collection of Specimens for Future Biomedical Research
The investigator or medically qualified designee will explain the future biomedical research 
consent/assent to the participant, or the participant’s legally acceptable representative, answer 
all of his/her questions, and obtain documented informed consent/assent before performing 
any procedure-related to future biomedical research. A copy of the informed consent/assent 
will be given to the participant before performing any procedure-related to future biomedical 
research.
8.1.1.3
Consent in the Event of a Positive Pregnancy Test
8.1.1.3.1
Consent for Open-label FTC/TDF
Part 1
Participants who have a first positive urine pregnancy test will stop taking all study 
intervention and provide a serum sample for confirmatory serum pregnancy test (Section 
8.11.3). These participants will be given the option to receive open-label FTC/TDF until a 
continuing pregnancy is confirmed. For a participant to receive open-label FTC/TDF, 
additional consent/assent is required. The investigator or medically qualified designee will 
explain the consent/assent to the participant or the participant’s legally acceptable 
representative, answer all of their questions, and obtain documented informed consent/assent 
before dispensing open-label FTC/TDF. A copy of the informed consent/assent will be given 
to the participant.
Part 2 and Part 3
Participants who have a first positive urine pregnancy test will provide a serum sample for 
confirmatory serum pregnancy test (Section 8.11.3.2). These participants will be given the 
option to receive FTC/TDF following a positive pregnancy test. For a participant to receive 
FTC/TDF, additional consent/assent is required. The investigator or medically qualified 
designee will explain the consent/assent to the participant or the participant’s legally 
acceptable representative, answer all of their questions, and obtain documented informed 
consent/assent before dispensing FTC/TDF. A copy of the informed consent/assent will be 
given to the participant.
8.1.1.3.2
Consent for Continuation or Interruption of Study Intervention During 
Pregnancy- Part 1 Only
Participants who become pregnant during the study and are confirmed to have a continuing 
pregnancy will be unblinded and given the option to: 1) continue in the study and receive 
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unblinded study intervention, or 2) interrupt study intervention. Upon confirmation of a 
continuing pregnancy, as outlined in Section 8.11.3, study intervention assignment will be 
unblinded and the investigator or medically qualified designee will discuss with the 
participant the potential benefits and risks of continuing (or discontinuing) study intervention 
(Section 8.11.3). Documentation of a separate additional consent/assent is required for 
participants with confirmed continuing pregnancy who decide to continue receiving 
unblinded study intervention. The investigator or medically qualified designee will explain 
the consent/assent to the participant or the participant’s legally acceptable representative, 
answer all of their questions, and obtain documented informed consent/assent before the 
participant may continue in the study and receive unblinded study intervention during the 
pregnancy. A copy of the informed consent/assent will be given to the participant.
8.1.1.4
Consent for Continuing Study Participation for Participants Who Choose to 
Breastfeed
Part 1
Participants who choose to breastfeed during the study will not be permitted to continue ISL, 
but will be given the option to receive open-label FTC/TDF after providing consent/assent to 
continue study participation (Section 8.11.3.1.1). The investigator or medically qualified 
designee will explain the consent/assent to the participant or the participant’s legally 
acceptable representative, answer all of their questions, and obtain documented informed 
consent/assent before delivery, ideally within the last trimester of the pregnancy. A copy of 
the informed consent/assent will be given to the participant.
Part 2 and Part 3
Participants who choose to breastfeed during Part 2 and Part 3 of the study will be given the 
option to continue receiving FTC/TDF after providing documented informed consent/assent 
to continue study participation (Section 8.11.3.2.1).
8.1.1.5
Consent for Infant Safety Data Collection
Part 1 and Part 2:
The investigator or medically qualified designee will explain the infant safety data collection 
consent/assent to the participant or the participant’s legally acceptable representative, answer 
all questions, and obtain documented informed consent/assent before collecting any data 
related to infant safety. A copy of the informed consent/assent will be given to the 
participant.
Part 3:
Infant Safety Data (1-year follow-up after birth) will not be collected by the Sponsor for 
pregnancies that occur during Part 3 of the study. Therefore a consent/assent is not required.
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8.1.2
Inclusion/Exclusion Criteria
All inclusion and exclusion criteria will be reviewed by the investigator, who is a qualified 
physician, to ensure that the participant qualifies for the study.
8.1.2.1
HIV Recency Assay Testing
Per Inclusion Criterion #1, all participants are to be confirmed HIV-uninfected based on 
negative HIV-1/HIV-2 test. Samples for recency assay testing will be collected from all 
participants at Screening and Day 1. For participants who are found to be HIV-1 infected at 
one of these 2 time points, samples will be analyzed to help estimate community-level HIV-1 
incidence rates (based on assessment of recent versus long-standing HIV-1 infection).
8.1.3
Participant Identification Card
All participants will be given a participant identification card identifying them as participants 
in a research study. The card will contain study site contact information (including direct 
telephone numbers) to be used in the event of an emergency. The investigator or qualified 
designee will provide the participant with a participant identification card immediately after 
the participant provides documented informed consent/assent. At the time of intervention
randomization, site personnel will add the treatment/randomization number to the participant 
identification card.
The participant identification card also contains contact information for the emergency 
unblinding call center so that a healthcare provider can obtain information about study 
intervention in emergency situations where the investigator is not available.
8.1.4
Medical History
A medical history will be obtained by the investigator or qualified designee.
8.1.5
Prior and Concomitant Medications Review
8.1.5.1
Prior Medications
The investigator or qualified designee will review prior medication use, and record prior 
medication taken by the participant within 30 days before first dose of study intervention.
Any prior or current HIV PrEP medications taken by the participant, regardless of timing, are 
to be recorded as prior medications.
8.1.5.2
Concomitant Medications
The investigator or qualified designee will record medication, if any, taken by the participant 
during the study (ie, from Screening and up to 42 days after the last dose of study 
intervention).
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8.1.6
Assignment of Screening Number
All consented participants will be given a unique screening number that will be used to 
identify the participant for all procedures that occur before randomization. Each participant 
will be assigned only 1 screening number. Screening numbers must not be reused for 
different participants.
Any participant who is screened multiple times will retain the original screening number 
assigned at the initial Screening Visit. Specific details on the screening/rescreening visit 
requirements are in Section 8.11.1.
8.1.7
Assignment of Treatment/Randomization Number
All eligible participants will be randomly allocated and will receive a 
treatment/randomization number. The treatment/randomization number identifies the 
participant for all procedures occurring after treatment randomization. Once a 
treatment/randomization number is assigned to a participant, it can never be reassigned to 
another participant.
A single participant cannot be assigned more than 1 treatment/randomization number.
8.1.8
Study Intervention Administration
Part 1
Study intervention will be provided per Table 2 (Section 6.1) and dispensed through the IRT 
system at visits indicated in the SoA (Section 1.3.1).
Part 2 and Part 3
Participants will receive PrEP therapy with FTC/TDF per Table 2 (Section 6.1).
8.1.8.1
Timing of Dose Administration
Part 1
For dosing of once-monthly tablets, all dosing can occur without regard to food.
For dosing of once daily tablets, please refer to the local product label as to whether or not 
doses should preferably be taken with food.
The monthly dose of ISL or matching placebo will be administered at the clinic/study site per 
the SoA (Section 1.3). The first dose of FTC/TDF or matching placebo will be administered 
at the study site on Day 1. Subsequent dosing will be performed once daily by the participant 
(ie, unsupervised at her home) at approximately the same time each day.
Participants should take the monthly dose of ISL or matching placebo within ± 7 days of the 
ideal dosing day (calculated based on Day 1).
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If a participant is late for a monthly dose of ISL or matching placebo (ie, beyond the 7-day 
dosing window), then the monthly dose should be skipped/missed, and the normal dosing 
schedule resumed (based on the ideal dosing day) at the next dosing visit. Participants should 
not double the next dose to compensate for what has been missed.
The guidance in the approved FTC/TDF label should be followed regarding missed doses of 
FTC/TDF or matching placebo.
Part 2 and Part 3
Participants will receive PrEP therapy with FTC/TDF. For dosing of once daily tablets, 
please refer to the local product label as to whether or not doses should preferably be taken 
with food.
If a participant misses a dose of FTC/TDF, guidance in the approved label should be 
followed.
8.1.8.2
HIV Risk Reduction
Site staff will administer the Sexual Activity Form to participants at visits per the SoA 
(Section 1.3). Participants will be offered condoms, lubricants, and HIV risk reduction
counseling.
8.1.8.3
Participant-reported Outcomes
Site staff will administer 2 questionnaires to participants at visits per the SoA (Sections 1.3.1, 
1.3.2, and 1.3.3). The questionnaires will be administered in no particular order using an 
interview format. Participant responses will be captured in the electronic database by site 
staff.
8.1.8.4
Interruption of Study Intervention
The site should encourage participants to remain adherent to study intervention per-protocol. 
Participants who intentionally or inadvertently interrupt study intervention, without 
withdrawing consent/assent to participate in the study, should not be discontinued from the 
study. The investigator and site personnel should make every reasonable effort to contact the 
participant and should have a discussion with her regarding resumption of study intervention. 
The discussion should be noted in source documentation. Participants may continue with 
study visits and procedures regardless of study intervention adherence.
Interruptions from the protocol-specified treatment plan due to an AE, pregnancy, or any 
other physician-directed interruption require consultation between the investigator and the 
Sponsor and written documentation of the collaborative decision on participant management.
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8.1.9
Discontinuation and Withdrawal
Participants who discontinue study intervention before completion of the treatment period
should be encouraged to continue to be followed for all remaining study visits as outlined in 
the SoA (Sections 1.3.1 and 1.3.2) and Section 8.11.4.
Participants who withdraw from the study should be encouraged to complete all applicable 
activities scheduled for the Early Withdrawal from Study visit (Section 1.3.2) at the time of 
withdrawal. Any AEs that are present at the time of withdrawal should be followed in 
accordance with the safety requirements outlined in Section 8.4.
8.1.9.1
Withdrawal From Future Biomedical Research
Participants may withdraw their consent/assent for future biomedical research. Participants 
may withdraw consent/assent at any time by contacting the investigator for the main study. If 
medical records for the main study are still available, the investigator will contact the 
Sponsor using the designated mailbox (clinical.specimen.management@MSD.com). 
Subsequently, the participant's consent/assent for future biomedical research will be 
withdrawn. A letter will be sent from the Sponsor to the investigator confirming the 
withdrawal. It is the responsibility of the investigator to inform the participant of completion 
of withdrawal. Any analyses in progress at the time of request for withdrawal or already 
performed prior to the request being received by the Sponsor will continue to be used as part 
of the overall research study data and results. No new analyses would be generated after the 
request is received.
In the event that the medical records for the main study are no longer available (eg, if the 
investigator is no longer required by regulatory authorities to retain the main study records) 
or the specimens have been completely anonymized, there will no longer be a link between 
the participant’s personal information and their specimens. In this situation, the request for 
specimen withdrawal cannot be processed.
8.1.10
Participant Blinding/Unblinding
This section is not applicable during Part 3 of the study since all participants will be 
unblinded to study intervention assignment.
STUDY INTERVENTION IDENTIFICATION INFORMATION IS TO BE UNMASKED 
ONLY IF NECESSARY FOR THE WELFARE OF THE PARTICIPANT. EVERY 
EFFORT SHOULD BE MADE NOT TO UNBLIND.
For emergency situations where the investigator or medically qualified designee (consistent 
with local requirements) needs to identify the intervention used by a participant and/or the 
dosage administered, he/she will contact the emergency unblinding call center by telephone 
and make a request for emergency unblinding. As requested by the investigator or medically 
qualified designee, the emergency unblinding call center will provide the information to 
him/her promptly and report unblinding to the Sponsor. Before contacting the emergency 
unblinding call center to request unblinding of a participant’s intervention assignment, the 
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investigator who is a qualified physician should make reasonable attempts to enter the 
toxicity grade of the AEs observed, the relation to study intervention, the reason thereof, etc, 
in the medical record. If it is not possible to record this assessment in the medical record 
before the unblinding, the unblinding should not be delayed.
If unblinding has occurred, the circumstances around the unblinding (eg, date, reason, and 
person performing the unblinding) must be documented promptly, and the Sponsor Clinical 
Director notified as soon as possible.
Once an emergency unblinding or unblinding due to pregnancy (8.11.3) has taken place, the 
investigator, site personnel, and Sponsor personnel may be unblinded so that the appropriate 
follow-up medical care can be provided to the participant.
Participants whose treatment assignment has been unblinded by the investigator or medically 
qualified designee and/or nonstudy treating physician should continue to be monitored in the 
study.
Additionally, the investigator or medically qualified designee must go into the IRT system 
and perform the unblind in the IRT system to update drug disposition. If the emergency 
unblinding call center is not available for a given site in this study, the IRT system should be 
used for emergency unblinding if this is required for participant safety.
At the end of the study, random code/disclosure envelopes or lists and unblinding logs are to 
be returned to the Sponsor or designee.
8.1.11
Calibration of Equipment
The investigator or qualified designee has the responsibility to ensure that any device or 
instrument used for a clinical evaluation/test during a clinical study that provides information 
about inclusion/exclusion criteria and/or safety or efficacy parameters shall be suitably 
calibrated and/or maintained to ensure that the data obtained are reliable and/or reproducible. 
Documentation of equipment calibration must be retained as source documentation at the 
study site.
8.2
Efficacy Assessments
8.2.1
HIV-1 Testing
HIV-1 testing (Point-of-Care HIV test, HIV-1/HIV-2 Antibody/Antigen test, and RealTime 
PCR for HIV-1 RNA quantitation) will be conducted per the SoA (Section 1.3), and per a 
predefined algorithm for HIV-1 testing and diagnosis (Appendix 11).
Point-of-Care HIV testing should be performed using an FDA-approved kit prior to 
administering/dispensing study intervention and prior to randomization on Day 1. 
Participants who have a positive Point-of-Care test on Day 1 should not be randomized and 
should be considered as a screening failure. Plasma HIV-1 RNA quantification will be 
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performed using a RealTime PCR assay for all participants who have a positive Point-of-
Care test, including screening failures.
Regardless of how many Point-of-Care tests are performed, if any (one or more) Point-of-
Care test is positive, the full study-specified HIV testing algorithm should be followed.
After randomization, in a case where a participant has a positive Point-of-Care HIV test 
and/or HIV-1/HIV-2 Antibody/Antigen Test, study intervention must be withheld and an 
“HIV Infection Confirmation” visit (Section 1.3.3) completed as soon as possible on a 
subsequent visit day, and no later than within 14 days of the positive test.
After randomization, in a case where a participant has a positive Point-of-Care HIV test, PK 
samples (both plasma and dried blood) must be collected at that visit, regardless of the 
planned PK collection schedule. The collection of prespecified PK samples should also be 
conducted according to the collection schedule.
If the confirmatory HIV testing is negative, the participant may be able to resume study 
intervention after investigator consultation with the Sponsor.
If the confirmatory HIV testing is positive, the participant should complete a “Poststudy 
Intervention Follow-up” visit, and then continue with the monthly visits per Section 1.3.3 (if 
possible, the monthly visits should resume at the previous schedule). The participant should 
be referred to local medical providers for HIV care and treatment and the site should 
prioritize and facilitate this linkage to care. No poststudy antiretroviral therapy for the 
treatment of HIV infection will be provided by the Sponsor.
8.2.2
Whole Blood Collection for HIV-1 Resistance Testing
Whole blood and/or plasma samples collected per the SoA will be sent for genotypic and 
phenotypic HIV-1 drug resistance testing to assess resistance-associated substitutions as 
applicable during the study.
8.3
Safety Assessments
Details regarding specific safety assessments to be performed in this study are provided. The 
total amount of blood to be drawn over the course of the study, including approximate blood 
volumes drawn by visit and by sample type per participant, can be found in Appendix 2.
Planned time points for all safety assessments are provided in the SoA.
8.3.1
Physical Examinations
At the Screening visit a complete physical examination will be conducted by an investigator 
or medically qualified designee (consistent with local requirements) as per institutional 
standard. The complete physical examination will include examination of body systems 
(including, but not limited to, general appearance, skin, neck, eyes, ears, nose, throat, breast, 
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lungs, heart, abdomen, back, lymph nodes, extremities, and nervous system). Height and 
weight will also be measured and recorded.
At all subsequent visits a brief directed physical examination will be conducted by an 
investigator or medically qualified designee (consistent with local requirements) per 
institutional standard. Weight will also be measured and recorded.
Pelvic examination is not required at screening or subsequent visits unless symptom-directed.
8.3.2
Vital Signs
Vital signs will be measured after approximately 5 to 10 minutes of rest and will include 
temperature, pulse, respiratory rate, and systolic and diastolic blood pressure.
Note: Oral temperatures should be taken. If an oral temperature measurement is not 
possible, a temporal, tympanic, rectal, or axillary temperature measurement may be taken 
and should be recorded appropriately. 
8.3.3
Confirmation of Contraception and Pregnancy Testing
WOCBP are required to use contraception to prevent pregnancy during the study and will be 
tested for pregnancy at each visit as outlined in Section 1.3, Section 5.1, and Appendix 5.
Participants who are not on contraception at screening should be counseled about available 
options and directed to start their chosen method prior to randomization.
Participants should be asked at study visits per the SoA to verbally confirm their use of 
contraception since the prior visit, according to the Contraceptive Guidance in Appendix 5. 
Confirmation should be noted in the source documents for each visit.
Pregnancy testing using a highly sensitive urine hCG pregnancy test kit will be performed at 
the study site. In the event of a positive urine pregnancy test result, a confirmatory highly 
sensitive serum hCG pregnancy test will be performed. If a participant becomes pregnant, 
refer to Section 8.11.3. Once a continuing pregnancy has been confirmed, monthly urine 
pregnancy tests should be deferred until 1 month following the end of the pregnancy.
8.3.4
Sexually Transmitted Infections
Testing for GC/CT, syphilis, vaginal trichomonas infection, bacterial vaginosis, and HSV-2 
serology will be performed at Screening and at visits as described in the SoA (Sections 1.3.1, 
1.3.2, and 1.3.3). Participants with a confirmed STI diagnosed at screening or during the 
study should either be referred for treatment/management of the STI or provided treatment at 
the study site depending on antimicrobial availability and following applicable STI 
guidelines. Sites should report STIs as per local reporting requirements.
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8.3.5
Clinical Safety Laboratory Assessments
Refer to Appendix 2 for the list of clinical laboratory tests to be performed and to the SoA for 
the timing and frequency.
•
The investigator or medically qualified designee (consistent with local requirements) 
must review the laboratory report, document this review, and record any clinically 
relevant changes occurring during the study in the AE section of the CRF. The laboratory 
reports must be filed with the source documents. Clinically significant abnormal 
laboratory findings are those which are not associated with the underlying disease, unless 
judged by the investigator to be more severe than expected for the participant's condition.
•
All protocol-required laboratory assessments, as defined in Appendix 2, must be 
conducted in accordance with the laboratory manual and the SoA.
•
If laboratory values from nonprotocol-specified laboratory assessments performed at the 
institution’s local laboratory require a change in study participant management or are 
considered clinically significant by the investigator (eg, SAE or AE or dose 
modification), then the results must be recorded in the appropriate CRF (eg, SLAB).
•
For any laboratory tests with values considered clinically significantly abnormal during 
participation in the study or within 42 days after the last dose of study intervention, every 
attempt should be made to perform repeat assessments until the values return to normal or 
baseline or if a new baseline is established as determined by the investigator.
8.3.6
Review of Social Harm Events
Social harm events are negative events occurring as a result of being involved in a research 
study, as reported by a participant. Examples of social harm events include unfair treatment, 
lack of acceptance by family and/or employer, or conflict with an intimate partner due to 
participation in an HIV prevention study, or due to potential stigma of being “at risk” for 
HIV infection. Social harm events will be collected and reported on CRFs during regular 
visits and every reasonable effort will be made by study staff to provide appropriate care and 
counseling to the participant as necessary, and/or referral to appropriate resources for the 
safety and wellbeing of the participant. Social harm events will be followed for reporting of 
resolution status.
8.4
Adverse Events, Serious Adverse Events, and Other Reportable Safety Events
The definitions of an AE or SAE, as well as the method of recording, evaluating, and 
assessing causality of AE and SAE and the procedures for completing and transmitting AE, 
SAE, and other reportable safety event reports can be found in Appendix 3.
Adverse events, SAEs, and other reportable safety events will be reported by the participant 
(or, when appropriate, by a caregiver, surrogate, or the participant's legally authorized 
representative).
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The investigator and any designees are responsible for detecting, documenting, and reporting 
events that meet the definition of an AE or SAE as well as other reportable safety events. 
Investigators need to document if an SAE was associated with a medication error, misuse, or 
abuse. Investigators remain responsible for following up AEs, SAEs, and other reportable 
safety events for outcome according to Section 8.4.3.
The investigator, who is a qualified physician, will assess events that meet the definition of 
an AE or SAE as well as other reportable safety events with respect to seriousness, 
intensity/toxicity and causality.
8.4.1
Time Period and Frequency for Collecting AE, SAE, and Other Reportable 
Safety Event Information
All AEs, SAEs, and other reportable safety events that occur after the participant provides 
documented informed consent/assent, but before intervention randomization, must be 
reported by the investigator if the participant is receiving placebo run-in or other run-in 
treatment, if the event causes the participant to be excluded from the study, or is the result of 
a protocol-specified intervention, including but not limited to washout or discontinuation of 
usual therapy, diet, or a procedure.
From the time of intervention randomization through 42 days following cessation of study 
intervention, all AEs, SAEs, and other reportable safety events must be reported by the 
investigator.
Additionally, any SAE brought to the attention of an investigator at any time outside of the 
time period specified in the previous paragraph must be reported immediately to the Sponsor 
if the event is considered related to study intervention.
For infants born to participants who become pregnant (during Part 1 and Part 2) and 
consent/assent to infant safety data collection, SAEs (including perinatal HIV-1 infection) 
occurring through 1-year of age must be reported by the investigator to the Sponsor within 24 
hours of learning of the event. This does not apply to infants born to participants who 
become pregnant in Part 3.
Investigators are not obligated to actively seek AEs or SAEs or other reportable safety events 
in former study participants. However, if the investigator learns of any SAE, including a 
death, at any time after a participant has been discharged from the study, and he/she 
considers the event to be reasonably related to the study intervention or study participation, 
the investigator must promptly notify the Sponsor.
All initial and follow-up AEs, SAEs, and other reportable safety events will be recorded and 
reported to the Sponsor or designee within the time frames as indicated in Table 3.
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Table 3
Reporting Time Periods and Time Frames for Adverse Events and Other 
Reportable Safety Events
Type of Event
Reporting Time 
Period:
Consent to 
Randomization/ 
Allocation
Reporting Time 
Period:
Randomization/ 
Allocation 
through Protocol-
specified Follow-
up Period
Reporting Time 
Period:
After the Protocol-
specified Follow-up 
Period
Time Frame to 
Report Event 
and Follow-up 
Information to 
Sponsor:
NSAE
Report if:
- due to protocol-
specified 
intervention
- causes exclusion
- participant is 
receiving placebo 
run-in or other run-
in treatment
Report all
Not required
Per data entry 
guidelines
SAE
Report if:
- due to protocol-
specified 
intervention
- causes exclusion
- participant is 
receiving placebo 
run-in or other run-
in treatment
Report all
Report if:
- drug/vaccine related.
(Follow ongoing to 
outcome)
Within 24 hours 
of learning of 
event
Pregnancy/Lactation 
Exposure
Report if:
- participant has 
been exposed to 
any protocol-
specified 
intervention (eg, 
procedure, washout 
or run-in treatment 
including placebo 
run-in)
Exception: A 
positive pregnancy 
test at the time of 
initial screening is 
not a reportable 
event unless the 
participant has 
received study 
intervention.
Report all
Previously reported –
Follow to 
completion/termination
; report outcome
Within 24 hours 
of learning of 
event
ECI (require 
regulatory reporting)
Report if:
- due to 
intervention
- causes exclusion
Report
- Potential DILI
- Require 
regulatory 
reporting
Not required
Within 24 hours 
of learning of 
event
ECI (do not require 
regulatory reporting)
Report if:
- due to 
intervention
- causes exclusion
Report
- non-DILI ECIs 
and those not 
requiring 
regulatory 
reporting
Not required
Within 5 calendar 
days of learning 
of event
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Type of Event
Reporting Time 
Period:
Consent to 
Randomization/ 
Allocation
Reporting Time 
Period:
Randomization/ 
Allocation 
through Protocol-
specified Follow-
up Period
Reporting Time 
Period:
After the Protocol-
specified Follow-up 
Period
Time Frame to 
Report Event 
and Follow-up 
Information to 
Sponsor:
Cancer
Report if:
- due to 
intervention
- causes exclusion
Report all
Not required
Within 5 calendar 
days of learning 
of event
(unless serious)
Overdose
Report if:
- receiving placebo 
run-in or other run-
in medication 
Report all
Not required
Within 5 calendar 
days of learning 
of event
DILI=drug-induced liver injury; ECI=event of clinical interest; NSAE=nonserious adverse event; SAE=serious adverse 
event.
8.4.2
Method of Detecting AEs, SAEs, and Other Reportable Safety Events
Care will be taken not to introduce bias when detecting AEs and/or SAEs and other 
reportable safety events. Open-ended and nonleading verbal questioning of the participant is 
the preferred method to inquire about AE occurrence.
8.4.3
Follow-up of AE, SAE, and Other Reportable Safety Event Information
After the initial AE/SAE report, the investigator is required to proactively follow each 
participant at subsequent visits/contacts. All AEs, SAEs, and other reportable safety events, 
including pregnancy and exposure during breastfeeding, ECIs, cancer, and overdose will be 
followed until resolution, stabilization, until the event is otherwise explained, or the 
participant is lost to follow-up (as defined in Section 7.3). In addition, the investigator will 
make every attempt to follow all nonserious AEs that occur in randomized participants for 
outcome. Further information on follow-up procedures is given in Appendix 3.
8.4.4
Regulatory Reporting Requirements for SAE
Prompt notification (within 24 hours) by the investigator to the Sponsor of SAE is essential 
so that legal obligations and ethical responsibilities towards the safety of participants and the 
safety of a study intervention under clinical investigation are met.
The Sponsor has a legal responsibility to notify both the local regulatory authority and other 
regulatory agencies about the safety of a study intervention under clinical investigation. The 
Sponsor will comply with country-specific regulatory requirements and global laws and 
regulations relating to safety reporting to regulatory authorities, IRB/IECs, and investigators.
Investigator safety reports must be prepared for SUSARs according to local regulatory 
requirements and Sponsor policy and forwarded to investigators as necessary.
An investigator who receives an investigator safety report describing an SAE or other 
specific safety information (eg, summary or listing of SAE) from the Sponsor will file it 
along with the IB and will notify the IRB/IEC, if appropriate according to local requirements.
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8.4.5
Pregnancy and Exposure During Breastfeeding
Although pregnancy and infant exposure during breastfeeding are not considered AEs, any 
pregnancy or infant exposure during breastfeeding in a participant (spontaneously reported to 
the investigator or their designee) that occurs during the study are reportable to the Sponsor.
All reported pregnancies must be followed to the completion/termination of the pregnancy.
Any pregnancy complication will be reported as an AE or SAE.
The medical reason (example: maternal health or fetal disease) for an elective termination of 
a pregnancy will be reported as an AE or SAE. Prenatal testing showing fetus will be born 
with severe abnormalities/congenital anomalies that leads to an elective termination of a 
pregnancy will be reported as an SAE for the fetus.
Pregnancy outcomes of ectopic pregnancy, spontaneous abortion, missed abortion, benign 
hydatidiform mole, blighted ovum, fetal death, intrauterine death, miscarriage, and stillbirth 
must be reported as serious events (Important Medical Events). If the pregnancy continues to 
term, the outcome (health of infant) must also be reported.
For infants born to participants who become pregnant (during Part 1 and Part 2) and 
consent/assent to infant safety data collection, SAEs (including perinatal HIV-1 infection) 
occurring through 1-year of age must be reported by the investigator to the Sponsor within 24 
hours of learning of the event. The 1-year safety follow-up does not apply to infants born to 
participants who became pregnant in Part 3.
The clinical management of pregnancy (Section 8.11.3) and breastfeeding (Section 8.11.3.1 
and Section 8.11.3.2) provide details on management of confirmed pregnancy and 
breastfeeding options for participants postpartum.
8.4.6
Disease-related Events and/or Disease-related Outcomes Not Qualifying as 
AEs or SAEs
This section is not applicable to this study.
8.4.7
Events of Clinical Interest
Selected serious and nonserious AEs are also known as ECIs and must be reported to the 
Sponsor.
Events of clinical interest for this study include:
1.   An elevated AST or ALT laboratory value that is greater than or equal to 3X the ULN
and an elevated total bilirubin laboratory value that is greater than or equal to 2X the 
ULN and, at the same time, an alkaline phosphatase laboratory value that is less than 2X 
the ULN, as determined by way of protocol-specified laboratory testing or unscheduled 
laboratory testing.*
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*Note: These criteria are based on available regulatory guidance documents. The purpose 
of the criteria is to specify a threshold of abnormal hepatic tests that may require an 
additional evaluation for an underlying etiology. The study-site guidance for assessment 
and follow-up of these criteria can be found in the Investigator Study File Binder (or 
equivalent).
2.   A lymphocyte count that meets DAIDS criteria for Grade 3 (<500 cells/mm3) or higher 
grade as determined by way of protocol-specified laboratory testing or unscheduled 
laboratory testing at any time during the study.
3.   A CD4+ T-cell count that meets DAIDS criteria for Grade 3 (<200 cells/mm3) or higher 
grade as determined by way of protocol-specified laboratory testing or unscheduled 
laboratory testing at any time during the study.
8.5
Treatment of Overdose
In this study, an overdose is >1 dose of ISL or matching placebo within 14 days, or >2 doses 
of FTC/TDF or matching placebo on any single calendar day.
Decisions regarding dose interruptions will be made by the investigator in consultation with 
the Sponsor Clinical Director based on the clinical evaluation of the participant.
8.6
Pharmacokinetics
Note: PK samples will not be collected in Part 3 of the study.
8.6.1
Blood (Plasma) Collection for PK
Note: PK samples will not be collected in Part 3 of the study.
Venous blood samples will be collected for measurement of ISL and TFV. Bioanalysis of 
TFV blood (plasma) samples will be performed in selected subset of study participants. 
Sample collection, storage, and shipment instructions for plasma samples will be provided in 
a laboratory or operations manual.
PK samples will be collected from all participants as outlined in Table 4 and Table 12. The 
exact time of dosing of study intervention prior to the sample collection and the time of PK 
sample collection will be recorded on the appropriate source documentation.
Additional sparse plasma PK samples will be collected from participants randomized to ISL 
who become pregnant and consent to continue open-label ISL during Part 1 only (Section 
8.6.4).
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Table 4
Collection of Plasma PK Samples
Study Visit (Day/Month)
Time Relative to Dosea, b
Day 1
Predose
Month 1
One sample to be collected predose
Month 3
One sample to be collected at any time during the visit
Month 6
One sample to be collected predose
Month 12
One sample to be collected at any time during the visit
Month 18
One sample to be collected at any time during the visit
Month 24
One sample to be collected predose
Month 30
One sample to be collected predose
Month 36/EOT
One sample to be collected at any time during the visit
EOT=end of treatment (all participants may not complete 36 months because this is a case-driven study);
PK=pharmacokinetic.
Note: PK samples will not be collected in Part 3 of the study.
a
Indicates time relative to monthly oral tablet administration. Not applicable in Part 2.
b
During Part 2, PK sample collection is irrespective of timing of dose.
Note: PK samples will not be collected in Part 3 of the study.
8.6.2
Blood (Plasma) for Investigational PK
Note: PK samples will not be collected in Part 3 of the study.
Blood (plasma) for investigational PK will be collected from all participants as outlined in 
the SoA (Section 1.3, Table 12 and Table 13). Analysis of the investigational samples will be 
triggered by the Sponsor, as needed. For Part 1, the investigational PK sample will be 
collected predose at Month 2 and at any time during the visit at Months 9, 15, 21, 27, and 33. 
For Part 2, investigational PK samples may be collected at any time during the visit.
Sample collection, storage, and shipment instructions for plasma samples will be provided in 
a laboratory or study operations manual.
8.6.3
Dried Blood Collection for PK
Note: PK samples will not be collected in Part 3 of the study.
The VAMS blood collection technique will be used to obtain dried blood. Further 
instructions on use of device, which follow VAMS blood collection technique will be 
provided in the laboratory/operations manual. Timepoints for the collection of these samples 
are provided in Table 5 and Table 12.
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Additional sparse dried blood samples will be collected from participants randomized to ISL 
who become pregnant and consent to continue open-label ISL (Section 8.6.4) in Part 1 only.
Table 5
Collection of Dried Blood PK Samples
Study Visit (Day/Month)
Time Relative to Dosea, b
Day 1
Predose
Month 1
One sample to be collected predose
Month 2
One sample to be collected predose
Month 3
One sample to be collected at any time during the visit
Month 6
One sample to be collected predose
Month 12
One sample to be collected at any time during the visit
Month 18
One sample to be collected at any time during the visit
Month 24
One sample to be collected predose
Month 30
One sample to be collected predose
Month 36/EOT
One sample to be collected at any time during the visit
EOT=end of treatment (all participants may not complete 36 months because this is a case-driven study).
Note: PK samples will not be collected in Part 3 of the study.
a
Indicates time relative to monthly oral tablet administration. Not applicable in Part 2.
b
During Part 2, PK sample collection is irrespective of timing of dose.
Note: PK samples will not be collected in Part 3 of the study.
8.6.4
Collection of PK Samples in Participants Who Become Pregnant and 
Continue ISL (Only Applicable for Part 1)
Note: PK samples will not be collected in Part 3 of the study.
Participants who were randomized to ISL and consent to continue ISL during pregnancy will 
undergo additional PK sampling (participants who were randomized to FTC/TDF do not 
need additional PK sampling, and should continue to follow the sampling schedule in SoA 
1.3.1). These PK samples will be used to evaluate how physiological changes that occur 
during pregnancy may affect ISL PK. The timing PK sampling relative to ISL dosing may 
vary based on trimester of pregnancy and the timing of collections must be recorded on the 
appropriate source documentation. Refer to Section 1.3.4 and Table 6 for detailed time points 
relative to ISL dosing.
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Table 6
Collection of Population PK Samples in Participants Who Become Pregnant and 
Continue ISL
Gestational Age
Study 
Visita
Time Relative to Dosea
PK Sample Types
≤12 Weeks
P1

One sample collected predose

One sample collected 0.5-2 hours postdose

Plasma

Dried blood
(using VAMS)
P2

One sample collected at any time during the visit
13-26 Weeks
P3

One sample collected predose

One sample collected 0.5-2 hours postdose
P4

One sample collected at any time during the visit
≥27 Weeks
P5

One sample collected predose

One sample collected 0.5-2 hours postdose
P6

One sample collected at any time during the visit
Postpartum
P7

One sample collected predose

One sample collected 0.5-2 hours postdose
PK=pharmacokinetic; VAMS=volumetric absorptive microsampling.
a
Study visits P1, P3, P5, and P7 should coincide with 1 planned monthly visit during the time period (See Section 
1.3.1). Study visits P2, P4, and P6 should occur approximately 2 weeks after study visits P1, P3 and P5, 
respectively. See Section 1.3.4 for more details.
Note: PK samples will not be collected in Part 3 of the study.
8.6.5
Collection of PK Samples in Participants Who Discontinue Study Intervention 
Early, Withdraw Consent/Assent, or Have a Positive HIV-1 Test
Note: PK samples will not be collected in Part 3 of the study.
Blood (plasma) PK and dried blood PK samples should be collected at the discontinuation 
visit, withdrawal visit, and/or HIV-1 infection confirmation visit, as applicable. For 
participants who do not withdraw consent/assent (ie, continuing to have study visits), both 
types of PK samples will also be collected monthly for 3 months, after which the participant 
should resume the PK schedule outlined in Section 1.3.1. All samples are to be collected at 
any time during the visit. For participants who have a positive HIV-1 test result, both types of 
PK samples should be collected at the time of the HIV-1 infection confirmation visit, the first 
3 monthly follow-up visits, and then every 3 months thereafter.
8.7
Pharmacodynamics
Pharmacodynamic parameters will not be evaluated in this study.
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8.8
Biomarkers
Collection of the following samples for biomarker research will be per the SoA (Section 1.3) 
and Appendix 2.
8.8.1
Planned Genetic Analysis Sample Collection
The planned genetic analysis sample should be drawn for planned analysis of the association 
between genetic variants in DNA and drug response. This sample will not be collected at the 
site if there is either a local law or regulation prohibiting collection, or if the IRB/IEC does 
not approve the collection of the sample for these purposes. If the sample is collected, 
leftover extracted DNA will be stored for future biomedical research if the participant 
provides documented informed consent/assent for future biomedical research consent/assent. 
If the participant provides consent/assent for future biomedical research, the following 
specimens will be obtained as part of future biomedical research.
Sample collection, storage, and shipment instruction for planned genetic analysis samples 
will be provided in the operations/laboratory manual.
8.8.2
Renal Biomarkers
Blood samples will be collected to evaluate renal function as measured by key indicators 
such as serum creatinine and serum cystatin-C (Appendix 2); and creatinine clearance 
(Appendix 9).
8.9
Future Biomedical Research Sample Collection
If consent/assent is provided for future biomedical research, the following specimens will be 
obtained as part of future biomedical research:
•
Leftover DNA for future biomedical research
•
Whole blood for future biomedical research
8.10
Medical Resource Utilization and Health Economics
Medical Resource Utilization and Health Economics are not evaluated in this study.
8.11
Visit Requirements
Visit requirements are outlined in Section 1.3. Specific procedure-related details are provided 
in Section 8.
8.11.1
Screening/Rescreening
Approximately 45 days prior to intervention randomization, potential participants will be 
evaluated to determine that they fulfill the entry requirements as set forth in Section 5. 
Screening procedures may be repeated after consultation with the Sponsor. Individuals with
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symptoms that could be consistent with acute retroviral syndrome at the time of Screening 
may proceed with screening procedures, including laboratory and HIV RNA testing, but will 
be asked to return after symptoms have resolved (and within 1 month) for repeat laboratory 
testing, as needed, and referred for local HIV testing and/or treatment as deemed appropriate.
The date of the participant’s most recent HIV test prior to screening will be collected, if 
known.
Rescreening
If the screening window has been exceeded, after approval from the Sponsor, participants 
may be allowed to rescreen 1 time. Once a participant has started the rescreening process, a 
new Screening period (ie, an additional ≤45-day window) will begin.
The following assessments must be repeated for participants who are rescreened:
•
Vital signs, weight, and directed physical examination
•
Review medical history and prior/concomitant medication for new information
•
All laboratory assessments
•
Review of AEs
If the informed consent/assent has been updated, participants should be reconsented before 
rescreening. If no updates have been made, documented informed consent/assent during the 
original Screening period should be reviewed with the participant and a verbal reconsent to 
continue in the study should be documented.
8.11.2
Treatment Period
All procedures and their timing should be completed as per the SoA (Section 1.3.1).
8.11.2.1
Off-site Visits
Visits are to be completed at the study site unless otherwise noted in Section 1.3. Under 
certain circumstances, in lieu of a participant traveling to the study site, an at home (or 
community-based location) visit by a health care provider (eg, site personnel, home health 
care company, visiting nurse, etc.) may be appropriate. Upon Sponsor approval (where 
available and when permitted by local regulations and IRB/IEC), off-site services may be 
used to collect study data and samples and dispense study interventions at any visit per the 
SoA (Section 1.3) after a participant is enrolled. Additionally, in such cases, the investigator 
should contact the participant by telephone on the same day as the off-site visit, or as soon as 
possible, to perform an investigator AE assessment.
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8.11.3
Clinical Management of Participants Who Become Pregnant
8.11.3.1
Clinical Management of Participants Who Become Pregnant - Part 1
In the event of a first positive urine pregnancy test, the following steps should be taken with 
the participant (Figure 4):
•
Hold administration/dispensation of all study intervention.
•
Obtain a venous blood sample for confirmatory testing of serum hCG.
•
Give the participant the option to receive open-label FTC/TDF while a continuing 
pregnancy is being confirmed. If the participant consents to receive open-label FTC/TDF, 
dispense a locally sourced 1-month supply of open-label FTC/TDF. Note that open-label 
FTC/TDF is considered to be an NIMP during this period and should be recorded as a 
concomitant medication on the appropriate eCRF. In this scenario the FTC/TDF will not 
be dispensed through the IRT system.
•
If the serum hCG test is negative and the participant is able to return to the site within the 
permitted window for that visit, resume regular dispensing of blinded study intervention.
-
If the serum hCG test is positive, the participant should return for her next regular 
monthly study visit, as follows below.
•
Participant returns for her next regular monthly study visit (approximately 28 days later) 
and a urine pregnancy test is repeated.
-
If urine pregnancy test is negative, return to regular dispensing of blinded study 
intervention.
-
If urine pregnancy test is positive, the participant should be unblinded and consented, 
as below. If, however, the urine pregnancy test is positive, but the participant reports 
menses or termination or loss of pregnancy since her last visit, or asserts a planned 
termination of the pregnancy within the next month, the above procedures should be 
repeated and a second month supply of open-label FTC/TDF should be dispensed. In 
these cases, the investigational product should not be resumed until serum hCG 
decreases to nonpregnant levels. Note that open-label FTC/TDF is considered to be 
an NIMP during this period and should be recorded as a concomitant medication on 
the appropriate eCRF. The FTC/TDF will not be dispensed through the IRT system.
Note: At each and every visit where there is a positive urine pregnancy test, a serum hCG 
test should be sent.
Note: A participant considered to have a nonviable pregnancy (eg, ectopic pregnancy or 
retained products of conception) may be allowed to resume blinded study intervention after 
consultation with the Sponsor.
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Figure 4
Pregnancy Confirmation Flow Chart (Only applicable for Part 1)
FTC/TDF=emtricitabine/tenofovir disoproxil (including TRUVADATM and all generic versions); hCG=human 
chorionic gonadotropin.
a
Participants are not required, but strongly encouraged to receive open-label FTC/TDF while blinded study intervention 
is held pending confirmation of continuing pregnancy.
b
Please refer to Figure 5 for next management steps.
Once a continuing pregnancy is confirmed (Figure 4), the participant must be unblinded to 
identify the study intervention to which they were randomly assigned, and monthly urine 
pregnancy tests should be deferred until 1 month following the end of the pregnancy. The 
participant will be counseled by the investigator or medically qualified designee regarding 
the potential risks and benefits of continuing and discontinuing study intervention. The 
participant, investigator, and Sponsor should assess the appropriateness of continuing study 
intervention based on available data and local standard of care guidelines. The final decision 
to continue study intervention (where allowed by local regulations) will be made by the 
participant and the investigator in consultation with the antenatal care provider. If the 
participant would like to consult with an antenatal care provider after unblinding and before 
making a decision about treatment, they may continue on FTC/TDF open-label until after the 
discussion takes place and a decision is made. The participant will provide documented 
consent and indicate their decision (Section 8.1.1.3.2). The following options will be 
available to participants with a continuing pregnancy (Figure 5):
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•
Continue Study Intervention: Participants with a confirmed, continuing pregnancy and 
consent/assent to continue study intervention (Section 8.1.1.3.2) should complete all
remaining protocol-specified visits and procedures per the regular schedule in the SoA 
(Section 1.3.1).
-
Participants who were randomized to ISL may choose to remain on ISL (open-label) 
or opt to switch to FTC/TDF (open-label) for the duration of the pregnancy.
◦
Those who choose to remain on ISL will have additional assessments as outlined 
in the SoA for participants who become pregnant and remain on ISL (Section 
1.3.4 and Section 8.6.4).
-
Participants who were randomized to FTC/TDF may remain on FTC/TDF.
-
FTC/TDF and ISL are dispensed through the IRT system and recorded as study 
intervention on the appropriate eCRF.
-
Participants who choose to breastfeed should follow Section 8.11.3.1.
•
Interrupt Study Intervention: If the decision is made to interrupt study intervention at 
any time during pregnancy, the participant should not be withdrawn from the study. The 
participant will continue with the protocol-specified visits per the regular schedule in the 
SoA (Section 1.3.1). Participants may resume study intervention at any time during or 
after pregnancy after consultation with the investigator and Sponsor. Participants 
resuming any study intervention after an interruption due to pregnancy should be 
reconsented (Section 8.1.1.3.2).
•
Withdraw Consent/Assent: At any time, participants who become pregnant may choose 
to withdraw consent/assent for the study. The Early Withdrawal from Study visit should 
be completed (Section 8.11.9).
Figure 5
Clinical Management of Participants Who Become Pregnant (Only applicable for 
Part 1)
FTC/TDF=emtricitabine/tenofovir disoproxil (including TRUVADATM and all generic versions); ISL=islatravir.
a
Processes following completion of steps in Figure 4.
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Active linkage to antenatal care will be made for participants who become pregnant. The 
investigator should review records from antenatal care at each study visit (see Sections 1.3.1 
and 1.3.4 for those who remain on ISL). The participant’s medical records will be collected 
and reviewed by the study site for:
•
Clinical safety laboratory assessments
•
Estimation of gestational age
•
Results of ultrasound(s)
•
Any complications associated with the pregnancy
•
Outcome of pregnancy
•
Information that could indicate congenital abnormalities
The site will also confirm breastfeeding status with the participant.
All reported pregnancies will be followed to the completion or termination of the pregnancy 
(Section 8.4.5). For any participant who is pregnant at the last scheduled study visit and 
reconsents to continue with study intervention (Section 6.7), the pregnancy will be followed 
to completion/termination with outcome reported in this original study. Infants born to these 
participants will have safety data collection through approximately 1-year of age (Section 
8.11.4). Exposure to antiretroviral therapy during pregnancy will be reported by the site to 
relevant registries.
8.11.3.1.1
Clinical Management of Participants Who Choose to Breastfeed – Part 1
Participants who choose to breastfeed will not be permitted to continue ISL, but may receive 
FTC/TDF while breastfeeding after obtaining documented informed consent/assent to 
continuing study participation. Options for breastfeeding and study intervention during and 
after breastfeeding are shown in Figure 6.
Figure 6
Clinical Management of Participants Who Choose to Breastfeed – Part 1
FTC/TDF=emtricitabine/tenofovir disoproxil (including TRUVADATM and all generic versions).
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8.11.3.2
Clinical Management of Participants Who Become Pregnant – Part 2 and 
Part 3
Procedures for Part 2:
In the event of a first positive urine pregnancy test, the following steps should be taken with 
the participant (Figure 7):
•
Obtain a venous blood sample for confirmatory testing of serum hCG.
•
Give the participant the option to:
-
Consent to continue to receive PrEP therapy with FTC/TDF while the pregnancy is 
being confirmed/during a pregnancy. If the participant consents to receive PrEP 
therapy with FTC/TDF, dispense accordingly.
-
Consent to not receive PrEP therapy with FTC/TDF, but remain in the study.
-
Withdraw from the study.
Figure 7
Pregnancy Confirmation Flow Chart (Only applicable for Part 2)
Active linkage to antenatal care will be made for participants who become pregnant. The 
investigator should review records from antenatal care at each study visit (see Section 1.3.1). 
The participant’s medical records will be collected and reviewed by the study site for:
•
Clinical safety laboratory assessments
•
Estimation of gestational age
•
Results of ultrasound(s)
•
Any complications associated with the pregnancy
•
Outcome of pregnancy
•
Information that could indicate congenital abnormalities
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The site will also confirm breastfeeding status with the participant.
All reported pregnancies will be followed up to the completion or termination of the 
pregnancy (Section 8.4.5). Exposure to antiretroviral therapy during pregnancy will be 
reported by the site to relevant registries.
For any participant who is pregnant at the last scheduled study visit and reconsents to 
continue with FTC/TDF (Section 6.7), the pregnancy will be followed to 
completion/termination with outcome reported in this original study. Infants born to these 
participants will have safety data collection through approximately 1-year of age (Section 
8.11.4). Exposure to antiretroviral therapy during pregnancy will be reported by the site to 
relevant registries.
Procedures for Part 3:
In the event of a first positive urine pregnancy test, the following steps should be taken with 
the participant (Figure 8):
•
Obtain a venous blood sample for confirmatory testing of serum hCG.
•
Give the participant the option to:
-
Consent to continue to receive PrEP therapy with FTC/TDF while the pregnancy is 
being confirmed/during a pregnancy. If the participant consents to receive PrEP 
therapy with FTC/TDF, dispense accordingly.
-
Consent to not receive PrEP therapy with FTC/TDF, but remain in the study.
-
Withdraw from the study.
Figure 8
Pregnancy Confirmation Flow Chart (Only applicable for Part 3)
Active linkage to antenatal care will be made for participants who become pregnant.
All reported pregnancies will be followed up to the completion or termination of the 
pregnancy (Section 8.4.5). Exposure to antiretroviral therapy during pregnancy will be 
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reported by the site to relevant registries. Any pregnancy-related complication should be 
reported as an AE.
For any participant who is pregnant at the last scheduled study visit and reconsents to 
continue with FTC/TDF (Section 6.7), the pregnancy will be followed to 
completion/termination with outcome reported in this original study. Infants born to these 
participants may have safety data collection through approximately 1 year of age (Section 
8.11.4) for reporting by the site to relevant registries. Exposure to antiretroviral therapy 
during pregnancy will be reported by the site to relevant registries.
8.11.3.2.1
Clinical Management of Participants Who Choose to Breastfeed – Part 2 
and Part 3
Participants who choose to breastfeed may receive FTC/TDF while breastfeeding after 
obtaining documented informed consent/assent to continue study participation. Options for 
receiving FTC/TDF during and after breastfeeding are shown in Figure 9.
Figure 9
Clinical Management of Participants Who Choose to Breastfeed – Part 2 & Part 3
8.11.4
Infant Safety Data Collection
Procedures for Part 1 and Part 2:
For participants who become pregnant while receiving study intervention, or within 42 days 
after the last dose of study intervention, the data in Section 8.11.4.1 should be obtained by 
the site within 12 weeks of each timepoint and entered the appropriate eCRF and source 
documentation. Study staff should also obtain results from any ultrasound studies performed 
per local standard of care.
Data for SAEs, including HIV-1 infection, reported for the infant will be collected as per 
Section 8.4.1 and should be reviewed at the participant’s scheduled study visits that occur 
during this time.
If the infant’s mother has completed her last scheduled study visit and consents to continue 
study intervention provided by the Sponsor (Section 6.7) before the completion of the 
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infant’s 1-year follow-up, the infant will complete the 1-year follow-up with data reported 
within this original study.
8.11.4.1
Schedule of Activities: Infant Safety Collection
Timepoint
At Birtha
1-Year After Birtha,b
Visit Name
N/A
Infant Follow-up-1
Administrative and Safety Procedures
Infant informed consent/assent
Xc
Gestational age at birth
X
Apgar scores
X
Length
X
X
Weight
X
X
Head Circumference
X
X
Directed pediatric examination
X
Concomitant medications reviewd
X
X
Review infant SAEse
X
HIV=human immunodeficiency virus; N/A=not applicable; SAE=serious adverse event.
a
Data should be collected and entered at the site within 12 weeks of each timepoint.
b
If a participant withdraws from the study, data from 1-year after birth should be collected at the time of withdrawal.
c
Consent for infant safety data collection can be obtained from the mother at any time after confirmation of 
continuing pregnancy.
d
Concomitant medications taken by the infant (for SAEs or HIV postpartum prophylaxis).
e
Collect SAEs, including any congenital anomalies and HIV infection in the infant, per Section 8.4.1 and review at 
participant’s regularly scheduled study visits.
Procedures for Part 3:
Aside from reporting pregnancy outcomes, no other infant follow-up procedures are required 
for pregnancies that occur in Part 3. Standard AE reporting requirements per Section 8.4 will 
apply.
8.11.5
Participants Who Discontinue Study Intervention
A participant must be discontinued from study intervention for any of the reasons listed in 
Section 7.1, but should be continued to be monitored during the study.
For discontinuations not related to pregnancy, including participants who discontinue study 
intervention due to decreased lymphocyte or CD4+ T-cell counts as described in Section 7.1, 
the participant should complete an Early Discontinuation of Treatment visit (Section 1.3.2) 
and be encouraged to complete remaining visits and assessments per the regular schedule in 
the SoA (Section 1.3.1), with the exception of dispensing study intervention.
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If a participant becomes pregnant (has a positive serum pregnancy test) while receiving study 
intervention, the participant, investigator, and Sponsor will assess if the participant should 
continue study intervention (Section 8.11.3).
8.11.6
Participants Who Withdraw Consent/Assent
Participants who withdraw from the study should be encouraged to complete all applicable 
activities scheduled for the Early Withdrawal from Study visit (Section 1.3.2) at the time of 
withdrawal.
If the participant withdraws consent/assent within 28 days of completing the Early 
Discontinuation of Treatment visit (Section 1.3.2), the Early Withdrawal from Study visit is 
not required.
8.11.7
Follow-up Phone Calls
Participants who complete the protocol-specified treatment period or who discontinue study 
intervention due to seroconversion will be contacted via phone call at 14 days and 42 days 
post last dose of study intervention per the SoA (Sections 1.3.1 and 1.3.3).
The investigator is responsible for ensuring that all telephone contacts are performed by a 
staff member who is a health care professional qualified to elicit a discussion with the 
participant that will lead to a clinically meaningful disclosure on the participant’s well-
being. Telephone contacts are to be documented in the source documents and the investigator 
must review the entry within 2 days. However, if the participant reports any clinically 
concerning events (eg, SAEs, ECIs) during a telephone call, then the investigator must be 
promptly notified. The investigator will contact the participant to determine if a clinic visit is 
warranted.
If the participant cannot be reached by telephone at the regularly scheduled time or misses a 
visit, the site should make at least 3 attempts (in addition to the initial phone call) to contact 
the participant within 48 hours of the missed scheduled time. The participant’s reliable 
contact person should be called if attempts to contact the participant are not successful. All 
phone contacts and attempts should be recorded in source documents.
9
STATISTICAL ANALYSIS PLAN
Note: As of Amendment-04, various subsections in Section 9 have been updated to clarify, 
which analyses will be performed and which will no longer be performed/applicable. Specific 
notes in relevant subsections have been inserted. No efficacy analyses will be performed. 
Safety data will be evaluated both for the blinded treatment period for most safety endpoints, 
and for the entire duration of the study to evaluate the recovery of total lymphocyte counts.
Note: Blinded study intervention administration (Part 1) has been stopped. During Part 2, all 
participants were switched to PrEP therapy with FTC/TDF. No new participants will be 
screened or randomized during Part 2. The participant, the investigator, and Sponsor 
personnel or delegate(s) directly involved in the clinical monitoring or evaluation of 
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participants will remain blinded to the participants’ original randomized study intervention 
group. Sponsor personnel or delegate(s) not directly involved in clinical monitoring or 
evaluation of the participants will be unblinded to the participants’ original randomized 
study intervention group. .During Part 3, ongoing participants will continue to receive open-
label PrEP therapy with FTC/TDF. No new participants will be screened or randomized 
during Part 3. Participants, investigators, and all Sponsor personnel will be unblinded to the 
participants’ original randomized study intervention group in Part 3.
This section outlines the statistical analysis strategy and procedures for the study. If, after the 
study has begun, but prior to any unblinding, changes are made to primary and/or key 
secondary hypotheses, or the statistical methods related to those hypotheses, then the 
protocol will be amended (consistent with ICH Guideline E-9). Changes to exploratory or 
other nonconfirmatory analyses made after the protocol has been finalized, but prior to 
unblinding, will be documented in an sSAP and referenced in the CSR for the study. Post hoc 
exploratory analyses will be clearly identified in the CSR. Other planned analyses (eg, those 
specific to the analysis of PK data), will be documented in separate analysis plans.
9.1
Statistical Analysis Plan Summary
Note: As of Amendment-04, no efficacy analyses will be performed. Safety data will be 
evaluated for the blinded treatment period for applicable safety endpoints, and for the entire 
duration of the study to evaluate the recovery of total lymphocyte counts. All safety data will 
be summarized descriptively.
Key elements of the statistical analysis plan are summarized below; the comprehensive plan 
is provided in Sections 9.2 through 9.12.
Study Design Overview
A Phase 3, Randomized, Active-Controlled, Double-blind Clinical 
Study to Evaluate the Efficacy and Safety of Oral Islatravir Once-
Monthly as Preexposure Prophylaxis in Cisgender Women at High Risk 
for HIV-1 Infection
Treatment Assignment
A total of ~4500 participants will be randomized, stratified by site and 
age, in a 1:1 ratio to receive either ISL QM and placebo matched to 
FTC/TDF QD or FTC/TDF QD and placebo matched to ISL QM.
Analysis Populations
Efficacy: mFAS
Safety: APaT
Primary Endpoint(s)
1.   Confirmed HIV-1 infection
2.   AEs and AEs leading to discontinuation of study intervention
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Statistical Methods for Key 
Efficacy Analyses
The primary hypothesis will be evaluated by comparing ISL QM to 
FTC/TDF QD with respect to incidence rate per year of confirmed
HIV-1 infections. This comparison is done in terms of Prevention 
Efficacy (PE). The p-value for testing the null hypothesis that PE ≤0% 
versus the alternative that PE >0%, as well as the 95% CI estimate of 
PE, will be computed using the exact binomial method proposed by 
Chan and Bohidar[Chan, I. S. F. and Bohidar, N. R. 1998]. The 
statistical criterion for success requires that the lower bound of the 2-
sided 95% CI for PE be >0%. If the target number of events are not
observed by the time the last participant randomized has been in the
study for approximately 2 years, consideration may be given to stopping 
the study early and conducting the analyses with all of the data 
collected up to that point.
Statistical Methods for Key 
Safety Analyses
Point estimates and 95% CIs will be provided using the Miettinen and 
Nurminen method [Miettinen, O. and Nurminen, M. 1985] for the 
difference in proportions between intervention groups while ANCOVA 
will be used to provide point estimates and 95% CIs for the difference 
in change from baseline between intervention groups (ISL QM minus 
FTC/TDF QD).
Interim Analyses
The following interim analyses are planned. An external unblinded 
statistician will provide results to be reviewed by the eDMC.
•
Sentinel Cohort IA: This will be conducted 3 months after the last 
participant in the Sentinel Cohort initiates the study intervention. 
All available data will be submitted to the eDMC for a safety 
evaluation.
•
Efficacy IA: This will be performed when at least 25 confirmed 
incident HIV-1 infections in the combined ISL QM and FTC/TDF 
QD Groups have been accumulated. Inferential analyses for 
incidence rate per year of confirmed HIV-1 infections will be 
provided.
•
Continuous safety and efficacy monitoring throughout the study: 
Accumulating safety and efficacy data at regular intervals 
throughout the study duration will be reviewed.
Multiplicity
The primary efficacy hypothesis will be tested at an overall (over the 
interim and final analyses) 1-sided Type 1 error ≤ 2.5% and alpha will 
be controlled based on the exact calculations for binary data described 
by Jennison and Turnbull [Jennison, C. and Turnbull, B. W. 2000].
Sample Size and Power
Approximately 4500 participants will be randomized to enable the 
timely accrual of 40 confirmed incident HIV-1 infections which 
provide approximately 93% power to demonstrate that ISL QM is 
superior to FTC/TDF QD.
9.2
Responsibility for Analyses/In-house Blinding
Note: As of Part 2, Sponsor personnel not directly involved with blinded safety monitoring of 
participants ongoing in the study will be unblinded to the participants’ original randomized 
study intervention group. As of Part 3, all Sponsor and site personnel as well as participants 
will be unblinded to the participants’ original randomized study intervention assignment.
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The statistical analysis of data obtained from this study will be the responsibility of the 
Clinical Biostatistics department of the Sponsor.
This study will be conducted as a double-blind study under in-house blinding procedures. 
The official, final database will not be unblinded until medical/scientific review has been 
performed, protocol deviations have been identified, and data have been declared final and 
complete.
The Clinical Biostatistics department will generate the randomized allocation schedule(s) for 
study intervention assignment. Randomization will be implemented using IRT.
Blinding issues related to the planned interim analyses are described in Section 9.7.
9.3
Hypotheses/Estimation
Objectives and hypotheses of the study are stated in Section 3.
9.4
Analysis Endpoints
Efficacy and safety endpoints that will be evaluated for within- and between-group 
differences are listed below. Exploratory endpoints are stated in Section 3 and described in 
Section 4.2.1.
9.4.1
Efficacy Endpoints
Note: As of Amendment-04, this section is no longer applicable.
The primary efficacy objective will be assessed based on the incidence rate per year of 
confirmed HIV-1 infections.
9.4.2
Safety Endpoints
An initial description of safety measures is provided in Section 4.
Safety and tolerability will be assessed by clinical review of all relevant parameters including 
AEs and laboratory tests.
9.5
Analysis Populations
Note: As of Amendment-04, Section 9.5.1 is no longer applicable since no efficacy analyses 
will be performed. The APaT will be used for safety assessments.
9.5.1
Efficacy Analysis Population
The mFAS will serve as the primary population for the analysis of efficacy data in this study. 
This includes participants who were randomized and received at least 1 dose of study 
intervention and excludes participants who had confirmed HIV infections prior to or at 
randomization.
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The screened population, which will include all individuals who come in for a screening visit 
for this study at one of the sites, will be used to estimate the background incidence rate.
9.5.2
Safety Analysis Population
Safety analyses will be conducted in the APaT population, which consists of all randomized 
participants who received at least 1 dose of study intervention. Participants will be included 
in the intervention group corresponding to the study treatment they actually received for the 
analysis of safety data using the APaT population. For most participants, this will be the 
treatment group to which they are randomized. Participants who take incorrect study 
intervention for the entire treatment period will be included in the intervention group 
corresponding to the study intervention actually received.
At least 1 laboratory measurement obtained after at least 1 dose of study intervention is 
required for inclusion in the analysis of the respective safety parameter. To assess change 
from baseline, a baseline measurement is also required.
9.6
Statistical Methods
This section describes the statistical methods that address the primary and secondary 
objectives. Methods related to PK analysis and modeling will be described in a separate 
modeling and simulation plan authored by the department of Pharmacokinetics, 
Pharmacodynamics & Drug Metabolism - Quantitative Pharmacology and Pharmacometrics. 
Methods related to exploratory objectives will be described in the sSAP.
9.6.1
Efficacy Analyses
Note: As of Amendment -04, this section is no longer applicable.
The primary efficacy hypothesis will be addressed by testing the following:
PE is the percent reduction in risk of becoming HIV-1 infected in the ISL QM group relative 
to the risk in the FTC/TDF QD group and is defined as,
are the incidence rates of HIV-1 in the experimental (ISL QM) and control (FTC/TDF QD) 
groups, respectively. CE is defined as the count of the HIV-1 infections in the ISL QM group 
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and TE as total person-years of follow-up for efficacy in the ISL QM group. CC and TC are 
defined similarly for the FTC/TDF QD group.
The primary hypothesis that prevention efficacy is >0% will be tested by computing a 
100*(1-α) % CI for PE with respect to the primary endpoint, denoted as (PEL, PEU). Success 
will be declared for the primary endpoint if PEL >0%.
To construct the CI, assume that TERE and TCRC are means of independent Poisson 
distributions. Given that there is a total of n = CE + CC HIV-1 infections observed across the 
2 treatment groups, CE ~ Binomial(n, π) with π = TERE/(TERE + TCRC).
The probability π is a person-years-adjusted estimate of the probability that a participant who 
became HIV-1 infected belongs to the ISL QM group. The lower bound of the 100*(1-α) % 
exact CI for the probability π is obtained by searching for the proportion πL such that the 
probability of observing CE or more HIV-1 infections out n total HIV-1 infections is ≤α/2. 
Similarly, the upper bound of the 100*(1-α) % exact CI for the probability π is obtained by 
searching for the proportion πU such that the probability of observing CE or fewer efficacy 
endpoint infections out n total efficacy infections is ≤α/2 [Chan, I. S. F. and Bohidar, N. R. 
1998]. PEL and PEU are then calculated from πL and πU as follows:
where θ = TC/TE is the ratio of the total person-years in the study in the FTC/TDF QD group 
over the ISL QM group.
If 40 confirmed HIV-1 infections are observed and ≤13 are in the ISL QM group, the primary 
efficacy hypothesis test would be successful and the efficacy of ISL QM relative to 
FTC/TDF QD would be demonstrated.
This study has an efficacy IA planned where the study may be stopped for efficacy or futility 
(Section 9.7). Moreover, the study may be stopped early if the number of events (25) needed 
to perform the IA is not accrued approximately 2 years from the time the last participant has 
been randomized, or if the IA was performed and the study continued, but the total number of 
events (40) needed to perform the final analysis is not accrued approximately 2 years from 
the time the last participant has been randomized.
The secondary efficacy objective will be addressed by comparing the incidence rate per year 
of confirmed HIV-1 infections in the ISL QM group to the background incidence rate using 
relative risk.
The relative risk, R, of becoming HIV-1 infected in the ISL QM group compared with the 
background population is defined as the ratio of the incidence rate per year of confirmed 
HIV-1 infections in the ISL QM group λ1 to the background incidence rate λ0,
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The methodology proposed by Gao et al. [Gao, F., et al 2020], which specifies the asymptotic 
property of R and the testing scheme, will be used to test the secondary hypothesis.
The background incidence rate λ0 will be estimated in the screened population using the 
methodology proposed by Kassanjee [Kassanjee, R., et al 2012]:
The incidence rate per year of confirmed HIV-1 infections in the ISL QM group λ1 will be 
estimated as:
Where,
nR
is the number of individuals in the screened population with HIV-1 infections and 
are identified as recent infections,
n+
is the number of individuals in the screened population with HIV-1 infections,
nS
is the number of individuals in the screened population without HIV-1 infection,
nevent
is the number of confirmed HIV-1 infections in the ISL QM group,
is the total person-years of treated participants in the ISL QM group,
is the estimated false-recent rate (FRR) (the probability that a participant who is 
infected for longer than the prespecified cutoff time, T, will be identified as 
“recent”),
is the estimated mean duration of recent infections (MDRI) (the average time 
individuals were “recently infected” [the time they were infected within the defined 
cutoff time, T, after infection]), and
T
is the cutoff time beyond which a “recent” result from the assay is considered to be 
falsely recent and is associated with the estimation of MDRI and FRR and generally 
defined as 2 years [Kassanjee, R., et al 2014].
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For nR, a participant is considered to be recently infected if all of the following criteria are 
met [Kassanjee, R., et al 2016] [Duong, Y. T., et al 2019]:
•
The participant is HIV-1 seropositive at screening AND
•
The normalized optical density (ODn) results from the Maxim HIV-1 LAg Avidity 
enzyme immunoassay are ≤1.5 AND
•
The participant has HIV-1 RNA viral load with ≥1000 copies/mL.
In addition, participants who were HIV-1 seronegative at screening, but have confirmed 
HIV-1 infection at baseline (Day 1) prior to receiving any intervention, will be counted as 
recently infected.
MDRI (and FRR) will be based on the weighted average of estimated MDRIs (and FRRs) 
reported for the dominant subtypes at the various geographic locations, with the weighting 
based on the proportion of participants screened at the different sites. The estimated MDRIs 
(and FRRs) and their associated variances will be obtained from published reports for the 
subtypes using recency tests based on LAg Avidity (eg, [Kassanjee, R., et al 2014] or 
[Duong, Y. T., et al 2015]).
A 95% CI for the relative risk will be constructed based on Gao et al. [Gao, F., et al 2020]. 
The statistical criterion for success requires the upper bound of this 95% CI to be less than 1.
Analyses will be based on data as observed. Stratification variables will not be factored into 
the analyses.
Participants who discontinue study medication with no evidence of HIV-1 infection and do 
not withdraw consent/assent will be included in the analyses.
In the event that a participant becomes pregnant and treatment allocation is unblinded 
(Sections 8.11.3 and 8.11.4), data for that participant collected after unblinding will be 
excluded from efficacy analysis.
9.6.2
Safety Analysis
Note: As of Amendment-04, safety data will be evaluated for the blinded treatment period for 
applicable safety endpoints (Table 7), and for the entire duration of the study to evaluate 
recovery of total lymphocyte counts. All safety data will be summarized descriptively.
The analysis of safety results will follow a tiered approach. The tiers differ with respect to 
the analyses that will be performed. AEs (specific terms as well as system organ class terms) 
and events that meet PDLC in laboratory parameters will be classified as belonging to “Tier 
2” or “Tier 3” based on the observed proportions of participants with an event. The safety 
analysis strategy is summarized in Table 7.
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Safety parameters or adverse events of interest that are identified a priori constitute “Tier 1” 
safety endpoints that will be subject to inferential testing for statistical significance. No a 
priori clinical events of concern have been identified for this study.
Tier 2 parameters will be assessed via point estimates with 95% CIs provided for differences 
in the proportion of participants with events (using the Miettinen and Nurminen method 
[Miettinen, O. and Nurminen, M. 1985]). Membership in Tier 2 requires that at least 1% of 
participants in any treatment group exhibit the event. Because many 95% CIs for Tier 2 
events may be provided without adjustment for multiplicity, the confidence intervals should 
be regarded as a helpful descriptive measure to be used in review, not a formal method for 
assessing the statistical significance of the between-group differences in AEs and safety 
parameters that meet PDLCs.
In addition to individual events that occur in at least 1% in any treatment group, the broad 
categories consisting of the percentage of participants with any AE, with a drug-related AE, 
with an SAE, with a Grade 3 to 4 AE, with an AE that is both drug-related and serious, with 
an AE that is both Grade 3 to 4 and drug-related, who discontinued study intervention due to 
an AE, who discontinued study intervention due to a drug-related AE, and with AE(s) 
leading to death will be considered Tier 2 endpoints. Safety endpoints that are not Tier 2 
events are considered Tier 3 events. Only point estimates will be provided by treatment 
group for Tier 3 safety parameters.
Tier 2 endpoints also include the change from baseline in renal biomarkers at Weeks 24 and 
48. The point estimate and 95% CI for change from baseline in treatment difference will be 
estimated between groups using ANCOVA models adjusted by baseline and intervention 
group (and any other participant characteristics that may be relevant).
For continuous measures such as change from baseline in laboratory parameters that are not 
prespecified as Tier 2 endpoints, summary statistics for baseline, on treatment, and change 
from baseline values will be provided by treatment group in table format.
Participants’ laboratory values (based on their most abnormal laboratory test values, in the 
direction of interest, while on study intervention) will be classified as to whether or not they 
fall outside the PDLC and are worse in grade (ie, more abnormal in the direction of interest) 
than at baseline. The criteria are adapted from DAIDS table for Grading the Severity of Adult 
and Pediatric Adverse Events, July 2017, version 2.1 (Appendix 3). A listing of the 
participants who meet the criteria will also be provided. Unless otherwise specified, missing 
safety parameters will not be imputed, and data will be used as observed. Change from 
baseline summaries require a baseline value. If a baseline value is missing, the latest 
pretreatment value will be used instead. If no pretreatment result is available, that participant 
will not be included in the summary.
For participants who become pregnant during the study, safety parameters assessed during 
the pregnancy period (estimated date of conception to date of conclusion of the pregnancy) 
may be summarized separately from the primary and secondary safety analyses. For 
continuous measures that are considered to be Tier 2 events, data collected after the 
estimated date of conception will be excluded from the analyses.
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Infant safety data will be reported separately. Additional details on how pregnancy and infant 
data will be handled in safety analyses will be provided in the sSAP and/or CSR.
Table 7
Analysis Strategy for Safety Parameters
Safety Tier
Safety Endpoint
95% CI for 
Treatment 
Difference
Descriptive 
Statistics
Tier 2

The percentage of participants with an AE in 
each of the following categories: 1 or more 
AE(s); drug-related AE(s), SAE(s), Grade 3 
to 4 AE(s), AE(s), which are both drug-
related and serious, AE(s), which are both 
Grade 3 to 4 and drug-related, AE(s) leading 
to discontinuation of study intervention, 
AE(s), which are both drug-related and 
leading to discontinuation of study 
intervention, and AE(s) leading to death

The percentage of participants with specific 
AEs (preferred terms), SOCs, or PDLCsa
occurring in ≥1% of participants in either 
treatment group

Change from baseline in renal biomarkers
X
X
Tier 3

The percentage of participants with specific 
AEs (preferred terms), SOCs, or PDLCsa
occurring in < 1% of participants in both 
treatment groups
X
AE=adverse event; CI=confidence interval; PDLC=predefined limit of change; SAE=serious adverse event; 
SOC=System Organ Class; X = results will be provided.
a
Includes only those endpoints not already prespecified as Tier 2 endpoints.
9.6.3
Demographic and Baseline Characteristics
The comparability of the intervention groups for each relevant demographic and baseline 
characteristic will be assessed by tables. No statistical hypothesis tests will be performed on 
these characteristics. The number and percentage of participants screened and randomized 
and the primary reasons for screening failure and discontinuation will be displayed. 
Demographic variables, baseline characteristics, and prior and concomitant therapies will be 
summarized by intervention either by descriptive statistics or categorical tables.
9.7
Interim Analyses
Note: As of Part 2, Sponsor personnel not directly involved with blinded safety monitoring of 
participants ongoing in the study will be unblinded to the participants’ original randomized 
study intervention group. As of Part 3, no further assessments will be made by the eDMC.
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Study enrollment is likely to be ongoing at the time of any interim analyses. Blinding to 
treatment assignment will be maintained at all investigational sites. The results of interim 
analyses will not be shared with the investigators prior to the completion of the study. 
Participant-level unblinding will be restricted to an external unblinded statistician and 
scientific programmer performing the interim analysis, who will have no other 
responsibilities associated with the study.
An eDMC will serve as the primary reviewer of the results of the interim efficacy and safety 
reviews and will make recommendations for discontinuation of the study or protocol 
modifications to an executive committee of the Sponsor. If the eDMC recommends 
modifications to the design of the protocol or discontinuation of the study, this executive 
committee (and potentially other limited Sponsor personnel) may be unblinded to results at 
the treatment level in order to act on these recommendations. The extent to which individuals 
are unblinded with respect to results of interim analyses will be documented by the unblinded 
statistician. Additional logistical details will be provided in the eDMC Charter.
Results from the interim analysis will be provided to the eDMC by the unblinded statistician. 
Prior to final study unblinding, the unblinded statistician will not be involved in any 
discussions regarding modifications to the protocol, statistical methods, identification of 
protocol deviations, or data validation efforts after the interim analyses.
The Sentinel Cohort IA will be conducted 3 months after the last participant in the Sentinel 
Cohort (defined in Section 4.1) has initiated study intervention. All available data for all 
participants enrolled by that time will be evaluated for safety at this interim analysis. The IA 
for efficacy and futility is planned when 25 confirmed incident HIV-1 infections in the 
combined ISL QM and FTC/TDF QD groups have been accumulated. If either the efficacy or 
futility criterion is met at the time of this IA, the study may be stopped based upon the 
recommendation of the eDMC. The proposed futility criterion is nonbinding and type I error 
is controlled.
The eDMC will also review accumulating safety and efficacy data at regular intervals 
throughout the study duration. The eDMC will recommend steps to ensure the safety of study 
participants and the integrity of the study and may make recommendations for protocol 
modifications or discontinuation of the study.
The method proposed by Jennison and Turnbull [Jennison, C. and Turnbull, B. W. 2000] will 
be used to control overall alpha. Table 8 shows the corresponding decision rules for the 
efficacy IA and final analyses. At the efficacy IA, the eDMC will review the data when at 
least 25 total confirmed HIV-1 infections have been accumulated. If 25 confirmed HIV-1 
infections are observed and ≤6 are in the ISL QM group, the efficacy of ISL QM relative to 
FTC/TDF QD will be demonstrated. If ≥16 of the 25 confirmed HIV-1 infections are in the 
ISL QM group, futility would be declared. This criterion is based on declaring futility only if 
there is evidence that the ISL QM group has reduced efficacy relative to the FTC/TDF QD 
group. If >6 and <16 of the confirmed HIV-1 infections are in the ISL QM group so that 
neither superior efficacy nor reduced efficacy is demonstrated, the study would continue until 
a total of 40 confirmed HIV-1 infections are accumulated. If the true PE is 69%, then the 
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probability of meeting the efficacy criterion at the time of the IA is 62%, and if the true PE is 
-50%, then the probability of meeting the futility criterion at the time of the IA is 42%.
If the study does not stop at the IA, the study would continue until at least 40 confirmed 
HIV-1 infections have been accrued, and the final efficacy analysis would be conducted.
In the event that more than 25 confirmed HIV-1 infections are accrued at the time of the 
interim analysis, the boundaries for stopping rules will be adjusted so that the alpha spent is 
no more than originally planned. Further details will be provided in the eDMC Charter.
Table 8
Decision Rule and Corresponding Type 1 Error and Power for Testing the 
Primary Efficacy Hypothesis
Analysis 
Time 
Point
Total 
Infections
Critical Infections Split for ISL 
QM
Cumulative
Type I Error
(%)
True PE (%) 
Efficacy
Futility/Failure
True PE=0%
-50%a
50%
69%b
Cumulative Power (%)
Interim
25
≤6
≥16
0.7
<0.1
22.1
61.6
Final
40
≤13
≥14
2.2
0.1
54.2
92.9
FTC/TDF=emtricitabine/tenofovir disoproxil (including TRUVADATM and all generic versions); ISL=islatravir; 
PE=prevention efficacy; QD=once daily; QM=once-monthly.
Probabilities of meeting the futility criterion at the interim for true PEs of 0%, -50%, 50%, and 69% are 11%, 42%, 
0.2%, and <0.1%, respectively
a
The incidence rate in the ISL QM group is 50% higher compared with the FTC/TDC QD group.
b
Corresponds to PE under alternative
9.8
Multiplicity
Note: As of Amendment -04, this section is no longer applicable.
The primary efficacy hypothesis will be tested at an overall (over the interim and final 
analyses) 1-sided Type 1 error ≤2.5%. Table 8 shows the decisions rules and details on alpha 
spent at the interim analysis. The method proposed by Jennison and Turnbull [Jennison, C. 
and Turnbull, B. W. 2000] will be used to control overall alpha.
9.9
Sample Size and Power Calculations
Note: As of Part 2 and continuing into Part 3, no new participants will be screened or 
randomized. The planned sample size was not reached, and this section is no longer 
applicable.
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9.9.1
Sample Size and Power for Efficacy Analyses
Approximately 4500 participants will be randomized in a 1:1 ratio to either the ISL QM + 
FTC/TDF-matched placebo group or the FTC/TDF QD group + ISL QM-match placebo 
group.
The projected accrual of incident HIV-1 infections is based on the following assumptions:
•
Background HIV-1 incidence, in the absence of any PrEP, is 2.5% per year.
•
ISL QM has 87.5% efficacy (incidence rate of 0.3125% per year).
•
FTC/TDF QD has 60% efficacy (incidence rate of 1.0% per year).
•
Average participant time in the study is 1.5 years.
•
Lost-to-follow-up/study discontinuation rate of 5% per year.
The assumed background rate is a conservative estimate based on 2 recent prospective 
studies (ECHO [Evidence for Contraceptive Options and HIV Outcomes Trial Consor 2019]
and HVTN 702 [Joint United Nations Programme on HIV/AIDS 2020]) conducted in Africa 
where the overall yearly incidence rates among women were 3.8% and ~4% respectively. 
The assumption regarding ISL QM efficacy is a conservative estimate based on a rhesus 
macaque SHIV intrarectal challenge model [Markowitz, M., et al 2019] where ISL provided 
protection against infection at drug levels that are projected to be achieved with the dose 
regimen used in this study. The assumption regarding FTC/TDF QD efficacy is an 
approximation based on the wide range of reported efficacy of FTC/TDF QD in previous 
studies, from not better than placebo to 64% to 84% in Partners PrEP [Murnane, P. M., et al 
2013]. The assumption regarding study discontinuation rate is consistent with HPTN 84 
[HIV Prevention Trials Network 2019].
A total of 40 confirmed HIV-1 infections across the ISL QM and FTC/TDF QD groups will 
result in 93% power to demonstrate that ISL QM is superior to FTC/TDF QD if the true PE is 
69% with 1-sided Type 1 error α ≤0.025.
For the secondary efficacy objective, given the above assumptions, the study has >99% 
power to demonstrate that ISL QM reduces the incidence of HIV-1 infections compared with
the background rate, for background rates ranging from 2% to 4%.
9.9.2
Sample Size and Power for Safety Analyses
The probability of observing at least 1 of a particular type of AE in this study depends on the 
number of participants treated and the underlying percentage of participants with that AE in 
the study population.
If the underlying percentage of participants with a particular AE is 0.1%, there is 89.5% 
chance of observing at least 1 AE among 2250 participants in a treatment group. If no AE of 
that type is observed among the 2250 participants in a treatment group, this study will 
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provide 97.5% confidence that the underlying percentage of participants with that particular 
AE is <0.2% (1 out every ~ 600 participants).
The estimate of, and the upper bound of the 95% CI for, the underlying percentage of 
participants with an AE given various hypothetical observed numbers of participants with the 
AE within each treatment group are provided in Table 9. These calculations are based on the 
exact binomial method proposed by Clopper and Pearson [Clopper, C. J. and Pearson, E. S. 
1934].
Table 9
Percentage of Participants With AEs and 95% Upper Confidence Bound Based on 
Hypothetical Numbers of Participants With AEs (2250 Participants per Group)
Hypothetical 
Numbers of 
Participants 
With AE
Percentage
95% Upper Confidence Bounda
0
0.0%
0.2%
50
2.2%
2.9%
100
4.4%
5.4%
150
6.7%
7.8%
200
8.9%
10.1%
AE=adverse event; CI=confidence interval.
a
Based on the 2-tailed exact CI for a binomial proportion (Clopper and Pearson method [Clopper, C. J. and Pearson, 
E. S. 1934]). In the 0-event case, the 95% CI is one sided (α=0.05 all in the upper tail).
Table 10 demonstrates the difference in the percentage of participants with an AE (ISL QM 
minus FTC/TDC QD) that can be ruled out with different power levels and 95% confidence 
when there are 2250 participants in each group. The underlying percentage of participants 
with the AE is assumed to be the same for the 2 intervention groups. For example, for an AE 
that occurs in 10% of participants in both groups, the study has 80% power to show with 
95% confidence that the true difference between the treatment groups is no more than 2.6% 
percentage points. The calculations are based on an asymptotic method proposed by 
Miettinen and Nurminen [Miettinen, O. and Nurminen, M. 1985].
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Table 10
Difference in Percentage of Participants With AEs (ISL QM Minus FTC/TDC 
QD) That can be Ruled Out With 2250 Participants in Each Group
Target 
Power
Underlying Percentage of Participants with AE
1%
5%
10%
20%
80
1.0%
2.0%
2.6%
3.4%
85
1.1%
2.1%
2.8%
3.7%
90
1.2%
2.3%
3.1%
4.0%
AE=adverse event; CI=confidence interval; FTC/TDF=emtricitabine/tenofovir disoproxil (including TRUVADATM
and all generic versions); ISL=islatravir; QD=once daily; QM=once-monthly.
Note: The upper bound of the 2-sided 95% CI (Miettinen and Nurminen method [Miettinen, O. and Nurminen, M. 
1985]) for the difference in percentages of participants with AEs (ISL QM minus FTC/TDF QD) assuming the 
percentages are the same.
9.10
Subgroup Analyses
Note: As of Amendment-04, no between-group comparisons will be conducted and this 
section is no longer applicable.
To assess whether the treatment effect is consistent across various subgroups, the estimate of 
the between-group treatment effect (with a nominal 95% CI) for the primary efficacy 
endpoint will be calculated within each category of the following classification variables.
•
Age category (<18, ≥18 years; <25, ≥25 years)
•
Site (all US sites – 1 level, each ex-US site is a separate level)
9.11
Compliance (Medication Adherence)
Note: As of Amendment-04, this section will only apply to the blinded treatment period (Part 
1).
Adherence to ISL QM or matching placebo will be recorded upon in-clinic dosing at each 
monthly visit. For each participant in the FTC/TDF QD or matching placebo group, the 
number of tablets remaining in study packaging will be counted, reviewed, and recorded by 
site personnel at regular intervals. These results will be used to calculate participant 
compliance.
For each participant, percent compliance will then be calculated using the following formula:
Summary statistics will be provided on percent compliance by intervention group for the 
mFAS population.
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9.12
Extent of Exposure
Note: As of Amendment-04, this section will only apply to the blinded treatment period (Part 
1).
The extent of exposure to study intervention will be evaluated by summary statistics by 
intervention group.
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10
SUPPORTING DOCUMENTATION AND OPERATIONAL 
CONSIDERATIONS
10.1
Appendix 1: Regulatory, Ethical, and Study Oversight Considerations
10.1.1
Code of Conduct for Clinical Trials
Merck Sharp & Dohme LLC, Rahway, NJ, USA (MSD)
Code of Conduct for Interventional Clinical Trials
I. Introduction
A. Purpose
MSD, through its subsidiaries, conducts clinical trials worldwide to evaluate the safety and effectiveness of our 
products. As such, we are committed to designing, implementing, conducting, analyzing, and reporting these trials 
in compliance with the highest ethical and scientific standards. Protection of participants in clinical trials is the 
overriding concern in the design and conduct of clinical trials. In all cases, MSD clinical trials will be conducted 
in compliance with local and/or national regulations (including all applicable data protection laws and
regulations), and International Council for Harmonisation Good Clinical Practice (ICH-GCP), and also in 
accordance with the ethical principles that have their origin in the Declaration of Helsinki.
B. Scope
Highest ethical and scientific standards shall be endorsed for all clinical interventional investigations sponsored by 
MSD irrespective of the party (parties) employed for their execution (e.g., contract research organizations, 
collaborative research efforts). This Code is not intended to apply to trials that are observational in nature, or 
which are retrospective. Further, this Code does not apply to investigator-initiated trials, which are not under the 
full control of MSD.
II. Scientific Issues
A. Trial Conduct
1. Trial Design
Except for pilot or estimation trials, clinical trial protocols will be hypothesis-driven to assess safety, efficacy 
and/or pharmacokinetic or pharmacodynamic indices of MSD or comparator products. Alternatively, MSD 
may conduct outcomes research trials, trials to assess or validate various endpoint measures, or trials to 
determine patient preferences, etc.
The design (i.e., participant population, duration, statistical power) must be adequate to address the specific 
purpose of the trial and shall respect the data protection rights of all participants, trial site staff and, where 
applicable, third parties. Participants must meet protocol entry criteria to be enrolled in the trial. 
2. Site Selection
MSD selects investigative sites based on medical expertise, access to appropriate participants, adequacy of 
facilities and staff, previous performance in clinical trials, as well as budgetary considerations. Prior to trial 
initiation, sites are evaluated by MSD personnel (or individuals acting on behalf of MSD) to assess the ability 
to successfully conduct the trial.
3. Site Monitoring/Scientific Integrity
Investigative trial sites are monitored to assess compliance with the trial protocol and Good Clinical Practice 
(GCP). MSD reviews clinical data for accuracy, completeness, and consistency. Data are verified versus 
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source documentation according to standard operating procedures. Per MSD policies and procedures, if
potential fraud, scientific/research misconduct, privacy incidents/breaches or Clinical Trial-related 
Significant Quality Issues are reported, such matters are investigated. When necessary, appropriate corrective 
and/or preventative actions are defined and regulatory authorities and/or ethics review committees are 
notified.
B. Publication and Authorship
Regardless of trial outcome, MSD commits to publish the primary and secondary results of its registered trials of 
marketed products in which treatment is assigned, according to the pre-specified plans for data analysis. To the 
extent scientifically appropriate, MSD seeks to publish the results of other analyses it conducts that are important 
to patients, physicians, and payers. Some early phase or pilot trials are intended to be hypothesis-generating rather 
than hypothesis testing; in such cases, publication of results may not be appropriate since the trial may be 
underpowered and the analyses complicated by statistical issues such as multiplicity.
MSD’s policy on authorship is consistent with the recommendations published by the International Committee of 
Medical Journal Editors (ICMJE). In summary, authorship should reflect significant contribution to the design and 
conduct of the trial, performance or interpretation of the analysis, and/or writing of the manuscript. All named 
authors must be able to defend the trial results and conclusions. MSD funding of a trial will be acknowledged in 
publications.
III. Participant Protection
A. Regulatory Authority and Ethics Committee Review (Institutional Review Board [IRB]/Independent Ethics 
Committee [IEC])
All protocols and protocol amendments will be submitted by MSD for regulatory authority 
acceptance/authorization prior to implementation of the trial or amendment, in compliance with local and/or 
national regulations.
The protocol, protocol amendment(s), informed consent form, investigator’s brochure, and other relevant trial 
documents must be reviewed and approved by an IRB/IEC before being implemented at each site, in compliance 
with local and/or national regulations. Changes to the protocol that are required urgently to eliminate an 
immediate hazard and to protect participant safety may be enacted in anticipation of ethics committee approval. 
MSD will inform regulatory authorities of such new measures to protect participant safety, in compliance with 
local and/or national regulations.
B. Safety
The guiding principle in decision-making in clinical trials is that participant welfare is of primary importance. 
Potential participants will be informed of the risks and benefits of, as well as alternatives to, trial participation. At 
a minimum, trial designs will take into account the local standard of care.
All participation in MSD clinical trials is voluntary. Participants enter the trial only after informed consent is 
obtained. Participants may withdraw from an MSD trial at any time, without any influence on their access to, or 
receipt of, medical care that may otherwise be available to them.
C. Confidentiality
MSD is committed to safeguarding participant confidentiality, to the greatest extent possible, as well as all 
applicable data protection rights. Unless required by law, only the investigator, Sponsor (or individuals acting on 
behalf of MSD), ethics committee, and/or regulatory authorities will have access to confidential medical records 
that might identify the participant by name.
D. Genomic Research
Genomic research will only be conducted in accordance with a protocol and informed consent authorized by an 
ethics committee.
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IV. Financial Considerations
A. Payments to Investigators
Clinical trials are time- and labor-intensive. It is MSD’s policy to compensate investigators (or the sponsoring 
institution) in a fair manner for the work performed in support of MSD trials. MSD does not pay incentives to 
enroll participants in its trials. However, when enrollment is particularly challenging, additional payments may be 
made to compensate for the time spent in extra recruiting efforts.
MSD does not pay for participant referrals. However, MSD may compensate referring physicians for time spent 
on chart review and medical evaluation to identify potentially eligible participants.
B. Clinical Research Funding
Informed consent forms will disclose that the trial is sponsored by MSD, and that the investigator or sponsoring 
institution is being paid or provided a grant for performing the trial. However, the local ethics committee may 
wish to alter the wording of the disclosure statement to be consistent with financial practices at that institution. As 
noted above, all publications resulting from MSD trials will indicate MSD as a source of funding.
C. Funding for Travel and Other Requests
Funding of travel by investigators and support staff (e.g., to scientific meetings, investigator meetings, etc.) will be 
consistent with local guidelines and practices.
V. Investigator Commitment
Investigators will be expected to review MSD’s Code of Conduct as an appendix to the trial protocol, and in signing the 
protocol, agree to support these ethical and scientific standards.
10.1.2
Financial Disclosure
Financial Disclosure requirements are outlined in the US Food and Drug Administration 
Regulations, Financial Disclosure by Clinical Investigators (21 CFR Part 54). It is the 
Sponsor's responsibility to determine, based on these regulations, whether a request for 
Financial Disclosure information is required. It is the investigator's/subinvestigator's 
responsibility to comply with any such request.
The investigator/subinvestigator(s) agree, if requested by the Sponsor in accordance with 21 
CFR Part 54, to provide his/her financial interests in and/or arrangements with the Sponsor to 
allow for the submission of complete and accurate certification and disclosure statements. 
The investigator/subinvestigator(s) further agree to provide this information on a 
Certification/Disclosure Form, commonly known as a financial disclosure form, provided by 
the Sponsor. The investigator/subinvestigator(s) also consent to the transmission of this 
information to the Sponsor in the United States for these purposes. This may involve the 
transmission of information to countries that do not have laws protecting personal data.
10.1.3
Data Protection
The Sponsor will conduct this study in compliance with all applicable data protection 
regulations.
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Participants will be assigned a unique identifier by the Sponsor. Any participant records or 
datasets that are transferred to the Sponsor will contain the identifier only; participant names 
or any information that would make the participant identifiable will not be transferred.
The participant must be informed that his/her personal study-related data will be used by the 
Sponsor in accordance with local data protection law. The level of disclosure must also be 
explained to the participant. 
The participant must be informed that his/her medical records may be examined by Clinical 
Quality Assurance auditors or other authorized personnel appointed by the Sponsor, by 
appropriate IRB/IEC members, and by inspectors from regulatory authorities.
10.1.3.1
Confidentiality of Data
By signing this protocol, the investigator affirms to the Sponsor that information furnished to 
the investigator by the Sponsor will be maintained in confidence, and such information will 
be divulged to the IRB, IEC, or similar or expert committee; affiliated institution and 
employees, only under an appropriate understanding of confidentiality with such board or 
committee, affiliated institution and employees. Data generated by this study will be 
considered confidential by the investigator, except to the extent that it is included in a 
publication as provided in the Publications section of this protocol.
10.1.3.2
Confidentiality of Participant Records
By signing this protocol, the investigator agrees that the Sponsor (or Sponsor representative), 
IRB/IEC, or regulatory authority representatives may consult and/or copy study documents to 
verify worksheet/CRF data. By signing the consent form, the participant agrees to this 
process. If study documents will be photocopied during the process of verifying 
worksheet/CRF information, the participant will be identified by unique code only; full 
names/initials will be masked prior to transmission to the Sponsor.
By signing this protocol, the investigator agrees to treat all participant data used and 
disclosed in connection with this study in accordance with all applicable privacy laws, rules 
and regulations.
10.1.3.3
Confidentiality of IRB/IEC Information
The Sponsor is required to record the name and address of each IRB/IEC that reviews and 
approves this study. The Sponsor is also required to document that each IRB/IEC meets 
regulatory and ICH GCP requirements by requesting and maintaining records of the names 
and qualifications of the IRB/IEC members and to make these records available for 
regulatory agency review upon request by those agencies.
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10.1.4
Committees Structure
10.1.4.1
Scientific Advisory Committee (SAC)
This study was developed in collaboration with a SAC. The SAC is comprised of both 
Sponsor and nonSponsor scientific experts who provide input with respect to study design, 
interpretation of study results, and subsequent peer-reviewed scientific publications.
10.1.4.2
External Data Monitoring Committee
To supplement the routine study monitoring outlined in this protocol, an external DMC will 
monitor the interim data from this study. The voting members of the committee are external 
to the Sponsor. The members of the DMC must not be involved with the study in any other 
way (eg, they cannot be study investigators) and must have no competing interests that could 
affect their roles with respect to the study.
The DMC will make recommendations to the EOC regarding steps to ensure both participant 
safety and the continued ethical integrity of the study. Also, the DMC will review interim 
study results, consider the overall risk and benefit to study participants (Section 9.7 [Interim 
Analysis]) and recommend to the EOC whether the study should continue in accordance with 
the protocol.
Specific details regarding composition, responsibilities, and governance, including the roles 
and responsibilities of the various members and the Sponsor protocol team; meeting 
facilitation; the study governance structure; and requirements for and proper documentation 
of DMC reports, minutes, and recommendations will be described in the DMC charter that is 
reviewed and approved by all the DMC members.
10.1.4.3
Clinical Adjudication Committee (CAC)
A CAC will evaluate the following events for the purposes of confirming them according to 
the criteria in Section 9, as well as evaluating the presence of confounding factors.
1.   Incident HIV infection
All personnel involved in the adjudication process will remain blinded to study intervention 
allocation throughout the study.
10.1.4.4
Executive Oversight Committee
The EOC is comprised of members of Sponsor Senior Management. The EOC will receive 
and decide on any recommendations made by the DMC regarding the study.
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10.1.4.5
Protocol Steering Committee
The Protocol Steering Committee provides scientific leadership for the study and is 
comprised of both Sponsor and external members such as:
•
Sponsor personnel,
•
Investigators participating in the study, and
•
Consulting therapeutic-area experts and clinical trialists.
The Protocol Steering Committee will be responsible for scientific aspects of the study, 
maintaining effective and independent scientific oversight, and will ensure that study 
execution and management are of the highest quality. The Protocol Steering Committee will 
convene regularly to discuss and report on ongoing supervision of the study. The Protocol 
Steering Committee will provide guidance on the operational aspects of the study, evaluate 
recommendations from the DMC and discuss these recommendations with the EOC. The 
Protocol Steering Committee is responsible for oversight of all public and scientific 
communications and publications, and for overseeing the development of ancillary, scientific 
studies.
Specific details regarding responsibilities and governance of the Protocol Steering 
Committee will be described in a separate charter.
10.1.5
Publication Policy
The results of this study may be published or presented at scientific meetings. The Sponsor 
will comply with the requirements for publication of study results. In accordance with 
standard editorial and ethical practice, the Sponsor will generally support publication of 
multicenter studies only in their entirety and not as individual site data. In this case, a 
coordinating investigator will be designated by mutual agreement.
If publication activity is not directed by the Sponsor, the investigator agrees to submit all 
manuscripts or abstracts to the Sponsor before submission. This allows the Sponsor to protect 
proprietary information and to provide comments.
Authorship will be determined by mutual agreement and in line with International Committee 
of Medical Journal Editors authorship requirements.
10.1.6
Compliance with Study Registration and Results Posting Requirements
Under the terms of the FDAAA of 2007 and the EMA clinical trial Directive 2001/20/EC, the 
Sponsor of the study is solely responsible for determining whether the study and its results 
are subject to the requirements for submission to http://www.clinicaltrials.gov, 
www.clinicaltrialsregister.eu or other local registries. MSD, as Sponsor of this study, will 
review this protocol and submit the information necessary to fulfill these requirements. MSD 
entries are not limited to FDAAA or the EMA clinical trial directive mandated trials. 
Information posted will allow participants to identify potentially appropriate studies for their 
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disease conditions and pursue participation by calling a central contact number for further 
information on appropriate study locations and study-site contact information.
By signing this protocol, the investigator acknowledges that the statutory obligations under 
FDAAA, the EMA clinical trials directive, or other locally mandated registries are that of the 
Sponsor and agrees not to submit any information about this study or its results to those 
registries.
10.1.7
Compliance with Law, Audit, and Debarment
By signing this protocol, the investigator agrees to conduct the study in an efficient and 
diligent manner and in conformance with this protocol; generally accepted standards of GCP 
(eg, International Council on Harmonisation of Technical Requirements for Registration of 
Pharmaceuticals for Human Use GCP: Consolidated Guideline and other generally accepted 
standards of GCP); and all applicable federal, state and local laws, rules and regulations 
relating to the conduct of the clinical study.
The Code of Conduct, a collection of goals and considerations that govern the ethical and 
scientific conduct of clinical investigations sponsored by MSD, is provided in this appendix 
under the Code of Conduct for Clinical Trials.
The investigator agrees not to seek reimbursement from participants, their insurance 
providers, or from government programs for procedures included as part of the study 
reimbursed to the investigator by the Sponsor.
The investigator will promptly inform the Sponsor of any regulatory authority inspection 
conducted for this study.
The investigator agrees to provide the Sponsor with relevant information from inspection 
observations/findings to allow the Sponsor to assist in responding to any citations resulting 
from regulatory authority inspection and will provide the Sponsor with a copy of the 
proposed response for consultation before submission to the regulatory authority. 
Persons debarred from conducting or working on clinical studies by any court or regulatory 
authority will not be allowed to conduct or work on this Sponsor’s studies. The investigator 
will immediately disclose in writing to the Sponsor if any person who is involved in 
conducting the study is debarred or if any proceeding for debarment is pending or, to the best 
of the investigator’s knowledge, threatened.
10.1.8
Data Quality Assurance
All participant data relating to the study will be recorded on printed or electronic CRF unless 
transmitted to the Sponsor or designee electronically (eg, laboratory data). The investigator 
or qualified designee is responsible for verifying that data entries are accurate and correct by 
physically or electronically signing the CRF.
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Detailed information regarding Data Management procedures for this protocol will be 
provided separately.
The investigator must maintain accurate documentation (source data) that supports the 
information entered in the CRF.
The investigator must permit study-related monitoring, audits, IRB/IEC review, and 
regulatory agency inspections and provide direct access to source data documents.
Study documentation will be promptly and fully disclosed to the Sponsor by the investigator 
upon request and also shall be made available at the study site upon request for inspection, 
copying, review, and audit at reasonable times by representatives of the Sponsor or any 
regulatory authorities. The investigator agrees to promptly take any reasonable steps that are 
requested by the Sponsor or any regulatory authorities as a result of an audit or inspection to 
cure deficiencies in the study documentation and worksheets/CRFs.
The Sponsor or designee is responsible for the data management of this study including 
quality checking of the data.
Study monitors will perform ongoing source data review and verification to confirm that data 
entered into the CRF by authorized site personnel are accurate, complete, and verifiable from 
source documents; that the safety and rights of participants are being protected; and that the 
study is being conducted in accordance with the currently approved protocol and any other 
study agreements, ICH GCP, and all applicable regulatory requirements.
Records and documents, including participants’ documented informed consent, pertaining to 
the conduct of this study must be retained by the investigator for 15 years after study 
completion unless local regulations or institutional policies require a longer retention period. 
No records may be destroyed during the retention period without the written approval of the 
Sponsor. No records may be transferred to another location or party without written 
notification to the Sponsor.
10.1.9
Source Documents
Source documents provide evidence for the existence of the participant and substantiate the 
integrity of the data collected. The investigator/institution should maintain adequate and 
accurate source documents and study records that include all pertinent observations on each 
of the site’s participants. Source documents and data should be attributable, legible, 
contemporaneous, original, accurate, and complete. Changes to source data should be 
traceable, should not obscure the original entry, and should be explained if necessary (eg, via 
an audit trail). Source documents are filed at the investigator’s site.
Data reported on the CRF or entered in the eCRF that are transcribed from source documents 
must be consistent with the source documents or the discrepancies must be explained. The 
investigator/institution may need to request previous medical records or transfer records, 
depending on the study. Also, current medical records must be available.
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10.1.10
Study and Site Closure
The Sponsor or its designee may stop the study or study-site participation in the study for 
medical, safety, regulatory, administrative, or other reasons consistent with applicable laws, 
regulations, and GCP.
In the event the Sponsor prematurely terminates a particular study site, the Sponsor or 
designee will promptly notify that study site’s IRB/IEC as specified by applicable regulatory 
requirement(s).
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10.2
Appendix 2: Clinical Laboratory Tests
•
The tests detailed in Table 11 will be processed by a central laboratory in the US, or by a 
local/regional laboratory in Africa.
•
Local laboratory results may be required in the event that the central laboratory results 
are not available in time for either study intervention administration and/or response 
evaluation. If a local sample is required, it is important that the sample for central 
analysis is obtained at the same time. Additionally, if the local laboratory results are used 
to make either a study intervention decision or response evaluation, the results must be 
entered the CRF.
•
Protocol-specific requirements for inclusion or exclusion of participants are detailed in 
Section 5.1 and Section 5.2 of the protocol.
•
Additional tests may be performed at any time during the study as determined necessary 
by the investigator or required by local regulations.
Table 11
Protocol-required Laboratory Assessments
Laboratory Assessments
Parameters
Pregnancy
Urine Pregnancy Test (WOCBP only) (Highly sensitive urine) 
human chorionic gonadotropin (hCG) pregnancy test
Positive urine pregnancy to be confirmed with serum pregnancy test 
- Highly sensitive serum human chorionic gonadotropin (hCG) 
pregnancy test
Hematology
Hematocrit (Hct)
Hemoglobin (Hb)
RBC Count
WBC Count
Platelet Count
Mean Corpuscular Hemoglobin (MCH)
Mean Corpuscular Hemoglobin Concentration (MCHC)
Mean Corpuscular Volume (MCV)
Mean Platelet Volume (MPV)
Red Cell Distribution Width (RDW)
CBC, Nucleated Red Blood Cell (%, abs)
WBC Differential, Basophils (%, abs)
WBC Differential, Eosinophils (%, abs)
WBC Differential, Immature Granulocyte (%, abs)
WBC Differential, Lymphocytes (%, abs)
WBC Differential, Monocytes (%, abs)
WBC Differential, Neutrophils, Total (%, abs)
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Laboratory Assessments
Parameters
CD4+ T-Cell 
count/Lymphocyte subset 
panel
CD4 + T-cell count/lymphocyte subset panel includes, but is not 
limited to:
CD3+ Percent
CD3+ Value/Absolute Count
CD3+CD4+ Percent
CD3+CD4+ Value/Absolute Count 
CD3+CD8+ Percent 
CD3+CD8+ Value/Absolute Count 
CD3-CD19+ Percent 
CD3-CD19+ Value/Absolute Count 
CD16+CD56+ Percent 
CD16+CD56+ Value/Absolute Count 
CD3+CD4+CD8+ Percent 
CD3+CD4+CD8+ Value/Absolute Count 
CD4/CD8 Ratio
Chemistry 
Albumin
Alkaline Phosphatase (ALP)
Alanine Aminotransferase (ALT/SGPT)
Aspartate Aminotransferase (AST/SGOT)
Amylase
Bicarbonate
Bilirubin, Direct
Bilirubin, Indirect
Bilirubin, Total
Calcium (Ca)
Chloride (Cl)
Cholesterol, Total
Creatine Phosphokinase (CPK)
Creatinine
Creatinine Clearance (calculated)
Cystatin-C
Gamma Glutamyl Transferase (GGT)
Glucose (fasting)
Glucose (random)
Lactate Dehydrogenase (LDH)
Lipase
Magnesium (Mg)
Phosphorous
Potassium (K)
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Laboratory Assessments
Parameters
Protein, Total 
Sodium (Na)
Triglycerides
Urea Nitrogen, Blood (BUN)
Uric Acid
Hepatitis screen (Screening)
Hepatitis B virus surface antigen (HBsAg)
Hepatitis B Serology (HBsAb/HBcAb)
Virology
Point-of-Care HIV-1 test 
HIV-1/HIV-2 antibody/antigen testing
Plasma HIV-1 viral RNA quantification (real time PCR) – to be 
performed if HIV-1 positive
Whole blood HIV-1 drug resistance testing - to be performed only if 
viremia is detected
STI Testing (Screening)
Syphilis Serologic Testing (rapid plasma reagin [RPR], RPR with 
titer, Treponema pallidum IgG, Treponema pallidum IgG index 
value) 
Vaginal Swab for bacterial vaginosis
Nucleic acid amplification from urine for Trichomonas
Nucleic acid amplification from urine for Gonorrhea and Chlamydia
HSV-2 Serology Testing
PK Sampling
Blood (Plasma) for PK 
Dried blood for PK 
Blood (Plasma) for Investigational PK
Biomarkers
HIV Recency Assay (Samples will be analyzed only in participants 
with confirmed HIV-1 infection at screening or Day 1)
Notes:
The investigator (or medically qualified designee) must document their review of each 
laboratory safety report.
If a participant is confirmed HIV-infected, results from HIV-1 drug resistance testing will 
not be provided to site personnel who are directly involved in supporting the study, as 
there is the potential for the data to unblind the participants intervention group. HIV 
Resistance results will be blinded to the study team and site personnel.
PK data will be blinded to site and Sponsor personnel during the study (Section 6.3.3).
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Table 12
PK Sample Collection Timepoints
Note: PK samples will not be collected in Part 3 of the study.
Visit Number
Visit 2
Visit 3
Visit 4
Visit 5
Visit 6
Visit 7
Visit 8
Visit 11
Visit 14
Visit 17
Visit 20
Visit 23
Visit 26
Visit 29
Visit 32
Visit 35
Visit 38
Notes
Day/Month
Day 1
Month 1
Month 2
Month 3
Month 4
Month 5
Month 6
Month 9 
Month 12
Month 15
Month 18
Month 21
Month 24
Month 27
Month 30
Month 33
Month 36/
EOT
A participant may have up to 40 
visits, but may have fewer visits 
(endpoint-driven study).
Blood (Plasma) for 
PK
X
X
X
X
X
X
X
X
X
See Section 8.6.1
The sample must be collected 
irrespective of the planned PK 
collection schedule, if a 
participant has a positive Point-
of-Care HIV test result at a visit.
Blood (Plasma) for 
Investigational PK
X
X
X
X
X
X
See Section 8.6.2
During Part 1, investigational PK 
samples will be collected predose 
at Month 2 and at any time 
during the visit at Months 9, 15, 
21, 27, and 33.
During Part 2, investigational PK 
samples may be collected at any 
time during the visit.
Samples will be stored and 
triggered for analysis by 
Sponsor, if needed.
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Visit Number
Visit 2
Visit 3
Visit 4
Visit 5
Visit 6
Visit 7
Visit 8
Visit 11
Visit 14
Visit 17
Visit 20
Visit 23
Visit 26
Visit 29
Visit 32
Visit 35
Visit 38
Notes
Day/Month
Day 1
Month 1
Month 2
Month 3
Month 4
Month 5
Month 6
Month 9 
Month 12
Month 15
Month 18
Month 21
Month 24
Month 27
Month 30
Month 33
Month 36/
EOT
A participant may have up to 40 
visits, but may have fewer visits 
(endpoint-driven study).
Dried Blood for PK
X
X
X
X
X
X
X
X
X
X
See Section 8.6.3
The sample must be collected 
irrespective of the planned PK 
collection schedule, if a 
participant has a positive Point-
of-Care HIV test result at a visit.
EOT=end of treatment (all participants may not complete 36 months because this is a case-driven study); HIV=human immunodeficiency virus; PK=pharmacokinetic.
Note: For participants who become pregnant and remain on ISL, see Section 1.3.4 and Section 8.6.4.
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Table 13
Blood Volumes
Note: PK samples will not be collected in Part 3 of the study.
Study Period
Screen
Study Intervention
Visit Number
1
2
3
4
5
6
7
8
Recurring Visits
38
HIV
Infection 
Confirmation
Early 
Discontinuation 
of Study 
Intervention
Early Withdrawal 
from Study
Scheduled Day/Month
Screening
Day 1
Month 1
Month 2
Month 3
Month 4
Month 5
Month 6
Every Montha
(Additional 
Assessments) Every 3 
Monthsb
(Additional 
Assessments) Every 
6 Monthsc
Month 36
Totals
Unscheduled
Unscheduled
Unscheduled
HBV/HIV (Serology) 
6
6
Syphilis Serologic Testing
4
4
4
36
4
52
HSV-2 serology
2
2
4
Hematology
6
6
6
6
6
6
6
6
174
6
228
6
6
6
CD4+ T-cell 
count/Lymphocyte subset 
panel
6
6
6
6
6
6
6
6
174
6
228
6
6
6
Chemistry
5
5
5
5
45
5
70
5
5
5
Cystatin-C
3.5
3.5
3.5
31.5
3.5
45.
5
3.5
3.5
Serum pregnancy test 
(WOCBP only)
Off 
Chem
2
2
2
2
2
40
50
Point-of-Care HIV Testingd
Not applicable; additional volume not required.
HIV-1/HIV-2 
Antibody/Antigen Testing
Off 
HBV/ 
HIV
3.5
3.5
3.5
3.5
3.5
3.5
3.5
101.5
3.5
129.5
3.5
3.5
3.5
Plasma HIV RNA (Real 
Time PCR)
6
6
6
6
6
6
6
6
174
6
228
6
6
6
HIV-1 Drug Resistance 
Testing
3
3
15 (180)e
12
12
HIV Recency Assay
4
4
8
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Study Period
Screen
Study Intervention
Visit Number
1
2
3
4
5
6
7
8
Recurring Visits
38
HIV
Infection 
Confirmation
Early 
Discontinuation 
of Study 
Intervention
Early Withdrawal 
from Study
Scheduled Day/Month
Screening
Day 1
Month 1
Month 2
Month 3
Month 4
Month 5
Month 6
Every Montha
(Additional 
Assessments) Every 3 
Monthsb
(Additional 
Assessments) Every 
6 Monthsc
Month 36
Totals
Unscheduled
Unscheduled
Unscheduled
Blood (Plasma) for PK
3
3
3
3
12
3
27 f
3
3
3
Blood (Plasma) for 
Investigational PK
3
15g
18
Dried Blood for PK
from PK 
tube
from 
PK 
tube
from 
investi-
gational PK 
tube
from 
PK 
tube
from 
PK 
tube
from PK 
tube
from 
PK 
tube
0
from PK 
tube
from PK 
tube
from PK 
tube
Blood for Genetic Analysis
8.5
8.5
Whole blood for FBR
4
4
4
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Study Period
Screen
Study Intervention
Visit Number
1
2
3
4
5
6
7
8
Recurring Visits
38
HIV
Infection 
Confirmation
Early 
Discontinuation 
of Study 
Intervention
Early Withdrawal 
from Study
Scheduled Day/Month
Screening
Day 1
Month 1
Month 2
Month 3
Month 4
Month 5
Month 6
Every Montha
(Additional 
Assessments) Every 3 
Monthsb
(Additional 
Assessments) Every 
6 Monthsc
Month 36
Totals
Unscheduled
Unscheduled
Unscheduled
Total Blood Volume per 
Visit in mLf,h
39
54.5
26.5
26.5
37
23.5 23.5
37
663.5
112.5
27 e
39
1109.
5
48.5 
(213.5)e
45
45
EOT=end of treatment (all participants may not complete 36 months because this is a case-driven study); FBR=future biological research; HBV=hepatitis B virus; HIV=human 
immunodeficiency virus; HSV = herpes simplex virus; PK=pharmacokinetic; RNA=ribonucleic acid; WOCBP=a woman/women of childbearing potential
Notes: All volumes are provided in mL. Serum pregnancy testing may be conducted using sample collected for chemistry (“off chem”) as indicated. HIV-1/HIV-2 
Antibody/Antigen Testing may be conducted using sample collected for HBV/HIV testing (“off HBV/HIV”) as indicated. Samples for PK may be used for dried blood testing 
for PK as indicated.
a
Samples are collected at every monthly visit up to Month 36 (29 visits for those who complete 3 years in study)
b
Samples are collected every 3 months up to Month 36 (9 additional visits for those who complete 3 years in study)
c
Samples are collected every 6 months up to Month 36 (4 additional visits for those who complete 3 years in study)
d.
Investigational PK is collected at one additional every 6 month visit due to different visit collection schedule 
e
Participants who become pregnant and remain on ISL, will have additional visits and PK samples amounting to approximately 21 mL total (not reflected in Table).
f
Negligible blood volume amount as sample is collected from another tube or fingerstick.
g
Blood volumes are calculated based on volume requirements at Central lab (US) and Regional lab (Africa). Slight variances may occur if a local lab is utilized.
h
Whole blood and Plasma Samples for HIV-1 Drug Resistance will be collected and analyzed every 3 months following HIV Infection Confirmation Visit (up to 12 
additional visit collections)
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10.3
Appendix 3: Adverse Events: Definitions and Procedures for Recording, 
Evaluating, Follow-up, and Reporting
10.3.1
Definitions of Medication Error, Misuse, and Abuse
Medication Error
This is an unintended failure in the drug treatment process that leads to or has the potential to 
lead to harm to the patient.
Misuse
This refers to situations where the medicinal product is intentionally and inappropriately used 
not in accordance with the terms of the product information.
Abuse
This corresponds to the persistent or sporadic, intentional excessive use of a medicinal 
product for a perceived psychological or physiological reward or desired non-therapeutic 
effect.
10.3.2
Definition of AE
AE definition
•
An AE is any untoward medical occurrence in a clinical study participant, temporally 
associated with the use of study intervention, whether or not considered related to the 
study intervention.
•
Note: An AE can therefore be any unfavorable and unintended sign (including an 
abnormal laboratory finding), symptom, or disease (new or exacerbated) temporally 
associated with the use of a study intervention.
•
Note: For purposes of AE definition, study intervention (also referred to as Sponsor’s 
product) includes any pharmaceutical product, biological product, vaccine, diagnostic 
agent, medical device, combination product, or protocol specified procedure whether 
investigational or marketed (including placebo, active comparator product, or run-in 
intervention), manufactured by, licensed by, provided by, or distributed by the Sponsor 
for human use in this study.
Events meeting the AE definition
•
Any abnormal laboratory test results (hematology, clinical chemistry, or urinalysis) or 
other safety assessments (eg, ECG, radiological scans, vital signs measurements), 
including those that worsen from baseline, considered clinically significant in the medical 
and scientific judgment of the investigator.
•
Exacerbation of a chronic or intermittent pre-existing condition including either an 
increase in frequency and/or intensity of the condition.
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•
New conditions detected or diagnosed after study intervention administration even 
though it may have been present before the start of the study.
•
Signs, symptoms, or the clinical sequelae of a suspected drug-drug interaction.
•
Signs, symptoms, or the clinical sequelae of a suspected overdose of either study 
intervention or a concomitant medication.
•
For all reports of overdose (whether accidental or intentional) with an associated AE, the 
AE term should reflect the clinical symptoms or abnormal test result. An overdose 
without any associated clinical symptoms or abnormal laboratory results is reported using 
the terminology “accidental or intentional overdose without adverse effect.”
•
Any new cancer or progression of existing cancer.
Events NOT meeting the AE definition
•
Medical or surgical procedure (eg, endoscopy, appendectomy): the condition that leads to 
the procedure is the AE.
•
Situations in which an untoward medical occurrence did not occur (social and/or 
convenience admission to a hospital).
•
Anticipated day-to-day fluctuations of pre-existing disease(s) or condition(s) present or 
detected at the start of the study that do not worsen.
•
Surgery planned prior to informed consent to treat a pre-existing condition that has not 
worsened.
•
Refer to Section 8.4.6 for protocol-specific exceptions.
10.3.3
Definition of SAE
If an event is not an AE per definition above, then it cannot be an SAE even if serious 
conditions are met.
An SAE is defined as any untoward medical occurrence that, at any dose:
a.
Results in death
b. Is life-threatening
•
The term “life-threatening” in the definition of “serious” refers to an event in which 
the participant was at risk of death at the time of the event. It does not refer to an 
event, which hypothetically might have caused death, if it were more severe.
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c.
Requires inpatient hospitalization or prolongation of existing hospitalization
•
Hospitalization is defined as an inpatient admission, regardless of length of stay, even 
if the hospitalization is a precautionary measure for continued observation. (Note: 
Hospitalization for an elective procedure to treat a pre-existing condition that has not 
worsened is not an SAE.) A pre-existing condition is a clinical condition that is 
diagnosed prior to the use of an MSD product and is documented in the participant’s 
medical history.
d. Results in persistent or significant disability/incapacity
•
The term disability means a substantial disruption of a person’s ability to conduct 
normal life functions.
•
This definition is not intended to include experiences of relatively minor medical 
significance such as uncomplicated headache, nausea, vomiting, diarrhea, influenza, 
and accidental trauma (eg, sprained ankle) that may interfere with or prevent 
everyday life functions but do not constitute a substantial disruption.
e.
Is a congenital anomaly/birth defect
•
In offspring of participant taking the product regardless of time to diagnosis.
f.
Other important medical events
•
Medical or scientific judgment should be exercised in deciding whether SAE 
reporting is appropriate in other situations such as important medical events that may 
not be immediately life-threatening or result in death or hospitalization but may 
jeopardize the participant or may require medical or surgical intervention to prevent 1 
of the other outcomes listed in the above definition. These events should usually be 
considered serious.
•
Examples of such events include invasive or malignant cancers, intensive treatment in 
an emergency room or at home for allergic bronchospasm, blood dyscrasias or 
convulsions that do not result in hospitalization, or development of drug dependency 
or drug abuse.
10.3.4
Additional Events Reported
Additional events that require reporting
In addition to the above criteria, AEs meeting either of the below criteria, although not 
serious per ICH definition, are reportable to the Sponsor.
•
Is a cancer
•
Is associated with an overdose
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10.3.5
Recording AE and SAE
AE and SAE recording
•
When an AE/SAE occurs, it is the responsibility of the investigator to review all 
documentation (eg, hospital progress notes, laboratory, and diagnostics reports) related to 
the event.
•
The investigator will record all relevant AE/SAE information on the AE 
CRFs/worksheets at each examination.
•
It is not acceptable for the investigator to send photocopies of the participant’s medical 
records to the Sponsor in lieu of completion of the AE CRF page.
•
There may be instances when copies of medical records for certain cases are requested by 
the Sponsor. In this case, all participant identifiers, with the exception of the participant 
number, will be blinded on the copies of the medical records before submission to the 
Sponsor.
•
The investigator will attempt to establish a diagnosis of the event based on signs, 
symptoms, and/or other clinical information. In such cases, the diagnosis (not the 
individual signs/symptoms) will be documented as the AE/SAE.
Assessment of intensity /toxicity
•
An event is defined as “serious” when it meets at least 1 of the predefined outcomes as 
described in the definition of an SAE, not when it is rated as severe.
•
The investigator will make an assessment of intensity for each AE and SAE (and other 
reportable safety event) by recording the grade according to the NIH DAIDS Table for 
Grading the Severity of Adult and Pediatric Adverse Events, version 2.1 
(https://rsc.niaid.nih.gov/sites/default/files/daidsgradingcorrectedv21.pdf). In addition, 
DAIDS Addendum 1 (Female Genital Grading Table for Use in Microbicide Studies) will 
be used as the primary grading table (and thus takes precedence over the main grading 
table) for obstetric and gynecologic AEs. Note exception to DAIDS Addendum 1: The 
presence of bacterial vaginosis detected by routine study collection is not considered an 
AE if, in the medical judgment of the investigator, it is not clinically significant 
(https://rsc.niaid.nih.gov/sites/default/files/addendum-1-female-genital-grading-table-v1-
nov-2007.pdf). Any AE, which changes DAIDS grade over the course of a given episode 
will have each change of grade recorded on the AE CRFs/worksheets.
-
Grade 1 Mild event: Mild symptoms causing no or minimal interference with usual 
social and functional activities with intervention not indicated.
-
Grade 2 Moderate event: Moderate symptoms causing greater than minimal 
interference with usual social and functional activities with intervention indicated.
-
Grade 3 Severe event: Severe symptoms causing inability to perform usual social and 
functional activities with intervention or hospitalization indicated.
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-
Grade 4 Potentially life-threatening event: Potentially life-threatening symptoms 
causing inability to perform basic self-care functions with intervention indicated to 
prevent permanent impairment, persistent disability, or death.
-
Grade 5 Death: Deaths related to an AE.
Assessment of causality
•
Did the Sponsor’s product cause the AE?
•
The determination of the likelihood that the Sponsor’s product caused the AE will be 
provided by an investigator who is a qualified physician. The investigator’s signed/dated 
initials on the source document or worksheet that supports the causality noted on the AE 
form, ensures that a medically qualified assessment of causality was done. This initialed 
document must be retained for the required regulatory time frame. The criteria below are 
intended as reference guidelines to assist the investigator in assessing the likelihood of a 
relationship between the test product and the AE based upon the available information.
•
The following components are to be used to assess the relationship between the 
Sponsor’s product and the AE; the greater the correlation with the components and 
their respective elements (in number and/or intensity), the more likely the Sponsor’s 
product caused the AE:
-
Exposure: Is there evidence that the participant was actually exposed to the 
Sponsor’s product such as: reliable history, acceptable compliance assessment (pill 
count, diary, etc), expected pharmacologic effect, or measurement of drug/metabolite 
in bodily specimen?
-
Time Course: Did the AE follow in a reasonable temporal sequence from 
administration of the Sponsor’s product? Is the time of onset of the AE compatible 
with a drug-induced effect (applies to studies with investigational medicinal product)?
-
Likely Cause: Is the AE not reasonably explained by another etiology such as 
underlying disease, other drug(s)/vaccine(s), or other host or environmental factors.
-
Dechallenge: Was the Sponsor’s product discontinued or dose/exposure/frequency 
reduced?
◦
If yes, did the AE resolve or improve?
◦
If yes, this is a positive dechallenge.
◦
If no, this is a negative dechallenge.
(Note: This criterion is not applicable if: (1) the AE resulted in death or permanent disability; 
(2) the AE resolved/improved despite continuation of the Sponsor’s product; (3) the study is 
a single dose drug study; or (4) Sponsor’s product(s) is/are only used 1 time.)
-
Rechallenge: Was the participant re-exposed to the Sponsor’s product in this study?
◦
If yes, did the AE recur or worsen?
◦
If yes, this is a positive rechallenge.
◦
If no, this is a negative rechallenge.
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(Note: This criterion is not applicable if: (1) the initial AE resulted in death or 
permanent disability, or (2) the study is a single dose drug study; or (3) Sponsor’s 
product(s) is/are used only 1 time.)
NOTE: IF A RECHALLENGE IS PLANNED FOR AN AE THAT WAS SERIOUS AND 
MAY HAVE BEEN CAUSED BY THE SPONSOR’S PRODUCT, OR IF RE-EXPOSURE 
TO THE SPONSOR’S PRODUCT POSES ADDITIONAL POTENTIAL SIGNIFICANT 
RISK TO THE PARTICIPANT THEN THE RECHALLENGE MUST BE APPROVED IN 
ADVANCE BY THE SPONSOR CLINICAL DIRECTOR, AND IF REQUIRED, THE 
IRB/IEC.
•
Consistency with study intervention profile: Is the clinical/pathological presentation of 
the AE consistent with previous knowledge regarding the Sponsor’s product or drug class 
pharmacology or toxicology?
•
The assessment of relationship will be reported on the case report forms/worksheets by 
an investigator who is a qualified physician according to his/her best clinical judgment, 
including consideration of the above elements.
•
Use the following scale of criteria as guidance (not all criteria must be present to be 
indicative of a Sponsor’s product relationship).
-
Yes, there is a reasonable possibility of Sponsor’s product relationship:
◦
There is evidence of exposure to the Sponsor’s product. The temporal sequence of 
the AE onset relative to the administration of the Sponsor’s product is reasonable. 
The AE is more likely explained by the Sponsor’s product than by another cause.
-
No, there is not a reasonable possibility of Sponsor’s product relationship:
◦
Participant did not receive the Sponsor’s product OR temporal sequence of the 
AE onset relative to administration of the Sponsor’s product is not reasonable OR 
the AE is more likely explained by another cause than the Sponsor’s product. 
(Also entered for a participant with overdose without an associated AE.)
•
For each AE/SAE, the investigator must document in the medical notes that he/she has 
reviewed the AE/SAE and has provided an assessment of causality.
•
There may be situations in which an SAE has occurred and the investigator has minimal 
information to include in the initial report to the Sponsor. However, it is very important 
that the investigator always make an assessment of causality for every event before the 
initial transmission of the SAE data to the Sponsor.
•
The investigator may change his/her opinion of causality in light of follow-up 
information and send an SAE follow-up report with the updated causality assessment.
•
The causality assessment is 1 of the criteria used when determining regulatory reporting 
requirements.
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Follow-up of AE and SAE
•
The investigator is obligated to perform or arrange for the conduct of supplemental 
measurements and/or evaluations as medically indicated or as requested by Sponsor to 
elucidate the nature and/or causality of the AE or SAE as fully as possible. This may 
include additional laboratory tests or investigations, histopathological examinations, or 
consultation with other health care professionals.
•
New or updated information will be recorded in the CRF.
•
The investigator will submit any updated SAE data to the Sponsor within 24 hours of 
receipt of the information.
10.3.6
Reporting of AEs, SAEs, and Other Reportable Safety Events to the Sponsor
AE, SAE, and other reportable safety event reporting to Sponsor via electronic data 
collection tool
•
The primary mechanism for reporting to the Sponsor will be the EDC tool.
-
Electronic reporting procedures can be found in the EDC data entry guidelines (or 
equivalent).
-
If the electronic system is unavailable for more than 24 hours, then the site will use 
the paper AE Reporting form.
◦
Reference Section 8.4.1 for reporting time requirements.
•
The site will enter the SAE data into the electronic system as soon as it becomes 
available.
•
After the study is completed at a given site, the EDC tool will be taken off-line to prevent 
the entry of new data or changes to existing data.
•
If a site receives a report of a new SAE from a study participant or receives updated data 
on a previously reported SAE after the EDC tool has been taken off-line, then the site can 
report this information on a paper SAE form or by telephone (see next section).
•
Contacts for SAE reporting can be found in the Investigator Study File Binder (or 
equivalent).
SAE reporting to the Sponsor via paper CRF
•
If the EDC tool is not operational, facsimile transmission or secure e-mail of the SAE 
paper CRF is the preferred method to transmit this information to the Sponsor.
•
In rare circumstances and in the absence of facsimile equipment, notification by 
telephone is acceptable with a copy of the SAE data collection tool sent by overnight 
mail or courier service.
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•
Initial notification via telephone does not replace the need for the investigator to 
complete and sign the SAE CRF pages within the designated reporting time frames.
•
Contacts and instructions for SAE reporting and paper reporting procedures can be found 
in the Investigator Study File Binder (or equivalent).
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10.4
Appendix 4: Device Events, Adverse Device Events, and Medical Device 
Incidents: Definitions, Collection, and Documentation
Not applicable.
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10.5
Appendix 5: Contraceptive Guidance
10.5.1
Definitions
Women of Childbearing Potential (WOCBP)
A woman is considered fertile following menarche and until becoming postmenopausal 
unless permanently sterile (see below):
If fertility is unclear (eg, amenorrhea in adolescents or athletes) and a menstrual cycle cannot 
be confirmed before first dose of study intervention, additional evaluation should be 
considered.
Women in the following categories are not considered WOCBP:
•
Premenarchal
•
Premenopausal female with 1 of the following:
-
Documented hysterectomy
-
Documented bilateral salpingectomy
-
Documented bilateral oophorectomy
For individuals with permanent infertility due to an alternate medical cause other than the 
above (eg, Mullerian agenesis, androgen insensitivity), investigator discretion should be 
applied to determining study entry.
Note: Documentation can come from the site personnel’s review of the participant’s 
medical records, medical examination, or medical history interview.
•
Postmenopausal female
-
A postmenopausal state is defined as no menses for 12 months without an alternative 
medical cause.
◦
A high FSH level in the postmenopausal range may be used to confirm a 
postmenopausal state in women not using hormonal contraception or HRT. 
However, in the absence of 12 months of amenorrhea, confirmation with 2 FSH 
measurements in the postmenopausal range is required.
Females on HRT and whose menopausal status is in doubt will be required to use one of the 
nonhormonal highly effective contraception methods if they wish to continue their HRT 
during the study. Otherwise, they must discontinue HRT to allow confirmation of
postmenopausal status before study enrollment.
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Women of Nonchildbearing Potential (WONCBP)
Women in the following categories are considered WONCBP:
•
Premenopausal female with 1 of the following:
-
Documented hysterectomy
-
Documented bilateral salpingectomy
-
Documented bilateral oophorectomy
For individuals with permanent infertility due to an alternate medical cause other than the 
above (eg, Mullerian agenesis, androgen insensitivity), investigator discretion should be 
applied to determining study entry.
Note: Documentation can come from the site personnel’s review of the participant’s 
medical records, medical examination, or medical history interview.
•
Postmenopausal female
-
A postmenopausal state is defined as no menses for 12 months without an alternative 
medical cause.
◦
A high FSH level in the postmenopausal range may be used to confirm a 
postmenopausal state in women not using hormonal contraception or HRT. 
However, in the absence of 12 months of amenorrhea, confirmation with 2 FSH 
measurements in the postmenopausal range is required.
-
Females on HRT and whose menopausal status is in doubt must discontinue HRT to 
allow confirmation of postmenopausal status before study enrollment.
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10.5.2
Contraception Requirements
Contraceptives allowed during the study includea:
Highly Effective Contraceptive Methods That Have Low User Dependencyb
Failure rate of <1% per year when used consistently and correctly.
•
Progestogen- only contraceptive implantc 
•
IUSd
•
Non-hormonal IUD
•
Bilateral tubal occlusion
•
Azoospermic partner (vasectomized or secondary to medical cause)
This is a highly effective contraception method provided that the partner is the sole male sexual partner of the WOCBP 
and the absence of sperm has been confirmed. If not, an additional highly effective method of contraception should be 
used. A spermatogenesis cycle is approximately 90 days.
Note: Documentation of azoospermia can come from the site personnel’s review of the participant’s medical records, 
medical examination, or medical history interview.
Highly Effective Contraceptive Methods That Are User Dependentb
Failure rate of <1% per year when used consistently and correctly.
•
Combined (estrogen- and progestogen- containing) hormonal contraceptionc
-
Oral
-
Intravaginal
-
Transdermal
-
Injectable
•
Progestogen-only hormonal contraceptionc
-
Oral
-
Injectable
Acceptable Contraceptive Methods
Failure rate of >1% per year when used consistently and correctly.
•
Progesterone-only hormonal contraception where inhibition of ovulation is not the primary mode of action
•
Male or female condom with or without spermicide
•
Cervical cap, diaphragm, or sponge with spermicide
•
A combination of male condom with either cervical cap, diaphragm, or sponge with spermicide (double barrier 
methods)e
a
Contraceptive use by men or women should be consistent with local regulations regarding the use of contraceptive 
methods for participants of clinical studies.
b
Typical use failure rates are higher than perfect-use failure rates (ie, when used consistently and correctly).
c
If locally required, in accordance with CTFG guidelines, acceptable contraceptive implants are limited to those which 
inhibit ovulation. 
d
IUS is a progestin releasing IUD.
e
A combination of male condom with either cap, diaphragm, or sponge with spermicide are considered acceptable, but 
not highly effective, birth control methods. 
Note: The following are not acceptable methods of contraception:
-  Periodic abstinence (calendar, symptothermal, post-ovulation methods), withdrawal (coitus interruptus), 
spermicides only, and LAM.
-  Male and female condom should not be used together (due to risk of failure with friction).
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10.6
Appendix 6: Collection and Management of Specimens for Future Biomedical 
Research
1.   Definitions
a.   Biomarker: A biological molecule found in blood, other body fluids, or tissues that is
a sign of a normal or abnormal process or of a condition or disease. A biomarker may
be used to see how well the body responds to a treatment for a disease or condition.1
b.   Pharmacogenomics: The investigation of variations of DNA and RNA characteristics 
as related to drug/vaccine response.2
c.   Pharmacogenetics: A subset of pharmacogenomics, pharmacogenetics is the influence 
of variations in DNA sequence on drug/vaccine response.2
d.   DNA: Deoxyribonucleic acid.
e.   RNA: Ribonucleic acid.
2.   Scope of Future Biomedical Research3, 4
The specimens consented and/or collected in this study as outlined in Section 8.9 will be 
used in various experiments to understand:
    The biology of how drugs/vaccines work
    Biomarkers responsible for how a drug/vaccine enters and is removed by the body
    Other pathways with which drugs/vaccines may interact
    The biology of disease
The specimen(s) may be used for future assay development and/or drug/vaccine 
development.
It is now well recognized that information obtained from studying and testing clinical 
specimens offers unique opportunities to enhance our understanding of how individuals 
respond to drugs/vaccines, enhance our understanding of human disease and ultimately 
improve public health through development of novel treatments targeted to populations 
with the greatest need. All specimens will be used by the Sponsor or those working for or 
with the Sponsor.
3.   Summary of Procedures for Future Biomedical Research3, 4
a.   Participants for Enrollment
All participants enrolled in the clinical study will be considered for enrollment in 
future biomedical research.
b.   Informed Consent
Informed consent for specimens (ie, DNA, RNA, protein, etc) will be obtained during 
screening for protocol enrollment from all participants or legal guardians, at a study 
visit by the investigator or his or her designate. Informed consent for future 
biomedical research should be presented to the participants on the visit designated in 
the SoA. If delayed, present consent at next possible Participant Visit. Consent forms 
signed by the participant will be kept at the clinical study site under secure storage for 
regulatory reasons.
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A template of each study site’s approved informed consent will be stored in the 
Sponsor’s clinical document repository.
c.   eCRF Documentation for Future Biomedical Research Specimens
Documentation of participant consent for future biomedical research will be captured 
in the eCRFs. Any specimens for which such an informed consent cannot be verified 
will be destroyed.
d.   Future Biomedical Research Specimen(s)
Collection of specimens for future biomedical research will be performed as outlined 
in the SoA. In general, if additional blood specimens are being collected for future 
biomedical research, these will usually be obtained at a time when the participant is 
having blood drawn for other study purposes.
4.   Confidential Participant Information for Future Biomedical Research3, 4
In order to optimize the research that can be conducted with future biomedical research
specimens, it is critical to link participants' clinical information with future test results. In 
fact, little or no research can be conducted without connecting the clinical study data to 
the specimen. The clinical data allow specific analyses to be conducted. Knowing 
participant characteristics like sex, age, medical history and intervention outcomes are 
critical to understanding clinical context of analytical results.
To maintain privacy of information collected from specimens obtained for future 
biomedical research, the Sponsor has developed secure policies and procedures. All 
specimens will be single-coded per ICH E15 guidelines as described below.
At the clinical study site, unique codes will be placed on the future biomedical research
specimens. This code is a random number which does not contain any personally 
identifying information embedded within it. The link (or key) between participant 
identifiers and this unique code will be held at the study site. No personal identifiers will 
appear on the specimen tube.
5.   Biorepository Specimen Usage3, 4
Specimens obtained for the Sponsor will be used for analyses using good scientific 
practices. Analyses utilizing the future biomedical research specimens may be performed 
by the Sponsor, or an additional third party (eg, a university investigator) designated by 
the Sponsor. The investigator conducting the analysis will follow the Sponsor’s privacy 
and confidentiality requirements. Any contracted third party analyses will conform to the 
specific scope of analysis outlined in future biomedical research protocol and consent. 
Future biomedical research specimens remaining with the third party after specific 
analysis is performed will be reported to the Sponsor.
6.   Withdrawal From Future Biomedical Research3, 4
Participants may withdraw their consent for future biomedical research and ask that their 
biospecimens not be used for future biomedical research. Participants may withdraw 
consent at any time by contacting the investigator for the main study. If medical records 
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for the main study are still available, the investigator will contact the Sponsor using the 
designated mailbox (clinical.specimen.management@MSD.com). Subsequently, the 
participant's specimens will be flagged in the biorepository and restricted to main study 
use only. If specimens were collected from study participants specifically for future 
biomedical research, these specimens will be removed from the biorepository and 
destroyed. Documentation will be sent to the investigator confirming withdrawal and/or 
destruction, if applicable. It is the responsibility of the investigator to inform the 
participant of completion of the withdrawal and/or destruction, if applicable. Any 
analyses in progress at the time of request for withdrawal/destruction or already 
performed prior to the request being received by the Sponsor will continue to be used as 
part of the overall research study data and results. No new analyses would be generated 
after the request is received.
In the event that the medical records for the main study are no longer available (eg, if the 
investigator is no longer required by regulatory authorities to retain the main study 
records) or the specimens have been completely anonymized, there will no longer be a 
link between the participant’s personal information and their specimens. In this situation, 
the request for withdrawal of consent and/or destruction cannot be processed.
7.   Retention of Specimens3, 4
Future biomedical research specimens will be stored in the biorepository for potential 
analysis for up to 20 years from the end of the main study. Specimens may be stored for 
longer if a regulatory or governmental authority has active questions that are being 
answered. In this special circumstance, specimens will be stored until these questions 
have been adequately addressed.
Specimens from the study site will be shipped to a central laboratory and then shipped to 
the Sponsor-designated biorepository. If a central laboratory is not utilized in a particular 
study, the study site will ship directly to the Sponsor-designated biorepository. The 
specimens will be stored under strict supervision in a limited access facility which 
operates to assure the integrity of the specimens. Specimens will be destroyed according 
to Sponsor policies and procedures and this destruction will be documented in the 
biorepository database.
8.   Data Security3, 4
Databases containing specimen information and test results are accessible only to the 
authorized Sponsor representatives and the designated study administrator research 
personnel and/or collaborators. Database user authentication is highly secure, and is 
accomplished using network security policies and practices based on international 
standards to protect against unauthorized access.
9.   Reporting of Future Biomedical Research Data to Participants3, 4
No information obtained from exploratory laboratory studies will be reported to the 
participant, family, or physicians. Principle reasons not to inform or return results to the 
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participant include: Lack of relevance to participant health, limitations of predictive 
capability, and concerns regarding misinterpretation.
If important research findings are discovered, the Sponsor may publish results, present 
results in national meetings, and make results accessible on a public website in order to
rapidly report this information to doctors and participants. Participants will not be 
identified by name in any published reports about this study or in any other scientific 
publication or presentation.
10. Future Biomedical Research Study Population3, 4
Every effort will be made to recruit all participants diagnosed and treated on Sponsor 
clinical studies for future biomedical research.
11. Risks Versus Benefits of Future Biomedical Research3, 4
For future biomedical research, risks to the participant have been minimized and are 
described in the future biomedical research informed consent.
The Sponsor has developed strict security, policies, and procedures to address participant 
data privacy concerns. Data privacy risks are largely limited to rare situations involving 
possible breach of confidentiality. In this highly unlikely situation, there is risk that the 
information, like all medical information, may be misused.
12. Questions
Any questions related to the future biomedical research should be emailed directly to 
clinical.specimen.management@MSD.com.
13. References
1.   National Cancer Institute [Internet]: Available from 
https://www.cancer.gov/publications/dictionaries/cancer-terms?cdrid=45618
2.   International Council on Harmonisation [Internet]: E15: Definitions for Genomic 
Biomarkers, Pharmacogenomics, Pharmacogenetics, Genomic Data and Sample 
Coding Categories. Available from 
http://www.ich.org/products/guidelines/efficacy/efficacy-single/article/definitions-
for-genomic-biomarkers-pharmacogenomics-pharmacogenetics-genomic-data-and-
sample-cod.html 
3.   Industry Pharmacogenomics Working Group [Internet]: Understanding the Intent, 
Scope and Public Health Benefits of Exploratory Biomarker Research: A Guide for 
IRBs/IECs and Investigational Site Staff. Available at http://i-pwg.org/ 
4.   Industry Pharmacogenomics Working Group [Internet]: Pharmacogenomics 
Informational Brochure for IRBs/IECs and Investigational Site Staff. Available at 
http://i-pwg.org/
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10.7
Appendix 7: Country-specific Requirements
There are no country-specific requirements.
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10.8
Appendix 8: Abbreviations
Abbreviation
Expanded Term
3TC
lamivudine
AE
adverse event 
ALT
alanine aminotransferase
ANCOVA
analysis of covariance
APaT
All-Participants-as-Treated
ART
antiretroviral therapy
AST
aspartate aminotransferase
BMI
body mass index
C168hr
concentration at 168 hours postdose
CAC
Clinical Adjudication Committee
CDC
Centers for Disease Control
CI
confidence interval
Cmax
maximum serum concentration
CONSORT
Consolidated Standards of Reporting Trials
CrCl
creatinine clearance
CRF
Case Report Form 
CSR
Clinical Study Report
CTCAE
Common Terminology Criteria for Adverse Events
CTR
Clinical Trial Regulation
DAIDS
Division of AIDS
DDI
drug-drug interaction
DILI
drug-induced liver injury
DMC
Data Monitoring Committee 
DNA
deoxyribonucleic acid 
DOR
doravirine
DP
diphosphate
EC90
90% effective concentration
ECG
electrocardiogram 
ECI
event of clinical interest
eCRF
electronic Case Report Form
EDC
electronic data collection 
EEA
European Economic Area
EFV
efavirenz
EMA
European Medicines Agency
EOC
Executive Oversight Committee 
FBR
Future Biomedical Research
FDA
Food and Drug Administration
FDAAA
Food and Drug Administration Amendments Act
FRR
false-recent rate
FSH
follicle-stimulating hormone
FSR
First Site Ready
FTC/TDF
emtricitabine/tenofovir disoproxil (including TRUVADATM
and all generic versions)
GCP
Good Clinical Practice 
GC/CT
Neisseria gonorrhoeae/Chlamydia trachomatis
HBsAg
Hepatitis B surface antigen
HBV
Hepatitis B virus
hCG
human chorionic gonadotropin
HIV
human immunodeficiency virus
HRT
hormone replacement therapy
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Abbreviation
Expanded Term
HSV
herpes simplex virus
IB
Investigator’s Brochure 
IA
interim analysis
IC50
half-maximal inhibitory concentration
ICF
Informed Consent Form
ICH
International Council for Harmonisation of Technical 
Requirements for Pharmaceuticals for Human Use
IEC
Independent Ethics Committee
IgG
immunoglobulin G
IMP
Investigational Medicinal Product
IND
Investigational New Drug 
iPrEx
Preexposure Prophylaxis Initiative
IRB
Institutional Review Board
IRT
interactive response technology
ISL
islatravir
LAg
Limiting Antigen
MDRI
mean duration of recent infections
mFAS
modified Full Analysis Set
NI
noninferiority
NIMP
Noninvestigational medicinal product
NNRTI
nonnucleoside reverse transcriptase inhibitor
NRTTI
nucleoside reverse transcriptase translocation inhibitor
PBMC
peripheral blood mononuclear cells
PCR
polymerase chain reaction
PDLC
predefined limit of change
PE
prevention efficacy
PEP
postexposure prophylaxis
PEPFAR
President’s Emergency Plan For AIDS Relief
PK
pharmacokinetic
PrEP
preexposure prophylaxis
PRO
participant-reported outcome
QD
once daily
QM
once-monthly
QW
Once-weekly
RNA
ribonucleic acid
SAC
Scientific Advisory Committee
SAE
serious adverse event 
SAP
Statistical Analysis Plan
SHIV
simian human immunodeficiency virus
SoA
schedule of activities
SOP
standard operating procedure
sSAP
supplemental Statistical Analysis Plan
STI
sexually transmitted infection
SUSAR
suspected unexpected serious adverse reaction
TFV
tenofovir
TP
triphosphate
ULN
Upper limit of normal
US
United States
USPSTF
United States Preventive Services Task Force
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Abbreviation
Expanded Term
VAMS
volumetric absorptive microsampling
VOICE
Vaginal and Oral Interventions to Control the Epidemic
WHO
World Health Organization
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10.9
Appendix 9: Calculation of Creatinine Clearance
Cockcroft-Gault equation (for female participants):
CrCL (mL/min) = (140-age [y]) × weight [kg]) × 0.85
72 × serum creatinine (mg/dL)
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10.10 Appendix 10: Document to Support Assessment of HIV-1 Infection Risk/CDC 
Criteria for PrEP
10.10.1
Background
Inclusion Criteria 3 of Protocol MK-8591 P022 references 2 commonly used HIV risk 
assessments to be utilized by investigators or study staff at screening for this study 
(depending upon study location). This document provides supporting information regarding 
the 2 assessments.
•
The VOICE risk score tool – to be used by sites in Africa
•
The CDC criteria for PrEP eligibility – to be used by sites in the US
The Protocol team has assembled this document to provide links to the full guidance and a 
brief presentation of specific information appropriate for evaluation in the trial.
Protocol Inclusion Criteria:
3. Is at high risk for HIV-1 infection as defined by a risk score ≥5 using a VOICE risk score 
tool (sites in Africa) or meets the CDC criteria for PrEP eligibility (sites in the US).
10.10.2
VOICE Risk Score – Sites in Africa
The Vaginal and Oral Interventions to Control the Epidemic (VOICE) trial was a 
randomized, placebo-controlled trial to assess oral tenofovir disoproxil fumarate (TDF), oral 
TDF-emtricitabine (FTC), or 1% tenofovir (TFV) vaginal gel as PrEP in women in South 
Africa, Uganda, and Zimbabwe (https://www.nejm.org/doi/full/10.1056/NEJMoa1402269). 
Of 12,320 women screened, 5,029 were enrolled. The rate of retention was 91% during 5,509 
person-years of follow-up. A total of 312 HIV-1 infections occurred; the incidence of HIV-1 
infection was 5.7 per 100 person-years. Although none of the drug regimens evaluated 
reduced the rates of HIV-1 acquisition in an intention-to-treat analysis, the data were used to 
develop: “An Empiric HIV Risk Scoring Tool to Predict HIV-1 Acquisition in Africa 
Women,” (https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4911322/pdf/nihms761084.pdf) 
in which data from the VOICE trial were analyzed and a risk score was derived; 2 other 
randomized trials of biomedical HIV prevention interventions among African women, 
HPTN 035 of microbicide gel and FEM-PrEP of TDF-FTC, were used to validate this risk 
score.
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10.10.2.1
VOICE Risk Score Tool
Per-Protocol MK-8591 P022: Is at high risk for HIV-1 infection as defined by a risk score 
≥5.
Risk Factor
Points
Age <25
2
Not married or living with primary partner
2
Partner does NOT provide financial or material support
1
Primary partner has other partners, yes or maybe
2
Alcohol use in past 3 months
1
Curable sexually transmitted infection at screen
1
Herpes simplex virus-2 seropositive
2
Maximum possible Points
11
10.10.3
CDC Criteria for PrEP – Sites in the US
The US Public Health Service Centers for Disease Control issued a Clinical Practice 
Guideline entitled PREEXPOSURE PROPHYLAXIS FOR THE PREVENTION OF HIV 
INFECTION IN THE UNITED STATES-2017 UPDATE: 
https://www.cdc.gov/hiv/pdf/risk/prep/cdc-hiv-prep-guidelines-2017.pdf
The criteria for assessment of high risk for HIV-1 infection for enrollment of female 
participants in US sites for Protocol MK-8591 P022 inclusion criterion #3 is provided below 
(modified from the CDC Guidance for MK-8591 P022):
Not in a (mutually) monogamous partnership with a recently tested (within the past 6 months) HIV-negative 
partner
AND at least one of the following:
•
Infrequently uses condoms during sex with 1 or more partners of unknown HIV status who are known to 
be at substantial risk of HIV infection (person who injects drugs or has injected drugs within the past 6 
months, or bisexual male partner) or has exchanged sex for commodities (eg, shelter, drugs, money) in 
the past 6 months
•
Is in an ongoing sexual relationship with an HIV-positive partner
•
A bacterial STI (syphilis, gonorrhea, chlamydia*) diagnosed or reported in past 6 months
*
We are including chlamydia because the CDC guidelines also state “In addition, for all sexually active 
patients, clinicians may want to consider reports of diagnoses of bacterial STIs (chlamydia, syphilis, 
gonorrhea) during the past 6 months as evidence of sexual activity that could result in HIV exposure.”
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Version 
Number
Date
Summary of Changes
1.0
Original Version (not originally a Protocol Appendix)
2.0
01-MAY-21
• Updated “Clinicians” to “investigators or study staff at screening”
• Updated References of “Non-US Sites” and “Ex-US Sites” to “sites in 
Africa”
• Updated References of “US Sites” to “sites in the US”
• Updated the parenthetical statement in the first bullet in the table of 
recommended indications for PrEP use by heterosexually active 
women (MK-8591 P022 Specific). The statement formerly read 
“(Person Who Injects Drugs or bisexual male partner)” and was 
updated to “(person who injects drugs or has injected drugs within the 
last 6 months, or bisexual male partner)”
• Removed an errant extra “)” in the table of recommended indications 
for PrEP use by heterosexually active women (MK-8591 P022 
Specific).
3.0
DD-MMM-
21
Updated the CDC Criteria for PrEP – Sites in the US as follows:
• Revised text from
Box B2 of the CDC Guideline provides Recommended Indications for 
PrEP Use by Heterosexually Active Men and Women.
The criteria for assessment of high risk for HIV-1 infection for 
enrollment of female participants in US sites for Protocol MK-8591 
P022 inclusion criteria #3 is provided below (modified for MK-8591 
P022 to be appropriate specific to women in the study).
Recommended indications for PrEP use by heterosexually active 
women (MK-8591 P022 Specific):
To
The criteria for assessment of high risk for HIV-1 infection for 
enrollment of female participants in US sites for Protocol MK-8591 
P022 inclusion criteria #3 is provided below (modified from the CDC 
Guidance for MK-8591 P022).
• Updated the first bullet in the criteria for assessment of high risk for 
HIV-1 infection to include “or has exchanged sex for commodities (eg, 
shelter, drugs, money) in the past 6 months.”
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10.11 Appendix 11: MK-8591 PrEP Program HIV Testing Algorithm
Ab=antibody; Ag=antigen; HIV=human immunodeficiency virus; POC=point-of-care; PrEP=preexposure prophylaxis; VL=viral load.
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11
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08J537


PRODUCT: MK-8591  
168
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MK-8591-022-04 FINAL PROTOCOL
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170
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MK-8591-022-04 FINAL PROTOCOL
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MK-8591-022-04 FINAL PROTOCOL
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