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 Men and Transgender Women Who Have Sex With Men, and Are at High Risk for HIV-1 Infection
Phase: PHASE3
Conditions: HIV Preexposure Prophylaxis
Sponsor: Merck Sharp & Dohme LLC

Official Protocol Title: 
NCT number: 
NCT04652700 
Document Date: 
02-DEC-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 Men and 
Transgender Women Who Have Sex With Men, and Are
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 Men and Transgender Women Who Have Sex With Men, and Are 
at High Risk for HIV-1 Infection 
Protocol Number: 024-05
Compound Number: MK-8591
Sponsor Name:
Merck Sharp & Dohme LLC
(hereafter referred to as 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
2020-003309-79
Approval Date: 02 December 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 05
02-DEC-2022
The protocol was amended to extend the study duration from Month 24 to Month 30 to 
allow for additional safety follow-up.
Amendment 04
03-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 or FTC/TAF, 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 FTC/TAF 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
06-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
07-JUN-2021
The protocol was amended to update the statistical methods for primary and secondary 
objectives, to add a blinded IA for sample size re-estimation, and to modify power 
assumptions.
Original Protocol
09-NOV-2020
Not applicable
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PROTOCOL AMENDMENT SUMMARY OF CHANGES
Amendment: 05
Overall Rationale for the Amendments:
This amendment is to extend the study duration from Month 24 to Month 30 to allow for additional safety follow-up.
Summary of Changes Table:
Section # and Name
Description of Change 
Brief Rationale 
Synopsis
Section 4.1 Overall Design
The duration of participation was updated from “up 
to 2.5 years” to “approximately 2.5 years”.
To extend the study duration for additional 
safety follow-up
Section 1.3.1 Schedule of 
Activities for Part 1, Part 2, 
and Part 3
The table and footnotes ‘b’ and ‘c’ were updated to
extend the study duration from Month 24 to Month 
30.
The table footnote ‘f’ was added.
To extend the study duration for additional 
safety follow-up
For clarity of operational visit tracking
Section 1.3.3 Schedule of 
Activities – Participants 
Who Have A Positive HIV-1 
Test
The table was updated to include lymphocyte subset 
panel in the CD4+ T-cell count.
Footnote ‘a’ was updated to extend the study 
duration from Month 24 to Month 30.
For clarity
To extend the study duration for additional 
safety follow-up
Section 8 Study Assessments 
and Procedures
Section 10.2 Clinical 
Laboratory Tests
The total volume of blood collected was updated in 
the text and in Table 14.
To reflect the volume of blood collected from 
the additional study visits
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Table of Contents
DOCUMENT HISTORY ........................................................................................................3
PROTOCOL AMENDMENT SUMMARY OF CHANGES...............................................4
1
PROTOCOL SUMMARY ............................................................................................13
1.1
Synopsis.................................................................................................................13
1.2
Schema ..................................................................................................................17
1.3
Schedule of Activities...........................................................................................19
1.3.1
Schedule of Activities for Part 1, Part 2, and Part 3 ....................................19
1.3.2
Schedule of Activities – Participants Who Discontinue Study 
Intervention Early and/or Withdraw Consent/Assent..................................29
1.3.3
Schedule of Activities – Participants Who Have A Positive HIV-1 Test....32
2
INTRODUCTION..........................................................................................................35
2.1
Study Rationale....................................................................................................35
2.2
Background ..........................................................................................................37
2.2.1
Pharmaceutical and Therapeutic Background .............................................37
2.2.2
Information on Other Study-related Therapy ..............................................37
2.3
Benefit/Risk Assessment......................................................................................38
3
HYPOTHESES, OBJECTIVES, AND ENDPOINTS................................................39
4
STUDY DESIGN............................................................................................................41
4.1
Overall Design......................................................................................................41
4.2
Scientific Rationale for Study Design.................................................................43
4.2.1
Rationale for Endpoints ...............................................................................44
4.2.1.1
Efficacy Endpoints.............................................................................44
4.2.1.2
Safety Endpoints................................................................................45
4.2.1.3
Participant-reported Outcomes ..........................................................45
4.2.1.4
Laboratory and Weight Markers........................................................45
4.2.1.5
Pharmacokinetic Endpoints ...............................................................46
4.2.1.6
Planned Exploratory Biomarker Research.........................................46
4.2.1.6.1
Planned Genetic Analysis ........................................................46
4.2.1.7
Future Biomedical Research..............................................................46
4.2.2
Rationale for the Use of Comparator/Placebo .............................................47
4.2.3
Rationale for Estimating Background HIV-1 Incidence Rate .....................48
4.2.4
Rationale for Collecting Behavioral Assessment Data................................49
4.2.5
Rationale for Collecting Race and Ethnicity Data.......................................49
4.3
Justification for Dose...........................................................................................49
4.3.1
Rationale for ISL QM Efficacious Exposure...............................................49
4.3.2
Rationale for Dose Selection .......................................................................51
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4.4
Beginning and End of Study Definition .............................................................52
4.4.1
Clinical Criteria for Early Study Termination .............................................52
5
STUDY POPULATION ................................................................................................52
5.1
Inclusion Criteria.................................................................................................53
5.2
Exclusion Criteria................................................................................................54
5.3
Lifestyle Considerations......................................................................................56
5.4
Screen Failures.....................................................................................................56
5.5
Participant Replacement Strategy......................................................................56
6
STUDY INTERVENTION............................................................................................56
6.1
Study Intervention(s) Administered...................................................................56
6.2
Preparation/Handling/Storage/Accountability .................................................59
6.2.1
Dose Preparation..........................................................................................59
6.2.2
Handling, Storage, and Accountability........................................................59
6.3
Measures to Minimize Bias: Randomization and Blinding..............................60
6.3.1
Intervention Assignment..............................................................................60
6.3.2
Stratification.................................................................................................60
6.3.3
Blinding........................................................................................................61
6.4
Study Intervention Compliance..........................................................................62
6.5
Concomitant Therapy..........................................................................................62
6.5.1
Rescue Medications and Supportive Care ...................................................64
6.6
Dose Modification (Escalation/Titration/Other)...............................................64
6.7
Intervention After the End of the Study............................................................64
6.8
Clinical Supplies Disclosure................................................................................64
6.9
Standard Policies..................................................................................................64
7
DISCONTINUATION OF STUDY INTERVENTION AND PARTICIPANT 
WITHDRAWAL............................................................................................................65
7.1
Discontinuation of Study Intervention...............................................................65
7.2
Participant Withdrawal From the Study...........................................................66
7.3
Lost to Follow-up .................................................................................................67
8
STUDY ASSESSMENTS AND PROCEDURES........................................................67
8.1
Administrative and General Procedures ...........................................................68
8.1.1
Informed Consent.........................................................................................68
8.1.1.1
General Informed Consent.................................................................68
8.1.1.2
Consent and Collection of Specimens for Future Biomedical 
Research.............................................................................................69
8.1.2
Inclusion/Exclusion Criteria ........................................................................69
8.1.2.1
HIV Recency Assay Testing..............................................................69
8.1.3
Participant Identification Card.....................................................................69
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8.1.4
Medical History ...........................................................................................69
8.1.5
Prior and Concomitant Medications Review...............................................70
8.1.5.1
Prior Medications...............................................................................70
8.1.5.2
Concomitant Medications..................................................................70
8.1.6
Assignment of Screening Number...............................................................70
8.1.6.1
Treatment Eligibility Assessment Form ............................................70
8.1.7
Assignment of Treatment/Randomization Number.....................................70
8.1.8
Study Intervention Administration ..............................................................71
8.1.8.1
Timing of Dose Administration.........................................................71
8.1.8.2
Interruption of Study Intervention .....................................................72
8.1.9
Discontinuation and Withdrawal .................................................................72
8.1.9.1
Withdrawal From Future Biomedical Research ................................72
8.1.10
Participant Blinding/Unblinding..................................................................72
8.1.11
Calibration of Equipment.............................................................................73
8.1.12
HIV Risk Reduction.....................................................................................74
8.1.13
Participant-reported Outcomes ....................................................................74
8.2
Efficacy Assessments ...........................................................................................74
8.2.1
HIV-1 Testing..............................................................................................74
8.2.2
Whole Blood Collection for HIV-1 Resistance Testing ..............................75
8.3
Safety Assessments...............................................................................................75
8.3.1
Physical Examinations.................................................................................75
8.3.2
Vital Signs....................................................................................................75
8.3.3
Sexually Transmitted Infections ..................................................................75
8.3.4
Clinical Safety Laboratory Assessments .....................................................76
8.3.5
Review of Social Harm Events....................................................................76
8.4
Adverse Events, Serious Adverse Events, and Other Reportable Safety 
Events....................................................................................................................76
8.4.1
Time Period and Frequency for Collecting AE, SAE, and Other 
Reportable Safety Event Information ..........................................................77
8.4.2
Method of Detecting AEs, SAEs, and Other Reportable Safety Events......79
8.4.3
Follow-up of AE, SAE, and Other Reportable Safety Event Information...79
8.4.4
Regulatory Reporting Requirements for SAE .............................................79
8.4.5
Pregnancy and Exposure During Breastfeeding ..........................................79
8.4.6
Disease-related Events and/or Disease-related Outcomes Not Qualifying 
as AEs or SAEs............................................................................................79
8.4.7
Events of Clinical Interest............................................................................80
8.5
Treatment of Overdose........................................................................................80
8.6
Pharmacokinetics.................................................................................................80
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8.6.1
Blood (Plasma) Collection for PK...............................................................80
8.6.2
Blood (Plasma) for Investigational PK........................................................81
8.6.3
Dried Blood Collection for PK ....................................................................81
8.6.4
Collection of PK Samples in Participants Who Discontinue Study 
Intervention Early, Withdraw Consent/Assent, or Have a Positive HIV-
1 Test............................................................................................................82
8.7
Pharmacodynamics..............................................................................................82
8.8
Biomarkers ...........................................................................................................82
8.8.1
Planned Genetic Analysis Sample Collection..............................................82
8.8.2
Renal Biomarkers.........................................................................................83
8.9
Future Biomedical Research Sample Collection...............................................83
8.10
Medical Resource Utilization and Health Economics.......................................83
8.11
Visit Requirements...............................................................................................83
8.11.1
Screening......................................................................................................83
8.11.2
Treatment Period..........................................................................................84
8.11.2.1
Off-site Visits.....................................................................................84
8.11.3
Participants Who Discontinue Study Intervention.......................................84
8.11.4
Participants Who Withdraw Consent/Assent...............................................85
8.11.5
Follow-up Phone Calls.................................................................................85
9
STATISTICAL ANALYSIS PLAN .............................................................................85
9.1
Statistical Analysis Plan Summary.....................................................................86
9.2
Responsibility for Analyses/In-house Blinding .................................................87
9.3
Hypotheses/Estimation ........................................................................................88
9.4
Analysis Endpoints...............................................................................................88
9.4.1
Efficacy Endpoint ........................................................................................88
9.4.2
Safety Endpoints..........................................................................................88
9.5
Analysis Populations............................................................................................88
9.5.1
Efficacy Analysis Population.......................................................................88
9.5.2
Safety Analysis Population..........................................................................88
9.6
Statistical Methods...............................................................................................89
9.6.1
Efficacy Analysis.........................................................................................89
9.6.2
Safety Analysis ............................................................................................91
9.6.3
Demographic and Baseline Characteristics .................................................93
9.7
Interim Analyses ..................................................................................................94
9.8
Multiplicity ...........................................................................................................95
9.9
Sample Size and Power Calculations .................................................................95
9.9.1
Sample Size and Power for Efficacy Analyses............................................95
9.9.2
Sample Size and Power for Safety Analyses ...............................................98
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9.10
Subgroup Analyses.............................................................................................100
9.11
Compliance (Medication Adherence)...............................................................100
9.12
Extent of Exposure.............................................................................................100
10
SUPPORTING DOCUMENTATION AND OPERATIONAL 
CONSIDERATIONS...................................................................................................101
10.1
Appendix 1: Regulatory, Ethical, and Study Oversight Considerations......101
10.1.1
Code of Conduct for Clinical Trials...........................................................101
10.1.2
Financial Disclosure...................................................................................103
10.1.3
Data Protection...........................................................................................104
10.1.3.1
Confidentiality of Data ....................................................................104
10.1.3.2
Confidentiality of Participant Records.............................................104
10.1.3.3
Confidentiality of IRB/IEC Information..........................................104
10.1.4
Committees Structure.................................................................................105
10.1.4.1
Scientific Advisory Committee (SAC)............................................105
10.1.4.2
External Data Monitoring Committee .............................................105
10.1.4.3
Clinical Adjudication Committee (CAC) ........................................105
10.1.4.4
Executive Oversight Committee......................................................105
10.1.5
Publication Policy......................................................................................105
10.1.6
Compliance with Study Registration and Results Posting Requirements .106
10.1.7
Compliance with Law, Audit, and Debarment ..........................................106
10.1.8
Data Quality Assurance .............................................................................107
10.1.9
Source Documents .....................................................................................108
10.1.10
Study and Site Closure...............................................................................108
10.2
Appendix 2: Clinical Laboratory Tests............................................................109
10.3
Appendix 3: Adverse Events: Definitions and Procedures for Recording, 
Evaluating, Follow-up, and Reporting.............................................................116
10.3.1
Definitions of Medication Error, Misuse, and Abuse................................116
10.3.2
Definition of AE ........................................................................................116
10.3.3
Definition of SAE ......................................................................................117
10.3.4
Additional Events Reported.......................................................................118
10.3.5
Recording AE and SAE .............................................................................119
10.3.6
Reporting of AEs, SAEs, and Other Reportable Safety Events to the 
Sponsor ......................................................................................................122
10.4
Appendix 4: Device Events, Adverse Device Events, and Medical Device 
Incidents: Definitions, Collection, and Documentation..................................124
10.5
Appendix 5: Contraceptive Guidance..............................................................125
10.6
Appendix 6: Collection and Management of Specimens for Future 
Biomedical Research..........................................................................................126
10.7
Appendix 7: Country-specific Requirements..................................................131
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10.7.1
Country-specific Request for Japan...........................................................131
10.7.2
Country-specific Request for France .........................................................131
10.8
Appendix 8: Abbreviations ...............................................................................132
10.9
Appendix 9: Calculation of Creatinine Clearance..........................................135
10.10 Appendix 10: MK-8591 PrEP Program HIV Testing Algorithm..................136
11
REFERENCES.............................................................................................................137
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LIST OF TABLES
Table 1
Laboratory Exclusion Criteria..........................................................................55
Table 2
Study Interventions..........................................................................................57
Table 3
Reporting Time Periods and Time Frames for Adverse Events and Other 
Reportable Safety Events.................................................................................78
Table 4
Collection of Plasma PK Samples ...................................................................81
Table 5
Collection of Dried Blood PK Samples...........................................................82
Table 6
Analysis Strategy for Safety Parameters..........................................................93
Table 7
Sample Size Adjustments Based on Interim Blinded Review of Background 
Incidence Rate of HIV-1 Infections.................................................................95
Table 8
Study Power With Various Sample Sizes Under Various Background 
Incidence Rates of HIV-1 Infection and Screen Failure Rates........................97
Table 9
Power to Meet the Secondary Objective With Various Sample Sizes Under 
Various Background Incidence Rates of Confirmed HIV-1 Infections...........98
Table 10
Percentage of Participants With AEs and 95% Upper Confidence Bound 
Based on Hypothetical Numbers of Participants With AEs (in the ISL QM 
Group With 1000 Participants)........................................................................99
Table 11
Difference in Percentage of Participants With AEs (ISL QM Group Minus 
FTC/TDF or FTC/TAF QD Group) That can be Ruled Out With 
1000 Participants in the ISL QM Group and 500 Participants in the FTC/TDF 
or FTC/TAF QD Group ...................................................................................99
Table 12
Protocol-required Laboratory Assessments...................................................109
Table 13
PK Sample Collection Timepoints.................................................................113
Table 14
Blood Volumes ..............................................................................................114
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LIST OF FIGURES
Figure 1
Study Schema – Part 1.....................................................................................17
Figure 2
Study Schema – Part 2.....................................................................................18
Figure 3
Study Schema – Part 3.....................................................................................18
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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 Men and Transgender Women Who Have Sex With Men, and Are 
at High Risk for HIV-1 Infection 
Short Title: Oral ISL QM as PrEP in MSM and TGW at High Risk for HIV-1 Infection
Acronym: Impower – 024
Hypotheses, Objectives, and Endpoints:
The hypothesis is 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 cisgender MSM and TGW ≥16 years of age 
who are at high risk for HIV-1 infection.
Primary Objectives
Primary Endpoints
- 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 
to the background incidence rate. 
- Confirmed HIV-1 infection
- To evaluate the safety and tolerability of 
oral ISL QM compared to FTC/TDF or 
FTC/TAF QD as assessed by review of the 
accumulated safety data.
- Adverse events
- Adverse events leading to discontinuation 
of study intervention
Secondary Objectives
Secondary Endpoints
- To compare the incidence rate per year of 
confirmed HIV-1 infections following 
administration of ISL QM and FTC/TDF or 
FTC/TAF QD.
- Confirmed HIV-1 infection
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Overall Design:
Study Phase
Phase 3
Primary Purpose
Prevention
Indication
HIV Preexposure prophylaxis 
Population
Cisgender men and transgender women who have sex 
with men, are at least 16 years of age, and are 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 with in-house blinding
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 4 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 1500 participants will be randomized. No participants will be randomized in
Parts 2 or 3.
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Intervention Groups and Duration:
Intervention 
Groups
Intervention 
Group Name
Drug
Dose 
Strength
Dose 
Frequency
Route of 
Adminis-
tration
Regimen/ 
Treatment 
Period
Use
Part 1
ISL QM group
ISL
60 mg
Once 
monthly
Oral
Day 1 
through 
Month 24
Test 
Product
Placebo to 
FTC/TDF 
or 
FTC/TAF
0 mg
Once daily
Oral
Day 1 
through 
Month 24
Placebo
Part 1
FTC/TDF or 
FTC/TAF QD 
group
FTC/TDF 
or 
FTC/TAFa
200/245 mgb
or 
200/25 mg
Once daily
Oral
Day 1 
through 
Month 24
Test 
Product
Placebo to 
ISL
0 mg
Once 
monthly
Oral
Day 1 
through 
Month 24
Placebo
Part 2
All 
Participants
FTC/TDF 
or 
FTC/TAFa
200/245 mgb
or 
200/25 mg
Once daily
Oral
Part 2
Test 
Product
Part 3
All 
Participants
FTC/TDF 
or 
FTC/TAFa
200/245 mgb
or 
200/25 mg
Once daily
Oral
Part 3
Test 
Product
FTC/TAF=emtricitabine/tenofovir alafenamide; FTC/TDF=emtricitabine/tenofovir disoproxil
(including TRUVADATM [Gilead] and all generic versions); ISL=islatravir (also known as 
MK-8591); PrEP=preexposure prophylaxis.
a FTC/TAF is only available for use as PrEP in the United States. If, during the course of the study, 
FTC/TAF is approved for use as PrEP in other countries, assignment is contingent upon availability of 
drug supply.
b 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).
Total 
Number of 
Intervention 
Groups/ 
Arms
2
Duration of 
Participation
After a screening phase of up to 45 days, participants will be in this study for 
approximately 2.5 years from the time the participant provides documented
informed consent/assent through the final contact.
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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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PROTOCOL/AMENDMENT NO.: 024-05
MK-8591-024-05 FINAL PROTOCOL
02-DEC-2022
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 or 
FTC/TAF. 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 or FTC/TAF. No new participants will be screened or randomized 
during Part 3.
Figure 1
Study Schema – Part 1
FTC/TAF=emtricitabine/tenofovir alafenamide; FTC/TDF=emtricitabine/tenofovir disoproxil (including 
TRUVADATM [Gilead] and all generic versions); ISL=islatravir (also known as MK-8591); N=number of 
participants in the study; n=number of participants in each intervention group; QD=once daily; QM=once 
monthly.
a Screening period of up to 45 days is allowed, but participants are expected to enroll as soon as possible after 
eligibility is confirmed.
b Sentinel Cohort (first approximately 150 enrolled participants) interim analysis will be conducted 3 months 
after the last participant in the Sentinel Cohort has initiated study intervention.
c End of study includes the safety follow-up period of 42 days after the last dose of study intervention.
08K6YR

PRODUCT: MK-8591  
18
PROTOCOL/AMENDMENT NO.: 024-05
MK-8591-024-05 FINAL PROTOCOL
02-DEC-2022
Figure 2
Study Schema – Part 2
FTC/TAF=emtricitabine/tenofovir alafenamide; 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 or FTC/TAF.
Figure 3
Study Schema – Part 3
FTC/TAF=emtricitabine/tenofovir alafenamide; 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 or FTC/TAF.
FTC/TDF (QD) or FTC/TAF (QD)
End of Part 1
Blinded study intervention stopped; all participants remain blinded to original study intervention assignments
Start of Part 2
All Participants Enrolled in Part 1 Were Included in Part 2
(no new participants will be screened or randomized during Part 2)
FTC/TDF (QD) or FTC/TAF (QD)
All Ongoing
Participants
08K6YR

PRODUCT: MK-8591  
19
PROTOCOL/AMENDMENT NO.: 024-05
MK-8591-024-05 FINAL PROTOCOL
02-DEC-2022
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 or FTC/TAF 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 or FTC/TAF.
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 or FTC/TAF. 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 or FTC/TAF.
1.3.1
Schedule of Activities for Part 1, Part 2, and Part 3
Study Period
Double-blind Intervention Period (Part 1)
PrEP Therapy With FTC/TDF or FTC/TAF (Part 2 and Part 3)
Follow-
up
Notes
Visit Number
1
2
3
4
5
6
7
8
Recurring 
Visits
14
20
26
32
33
34
Scheduled 
Day/Month
Screening
(N/A during
Part 2 and Part 3)
Day 1
(N/A During
Part 2 and Part 3)
Month 1
Month 2
Month 3
Month 4
Month 5
Month 6
Every Monthb
(Addnl Assessments)
Every 3 Monthsc
(Addnl Assessments)
Month 12
(Addnl Assessments)
Month 18
Month 24
Month 30
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. 
Visit Window 
≤45 daysa
N/A
±7 Days
Visit windows for Part 3 are 
extended to ±14 Days.
Administrative Procedures
Informed 
consent/assent
X
Informed 
consent/assent for 
FBR
X
Inclusion/exclusion 
criteria
X
X
Review prior to randomization 
on Day 1 to confirm no changes 
in eligibility.
08K6YR

PRODUCT: MK-8591  
20
PROTOCOL/AMENDMENT NO.: 024-05
MK-8591-024-05 FINAL PROTOCOL
02-DEC-2022
Study Period
Double-blind Intervention Period (Part 1)
PrEP Therapy With FTC/TDF or FTC/TAF (Part 2 and Part 3)
Follow-
up
Notes
Visit Number
1
2
3
4
5
6
7
8
Recurring 
Visits
14
20
26
32
33
34
Scheduled 
Day/Month
Screening
(N/A during
Part 2 and Part 3)
Day 1
(N/A During
Part 2 and Part 3)
Month 1
Month 2
Month 3
Month 4
Month 5
Month 6
Every Monthb
(Addnl Assessments)
Every 3 Monthsc
(Addnl Assessments)
Month 12
(Addnl Assessments)
Month 18
Month 24
Month 30
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. 
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
Register study visit in 
IRT
X
X
X
X
X
X
X
X
Xf
Xf
Xf
Xf
Medical history
X
Prior and concomitant 
medication review
X
X
X
X
X
X
X
X
X
X
X
X
X
Intervention 
randomization
X
Assessment for acute 
retroviral syndrome
X
See Section 8.11.1.
Treatment Eligibility 
Assessment (TEA)
X
To be completed prior to 
randomization.
08K6YR

PRODUCT: MK-8591  
21
PROTOCOL/AMENDMENT NO.: 024-05
MK-8591-024-05 FINAL PROTOCOL
02-DEC-2022
Study Period
Double-blind Intervention Period (Part 1)
PrEP Therapy With FTC/TDF or FTC/TAF (Part 2 and Part 3)
Follow-
up
Notes
Visit Number
1
2
3
4
5
6
7
8
Recurring 
Visits
14
20
26
32
33
34
Scheduled 
Day/Month
Screening
(N/A during
Part 2 and Part 3)
Day 1
(N/A During
Part 2 and Part 3)
Month 1
Month 2
Month 3
Month 4
Month 5
Month 6
Every Monthb
(Addnl Assessments)
Every 3 Monthsc
(Addnl Assessments)
Month 12
(Addnl Assessments)
Month 18
Month 24
Month 30
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. 
Dispense study 
intervention 
X
X
X
X
X
X
X
Xf
Xf
During Part 1, in-clinic dosing of 
study intervention. The 
remaining monthly supply of 
FTC/TDF or FTC/TAF will be 
dispensed at each visit. Do NOT 
dispense study intervention if the 
participant’s Point-of-Care HIV 
test is positive.
During Part 2 and Part 3, 
participants will receive only
FTC/TDF or FTC/TAF. 
Participants should stop 
FTC/TDF or FTC/TAF if Point-
of-Care HIV Test is positive
while further testing is 
conducted. No other study 
intervention is to be dosed.
08K6YR

PRODUCT: MK-8591  
22
PROTOCOL/AMENDMENT NO.: 024-05
MK-8591-024-05 FINAL PROTOCOL
02-DEC-2022
Study Period
Double-blind Intervention Period (Part 1)
PrEP Therapy With FTC/TDF or FTC/TAF (Part 2 and Part 3)
Follow-
up
Notes
Visit Number
1
2
3
4
5
6
7
8
Recurring 
Visits
14
20
26
32
33
34
Scheduled 
Day/Month
Screening
(N/A during
Part 2 and Part 3)
Day 1
(N/A During
Part 2 and Part 3)
Month 1
Month 2
Month 3
Month 4
Month 5
Month 6
Every Monthb
(Addnl Assessments)
Every 3 Monthsc
(Addnl Assessments)
Month 12
(Addnl Assessments)
Month 18
Month 24
Month 30
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. 
Evaluation to receive 
continued study 
intervention
X
Study intervention 
adherence review
X
X
X
X
X
X
X
X
X
X
Reconcile doses, assess study 
intervention adherence, and offer 
adherence counseling.
HIV Risk Reduction
X
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
X
PRO: preference
X
X
X
X
X
Not applicable for Part 3.
08K6YR

PRODUCT: MK-8591  
23
PROTOCOL/AMENDMENT NO.: 024-05
MK-8591-024-05 FINAL PROTOCOL
02-DEC-2022
Study Period
Double-blind Intervention Period (Part 1)
PrEP Therapy With FTC/TDF or FTC/TAF (Part 2 and Part 3)
Follow-
up
Notes
Visit Number
1
2
3
4
5
6
7
8
Recurring 
Visits
14
20
26
32
33
34
Scheduled 
Day/Month
Screening
(N/A during
Part 2 and Part 3)
Day 1
(N/A During
Part 2 and Part 3)
Month 1
Month 2
Month 3
Month 4
Month 5
Month 6
Every Monthb
(Addnl Assessments)
Every 3 Monthsc
(Addnl Assessments)
Month 12
(Addnl Assessments)
Month 18
Month 24
Month 30
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. 
Efficacy Procedures
Point-of-Care HIV 
testing
X
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 the test 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.
During Part 2 and Part 3, 
participants should stop taking 
FTC/TDF or FTC/TAF if Point-
of-Care HIV Test is positive
while further testing is 
conducted.
HIV-1/HIV-2 
X
X
X
X
X
X
X
X
X
X
X
08K6YR

PRODUCT: MK-8591  
24
PROTOCOL/AMENDMENT NO.: 024-05
MK-8591-024-05 FINAL PROTOCOL
02-DEC-2022
Study Period
Double-blind Intervention Period (Part 1)
PrEP Therapy With FTC/TDF or FTC/TAF (Part 2 and Part 3)
Follow-
up
Notes
Visit Number
1
2
3
4
5
6
7
8
Recurring 
Visits
14
20
26
32
33
34
Scheduled 
Day/Month
Screening
(N/A during
Part 2 and Part 3)
Day 1
(N/A During
Part 2 and Part 3)
Month 1
Month 2
Month 3
Month 4
Month 5
Month 6
Every Monthb
(Addnl Assessments)
Every 3 Monthsc
(Addnl Assessments)
Month 12
(Addnl Assessments)
Month 18
Month 24
Month 30
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. 
antibody/ antigen
testing
Plasma HIV-1 RNA 
quantification (Real
Time PCR)
X
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 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
X
Weight
X
X
X
X
X
X
X
X
X
X
X
Symptom-directed 
physical examination
X
X
X
X
X
X
X
X
X
X
Vital signs
X
X
X
X
X
X
X
X
X
X
X
Includes pulse, blood pressure, 
temperature, and respiratory rate.
Review of adverse 
events
X
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
X
08K6YR

PRODUCT: MK-8591  
25
PROTOCOL/AMENDMENT NO.: 024-05
MK-8591-024-05 FINAL PROTOCOL
02-DEC-2022
Study Period
Double-blind Intervention Period (Part 1)
PrEP Therapy With FTC/TDF or FTC/TAF (Part 2 and Part 3)
Follow-
up
Notes
Visit Number
1
2
3
4
5
6
7
8
Recurring 
Visits
14
20
26
32
33
34
Scheduled 
Day/Month
Screening
(N/A during
Part 2 and Part 3)
Day 1
(N/A During
Part 2 and Part 3)
Month 1
Month 2
Month 3
Month 4
Month 5
Month 6
Every Monthb
(Addnl Assessments)
Every 3 Monthsc
(Addnl Assessments)
Month 12
(Addnl Assessments)
Month 18
Month 24
Month 30
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. 
Laboratory Assessments
Hepatitis serology
(HBsAb/HBcAb)
X
Participants who do not 
demonstrate immunity to HBV 
should be encouraged to be 
vaccinated against HBV.
HBsAg
X
HCV testing
X
X
X
Syphilis serologic 
testing
X
X
X
X
X
X
Rectal swab for 
GC/CT testing
X
X
X
X
X
X
Oropharyngeal 
GC/CT testing
X
X
X
X
X
X
Urine GC/CT testing
X
X
X
X
X
X
Collect the sample according to 
the laboratory manual.
Hematology
X
X
X
X
X
X
X
X
X
X
X
CD4+ T-cell 
count/Lymphocyte 
subset panel
X
X
X
X
X
X
X
X
X
X
X
Chemistry
X
X
X
X
X
X
X
Creatinine clearance 
calculation
X
X
X
X
X
X
X
See Appendix 9.
Cystatin-C
X
X
X
X
X
X
08K6YR

PRODUCT: MK-8591  
26
PROTOCOL/AMENDMENT NO.: 024-05
MK-8591-024-05 FINAL PROTOCOL
02-DEC-2022
Study Period
Double-blind Intervention Period (Part 1)
PrEP Therapy With FTC/TDF or FTC/TAF (Part 2 and Part 3)
Follow-
up
Notes
Visit Number
1
2
3
4
5
6
7
8
Recurring 
Visits
14
20
26
32
33
34
Scheduled 
Day/Month
Screening
(N/A during
Part 2 and Part 3)
Day 1
(N/A During
Part 2 and Part 3)
Month 1
Month 2
Month 3
Month 4
Month 5
Month 6
Every Monthb
(Addnl Assessments)
Every 3 Monthsc
(Addnl Assessments)
Month 12
(Addnl Assessments)
Month 18
Month 24
Month 30
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. 
Pharmacokinetics
Blood (Plasma) for 
PKd
X
X
X
X
X
X
X
Not applicable for Part 3.
See Section 8.6.1 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 at a visit. 
Blood (Plasma) for 
Investigational PKe
X
Not applicable for Part 3.
During Part 1, investigational PK 
samples will be collected predose 
at Month 2 and at any time
during the visit at Months 9, 15, 
and 21. During Part 2, 
investigational PK samples can 
be collected at any time during 
the visit.
See Section 8.6.2 and Table 13.
Samples will be stored and 
triggered for analysis by Sponsor, 
if needed 
08K6YR

PRODUCT: MK-8591  
27
PROTOCOL/AMENDMENT NO.: 024-05
MK-8591-024-05 FINAL PROTOCOL
02-DEC-2022
Study Period
Double-blind Intervention Period (Part 1)
PrEP Therapy With FTC/TDF or FTC/TAF (Part 2 and Part 3)
Follow-
up
Notes
Visit Number
1
2
3
4
5
6
7
8
Recurring 
Visits
14
20
26
32
33
34
Scheduled 
Day/Month
Screening
(N/A during
Part 2 and Part 3)
Day 1
(N/A During
Part 2 and Part 3)
Month 1
Month 2
Month 3
Month 4
Month 5
Month 6
Every Monthb
(Addnl Assessments)
Every 3 Monthsc
(Addnl Assessments)
Month 12
(Addnl Assessments)
Month 18
Month 24
Month 30
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. 
Dried blood for PKd
X
X
X
X
X
X
X
X
Not applicable for Part 3.
See Section 8.6.3 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 at a visit.
Biomarkers
Blood for genetic 
analysis 
X
See Section 8.8.1
Whole blood for FBR
X
Optional participation, requires 
FBR consent/assent.
08K6YR

PRODUCT: MK-8591  
28
PROTOCOL/AMENDMENT NO.: 024-05
MK-8591-024-05 FINAL PROTOCOL
02-DEC-2022
Study Period
Double-blind Intervention Period (Part 1)
PrEP Therapy With FTC/TDF or FTC/TAF (Part 2 and Part 3)
Follow-
up
Notes
Visit Number
1
2
3
4
5
6
7
8
Recurring 
Visits
14
20
26
32
33
34
Scheduled 
Day/Month
Screening
(N/A during
Part 2 and Part 3)
Day 1
(N/A During
Part 2 and Part 3)
Month 1
Month 2
Month 3
Month 4
Month 5
Month 6
Every Monthb
(Addnl Assessments)
Every 3 Monthsc
(Addnl Assessments)
Month 12
(Addnl Assessments)
Month 18
Month 24
Month 30
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. 
Addnl=additional; DNA=deoxyribonucleic acid; FBR=Future Biomedical Research; FTC/TAF=emtricitabine/tenofovir alafenamide; 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; HCV=hepatitis C virus; HIV=human immunodeficiency virus; 
IRT=Interactive Response Technology; N/A=not applicable; PCR=polymerase chain reaction; PK=pharmacokinetic(s); PRO=participant-reported outcome; RNA=ribonucleic 
acid.
a Screening period of up to 45 days is allowed, but participants are expected to enroll as soon as possible after eligibility is confirmed.
b Assessments noted in this column will be repeated every month from Month 7 through Month 30 (Visits 9 through 32).  Note: The Month 24 (Visit 26) and Month 30
(Visit 32) monthly assessments are listed in stand-alone columns.
c Additional assessments noted in this column will be repeated every 3 months through Month 30 – 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), and Month 30 (Visit 32). Note: The Month 24 (Visit 26) and Month 30
(Visit 32) every 3 month assessments are listed in stand-alone columns.
d Additional timepoints for Blood (Plasma) and Dried Blood PK collection: Month 12 (Visit 14), Month 18 (Visit 20), and Month 24 (Visit 26). PK samples will not be 
collected in Part 3.
e Additional timepoints for Blood (Plasma) for Investigational PK collection: Month 9 (Visit 11), Month 15 (Visit 17), and Month 21 (Visit 23). PK samples will not be 
collected in Part 3.
f. After March 2023, study intervention will not be dispensed via the IRT system and scheduled study visits, including the follow-up phone calls, will not be registered in the 
IRT system (exceptions to this need to be discussed and agreed upon by the Sponsor).
08K6YR

PRODUCT: MK-8591  
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PROTOCOL/AMENDMENT NO.: 024-05
MK-8591-024-05 FINAL PROTOCOL
02-DEC-2022
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 from 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
HIV Risk Reduction
X
X
Completion of the Sexual Activity Form; offer 
condoms, lubricants, and HIV risk reduction 
counseling.
PRO: HIV-infection Risk
X
X
PRO: Preference 
X
X
Not applicable for Part 3.
Efficacy Procedures
Point-of-Care HIV 
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 at every visit 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
Weight
X
X
Vital signs
X
X
Includes pulse, blood pressure, temperature, and 
respiratory rate.
Review of adverse events
X
X
08K6YR

PRODUCT: MK-8591  
30
PROTOCOL/AMENDMENT NO.: 024-05
MK-8591-024-05 FINAL PROTOCOL
02-DEC-2022
Study Period
Early Discontinuation from Study Intervention
Notes
Visit Number
Unscheduled Visits
Scheduled Day/Week
Early Discontinuation from Study 
Intervention
Early Withdrawal from Study 
Visit Window
N/A
N/A 
Review of social harm 
events
X
X
Laboratory Assessments
Hematology
X
X
CD4+ T-cell 
count/Lymphocyte subset 
panel
X
X
Chemistry
X
X
Creatinine clearance 
calculation
X
X
See Appendix 9.
Cystatin-C
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.
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 (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.
08K6YR

PRODUCT: MK-8591  
31
PROTOCOL/AMENDMENT NO.: 024-05
MK-8591-024-05 FINAL PROTOCOL
02-DEC-2022
Study Period
Early Discontinuation from Study Intervention
Notes
Visit Number
Unscheduled Visits
Scheduled Day/Week
Early Discontinuation from Study 
Intervention
Early Withdrawal from Study 
Visit Window
N/A
N/A 
HIV=human immunodeficiency virus; IRT=Interactive Response Technology; N/A=Not applicable; PCR=polymerase chain reaction; PRO=participant-reported outcome; 
RNA=ribonucleic acid.
For details on the Early Discontinuation of Study Intervention visit, see Section 8.11.3.
For details on the Early Withdrawal from Study visit, see Section 8.11.4.
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1.3.3
Schedule of Activities – Participants Who Have A Positive HIV-1 Test
Study Period
Follow-up After Seroconversion
Notes
Visit Number
Unscheduled
Variesa
Scheduled Day
HIV-1 Infection 
Confirmation 
Follow-up
Monthly Visits
Post-Study 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, participant 
should stop taking FTC/TDF or 
FTC/TAF while further testing is 
conducted.
Link to HIV Treatment Services
X
Upon confirmation of HIV-1 infection.
Concomitant medication review
X
X
X
X
Including ART regimens.
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-1
Infection Confirmation visit.
Safety Procedures
Symptom-directed physical 
examination
X
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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
Post-Study 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.
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/Lymphocyte 
subset panel
X
X
Chemistry
X
Pharmacokinetics
Blood (Plasma) 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. 
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
Post-Study 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; IRT=Interactive Response Technology; PCR=polymerase chain reaction; 
PK=pharmacokinetic(s); PRO=participant-reported outcome; RNA=ribonucleic acid.
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 30 visit (ie, participants will not be in the study for >30 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 FTC/TDF or FTC/TAF.
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2
INTRODUCTION
ISL (also known as MK-8591) is a novel, 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-1
acquisition are urgently needed.
One proven biomedical intervention for the prevention of HIV-1 infection is PrEP. In late 
2015, the WHO-recommended PrEP as an additional prevention option for people who are 
HIV-negative and at substantial risk for HIV [World Health Organization 2015]. 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 daily FTC/TDF is, however, suboptimal in many people at risk for HIV-1 
infection [Marrazzo, J. M., et al 2015] [Hojilla, J. C., et al 2018]. An additional PrEP option, 
DESCOVYTM (emtricitabine/tenofovir alafenamide [FTC/TAF], Gilead) has been approved 
for use in certain populations in the United States, though it still requires daily dosing.
Globally, the risk of acquiring HIV is 26 times higher among MSM than among all adult men
[Joint United Nations Programme on HIV/AIDS 2020] and novel strategies to prevent HIV 
acquisition in this population are urgently needed. Gay men and other MSM accounted for an 
estimated 17% of new HIV infections globally, including more than half of new HIV 
infections in western and central Europe, and North America; 40% in Latin America; 30% in
Asia and the Pacific; 22% in the Caribbean; 22% in eastern Europe and central Asia; 18% in 
the Middle East and North Africa; and 17% in western and central Africa [Joint United 
Nations Programme on HIV/AIDS 2019]. Further, the risk of acquiring HIV is 13 times 
higher for transgender people [Joint United Nations Programme on HIV/AIDS 2020], 
defined as those whose gender identities and/or expressions differ from the sex assigned to 
them at birth. In terms of prevalence, TGW are approximately 49 times more likely to be 
living with HIV than other adults of reproductive age with an estimated worldwide HIV 
prevalence of 19%; in some countries the HIV prevalence rate in TGW is 80 times that of the 
general adult population [World Health Organization 2020].
Gay, bisexual, and other MSM are the population most affected by HIV in the US [Centers 
for Disease Control and Prevention 2020]. In 2018, adult and adolescent gay and bisexual 
men made up 69% (26,305) of the 37,968 new HIV diagnoses in the US and dependent areas
[Centers for Disease Control and Prevention 2020]. In the US, the problem is particularly 
concentrated among African American MSM. Black/African American gay, bisexual, and 
other MSM are more affected by HIV than any other group in the US [Centers for Disease 
Control and Prevention 2020]. In 2018, black/African American gay and bisexual men 
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accounted for 26% (9,756) of the 37,832 new HIV diagnoses and 37% of new diagnoses 
among all gay and bisexual men in the US and dependent areas. In the US, >50% of new 
HIV diagnoses in the US were in the South and 69% of new HIV diagnoses were in 
black/African American and Hispanic/Latino MSM [Centers for Disease Control and 
Prevention 2018].
Adolescents and young people also represent a growing share of people living with HIV 
globally. In 2019 alone, 460,000 young people between the ages of 10 to 24 were newly 
infected with HIV, of whom 170,000 were adolescents between the ages of 10 and 19.
Adolescents account for about 5% of all people living with HIV and about 10% of new adult 
HIV infections [United Nations Children's Fund 2020].
Although use and awareness of HIV PrEP in the MSM population have increased in the US, 
further improvements are needed [Finlayson, T., et al 2019]. In particular, uptake in the use 
of daily, oral PrEP in the black/African American MSM population has been significantly 
lower than in other at-risk groups [Ezennia, O., et al 2019]. Cisgender MSM and TGW have 
an ongoing unmet medical need for alternatives to FTC/TDF and FTC/TAF QD for PrEP, 
particularly from a long-term safety perspective and to expand options for alternative dosing 
regimens.
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. ISL has the potential to be an 
effective agent for HIV-1 PrEP due to its long half-life and favorable tolerability 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 in cisgender MSM and 
TGW who are at high risk for HIV-1 infection, ultimately leading to greater effectiveness for 
HIV-1 prevention than what is currently observed with FTC/TDF or FTC/TAF QD. Such a 
simplified regimen may also be of particular benefit to adolescents who typically have 
challenges with adherence.
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 
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.
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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 therapy with 
FTC/TDF or FTC/TAF and undergoing the same study procedures regardless of original 
assignment, continued blinding is 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, that 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).
2.2.2
Information on Other Study-related Therapy
Products containing emtricitabine and tenofovir are 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 MSM, 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 
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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.
FTC/TAF was approved for PrEP in high risk adults (excluding individuals at risk from 
receptive vaginal sex) in 2019 in the US.
FTC/TDF and FTC/TAF will be administered at the approved marketed dose. Refer to 
approved labeling for detailed information on FTC/TDF and FTC/TAF. See Appendix 7 for 
dosing instructions for Japan.
In this study, participants receiving FTC/TDF will be administered either TRUVADATM or a 
generic product (emtricitabine/tenofovir disoproxil). The tenofovir disoproxil component of 
the generic product contains a different salt form (phosphate) compared to 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 
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.
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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-8591A 017) and 8.5% (MK-8591A 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-1
PrEP has not yet been shown 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 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 or FTC/TAF. 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 or FTC/TAF.
Additional details regarding specific benefits and risks for participants in this clinical study 
may be found in the accompanying IBs and informed consent documents.
3
HYPOTHESES, OBJECTIVES, AND ENDPOINTS
The hypothesis is 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.
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The following objectives will be evaluated in cisgender MSM and TGW ≥16 years of age 
who are at high risk for HIV-1 infection.
Objectives
Endpoints
Primary
•
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 to the background 
incidence rate.
•
Confirmed HIV-1 infection
•
To evaluate the safety and tolerability of 
oral ISL QM compared to FTC/TDF or 
FTC/TAF QD as assessed by review of 
the accumulated safety data.
•
Adverse events
•
Adverse events leading to 
discontinuation of study intervention
Secondary
•
To compare the incidence rate per year of
confirmed HIV-1 infections following 
administration of ISL QM and FTC/TDF
or FTC/TAF QD.
•
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, FTC/TAF 
QD, and ISL QM.
•
Pharmacokinetic-adherence 
relationship
•
To evaluate the impact of ISL QM on 
renal function compared to FTC/TDF or 
FTC/TAF QD as measured by the change 
from baseline in renal biomarkers at 
Weeks 24 and 48.
•
Renal biomarkers
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Objectives
Endpoints
•
To evaluate the impact of ISL QM on 
weight and body mass index compared to 
FTC/TDF or FTC/TAF QD as measured 
by the change from baseline at Weeks 24 
and 48.
•
Weight and body mass index
•
To assess viral drug resistance in 
participants who seroconvert to HIV-1.
•
Viral resistance-associated 
substitutions
•
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. 
4
STUDY DESIGN
Blinded study intervention administration (Part 1), including ISL or its placebo, has been 
stopped. During Part 2, all participants have been switched to PrEP therapy with FTC/TDF or 
FTC/TAF.
Study assessments conducted prior to 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 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 or FTC/TAF 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, double-blind, double-dummy study to evaluate the 
efficacy and safety of oral ISL QM as PrEP in cisgender MSM and TGW 16 years of age 
who have sex with men and who are at high risk of HIV-1 infection. The active comparator
in this study will be based on local standard of care and will be either FTC/TDF or FTC/TAF
QD, as selected by the investigator prior to randomization.
Approximately 1500 cisgender MSM and TGW uninfected with HIV-1 will be randomized 
in a 2:1 ratio to 1 of 2 intervention groups, the ISL QM group or the FTC/TDF or FTC/TAF
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QD group. Randomization will be stratified by geographic region/race. The duration of 
participation will be approximately 2.5 years and has the following enrollment targets:
•
Approximately 50% of the global study population will be <30 years of age
•
Approximately 50% of participants in the US will be black/African American OR 
Hispanic or Latino
The first approximately 150 enrolled participants 18 years of age will be identified as the 
Sentinel Cohort. An IA (Sentinel Cohort IA) will be conducted by an external unblinded 
statistician 3 months after the last participant in the Sentinel Cohort has initiated study 
intervention. All available data for all participants enrolled by that time will be submitted to 
an independent eDMC for a safety evaluation. Enrollment will continue, but be capped at no 
more than 375 participants until safety and tolerability have been assessed. Upon completion 
of the Sentinel Cohort IA and review of IA results by the eDMC, enrollment for participants 
16 or 17 years of age can begin.
An additional blinded IA will be conducted by the Sponsor when approximately 
1000 individuals have been screened for the purpose of sample size re-estimation. The goal 
of this IA is to assess the estimated background incidence rate of HIV-1 infection and the 
screen failure rate, and to determine the need of sample size adjustment to ensure adequate
power to meet the success criteria for the primary endpoint.
Samples for efficacy assessments will be collected at all monthly visits from participants 
receiving study intervention (Section 1.3.1). The primary efficacy and safety analysis will be 
performed after:
•
All participants have either reached Week 48 or have discontinued prior to Week 48
and
•
50% of participants have either reached Week 96 or have discontinued prior to Week 96.
Any participants with confirmed HIV infection will be discontinued from study intervention
and 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.
Safety assessments will include all accumulated safety data until the end of the 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 the eDMC through 
review of accumulating safety and efficacy data at regular intervals throughout study 
duration.
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Part 2
Blinded study intervention administration (Part 1), including ISL or its placebo, has been 
stopped, as noted above. During Part 2, all participants have been switched to PrEP therapy 
with FTC/TDF or FTC/TAF.
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.
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 or FTC/TAF 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, as well as their prescribed times and 
associated visit windows, are outlined in the SoA in Section 1.3. Details of each procedure 
are provided in Section 8.
4.2
Scientific Rationale for Study Design
Part 1
This study is designed to demonstrate the superiority of oral ISL QM compared to the 
background HIV-1 incidence rate as PrEP in MSM and TGW. The study design represents an
efficient study design and is deemed appropriate to provide safety and efficacy data in 
cisgender males and TGW at high risk for HIV-1 infection to demonstrate oral ISL QM as an 
effective option for HIV-1 PrEP in this population [Murray, J. 2019].
A traditional NI design for evaluation of a new PrEP modality in this population would 
require an unfeasibly large study population [Murray, J. 2019]. The anticipated reduction in 
infection is dependent on the investigational agent, and for studies of FTC/TDF (or 
FTC/TAF) in men, there is little reason to expect an improvement in efficacy; recent studies 
demonstrated incidence rates of 0.16 infections per 100 person-years with the use of
FTC/TAF and noninferiority to FTC/TDF [Mayer, K. H., et al 2020] and incidence rates of 
0.41 infections per 100 person-years with the use of cabotegravir (administered via 
intramuscular injections) and superiority to FTC/TDF [Landovitz, R. J., et al 2020]. 
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Depending on assumptions made, classic NI designs could potentially require up to hundreds 
of events to demonstrate NI [Murray, J. 2019] [Cutrell, A., et al 2017].
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 used to 
estimate the background incidence of HIV-1 infection from the same site areas/time period. 
The primary method will calculate HIV-1 incidence based on use of a recency assay 
(assessment of recent infection biomarkers) in the population at the Screening visit and prior 
to randomization in this study [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. This method will be used to estimate the background rate for 
the comparison in the primary objective. A second method will use local data on new HIV-1
diagnoses to estimate incidence. These data will be referenced as external benchmarks to 
contextualize the study data and characterize the natural history of HIV-1 acquisition in the 
population at large versus the enrolled population.
Because of the long intracellular half-life of the pharmacologically active TP (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.
Participants will be randomized in a 2:1 ratio to the ISL QM group OR FTC/TDF or 
FTC/TAF QD group to ensure maximum exposure to ISL and still allow for comparison 
between the ISL QM group and the FTC/TDF or FTC/TAF QD group.
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 was stopped in 
this study, and all participants have been switched to PrEP therapy with FTC/TDF or 
FTC/TAF. 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.
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-1 infection in participants 
receiving ART for PrEP [Elliott, T., et al 2019] [Peluso, M. J., et al 2020]. The study site 
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guidance for assessment and confirmation of HIV-1 infection based on this algorithm can be 
found in Appendix 10.
Frequent testing for HIV 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 SoA (Section 1.3). AEs 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-1 PrEP in 
the lives of individuals who are receiving it. In conjunction with efficacy and safety, 
capturing data from the participant’s perspective may help clinicians, policy-makers, and 
individuals at risk for HIV-1 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-1 PrEP medication (not applicable in 
Part 3). The HIV infection risk questionnaire will have 15 items that 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
Laboratory and Weight Markers
The study will compare mean changes in laboratory and weight markers from baseline in the 
intervention groups to evaluate the impact of ISL on the following:
Renal Function
Studies have shown that impaired kidney function (usually mild or moderate) may occur in a 
small proportion of people on FTC/TDF for PrEP, especially if they have other risk factors 
[Tetteh, R. A., et al 2017]. This study provides the opportunity to evaluate the impact of ISL
on renal functions as measured by creatinine, cystatin-C, and creatinine clearance.
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Weight
Compared with other antiretroviral classes, use of integrase inhibitors as well as tenofovir 
alafenamide in patients with HIV-1 has been associated with greater increases in body weight 
[Hill, A., et al 2019] [Venter, W. D. F., et al 2019]. This study provides the opportunity to 
evaluate the impact of ISL on body weight and BMI.
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 (either 
from FTC/TDF or FTC/TAF) will be measured and analyzed (in a subset of study
participants), as needed and may be used for exploratory study intervention adherence 
assessments.
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 
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 
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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 on 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 and FTC/TAF have been shown 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 oral ISL QM to placebo, the primary safety objective of 
this study will be to evaluate the safety and tolerability of oral ISL QM compared to 
FTC/TDF or FTC/TAF QD for the prevention of HIV-1 infection. The comparison of 
efficacy of oral ISL QM to FTC/TDF or FTC/TAF is a secondary objective.
FTC/TDF is approved in many countries as PrEP and is currently standard of care for 
individuals at high risk for HIV-1 infection. In the US, FTC/TAF is used as PrEP in at risk 
adults and adolescents weighing at least 35 kg to reduce the risk of HIV-1 infection from 
sexual acquisition, excluding individuals at risk from receptive vaginal sex [Tanner, M. R., et 
al 2020].
Matching placebo will be used in the ISL and FTC/TDF or FTC/TAF arms to provide a 
robust evaluation of the safety and tolerability profile of ISL by maintaining double-blind,
double-dummy study intervention.
Part 2
Blinded study intervention administration in Part 1, including ISL, its placebo, or placebo to 
FTC/TDF or FTC/TAF has been stopped; all participants were switched to PrEP therapy with 
FTC/TDF or FTC/TAF.
Part 3
All participants will receive open-label FTC/TDF or FTC/TAF in Part 3. No 
comparator/placebo or ISL/placebo will be administered.
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4.2.3
Rationale for Estimating Background HIV-1 Incidence Rate
The primary objective of this study is 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-1 incidence: direct observation of 
HIV-1 incidence through longitudinal follow-up of persons at risk for new HIV-1 infection, 
indirect measurement of HIV-1 incidence using data on HIV-1 prevalence in a defined 
population (such as women attending antenatal clinics), and estimates of HIV-1 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 over-
estimation of the HIV incidence rate [Gonese, E., et al 2020]. In contrast, Recent Infection
Testing Algorithms combining 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 
<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-1
incidence rate in this study.
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4.2.4
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 1 type of behavior inversely associated with risk of 
acquiring HIV. There are many other behaviors that have been identified as 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 Collecting Race and Ethnicity Data
The differential effect on the safety and efficacy based on any demographic parameter, 
including race or ethnicity, cannot be predicted when evaluating a new investigational drug. 
Therefore, it is important to collect race and ethnicity data to ensure that there is not a 
differential effect based on these parameters and to gain assurance the results observed in the 
clinical study will be representative of the drug’s use in a broader patient population. As an
example, non-Caucasian females and males were found to have higher plasma concentrations 
of EFV (an NNRTI) than their Caucasian counterparts, indicating an increased risk of EFV-
induced toxicity in non-Caucasian patients [Burger, D., et al 2005]. As another example, 
among the population with HIV in the US, those of African heritage have been found to be 
less likely to maintain virologic suppression compared with other groups, and the factors 
contributing to this remain to be elucidated [Weintrob, A. C., et al 2009] [Ribaudo, H. J., et 
al 2013]. Thus, subgroup analyses on race and ethnicity will be performed to better 
understand how these parameters may influence clinical outcomes and toxicity.
It is also important to look at PROs, specifically preference, by race and ethnicity. Despite 
having higher incidences of HIV infection, black and Hispanic/Latino MSM are less likely to 
use HIV PrEP than white MSM [Goedel, W. C., et al 2018]. In addition, despite the increased 
risk of acquiring HIV, TGW are an underserved population in terms of HIV prevention
[Marquez, S. 2016]. Analyzing preference data by ethnicity and race, may help to determine 
if differences in PrEP use are associated with racial and ethnic differences in preference.
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 as 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 
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and 2-fold above the EC90 (≈0.024 pmol/106 cells) in rhesus macaques [Grobler, J., et al 
2019]. See the IB for additional details.
In the Phase 1 proof-of-concept clinical study (MK-8591 Protocol 003) with treatment-naïve 
participants infected with HIV-1, 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 C168h was 
0.116 pmol/106 cells, with the lowest concentration associated with antiviral efficacy at 
0.0513 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 C168h concentration 
is approximately12-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 of 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 MSM, 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.
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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).
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 
results from earlier MK-8591 Phase 1 and other Phase 2 studies. In MK-8591 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-1 and ~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 MK-8591 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.
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 MK-8591 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 sufficient and adequate systemic 
threshold that will be efficacious for 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.
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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 
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 EEA, the local start of the study in the EEA is defined 
as 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 the Sentinel Cohort IA 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.
Male participants and TGW who are at high risk for 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.
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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 result 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 
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. Is sexually active with male (assigned male sex at birth) or transgender female partners 
defined as having anal sexual intercourse with a man or TGW at least once in the past 
month.
3. Is at high risk for sexually acquiring HIV-1 infection based on self-report of at least 1 of 
the following:

Condomless receptive anal intercourse in the 6 months prior to screening occurring 
outside a mutually monogamous HIV seronegative concordant relationship

More than 5 partners (anal intercourse) in the 6 months prior to screening (regardless 
of condom use and HIV serostatus, as reported by the enrollee)

Any unprescribed stimulant drug use in the 6 months prior to screening

Rectal or urethral gonorrhea or chlamydia or incident syphilis in the 6 months prior to 
screening
Demographics
4. Is cisgender male or transgender female (assigned male sex at birth), and ≥16 years of 
age at the time of providing informed consent/assent.
Note: Participants 16 or 17 years of age must weigh ≥35 kg. Enrollment for 16- to 17-
year-old participants will begin only after completion of the Sentinel Cohort IA and 
review of IA results by the eDMC.
Informed Consent/Assent
5. 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.
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Additional Categories
6. 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 component 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. Has known 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 evidence of 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 anal cancers.
5. Has a history or current evidence of any condition (including active tuberculosis 
infection), therapy, laboratory abnormality or other circumstance (including drug or 
alcohol abuse 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.
Prior/Concomitant Therapy
6. Has taken cabotegravir, lenacapavir, or any other long-acting HIV prevention product at 
any time (past or current).
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 FTC/TDF or FTC/TAF for PrEP at screening may continue 
their regimen until 1 day prior to Day 1.
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•
Note: Any prior or current HIV-1 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 or prevention 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 in the study 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.
Table 1
Laboratory Exclusion Criteria
Laboratory Assessment
Exclusionary Values
Absolute neutrophil count
≤750 cells/mm3
Alkaline phosphatase
>3 × ULN
ALT
>3 × ULN
AST 
>3 × ULN
Total bilirubin
≥2.5 × ULN
Calculated CrCl
<60 mL/mina based on the Cockcroft-Gault equation (use 
sex at birth for calculation; 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.
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5.3
Lifestyle Considerations
All participants should be counseled on safer sex practices to prevent acquisition of HIV or 
other sexually transmitted infections.
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.
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
Intervention 
Name
Inter-
vention 
Type
Dose 
Formu-
lation
Unit Dose 
Strength(s)
Dosage 
Level(s)
Route of 
Adminis-
tration
Regimen/
Treatment 
Period
Use
IMP or
NIMP/
AxMP
Sourcing
Part 1
ISL QM group
Experi-
mental
ISL
Drug
Tablet
60 mg
60 mg
Oral
QM Day 1 
through 
Month 24
Test 
Product
IMP
Provided 
centrally 
by the 
Sponsor
Part 1
ISL QM group
Experi-
mental
Placebo to 
FTC/TDF or 
placebo to 
FTC/TAF
Drug
Tablet
0 mg
0 mg
Oral
QD Day 1 
through 
Month 24
Placebo
IMP
Provided 
centrally 
by the 
Sponsor
Part 1
FTC/TDF or 
FTC/TAF QD 
group
Active 
Com-
parator
FTC/TDF or 
FTC/TAF
Drug
Tablet
200/245 mg
or 200/25 mg
200/245 
mg or 
200/25 mg
Oral
QD Day 1 
through 
Month 24
Test 
Product
IMP
Provided 
centrally 
by the 
Sponsor
Part 1
FTC/TDF or 
FTC/TAF QD 
group
Active 
Com-
parator
Placebo to 
ISL
Drug
Tablet
0 mg
0 mg
Oral
QM Day 1 
through 
Month 24
Placebo
IMP
Provided 
centrally 
by the 
Sponsor
Part 2
All 
Participants
Active 
Compar
ator
FTC/TDF or 
FTC/TAF
Drug
Tablet
200/245 mg 
or 200/25 mg
200/245 
mg or 
200/25 mg
Oral
QD in 
Part 2
Test 
Product
IMP
Provided 
centrally 
by the 
Sponsor
Part 3
All 
Participants
Active 
Compar
ator
FTC/TDF or 
FTC/TAF
Drug
Tablet
200/245 mg 
or 200/25 mg
200/245 
mg or 
200/25 mg
Oral
QD in 
Part 3
Test 
Product
IMP
Provided 
centrally 
by the 
Sponsor
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Arm Name
Arm 
Type
Intervention 
Name
Inter-
vention 
Type
Dose 
Formu-
lation
Unit Dose 
Strength(s)
Dosage 
Level(s)
Route of 
Adminis-
tration
Regimen/
Treatment 
Period
Use
IMP or
NIMP/
AxMP
Sourcing
EEA =European Economic Area; FTC/TAF=emtricitabine/tenofovir alafenamide; 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; PrEP=preexposure
prophylaxis; QD=once daily; QM=once monthly.
FTC/TAF is only available in the United States for use as PrEP. If, during the course of the study, FTC/TAF is approved for use as PrEP in other countries, assignment is 
contingent upon availability of drug supply.
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 or FTC/TAF may also be locally sourced.
For specific sourcing requirements in Japan, see Section 10.7.1.
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, Table 3, and Table 4 will be provided per the "Sourcing" 
column depending upon 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 2:1 ratio to either ISL QM and 
placebo to FTC/TDF or FTC/TAF QD OR FTC/TDF or FTC/TAF QD and placebo to ISL 
QM, respectively.
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 or FTC/TAF.
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 or FTC/TAF.
6.3.2
Stratification
Part 1
Intervention randomization will be stratified according to the following factor:
Geographic region/race:

US (black/African American)

US (nonblack/non-African American)

Africa

Other
Geographic region is included as a stratification factor due to regional differences in linkages 
to care, likelihood of sexual partners knowing HIV-1 status (infection or viral suppression),
and the burden of untreated HIV-1 infection in sexual partners. Risk may also vary by race 
within the US [Centers for Disease Control and Prevention 2020]. Stratification ensures that 
the intervention groups are well-balanced within each stratum level.
Part 2
No new participants will be screened or randomized; therefore there is no stratification for 
Part 2.
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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 and 
FTC/TAF will be packaged identically relative 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 drug concentration data and information relevant for population PK 
modeling (eg, including, but not limited to PK sampling schedules, dosing records, etc.) may 
be requested. No clinical efficacy and safety data will be unblinded. No personnel directly 
associated with study conduct will be unblinded before database lock. Before granting select 
personnel access to unblinded PK and relevant 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 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 participants intervention group. HIV-1 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 or FTC/TAF. 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 FTC/TAF or matching 
placebo to their visits. At each visit, the site personnel will count the number of tablets of 
FTC/TDF or FTC/TAF 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 or FTC/TAF. At each 
visit, site personnel will review the participant’s FTC/TDF or FTC/TAF 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 
or FTC/TAF. At each visit, site personnel will review the participant’s FTC/TDF or 
FTC/TAF 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 
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the participant on study intervention requires the mutual agreement of the investigator, the 
Sponsor, and the participant.
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 the 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 FTC/TDF or FTC/TAF for PrEP at screening may 
continue their regimen until 1 day prior to Day 1.
-
Part 2: All participants have been switched to PrEP therapy with FTC/TDF or 
FTC/TAF.
•
Any nonstudy investigational agents (including devices)
•
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 or FTC/TAF
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 and therapeutics for COVID-19 approved locally for Emergency Authorized 
Use, or equivalent, that do not have a known or anticipated DDI with ISL, are permitted.
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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.
6.6
Dose Modification (Escalation/Titration/Other)
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.
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.”
DESCOVYTM
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 
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the drug DESCOVYTM 200 mg/25 mg (emtricitabine/tenofovir alafenamide) as much as 
possible. You did not receive the active drug DESCOVYTM 200 mg/25 mg 
(emtricitabine/tenofovir alafenamide) 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 emtricitabine/tenofovir disoproxil 200 mg/245 mg as much as possible. You did not 
receive the active drug emtricitabine/tenofovir disoproxil 200 mg/245 mg as manufactured 
by Ratiopharm GmbH.”
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 TRUVADATM 200 mg/245 mg (emtricitabine/tenofovir disoproxil) as much as 
possible. You did not receive the active drug 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 prior to completion of the protocol-specified treatment 
period will still continue to participate in the study as specified in Section 8.11.3.
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 8.11.3.
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A participant must be discontinued from study intervention but continue to be monitored per 
Section 8.11.3 for any of the following reasons:
•
The participant or participant’s legally acceptable representative requests to discontinue 
study intervention.
•
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 post-study antiretroviral therapy will be 
provided by the study.
•
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 or FTC/TAF) 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 is life-threatening or results in prolonged 
hospitalization.
•
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 the participant 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 or FTC/TAF, 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.
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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 
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 or FTC/TAF 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 or FTC/TAF 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 medical decisions must be made by an investigator who is a qualified 
physician.
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•
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.
•
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/assent 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 909 mL, with approximately 45 to 49 mL each for any unscheduled 
visits for HIV-1 confirmation, early discontinuation of study intervention, or early 
withdrawal from the study (Table 14).
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 written 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 
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original consent/assent form that captures the participant’s or the participant’s legally 
acceptable representative’s dated signature.

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.
8.1.2
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.
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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 the 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).
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 prior to randomization. Each participant 
will be assigned only 1 screening number. Screening numbers must not be re-used 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.
8.1.6.1
Treatment Eligibility Assessment Form
A TEA form is included in this study to document the investigator assessment of participant
suitability for potential treatment with FTC/TDF or FTC/TAF and the rationale. These data 
may be required to support reimbursement efforts for ISL QM .
The investigator must complete this form and provide rationale to document the choice of
FTC/TDF or FTC/TAF prior to randomization.
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 re-assigned to 
another participant.
A single participant cannot be assigned more than 1 treatment/randomization number.
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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).
The first dose of study intervention should begin on the day of randomization.
Part 2 and Part 3
Participants will receive PrEP therapy with FTC/TDF or FTC/TAF 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 to 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 1.3.1). The first dose of FTC/TDF or FTC/TAF or their matching placebos 
will be administered at the study site on Day 1. Subsequent dosing of FTC/TDF or FTC/TAF 
or their matching placebos will be performed once daily by the participant (ie, unsupervised 
at his 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).
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.
If a participant misses a dose of FTC/TDF or FTC/TAF or their matching placebos, guidance 
in the approved label should be followed.
Part 2 and Part 3
Participants will receive PrEP therapy with FTC/TDF or FTC/TAF. 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 or FTC/TAF, guidance in the approved label 
should be followed.
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8.1.8.2
Interruption of Study Intervention
The site should encourage participants to remain compliant with the protocol-specified 
treatment plan. Participants who intentionally or inadvertently interrupt study intervention, 
without withdrawing consent/assent to participate in the study should not be discontinued 
from the study.
Interruptions from the protocol-specified treatment plan due to an AE or any other physician-
directed interruption require consultation between the investigator and the Sponsor and 
written documentation of the collaborative decision on participant management.
8.1.9
Discontinuation and Withdrawal
Participants who discontinue study intervention prior to 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 8.11.3.
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.
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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 
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 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.
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8.1.12
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.
8.1.13
Participant-reported Outcomes
Site staff will administer 2 questionnaires to participants at visits per the SoA (Section 1.3). 
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.
8.2
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 10).
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 
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-1 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 “Post-Study 
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 
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prioritize and facilitate this linkage to care. No post-study 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 (Section 1.3) 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 procedures/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, 
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.
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
Sexually Transmitted Infections
Testing for GC/CT and syphilis will be performed at study visits as described in the SoA 
(Section 1.3.1). 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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8.3.4
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.
8.3.5
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 their families 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 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.
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)
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
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
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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.
8.4.5
Pregnancy and Exposure During Breastfeeding
Information in this section is not applicable since participants are cisgender male or 
transgender female (assigned male sex at birth) and partner pregnancy/lactation information 
is not required.
8.4.6
Disease-related Events and/or Disease-related Outcomes Not Qualifying as 
AEs or SAEs
This section is not applicable to the study.
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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 lab value that is greater than or equal to 3X the upper limit of 
normal and an elevated total bilirubin lab value that is greater than or equal to 2X the 
upper limit of normal and, at the same time, an alkaline phosphatase lab value that is less 
than 2X the upper limit of normal, as determined by way of protocol-specified laboratory 
testing or unscheduled laboratory testing.*
*Note: These criteria are based upon 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 FTC/TAF or matching placebo on any single calendar day. 
Decisions regarding dose interruptions or modifications 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. 
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PK samples will be collected from all participants as outlined in Table 4 and Table 13. 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.
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 predose
Month 24
One sample to be collected at any time during the visit
a
Indicates time relative to monthly oral tablet administration. Not applicable in Part 2.
b
During Part 2, plasma 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 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, and 21. For Part 2,
investigational PK sample collection is irrespective of timing of dose.
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 the 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 13.
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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 predose
Month 24
One sample to be collected at any time during the visit
a
Indicates time relative to monthly oral tablet administration. Not applicable in Part 2.
b
During Part 2, dried blood 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 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 the next 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, 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.
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 
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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. 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 instructions for planned genetic analysis samples 
will be 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 (Table 12; 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
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 
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 last HIV test will be collected, if known.
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Rescreening
If the screening window has been exceeded, after approval from the Sponsor, participants are 
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.
8.11.3
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 all discontinuations, including participants who discontinue study intervention due to 
decreased lymphocyte or CD4+ T-cell counts, the participant should complete an Early 
Discontinuation from Study Intervention 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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8.11.4
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 from Study Intervention visit (Section 1.3.2), the Early Withdrawal from 
Study visit is not required.
8.11.5
Follow-up Phone Calls
Participants who complete the protocol-specified intervention period or who discontinue 
study intervention due to seroconversion will be contacted via phone call at 14 days and 
42 days post the 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 for the blinded treatment period for applicable safety endpoints, 
and for the entire duration of the study to evaluate 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 or FTC/TAF. 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 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 
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receive open-label PrEP therapy with FTC/TDF or FTC/TAF. 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 recovery of total lymphocyte counts. All safety data will be 
summarized descriptively.
Key elements of the SAP 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 Men and Transgender Women Who 
Have Sex With Men, and Are at High Risk for HIV-1 Infection
Treatment Assignment
A total of ~1500 participants will be randomized in a 2:1 ratio to receive 
either ISL QM and placebo matched to FTC/TDF or FTC/TAF QD, OR
FTC/TDF or FTC/TAF QD and placebo matched to ISL QM. The 
randomization will be stratified by region/race.
Analysis Populations
Efficacy: mFAS
Safety: APaT
Primary Endpoint(s)
1. Confirmed HIV-1 infection
2. AEs and AEs leading to discontinuation of study intervention
Statistical Methods for Key 
Efficacy Analyses
The primary objective will be assessed 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 [Gao, F., et al 2020]. The 
background incidence rate will be estimated in the screened population 
using the Kassanjee methodology [Kassanjee, R., et al 2012]. The 
statistical criteria for success require the point estimate of the relative risk 
of the incidence rate of confirmed HIV-1 infections in the ISL QM group 
compared to the background incidence rate to be at most 0.5 and the upper
bound of the 95% CI for the relative risk to be less than 0.8.
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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 or FTC/TAF 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 performed 3 months after the last 
participant in the Sentinel Cohort has initiated study intervention. All 
available data for all participants enrolled by that time will be 
reviewed. 

Continuous safety and efficacy monitoring throughout the study:
Accumulating safety and efficacy data at regular intervals throughout 
the study duration will be reviewed.
An additional blinded IA will be conducted by the Sponsor when 
approximately 1000 individuals have been screened in the study for the 
purpose of sample size re-estimation. The goal of this IA is to assess the 
estimated background incidence rate and the screen failure rate, and to 
determine the need of increasing the sample size to ensure that the study will 
have at least 90% power to meet the success criteria for the primary 
objective. 
Multiplicity
No multiplicity adjustment is planned.
Sample Size and Power 
Approximately 1500 participants will be randomized in a 2:1 ratio to either 
the ISL QM or FTC/TDF or FTC/TAF QD groups. With 1000 participants 
in the ISL QM group and assuming ISL QM has 87.5% efficacy, the 
average participant time in the study is 1.5 years and the lost-to-follow-
up/study discontinuation rate is 15% per year, there is >90% power to meet
the success criteria for the primary objective for background incidence
rates ranging from 3% to 4%.
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 group.
The statistical analysis of the 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.
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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 Endpoint
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 population 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 with confirmed HIV infections prior to or at 
randomization.
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 intervention they actually received for 
the analysis of safety data using the APaT population. For most participants, this will be the 
intervention group to which they are randomized. Participants who take incorrect study 
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intervention for the entire intervention 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 Analysis
Note: As of Amendment -04, this section is no longer applicable.
The primary efficacy objective will be assessed in terms of relative risk by comparing the
incidence rate per year of confirmed HIV-1 infections in the ISL QM group to the
background incidence rate. The primary hypothesis can be written as the following:
R is the relative risk of becoming HIV-1 infected in the ISL QM group compared to the 
population not taking any PrEP, 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.
The methodology proposed by Gao et al. [Gao, F., et al 2020], which specifies the asymptotic 
property of the relative risk R and the testing scheme, will be used to test the primary 
hypothesis.
The incidence rate per year of confirmed HIV-1 infections in the ISL QM group λ1 will be 
estimated by:
The background incidence rate λ0 will be estimated in the screened population using the 
methodology proposed by Kassanjee [Kassanjee, R., et al 2012]:
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Where,
nR
is the number of individuals in the screened population with HIV-1 infection and 
who are identified as recent infections,
n+
is the number of individuals in the screened population with HIV-1 infection,
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 that 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].
For nR, an individual is considered to be recently infected if all of the following criteria 
[Kassanjee, R., et al 2016] [Duong, Y. T., et al 2019] are met:
•
The individual 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 individual has HIV-1 RNA viral load with ≥1,000 copies/mL
In addition, individuals 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 individuals screened at the different sites. The estimated MDRIs 
(and FRRs) and their associated variances will be obtained from published reports for the 
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subtypes using recency tests based on LAg-Avidity [Kassanjee, R., et al 2014] [Duong, Y. 
T., et al 2015]. 
The point estimate of the relative risk will be calculated as 
The primary hypothesis that the relative risk R <0.8 will be tested by computing the 95% CI 
of R, denoted as (RL, RU). Success will be declared for the primary objective if the point 
estimate of the relative risk 
≤ 0.5 and the upper bound of the 95% CI of the relative risk
RU<0.8. The 95% CI will be constructed as follows:
where 
and 
are the estimated variance of 
and
, respectively [Gao, F., et al 
2020].
The key secondary objective to compare the incidence rate of confirmed HIV-1 infections
following administration of ISL QM and either FTC/TDF or FTC/TAF QD will be assessed 
by a 95% CI of the difference of the incidence rate of confirmed HIV-1 infections in the ISL 
QM group compared to the FTC/TDF or FTC/TAF QD group. The CI will be constructed 
using the Miettinen and Nurminen method [Miettinen, O. and Nurminen, M. 1985] based on 
the Poisson distribution. Success for the key secondary objective will be declared if the upper 
bound of the 95% CI is less than 0.8 per 100 person-years.
Imputation methods will not be used to replace missing data for HIV-1 infection and data 
will be used as observed.
Participants who discontinue study intervention with no evidence of HIV-1 infection and 
who do not withdraw consent/assent will be included in the analyses.
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 6), 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 6.
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Safety parameters or AEs 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 intervention group exhibit the event. Because many 95% CIs for Tier 2 
events may be provided without adjustment for multiplicity, the CIs 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 intervention
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 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 
intervention group for Tier 3 safety parameters. 
Tier 2 endpoints also include the change from baseline in renal biomarkers, body weight, and 
BMI 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 intervention 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 they fall 
outside of 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, JUL-2017, version 2.1 (Appendix 3). A listing of the 
participants who meet the criteria will also be provided.
A descriptive presentation of the safety endpoints for ISL QM vs each of FTC/TDF QD and 
FTC/TAF QD 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.
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Table 6
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 
intervention group
Change from baseline in body weight and 
BMI
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 
intervention groups
X
AE=adverse event; BMI=body mass index; 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.
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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.
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 interim 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 has initiated study intervention. All available data for all participants enrolled by that 
time will be evaluated for safety at this interim analysis.
An additional blinded IA will be conducted by the Sponsor when approximately 1000 
individuals have been screened in the study for the purpose of sample size re-estimation. The 
goal of this IA is to assess the estimated background incidence rate and the screen failure 
rate, and to determine the need of increasing the sample size to ensure that the study will 
have at least 90% power to meet the success criteria for the primary objective. The sample 
size can be increased up to 3000. The background incidence rate will be estimated using the 
Kassanjee method as described in Section 9.6.1. Table 7 presents the possible sample size 
adjustments based on the blinded review of the estimated background incidence rate and the 
screen failure rate. Table 8 in Section 9.9.1 displays the power to meet the primary objective 
as a reference for the sample size re-estimation. Any changes resulting from this analysis will 
be shared and discussed with the eDMC.
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Table 7
Sample Size Adjustments Based on Interim Blinded Review of Background 
Incidence Rate of HIV-1 Infections
Screen
Failure 
Rate
Background 
Incidence Rate of 
HIV-1 Infections
Total Sample Size
(2:1 Randomization Ratio of ISL
QM vs Active Control)
Power to Meet 
the Primary 
Objective
30%
4.0%
1500
99%
3.5%
1500
98%
3.0%
1500
95%
2.5%
1800
94%
2.0%
2100
90%
10%
4.0%
1500
98%
3.5%
1500
95%
3.0%
1500
91%
2.5%
1800
90%
2.0%
2550
92%
HIV=human immunodeficiency virus; ISL=islatravir (also known as MK-8591); QM=once monthly.
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.
9.8
Multiplicity
No multiplicity adjustment is planned for this study.
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.
9.9.1
Sample Size and Power for Efficacy Analyses
Approximately 1500 participants will be randomized in a 2:1 ratio to either the ISL QM 
group or the active control (FTC/TDF or FTC/TAF) QD group. With 1000 participants in the 
ISL QM group, there is 90% power to meet the success criteria for the primary objective for 
background incidence rates ranging from 3% to 4%. The power calculation is based on the 
following assumptions:
•
ISL QM has 87.5% efficacy
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•
Average participant time is 1.5 years
•
Lost-to-follow-up/study discontinuation rate is 15% per year
•
Screen failure rate is 30%
•
HIV-1 subtypes in the screened population comprises of: 60% Type B, 22% Type C, 15% 
Type A/E, 3% Type A or D
•
Weighted averages of prevalence, MDRI, FRR, and associated standard errors are
calculated based on the proportions of each subtype expected to be screened [Grebe, E., 
et al 2019] [Gao, F., et al 2020]
Incidence rates of >3% have been reported among MSM in the US [Mera, R., et al 2019], 
South Africa [Lane, T., et al 2016], and Thailand [Centers for Disease Control and 
Prevention 2013]. The assumption regarding ISL QM efficacy is a conservative estimate 
based on a rhesus macaque SHIV intrarectal challenge model [Markowitz, M., et al 2019] in 
which 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 study 
discontinuation rate is consistent with HIV Prevention Trials Network 083 study [Landovitz, 
R. J., et al 2020] and allows for challenges in retention (eg, COVID-19 pandemic).
For background incidence rates <3%, the study power is less than 90% under the above 
assumptions. Also, if the screen failure rate is lower than the assumed 30%, the smaller 
number of screened individuals will lead to a decrease in power. As described in Section 9.7, 
the sample size may be increased based on the IA assessment of estimated background 
incidence rate and screen failure rate. Table 8 displays the study power under various
assumptions including background incidence rates ranging from 2% to 4%, screen failure 
rates of 30% and 10%, and under different total sample sizes of 1500, 1800, 2100, 2550, and 
3000. 
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Table 8
Study Power With Various Sample Sizes Under Various Background Incidence 
Rates of HIV-1 Infection and Screen Failure Rates 
Screen 
Failure
Rate
Background 
Incidence Rate of 
HIV-1 Infections
Power with Various Total Sample Size (2:1 
Randomization Ratio of ISL QM vs Active 
Control)
1500
1800
2100
2550
3000
30%
2.0%
77%
86%
90%
95%
98%
2.5%
89%
94%
96%
98%
99%
3.0%
95%
97%
99%
>99%
>99%
3.5%
98%
99%
>99%
>99%
>99%
4.0%
99%
>99%
>99%
>99%
>99%
10%
2.0%
72%
81%
87%
92%
95%
2.5%
84%
90%
94%
97%
99%
3.0%
91%
95%
98%
99%
>99%
3.5%
95%
98%
99%
>99%
>99%
4.0%
98%
99%
>99%
>99%
>99%
HIV=human immunodeficiency virus; ISL=islatravir (also known as MK-8591); QM=once monthly.
Power is calculated based on the success criteria that the upper bound of the 95% CI of the relative risk (ISL:background 
incidence rate) <0.8 and the point estimate of the relative risk is ≤0.5.
Estimated via simulations with 100,000 iterations.
Table 9 displays the power to meet the key secondary objective under various background 
incidence rates of HIV-1 infections for different sample sizes. The assumptions for the power 
calculations include: efficacy of 87.5% and 75% for ISL QM and active control, respectively, 
the same assumed average participant time and lost to follow-up rate as for the primary 
objective.
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Table 9
Power to Meet the Secondary Objective With Various Sample Sizes Under 
Various Background Incidence Rates of Confirmed HIV-1 Infections
Power with Various Total Sample Size (2:1 Randomization Ratio of 
ISL QM vs Active Control)
Background 
Incidence Rate
1500
1800
2100
2550
3000
2.0%
93%
97%
99%
>99%
>99%
2.5%
91%
96%
98%
99%
>99%
3.0%
90%
95%
97%
99%
>99%
3.5%
89%
94%
97%
99%
>99%
4.0%
88%
94%
97%
99%
99%
HIV=human immunodeficiency virus; ISL=islatravir (also known as MK-8591); QM=once monthly.
Power is calculated based on the success criterion that the upper bound of the 95% CI of the risk difference < 0.8 per 100 
person-years.
Estimated via simulations with 100,000 iterations.
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 a 63.2%
chance of observing at least 1 AE among 1000 participants in the ISL group. If no AE of that 
type is observed among the 1000 participants in the ISL group, this study will provide 97.5% 
confidence that the underlying percentage of participants with that particular AE is <0.37% 
(1 of every 270 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 the ISL group are provided in Table 10. These calculations are based on the exact 
binomial method proposed by Clopper and Pearson [Clopper, C. J. and Pearson, E. S. 1934].
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Table 10
Percentage of Participants With AEs and 95% Upper Confidence Bound Based on
Hypothetical Numbers of Participants With AEs (in the ISL QM Group With 
1000 Participants)
Hypothetical Numbers of 
Participants With AE
Percentage
95% Upper Confidence 
Bounda
(ISL QM group)
0
0.0%
0.4%
20
2%
3.1%
50
5%
6.5%
100
10%
12.0%
150
15%
17.3%
AE=adverse event; CI=confidence interval; ISL=islatravir (also known as MK-8591); QM=once monthly.
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 11 demonstrates the difference in the percentage of participants with an AE (ISL QM 
group minus FTC/TDF or FTC/TAF QD group) that can be ruled out with different power
levels and 95% confidence when there are 1000 participants in the ISL QM group and 500 in 
the FTC/TDF or FTC/TAF QD group. The underlying percentage of participants with the AE 
is assumed to be the same for the 2 intervention groups. For example, for a reasonably 
common AE, which occurs in 20% of participants in both groups, the study has 80% power 
to declare with 95% confidence that the true difference between the intervention groups is no 
more than 6.4 percentage points. The calculations are based on an asymptotic method 
proposed by Miettinen and Nurminen [Miettinen, O. and Nurminen, M. 1985].
Table 11
Difference in Percentage of Participants With AEs (ISL QM Group Minus 
FTC/TDF or FTC/TAF QD Group) That can be Ruled Out With 1000 Participants in the ISL 
QM Group and 500 Participants in the FTC/TDF or FTC/TAF QD Group
Target 
Power
Underlying Percentage of Participants with AE
1%
5%
10%
20%
80
2.1%
3.8%
5%
6.4%
85
2.3%
4.1%
5.4%
6.9%
90
2.5%
4.6%
5.9%
7.5%
AE=adverse event; CI=confidence interval; FTC/TAF=emtricitabine/tenofovir alafenamide; 
FTC/TDF=emtricitabine/tenofovir disoproxil (including TRUVADATM and all generic versions);
ISL=islatravir (also known as MK-8591); 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 the percentage of participants with AEs (ISL QM group minus 
FTC/TDF QD or FTC/TAF QD group) assuming the percentages are the same.
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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; <30, ≥30 years)
•
Geographic regions (US, Africa, Other)
•
Race (black, not black)
•
Ethnicity (Hispanic or Latino, not Hispanic or Latino)
•
Circumcised (yes, no)
•
Risk group (MSM, TGW)
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 will be recorded upon in-clinic dosing of ISL QM at each monthly 
visit. For each participant in the FTC/TDF or FTC/TAF QD 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.
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.
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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 
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.
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D. Genomic Research
Genomic research will only be conducted in accordance with a protocol and informed consent authorized by an 
ethics committee.
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.
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10.1.3
Data Protection
The Sponsor will conduct this study in compliance with all applicable data protection 
regulations.
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 non-Sponsor 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 incident HIV-1 infection for the purposes of confirmation.  Specific 
details regarding composition, responsibilities, and governance, including the roles of the 
various members and the Sponsor protocol team will be described in the Adjudication 
charter. 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.
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.
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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 
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 
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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.
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.
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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.
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 12 will be processed by a local/regional laboratory in Africa or 
by the central laboratory in all other countries participating in the study.
•
Local laboratory results are only 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 12
Protocol-required Laboratory Assessments
Laboratory 
Assessments
Parameters
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 Granulocytes (%, 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
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Laboratory 
Assessments
Parameters
Magnesium (Mg)
Phosphorous 
Potassium (K)
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)
Hepatitis C virus (HCV) antibody 
Plasma Hepatitis C virus PCR quantitative test (performed if Hepatitis C 
virus antibody is positive)
Virology
Point-of-Care HIV 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
Sexually 
Transmitted 
Infection (STI) 
Testing 
Rectal swab Neisseria gonorrhoae (GC)/Chlamydia trachomatis (CT) 
testing
Oeopharyngeal GC/CT testing
Nucleic acid amplification from urine for GC/CT
Syphilis serologic testing (rapid plasma regain [RPR], RPR with titer, 
Treponema pallidum IgG, Treponema pallidum IgG index value)
Pharmacokinetic 
(PK) Testing
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.
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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-1 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 13
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
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
Blood (Plasma) for PK
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 at a visit.
Blood (Plasma) for 
Investigational PK
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, and 21. During Part 2, 
investigational PK samples can be 
collected at any time during the visit.
Samples will be stored and triggered for 
analysis by Sponsor, if needed.
Dried Blood for PK
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 at a visit.
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Table 14
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
14
20
26
32
HIV-1
Infection 
Confirmation
Early 
Discontinuati
on 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
(Additional 
Assessments)
Month 12
(Additional 
Assessments)
Month 18
Month 24
Month 30
Totals
Unscheduled
Unscheduled
Unscheduled
HCV/HBV/HIV (Serology) 
9.5
9.5
9.5
28.5
Syphilis Serologic Testing
4
4
4
24
4
4
44
Hematology
6
6
6
6
6
6
6
6
132
6
6
192
6
6
6
CD4+ T-cell
count/Lymphocyte subset 
panel
6
6
6
6
6
6
6
6
132
6
6
192
6
6
6
Chemistry
5
5
5
5
30
5
5
60
5
5
5
Cystatin-C
3.5
3.5
3.5
21
3.5
3.5
38.5
3.5
3.5
Point-of-Care HIV Testingd
Additional volume not applicable 
HIV-1/HIV-2 
Antibody/Antigen Testing
Off 
HCV/
HBV/
HIV
3.5
3.5
3.5
3.5
3.5
3.5
3.5
77
Off 
HCV/
HBV/
HIV
Off 
HCV/
HBV/
HIV
3.5
105
3.5
3.5
3.5
Plasma HIV RNA (Real 
Time PCR)
6
6
6
6
6
6
6
6
132
6
6
192
6
6
6
HIV-1 Drug Resistance 
Testing
3
3
15
(135)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
14
20
26
32
HIV-1
Infection 
Confirmation
Early 
Discontinuati
on 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
(Additional 
Assessments)
Month 12
(Additional 
Assessments)
Month 18
Month 24
Month 30
Totals
Unscheduled
Unscheduled
Unscheduled
Blood (Plasma) for PK
3
3
3
3
3
3
3
21
3
3
3
Blood (Plasma) for 
Investigational PK
3
9
12
Dried Blood for PK
from 
PK 
tube
from 
PK 
tube
from. 
PK 
tube
from 
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
Total Blood Volume per 
Visit in mLf
40.5
52.5
24.5
24.5
37.0
21.5
21.5
37.0
473
75
9
12.5
3
43.0
34
908.5
48.5
(168.5)e
45.0
45.0
DNA=deoxyribonucleic acid; FBR=Future Biomedical Research; HBV=hepatitis B virus; HIV=human immunodeficiency virus; HCV=hepatitis C virus; PCR=polymerase chain 
reaction; PK=pharmacokinetic; RNA=ribonucleic acid.
Note: All volumes are provided in mL. HIV-1/HIV-2 Antibody/Antigen Testing may be conducted using sample collected for HCV/HBV/HIV testing (“off HCV/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 30 (22 visits for those who complete the study).
b Samples are collected every 3 months up to Month 30 (6 additional visits for those who complete the study).
c Samples are collected every 6 months up to Month 24 (3 additional visits for those who complete the study).
d Negligible blood volume amount as sample is collected from another tube or finger stick.
e 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 8 additional visit 
collections).
f Blood volumes are calculated based on volume requirements at Central lab (US) and Regional lab (Africa). In cases where different volume requirements between the Central 
and Regional laboratories exist, the higher of the 2 volumes is used. Slight variances may occur if a local lab is used.
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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 [National 
Institute of Allergy and Infectious Diseases 2017]. 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.
-
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.
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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?
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◦
If yes, this is a positive rechallenge.
◦
If no, this is a negative rechallenge.
(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.
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•
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.
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).
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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.

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
This section is not applicable.
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10.5
Appendix 5: Contraceptive Guidance
This section is not applicable.
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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.
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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.
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.
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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 
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 
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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 
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.
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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
10.7.1
Country-specific Request for Japan
Although not approved in Japan for PrEP, FTC/TDF was administered as an active 
comparator at a dose per product label in Part 1.
In a letter to the study communication via Dear Investigator Letter dated 13-DEC-2021, it 
was announced that dosing of investigational product for all participants is to be stopped and 
that all participants will be offered open-label PrEP therapy with daily FTC/TDF. This 
decision is stipulated based on ethical consideration and safety and wellbeing of study 
population who are at high risk for HIV-1 infection, as abrupt interruption of treatment 
exposes participants to risk of infection. As FTC/TDF is not yet approved in Japan for PrEP 
indication nor are there any alternative approved medication that participants have access to, 
open-label FTC/TDF will be offered to study participants as part of this study protocol. 
Open-label FTC/TDF used in Part 2 and Part 3 is categorized as "product(s) used in the 
clinical trial other than test product(s)" in Japan local regulation.
10.7.2
Country-specific Request for France
In France, only participants ≥18 years of age at the time of providing informed consent can 
be enrolled.
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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
C168h
concentration at 168 hours postdose
CAC
Clinical Adjudication Committee
CI
confidence interval
CONSORT
Consolidated Standards of Reporting Trials
COVID-19
coronavirus disease caused by severe acute respiratory syndrome coronavirus 2
CrCl
creatinine clearance
CRF
Case Report Form 
CSR
Clinical Study Report
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 
eDMC
external data monitoring committee
EEA
European Economic Area
EFV
efavirenz
EMA
European Medicines Agency
EOC
Executive Oversight Committee 
ePROs
electronic participant-reported outcomes
EU
European Union
FDA
Food and Drug Administration
FDAAA
Food and Drug Administration Amendments Act
FRR
false-recent rate
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Abbreviation
Expanded Term
FSR
first site ready
FTC/TAF
emtricitabine/tenofovir alafenamide
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
HIV
human immunodeficiency virus
IB
Investigator Brochure 
IA(s)
interim analysis(ses)
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
IND
Investigational New Drug 
INR
international normalized ratio
iPrEx
Preexposure Prophylaxis Initiative
IRB
Institutional Review Board
IRT
interactive response technology
ISL
islatravir (also known as MK-8591)
LAg
limiting antigen 
MDRI
mean duration of recent infections
mFAS
modified full analysis set
MSM
men who have sex with men
NI
noninferiority
NNRTI
nonnucleoside reverse transcriptase inhibitor
NRTTI
nucleoside reverse transcriptase translocation inhibitor
ODn
normalized optical density
PBMC
peripheral blood mononuclear cells
PCR
polymerase chain reaction
PDLC
predefined limit of change
PEP
postexposure prophylaxis
PEPFAR
President’s Emergency Plan for AIDS Relief
PK
pharmacokinetic(s)
PrEP
preexposure prophylaxis
PRO
participant-reported outcome
QD
once daily
QM
once monthly
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Abbreviation
Expanded Term
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
TEA
Treatment Eligibility Assessment
TFV
tenofovir
TGW
transgender woman/women
TP
triphosphate
US
United States
USPSTF
United States Preventive Services Task Force
VAMS
volumetric absorptive microsampling
VL
viral load
WHO
World Health Organization
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10.9
Appendix 9: Calculation of Creatinine Clearance
Cockcroft-Gault equation (for male participants):
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10.10 Appendix 10: 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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