A Phase 2b, Randomized, Active-Controlled, Double-Blind, Dose-Ranging Clinical Study to Evaluate a Switch to Islatravir (ISL) and MK-8507 Once-Weekly in Adults With HIV-1 Virologically Suppressed on Bictegravir/Emtricitabine/Tenofovir Alafenamide (BIC/FTC/TAF) Once-Daily
Phase: PHASE2
Conditions: HIV-1 Infection
Sponsor: Merck Sharp & Dohme LLC

Official Protocol Title:
NCT Number:  
    NCT04564547
Document Date: 
    20-Oct-2022
A Phase 2b, Randomized, Active-Controlled, Double-
Blind, Dose-Ranging Clinical Study to Evaluate a Switch 
to Islatravir (ISL) and MK-8507 Once-Weekly in Adults 
with HIV-1 Virologically Suppressed on Bictegravir/
Emtricitabine/Tenofovir Alafenamide (BIC/FTC/TAF) 
Once-Daily

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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 2b, Randomized, Active-Controlled, Double-Blind, Dose-Ranging 
Clinical Study to Evaluate a Switch to Islatravir (ISL) and MK-8507 Once-Weekly in Adults 
with HIV-1 Virologically Suppressed on Bictegravir/Emtricitabine/Tenofovir Alafenamide 
(BIC/FTC/TAF) Once-Daily
Protocol Number: 013-04
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):
EudraCT
2020-003071-18
IND
128,595
Approval Date: 20 October 2022
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Sponsor Signatory
Typed Name:
Title:
Date
Protocol-specific Sponsor contact information can be found in the Investigator Study
File Binder (or equivalent).
Investigator Signatory
I agree to conduct this clinical study in accordance with the design outlined in this protocol 
and to abide by all provisions of this protocol.
Typed Name:
Title:
Date
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DOCUMENT HISTORY
Document
Date of Issue
Overall Rationale
Amendment 04
20-OCT-2022
Merck Sharp & Dohme Corp. underwent an entity name and address change to Merck Sharp 
& Dohme LLC, Rahway, NJ, USA. This conversion resulted only in an entity name change 
and update to the address.
Additionally, the protocol was amended to clarify analysis visits during the unblinded safety 
monitoring and long-term unblinded safety monitoring periods to be relative to the last dose 
of study treatment.
Amendment 03
01-MAR-2022
The protocol was amended to expand lymphocyte analysis to include B-cells and NK cells 
(TBNK panel), to update the recovery to baseline criteria for total lymphocyte and CD4+ T-
cell counts, to extend the follow-up period, and to clarify that the only study objective is to 
evaluate the safety and tolerability of ISL + MK-8507.
Amendment 02
01-DEC-2021
To make updates consistent with recommendations of the eDMC after an ad hoc review of 
the data; specifically, that all participants stop study intervention and participants receiving 
ISL + MK-8507 be followed. The study will continue so that participants who received ISL 
+ MK-8507 can be followed for at least 6 months. After 6 months, participants with 
lymphocyte and CD4+ T-cell counts recovered to within 30% of baseline (Day 1) values for 
2 consecutive visits and/or participants whose lymphocyte and CD4+ T-cell counts are 
stabilized in the opinion of the investigator can discontinue follow-up. Participants that have 
not met these criteria at 6 months should continue follow-up every 8 weeks for an additional 
6 months for lymphocyte and CD4+ T-cell monitoring.
Amendment 01
26-FEB-2021
Country-specific amendment to add an additional study intervention discontinuation 
criterion that is required for France.
Original Protocol
30-JUL-2020
Not applicable
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PROTOCOL AMENDMENT SUMMARY OF CHANGES
Amendment: 04
Overall Rationale for the Amendments:
Sponsor underwent an entity name change and update to the address. Additionally, the protocol was amended to clarify analysis visits 
during the unblinded safety monitoring and long-term unblinded safety monitoring periods to be relative to the last dose of study 
treatment.
Summary of Changes Table:
Section # and Name
Description of Change 
Brief Rationale 
Title Page 
Section 10.1.1 Code of 
Conduct for Clinical Trials
Throughout
Sponsor entity name and address change
Merck Sharp & Dohme Corp. underwent an entity 
name and address change to Merck Sharp & 
Dohme LLC, Rahway, NJ, USA. This conversion 
resulted only in an entity name change and update 
to the address.
Section 9.6.1.2
Refined “Day Range Rules” for analysis visits 
after the last dose to be every 4 weeks for the 
follow-up visits during the unblinded safety 
monitoring and every 12 weeks for the long-
term unblinded safety monitoring period.
To clarify the analysis visits during the unblinded 
safety monitoring and long-term unblinded safety 
monitoring periods to be relative to the last dose 
of study treatment.
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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 ..................................................................................................................19
1.3
Schedule of Activities...........................................................................................21
1.3.1
Schedule of Activities..................................................................................21
1.3.2
Schedule of Activities – Viremia Confirmation, Skeletal Fluorosis, and 
End of Treatment .........................................................................................27
1.3.3
Schedule of Activities – Unblinded Safety Monitoring...............................30
1.3.4
Schedule of Activities – Long-term Unblinded Safety Monitoring.............32
2
INTRODUCTION..........................................................................................................33
2.1
Study Rationale....................................................................................................33
2.2
Background ..........................................................................................................34
2.2.1
ISL (MK-8591)............................................................................................34
2.2.2
MK-8507......................................................................................................35
2.2.3
Information on Other Study-related Therapy ..............................................36
2.3
Benefit/Risk Assessment......................................................................................36
3
HYPOTHESES, OBJECTIVES, AND ENDPOINTS................................................37
4
STUDY DESIGN............................................................................................................41
4.1
Overall Design......................................................................................................41
4.2
Scientific Rationale for Study Design.................................................................42
4.2.1
Rationale for Endpoints ...............................................................................43
4.2.1.1
Efficacy Endpoints.............................................................................43
4.2.1.1.1
HIV-1 RNA Measurements .....................................................43
4.2.1.1.2
Definition of Clinically-significant Confirmed Viremia .........43
4.2.1.2
Safety Endpoints................................................................................44
4.2.1.2.1
Fluorosis Monitoring ...............................................................44
4.2.1.3
Laboratory and Radiological Markers ...............................................45
4.2.1.4
Pharmacokinetic Endpoints ...............................................................45
4.2.1.5
Patient-reported Outcomes.................................................................46
4.2.1.6
Planned Exploratory Biomarker Research.........................................47
4.2.1.6.1
Planned Genetic Analysis ........................................................47
4.2.1.7
Future Biomedical Research..............................................................47
4.2.2
Rationale for the Use of Comparator/Placebo .............................................47
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4.2.3
Rationale for the Study Population..............................................................48
4.2.4
Rationale for Collecting Specific Data ........................................................48
4.3
Justification for Dose...........................................................................................49
4.4
Beginning and End of Study Definition .............................................................52
4.4.1
Clinical Criteria for Early Study Termination .............................................53
4.4.2
Clinical Criteria for Closing a Treatment Group .........................................53
5
STUDY POPULATION ................................................................................................53
5.1
Inclusion Criteria.................................................................................................54
5.2
Exclusion Criteria................................................................................................55
5.3
Lifestyle Considerations......................................................................................57
5.4
Screen Failures.....................................................................................................58
5.5
Participant Replacement Strategy......................................................................58
6
STUDY INTERVENTION............................................................................................58
6.1
Study Intervention(s) Administered...................................................................58
6.2
Preparation/Handling/Storage/Accountability .................................................61
6.2.1
Dose Preparation..........................................................................................61
6.2.2
Handling, Storage, and Accountability........................................................61
6.3
Measures to Minimize Bias: Randomization and Blinding..............................62
6.3.1
Intervention Assignment..............................................................................62
6.3.2
Stratification.................................................................................................62
6.3.3
Blinding........................................................................................................62
6.4
Study Intervention Compliance..........................................................................63
6.5
Concomitant Therapy..........................................................................................63
6.5.1
Rescue Medications and Supportive Care ...................................................67
6.6
Dose Modification ................................................................................................67
6.7
Intervention After the End of the Study............................................................67
6.8
Clinical Supplies Disclosure................................................................................67
6.9
Standard Policies..................................................................................................67
7
DISCONTINUATION OF STUDY INTERVENTION AND PARTICIPANT 
WITHDRAWAL............................................................................................................68
7.1
Discontinuation of Study Intervention...............................................................68
7.2
Participant Withdrawal From the Study...........................................................69
7.3
Lost to Follow-up .................................................................................................69
8
STUDY ASSESSMENTS AND PROCEDURES........................................................69
8.1
Administrative and General Procedures ...........................................................70
8.1.1
Informed Consent.........................................................................................70
8.1.1.1
General Informed Consent.................................................................70
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8.1.1.2
Consent and Collection of Specimens for Future Biomedical 
Research.............................................................................................71
8.1.1.3
Consent and At-Home Collection of Dried Blood Samples with 
TassoTM OnDemandTM for PK Sampling of ISL ...............................71
8.1.1.4
Consent for Infant Safety Follow-up .................................................71
8.1.2
Inclusion/Exclusion Criteria ........................................................................71
8.1.3
Participant Identification Card.....................................................................72
8.1.4
Medical History ...........................................................................................72
8.1.5
Prior and Concomitant Medications Review...............................................72
8.1.5.1
Prior Medications...............................................................................72
8.1.5.2
Concomitant Medications..................................................................72
8.1.6
Assignment of Screening Number...............................................................72
8.1.7
Assignment of Treatment/Randomization Number.....................................73
8.1.8
Study Intervention Administration ..............................................................73
8.1.8.1
Timing of Dose Administration.........................................................73
8.1.8.1.1
Missed Dose(s).........................................................................74
8.1.9
Discontinuation and Withdrawal .................................................................74
8.1.9.1
Withdrawal From Future Biomedical Research ................................75
8.1.10
Participant Blinding/Unblinding..................................................................75
8.1.11
Calibration of Equipment.............................................................................76
8.1.12
Administration of Participant Questionnaires..............................................76
8.2
Efficacy Assessments ...........................................................................................77
8.2.1
HIV-1 RNA..................................................................................................77
8.2.2
Management of Study Participants With Viremia.......................................77
8.2.2.1
Viremia Confirmation........................................................................77
8.2.2.2
Participants With Clinically-significant Viremia (≥200 
copies/mL) .........................................................................................77
8.2.2.3
Participants With Low-level Viremia (≥50 and <200 copies/mL) ....78
8.2.2.4
Viral Drug Resistance Testing...........................................................78
8.2.3
T- and B- Lymphocyte and Natural Killer Cell Panel Including CD4+ 
T-cell Counts................................................................................................78
8.3
Safety Assessments...............................................................................................78
8.3.1
Physical Examinations.................................................................................79
8.3.1.1
Weight................................................................................................79
8.3.2
Vital Signs....................................................................................................79
8.3.3
Electrocardiograms ......................................................................................79
8.3.4
Confirmation of Contraception and Pregnancy Testing ..............................80
8.3.5
Clinical Safety Laboratory Assessments .....................................................80
8.3.6
Fluorosis Monitoring Assessments..............................................................81
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8.3.6.1
Plasma Fluoride .................................................................................81
8.3.6.2
Urine Fluoride....................................................................................81
8.3.6.3
Serum PTH.........................................................................................81
8.3.7
Bone Scan (Skeletal Scintigraphy) ..............................................................81
8.3.8
HBV Assessments........................................................................................82
8.3.9
Tobacco and Alcohol Assessments..............................................................82
8.3.10
Infant Safety Follow-up Assessments..........................................................82
8.4
Adverse Events, Serious Adverse Events, and Other Reportable Safety 
Events....................................................................................................................83
8.4.1
Time Period and Frequency for Collecting AE, SAE, and Other 
Reportable Safety Event Information ..........................................................83
8.4.2
Method of Detecting AEs, SAEs, and Other Reportable Safety Events......85
8.4.3
Follow-up of AE, SAE, and Other Reportable Safety Event Information...85
8.4.4
Regulatory Reporting Requirements for SAE .............................................85
8.4.5
Pregnancy and Exposure During Breastfeeding ..........................................86
8.4.6
Disease-related Events and/or Disease-related Outcomes Not Qualifying 
as AEs or SAEs............................................................................................86
8.4.7
Events of Clinical Interest............................................................................86
8.5
Treatment of Overdose........................................................................................87
8.6
Pharmacokinetics.................................................................................................87
8.6.1
Blood Collection for ISL and MK-8507 Pharmacokinetics ........................87
8.6.1.1
Venous Blood (Plasma) PK Sampling...............................................87
8.6.1.2
Dried Blood (TassoTMOnDemandTM) PK Sampling..........................88
8.7
Pharmacodynamics..............................................................................................89
8.8
Biomarkers ...........................................................................................................89
8.8.1
Planned Genetic Analysis Sample Collection..............................................89
8.8.2
Fasting Lipids...............................................................................................90
8.8.3
Waist and Hip Measurements......................................................................90
8.8.4
DEXA Assessments.....................................................................................90
8.9
Future Biomedical Research Sample Collection...............................................91
8.10
Medical Resource Utilization and Health Economics.......................................91
8.11
Visit Requirements...............................................................................................91
8.11.1
Screening......................................................................................................91
8.11.2
Treatment Period..........................................................................................92
8.11.2.1
Fasting................................................................................................92
8.11.2.2
Optional Nurse Visits and Telephone Visits......................................93
8.11.3
Discontinued Participants Continuing to be Monitored in the Study ..........93
8.11.3.1
Participants Who Become Pregnant...................................................93
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8.11.3.2
Early Discontinuation of Treatment...................................................94
8.11.3.3
End of Treatment Follow-up Visit.....................................................94
8.11.4
Viremia Confirmation..................................................................................94
8.11.5
Skeletal Fluorosis Evaluation ......................................................................94
9
STATISTICAL ANALYSIS PLAN .............................................................................95
9.1
Statistical Analysis Plan Summary.....................................................................95
9.2
Responsibility for Analyses/In-house Blinding .................................................96
9.3
Hypotheses/Estimation ........................................................................................97
9.4
Analysis Endpoints...............................................................................................97
9.4.1
Efficacy Endpoints.......................................................................................97
9.4.2
Safety Endpoints..........................................................................................99
9.4.3
Pharmacokinetic Endpoints .......................................................................100
9.4.4
Patient-reported Outcome Endpoints.........................................................100
9.5
Analysis Populations..........................................................................................101
9.5.1
Efficacy Analysis Populations...................................................................101
9.5.1.1
Full Analysis Set..............................................................................101
9.5.1.2
Resistance Analysis Subset..............................................................101
9.5.2
Safety Analysis Population........................................................................101
9.6
Statistical Methods.............................................................................................102
9.6.1
Statistical Methods for Efficacy Analyses.................................................102
9.6.1.1
Missing Data Approaches................................................................104
9.6.1.2
Definition of Time Points (or Analysis Visit)..................................106
9.6.2
Statistical Methods for Safety Analyses ....................................................107
9.7
Interim Analyses ................................................................................................110
9.8
Multiplicity .........................................................................................................111
9.9
Sample Size and Power Calculations ...............................................................111
9.9.1
Sample Size and Power for Efficacy Analyses..........................................111
9.9.2
Sample Size and Power for Safety Analyses .............................................113
9.10
Subgroup Analyses.............................................................................................116
9.11
Compliance (Medication Adherence)...............................................................116
9.12
Extent of Exposure.............................................................................................117
10
SUPPORTING DOCUMENTATION AND OPERATIONAL 
CONSIDERATIONS...................................................................................................118
10.1
Appendix 1: Regulatory, Ethical, and Study Oversight Considerations......118
10.1.1
Code of Conduct for Clinical Trials...........................................................118
10.1.2
Financial Disclosure...................................................................................120
10.1.3
Data Protection...........................................................................................120
10.1.3.1
Confidentiality of Data ....................................................................121
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10.1.3.2
Confidentiality of Participant Records.............................................121
10.1.3.3
Confidentiality of IRB/IEC Information..........................................121
10.1.4
Committees Structure.................................................................................122
10.1.4.1
Executive Oversight Committee......................................................122
10.1.4.2
External Data Monitoring Committee .............................................122
10.1.4.3
Scientific Advisory Committee (SAC)............................................122
10.1.5
Publication Policy......................................................................................122
10.1.6
Compliance with Study Registration and Results Posting Requirements .123
10.1.7
Compliance with Law, Audit, and Debarment ..........................................123
10.1.8
Data Quality Assurance .............................................................................124
10.1.9
Source Documents .....................................................................................124
10.1.10
Study and Site Closure...............................................................................125
10.2
Appendix 2: Clinical Laboratory Tests............................................................126
10.3
Appendix 3: Adverse Events: Definitions and Procedures for Recording, 
Evaluating, Follow-up, and Reporting.............................................................134
10.3.1
Definition of AE ........................................................................................134
10.3.2
Definition of SAE ......................................................................................135
10.3.3
Additional Events Reported.......................................................................136
10.3.4
Recording AE and SAE .............................................................................136
10.3.5
Reporting of AEs, SAEs, and Other Reportable Safety Events to the 
Sponsor ......................................................................................................140
10.4
Appendix 4: Device Events, Adverse Device Events, and Medical Device 
Incidents: Definitions, Collection, and Documentation..................................142
10.5
Appendix 5: Contraceptive Guidance..............................................................143
10.5.1
Definitions..................................................................................................143
10.5.2
Contraception Requirements......................................................................145
10.6
Appendix 6: Collection and Management of Specimens for Future 
Biomedical Research..........................................................................................146
10.7
Appendix 7: Country-specific Requirements..................................................151
10.7.1
Country-Specific Requirement for France.................................................151
10.8
Appendix 8: Calculation of Creatinine Clearance..........................................152
10.9
Appendix 9: Abbreviations ...............................................................................153
11
REFERENCES.............................................................................................................156
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LIST OF TABLES
Table 1
Laboratory Exclusion Criteria..........................................................................57
Table 2
Study Interventions..........................................................................................59
Table 3
Prohibited Therapies ........................................................................................66
Table 4
Infant Safety Follow-up: Data Collection Through 1 Year of Age .................82
Table 5
Reporting Time Periods and Time Frames for Adverse Events and Other 
Reportable Safety Events.................................................................................84
Table 6
Collection of PK Samples................................................................................87
Table 7
In-Clinic TassoOnDemandPK Sampling................................................88
Table 8
At-Home TassoOnDemandPK Sampling...............................................89
Table 9
Analysis Strategy for Key Efficacy Endpoints..............................................103
Table 10
Definition of Time Points (or Analysis Visit)................................................106
Table 11
Analysis Strategy for Key Safety Endpoints .................................................109
Table 12
Treatment Differences in Efficacy Event Rate Associated with 80% 
Probability (N=35 vs 35) ...............................................................................111
Table 13
Minimum Treatment Difference with the Lower Bound of 95% CI that 
Excludes 0 (N=35 vs 35) ...............................................................................112
Table 14
Estimate of Incidence of AEs and 95% Upper Confidence Bound Based 
on Hypothetical Number of Participants with AEs........................................114
Table 15
Difference in Incidence of AEs (either Groups 1-3 minus Group 4) That 
Can Be Ruled Out (N=35 vs 35)....................................................................114
Table 16
Power Calculations for Differences in 4-hour Urine Fluoride using a T-
Test and ANCOVA........................................................................................115
Table 17
Protocol-required Safety Laboratory Assessments........................................127
Table 18
Blood Volumes – Screening and Parts 1, 2, and 3.........................................129
Table 19
Blood Volumes – Unscheduled Visits...........................................................131
Table 20
Blood Volumes – Amendment 02..................................................................132
Table 21
Blood Volumes – Amendment 03..................................................................133
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LIST OF FIGURES
Figure 1
Study Schema and Treatment Plan (Original Study Design)...........................19
Figure 2
Unblinded Safety Monitoring Study Schema – Amendments 02 and 03 ........20
Figure 3
Comparison of ISL-TP Trough Concentrations After ISL 20 mg QW and 
ISL 0.75 mg QD Dosing to Steady State.........................................................50
Figure 4
MK-8507 QW Pharmacokinetics at Steady State............................................51
Figure 5
Log10 Viral Load Change from Baseline as a Function of Time Following 
Single Oral Doses of MK-8507 to Treatment-naïve Adults with HIV-1 
(N=6/dose level) ..............................................................................................52
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1
PROTOCOL SUMMARY
1.1
Synopsis
Protocol Title: A Phase 2b, Randomized, Active-Controlled, Double-Blind, Dose-Ranging 
Clinical Study to Evaluate a Switch to Islatravir (ISL) and MK-8507 Once-Weekly in Adults 
with HIV-1 Virologically Suppressed on Bictegravir/Emtricitabine/Tenofovir Alafenamide 
(BIC/FTC/TAF) Once-Daily
Short Title: Dose-Ranging, Switch Study of ISL and MK-8507 Once Weekly
Acronym: Not applicable
Hypotheses, Objectives, and Endpoints:
Note: As of Amendment 013-02, formal comparisons between study treatment arms will 
no longer be conducted; therefore, evaluation of the percentage of participants with 
HIV-1 RNA ≥50 copies/mL at Week 48 will no longer be considered a primary 
endpoint. Imaging, PROs, and biomarkers are no longer being collected. The only study 
objective is to evaluate the safety and tolerability of ISL + MK 8507 once-weekly as 
assessed by review of the accumulated safety data. Updated analyses are described in 
Section 9.
In participants ≥18 years of age with HIV-1 who have been virologically suppressed for 
≥6 months on BIC/FTC/TAF:
Primary Objectives
Primary Endpoints
- To evaluate the safety and tolerability of 
ISL + MK-8507 once-weekly as assessed 
by review of the accumulated safety data.
- Adverse events
- Adverse events leading to discontinuation 
of study intervention
- [No longer an objective as of Amendment 
013-02] To evaluate the antiretroviral 
activity of ISL administered with different 
doses of MK-8507 once-weekly after 
switching from BIC/FTC/TAF compared to 
continued treatment with BIC/FTC/TAF 
once-daily as assessed by the percentage of 
participants with HIV-1 RNA 
≥50 copies/mL at Week 48.
- HIV-1 RNA
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Secondary Objectives
Secondary Endpoints
- [No longer an objective as of Amendment 
013-02] To evaluate the antiretroviral 
activity following switch to ISL + MK-8507 
compared to continued treatment with 
BIC/FTC/TAF as assessed by the 
percentage of participants with the 
following at Week 48:
HIV-1 RNA <50 copies/mL
HIV-1 RNA <40 copies/mL
- HIV-1 RNA
- [No longer an objective as of Amendment 
013-02] To evaluate the antiretroviral 
activity following switch to ISL + MK-8507 
compared to continued treatment with 
BIC/FTC/TAF as assessed by the 
percentage of participants with the 
following at Week 24:
HIV-1 RNA ≥50 copies/mL
HIV-1 RNA <50 copies/mL
HIV-1 RNA <40 copies/mL
- HIV-1 RNA
- [No longer an objective as of Amendment 
013-02] To evaluate the sustained 
antiretroviral suppression in participants 
who switch to ISL + MK-8507 compared to 
continued treatment with BIC/FTC/TAF as 
assessed by the percentage of participants 
with the following at Week 96:
HIV-1 RNA ≥50 copies/mL
HIV-1 RNA <50 copies/mL
HIV-1 RNA <40 copies/mL
- HIV-1 RNA
- [No longer an objective as of Amendment 
013-02] To evaluate the immunologic effect 
of switching to ISL + MK-8507 compared 
to continued treatment with BIC/FTC/TAF 
as measured by change from baseline in 
CD4+ T-cell count at Weeks 24, 48, and 96.
- CD4+ T-cell count
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MK-8591-013-04 FINAL PROTOCOL
20-OCT-2022
- [No longer an objective as of Amendment 
013-02] To evaluate the antiretroviral 
suppression and immunologic effect of ISL 
+ MK-8507 as assessed by the following at 
Week 144: 
Percentage of participants with HIV-1 RNA 
≥50 copies/mL 
Change from baseline in CD4+ T-cell count
- HIV-1 RNA
- CD4+ T-cell count
- [No longer an objective as of Amendment 
013-02] To evaluate the development of 
viral drug resistance to any study 
intervention in participants who switch to 
ISL + MK-8507 and in participants who 
continue treatment with BIC/FTC/TAF.
- Viral resistance-associated substitutions
Overall Design:
Study Phase
Phase 2
Primary Purpose
Treatment
Indication
HIV-1 infection
Population
Participants ≥18 years of age with HIV-1 who have been 
virologically suppressed for ≥6 months on BIC/FTC/TAF.
Study Type
Interventional
Intervention Model
Parallel
This is a multi-site study.
Note: As of Amendment 013-02, all participants have been
unblinded and will be switched to non-study ART.
Type of Control
Active Control
Note: As of Amendment 013-02, all participants have been 
unblinded, will be switched to non-study ART, and there will 
not be a control.
Study Blinding
Double-blind with in-house blinding
Note: As of Amendment 013-02, all participants have been 
unblinded and will be switched to non-study ART.
08HRMY

PRODUCT: MK-8591  
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PROTOCOL/AMENDMENT NO.: 013-04
MK-8591-013-04 FINAL PROTOCOL
20-OCT-2022
Blinding Roles
Participants or Subjects
Investigator
Sponsor
Note: As of Amendment 013-02, all participants, investigators,
and the Sponsor have been unblinded and participants will be 
switched to non-study ART.
Estimated Duration 
of Study
The Sponsor estimates that the study will require approximately 2 
years from the time the first participant signs the informed consent 
until the last participant’s last study-related telephone call or visit.
Number of Participants:
Approximately 140 participants will be randomized. As of Amendment 013-02, enrollment 
completed with 161 participants randomized into the study.
08HRMY

PRODUCT: MK-8591  
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PROTOCOL/AMENDMENT NO.: 013-04
MK-8591-013-04 FINAL PROTOCOL
20-OCT-2022
Intervention Groups and Duration:
Intervention 
Groups
Note: As of Amendment 013-02, all groups have stopped study 
intervention administration. All participants remaining in the study
will be switched to non-study ART.
Inter-
vention 
Group 
Name
Drug
Dose 
Strength
Dose 
Fre-
quency
Route of 
Adminis-
tration
Treatment 
Period
Use
Group 1
(n=35)
ISL
20 mg
QW
Oral
Parts 1, 2a, 
and 3
Experi-
mental
MK-8507
100 mg
QW
Oral
Part 1
Experi-
mental
Placebo to MK-8507
0 mg
QW
Oral
Part 1
Placebo
Placebo to 
BIC/FTC/TAF
0 mg
QD
Oral
Part 1
Placebo
MK-8507
TBD
QW
Oral
Parts 2a
and 3
Experi-
mental
Group 2
(n=35)
ISL
20 mg
QW
Oral
Parts 1, 2a, 
and 3
Experi-
mental
MK-8507
200 mg
QW
Oral
Part 1
Experi-
mental
Placebo to MK-8507
0 mg
QW
Oral
Part 1
Placebo
Placebo to BIC/FTC/
TAF
0 mg
QD
Oral
Part 1
Placebo
MK-8507
TBD
QW
Oral
Parts 2a
and 3
Experi-
mental
Group 3
(n=35)
ISL
20 mg
QW
Oral
Parts 1, 2a, 
and 3
Experi-
mental
MK-8507
400 mg
QW
Oral
Part 1
Experi-
mental
Placebo to 
BIC/FTC/TAF
0 mg
QD
Oral
Part 1
Placebo
MK-8507
TBD
QW
Oral
Parts 2a
and 3
Experi-
mental
Group 4
(n=35)
Placebo to ISL
0 mg
QW
Oral
Part 1
Placebo
Placebo to MK-8507
0 mg
QW
Oral
Part 1
Placebo
BIC/FTC/
TAF
50 mg/
200 mg/
25 mg
QD
Oral
Parts 1 and 
2a
Experi-
mental
ISL
20 mg
QW
Oral 
Part 3
Experi-
mental
MK-8507
TBD
QW
Oral
Part 3
Experi-
mental
BIC=bictegravir; FTC=emtricitabine; ISL=islatravir; n=number enrolled in each group; QD=once daily; 
QW=once weekly; TAF=tenofovir alafenamide; TBD=to be determined based on dose selected in Part 1 of the 
study.
a.
Part 2 will begin after the MK-8507 dose is confirmed based on the Week 48 data from all participants. 
Once Part 2 is initiated, participants will begin open-label study intervention at their next study visit. 
Participants who reach their next study visit (eg, Week 60, Week 72, etc.) before Part 2 initiates will 
continue taking blinded study intervention until their next visit after Part 2 initiation.
08HRMY

PRODUCT: MK-8591  
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PROTOCOL/AMENDMENT NO.: 013-04
MK-8591-013-04 FINAL PROTOCOL
20-OCT-2022
Total 
Number of 
Intervention 
Groups/ 
Arms
Note: As of Amendment 013-02, all participants will be switched to
non-study ART; therefore, there are no intervention groups/arms.
4
Duration of 
Participation
Note: As of Amendment 013-02, all study groups have stopped study 
intervention administration. All participants remaining in the study
will be switched to non-study ART and will be followed for at least 
6 months. Participants whose total lymphocyte and CD4+ T-cell counts 
have not recovered to within 10% of baseline should be followed until 
the recovery criteria are met.
Each participant will be in the study for approximately 156 weeks from the 
time the participant signs the Informed Consent Form through the final 
contact. After a screening period of up to 45 days, each participant will 
receive blinded study intervention for at least 48 weeks and then open-label 
study intervention through Week 144. Participants who discontinue study 
intervention will be followed as described in the protocol.
Study Governance Committees:
Note: As of Amendment 013-02, administration of study intervention for all treatment 
groups has been stopped based on Sponsor acceptance of the eDMC recommendation; 
therefore, there is no longer a need to convene these committees.
Steering Committee
No
Executive Oversight Committee
Yes
Data Monitoring Committee
Yes
Clinical Adjudication Committee
No
Scientific Advisory Committee
Yes
Study governance considerations are outlined in Appendix 1.
Study Accepts Healthy Volunteers: No
A list of abbreviations used in this document can be found in Appendix 9.
08HRMY

PRODUCT: MK-8591  
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PROTOCOL/AMENDMENT NO.: 013-04
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20-OCT-2022
1.2
Schema
The original study design is depicted in Figure 1. The revised study design as of Amendment 
013-02 is depicted in Figure 2.
Figure 1
Study Schema and Treatment Plan (Original Study Design)
BIC=bictegravir; FTC=emtricitabine; ISL=islatravir; N=total number of participants in the study; n=total 
number of participants per group; QD=once daily; QW=once weekly; TAF=tenofovir alafenamide.
a.
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.
Part 2 will begin after the MK-8507 dose is confirmed based on the Week 48 data from all participants. 
Once Part 2 is initiated, participants will begin open-label study intervention at their next study visit.
Participants who reach their next study visit (eg, Week 60, Week 72, etc.) before Part 2 initiates will 
continue taking blinded study intervention until their next visit after Part 2 initiation.
08HRMY

PRODUCT: MK-8591  
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PROTOCOL/AMENDMENT NO.: 013-04
MK-8591-013-04 FINAL PROTOCOL
20-OCT-2022
Figure 2
Unblinded Safety Monitoring Study Schema – Amendments 02 and 03
ART=anti-retroviral therapy; BIC=bictegravir; FTC=emtricitabine; ISL=islatravir; QD=once daily; QW=once 
weekly; TAF=tenofavir alafenamide.
a.
The Unblinded Safety Monitoring period will be 6 months for Groups 1-3 participants and will continue if 
total lymphocyte and CD4+ T-cell counts have not recovered to within 10% of baseline.
08HRMY

PRODUCT: MK-8591  
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PROTOCOL/AMENDMENT NO.: 013-04
MK-8591-013-04 FINAL PROTOCOL
20-OCT-2022
1.3
Schedule of Activities
1.3.1
Schedule of Activities
Note: As of Amendment 013-02, all participants should follow the SoA in Section 1.3.3 and Section 1.3.4.
Study Period:
Screen
Part 1
Double-blind
Dose-Ranging`
Part 2
Selected Dose 
Open-labelb
Part 3
ISL + MK-8507
Open-Label
Notes
Visit Number
1
2
3
4
5
6
7
8
9
10
11b
12b
13b
14b,c
15
16
17
18
19
Scheduled Day/Week
Screening
Day 1
(Fasting)
Week 2
Week 4
(Fasting)
Week 8
Week 12
Week 16
Week 24
(Fasting)
Week 36
Week 48
(Fasting)
Week 60
Week 72
(Fasting)
Week 84
Week 96
(Fasting)
Week 100
Week 108
Week 120
(Fasting)
Week 132
Week 144
(Fasting)
Each visit should be calculated 
from date of Day 1. A visiting 
nurse may be used for visits 
after randomization per Section 
8.11.2.2.
Week 100 is only for 
participants in Group 4.
Visit Window
45 
daysa
NA
± 5 days
± 7 days
± 7 days
Administrative 
Procedures
Informed Consent
X
Informed Consent for 
Future Biomedical 
Research
X
Inclusion/Exclusion 
Criteria
X
X
Review prior to randomization 
on Day 1 to confirm changes in 
eligibility
Participant 
Identification Card
X
X
At the time of randomization, 
site personnel will add the 
randomization number to the 
participant identification card
CCI
08HRMY

PRODUCT: MK-8591  
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PROTOCOL/AMENDMENT NO.: 013-04
MK-8591-013-04 FINAL PROTOCOL
20-OCT-2022
Study Period:
Screen
Part 1
Double-blind
Dose-Ranging`
Part 2
Selected Dose 
Open-labelb
Part 3
ISL + MK-8507
Open-Label
Notes
Visit Number
1
2
3
4
5
6
7
8
9
10
11b
12b
13b
14b,c
15
16
17
18
19
Scheduled Day/Week
Screening
Day 1
(Fasting)
Week 2
Week 4
(Fasting)
Week 8
Week 12
Week 16
Week 24
(Fasting)
Week 36
Week 48
(Fasting)
Week 60
Week 72
(Fasting)
Week 84
Week 96
(Fasting)
Week 100
Week 108
Week 120
(Fasting)
Week 132
Week 144
(Fasting)
Each visit should be calculated 
from date of Day 1. A visiting 
nurse may be used for visits 
after randomization per Section 
8.11.2.2.
Week 100 is only for 
participants in Group 4.
Visit Window
45 
daysa
NA
± 5 days
± 7 days
± 7 days
Medical History
X
X
Prior/Concomitant 
Medication Review
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Register Study Visit in 
IRT
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Intervention 
Randomization
X
All procedures should be 
completed prior to dose on 
Day 1
Dispense study 
intervention using IRT
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Evaluation to receive 
continued study 
intervention
X
See Section 6.7
Study Intervention 
Compliance Review
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Reconcile doses and assess 
study intervention compliance 
Administration of 
HIVTSQs and HAT-
QoL Questionnaires
X
X
X
Administer prior to being seen 
by investigator and discussions 
about medical conditions or 
test results. 
Administration of 
Treatment Preference 
Questionnaire
X
X
Week 96: Groups 1-3 only.
Administration of HIV 
Stigma Scale 
Questionnaire
X
08HRMY

PRODUCT: MK-8591  
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PROTOCOL/AMENDMENT NO.: 013-04
MK-8591-013-04 FINAL PROTOCOL
20-OCT-2022
Study Period:
Screen
Part 1
Double-blind
Dose-Ranging`
Part 2
Selected Dose 
Open-labelb
Part 3
ISL + MK-8507
Open-Label
Notes
Visit Number
1
2
3
4
5
6
7
8
9
10
11b
12b
13b
14b,c
15
16
17
18
19
Scheduled Day/Week
Screening
Day 1
(Fasting)
Week 2
Week 4
(Fasting)
Week 8
Week 12
Week 16
Week 24
(Fasting)
Week 36
Week 48
(Fasting)
Week 60
Week 72
(Fasting)
Week 84
Week 96
(Fasting)
Week 100
Week 108
Week 120
(Fasting)
Week 132
Week 144
(Fasting)
Each visit should be calculated 
from date of Day 1. A visiting 
nurse may be used for visits 
after randomization per Section 
8.11.2.2.
Week 100 is only for 
participants in Group 4.
Visit Window
45 
daysa
NA
± 5 days
± 7 days
± 7 days
Efficacy Procedures
Plasma HIV-1 RNA 
Quantification (Real 
Time PCR)
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
CD4+ T-cell 
Count/TBNK Panel
X
X
X
X
X
X
X
X
X
X
Plasma for HIV Viral 
Drug Resistance 
Testing
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Samples will be stored and 
used if needed
Safety Procedures
Full physical 
examination
X
X
X
Height
X
X
X
X
Weight
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Directed Physical 
Examination
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Vital Signs
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Includes pulse, bp, temp, and rr
12-lead ECG
X
X
X
X
X
Contraceptive Use 
Confirmation (WOCBP 
Only)
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Serum Pregnancy Test 
(hCG; WOCBP only)
X
Urine Pregnancy Test 
(WOCBP only)
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Confirm with serum test if 
urine test is positive
08HRMY

PRODUCT: MK-8591  
24
PROTOCOL/AMENDMENT NO.: 013-04
MK-8591-013-04 FINAL PROTOCOL
20-OCT-2022
Study Period:
Screen
Part 1
Double-blind
Dose-Ranging`
Part 2
Selected Dose 
Open-labelb
Part 3
ISL + MK-8507
Open-Label
Notes
Visit Number
1
2
3
4
5
6
7
8
9
10
11b
12b
13b
14b,c
15
16
17
18
19
Scheduled Day/Week
Screening
Day 1
(Fasting)
Week 2
Week 4
(Fasting)
Week 8
Week 12
Week 16
Week 24
(Fasting)
Week 36
Week 48
(Fasting)
Week 60
Week 72
(Fasting)
Week 84
Week 96
(Fasting)
Week 100
Week 108
Week 120
(Fasting)
Week 132
Week 144
(Fasting)
Each visit should be calculated 
from date of Day 1. A visiting 
nurse may be used for visits 
after randomization per Section 
8.11.2.2.
Week 100 is only for 
participants in Group 4.
Visit Window
45 
daysa
NA
± 5 days
± 7 days
± 7 days
HIV-1 & HIV-2 
Serology
X
Hepatitis Serology
X
Participants who do not 
demonstrate immunity to HBV 
should be encouraged to be 
vaccinated against HBV
HBsAg
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
All participants at screening; 
only anti-HBc positive 
participants thereafter
HBV DNA
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Chemistry
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Fasting is required at Day 1 
and Weeks 4, 24, 48, 72, 96, 
120, and 144.
Hematology
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Fasting Lipids
X
X
X
X
X
X
X
X
PT/INR
X
Urine fluoride and 
creatinine
X
X
Based on 4-hour urine 
collection
Plasma fluoride
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
A bone scan will be performed 
in participants with plasma 
fluoride >4.0 mol/L 
(>0.076 mg/L) who also 
experience an AE of bone pain
(see Section 8.3.7).
Serum PTH
X
X
X
Urinalysis
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
08HRMY

PRODUCT: MK-8591  
25
PROTOCOL/AMENDMENT NO.: 013-04
MK-8591-013-04 FINAL PROTOCOL
20-OCT-2022
Study Period:
Screen
Part 1
Double-blind
Dose-Ranging`
Part 2
Selected Dose 
Open-labelb
Part 3
ISL + MK-8507
Open-Label
Notes
Visit Number
1
2
3
4
5
6
7
8
9
10
11b
12b
13b
14b,c
15
16
17
18
19
Scheduled Day/Week
Screening
Day 1
(Fasting)
Week 2
Week 4
(Fasting)
Week 8
Week 12
Week 16
Week 24
(Fasting)
Week 36
Week 48
(Fasting)
Week 60
Week 72
(Fasting)
Week 84
Week 96
(Fasting)
Week 100
Week 108
Week 120
(Fasting)
Week 132
Week 144
(Fasting)
Each visit should be calculated 
from date of Day 1. A visiting 
nurse may be used for visits 
after randomization per Section 
8.11.2.2.
Week 100 is only for 
participants in Group 4.
Visit Window
45 
daysa
NA
± 5 days
± 7 days
± 7 days
Review of Adverse 
Events
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Pharmacokinetics
Blood (Plasma) for ISL 
and MK-8507 PK
X
X
X
X
X
X
X
X
X
The sample at Day 1, Week 72, 
Week 96, & Week 144 will be 
taken predose. A predose & 
postdose sample will be taken
at Weeks 4, 24, & 48. A single 
sample will be collected at any 
time at Weeks 8 and 12.
Blood (Plasma) for 
Investigational PK
X
X
X
X
X
X
Samples will be stored and 
used if needed.
Biomarkers
Blood for Genetic 
Analysis
X
See Section 8.8
CCI
08HRMY

PRODUCT: MK-8591  
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PROTOCOL/AMENDMENT NO.: 013-04
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20-OCT-2022
Study Period:
Screen
Part 1
Double-blind
Dose-Ranging`
Part 2
Selected Dose 
Open-labelb
Part 3
ISL + MK-8507
Open-Label
Notes
Visit Number
1
2
3
4
5
6
7
8
9
10
11b
12b
13b
14b,c
15
16
17
18
19
Scheduled Day/Week
Screening
Day 1
(Fasting)
Week 2
Week 4
(Fasting)
Week 8
Week 12
Week 16
Week 24
(Fasting)
Week 36
Week 48
(Fasting)
Week 60
Week 72
(Fasting)
Week 84
Week 96
(Fasting)
Week 100
Week 108
Week 120
(Fasting)
Week 132
Week 144
(Fasting)
Each visit should be calculated 
from date of Day 1. A visiting 
nurse may be used for visits 
after randomization per Section 
8.11.2.2.
Week 100 is only for 
participants in Group 4.
Visit Window
45 
daysa
NA
± 5 days
± 7 days
± 7 days
Whole Blood for 
Future Biomedical 
Research
X
X
X
X
X
Optional participation; requires 
FBR consent
DEXA Scan (Only 
Where Permitted by 
Local Law)
X
X
X
X
Perform after all eligibility 
criteria are confirmed & within 
14 days after Day 1. At Weeks 
48, 96, & 144, scans may be 
performed ± 14 days of the 
scheduled visit. May require 
additional planning/scheduling.
Waist and Hip 
Measurements
X
X
X
X
AE=adverse event; anti-HBc=Hepatitis B core antibody; bp=blood pressure; CD4+=CD4-positive; DEXA=Dual X-ray Absorptiometry; DNA=deoxyribonucleic acid; 
ECG=electrocardiogram; FBR=future biomedical research; HAT-QoL=HIV/AIDS-Targeted Quality of Life; HBsAg=Hepatitis B surface antigen; HBV=Hepatitis B 
virus; hCG=human chorionic gonadotropin; HIV=human immunodeficiency virus; HIV-1=human immunodeficiency virus Type 1; HIV-2=human immunodeficiency 
virus Type 2; HIVTSQs=HIV Treatment Satisfaction Questionnaire, status version; INR=international normalized ratio; IRT=Interactive Response Technology; 
ISL=islatravir; NA=not applicable; PCR=polymerase chain reaction; PK=pharmacokinetics; PT=prothrombin time; PTH=parathyroid hormone; RNA=ribonucleic acid; 
rr=respiratory rate; TBNK=T- and B- Lymphocyte and Natural Killer Cell; temp=body temperature; WOCBP=a woman/women of childbearing potential.
a.
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.
Part 2 will begin after the MK-8507 dose is confirmed based on the Week 48 data from all participants. Once Part 2 is initiated, participants will begin open-label 
study intervention at their next study visit. Participants who reach their next study visit (eg, Week 60, Week 72, etc.) before Part 2 initiates will continue taking 
blinded study intervention until their next visit after Part 2 initiation.
c.
Week 96 is the end of Part 2 and the start of Part 3.
08HRMY

PRODUCT: MK-8591  
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20-OCT-2022
1.3.2
Schedule of Activities – Viremia Confirmation, Skeletal Fluorosis, and End of Treatment
Note: As of Amendment 013-02, all participants should follow the SoA in Section 1.3.3 and Section 1.3.4.
Study Period
Viremia 
Confirmation
Skeletal Fluorosis 
Evaluationa
End of Treatment
Notes
Visit Number
Unscheduled
Unscheduled
Unscheduled
Scheduled Day/Week
Viremia 
Confirmation
Skeletal Fluorosis 
Evaluation
Early 
Discontinuation of 
Treatment
End of Treatment 
Follow-up
The End of Treatment Follow-up 
visit should also be performed for 
participants who will not continue 
study intervention after Week 144.
Visit Window
Within 2 to 4 Weeks 
of HIV-1 Viremia 
(≥50 copies/mL)
NA
NA
42 (+ 7) days after 
the end of 
treatment
Administrative Procedures
Prior and Concomitant 
Medications Review
X
X
X
X
Register Study Visit in 
IRT
X
X
X
Study Intervention 
Compliance Review 
X
X
X
Reconcile doses and study 
intervention compliance.
Administration of 
HIVTSQs, HAT-QoL, 
and Treatment Preference
Questionnaires
X
Administered prior to being seen by 
investigator & discussions about 
medical conditions or test results.
Administered to participants who 
received 4 weeks of open-label 
study intervention
Efficacy Procedures
Plasma HIV-1 RNA 
Quantification (Real Time 
PCR)
X
X
X
CD4+ T-cell 
Count/TBNK Panel
X
X
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Study Period
Viremia 
Confirmation
Skeletal Fluorosis 
Evaluationa
End of Treatment
Notes
Visit Number
Unscheduled
Unscheduled
Unscheduled
Scheduled Day/Week
Viremia 
Confirmation
Skeletal Fluorosis 
Evaluation
Early 
Discontinuation of 
Treatment
End of Treatment 
Follow-up
The End of Treatment Follow-up 
visit should also be performed for 
participants who will not continue 
study intervention after Week 144.
Visit Window
Within 2 to 4 Weeks 
of HIV-1 Viremia 
(≥50 copies/mL)
NA
NA
42 (+ 7) days after 
the end of 
treatment
Plasma for HIV Viral 
Drug Resistance Testing
X
X
X
If HIV drug resistance sample is 
collected at Viremia Confirmation 
visit, it is not necessary to collect 
another sample at Early 
Discontinuation of Treatment visit. 
Analysis of samples collected at 
Early Discontinuation of Treatment 
or End of Treatment Follow-up visits 
triggered by Sponsor as needed.
Safety Procedures
Full Physical 
Examination 
X
X
X
Vital Signs 
X
X
X
Includes weight, pulse, bp, temp, and 
rr.
Contraceptive Use 
Confirmation (WOCBP 
Only)
X
X
X
X
Serum Pregnancy Test 
(WOCBP Only)
X
X
Chemistry
X
X
Hematology
X
X
Plasma fluoride
X
X
Bone Scan
X
See Section 8.3.7
Urinalysis
X
X
Review of Adverse 
Events
X
X
X
X
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Study Period
Viremia 
Confirmation
Skeletal Fluorosis 
Evaluationa
End of Treatment
Notes
Visit Number
Unscheduled
Unscheduled
Unscheduled
Scheduled Day/Week
Viremia 
Confirmation
Skeletal Fluorosis 
Evaluation
Early 
Discontinuation of 
Treatment
End of Treatment 
Follow-up
The End of Treatment Follow-up 
visit should also be performed for 
participants who will not continue 
study intervention after Week 144.
Visit Window
Within 2 to 4 Weeks 
of HIV-1 Viremia 
(≥50 copies/mL)
NA
NA
42 (+ 7) days after 
the end of 
treatment
Pharmacokinetics
Blood (Plasma) for 
Investigational PK
X
X
X
X
Samples will be stored and used if 
needed
Biomarkers
Whole Blood for Future 
Biomedical Research
X
X
If FBR sample was collected at 
Viremia Confirmation visit, it is not 
necessary to collect another sample at 
Early Discontinuation of Treatment 
visit. 
AE=adverse event; bp=blood pressure; CD4+=CD4-positive; FBR=future biomedical research; HAT-QoL=HIV/AIDS-Targeted Quality of Life; HIV=human 
immunodeficiency virus; HIV-1=human immunodeficiency virus Type 1; HIVTSQs=HIV Treatment Satisfaction Questionnaire, status version; IRT=Interactive Response 
Technology; NA=not applicable; PCR=polymerase chain reaction; PK=pharmacokinetics; RNA=ribonucleic acid; rr=respiratory rate; TBNK=T- and B- Lymphocyte and 
Natural Killer Cell; temp=body temperature; WOCBP=a woman/women of childbearing potential.
a.
Skeletal Fluorosis Evaluation visit to be completed only if participant experiences an AE of bone pain and has elevated plasma fluoride >4.0 µmol/L (>0.076 mg/L) (See 
Section 8.11.5).
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1.3.3
Schedule of Activities – Unblinded Safety Monitoring
Study Period
Early 
Discon 
of Txa
Unblinded Safety Monitoring (Groups 1, 2, and 3 Only)a, b
End of Tx 
Telephone 
Contactc
(42 days 
after last 
dose)
Notes: Each visit should be 
calculated from date of Day 1b.  
For Groups 1-3, Unblinded 
Safety Monitoring should 
continue for ≥6 months after 
switch to non-study ART or 
until lab results recovera.
Visit Number
7
8
UNS
9
UNS
10
UNS
11
12
13
Scheduled Day/Week
WK 20
WK 24
WK 28
WK 32
WK 36
WK 40
WK 44
WK 48
WK 52
WK 56
WK 60
WK 72
WK 84
Visit Window (Days)d
±7 days
+7
Administrative Procedures
Informed Consent for Amendment
<-------------------------------------------------------------------------->
Study Intervention Compliance Review
X
Initiate Non-study ART
X
ART recorded on CM eCRF
Register Study Visit in IRT
X
Concomitant Medication Review
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Efficacy Procedures
Plasma HIV-1 RNA Quantification (RT PCR)
X
X
X
X
CD4+ T-cell Count/TBNK Panel
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Safety Procedures
Vital Signs
X
Includes pulse, bp, temp, & rr
Weight
X
Directed Physical Examination
X
X
X
X
X
Full examination as needed
Chemistry
X
X
X
X
X
Hematology
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Urinalysis
X
HBsAg
X
Only if anti-HBc positive at 
screening
HBV DNA
X
Contraceptive Use Confirm (WOCBP only)
X
Urine Pregnancy Test (WOCBP only)
X
X
X
X
X
If urine +, confirm with serum 
Review of Adverse Events
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Pharmacokinetics
Blood (Plasma) for ISL and MK-8507 PK
Xd
X
X
X
X
X
X
X
X
Groups 1, 2, & 3 only
Xd
ART=anti-retroviral therapy; bp=blood pressure; CM=concomitant medication; DNA=deoxyribonucleic acid; eCRF=electronic case report form; HBc=hepatitis B core antibody; 
HBsAg=hepatitis B surface antigen; HBV=hepatitis B virus; HIV=human immunodeficiency virus; IRT=interactive response technology; ISL=islatravir; PK=pharmacokinetics; 
RNA=ribonucleic acid; rr=respiratory rate; RT PCR=real time polymerase chain reaction; TBNK=T- and B- Lymphocyte and Natural Killer Cell; temp=body temperature; 
Tx=treatment; UNS=unscheduled; WK=Week; WOCBP=women of child bearing potential.
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Study Period
Early 
Discon 
of Txa
Unblinded Safety Monitoring (Groups 1, 2, and 3 Only)a, b
End of Tx 
Telephone 
Contactc
(42 days 
after last 
dose)
Notes: Each visit should be 
calculated from date of Day 1b.  
For Groups 1-3, Unblinded 
Safety Monitoring should 
continue for ≥6 months after 
switch to non-study ART or 
until lab results recovera.
Visit Number
7
8
UNS
9
UNS
10
UNS
11
12
13
Scheduled Day/Week
WK 20
WK 24
WK 28
WK 32
WK 36
WK 40
WK 44
WK 48
WK 52
WK 56
WK 60
WK 72
WK 84
Visit Window (Days)d
±7 days
+7
a. As of Amendment 013-02, all participants have been unblinded and brought to the clinic for an Early Discontinuation of Treatment visit so that non-study ART could be 
initiated. Subsequently, participants in Group 4 will undergo an End of Treatment Telephone Contact 42 days after last dose, whereas participants in Groups 1-3 will undergo 
at least 6 months of Unblinded Safety Monitoring. Participants in Groups 1-3 are considered to have completed the study if, at or after the 6-month Unblinding Safety 
Monitoring, the participant has 2 total lymphocyte and 2 CD4+ T-cell counts that have recovered to within 10% of baseline (average between screening and Day 1) that were 
assessed approximately 12 weeks apart with no more than 1 intervening value that is outside of the 10% margin. Participants who have not met these criteria at 6 months 
should continue the Unblinded Safety Monitoring follow-up every 12 weeks for total lymphocyte and CD4+ T-cell monitoring.
b. If during the Unblinded Safety Monitoring period, if a participant has a visit within 2 weeks of another visit, it will be at the discretion of the investigator, taking into 
consideration the current laboratory results, whether the participant should return in 2 weeks or 6 weeks.
c. The End of Treatment Telephone Contact 42 days after last dose is applicable to ALL participants in Group 4, and participants in Groups 1-3 if they have less than 42-days of 
Unblinded Safety Monitoring.
d. Plasma PK and 
collection should only be performed in participants in Groups 1-3.
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1.3.4
Schedule of Activities – Long-term Unblinded Safety Monitoring
Study Period
Long-term Unblinded Safety Monitoring
(Groups 1, 2, and 3 Only)a
Notes: 
Each visit should be calculated from date of Day 1. For 
Groups 1-3, long-term Unblinded Safety Monitoring 
should continue every 12 weeks until total lymphocyte 
and CD4+ T-cell lab results recovera.
Visit Number
Unscheduled
Scheduled Day/Week
Every 12 weeksa
Visit Window (Days)
±7 days
Administrative Procedures
Concomitant Medication Review
X
Efficacy Procedures
CD4+ T-cell Count/TBNK Panel
X
Safety Procedures
Directed Physical Examination
X
Full examination as needed
Chemistry
X
Hematology
X
Urine Pregnancy Test (WOCBP only)b
Xb
If urine positive, confirm with serum 
Review of Adverse Events
X
See Section 8.4 for reportable events during follow-up
TBNK=T- and B- Lymphocyte and Natural Killer Cell; WOCBP=women of childbearing potential.
a.
Long-term Unblinded Safety Monitoring is required for participants in Groups 1-3 of whom total lymphocyte and CD4+ T-cell counts have not recovered within 10% of 
baseline during the initial 12-months of follow-up as outlined in Section 1.3.3. Participants in Groups 1-3 will continue to be followed up every 12 weeks ±7 days until total 
lymphocyte and CD4+ T-cell criteria for recovery are met which is defined as having 2 values approximately 12 weeks apart within 10% of the baseline with no more than 1
intervening value that is outside of the 10% margin. The baseline value for total lymphocyte and CD4+ T-cell safety monitoring is defined as the average value between 
Visit 1 Screening and Visit 2 Day 1.
b.
Urine pregnancy testing should be performed only if locally required.
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2
INTRODUCTION
ISL (also known as MK-8591) is a first-in-class investigational NRTTI. MK-8507 is a potent 
novel NNRTI. The combination of ISL and MK-8507 is being developed for QW treatment 
of HIV-1 infection in adults.
2.1
Study Rationale
Rationale for Amendment 013-02:
Downward trends of total lymphocytes and CD4+ T-cell counts were observed which 
triggered ad hoc eDMC recommendations to immediately discontinue study intervention 
administration for all participants and to initiate an Unblinded Safety Monitoring of 
participants who were randomized to ISL + MK-8507. 
Original Study Rationale:
As treatment regimens have improved, HIV-1 infection has become a chronic, manageable 
condition, and those receiving effective ART regimens can expect to live near-normal 
lifespans [Trickey, A., et al 2017]. With anticipation of life-long treatment, long-term 
tolerability and safety of antiretrovirals as well as patient adherence and preference have 
become increasingly important considerations. Furthermore, as the population living with 
HIV ages, there is also increasing concern for the risks of long-term toxicity and DDIs with 
respect to comorbid conditions (ie, neuropsychiatric, cardiovascular).
The current standard-of-care for the treatment of HIV-1 is a combination of 2 NRTIs with a 
third agent (eg, InSTI, NNRTI, or PI) taken daily [AIDS info 2017] [European AIDS Clinical 
Society 2016] [World Health Organization 2016]. Although such regimens have become 
increasingly well tolerated and highly efficacious, the current paradigm of life-long treatment 
is associated with a need for simpler and safer regimens, with reduced long-term drug 
exposure. There is accumulating evidence that simplified 2-drug regimens can achieve
efficacy comparable to that of 3-drug regimens, better tolerability, and improved quality of 
life, which can help to sustain virologic suppression [Llibre, J. M., et al 2018] [Cahn, P., et al 
2019] [Panel on Antiretroviral Guidelines for Adults and Adolescents 2018]. The viability of 
2-drug regimens depends on both components having distinct mechanisms of action with at 
least 1 of the components having a relatively high barrier to resistance.
A well-tolerated, effective extended duration regimen may provide additional convenience 
advantages for life-long treatment, such as ease of administration, improved adherence, 
treatment anonymity, and long-term patient acceptance as compared with traditional QD
regimens. This has the potential to decrease pill burden and daily dosing frequency; factors 
that have been identified as barriers to adherence. Poor adherence is a predictor of virologic 
failure, development of resistance, and increased mortality among people living with HIV-1
[Lima, V. D., et al 2009] [Genberg, B. L., et al 2012] [von Wyl, V., et al 2013].
Extended duration parenteral regimens are currently in development [Orkin, C., et al 2020]. 
However, most parenteral options use an extended-release formulation. Limitations of these 
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regimens may include potential local tolerability issues, the requirement for an oral lead-in,
and the potential for late-onset toxicity or AEs, which may be difficult to manage without a 
removable formulation [Gulick, R. M. 2019]. Additionally, not all patients will prefer an 
injectable formulation. Therefore, there remains a need for extended duration oral treatment 
regimens.
The combination of ISL and MK-8507 is a novel 2-drug regimen for the treatment of HIV-1 
infection due to its potent antiretroviral activity in vitro (including activity against common 
NRTI- and NNRTI-resistant variants) by multiple mechanisms of action, lack of food 
requirements, PK profiles consistent with oral QW administration, and favorable safety and 
DDI profiles observed to-date.  
2.2
Background
Refer to the IBs for detailed background information on ISL and MK-8507.
2.2.1
ISL (MK-8591)
Note: As of Amendment 013-02, this section is no longer applicable.
ISL is the first member of a new class of antiretroviral agents, known as NRTTIs, that block 
HIV-1 reverse transcriptase by novel mechanisms of action. It is an inactive nucleoside 
analogue 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 differentiated from other HIV-1 antiretrovirals by its high potency, long half-life
(ISL-TP, 79 to 214 hours), and favorable drug resistance profile. At concentrations 
equivalent to or above the trough levels of the proposed dose of 20 mg QW, ISL exhibits 
potent antiviral activity against wild-type HIV-1 and variants bearing the most prevalent 
NRTI resistance-associated mutations, including M184V in vitro, and as part of a QW 
regimen should provide durable efficacy.
ISL has been extensively evaluated in preclinical safety studies, including genetic toxicity 
assays and repeat-dose oral toxicity studies. ISL monotherapy safety studies did not reveal 
any specific cause of concern at acceptable exposure margins. The preclinical toxicity profile 
of ISL administered orally supports the continued development in participants with or 
without HIV-1.
ISL administered at a daily dose of 0.75 mg in combination with DOR is being evaluated in 
ongoing Phase 2 and 3 studies. In the Phase 2 study MK-8591 Protocol 011, all ISL QD 
doses (0.25 to 2.25 mg) administered in combination with DOR+3TC for 24 weeks and then 
with DOR alone, demonstrated potent antiretroviral activity comparable to DOR/3TC/TDF 
as assessed by the percentage of participants with HIV-1 RNA <50 copies/mL through 
Week 96. DOR + ISL, administered with 3TC or alone, had a favorable safety and 
tolerability profile through Week 96, comparable to that of DOR/3TC/TDF.
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The safety and PK of ISL QW was characterized in 18 healthy adult participants in a Phase 1 
double-blind, randomized, placebo-controlled study (MK-8591 Protocol 002). Weekly oral 
doses of ISL (10 mg, 30 mg, and 100 mg) or placebo were administered for 3 weeks. All
doses of ISL were generally well tolerated with no SAEs or discontinuations due to an AE. 
ISL plasma exposure and ISL-TP levels increased in an approximately dose-proportional 
manner over the entire dose range.
2.2.2
MK-8507
Note: As of Amendment 013-02, this section is no longer applicable.
MK-8507 is a novel NNRTI that blocks HIV-1 reverse transcriptase by binding to the classic
NNRTI binding pocket. It has potent in vitro activity against wild-type HIV-1 virus and 
variants bearing the most common NNRTI resistance-associated mutations. Unlike currently 
approved NNRTI agents, which require QD or BID regimens, 
 
The results of completed preclinical toxicity studies in rodents and dogs support the 
evaluation of MK-8507 in Phase 2. 
 
 
 
 
 
In Phase 1 clinical studies, MK-8507 demonstrated favorable clinical safety, tolerability, PK, 
and PD profiles when evaluated in 64 adult participants, with or without HIV-1. Based on a 
Phase 1 clinical study 
 
 
 
 
 
 
 
 
 
In a Phase 1b study in treatment-naïve adult participants with HIV-1 (MK-8507 Protocol 
003), single doses of MK-8507 from 40 mg to 600 mg achieved robust viral load declines by 
7-days postdose, comparable to those observed with daily administration of other NNRTIs 
(ie, >1 log10 drop in viral load) (see Section 4.3).
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2.2.3
Information on Other Study-related Therapy
Note: As of Amendment 013-02, this section is no longer applicable.
BIC/FTC/TAF was first approved in 2018 for the treatment of HIV-1 infection and will be 
administered at the approved marketed dose. Refer to approved labeling for detailed 
information on BIC/FTC/TAF.
2.3
Benefit/Risk Assessment
Note: As of Amendment 013-02, this section is no longer applicable.
It cannot be guaranteed that participants in clinical studies will directly benefit from 
treatment during participation, as clinical studies are designed to provide information about 
the safety and efficacy of an investigational medicine. Safety of the combination of ISL + 
MK-8507 in humans has not been studied. However, based on available data from preclinical 
and clinical studies, both ISL and MK-8507 have the potential to be highly potent and 
effective ART agents with favorable safety and tolerability profiles and PK properties that 
support QW administration. Switching to a QW oral regimen that is as efficacious and safe as 
a QD oral regimen has the potential to reduce pill/treatment fatigue, HIV stigma and desire 
for anonymity, and ultimately improve treatment adherence and outcomes. The 
comprehensive preclinical safety evaluations of ISL and MK-8507, as single entity or in 
combination, have not revealed toxicities of concern at acceptable exposure margins and 
support the clinical evaluation of these 2 compounds.
Across the ISL clinical development program, as of 14-JAN-2020, approximately 
300 participants with or without HIV-1 received oral ISL in Phase 1 and 2 clinical studies. 
Overall, ISL was generally well-tolerated with no dose-dependent increases in AEs and no 
drug-related SAEs or deaths reported. The combination of DOR and ISL QD has 
demonstrated effective antiretroviral activity through Week 96 in approximately 
90 treatment-naïve participants with HIV-1 in the ongoing Phase 2 clinical study (MK-8591 
Protocol 011).
MK-8507 has been evaluated in 4 Phase 1 studies involving 46 healthy adult participants and 
18 adult participants with HIV-1. A single oral dose (up to 1200 mg) or multiple doses (up to 
800 mg, QW, × 3 doses) of MK-8507 has been generally well-tolerated with no treatment-
related SAEs, no AEs causing discontinuation of study intervention, and no deaths reported.
 
. Increased urinary fluoride excretion
was also observed in a Phase 1 study with MK-8507 (MK-8507 Protocol 005). A potential 
concern with excess fluoride intake is the development of skeletal fluorosis characterized by 
bone pain and radiologic evidence of periostitis [Tan, I., et al 2019]. However, the amount of 
fluoride estimated to be released at the 400 mg weekly dose of MK-8507 (1.2 mg/day of 
fluoride) is expected to be well below the US EPA RfD. Even when typical daily fluoride 
intake from other sources (~2.9 mg/day) is considered, the total daily fluoride intake would 
be expected to be ~4.1 mg, which is 15% below the US EPA RfD (4.8 mg/day) 
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[Health and Ecological Criteria Division, et al 2010]and 42% below the EU Scientific 
Committee on Health and Environmental Risks upper limit (7.0 mg/day) [Scientific 
Committee on Health and Environmental Risks 2011]. Although elevated plasma fluoride 
levels are not expected at the doses of MK-8507 in this study, participants will have plasma 
fluoride concentrations measured throughout the study. If a participant experiences an AE of 
bone pain and his or her plasma fluoride concentration exceeds 4.0 µmol/L (>0.076 mg/L), a 
bone scan will be performed to diagnose periostitis (see Section 8.3.7). 
Additional details regarding the benefits and risks for participants participating in this clinical 
study may be found in the accompanying IBs and informed consent documents.
3
HYPOTHESES, OBJECTIVES, AND ENDPOINTS
Note: As of Amendment 013-02, formal comparisons between study treatment arms will 
no longer be conducted; therefore, evaluation of the percentage of participants with 
HIV-1 RNA ≥50 copies/mL at Week 48 will no longer be considered a primary 
endpoint. Imaging, PROs, and biomarkers are no longer being collected. The only study 
objective is to evaluate the safety and tolerability of ISL + MK 8507 once-weekly as 
assessed by review of the accumulated safety data. Updated analyses are described in 
Section 9.
In participants ≥18 years of age with HIV-1 who have been virologically suppressed for 
≥6 months on BIC/FTC/TAF:
Objectives
Endpoints
Primary

To evaluate the safety and tolerability of 
ISL + MK-8507 once-weekly as 
assessed by review of the accumulated 
safety data.

Adverse events

Adverse events leading to 
discontinuation of study intervention

[No longer an objective as of 
Amendment 013-02] To evaluate the 
antiretroviral activity of ISL 
administered with different doses of 
MK-8507 once-weekly after switching
from BIC/FTC/TAF compared to 
continued treatment with BIC/FTC/TAF 
once-daily as assessed by the percentage 
of participants with HIV-1 RNA 
≥50 copies/mL at Week 48.

HIV-1 RNA
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Objectives
Endpoints
Secondary

[No longer an objective as of 
Amendment 013-02] To evaluate the 
antiretroviral activity following switch to 
ISL + MK-8507 compared to continued 
treatment with BIC/FTC/TAF as 
assessed by the percentage of 
participants with the following at Week 
48:
HIV-1 RNA <50 copies/mL
HIV-1 RNA <40 copies/mL

HIV-1 RNA

[No longer an objective as of 
Amendment 013-02] To evaluate the 
antiretroviral activity following switch to 
ISL + MK-8507 compared to continued 
treatment with BIC/FTC/TAF as 
assessed by the percentage of 
participants with the following at Week 
24:
HIV-1 RNA ≥50 copies/mL
HIV-1 RNA <50 copies/mL
HIV-1 RNA <40 copies/mL

HIV-1 RNA

[No longer an objective as of 
Amendment 013-02] To evaluate the 
sustained antiretroviral suppression in 
participants who switch to ISL + MK-
8507 compared to continued treatment 
with BIC/FTC/TAF as assessed by the 
percentage of participants with the 
following at Week 96:
HIV-1 RNA ≥50 copies/mL
HIV-1 RNA <50 copies/mL
HIV-1 RNA <40 copies/mL

HIV-1 RNA
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Objectives
Endpoints

[No longer an objective as of 
Amendment 013-02] To evaluate the 
immunologic effect of switching to ISL
+ MK-8507 compared to continued 
treatment with BIC/FTC/TAF as 
measured by change from baseline in 
CD4+ T-cell count at Weeks 24, 48, and 
96.

CD4+ T-cell count

[No longer an objective as of 
Amendment 013-02] To evaluate the 
antiretroviral suppression and 
immunologic effect of ISL + MK-8507 
as assessed by the following at Week 
144:
Percentage of participants with HIV-1 
RNA ≥50 copies/mL
Change from baseline in CD4+ T-cell 
count

HIV-1 RNA

CD4+ T-cell count

[No longer an objective as of 
Amendment 013-02] To evaluate the 
development of viral drug resistance to 
any study intervention in participants 
who switch to ISL + MK-8507 and in 
participants who continue treatment with 
BIC/FTC/TAF.

Viral resistance-associated substitutions
Tertiary/Exploratory

[No longer an objective as of 
Amendment 013-02] To evaluate the 
effect of MK-8507 on urinary fluoride 
excretion as measured by levels of urine 
fluoride at baseline and Week 4.

Urinary fluoride levels
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Objectives
Endpoints

[No longer an objective as of 
Amendment 013-02] To evaluate the 
effect on fasting lipid and metabolic 
profiles, and body composition 
following switch to ISL + MK-8507
compared to continued treatment with 
BIC/FTC/TAF as measured by the mean 
change in laboratory and radiological 
markers from baseline at Weeks 48 and 
96.

Laboratory and radiological markers

[No longer an objective as of 
Amendment 013-02] To evaluate the 
pharmacokinetics of ISL + MK-8507 
when administered in combination.

Pharmacokinetic parameters, such as 
AUC, Cmax, and C168

[No longer an objective as of 
Amendment 013-02] To describe the 
following PRO concepts:
Change from baseline to Week 96 and
Week 144 in treatment satisfaction, life 
satisfaction, disclosure worries, and 
medication concerns.
Stigma at baseline.
Treatment preference at Week 96
(participants in Groups 1-3) and at Week 
144 (all participants).

HIVTSQs

Shortened HAT-QoL

HIV Stigma Scale

Treatment preference

[No longer an objective as of 
Amendment 013-02] 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.
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4
STUDY DESIGN
4.1
Overall Design
Amendment 013-02
As of Amendment 013-02, all participants have been unblinded and brought to the clinic for 
an Early Discontinuation of Treatment visit so that non-study ART could be initiated. 
Subsequently, participants in Group 4 will undergo an End of Treatment Safety Telephone 
Contact, whereas participants in Groups 1-3 should undergo monthly safety follow-up visits 
for a duration of at least 6 months. Participants in Groups 1-3 are considered to have 
completed the study if, at or after the 6-month Unblinding Safety Monitoring, the participant 
has 2 total lymphocyte and 2 CD4+ T-cell counts that have recovered to within 10% of 
baseline that were assessed approximately 12 weeks apart with no more than 1 intervening 
value that is outside of this margin. The baseline value for total lymphocyte and CD4+ T-cell 
counts is defined as the average value between screening (within 45 days before the first dose 
of study medication) and Day 1. Participants in Group 1-3 who have not met these criteria at 
6 months should continue the Unblinded Safety Monitoring every 12 weeks for total 
lymphocyte and CD4+ T-cell monitoring until the criteria to complete the study outlined 
above are met. Participants who no longer want to undergo monthly monitoring should be 
advised to follow up with their HIV care provider.
Original Design:
This is a 3-part dose-ranging, randomized, active-controlled study to evaluate a switch from 
BIC/FTC/TAF QD to ISL + MK-8507 QW in participants with HIV-1 who have been 
virologically suppressed on BIC/FTC/TAF for ≥6 months.
Part 1 (Double-blind Dose-ranging Treatment Period)
Part 1 is a double-blind, double-dummy treatment period in which approximately 
140 participants will be randomized in a 1:1:1:1 ratio into 1 of the following 4 blinded 
treatment groups (Figure 1):
•
Group 1 (n~35): ISL (20 mg) + MK-8507 (100 mg) QW 
•
Group 2 (n~35): ISL (20 mg) + MK-8507 (200 mg) QW 
•
Group 3 (n~35): ISL (20 mg) + MK-8507 (400 mg) QW 
•
Group 4 (n~35): BIC/FTC/TAF QD 
After all participants have completed Week 24 visit assessments, an interim analysis will be 
conducted on safety and efficacy data through Week 24 to select a preliminary dose of 
MK-8507 for Part 2 (Section 9.7). After all participants have completed Week 48 visit 
assessments, the preliminary dose of MK-8507 will be confirmed by analysis of safety and 
efficacy data through Week 48 (Section 9.7). Since the Week 48 interim analysis is not 
conducted until all participants complete their Week 48 visit, participants who enroll earlier 
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into the study may continue in Part 1 on blinded study intervention beyond Week 60 until the 
MK-8507 dose is selected and communicated to sites.
Part 2 (Selected-dose Open-label Treatment Period)
Part 2 of the study will be initiated once sites have been notified of the selected dose of 
MK-8507. Participants will receive open-label study intervention starting at their next 
scheduled study visit as follows (Figure 1):

Groups 1, 2, and 3: ISL + MK-8507 QW (at the selected dose)

Group 4: BIC/FTC/TAF QD
Each participant will continue in Part 2 through their Week 96 visit.
Part 3 (ISL+MK-8507 Open-label Treatment Period)
In Part 3, all participants will receive open-label ISL + MK-8507 QW (at the selected dose)
from Week 96 through Week 144. Participants randomized to Group 4, who received open-
label BIC/FTC/TAF QD in Part 2, will switch to receive open-label ISL + MK-8507 QW
beginning at their Week 96 visit to allow for all participants in the study to experience the 
QW dosing regimen.
Clinical site personnel and participants will remain blinded through Part 1. To allow timely 
completion of dose response and population PK modeling, select Sponsor personnel (not 
affiliated with the study team) will be unblinded for the Week 24 interim analysis. No 
Sponsor personnel directly associated with study conduct will be unblinded to participant 
treatment assignments before Week 48 (see Section 6.3.3). Participant safety will be 
monitored by an independent eDMC through periodic review of safety and efficacy data 
(received from an unblinded statistician) (Appendix 1). 
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. At any point in the study, participants with confirmed viremia, as 
described in Section 4.2.1.1.2, will be assessed for development of viral drug resistance and 
potential discontinuation from study intervention. Viral resistance data will remain masked 
for each participant until he/she switches to open-label therapy.
4.2
Scientific Rationale for Study Design
Amendments 013-02 and 013-03
Based on the recommendation of the eDMC to stop study intervention administration in this 
study, Amendments 013-02 and 013-03 are designed to allow for the discontinuation of study 
intervention for all participants, the safety follow-up of participants who were randomized to 
Groups 1-3, and the discontinuation from the study for participants who were randomized to 
Group 4.
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Original rationale:
This randomized blinded active-controlled Phase 2 study design is considered appropriate to 
support MK-8507 dose selection in combination with ISL 20 mg QW for further evaluation 
in Phase 3. Part 1 of the study is blinded and will provide 48 weeks of efficacy, safety, and 
PK data of ISL 20 mg + MK-8507 (dose-ranged) QW compared with BIC/FTC/TAF to 
support MK-8507 dose selection. Part 2 and Part 3 of the study are open-label and will 
provide longer term efficacy and safety data and allow for assessment of participants’ 
adherence to a QW regimen without daily BIC/FTC/TAF placebos.
4.2.1
Rationale for Endpoints
4.2.1.1
Efficacy Endpoints
Note: As of Amendment 013-02, HIV-1 RNA measurements will be collected 
periodically but will not be considered efficacy endpoints. Management of viremia will 
be at the discretion of the investigator outside of the study.
4.2.1.1.1
HIV-1 RNA Measurements
The primary efficacy endpoint in this study is plasma HIV-1 RNA ≥50 copies/mL. Eligible 
participants in the switch population being studied are virologically suppressed, with HIV-1 
RNA <50 copies/mL at baseline. The assessment of interest is the percentage of participants 
who are unable to maintain virologic suppression after switching to a new antiretroviral 
regimen [Food and Drug Administration (CDER) 2015].
Clinical studies of antiretroviral agents in multiple drug classes have shown that virologic 
suppression of HIV-1 RNA to <50 copies/mL reflects a clinically-relevant standard used 
across development programs for antiretroviral therapies and in clinical practice 
[Vandenhende, M. A., et al 2015]. Suppressing HIV-1 RNA to <50 copies/mL preserves the 
immune system and minimizes the risk of opportunistic infections and disease progression.
The efficacy endpoint of plasma HIV-1 RNA <40 copies/mL corresponds to the LLOQ of the 
assay being used in this study.
4.2.1.1.2
Definition of Clinically-significant Confirmed Viremia
For the purpose of managing participants in this study, clinically-significant confirmed 
viremia is defined as:

Virologic Rebound: Two consecutive (2 to 4 weeks apart) occurrences of HIV-1 RNA 
≥200 copies/mL at any time during the study.
There is currently no global standard for definition of patients with low-level viremia (viral 
load ≥50 and <200 copies/mL), and the predictive implication of such low-level viremia is 
uncertain [Vandenhende, M. A., et al 2015] [Charpentier, C., et al 2014]. The US Department 
of Health and Human Services guidelines currently define virologic failure as confirmed HIV 
RNA ≥200 copies/mL and do not recommend that low-level viremia (detectable HIV RNA 
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<200 copies/mL) automatically result in treatment modification or more frequent virologic 
monitoring [Panel on Antiretroviral Guidelines for Adults and Adolescents 2018]. 
Participants with HIV-1 RNA between 50 and 200 copies/mL have a lower risk of 
developing resistance compared to those with HIV-1 RNA >200 copies/mL and should 
continue on their current regimen, with HIV-1 RNA levels monitored as outlined in 
Section 8.2.2.
An HIV-1 RNA level of ≥50 copies/mL must be confirmed and requires further management 
as described in Section 8.2.2.
4.2.1.2
Safety Endpoints
Note: As of Amendment 013-02, study intervention administration has been stopped
but the study will continue so that participants who received ISL + MK-8507 can be 
followed for at least 6 months. Participants in Groups 1-3 are considered to have completed 
the study if, at or after the 6-month Unblinding Safety Monitoring follow-up, the participant 
has 2 total lymphocyte and 2 CD4+ T-cell counts that have recovered to within 10% of 
baseline (average between screening and Day 1) that were assessed approximately 12 weeks 
apart with no more than 1 intervening value that is outside of this margin. Participants who
have not met these criteria at 6 months should continue the Unblinded Safety Monitoring 
every 12 weeks for total lymphocyte and CD4+ T-cell monitoring until the criteria for 
completion of the study have been met.
Safety evaluations will include physical examinations (including vital signs) and laboratory 
tests (hematology, chemistry, and urinalysis) performed per the SoA to provide an overall 
assessment of the safety and tolerability of ISL + MK-8507 administered QW. 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.
4.2.1.2.1
 
In 
 Phase 1 clinical study (MK-8507 Protocol 005), MK-8507 has 
been shown to release fluoride (see Section 2.2.2). Therefore, this study will include the 
following assessments to monitor fluoride and serum PTH levels in all participants:

4-hour urine collection at Day 1 (baseline) and Week 4 (steady-state accumulation)

Plasma fluoride levels at Day 1, Weeks 8, 16, 24, and every 12-weeks thereafter

Serum PTH at Day 1, Week 24, and Week 48
The selected 4-hour duration to assess urinary fluoride excretion levels was based on the 
correlation data collected in MK-8507 Protocol 005. 
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In addition, to further evaluate the potential impact of elevated fluoride levels, the following
assessments will be conducted in participants with plasma fluoride levels >4.0 µmol/L
(>0.076 mg/L):

Association between serum alkaline phosphatase levels and plasma fluoride levels

Association between relevant AEs and plasma fluoride levels

Analysis of the potential fluorosis-related AEs stratified by baseline fluoride levels

If participant is also experiencing an AE of bone pain: Bone scan (or other imaging 
method per local standard-of-care) (see Sections 8.3.7 and 8.11.5)
To monitor for potential signs of fluorosis, AEs of periostitis, fracture, and bone pain will be 
listed as events of clinical interest.
4.2.1.3
Laboratory and Radiological Markers
Note: As of Amendment 013-02, lipid and radiological markers will no longer be 
collected.
The study will evaluate changes in laboratory and radiological markers from baseline to 
Weeks 48 and 96 following the switch to ISL + MK-8507 compared to continued treatment 
with BIC/FTC/TAF.
Fasting Lipids
Some antiretrovirals have been associated with lipid abnormalities [U.S. Prescribing 
Information 2017]; thus, key indicators of fasting lipid profiles will be measured (Section 
8.8.2).
Body Composition
Decreases in BMD and lipodystrophy (peripheral and central fat redistribution) have been 
reported in patients with HIV-1 receiving ART [AIDS info 2017], particularly with the use of 
certain NRTIs. Key indicators of body composition (including DEXA assessments) will be 
measured (Section 8.8.4).
4.2.1.4
Pharmacokinetic Endpoints
Note: As of Amendment 013-02, sparse plasma PK will be collected, as described in the 
SoA (Section 1.3.3), and the
 
.
The sparse PK data (collected as described in the SoA and Section 8.6.1.) will be used for 
updating the population PK model for ISL and MK-8507.
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Venous blood samples will be collected for measurement of ISL and MK-8507 plasma 
concentrations.
 
 
 
 
 
 
4.2.1.5
Patient-reported Outcomes
Note: As of Amendment 013-02, PROs will no longer be collected.
While current HIV ARTs have conferred high efficacy and good tolerability overall, the 
focus has shifted to treatment satisfaction and improvement in quality of life. A treatment 
modality that minimally interferes with a patients’ lifestyle, helps maintain HIV-status 
anonymity, reduces stigma, and/or facilitates adherence may be the preferred treatment 
choice by patients living with HIV. Because the HIV treatment experience is largely 
subjective, PRO instruments are important in the evaluation and differentiation of treatment 
strategies.
This study will include 4 self-administered PRO questionnaires:

The HIVTSQs is a validated 10-item instrument used to measure satisfaction with 
medications for people with HIV infection and covers 3 domains (convenience, ease of 
use, and flexibility). 

The HAT-QoL is a validated 34-item instrument used for the measurement of quality of 
life in participants with HIV/AIDS and covers 9 domains. The version of this 
questionnaire used for this study will include 3 domains hypothesized to be most 
impacted by the study design (disclosure worries, life satisfaction, and medication 
concerns).

A novel, 5-item treatment preference questionnaire developed specifically for this study
will be administered to participants treated with ISL + MK-8507 to assess preference 
between weekly and daily dosing of ART.

The 12-item HIV Stigma Scale is a validated, shortened version of the frequently used 
40-item HIV Stigma Scale with 3 questions from each of the 4 stigma subscales/domains 
(personalized stigma, disclosure concerns, concerns with public attitudes, and negative 
self-image).
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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
Note: As of Amendment 013-02, samples for FBR will no longer be collected.
The Sponsor will conduct future biomedical research on specimens for which consent was 
provided during this study. This research may include genetic analyses (DNA), gene 
expression profiling (RNA), proteomics, metabolomics (serum, plasma), and/or the 
measurement of other analytes, depending on which specimens are consented for future 
biomedical research.
Such research is for biomarker testing to address emergent questions not described elsewhere 
in the protocol (as part of the main study) and will only be conducted on specimens from 
appropriately consented participants. The objective of collecting/retaining specimens for 
future biomedical research is to explore and identify biomarkers that inform the scientific 
understanding of diseases and/or their therapeutic treatments. The overarching goal is to use 
such information to develop safer, more effective drugs/vaccines, and/or to ensure that 
participants receive the correct dose of the correct drug/vaccine at the correct time. The 
details of future biomedical research are presented in Appendix 6.
4.2.2
Rationale for the Use of Comparator/Placebo
Note: As of Amendment 013-02, all study intervention administration has been stopped.
The approved 3-drug regimen of BIC/FTC/TAF will be the comparator in this study. 
BIC/FTC/TAF has been approved by the EMA and the FDA for both treatment-naïve and 
switch patients and is a recommended initial regimen for most people living with HIV-1
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[Panel on Antiretroviral Guidelines for Adults and Adolescents 2018]. Although some 
previous switch studies have been conducted within-class (eg, from one NNRTI to another), 
this study is designed to compare switching to ISL + MK-8507 from an InSTI-containing 
regimen. The InSTI-containing regimen was chosen as the comparator because the InSTI 
class is recommended by both the US Department of Health and Human Services [Panel on 
Antiretroviral Guidelines for Adults and Adolescents 2018] and the European AIDS Clinical 
Society[European AIDS Clinical Society 2018] as part of all first-line, standard-of-care 
treatment regimens. However, emerging data suggest that some InSTIs may have tolerability 
issues including possible weight gain and CNS side effects. Furthermore, long-term renal and 
bone defects have been associated with the use of TAF [U.S. Prescribing Information 2016]. 
Thus, some patients may want to switch from the combination of BIC/FTC/TAF [Norwood, 
J., et al 2017] [Hoffmann, C., et al 2017].
Matching placebo will be used to provide a robust evaluation of the safety and tolerability 
profile of ISL + MK-8507 by maintaining double-blind, double-dummy study intervention in
Part 1.
4.2.3
Rationale for the Study Population
Patients who have achieved virologic suppression for ≥6 months on an oral 3-drug QD 
regimen have already demonstrated the ability to be adherent to ART but the high dosing 
frequency of the QD regimen may result in pill fatigue. An oral 2-drug QW regimen provides 
convenience advantages and also reduces exposure to the number of ARV medications,
which can lower the potential for DDIs with concomitant medications. By decreasing the 
dosing frequency, an extended duration oral QW regimen may lead to better life-long 
adherence to ART and offer greater treatment anonymity. 
It is anticipated that the extended duration regimen of ISL + MK-8507 QW will be used most 
often in this patient population looking to switch from their QD regimens after achieving and 
maintaining virologic suppression. Clinicians will have an understanding of their patients’ 
abilities to adhere to their QD regimens and can evaluate their potential for success on a less 
frequent, QW regimen. 
4.2.4
Rationale for Collecting Specific Data

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, collecting race and ethnicity data is 
important in order to understand any potential differential effects 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 to other 
groups, and the factors contributing to this remain to be elucidated 
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[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 outcome and toxicity.

Gender Identity Data: Transgender people, defined as those whose gender identities 
and/or expressions differ from the sex assigned to them at birth, have a high 
prevalence and incidence of HIV infection globally [Poteat, T., et al 2016]. 
Specifically, transgender women have an increased risk of HIV infection attributed to 
challenges associated with coping with psychosocial issues such as discrimination, 
stigmatization, and marginalization [Centers for Disease Control and Prevention 
2019] [Department of HIV/AIDS 2015]. When considering HIV treatment, the WHO 
considers transgender people to be a separate key population because of their specific 
health needs and high vulnerability [Department of HIV/AIDS 2015]. Data will be 
collected in this study to assess clinical outcomes in the transgender population.

Infant Follow-up Data: Follow-up through 1 year of age for infants born to 
participants who become pregnant while receiving study intervention provides the 
ability to monitor growth and development as well as potential adverse effects that 
may be associated with prenatal drug exposure. Growth parameters (ie, length, 
weight, and head circumference) within normal range at approximately 1 year of age 
are key noninvasive indicators that a serious congenital malformation caused by in 
utero drug exposure is unlikely.
4.3
Justification for Dose
Note: As of Amendment 013-02, study intervention administration has been stopped.
The doses of ISL + MK-8507 selected for this study were based on the following rationale.
ISL 20 mg QW
A single dose of ISL 20 mg QW 
 
 
 
 
 
 
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MK-8507 100 to 400 mg QW

MK-8507 100 mg:
 
 
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
MK-8507 200 mg: This dose was selected to be bracketed by the 100 mg and 400 mg 
doses to account for the potential impact of intrinsic or extrinsic factors on MK-8507 
PK.

MK-8507 400 mg: This dose level was selected to establish safety of the regimen 
over a range of exposures (ie, from 100 mg to 400 mg QW). Preclinical and clinical 
data indicate that MK-8507 undergoes metabolic defluorination. Data from a Phase 1 
pilot fluoride study and MK-8507 Protocol 005 provide estimates of daily fluoride 
release across a range of MK-8507 doses, enabling a selection of doses that when 
combined with the average total daily fluoride intake would remain below the EPA 
reference dose of 4.8 mg/day [Health and Ecological Criteria Division, et al 2010]. 
This level is likely to be without an appreciable risk of deleterious effects during a 
lifetime, such as severe fluorosis of primary teeth, skeletal fluorosis, and increased 
risk of bone fracture in adults. The average adult daily intake of fluoride in the US is 
approximately 2.9 mg/day, with a range of 1.4 to 3.4 mg/day in people from the US 
and Canada. The proposed highest MK-8507 dose of 400 mg QW is estimated to 
release an average of 1.24 mg/day of fluoride across the 7-day dosing interval. At the 
upper end of the range of daily fluoride intake in US adults (3.4 mg), the 400 mg QW 
dose of MK-8507 would result in a combined average daily intake of 4.64 mg/day, 
which is below the EPA reference dose [Health and Ecological Criteria Division, et al 
2010].

Viral load decline: In the Phase 1b, proof-of-concept, open-label study in 
treatment-naïve adult participants with HIV-1 (MK-8507 Protocol 003), 3 panels of 
6 participants each were administered single doses of 600 mg, 80 mg, and 40 mg of 
MK-8507. These single doses resulted in HIV-1 plasma viral load declines of >1.0 
log10 copies/mL from baseline at Day 7 at all dose levels (Figure 5).
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Figure 5
Log10 Viral Load Change from Baseline as a Function of Time
Following Single Oral Doses of MK-8507 to Treatment-naïve Adults with HIV-1
(N=6/dose level)
ISL 20 mg QW + MK-8507 400 mg QW
4.4
Beginning and End of Study Definition
The overall study begins when the first participant signs the ICF. The overall study ends 
when the last participant completes the last study-related telephone-call or visit, withdraws 
consent, or is lost to follow-up (ie, the participant is unable to be contacted by the 
investigator).
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4.4.1
Clinical Criteria for Early Study Termination
Early study termination will be the result of the following specified criteria:
1. The eDMC recommends termination of the study and the Executive Oversight 
Committee agrees per Appendix 1, or as stated in the eDMC charter.
2. The extent (incidence and/or severity) of emerging effects/clinical endpoints is such that 
the risk/benefit ratio to the overall study population is unacceptable.
3. Plans to modify or discontinue the development of ISL and/or MK-8507.
In addition, further recruitment in the study or at a particular study site may be stopped due to 
insufficient compliance with the protocol, GCP, and/or other applicable regulatory 
requirements, procedure-related problems or excessive discontinuations for administrative 
reasons.
4.4.2
Clinical Criteria for Closing a Treatment Group
5
STUDY POPULATION
Participants ≥18 years of age with HIV-1 who have been virologically suppressed for 
≥6 months on BIC/FTC/TAF 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 HIV-1 positive with plasma HIV-1 RNA <50 copies/mL at screening.
Note: A single repeat of the plasma HIV-1 RNA screening test will be allowed, provided 
results are available within the 45-day screening window.
2. Has a screening CD4+ T-cell count 200 cells/mm3 (completed by the central 
laboratory).
Note: A single repeat of the CD4+ T-cell count screening test will be allowed, provided 
results are available within the 45-day screening window.
3. Has been receiving BIC/FTC/TAF therapy with documented viral suppression (HIV-1 
RNA <50 copies/mL) for ≥6 months prior to signing informed consent and has no history 
of prior virologic treatment failure on any past or current regimen. 
Note: A nonclinically-significant HIV-1 RNA result above the limit of quantification 
(ie, transient detectable viremia) during the 6 months prior to screening is acceptable.
Note: Previous regimen switches for tolerability, side effects, dosing convenience, or cost 
are permitted if they occurred >6 months prior to signing informed consent.
Demographics
4. Is male or female, at least 18 years of age, at the time of signing the informed consent.
Contraception/Pregnancy
Female Participants
5. A female participant is eligible to participate if she is not pregnant or breastfeeding, and 
at least one of the following conditions applies: 
•
Is not a WOCBP
OR
•
Is a WOCBP and using a contraceptive method that is highly effective (with a failure 
rate of <1% per year), or be abstinent from heterosexual intercourse as their preferred 
and usual lifestyle (abstinent on a long term and persistent basis), as described in 
Appendix 5 during the intervention period and for at least 6 weeks, corresponding to 
the time needed to eliminate any study intervention(s) (eg, 5 terminal half-lives) after 
the last dose of study intervention. The investigator should evaluate the potential for 
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contraceptive method failure (ie, noncompliance, recently initiated) in relationship to 
the first dose of study intervention.
•
A WOCBP must have a negative highly sensitive pregnancy test (urine or serum) as 
required by local regulations) within 24 hours before the first dose of study 
intervention.
•
If a urine test cannot be confirmed as negative (eg, an ambiguous result), a serum 
pregnancy test is required. In such cases, the participant must be excluded from 
participation if the serum pregnancy result is positive.
•
Additional requirements for pregnancy testing during and after study intervention are 
located in Appendix 2.
•
The investigator is responsible for review of medical history, menstrual history, and 
recent sexual activity to decrease the risk for inclusion of a woman with an early 
undetected pregnancy.
•
Contraceptive use by women should be consistent with local regulations regarding the 
methods of contraception for those participating in clinical studies.
Informed Consent
6. The participant (or legally acceptable representative if applicable) provides written 
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.
5.2
Exclusion Criteria
The participant must be excluded from the study if the participant:
Medical Conditions
1. Has HIV-2 infection.
2. Has hypersensitivity or other contraindication to any of the components of the study 
interventions as determined by the investigator.
3. Has active HCV coinfection (defined as detectable HCV RNA) or HBV coinfection 
(defined as HBsAg-positive or HBV DNA positive) (completed by the central 
laboratory).
Note: Participants with prior/inactive HCV infection (defined as undetectable HCV RNA) 
or past HBV infection (defined as HBsAg-negative and positive for antibody against 
HBsAg) may be enrolled.
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4. Has a current (active) diagnosis of acute hepatitis due to any cause.
5. Has a history of malignancy ≤5 years prior to signing informed consent except for 
adequately treated basal cell or squamous cell skin cancer, in situ cervical cancer, or 
cutaneous Kaposi’s sarcoma.
6. Has a history or current evidence of any condition (including active tuberculosis 
infection), therapy, laboratory abnormality or other circumstance (including drug or 
alcohol use or dependence) that might, in the opinion of the investigator, confound the 
results of the study or interfere with the participant’s participation for the full duration of 
the study, such that it is not in the best interest of the participant to participate.
Prior/Concomitant Therapy
7. Is taking or is anticipated to require systemic immunosuppressive therapy, immune 
modulators, or any prohibited therapies outlined in Section 6.5 from 45 days prior to 
Day 1 through the study treatment period.
Note: Time-limited courses of corticosteroids (eg, for asthma exacerbation) will be 
allowed.
Prior/Concurrent Clinical Study Experience
8. Is currently participating in or has participated in a clinical study with an investigational 
compound or device from 45 days prior to Day 1 through the study treatment period.
Note: BIC/FTC/TAF is not considered as investigational in countries where it has 
received health authority approvals, regardless of commercial availability.
Note: Concurrent participation in observational or noninterventional studies may be 
permitted and should be discussed with the Sponsor prior to enrollment and through 
study duration.
Diagnostic Assessments
9. Has a documented or known virologic resistance to:

 
 
 
 
 

Note: Prior resistance testing results are not required for enrollment.
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10. Has exclusionary laboratory values (completed by the central laboratory) 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 based on documented prior laboratory results, but the repeat test results 
must be available within the 45-day screening window.
Table 1
Laboratory Exclusion Criteria
Laboratory Assessment
Exclusionary Values
Alkaline Phosphatase
1.5 × ULN
ALT and AST 
1.5 × ULN
Hemoglobin
<9.0 g/dL (female) or <10.0 g/dL (male)
INR
>1.2
Urine protein
Outside of normal limits (more than trace 
protein by urine dipstick)
Absolute neutrophil count
<1000/mm3
Platelet count
<100,000/mm3
Total serum bilirubin
>ULN
Calculated Crcl
≤30 mL/min based on the Cockcroft-Gault 
equation (Appendix 8).
ALT=alanine aminotransferase; AST=aspartate aminotransferase; Crcl=creatinine clearance; 
INR=International Normalized Ratio; ULN=upper limit of normal.
Other Exclusions
11. Is female and expecting to conceive or donate eggs at any time during the study.
Note: Investigators should provide appropriate guidance to female participants 
regarding egg donation after completion of the study intervention. Consistent with the 
recommendations for contraceptive use, it is recommended that all female participants 
refrain from egg donation for 6 weeks following their last dose of study intervention.
Note: Donation of sperm should follow local guidelines for individuals who are HIV-
positive.
5.3
Lifestyle Considerations
There are no lifestyle restrictions in this study.
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5.4
Screen Failures
Screen failures are defined as participants who consent 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.
5.5
Participant Replacement Strategy
A participant who discontinues from study intervention OR withdraws from the study will 
not be replaced.
6
STUDY INTERVENTION
Note: As of Amendment 013-02, study intervention administration has been stopped
and all participants will be switched to non-study ART.
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 (ISL, MK-8507, BIC/FTC/TAF, and placebos for each study intervention)
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 
Administration
Treatment 
Period
Use
IMP/
NIMP
Sourcing
Group 1
Experi
mental
ISL
Drug
Capsule
20 mg
20 mg QW
Oral
Parts 1, 
2[a], and 3
Experi
mental
IMP
Central
Group 1
Experi
mental
MK-8507
Drug
Tablet
100 mg
100 mg QW
Oral
Part 1
Experi
mental
IMP
Central
Group 1
Experi
mental
Placebo to 
MK-8507
Drug
Tablet
0 mg
0 mg QW
Oral
Part 1
Placebo
IMP
Central
Group 1
Experi
mental
Placebo to 
BIC/FTC/
TAF
Drug
Tablet
0 mg
0 mg QD
Oral
Part 1
Placebo
IMP
Central
Group2
Experi
mental
ISL
Drug
Capsule
20 mg
20 mg QW
Oral
Parts 1, 
2[a], and 3
Experi
mental
IMP
Central
Group 2
Experi
mental
MK-8507
Drug
Tablet
100 mg
200 mg QW
Oral
Part 1
Experi
mental
IMP
Central
Group 2
Experi
mental
Placebo to 
MK-8507
Drug
Tablet
0 mg
0 mg QW
Oral
Part 1
Placebo
IMP
Central
Group 2
Experi
mental
Placebo to 
BIC/FTC/
TAF
Drug
Tablet
0 mg
0 mg QD
Oral
Part 1
Placebo
IMP
Central
Group3
Experi
mental
ISL
Drug
Capsule
20 mg
20 mg QW
Oral
Parts 1, 
2[a], and 3
Experi
mental
IMP
Central
Group 3
Experi
mental
MK-8507
Drug
Tablet
100 mg
400 mg QW
Oral
Part 1
Experi
mental
IMP
Central
Group 3
Experi
mental
Placebo to 
BIC/FTC/
TAF
Drug
Tablet
0 mg
0 mg QD
Oral
Part 1
Placebo
IMP
Central
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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 
Administration
Treatment 
Period
Use
IMP/
NIMP
Sourcing
Group 4
Active 
Compar
ator
Placebo to 
ISL
Drug
Capsule
0 mg
0 mg QW
Oral
Part 1
Placebo
IMP
Central
Group 4
Active 
Compar
ator
Placebo to 
MK-8507
Drug
Tablet
0 mg
0 mg QW
Oral
Part 1
Placebo
IMP
Central
Group 4
Active 
Compar
ator
BIC/FTC/T
AF
Drug
Tablet
50/200/25
mg
50/200/25 mg
QD
Oral
Parts 1 and 
2[a]
Experi
mental
IMP
Central
Group 4
Active 
Compar
ator
ISL
Drug
Capsule
20 mg
20 mg QW
Oral
Part 3
Experi
mental
IMP
Central
Group 4
Active 
Compar
ator
MK-8507
Drug
Tablet
100 mg
100, 200, or 
400 mg QW
Oral
Part 3
Experi
mental
IMP
Central
Groups 
1,2, and 
3
Experi
mental
MK-8507
Drug
Tablet
100 mg
100, 200, or 
400 mg QW
Oral
Parts 2[a] 
and 3
Experi
mental
IMP
Central
BIC=bictegravir; FTC=emtricitabine; ISL=islatravir; QD=once daily; QW=once weekly; TAF=tenofovir alafenamide.
The classification of Investigational Medicinal Product (IMP) and Non-Investigational Medicinal Product (NIMP) in this table is based on guidance issued by the European 
Commission and applies to countries in the European Economic Area (EEA). Country differences with respect to the definition/classification of IMP/NIMP may exist. In these 
circumstances, local legislation is followed.
a.
Part 2 will begin after the MK-8507 dose is confirmed based on the Week 48 data from all participants. Once Part 2 is initiated, participants will begin open-label study 
intervention at their next study visit. Participants who reach their next study visit (eg, Week 60, Week 72, etc.) before Part 2 initiates will continue taking blinded study 
intervention until their next visit after Part 2 initiation.
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All supplies indicated in Table 2 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
Note: As of Amendment 013-02, study intervention administration has been stopped 
and all participants will be switched to non-study ART.
Intervention randomization will occur centrally using an IRT system. There are 4 study 
intervention arms. Participants will be assigned randomly in a 1:1:1:1 ratio to 1 of 3 doses of 
MK-8507 administered QW with ISL and placebo to BIC/FTC/TAF QD (Groups 1-3) or 
BIC/FTC/TAF QD and placebos to MK-8507 and ISL QW (Group 4).
6.3.2
Stratification
No stratification based on age, sex, or other characteristics will be used in this study.
6.3.3
Blinding
Note: As of Amendment 013-02, all participants have been unblinded, study 
intervention administration has been stopped, and all participants will be switched to
non-study ART.
In Part 1 of the study, a double-blinding technique with in-house blinding will be used. 
MK-8507, ISL, and BIC/FTC/TAF will be packaged identically relative to their matching 
placebos so that the 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.
Clinical site personnel and participants will remain blinded through Part 1 (see Section 4.1).
To allow timely completion of dose response and population PK modeling, select Sponsor 
personnel (not affiliated with the study team) will be unblinded for the Week 24 interim 
analysis. No Sponsor personnel directly associated with study conduct will be unblinded to 
participant treatment assignments before the Week 48 (ie, when the last participant completes 
their Week 48 visit) interim analysis database lock. However, some Sponsor personnel, 
including some study team members, will have access to the treatment-group level 
summaries from the Week 24 interim analyses (including dose response and population PK 
modeling and efficacy and safety summaries) to support a preliminary dose selection. Before 
granting access to select personnel to unblinded data at the individual participant level, an 
official memo detailing the unblinding procedures and listing the personnel who will have 
access (before the Week 24 interim analysis) to the unblinded data will be generated per 
Sponsor SOP.
Part 2 and Part 3 of this study are conducted as open label; therefore, the Sponsor, 
investigator, and participant will know the intervention administered.
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6.4
Study Intervention Compliance
Two methods to determine compliance with study intervention will be used based on the 
study intervention packaging:

Electronic tracking for ISL and MK-8507 in blister packs 

Pill count for BIC/FTC/TAF in bottles
Participants should be instructed to bring the study intervention blister packs and bottles
(empty, partially empty, or full) to each visit.
 
 
 
 
 
BIC/FTC/TAF (Bottles)
At each visit, the number of tablets remaining in the bottles will be counted and reviewed;
the results will be used to assess participant compliance. If a discrepancy is noted, the 
investigator/study coordinator must discuss the discrepancy with the participant and the 
explanation must be documented.
Decisions to temporarily withhold study intervention because of an AE or other reason(s) 
will be reviewed on a case-by-case basis by the investigator. Interruptions from the protocol-
specified treatment plan that are expected to be ≥14 consecutive days for QW administration 
or ≥7 consecutive days for QD administration 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 or capsules dispensed to and taken by 
each participant must be maintained and reconciled with study intervention and compliance 
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.
6.5
Concomitant Therapy
Note: As of Amendment 013-02, there are no study defined prohibited medications. The 
local label for the non-study ART should be consulted for potential drug interactions.
Medications specifically prohibited in the exclusion criteria are not allowed during time 
periods specified by this protocol. If there is a clinical indication for any medications
specifically prohibited, discontinuation from study intervention may be required. The 
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investigator should discuss any questions regarding this with the Sponsor Clinical Director. 
The final decision on any supportive therapy rests with the investigator and/or the 
participant’s primary physician. However, the decision to continue the participant on study 
intervention requires the mutual agreement of the investigator, the Sponsor, and the 
participant.
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
Prior and concomitant therapies listed in Table 3 are not permitted from 45 days prior to 
Day 1 through the study treatment period. The therapies listed in Table 3 are only prohibited 
based on the part of the study a participant is in and, once in the open-label parts of the study, 
the treatment group assigned. Table 3 is not comprehensive, and the investigator should use 
his/her medical judgment when assessing a participant’s prior and concomitant therapy(ies). 
The Sponsor’s Clinical Director or designee should be contacted if there are any questions 
about a therapy not listed or regarding potential DDIs with a specific treatment that the 
participant may plan to receive. 
ISL
ISL metabolism occurs primarily via adenosine deaminase, a non–CYP-mediated process. 
Given the very low propensity for patients with HIV-1 to require an adenosine deaminase 
inhibitor (eg, pentostatin), the likelihood of ISL being a victim of DDI is low. ISL is not 
metabolized by CYP enzymes and therefore is not expected to be a victim of CYP-mediated 
drug interactions.
MK-8507
 
 
 
 
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BIC/FTC/TAF
Refer to the local product circular for BIC/FTC/TAF for information regarding metabolism 
and potential drug interactions.
For participants taking metformin, close monitoring is recommended (BIC/FTC/TAF may 
increase metformin levels). Sucralfate and inhibitors of P-gp and/or BCRP should be used 
with caution. 
For participants taking medications or oral supplements containing polyvalent cations 
(eg Mg, Al, Ca, Fe), BIC/FTC/TAF (or its placebo) should be taken either 2 hours before or 
6 hours after taking any polyvalent cation-containing medicine.
In instances where the local product circular for BIC/FTC/TAF is more restrictive with 
regard to prohibited (ie, contraindicated or not recommended) therapy(ies), the local product 
circular supersedes this section.
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Table 3
Prohibited Therapies
Parts 1, 2, and 3
Nonstudy ART
All nonstudy antiretrovirals
Immunosuppressive or 
immunomodulating therapies
Immune therapy agents, immune modulators or other systemic immunosuppressive therapy, including interferon-based treatment 
for hepatitis
Time-limited courses of corticosteroids (eg, for asthma exacerbation) are permitted.
Investigational agents
All nonstudy investigational agents including devices
Part 1
Part 2
Part 3
All participants
Groups 1-3 
Group 4
All participants
ART=antiretroviral therapy; CYP3A=cytochrome P450 3A; ISL=islatravir.
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6.5.1
Rescue Medications and Supportive Care
No rescue or supportive medications are specified for use in this study.
6.6
Dose Modification
No dose modification of ISL, MK-8507, or BIC/FTC/TAF is allowed during the study with 
the exception of participants who will switch to the selected dose of MK-8507 in Part 2 of 
the study.
6.7
Intervention After the End of the Study
Note: As of Amendment 013-02, study intervention administration has been stopped so
the section is no longer applicable.
Provided development of ISL and MK-8507 continues, there will be a mechanism for all 
eligible participants to continue receiving study intervention without interruption until it 
becomes commercially available. Eligible participants are those who have completed the last 
scheduled study visit and are considered by the investigator to derive clinical benefit from 
continued administration of their current regimen.
6.8
Clinical Supplies Disclosure
Note: As of Amendment 013-02, this section is no longer applicable.
The emergency unblinding call center will use the intervention/randomization schedule for 
the study to unblind participants and to unmask study intervention identity during Part 1 of 
this study. The emergency unblinding call center should only be used in cases of emergency 
(see Section 8.1.10). In the event that 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.
Clinical site personnel and participants will remain blinded through Part 1 while Sponsor 
personnel will remain blinded through the Week 48 interim analysis database lock.
Part 2 and Part 3 of the study will be open-label.
6.9
Standard Policies
Note: As of Amendment 013-02, this section is no longer applicable.
At the close of the study after unblinding, a letter is to be sent by the investigator to those 
participants who received placebos in the image of the comparator 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 BIKTARVY 50/200/25 mg
(BICTEGRAVIR/EMTRICITABINE/TENOFOVIR ALAFENAMIDE) as much as possible. 
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You did not receive the active drug/vaccine BIKTARVY 50/200/25 mg 
(BICTEGRAVIR/EMTRICITABINE/TENOFOVIR ALAFENAMIDE) as manufactured by
Gilead Sciences Inc.”
7
DISCONTINUATION OF STUDY INTERVENTION AND PARTICIPANT 
WITHDRAWAL
7.1
Discontinuation of Study Intervention
Note: As of Amendment 013-02, study intervention administration has been stopped so 
the section is no longer applicable.
Discontinuation of study intervention does not represent immediate 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 8.11.3.
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 a medical condition or personal circumstance which, in the opinion of 
the investigator and/or Sponsor, placed the participant at unnecessary risk from continued 
administration of study intervention.

The participant has confirmed HIV-1 virologic rebound as defined in Section 4.2.1.1.2.

The participant has a positive serum pregnancy test.

The participant has a Crcl of <30 mL/min based on the Cockcroft-Gault equation.
Note: Creatinine clearance should be confirmed by repeat analysis prior to discontinuing 
study intervention.
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
The participant has an SAE or Grade 4 laboratory AE assessed by the investigator to be 
related to study intervention AND is life-threatening or results in prolonged 
hospitalization.

The participant becomes HBsAg or HBV DNA positive.

For country-specific study intervention discontinuation requirements, see 
Appendix 7 (Section 10.7.1).
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 from the study.
If a participant withdraws from the study, they will no longer receive study intervention or be 
followed at scheduled protocol visits.
Specific details regarding procedures to be performed at the time of withdrawal from the 
study, as well as specific details regarding withdrawal from future biomedical research, are 
outlined in Section 8.1.9. The procedures to be performed should a participant repeatedly fail 
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

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.
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
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.

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 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
is presented in Appendix 2.
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 consent from each potential participant or each participant’s legally 
acceptable representative prior to participating in a 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 consent is in place.
8.1.1.1
General Informed Consent
Consent must be documented by the participant’s dated signature or by the participant’s 
legally acceptable representative’s dated signature on a consent form along with the dated 
signature of the person conducting the consent discussion.
A copy of the signed and dated consent form should be given to the participant before 
participation in the study.
The initial ICF, any subsequent revised written ICF, and any written information provided to 
the participant must receive the IRB/IEC’s approval/favorable opinion in advance of use. The 
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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 form or addendum to the original consent form that 
captures the participant’s dated signature or by the participant’s legally acceptable 
representative’s dated signature.
Specifics about a study and the study population will be added to the consent form template 
at the protocol level.
The informed consent 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
Note: As of Amendment 013-02, collection of specimens for FBR will no longer be done 
so this section is not applicable.
The investigator or medically qualified designee will explain the future biomedical research 
consent to the participant, answer all of his/her questions, and obtain written informed 
consent before performing any procedure related to future biomedical research. A copy of the 
informed consent will be given to the participant.
8.1.1.3
 
 
8.1.1.4
Consent for Infant Safety Follow-up
Depending on applicable laws and regulations, a separate informed consent may be required 
for participation in the infant safety follow-up period (Section 8.3.10). If a separate consent is 
required, the investigator or medically qualified designee will explain the infant safety 
follow-up consent to the participant, answer all questions, and obtain written informed 
consent before collecting any data related to the infant follow-up. A copy of the informed 
consent will be given to the participant.
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.
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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 written informed consent. 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. The medical 
history should include information pertaining to the diagnosis of HIV-1 and AIDS (if 
applicable) and year diagnosed. If the participant has been previously diagnosed with any 
AIDS-defining conditions or CD4+ T-cell count <200 cells/mm3, the condition as well as a 
corresponding medical history of AIDS must be reported. In addition, participants’ history of 
tobacco use and alcohol consumption should be obtained and recorded on the appropriate 
eCRF.
8.1.5
Prior and Concomitant Medications Review
8.1.5.1
Prior Medications
The investigator or qualified designee will review prior medication use, including any 
protocol-specified washout requirement, and record prior medication taken by the participant 
within 45 days before the first dose of study intervention.
All prior ARTs taken by the participant from the initiation of treatment (if available) will be
recorded before the first dose of study intervention.
8.1.5.2
Concomitant Medications
The investigator or qualified designee will record medication, if any, taken by the participant 
during the study.
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.
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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 provided in Section 8.11.1.
8.1.7
Assignment of Treatment/Randomization Number
All eligible participants will be randomly allocated and will receive a 
treatment/randomization number. The treatment/randomization number identifies the 
participant for all procedures occurring after treatment randomization. Once a 
treatment/randomization number is assigned to a participant, it can never be re-assigned to 
another participant.
A single participant cannot be assigned more than 1 treatment/randomization number.
8.1.8
Study Intervention Administration
Note: As of Amendment 013-02, study intervention administration has been stopped so 
the section is no longer applicable.
Study intervention will be provided as per Table 2 and dispensed through the IRT system at 
visits indicated in the SoA (Section 1.3.1).
Study intervention should begin on the day of randomization.
8.1.8.1
Timing of Dose Administration
Note: As of Amendment 013-02, study intervention administration has been stopped so 
the section is no longer applicable.
Study intervention will be taken without regard to food. If more than 1 bottle of 
BIC/FTC/TAF or matching placebo is dispensed, the participant is instructed to use all of the 
medication in 1 bottle before opening another bottle. Study intervention should be taken at 
approximately the same time each dosing day.
Part 1
All participants will take the following:

1 capsule of ISL or matching placebo and 4 tablets of MK-8507 or matching placebo 
once-weekly from a single blister pack.

1 tablet of BIC/FTC/TAF or matching placebo once-daily from a bottle.
Part 2
Participants in Groups 1 to 3 will take 1 capsule of ISL and MK-8507 (number of tablets to 
be determined based on selected dose) once-weekly from a single blister pack. 
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Participants in Group 4 will take 1 tablet of BIC/FTC/TAF once-daily from a bottle.
Part 3
All participants will take 1 capsule of ISL and MK-8507 (number of tablets to be determined 
based on selected dose) once-weekly from a single blister pack.
8.1.8.1.1
Missed Dose(s)
Note: As of Amendment 013-02, study intervention administration has been stopped so 
the section is no longer applicable.
ISL and MK-8507
ISL (or matching placebo) and MK-8507 (or matching placebo) should be dosed once-
weekly, on the same day of each week (scheduled day of dosing). If a participant misses a 
dose of ISL (or matching placebo) or MK-8507 (or matching placebo) on the scheduled day 
of dosing, the missed dose should be taken as soon as the participant remembers. The missed 
dose can be taken at any day of the 7-day dosing period up to the day before the next 
scheduled dose. The day of the week of the scheduled dosing should not change as a result of 
the missed dose. For example, if a participant has a scheduled day of dosing each Monday, 
the participant can take a missed dose up until Sunday. The next scheduled dose is still taken
on Monday, even if the missed dose was taken the day before (Sunday). 
If a participant misses a dose of ISL (or matching placebo) or MK-8507 (or matching 
placebo) for more than 1 consecutive week, only the missed dose for the last week should be 
taken before the next scheduled dose.
BIC/FTC/TAF
If a participant misses a dose of BIC/FTC/TAF or matching placebo, the following guidance 
should be followed:

If ≤12 hours from the missed dose, the missed dose should be taken, and the normal 
dosing schedule resumed.

If >12 hours from the missed dose, the missed dose should be skipped, and the normal 
dosing schedule resumed. The participant should not double the next dose to compensate 
for what has been missed.
8.1.9
Discontinuation and Withdrawal
Participants who discontinue study intervention prior to completion of the treatment period
should have an Early Discontinuation visit performed per SoA (Section 1.3) and be 
encouraged to continue to be followed as outlined in Section 8.11.3.
When a participant withdraws from participation in the study, all applicable activities 
scheduled for the Early Discontinuation visit should be performed (at the time of 
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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 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 consent 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
Note: As of Amendment 013-02, the study has been unblinded so this section is no 
longer applicable.
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. Prior to 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 
intensity of the AEs observed, the relation to study intervention, the reason thereof, etc., in 
the medical chart. If it is not possible to record this assessment in the chart prior to the 
unblinding, the unblinding should not be delayed.
In the event that 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.
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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. In the event that the 
emergency unblinding call center is not available for a given site in this study, the IRT 
system should be used for emergency unblinding in the event that this is required for 
participant safety.
8.1.11
Calibration of Equipment
The investigator or qualified designee has the responsibility to ensure that any device or 
instrument used for a clinical evaluation/test during a clinical study that provides information 
about inclusion/exclusion criteria and/or safety or efficacy parameters shall be suitably 
calibrated and/or maintained to ensure that the data obtained are reliable and/or reproducible. 
Documentation of equipment calibration must be retained as source documentation at the 
study site.
8.1.12
Administration of Participant Questionnaires
Note: As of Amendment 013-02, participant questionnaires will no longer be 
administered so the section is no longer applicable.
Participants will complete 4 PRO questionnaires during the study: 

HIVTSQs and HAT-QoL at Day 1, Week 96, Week 144 and/or the Early Discontinuation 
Visit 

Treatment Preference at Week 96 (Groups 1-3 only), Week 144, and/or the Early 
Discontinuation Visit

HIV Stigma Scale Questionnaire at Day 1
Only participants who have received 4 weeks of open-label study intervention will complete 
PRO questionnaires at the Early Discontinuation visit.
Participants are to complete the questionnaires on their own at the site on paper during the 
appropriate study visit (see SoA) prior to being seen by the investigator, discussing any 
medical conditions with the study personnel, or receiving any medical results. The 
questionnaires will not be administered to participants if native language translations are not 
available for all questionnaires.
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The participant responses to questionnaires will be entered in the appropriate eCRF by site 
staff according to data entry guidelines.
8.2
Efficacy Assessments
8.2.1
HIV-1 RNA
Note: As of Amendment 013-02, HIV-1 RNA collection is according to the schedule in
the SoA (Section 1.3.3). 
Plasma HIV-1 RNA quantification will be performed at the central laboratory using a real 
time PCR assay with a lower limit of detection of 40 copies/mL.
8.2.2
Management of Study Participants With Viremia
Note: As of Amendment 013-02, management of participants with viremia will be at the 
discretion of the investigator outside of the study. 
When viremia (HIV-1 RNA ≥50 copies/mL) is detected (Section 4.2.1.1.2), the investigator 
should query the participant regarding adherence to study intervention, intercurrent illness, or 
recent immunization. All cases of viremia must be confirmed, and the participant should 
continue to take the full assigned dosage of study intervention while awaiting 
confirmation.
8.2.2.1
Viremia Confirmation
Confirmation of viremia requires 2 consecutive plasma HIV-1 RNA results of ≥50 copies/mL 
(Section 4.2.1.1.2) with the second sample collected at a “Viremia Confirmation” visit at 
least 2 weeks but not more than 4 weeks from the date of the initial sample. This timeframe 
may be extended if study intervention is interrupted for 1 of the following circumstances:

Intercurrent illness: redraw 2 to 4 weeks following resolution of the illness, during 
which time the participant should continue to receive the assigned dosage of study 
intervention(s) without interruption;

Immunization: redraw at least 4 weeks following any immunization, during which time 
the participant should continue to receive the assigned dosage of study intervention(s) 
without interruption;

Toxicity management, noncompliance, or other reason: redraw 2 to 4 weeks following 
resuming the assigned dosage of study intervention(s).
8.2.2.2
Participants With Clinically-significant Viremia (≥200 copies/mL)
Study participants with confirmed HIV-1 RNA of ≥200 copies/mL will be assessed for 
development of viral drug resistance (Section 8.2.2.4) and discontinuation from study 
intervention (Section 7.1). Once it is determined that study intervention discontinuation is 
appropriate, Early Discontinuation and End of Treatment visit procedures should be 
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completed (Sections 1.3.2 and 8.11.3) and the participant managed by the investigator per 
local standard-of-care.
8.2.2.3
Participants With Low-level Viremia (≥50 and <200 copies/mL)
Study participants with confirmed HIV-1 RNA of ≥50 and <200 copies/mL should continue 
study intervention and all regularly-scheduled study visits during which HIV-1 RNA levels 
will be monitored per SoA (approximately every 3 months). Additional visits may be 
conducted to monitor HIV-1 RNA levels more frequently than every 3 months, if 
appropriate, after discussion with the Sponsor. Participants with confirmed low-level viremia 
at Week 48 will not be automatically discontinued from study intervention but will be 
included in the virologic failure rate calculated for the purposes of the primary analyses 
(Section 9.6.1).
Investigators should use their clinical judgment regarding the most appropriate clinical 
management of participants, if more stringent local guidelines apply, and may contact the 
Sponsor’s Clinical Director to discuss questions on clinical management of individual 
participants.
8.2.2.4
Viral Drug Resistance Testing
Participants with HIV-1 RNA ≥200 copies/mL at any time during the study will be assessed 
for development of viral drug resistance. Genotypic and phenotypic resistance will be 
assessed at Monogram Biosciences using the commercially available GenoSure PRIme® and 
PhenoSense assays®, respectively.
Samples will be collected for genotypic and phenotypic HIV-1 drug resistance testing per 
SoA (Section 1.3) and used to assess resistance-associated substitutions as applicable during 
the study.
8.2.3
T- and B- Lymphocyte and Natural Killer Cell Panel Including CD4+ T-cell 
Counts
A TBNK panel, including CD4+ T-cell count, will be performed at the central laboratory (see 
Table 17 in Appendix 2). A subset of the TBNK panel results will be added on previously 
collected and tested samples.
8.3
Safety Assessments
Details regarding specific safety procedures/assessments to be performed in this study are 
provided. The total amount of blood/tissue to be drawn/collected over the course of the study 
(from prestudy to poststudy visits), including approximate blood/tissue volumes 
drawn/collected by visit and by sample type per participant, can be found in 
Table 18, Table 19, and Table 20 in Appendix 2.
Planned time points for all safety assessments are provided in the SoA.
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8.3.1
Physical Examinations
Note: As of Amendment 013-02, height and full physical examinations are no longer 
performed. Only directed physical examinations and weight will be performed 
according to the SoA (Section 1.3.3 and Section 1.3.4).
A complete physical examination will be conducted by an investigator or medically qualified 
designee (consistent with local requirements) as per institutional standard at the visits 
specified in the SoA (Section 1.3.1). The full 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 will also be measured and recorded at the visits specified in the SoA (Section 1.3.1). 
Height measurements should be taken using a stadiometer (recommended but not required). 
Participants should remove their shoes and stand as tall and straight as possible.
A brief directed physical examination will be conducted by an investigator or medically 
qualified designee (consistent with local requirements) per institutional standard at the visits 
specified in the SoA (Section 1.3.1). This examination will be sign- and symptom-directed 
and based on the participant’s condition and circumstances. The investigator should note any 
changes in the participant’s condition (body systems) since the last examination, not 
precluding examination of any body system(s) as clinically indicated.
Investigators should pay special attention to clinical signs related to previous serious 
illnesses.
8.3.1.1
Weight
Weight will be measured and recorded at the visits specified in the SoA (Section 1.3.1). 
Participants should remove their shoes and wear a single layer of clothing at each 
measurement.
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 are preferred but not required.
8.3.3
Electrocardiograms
Note: As of Amendment 013-02, ECGs will no longer be collected so the section is no 
longer applicable.
A local 12-lead ECG will be obtained and reviewed by an investigator or medically qualified 
designee (consistent with local requirements) within 7 days prior to the Day 1 visit and prior 
to the first dose of study intervention as indicated in the SoA. Results must be available prior 
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to randomization. Sites are to use an ECG machine that automatically calculates the heart 
rate and measures PR, QRS, QT, and QTc intervals. Clinically-significant findings must be 
documented in the source documents and captured in the appropriate eCRF.
If an ECG is performed for any medical reason while the participant is on study intervention 
or during the follow-up period, any clinically-significant changes compared with the baseline 
ECG must be captured as AEs.
8.3.4
Confirmation of Contraception and Pregnancy Testing
WOCBP are required to use contraception to prevent pregnancy during the study and will be 
tested for pregnancy at each visit as outlined in Section 1.3, Section 5.1, and Appendix 5. 
Participants should be asked at study visits per SoA to verbally confirm their use of 
contraception since the prior visit, according to the Contraceptive Guidance in Appendix 5. 
Confirmation should be noted in the source documents for each visit.
Urine pregnancy test kits will be provided by the central laboratory, and routine testing will 
be performed by the site or local laboratory. In the event of a positive urine pregnancy test 
result, serum pregnancy testing must be performed by the central laboratory. If a participant 
becomes pregnant, refer to Section 7.1.
8.3.5
Clinical Safety Laboratory Assessments
Refer to Appendix 2 for the list of clinical laboratory tests to be performed and to the SoA for 
the timing and frequency.

The investigator or medically qualified designee (consistent with local requirements) 
must review the laboratory report, document this review, and record any clinically 
relevant changes occurring during the study in the AE section of the CRF. The laboratory 
reports must be filed with the source documents. Clinically significant abnormal 
laboratory findings are those which are not associated with the underlying disease, unless 
judged by the investigator to be more severe than expected for the participant's condition.

All protocol-required laboratory assessments, as defined in Appendix 2, must be 
conducted in accordance with the laboratory manual and the SoA.

If laboratory values from nonprotocol-specified laboratory assessments performed at the 
institution’s local laboratory require a change in study participant management or are
considered clinically significant by the investigator (eg, SAE or AE or dose 
modification), then the results must be recorded in the appropriate CRF (eg, SLAB).

For any laboratory tests with values considered clinically significantly abnormal during 
participation in the study or within 42 days after the last dose of study intervention, every 
attempt should be made to perform repeat assessments until the values return to normal or 
baseline or if a new baseline is established as determined by the investigator.
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8.3.6
 
8.3.6.1
 
8.3.6.2
 
 
8.3.6.3
8.3.7
 
 
 
 
 
 
 
 
 
 
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI
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8.3.8
HBV Assessments
Note: As of Amendment 013-02, HBV monitoring will not be performed after the Early 
Discontinuation of Treatment visit.
All eligible participants must be HBsAg-negative at screening. Participants who are anti-HBc 
positive and HBV DNA positive at screening are excluded. Participants who are anti-HBc 
positive but HBV DNA negative at screening are eligible to enroll. For the duration of the 
study, participants positive for anti-HBc should be monitored for possible HBV reactivation. 
Samples will be taken to monitor HBsAg and HBV DNA per the SoA (Section 1.3). 
Investigators should also pay close attention to changes from baseline in ALT, AST, 
bilirubin, and alkaline phosphatase (included in chemistry laboratory assessments).
8.3.9
Tobacco and Alcohol Assessments
Note: As of Amendment 013-02, tobacco and alcohol assessments will not be conducted
so the section is no longer applicable.
Participants’ use of tobacco and alcohol will be obtained and recorded at Weeks 48, 96, and 
144.
8.3.10
Infant Safety Follow-up Assessments
Infants, born to participants who become pregnant while receiving study intervention (which 
would include the protocol-specified follow-up period) and consent to infant follow-up, will 
have safety follow-up through approximately 1 year of age as outlined in Table 4. This infant 
safety follow-up data may be collected by phone call or in person. Length, weight, and head 
circumference measurements will be collected at birth and at 1 year of age. Infant SAEs, 
including congenital anomalies identifiable on physical examination at birth or shortly after 
birth, will be collected as per Section 8.4.1 and should be reviewed at the participant’s 
scheduled study visits that occur during this time.
Table 4
Infant Safety Follow-up: Data Collection Through 1 Year of Age
Study Period
Infant Safety Follow-up
Scheduled Day
At Birth
1 Year After Birtha
Data Collection Window
+90 days
+90 days
Administrative and Safety Procedures
Informed Consent (if applicable)b
X
Review pregnancy outcomec
X
Length
X
X
Weight
X
X
Head Circumference
X
X
Review infant SAEsd
X ----------------------------------X
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Study Period
Infant Safety Follow-up
Scheduled Day
At Birth
1 Year After Birtha
Data Collection Window
+90 days
+90 days
SAE=serious adverse event.
a If a participant withdraws from the study, data from 1 year after birth should be collected at the time of withdrawal.
b Depending on applicable laws and regulations, a separate informed consent may be required (Section 8.1.1.4).
c Collect and report pregnancy outcome (health of infant) per Section 8.4.5.
d Collect SAEs, including any congenital anomalies, per Section 8.4.1 and review at participant’s regularly scheduled 
study visits.
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).
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 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 consent form is signed 
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 study duration, all AEs, SAEs, and 
other reportable safety events must be reported by the investigator.
Additionally, any SAE brought to the attention of an investigator at any time outside of the 
time period specified in the previous paragraph must be reported immediately to the Sponsor 
if the event is considered related to study intervention.
For infants born to participants who become pregnant while receiving study intervention and 
consent to infant follow-up, SAEs occurring (in these infants) from the time of birth through 
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1 year of age must be reported by the investigator to the Sponsor within 24 hours of learning 
of the event.
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 5.
Table 5
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
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Type of 
Event
Reporting Time Period:
Consent to 
Randomization/ 
Allocation
Reporting Time 
Period:
Randomization/ 
Allocation 
through Protocol-
specified 
Follow-up Period
Reporting Time 
Period:
After the 
Protocol-specified 
Follow-up Period
Time Frame to 
Report Event 
and Follow-up 
Information to 
Sponsor:
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
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.
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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
Although pregnancy and infant exposure during breastfeeding are not considered AEs, any 
pregnancy or infant exposure during breastfeeding in a participant (spontaneously reported to 
the investigator or their designee) that occurs during the study are reportable to the Sponsor.
All reported pregnancies must be followed to the completion/termination of the pregnancy. 
Pregnancy outcomes of spontaneous abortion, missed abortion, benign hydatidiform mole, 
blighted ovum, fetal death, intrauterine death, miscarriage, and stillbirth must be reported as 
serious events (Important Medical Events). If the pregnancy continues to term, the outcome 
(health of infant) must also be reported.
For infants born to participants who become pregnant while receiving study intervention and 
consent to infant follow-up, SAEs occurring (in these infants) from the time of birth through 
1 year of age must be reported by the investigator to the sponsor within 24 hours of learning 
of the event.
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.
8.4.7
Events of Clinical Interest
Note: as of Amendment 013-02, ECIs will be reported through 42 days after the last 
dose of study intervention.
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 
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assessment and follow-up of these criteria can be found in the Investigator Study File 
Binder (or equivalent).
2.
8.5
Treatment of Overdose
In this study, an overdose of study intervention is defined as:

QW Regimen: >3 doses within 14 calendar days

QD Regimen: >1 dose in a single calendar day
No specific information is available on the treatment of overdose.
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
8.6.1
Blood Collection for ISL and MK-8507 Pharmacokinetics
8.6.1.1
Venous Blood (Plasma) PK Sampling
Note: As of Amendment 013-02, plasma PK sample collection was revised and 
investigational PK sample collection has been removed, as outlined in the SoA 
(Section 1.3.3).
Venous blood samples will be collected for measurement of ISL and MK-8507. Sample 
collection, storage, and shipment instructions for plasma samples will be provided in the 
laboratory manual. Investigational PK samples will be collected from all participants as 
outlined in the SoA (Section 1.3). Analysis of these samples will be triggered by the Sponsor 
as needed.
PK samples will be collected from all participants as outlined in Table 6. 
Table 6
Collection of PK Samples
Study Visit
Time Relative to Dose (ISL + MK-8507)
Day 1
Predose
Week 4a
Samples to be collected predose and within 0.5 to 4 hours postdose
Week 8
One sample to be collected at any time during the visit
Week 12
One sample to be collected at any time during the visit
Week 24a
Samples to be collected predose and within 0.5 to 4 hours postdose
Week 48a
Samples to be collected predose and within 0.5 to 4 hours postdose
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Study Visit
Time Relative to Dose (ISL + MK-8507)
Week 72a
One sample to be collected predose
Week 96a
One sample to be collected predose
Week 144a
One sample to be collected predose
ISL=islatravir; PK=pharmacokinetic.
a. For participants who have taken ISL + MK-8507 (or matching placebos) prior to coming to the clinic 
during Weeks 4, 24, 48, 72, 96, and 144, one sample will be collected at any time during the visit.
8.6.1.2
 
 
 
 
 
 
 
 
 
 
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8.7
Pharmacodynamics
Pharmacodynamic parameters will not be evaluated in this study.
8.8
Biomarkers
Note: As of Amendment 013-02, samples for biomarker research will no longer be 
collected so the section is no longer applicable.
Collection of samples for other biomarker research is also part of this study. The following 
samples for biomarker research are required and will be collected from all participants as 
specified in the SoA:

Blood for Genetic Analysis

Blood for fasting lipids and metabolic profile
8.8.1
Planned Genetic Analysis Sample Collection
The planned genetic analysis sample should be drawn for planned analysis of the association 
between genetic variants in DNA and drug response. This sample will not be collected at the 
site if there is either a local law or regulation prohibiting collection, or if the IRB/IEC does 
not approve the collection of the sample for these purposes. If the sample is collected, 
leftover extracted DNA will be stored for future biomedical research if the participant signs 
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the future biomedical research consent. If the planned genetic analysis is not approved, but 
future biomedical research is approved and consent is given, this sample will be collected for 
the purpose of future biomedical research.
Sample collection, storage, and shipment instruction for planned genetic analysis samples 
will be provided in the operations/laboratory manual.
8.8.2
Fasting Lipids
Note: As of Amendment 013-02, samples for analysis of fasting lipids will no longer be 
collected so the section is no longer applicable.
Participants will be asked to fast for at least 8 hours prior to visits where blood will be taken 
to measure HDL-C, LDL-C, TGs, TC, and non-HDL-C. 
8.8.3
Waist and Hip Measurements
Note: As of Amendment 013-02, waist and hip measurements will no longer be collected
so the section is no longer applicable.
Participants should be asked to stand erect, relaxed and should not hold in their stomach 
during measurements. Waist circumference will be measured midway between the iliac crest 
and the lower rib margin. Hip circumference will be measured at the intertrochanteric level. 
Measurements should be taken with a stretch-resistant measuring tape held parallel to the 
floor. Waist-to-hip ratios will be calculated as waist (cm)/hip (cm) circumferences.
BMI will be calculated using weight and height measurements taken as specified in the SoA 
(Section 1.3).
8.8.4
DEXA Assessments
Note: As of Amendment 013-02, DEXA assessments will no longer be conducted so the 
section is no longer applicable.
DEXA images to monitor fat distribution and BMD should be collected from all 
participants/sites willing and able to have the test performed and according to country law 
(Section 1.3). These participants will undergo total body DEXA scans for BMD of the spine 
and hip as well as peripheral and trunk fat. Participants will not be excluded from 
participation in the study if unwilling/unable to have DEXA images performed.
Only those participants who are confirmed eligible to be randomized will undergo DEXA 
images for BMD of the spine and hip as well as peripheral and trunk fat. For Day 1 
(baseline), DEXA images should be performed after eligibility is confirmed and may be 
performed up to 14 days after randomization. The DEXA images at subsequent visits should 
be performed ± 14 days of the scheduled visit. Only participants with valid baseline DEXA 
images should have DEXA images performed at subsequent visits as indicated in the SoA 
(Section 1.3). 
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DEXA images will be evaluated by a central imaging reader; these analyses are not 
performed in real-time and will not be provided to the site/participant. For clinical 
management of the participant, the DEXA images should be reviewed and interpreted locally 
by a qualified individual. Clinically-significant findings noted in the local interpretation of 
the baseline DEXA images should be recorded in the participant’s medical history. 
Clinically-significant findings noted in the local interpretation of the DEXA images during 
the treatment period should be recorded appropriately. Refer to the Site Imaging Manual for 
additional details regarding DEXA procedures including participant preparation instructions 
to be considered before DEXA imaging.
8.9
Future Biomedical Research Sample Collection
Note: As of Amendment 013-02, this section is no longer applicable.
If the participant signs the future biomedical research consent, the following specimens will 
be obtained as part of future biomedical research:

Leftover extracted DNA for future research

Leftover main study plasma from HIV-1 RNA quantification

Leftover main study plasma from HIV drug resistance samples

Whole blood for future biomedical research
Sample collection, storage, and shipment instruction for whole blood future biomedical 
research samples will be provided in the laboratory manual. Refer to the SoA (Section 1.3) 
for timing of sample collection.
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
Note: As of Amendment 013-02, this section is no longer applicable.
Screening
Prior to randomization, potential participants will be evaluated to determine that they fulfill 
the entry requirements as set forth in Section 5. A screening period of up to 45 days is 
allowed but participants are expected to enroll as soon as possible after eligibility is 
confirmed.
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Rescreening
If the screening window has been exceeded, participants are allowed to rescreen 1 time after 
approval from the Sponsor. Once a participant has started the rescreening process, a new 
screening period (ie, an additional ≤45-day window) will begin, during which time screening 
procedures will be repeated.
The following assessments must be repeated for participants who are rescreened:

Vital signs, weight, and directed physical examination

Review medical history and prior/concomitant medications for new information

All laboratory assessments (includes serum hCG pregnancy testing for WOCBP)

Review of AEs
If the informed consent form has been updated, participants should be reconsented before 
rescreening. If no updates have been made, written informed consent signed during the 
original screening period should be reviewed with the participant and a verbal reconsent to 
continue in the study should be documented.
If a participant had a Day 1 ECG during the original screening period, it should be repeated 
(at the Day 1 visit or within 7 days prior).
If a participant had a baseline Day 1 DEXA scan during the original screening period, and 
>30 days have elapsed, the Day 1 DEXA should be repeated. If <30 days have elapsed since 
the DEXA it is not necessary to repeat the Day 1 DEXA scan during rescreening.
Participants who were previously considered screen failures because the duration of baseline 
ART was <6 months are allowed to rescreen if they have continued to receive BIC/FTC/TAF 
therapy with documented viral suppression (HIV-1 RNA <50 copies/mL) for ≥6 months 
before the rescreening visit and have no history of prior virologic treatment failure on any 
past or current regimen.
8.11.2
Treatment Period
All procedures and their timing should be completed as per SoA (Section 1.3).
8.11.2.1
Fasting
Note: As of Amendment 013-02, this section is no longer applicable.
Visits at Day 1, Week 4, Week 24, Week 48, Week 72, Week 96, Week 120, and Week 144
require that participants fast (ie, do not consume any food or beverages except water) for at 
least 8 hours prior to the visit. The investigator/study coordinator are responsible to remind 
participants to fast prior to these visits and to confirm with participants their fasting status in 
the appropriate source documentation.
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8.11.2.2
Optional Nurse Visits and Telephone Visits
Note: As of Amendment 013-02, this section is no longer applicable.
A visiting nurse service may be used (if locally available and approved for use) at any visit 
after a participant is randomized. If a visiting nurse service is used for any visit, the 
investigator should contact the participant by phone on the same day as the nurse visit, or as 
soon as possible to perform an investigator AE assessment. Refer to the nursing manual for 
additional details.
For visits conducted by the visiting nurse, whole blood for FBR samples will not be collected 
by the visiting nurse. Participants should be instructed to return to the site within 2 to 4 
weeks from the scheduled visit for collection of whole blood for FBR, when possible. If an 
unscheduled visit for collection of whole blood for FBR is not possible, the sample should be 
drawn at the next scheduled visit at the site.
8.11.3
Discontinued Participants Continuing to be Monitored in the Study
Note: As of Amendment 013-02, this section is no longer applicable.
A participant must be discontinued from study intervention for any of the reasons listed in 
Section 7.1.
For all discontinuations which are not related to pregnancy, when it is determined that 
discontinuation from study intervention is appropriate, the participant should have both an 
Early Discontinuation of Treatment visit (Section 8.11.3.2) and an End of Treatment Follow-
up visit (Section 8.11.3.3) conducted. After the visit procedures are completed, the 
participant will be withdrawn from the study and managed by the investigator per local 
standard-of-care.
8.11.3.1
Participants Who Become Pregnant
If a participant becomes pregnant during the study (has a positive serum pregnancy test), 
study intervention should be discontinued, and the participant may be unblinded to be 
managed by the investigator per local standard-of-care, as appropriate.
The participant should not be withdrawn from the study but should have an Early 
Discontinuation of Treatment visit (Section 8.11.3.2). If the pregnancy is reported at a 
scheduled study visit, the assessments for the Early Discontinuation of Treatment visit should 
be conducted at that time. The participant will then continue with the protocol-specified visits 
for the duration of their pregnancy per the regular schedule in the SoA for the duration of 
their pregnancy (Section 1.3.1). At these visits (in-person or via telephone), concomitant 
medications will be reviewed, and safety assessments will be completed. 
All reported pregnancies occurring during the study must be followed to the 
completion/termination of the pregnancy (Section 8.4.5). The participant will be asked to join 
a pregnancy registry, which collects information about the outcome of the pregnancy. Infants 
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born to participants who become pregnant while receiving study intervention and consent to 
infant follow-up, will have safety follow-up through approximately 1 year of age 
(Section 8.3.10).
8.11.3.2
Early Discontinuation of Treatment
Participants who discontinue treatment early for any reason should have an Early 
Discontinuation of Treatment visit as outlined in Section 1.3.2. If early discontinuation 
occurs during the timeframe of a scheduled study visit, the assessments for the Early 
Discontinuation of Treatment visit should be conducted.
8.11.3.3
End of Treatment Follow-up Visit
Participants who discontinue study intervention at any time (including at the Week 144 visit) 
for any reason(s) not related to pregnancy will have a safety follow-up visit in-clinic 
approximately 42 days after the last dose of study intervention. Assessments for this visit are 
outlined in Section 1.3.2.
8.11.4
Viremia Confirmation
Note: As of Amendment 013-02, this section is no longer applicable.
If a participant has a viral load of ≥50 copies/mL at any time during the study, a Viremia 
Confirmation visit must be conducted within 2 to 4 weeks of the initial HIV-1 viremia 
(Sections 1.3.2 and 4.2.1.1). If a scheduled visit is to occur within the timeframe that a 
participant would return for a viremia confirmation visit, the assessments for the scheduled 
visit should be conducted, and the HIV viral drug resistance sample must be collected.
8.11.5
 
 
 
 
 
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9
STATISTICAL ANALYSIS PLAN
Note: As of Amendment 013-02, overall Section 9 is no longer applicable unless 
otherwise specified here or in each specific subsection, including Sections 9.4.1, 9.4.2, 
9.5, 9.6, 9.6.1.2, 9.6.2, 9.11, and 9.12. Efficacy and safety data will be summarized for
available data from Part 1 and from the Unblinded Safety Monitoring period
separately. Safety data will be evaluated for the following periods:

From Day 1 through on-treatment before Unblinded Safety Monitoring period

Unblinded Safety Monitoring period
This section outlines the statistical analysis strategy and procedures for the study. Changes to 
analyses made after the protocol has been finalized will be documented in a sSAP and 
referenced in the CSR for the study. Post hoc exploratory analyses will be clearly identified 
in the CSR. Exploratory analyses will be described in the sSAP.
9.1
Statistical Analysis Plan Summary
Key elements of the statistical analysis plan are summarized below.
Study Design 
Overview
A Phase 2b, Randomized, Active-Controlled, Double-Blind, Dose-Ranging 
Clinical Study to Evaluate a Switch to ISL + MK-8507 QW in Adults with HIV-1 
Virologically Suppressed on BIC/FTC/TAF QD
Treatment 
Assignment
Part 1 (Double-blind Dose Ranging Treatment Period): 
~140 participants will be randomized in a 1:1:1:1 ratio to receive 1 of the 4 
following study interventions:
•
Group 1: ISL 20 mg QW + MK-8507 100 mg QW (n=35)
•
Group 2: ISL 20 mg QW + MK-8507 200 mg QW (n=35)
•
Group 3: ISL 20 mg QW + MK-8507 400 mg QW (n=35)
•
Group 4: BIC/FTC/TAF QD (n=35)
All participants will remain in Part 1 and receive assigned study intervention until 
the MK-8507 dose is confirmed for Part 2 based on Week 48 results.
Part 2 (Selected-dose Open-label Treatment Period):
Once the MK-8507 dose is confirmed and communicated to sites, participants will 
receive the following open-label study intervention through Week 96:
•
Groups 1, 2, and 3: ISL 20 mg QW + MK-8507 QW (at the selected dose)
•
Group 4: BIC/FTC/TAF QD
Part 3 (ISL + MK-8507 Open-label Treatment Period):
All participants will receive ISL 20 mg QW + MK-8507 QW (at the selected dose) 
from Week 96 through Week 144.    
Analysis Populations
Efficacy: Full Analysis Set (FAS)
Safety: All Participants as Treated (APaT)
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Primary Endpoint(s)
Efficacy: [No longer an endpoint as of Amendment 013-02]
Percentage of participants with HIV-1 RNA ≥50 copies/mL at Week 48
Safety:
1.
Percentage of participants experiencing AEs
2.
Percentage of participants experiencing AEs leading to discontinuation of 
study intervention 
Statistical Methods 
for Efficacy and 
Safety Analyses
The primary efficacy and safety objectives will be assessed using 2-sided 95% CIs 
for the treatment difference in the primary efficacy and safety endpoints between 
each of treatment Groups 1-3 and active control Group 4.
The CIs will be based on unstratified Miettinen and Nurminen method [Miettinen, 
O. and Nurminen, M. 1985].
Multiplicity
Since there are no formal hypothesis tests, no multiplicity adjustment is needed in 
this study.
Interim Analysis
After all participants have reached Week 24, an interim analysis will be conducted 
to assess the safety, efficacy, and PK objectives and to support a preliminary dose 
selection for MK-8507. Select Sponsor personnel (not affiliated with the study 
team) will be unblinded for the Week 24 interim analysis to support dose response 
and population PK modeling. The external unblinded statistician will conduct the 
efficacy and safety analyses associated with the Week 24 interim analysis. Site 
personnel, study participants, and Sponsor study-team personnel will remain 
blinded to participant treatment assignments, although the Sponsor study-team 
will have access to treatment-level summaries presented in the interim analysis
report and the preliminary dose selection at the Week 24 interim analysis.  
After all participants have reached Week 48, the Sponsor study-team will be 
unblinded and safety and efficacy data through Week 48 will be analyzed to
support final dose selection for Part 2.
Periodic safety and efficacy reviews by an eDMC will be performed as specified 
in the eDMC charter.
Sample Size
The planned sample size is 140 participants to be randomized in a 1:1:1:1 ratio to 
Groups 1-4 (35 participants per treatment group). With 35 participants in each 
treatment group, there is approximately 80% probability to obtain a 2-sided 95% 
CI for the treatment difference in the proportions of participants with HIV-1 RNA 
≥50 copies/mL that would exclude a 22.2% treatment difference when the true 
proportions are, in fact, equal to 2% in both treatment groups. This statement 
applies to the 3 treatment differences corresponding to the difference between 
each specific ISL + MK-8507 treatment group and the active control group, for 
each applicable time point. Detailed information is in Section 9.9.1.
9.2
Responsibility for Analyses/In-house Blinding
The statistical analysis of the data obtained from this study will be the responsibility of the 
Clinical Biostatistics department of the Sponsor. 
Part 1 is double-blinded with in-house blinding through Week 48 (eg, the participant, the 
investigator, and Sponsor personnel are unaware of the intervention assignments). Clinical 
site personnel and participants will remain blinded in Part 1 (through at least Week 48). To 
support the Week 24 interim analysis, select sponsor personnel (not affiliated with the study 
team) will be unblinded to participant treatment assignments to support the dose response 
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and population PK modeling. The external unblinded statistician will conduct the efficacy 
and safety analyses associated with the Week 24 interim analysis. Sponsor study-team 
personnel will remain blinded to participant treatment assignments until the unblinding to 
support the Week 48 interim analysis; however, they will have access to treatment-group 
summaries presented in the Week 24 interim analysis report as well as knowledge of the 
preliminary dose selection.
Part 2 and Part 3 of this study are conducted as open label; therefore, the Sponsor, 
investigator, and participant will know the intervention administered.
The Clinical Biostatistics department will generate the randomized allocation schedule(s) for 
study intervention assignment. Randomization will be implemented via an IRT.
9.3
Hypotheses/Estimation
There are no hypotheses to be tested in this study. The study objectives are stated in 
Section 3.
9.4
Analysis Endpoints
Efficacy and safety endpoints for the study, which will be evaluated for within-and/or 
between-treatment differences, are listed below, followed by the descriptions of the 
derivations of selected endpoints. These endpoints will be evaluated by treatment group
according to study part.
9.4.1
Efficacy Endpoints
Note: As of Amendment 013-02, this section is no longer applicable except CD4+ T-cell 
counts will continue to be monitored through the Unblinded Safety Monitoring period,
according to Section 1.3.3 and Section 1.3.4.
Unless otherwise specified, the efficacy endpoints will be evaluated by the Part 1 treatment 
group for Part 1 summaries. In Part 2, the efficacy endpoints will be evaluated by treatment 
group in Part 1 and by treatment group in Part 2 (ie, participants from Group 4 will remain in 
Group 4 as an active control and participants from Groups 1-3 will be in a combined group). 
In Part 3, the efficacy endpoints will be evaluated by Part 2 treatment group (Groups 1-3
combined and Group 4 presented separately).
An initial description of efficacy measures is provided in Section 4.
Percentage of Participants with Predefined HIV-1 RNA Levels
The Abbott Real Time PCR assay with a reliable LLOQ of 40 copies/mL will be used to 
measure the HIV-1 RNA level in blood samples obtained at each visit. The following 
efficacy endpoints associated with HIV-1 RNA will be derived based on HIV-1 RNA test 
results and reconfirmed results, if applicable.
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Primary Efficacy Endpoints

Percentage of participants with HIV-1 RNA ≥50 copies/mL at Week 48
Secondary Efficacy Endpoints

Percentage of participants with HIV-1 RNA ≥50 copies/mL at Week 24

Percentage of participants with HIV-1 RNA <50 copies/mL at Week 24

Percentage of participants with HIV-1 RNA <40 copies/mL at Week 24

Percentage of participants with HIV-1 RNA <50 copies/mL at Week 48

Percentage of participants with HIV-1 RNA <40 copies/mL at Week 48

Percentage of participants with HIV-1 RNA ≥50 copies/mL at Week 96

Percentage of participants with HIV-1 RNA <50 copies/mL at Week 96

Percentage of participants with HIV-1 RNA <40 copies/mL at Week 96

Percentage of participants with HIV-1 RNA ≥50 copies/mL at Week 144
Change from Baseline in CD4+ T-cell Count
Results of CD4+ T-cell counts from the central laboratory will be used to evaluate the 
immunologic effect. Changes in CD4+ T-cell count will be estimated at each applicable 
timepoint. Specific secondary efficacy endpoints include the following:

Change from baseline in CD4+ T-cell count at Week 24

Change from baseline in CD4+ T-cell count at Week 48

Change from baseline in CD4+ T-cell count at Week 96

Change from baseline in CD4+ T-cell count at Week 144
For analyses of change from baseline, baseline measurements are defined as the Day 1 value 
for each participant. In the rare event when data for this visit are missing, the value obtained 
at the most recent screening visit will be used as baseline. For assessments of change from 
baseline in Group 4 at Week 144, baseline will be the Week 96 measurement (or the last 
measurement prior to the switch to ISL + MK-8507 QW).  
Clinically-significant Confirmed Viremia
Participants with confirmed virologic rebound as defined in Section 4.2.1.1.2 will be 
identified.
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Viral Resistance-associated Substitutions
Participants who meet the definition of confirmed virologic rebound (Section 4.2.1.1.2), or 
who discontinue study intervention for another reason and have HIV-1 RNA ≥200 copies/mL
at the time of discontinuation, will be assessed for development of viral drug resistance. 
Among such participants, those with HIV-1 RNA ≥400 copies/mL or anyone for whom 
available genotypic or phenotypic data show evidence of resistance, irrespective of viral load, 
will be included for resistance analyses. The resistance analysis will count the number of 
participants who have evidence of resistance associated with each study intervention and will 
be summarized through study duration, with primary interest at Weeks 48 and 96.
9.4.2
Safety Endpoints
Note: As of Amendment 013-02, this section is no longer applicable except AEs, DILI 
laboratory criteria, PDLC, and selected laboratory parameters will continue to be 
monitored through the Unblinded Safety Monitoring period, according to Section 1.3.3
and Section 1.3.4.
Unless otherwise specified, the safety endpoints will be evaluated for the following periods:

Day 1 through Week 48

Day 1 through Week 96

Day 1 through Week 144 for Groups 1-3

Week 96 through Week 144 for Group 4
Unless otherwise indicated, safety summaries will be presented by Part 1 treatment group, 
and by combining Groups 1-3 where appropriate. Further details on the safety comparisons 
and treatment group pooling strategy for each study part will be provided in the sSAP.
An initial description of safety measures is provided in Section 4.
Adverse Events
The analysis of safety results will follow a tiered approach (Table 11). The tiers differ with 
respect to the analyses that will be performed.
 
 
 
 
 
 
The percentage of participants falling into the following clinical AE categories will be 
summarized as Tier 2 endpoints: 1) at least 1 AE; 2) at least 1 drug-related AE; 3) at least 1
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SAE; 4) at least 1 serious and drug-related AE; 5) AEs leading to discontinuation of study 
intervention; and 6) AE(s) leading to death.
Events of Clinical Interest (ECI)
Specific ECIs, including events meeting DILI lab criteria
 
 (predefined in Section 8.4.7), will be summarized.
Predefined Limits of Change in Laboratory Parameters
For the summaries of laboratory tests, participants must have both a baseline and 
postrandomization on-treatment measurement to be included. 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, July 2017, Version 2.1 (Appendix 3). A listing of the participants who meet the 
criteria will also be provided.
Selected Laboratory Parameters
The mean change from baseline to Weeks 48, 96, and 144 in select laboratory parameters
will be summarized.
For analyses of change from baseline, baseline measurements are defined as the Day 1 value 
for each participant. In the rare event when data for this visit are missing, the value obtained 
at the most recent screening visit will be used as baseline. For assessments of change from 
baseline in Group 4 at Week 144, baseline will be the Week 96 measurement (or the last 
measurement prior to the switch to ISL + MK-8507 QW).
9.4.3
Pharmacokinetic Endpoints
PK samples collected from all participants as described in the SoA and Section 8.6.1 will be 
used for updating the population PK model for ISL and MK-8507, and as appropriate, 
evaluate the PK-efficacy, and PK-AE relationships of ISL and MK-8507.
9.4.4
Patient-reported Outcome Endpoints
An initial description of patient-reported outcome measures is provided in Section 4.2.1.5.
HIVTSQs and shortened HAT-QOL at Day 1 and Weeks 96 and 144 will be summarized for
each treatment group. Participants who do not experience a minimum of 4 weeks of 
open-label study intervention in Part 2 will be excluded from the Week 96 analysis. HIV 
stigma scale results at Day 1 will be summarized for each treatment group. Results from the 
preference questionnaire will be summarized for participants in Groups 1-3 at Week 96 and 
for all participants at Week 144.
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9.5
Analysis Populations
Note: As of Amendment 013-02, this section is no longer applicable except FAS and 
APaT populations for summaries associated with available data of Part 1. The 
Unblinded Non-study ART Treated population is defined as participants who were in 
Groups 1, 2, and 3 and were to switch to non-study ART treatment.
9.5.1
Efficacy Analysis Populations
9.5.1.1
Full Analysis Set
The FAS population will serve as the primary population for the analysis of efficacy data in 
this study. The FAS population consists of all randomized participants who:

Received at least 1 dose of study treatment, and 

Have baseline data for those analyses that require baseline data.
Participants will be included in the treatment group to which they are randomized for the 
analyses of efficacy data using the FAS population.
9.5.1.2
Resistance Analysis Subset
The resistance analysis subset will include all participants in the FAS with confirmed HIV-1 
RNA ≥400 copies/mL and any participants for whom available genotypic or phenotypic data 
show evidence of resistance, irrespective of viral load.
9.5.2
Safety Analysis Population
The APaT population will be used for the analysis of safety data in this study. The APaT 
population consists of all randomized participants who received at least 1 dose of study 
intervention. Participants will be included in the treatment 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 treatment group to which they are randomized. 
Participants who take incorrect study intervention for the entire treatment period will be 
included in the treatment group corresponding to the study intervention actually received.
Participants in Group 4 who receive at least 1 dose of weekly study intervention (ISL +
MK-8507) in Part 3 will be included in summaries and analyses from Week 96 through 
Week 144.
At least 1 laboratory or vital sign measurement obtained after at least 1 dose of study 
intervention is required for inclusion in the analysis of each specific parameter. To assess 
change from baseline, a baseline measurement is also required.
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9.6
Statistical Methods
Note: As of Amendment 013-02, this section is no longer applicable. Efficacy data will 
be summarized separately for available data observed from Part 1 and the Unblinded 
Safety Monitoring period.
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 Quantitative Pharmacology and 
Pharmacometrics. Methods related to exploratory objectives will be described in the sSAP.
Unless otherwise specified, efficacy and safety data will be summarized and analyzed
separately according to study part. Additional pooled or sliced analyses may be provided in 
sSAP. 
9.6.1
Statistical Methods for Efficacy Analyses
Percentage of Participants with Predefined HIV-1 RNA Levels
For Part 1, the percentage of participants with HIV-1 RNA ≥50 copies/mL at Week 48 will 
be summarized by treatment group. The treatment difference in the percentage of participants 
with HIV-1 RNA ≥50 copies/mL between each of Groups 1-3 and Group 4 at Week 48 and 
the associated 95% CIs will be calculated using the unstratified Miettinen and Nurminen
method [Miettinen, O. and Nurminen, M. 1985]. The same efficacy analysis approach will be 
performed for the secondary efficacy endpoints (as specified in Section 9.4.1) at Week 24, 
Week 48, and Week 96 according to study part.
For the efficacy endpoints at Week 144, summary statistics will be provided.
The missing data will be handled based on the approaches defined in Section 9.6.1.1. The 
primary missing data approach for primary efficacy analysis is based on FDA Snapshot 
approach. The rest of missing data approaches are supportive for sensitivity analyses.
For the primary efficacy endpoints, the following categorization of virologic outcome at a 
timepoint by the snapshot approach will further be summarized by treatment group: 1) HIV-1 
RNA <50 copies/mL, 2) HIV-1 RNA ≥50 copies/mL, and 3) no virologic data in window for 
reasons of a) discontinued study due to an AE/death, b) discontinued study for other reasons 
(includes withdrawal of consent, loss to follow-up, move, etc.), or c) on study but missing 
data in window.
Change from Baseline in CD4+ T-cell Count
Change from baseline in CD4+ T-cell count will be summarized at each time point, with 
particular interest in Weeks 24, 48, 96, and 144 as specified in Section 9.4.1. For Week 144, 
the change from baseline will be based on the Week 96 baseline for Group 4.
The treatment difference in change from baseline in CD4+ T-cell count at Weeks 24, 48, and 
96 will be estimated using an ANCOVA model adjusted by baseline CD4+ T-cell count and 
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treatment group and will be based on study part. The DAO approach will be used to handle 
missing data for these analyses. Under the DAO approach, participants must have both a 
baseline measurement and at least 1 postbaseline measurement within the analysis window 
specified in Table 10 in Section 9.6.1.2 for the time point of interest to be included in the 
analyses of the mean change from baseline in CD4+ T-cell count by time point. Supportive 
analyses will also be provided using the LOCF method to account for missing data.
Clinically-significant Confirmed Viremia
The number of participants with confirmed virologic rebound, as defined in Section 4.2.1.1.2, 
will be summarized according to study part through Week 144.
Viral Resistance-associated Substitutions
The number of participants in the resistance analysis subset with genotypic and/or phenotypic 
resistance to each study intervention will be summarized according to study part with 
primary interest at Weeks 48 and 96.
Table 9 summarizes the key efficacy analyses of the study.
Table 9
Analysis Strategy for Key Efficacy Endpoints
Endpoint
Primary vs 
Supportive 
Approach
Statistical 
Method
Analysis 
Population
Missing Data 
Approach
Primary Efficacy Endpoints
Percentages of participants with 
HIV-1 RNA ≥50 copies/mL at 
Week 48
P
M&N 
FAS
Snapshot
S
M&N 
FAS
OF
Secondary Efficacy Endpoints
Percentages of participants with 
HIV-1 RNA <50 copies/mL and 
<40 copies/mL at Weeks 24, 48,
and 96
P
M&N 
FAS
Snapshot
S
M&N 
FAS
OF
Percentages of participants with 
HIV-1 RNA ≥50 copies/mL at 
Weeks 24 and 96
P
M&N 
FAS
Snapshot
Percentages of participants with 
HIV-1 RNA ≥50 copies/mL at 
Week 144
P
Descriptive 
Statistics
FAS
Snapshot
Change from baseline to Weeks 24,
48, and 96 in CD4+ T-cell count 
P
ANCOVA
FAS
DAO
S
ANCOVA
FAS
LOCF
Change from baseline to Week 144 
in CD4+ T-cell count
P
Descriptive 
Statistics
FAS
DAO
S
Descriptive 
Statistics
FAS
LOCF
ANCOVA=analysis of covariance; DAO=Data-As-Observed; FAS=Full Analysis Set; HIV-1=human 
immunodeficiency virus type 1; LOCF=Last Observation Carried Forward; M&N=Miettinen and Nurminen; 
OF=Observed Failure; P=Primary approach; RNA=ribonucleic acid; S=Supportive approach; vs=versus.
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9.6.1.1
Missing Data Approaches
There are 3 types of missing values: 

intermittent missing values due to a missed or skipped visit or due to an inadequate 
sample; 

nonintermittent missing values due to premature discontinuations because of 
treatment-related reasons such as, “adverse event” (regardless of relationship to study 
intervention) and “withdrew based on HIV-1 RNA results”; 

nonintermittent missing values due to premature discontinuations because of other 
reasons which are not related to study intervention such as loss to follow-up, protocol 
violation, participant withdrew consent, etc. 
Two approaches will be used to handle missing values: 1) FDA “snapshot” approach; and 2) 
the OF approach.
FDA Snapshot Approach
The primary approach for analysis of the percentage of participants with HIV-1 RNA 
≥50 copies/mL is the FDA “snapshot” approach [Food and Drug Administration (CDER) 
2015]. Virologic outcome will be defined according to the following categories:

HIV-1 RNA <50 copies/mL: participants who have the last available on-treatment 
HIV-1 RNA measurement <50 copies/mL at the timepoint of interest within the time 
window specified in Table 10 in Section 9.6.1.2. 

HIV-1 RNA ≥50 copies/mL: this includes participants 
1) Who have the last available on-treatment HIV-1 RNA measurement ≥50
copies/mL at the timepoint of interest within the time window specified in 
Table 10 in Section 9.6.1.2. 
2) Who do not have on-treatment HIV-1 RNA data in timepoint of interest analysis 
window and 
a) Who discontinue study intervention prior to or in the timepoint of interest 
analysis window due to lack of efficacy, or 
b) Who discontinue study intervention prior to or in the point of interest analysis 
window due to reasons other than lack of efficacy and whose last available 
on-treatment HIV-1 RNA measurement is ≥50 copies/mL.
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
No Virologic Data in Specified Analysis Time Window: this includes participants 
who do not have on-treatment HIV-1 RNA data in the timepoint of interest analysis 
window because of the following:
1) Discontinued study intervention due to AE or death: this includes participants 
who discontinued because of an AE or death at any timepoint from Day 1 
through the time window if this resulted in no virologic data on treatment 
during the specified window and have the last available on-treatment HIV-1 
RNA measurement <50 copies/mL.
2) Discontinued study intervention for other reasons: this includes participants 
who discontinued study intervention prior to or in the timepoint of interest 
analysis window due to reasons other than lack of efficacy or AE/death 
(ie, lost to follow-up, noncompliance with study intervention, physician 
decision, protocol deviation, withdrawal by participant, etc.) and have the last 
available on-treatment HIV-1 RNA measurement <50 copies/mL.
3) On study but missing data in window: only data in the predefined analysis 
window can be used for participants remaining on study intervention. 
Participants should be classified as on study but missing data in window 
regardless of the HIV-1 RNA results outside of the timepoint of interest 
analysis window.
For primary and secondary efficacy endpoints associated with predefined HIV-1 RNA level, 
the numerators will be evaluated according to the FDA snapshot algorithm for missing data, 
divided by the number of participants in the FAS population, and multiplied by 100.
Observed Failure Approach
A second approach, the OF approach will also be performed as a sensitivity analysis for the 
HIV-1 RNA measurement <50 copies/mL endpoint. Under this approach, participants with
nonintermittent missing data who prematurely discontinue study intervention due to lack of 
efficacy or who discontinue study intervention for other reasons and are virologic failures 
(HIV-1 RNA ≥50 copies/mL) at the time of study intervention discontinuation are considered 
as failures at timepoints thereafter. Participants who discontinue study intervention for 
reasons other than lack of efficacy and who are not failures at the time of study intervention
discontinuation will be excluded from the analyses at subsequent timepoints. Participants 
with intermittent missing data will be considered as successes (HIV-1 RNA <50 copies/mL) 
if both the immediately preceding and immediately subsequent on-treatment HIV-1 RNA 
measurements are <50 copies/mL; all other intermittent missing results will be imputed as 
failures.
The same sensitivity analyses based on the OF approach will also be performed on primary 
and secondary efficacy endpoints related to percentage of participants achieving HIV-1 RNA 
<40 copies/mL.
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9.6.1.2
Definition of Time Points (or Analysis Visit)
Note: As of Amendment 013-02, the definition of time points after Week 24 associated 
with Parts 1, 2, and 3 in this section is no longer applicable. The definition of time 
windows for Unblinded Safety Monitoring period (in Section 1.3.3 and Section 1.3.4) is 
presented in Table 10.
Table 10 lists the definition of timepoint by time windows (day-ranges) that will be used for 
the purposes of the statistical analyses and the target relative day for the scheduled visits in 
the study which will be used for all analyses by timepoint. The last available on-treatment 
measurement within a window will be used for analyses at a specific timepoint, unless 
otherwise specified. Results from additional timepoints beyond Week 144 may be 
summarized, and day-range rules for determining the analysis time windows will follow the 
same pattern where the ranges start and end at the midpoints between target days.
Assignment of a particular analysis visit to Part 1 or Part 2 will depend on the timing of 
communication of the selected dose of MK-8507 and the introduction of open-label study 
intervention. It is likely that Part 2 will not begin until at least Week 60 for all participants, 
and depending on the duration of enrollment, may not begin until Week 72 or later for at 
least some participants.
Table 10
Definition of Time Points (or Analysis Visit)
Treatment 
Phase
Treatment Period
Analysis Visit
Day-Range Rules
Target 
Daya
Pretreatment
Baseline
Day 1
≤1
1
Treatment
Double-blind 
Dose-ranging 
Treatment Period 
(Part 1) or
Selected-dose 
Open-label 
Treatment Period 
(Part 2)b
Week 2
≥2 and ≤21
15
Week 4
≥22 and ≤42
29
Week 8
≥43 and ≤70
57
Week 12
≥71 and ≤98
85
Week 16
≥99 and ≤126
113
Week 24
≥127 and ≤210
169
Week 36
≥211 and ≤294
253
Week 48
≥295 and ≤378
337
Week 60
≥379 and ≤462
421
Week 72
≥463 and ≤546
505
Week 84
≥547 and ≤630
589
Week 96
≥631 and ≤714
673
ISL + MK-8507 
Open-label 
Treatment Period 
(Part 3)
Week 100
≥687 and ≤728
701
Week 108
≥729 and ≤798
757
Week 120
≥799 and ≤882
841
Week 132
≥883 and ≤966
925
Week 144
≥967 and ≤1022
1009
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Treatment 
Phase
Treatment Period
Analysis Visit
Day-Range Rules
Target 
Daya
Non-study ART 
Treatment
Unblinded Safety 
Monitoring Period
Follow-up Through Day 42
Within 42 days after the 
last dose
NA
Follow-up Week 8
Between 43 and 56 days 
after the last dose
NA
For visits beyond Follow-
up Week 8 until 60 weeks 
after last dose, analysis 
visits will be performed 
every 4 weeks
Between the upper limit 
of last follow-up 
window +1 and the 
upper limit of last 
follow-up window +29 
after the last dose
NA
Long-term 
Unblinded Safety 
Monitoring
For visits beyond 60 weeks 
after last dose, analysis 
visits will be performed 
every 12 weeks
Between the upper limit 
of last follow-up 
window +1 and the 
upper limit of last 
follow-up window +85 
after the last dose
NA
ISL=islatravir. NA=not applicable
a Relative days and target days are computed from the first day of study intervention.
b All participants will remain in Part 1 and continue to receive double-blind study intervention until the dose 
selection decision is confirmed to switch to the selected dose for Part 2. 
9.6.2
Statistical Methods for Safety Analyses
Note: As of Amendment 013-02, only descriptive statistics based on available data for 
Part 1 and Unblinded Safety Monitoring period is applicable for this section. Events 
that are described below as either Tier 1, 2, or 3 events will now all be summarized 
descriptively.
Safety and tolerability will be assessed by clinical review of all relevant parameters including 
AEs, laboratory tests, and vital signs. The analysis of safety results will follow a tiered 
approach by study part (Table 11). The tiers differ with respect to the analyses that will be 
performed. Adverse events of special interest that are predefined in Section 9.4.2 constitute 
“Tier 1” safety endpoints. Other safety parameters will be considered as Tier 2 or Tier 3. 
Tier 1 and Tier 2 parameters will be assessed via point estimates and 95% CIs provided for 
between-treatment differences in the percentage of participants with Tier 1 and Tier 2 events
according to study part. While there is no inferential testing planned for Tier 1, p-Values will 
be presented and 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 
comparisons. These analyses will be performed using the Miettinen and Nurminen method 
[Miettinen, O. and Nurminen, M. 1985], an unconditional, asymptotic method. Change from 
baseline analyses for appropriate Tier 1 and Tier 2 endpoints will be assessed by ANCOVA 
models, adjusted by the baseline value.  
AEs (specific terms as well as system organ class terms), predefined limits of change in
laboratory parameters, and vital signs that are not prespecified as Tier 1 endpoints will be 
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classified as belonging to “Tier 2” or “Tier 3”, based on the number of participants who 
exhibit the event. Membership in Tier 2 requires that at least 4 participants in each treatment 
group exhibit the event during the period under evaluation. 
The threshold of at least 4 participants was chosen because the 95% CI for the between-
group difference in percent incidence will always include zero when treatment groups of 
equal size each have less than 4 participants that exhibit the event and would add little to the 
interpretation of potentially meaningful differences. Because many 95% CIs for Tier 2 events 
may be provided without adjustment for multiplicity, the CIs should also 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 laboratory parameters 
that meet predefined limits of change.
Safety endpoints that are not Tier 2 events are considered Tier 3 events. Only point estimates 
will be provided by treatment group for Tier 3 safety parameters.
The rest of continuous measures such as change from baseline in laboratory and vital signs 
parameters that are not prespecified as Tier 2 endpoints, summary statistics for baseline, on
treatment, and change from baseline values will be provided by treatment group according to 
study part in table format.
Missing safety parameters, unless otherwise specified, will be handled using the DAO 
approach, that is, any participant with a missing value will be excluded from the analysis. 
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.
Table 11 summarizes the key safety analyses of the study.
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Table 11
Analysis Strategy for Key Safety Endpoints
Safety 
Tier
Safety Endpointa
p-Value
95% CI for 
Treatment 
Difference
Descriptive 
Statistics
Tier 1
X
X
X
Tier 2
The percentage of participants 
with an AE in each of the 
following categories: 1 or more 
AE(s); drug-related AE(s), serious 
AE(s), AE(s) which are both drug-
related and serious, AE(s) [drug-
related and nondrug-related] 
leading to discontinuation of study 
intervention, and AE(s) leading to 
death 
Specific AEs (preferred terms), 
SOCs, or PDLCs occurring with 
an incidence ≥4 participants in at 
least 1 treatment group
Change from baseline in select 
laboratory parameters
X
X
Tier 3
Specific AEs (preferred terms), 
SOCs, or PDLCs occurring with 
an incidence <4 participants in all 
treatment groups
Change from baseline in 
laboratory measurements and vital 
signs
ECIs
X
AE=adverse event; CI=confidence interval; ECIs=events of clinical interest; PDLC=predefined 
limit of change; SOC=System Organ Class. 
a Adverse Experience references refer to both Clinical and Laboratory AEs. 
b Includes AEs predefined in Section 9.4.2.
 
 
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
 
More details of these analyses will be provided in the sSAP.
9.7
Interim Analyses
In addition to routine safety and efficacy monitoring by an eDMC, 2 formal interim analyses
will be conducted at Week 24 and Week 48 to aid in dose selection. Although the eDMC 
may make recommendations regarding the dose selection, the final dose selection will be 
made by the Sponsor.
Interim Analysis at Week 24
Note: As of Amendment 013-02, interim analysis at Week 24 will no longer be 
conducted.
Efficacy and safety summaries in support of the Week 24 interim analysis will be conducted 
by an external unblinded statistician. In addition, select Sponsor personnel (not affiliated with 
the study team) will be unblinded to support the PK objectives and additional dose selection 
analyses, including dose response and population PK modeling. The Sponsor study team will 
remain blinded to participant treatment assignments through the Week 48 interim analysis, 
although the study team will have access to the treatment-level summaries presented in the 
Week 24 interim analysis report and will be aware of the preliminary dose selection.
The Week 24 interim analysis report will summarize safety and key secondary efficacy 
endpoints at Week 24 as well as summarize all accumulated efficacy and safety data received 
at the time of data cutoff.
Interim Analysis at Week 48
Note: As of Amendment 013-02, interim analysis at Week 48 will no longer be 
conducted.
When all participants have either reached Week 48 (or discontinued prior), safety and 
efficacy results through Week 48 will be assessed to support confirmation of MK-8507 dose 
selection for Part 2. The Sponsor study-team will be unblinded at this time and will prepare 
the efficacy and safety summaries in support of this interim analysis.  
The Week 48 interim analysis report will summarize the primary and secondary efficacy and 
safety endpoints at Week 48 as well as summarize all accumulated efficacy and safety data
received at the time of data cutoff.
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Periodic Safety and Efficacy Assessments
Periodic safety and efficacy reviews by an eDMC will be performed regularly as specified in 
the eDMC charter. The analyses and summaries in support of these reviews will be 
performed by the external unblinded statistician.
If any of the safety and efficacy criteria defined in Section 4.4.2 are met, the external 
unblinded statistician will report it to the eDMC who may recommend closing a treatment 
group on the basis of those criteria. The AEs related to fluorosis and lack of efficacy due to 
viremia are defined in Sections 9.4.2 and 4.2.1.1.2, respectively.
9.8
Multiplicity
Since there are no formal hypothesis tests, no multiplicity adjustment is planned in this study.
9.9
Sample Size and Power Calculations
Note: As of Amendment 013-02, no between group comparisons will be conducted and 
power calculations are no longer applicable.
9.9.1
Sample Size and Power for Efficacy Analyses
This study will include approximately 140 participants randomized in a 1:1:1:1 ratio to 1 of 4
treatment groups (35 participants per treatment group). The sample size of the study was not 
based on formal statistical criteria but there is interest in quantifying the magnitude of 
treatment differences that can be detected with reasonable certainty. Table 12 displays the 
treatment differences (ISL + MK-8507 treatment group [either Groups 1-3] minus 
BIC/FTC/TAF active control group [Group 4]) in event rates (the percentage of participants 
with HIV-1 RNA ≥50 copies/mL) associated with 80% probability and 35 participants per
treatment group. The calculations are based on an asymptotic method proposed by Farrington 
and Manning [Farrington, C. P. and Manning, G. 1990].
Table 12
Treatment Differences in Efficacy Event Rate Associated with 80% Probability 
(N=35 vs 35)
Hypothetical True Control 
Event Rate (≥50 copies/mL)
in Group 4 (BIC/FTC/TAF)
Hypothetical True 
Treatment Event Rate 
(≥50 copies/mL) in ISL + 
MK-8507
Treatment Difference 
(ISL + MK-8507 minus 
BIC/FTC/TAF) 
1%
22.0%
21.0%
2%
24.2%
22.2%
3%
26.3%
23.3%
4%
28.2%
24.2%
5%
30.0%
25.0%
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Hypothetical True Control 
Event Rate (≥50 copies/mL)
in Group 4 (BIC/FTC/TAF)
Hypothetical True 
Treatment Event Rate 
(≥50 copies/mL) in ISL + 
MK-8507
Treatment Difference 
(ISL + MK-8507 minus 
BIC/FTC/TAF) 
6%
31.8%
25.8%
7%
33.5%
26.5%
8%
35.1%
27.1%
9%
36.6%
27.6%
10%
38.2%
28.2%
BIC=bictegravir; FTC=emtricabine; ISL=islatravir; TAF=tenofovir disoproxil fumarate.
Calculated using SAS v9.4.
For example, with 35 participants per treatment group, there is approximately 80% 
probability of obtaining a 2-sided 95% CI for the treatment difference in the proportions of 
participants with HIV-1 RNA ≥50 copies/mL that would exclude a 22.2% treatment 
difference (in both directions) when the true proportions are, in fact, equal to 2% in both of 
the treatment groups. This probability statement applies to the 3 treatment differences 
corresponding to the difference between each specific ISL + MK-8507 treatment group and 
the active control group, for each applicable time point.
Table 13 provides a selection of observed minimum treatment differences associated with 
95% CIs that exclude 0 to give examples of treatment effect sizes that can be detected in a 
study of this size. This table presents these possible outcomes for a variety of potential 
observed event rates in the control group (Group 4).
Table 13
Minimum Treatment Difference with the Lower Bound of 95% CI that Excludes 0
(N=35 vs 35)
Minimum Treatment Difference with 95% CI that Excludes 0
Group 4 (N=35)
Either Groups 1-3 (N=35)
Treatment 
Difference 
(Either Groups 1-
3 – Group 4)
(Percentage 
Points)
95% CI
Observed 
Number ≥50 
copies/mL
Observed 
Event 
Rate ≥50 
copies/mL
Observed 
Number ≥50 
copies/mL
Observed 
Event 
Rate ≥50 
copies/mL
0
0.0%
4
11.4%
11.4
(0.8, 26.1)
1
2.9%
6
17.1%
14.3
(0.2, 30.5)
2
5.7%
8
22.9%
17.1
(0.7, 34.5)
3
8.6%
10
28.6%
20.0
(1.8, 38.2)
4
11.4%
11
31.4%
20.0
(0.7, 38.8)
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Minimum Treatment Difference with 95% CI that Excludes 0
Group 4 (N=35)
Either Groups 1-3 (N=35)
Treatment 
Difference 
(Either Groups 1-
3 – Group 4)
(Percentage 
Points)
95% CI
Observed 
Number ≥50 
copies/mL
Observed 
Event 
Rate ≥50 
copies/mL
Observed 
Number ≥50 
copies/mL
Observed 
Event 
Rate ≥50 
copies/mL
5
14.3%
13
37.1%
22.9
(2.3, 42.2)
6
17.1%
14
40.0%
22.9
(1.6, 42.6)
7
20.0%
15
42.9%
22.9
(1.0, 43.0)
8
22.9%
16
45.7%
22.9
(0.5, 43.3)
9
25.7%
17
48.6%
22.9
(0.1, 43.5)
10
28.6%
19
54.3%
25.7
(2.5, 46.4)
CI=confidence interval.
Calculated using SAS v9.4.
For example, with 35 participants per treatment group and an observed event rate of 2.9% in 
Group 4 (1 out of 35 participants with HIV-1 RNA ≥50 copies/mL), the minimum treatment 
difference that results in a 95% CI whose lower bound is >0 is 14.3 percentage points, which 
corresponds to an observed event rate (percentage of participants with HIV-1 RNA ≥50 
copies/mL) of 17.1% in either Groups 1-3.
9.9.2
Sample Size and Power for Safety Analyses
Adverse Events
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 incidence of a particular AE is 1%, there is a 29.7% chance of observing at 
least 1 AE among 35 participants in a treatment group. If no AE of that type is observed 
among the participants, this study will provide 95% confidence that the underlying 
percentage of participants with that particular AE is <10.0% for a treatment group.
The estimate of, and the upper bound of the 95% CI for, the underlying percentage of 
participants with an AE given various hypothetical observed number of participants with the 
AE within each treatment group and active control group are provided in Table 14. 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 14
Estimate of Incidence of AEs and 95% Upper Confidence Bound Based on 
Hypothetical Number of Participants with AEs
Sample Size
Hypothetical Number 
of Participants With 
Adverse Event
Estimate of 
Incidence
95% Upper Confidence 
Bounda
35
0
0.0%
10.0%
35
1
2.9%
14.9%
35
2
5.7%
19.2%
35
5
14.3%
30.3%
35
7
20.0%
36.9%
35
10
28.6%
46.3%
a Based on the 2-tailed exact confidence interval of a binomial proportion [Clopper, C. J. and Pearson, E. S. 
1934].
Table 15 gives the difference in the incidence of an AE (either Groups 1-3 minus Group 4) 
that can be ruled out with different probability levels and 95% confidence when there are 35
participants in each treatment group. The underlying incidence of the AE is assumed to be 
the same for a treatment and active control groups. For example, for a reasonably common 
AE, which occurs in 20% of participants in both groups, the study has 80% probability to 
declare with 95% confidence that the true difference between the treatment groups is no more 
than 31.6 percentage points. The calculations are based on an asymptotic method proposed 
by Farrington and Manning [Farrington, C. P. and Manning, G. 1990].
Table 15
Difference in Incidence of AEs (either Groups 1-3 minus Group 4) That Can Be 
Ruled Out (N=35 vs 35)
Target 
Probability
Underlying AE Incidence Rate
1%
5%
10%
20%
30%
40%
50%
80%
21.0
25.0
28.2
31.6
32.8
32.7
31.3
85%
23.3
27.3
30.4
33.8
35.0
34.7
33.1
90%
26.2
30.1
33.2
36.6
37.6
37.1
35.2
95%
30.5
34.3
37.4
40.5
41.3
40.5
38.2
AE=adverse event; CI=confidence interval. 
Note: The upper bound of the 2-sided 95% CI (Farrington and Manning [Farrington, C. P. and Manning, G. 
1990]) for the difference in AE incidences (either Groups 1-3 minus Group 4). 
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9.10
Subgroup Analyses
Note: As of Amendment 013-02, subgroups analyses will no longer be conducted.
The estimate of the between-group treatment effect for the primary efficacy endpoints will be 
assessed and plotted within each category of the following classification variables:

Age category (<50, ≥50) 

Sex (female, male) 

Race (White, Black, Asian, Other) 

Ethnicity (Hispanic/Latino, not Hispanic/Latino) 

 
The OF approach will be used to handle missing values in these subgroup analyses. No 
stratification will be used for these analyses. Nominal 2-sided 95% CIs will be calculated for 
subgroups with at least 10% (4 or more) of participants in both treatment groups of a
comparison.
9.11
Compliance (Medication Adherence)
Note: As of Amendment 013-02, summaries associated with Part 1 are applicable and 
summaries associated with Parts 2 and 3 are no longer applicable for this section.
Compliance will be summarized separately for Part 1 (double-blind period) and Parts 2 and 3
(open-label periods). In addition, compliance will be presented separately for weekly 
treatments (ISL and its placebo, MK-8507 and its placebo, ISL, and MK-8507) from daily 
treatments (BIC/FTC/TAF and its placebo).  
Daily Compliance:
For a participant who is followed for the entire period, the “Number of Days Should be on 
Therapy” is the total number of days from the first dose day to the last scheduled day for 
treatment administration for that participant per period. For a participant who discontinued 
from the study permanently, the “Number of Days Should be on Therapy” is the total number 
of days from the first dose day to the date of the last dose of study medication. 
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For each participant, percent compliance will then be calculated using the following formula:
Summary statistics will be provided on percent compliance for daily treatments by treatment 
group according to study part for the FAS population. There will be no daily treatments for 
Groups 1-3 in Part 2 and Part 3 by design.  
Weekly Compliance:
For a participant who is followed for the entire period, the “Number of Weeks Should be on 
Therapy” is the total number of complete weeks from the first dose day to the last scheduled 
day for treatment administration for that participant per period. For a participant who 
discontinued from the study permanently, the “Number of Weeks Should be on Therapy” is 
the total number of complete weeks from the first dose day to the date of the last dose of 
study medication. A participant must take all required study intervention during a week to be 
counted in the numerator for a given week.  
Summary statistics will be provided on percent compliance for weekly treatments by 
treatment group according to the study part for the FAS population. There will be no weekly 
treatments for Group 4 in Part 2 by design.
Because this assessment does not account for when these weekly treatments are taken
relative to the target/scheduled day, additional summaries (including graphical presentations) 
will be made looking at when doses were taken over time and how dosing deviates from 
scheduled dosing days.  
9.12
Extent of Exposure
Note: As of Amendment 013-02, the summary associated with Part 1 is applicable and 
summaries associated with Parts 2 and 3 are no longer applicable for this section.
The extent of exposure to study therapy for all randomized and treated participants will be 
summarized. The number of participants exposed to various doses (actual total daily dose) 
for defined periods of time will be listed, along with a summary of the mean (range) duration 
participants were exposed to various doses.
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10
SUPPORTING DOCUMENTATION AND OPERATIONAL 
CONSIDERATIONS
10.1
Appendix 1: Regulatory, Ethical, and Study Oversight Considerations
10.1.1
Code of Conduct for Clinical Trials
Merck Sharp & Dohme LLC, Rahway, NJ, USA (MSD)
Code of Conduct for Interventional Clinical Trials
I. Introduction
A. Purpose
MSD, through its subsidiaries, conducts clinical trials worldwide to evaluate the safety and effectiveness of our 
products. As such, we are committed to designing, implementing, conducting, analyzing, and reporting these trials 
in compliance with the highest ethical and scientific standards. Protection of participants in clinical trials is the 
overriding concern in the design and conduct of clinical trials. In all cases, MSD clinical trials will be conducted 
in compliance with local and/or national regulations (including all applicable data protection laws and
regulations), and International Council for Harmonisation Good Clinical Practice (ICH-GCP), and also in 
accordance with the ethical principles that have their origin in the Declaration of Helsinki.
B. Scope
Highest ethical and scientific standards shall be endorsed for all clinical interventional investigations sponsored by 
MSD irrespective of the party (parties) employed for their execution (e.g., contract research organizations, 
collaborative research efforts). This Code is not intended to apply to trials that are observational in nature, or 
which are retrospective. Further, this Code does not apply to investigator-initiated trials, which are not under the 
full control of MSD.
II. Scientific Issues
A. Trial Conduct
1. Trial Design
Except for pilot or estimation trials, clinical trial protocols will be hypothesis-driven to assess safety, efficacy 
and/or pharmacokinetic or pharmacodynamic indices of MSD or comparator products. Alternatively, MSD 
may conduct outcomes research trials, trials to assess or validate various endpoint measures, or trials to 
determine patient preferences, etc.
The design (i.e., participant population, duration, statistical power) must be adequate to address the specific 
purpose of the trial and shall respect the data protection rights of all participants, trial site staff and, where 
applicable, third parties. Participants must meet protocol entry criteria to be enrolled in the trial. 
2. Site Selection
MSD selects investigative sites based on medical expertise, access to appropriate participants, adequacy of 
facilities and staff, previous performance in clinical trials, as well as budgetary considerations. Prior to trial 
initiation, sites are evaluated by MSD personnel (or individuals acting on behalf of MSD) to assess the ability 
to successfully conduct the trial.
3. Site Monitoring/Scientific Integrity
Investigative trial sites are monitored to assess compliance with the trial protocol and Good Clinical Practice 
(GCP). MSD reviews clinical data for accuracy, completeness, and consistency. Data are verified versus 
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source documentation according to standard operating procedures. Per MSD policies and procedures, if
potential fraud, scientific/research misconduct, privacy incidents/breaches or Clinical Trial-related
Significant Quality Issues are reported, such matters are investigated. When necessary, appropriate corrective 
and/or preventative actions are defined and regulatory authorities and/or ethics review committees are 
notified.
B. Publication and Authorship
Regardless of trial outcome, MSD commits to publish the primary and secondary results of its registered trials of 
marketed products in which treatment is assigned, according to the pre-specified plans for data analysis. To the 
extent scientifically appropriate, MSD seeks to publish the results of other analyses it conducts that are important 
to patients, physicians, and payers. Some early phase or pilot trials are intended to be hypothesis-generating rather 
than hypothesis testing; in such cases, publication of results may not be appropriate since the trial may be 
underpowered and the analyses complicated by statistical issues such as multiplicity.
MSD’s policy on authorship is consistent with the recommendations published by the International Committee of 
Medical Journal Editors (ICMJE). In summary, authorship should reflect significant contribution to the design and 
conduct of the trial, performance or interpretation of the analysis, and/or writing of the manuscript. All named 
authors must be able to defend the trial results and conclusions. MSD funding of a trial will be acknowledged in 
publications.
III. Participant Protection
A. Regulatory Authority and Ethics Committee Review (Institutional Review Board [IRB]/Independent Ethics 
Committee [IEC])
All protocols and protocol amendments will be submitted by MSD for regulatory authority 
acceptance/authorization prior to implementation of the trial or amendment, in compliance with local and/or 
national regulations.
The protocol, protocol amendment(s), informed consent form, investigator’s brochure, and other relevant trial 
documents must be reviewed and approved by an IRB/IEC before being implemented at each site, in compliance 
with local and/or national regulations. Changes to the protocol that are required urgently to eliminate an 
immediate hazard and to protect participant safety may be enacted in anticipation of ethics committee approval. 
MSD will inform regulatory authorities of such new measures to protect participant safety, in compliance with 
local and/or national regulations.
B. Safety
The guiding principle in decision-making in clinical trials is that participant welfare is of primary importance. 
Potential participants will be informed of the risks and benefits of, as well as alternatives to, trial participation. At 
a minimum, trial designs will take into account the local standard of care.
All participation in MSD clinical trials is voluntary. Participants enter the trial only after informed consent is 
obtained. Participants may withdraw from an MSD trial at any time, without any influence on their access to, or 
receipt of, medical care that may otherwise be available to them.
C. Confidentiality
MSD is committed to safeguarding participant confidentiality, to the greatest extent possible, as well as all 
applicable data protection rights. Unless required by law, only the investigator, Sponsor (or individuals acting on 
behalf of MSD), ethics committee, and/or regulatory authorities will have access to confidential medical records 
that might identify the participant by name.
D. Genomic Research
Genomic research will only be conducted in accordance with a protocol and informed consent authorized by an 
ethics committee.
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IV. Financial Considerations
A. Payments to Investigators
Clinical trials are time- and labor-intensive. It is MSD’s policy to compensate investigators (or the sponsoring 
institution) in a fair manner for the work performed in support of MSD trials. MSD does not pay incentives to 
enroll participants in its trials. However, when enrollment is particularly challenging, additional payments may be 
made to compensate for the time spent in extra recruiting efforts.
MSD does not pay for participant referrals. However, MSD may compensate referring physicians for time spent 
on chart review and medical evaluation to identify potentially eligible participants.
B. Clinical Research Funding
Informed consent forms will disclose that the trial is sponsored by MSD, and that the investigator or sponsoring 
institution is being paid or provided a grant for performing the trial. However, the local ethics committee may 
wish to alter the wording of the disclosure statement to be consistent with financial practices at that institution. As 
noted above, all publications resulting from MSD trials will indicate MSD as a source of funding.
C. Funding for Travel and Other Requests
Funding of travel by investigators and support staff (e.g., to scientific meetings, investigator meetings, etc.) will be 
consistent with local guidelines and practices.
V. Investigator Commitment
Investigators will be expected to review MSD’s Code of Conduct as an appendix to the trial protocol, and in signing the 
protocol, agree to support these ethical and scientific standards.
10.1.2
Financial Disclosure
Financial Disclosure requirements are outlined in the US Food and Drug Administration 
Regulations, Financial Disclosure by Clinical Investigators (21 CFR Part 54). It is the 
Sponsor's responsibility to determine, based on these regulations, whether a request for 
Financial Disclosure information is required. It is the investigator's/subinvestigator's 
responsibility to comply with any such request.
The investigator/subinvaestigator(s) agree, if requested by the Sponsor in accordance with 21 
CFR Part 54, to provide his/her financial interests in and/or arrangements with the Sponsor to 
allow for the submission of complete and accurate certification and disclosure statements. 
The investigator/subinvestigator(s) further agree to provide this information on a 
Certification/Disclosure Form, commonly known as a financial disclosure form, provided by 
the Sponsor. The investigator/subinvestigator(s) also consent to the transmission of this 
information to the Sponsor in the United States for these purposes. This may involve the 
transmission of information to countries that do not have laws protecting personal data.
10.1.3
Data Protection
The Sponsor will conduct this study in compliance with all applicable data protection 
regulations.
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Participants will be assigned a unique identifier by the Sponsor. Any participant records or 
datasets that are transferred to the Sponsor will contain the identifier only; participant names 
or any information that would make the participant identifiable will not be transferred.
The participant must be informed that his/her personal study-related data will be used by the 
Sponsor in accordance with local data protection law. The level of disclosure must also be 
explained to the participant. 
The participant must be informed that his/her medical records may be examined by Clinical 
Quality Assurance auditors or other authorized personnel appointed by the Sponsor, by 
appropriate IRB/IEC members, and by inspectors from regulatory authorities.
10.1.3.1
Confidentiality of Data
By signing this protocol, the investigator affirms to the Sponsor that information furnished to 
the investigator by the Sponsor will be maintained in confidence, and such information will 
be divulged to the IRB, IEC, or similar or expert committee; affiliated institution and 
employees, only under an appropriate understanding of confidentiality with such board or 
committee, affiliated institution and employees. Data generated by this study will be 
considered confidential by the investigator, except to the extent that it is included in a 
publication as provided in the Publications section of this protocol.
10.1.3.2
Confidentiality of Participant Records
By signing this protocol, the investigator agrees that the Sponsor (or Sponsor representative), 
IRB/IEC, or regulatory authority representatives may consult and/or copy study documents to 
verify worksheet/CRF data. By signing the consent form, the participant agrees to this 
process. If study documents will be photocopied during the process of verifying 
worksheet/CRF information, the participant will be identified by unique code only; full 
names/initials will be masked prior to transmission to the Sponsor.
By signing this protocol, the investigator agrees to treat all participant data used and 
disclosed in connection with this study in accordance with all applicable privacy laws, rules 
and regulations.
10.1.3.3
Confidentiality of IRB/IEC Information
The Sponsor is required to record the name and address of each IRB/IEC that reviews and 
approves this study. The Sponsor is also required to document that each IRB/IEC meets 
regulatory and ICH GCP requirements by requesting and maintaining records of the names 
and qualifications of the IRB/IEC members and to make these records available for 
regulatory agency review upon request by those agencies.
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10.1.4
Committees Structure
Note: As of Amendment 013-02, administration of study intervention for all treatment 
groups has been stopped based on Sponsor acceptance of the eDMC recommendation; 
therefore, there is no longer a need to convene these committees. 
10.1.4.1
Executive Oversight Committee
The EOC is comprised of members of Sponsor Senior Management. The EOC will receive 
and decide upon any recommendations made by the DMC regarding the study.
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
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.
10.1.5
Publication Policy
The results of this study may be published or presented at scientific meetings. The Sponsor 
will comply with the requirements for publication of study results. In accordance with 
standard editorial and ethical practice, the Sponsor will generally support publication of 
multicenter studies only in their entirety and not as individual site data. In this case, a 
coordinating investigator will be designated by mutual agreement.
If publication activity is not directed by the Sponsor, the investigator agrees to submit all 
manuscripts or abstracts to the Sponsor before submission. This allows the Sponsor to protect 
proprietary information and to provide comments.
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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 
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 
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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 signed ICF, pertaining to the conduct of this study must 
be retained by the investigator for 15 years after study completion unless local regulations or 
institutional policies require a longer retention period. No records may be destroyed during 
the retention period without the written approval of the Sponsor. No records may be 
transferred to another location or party without written notification to the Sponsor.
10.1.9
Source Documents
Source documents provide evidence for the existence of the participant and substantiate the 
integrity of the data collected. The investigator/institution should maintain adequate and 
accurate source documents and study records that include all pertinent observations on each 
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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 17 will be performed by the central laboratory.

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 into the CRF.

Protocol-specific requirements for inclusion or exclusion of participants are detailed in 
Section 5 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.

Pregnancy testing:
-
Pregnancy testing requirements for study inclusion are described in Section 5.1.
-
Additional serum or urine pregnancy tests may be performed, as determined 
necessary by the investigator or required by local regulation, to establish the 
absence of pregnancy at any time during the subject's participation in the study.
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Table 17
Protocol-required Safety Laboratory Assessments
Laboratory 
Assessments
Parameters
Hematology
Platelet Count 
RBC Indices:
MCV
MCH
MCH concentration
RDW
WBC count with Differential:
Neutrophils
Lymphocytes
Monocytes
Eosinophils
Basophils
RBC Count
Hemoglobin
Hematocrit
CD4+ T-cell 
Count/TBNK Panel
CD4/CD8 ratio
CD3+CD4+% and absolute
CD3+CD8+% and absolute
CD3+ CD4+ CD8+ % and absolute 
CD3- CD19+ % and absolute 
CD3+ CD45+ % and absolute 
CD16+ CD56+ % and absolute
Coagulation
PT/INR
Chemistry
BUN
Potassium
AST
Total bilirubin

Direct bilirubin

Indirect bilirubin
Albumin
Bicarbonate
Chloride
Phosphorous
Creatinine
Sodium
ALT
Total Protein
Glucose,
nonfasting
Calcium
Alkaline phosphatase
Creatinine Clearance
Creatine 
kinase
Lipase
Amylase
Magnesium
Additional chemistry 
at fasting visits 
(fasting for at least 8h)
Glucose (fasting)
HDL-C
LDL-C
TGs
TC
Non-HDL-C
Routine Urinalysis
•
Specific gravity
•
pH, glucose, protein, blood, ketones, bilirubin, urobilinogen, nitrite, 
leukocytes
Fluorosis monitoring
Plasma fluoride
Urine fluoride
PTH
Pregnancy testing
Serum and urine hCG pregnancy test (for WOCBP)
Hepatitis screening 
and monitoringa
HBsAg
Hepatitis B surface antibody 
Anti-HBc
HBV DNA 
Hepatitis C antibody (if positive perform plasma hepatitis C virus quantitative test) 
(at screening only)
HIV-1 serology
HIV 1/2 antibody test
Virology
HIV-1 viral RNA quantification (Real Time PCR)
Pharmacokinetics
Plasma ISL PK
Plasma MK-8507 PK
CCI
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Laboratory 
Assessments
Parameters
ALT=alanine aminotransferase; anti-HBc=Hepatitis B core antibody; AST=aspartate aminotransferase; BUN=blood 
urea nitrogen; DNA=deoxyribonucleic acid; HBV=Hepatitis B virus; HBsAg=Hepatitis B surface antigen; hCG=human 
chorionic gonadotropin; HDL-C=high-density lipoprotein cholesterol; HIV-1=human immunodeficiency virus, Type 1; 
INR=international normalized ratio; ISL=islatravir; LDL-C=low density lipoprotein cholesterol; MCH=mean 
corpuscular hemoglobin; MCV=mean corpuscular volume; non-HDL-C=non-high density lipoprotein cholesterol; 
PCR=polymerase chain reaction; PK=pharmacokinetics; PT=prothrombin time; PTH=parathyroid hormone; RBC=red 
blood cell; RDW=red cell distribution width; RNA=ribonucleic acid; TBNK=T- and B- Lymphocyte and Natural Killer 
Cell; TC=total cholesterol; TGs=triglycerides; WBC=white blood cell; WOCBP=a woman/women of childbearing 
potential.
a All participants will be screened for HBsAg, Hepatitis B surface antibody, anti-HBc, and HBV DNA. Participants that 
are anti-HBc positive but HBV DNA negative will have HBsAg and HBV DNA monitored for the duration of the study.
The investigator (or medically qualified designee) must document their review of each 
laboratory safety report.
Note: As of Amendment 013-02, Table 20 outlines the blood volume collection for the 
remainder of the study per the SoA in Section 1.3.3. Table 18 and Table 19 are no 
longer applicable.
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Table 18
Blood Volumes – Screening and Parts 1, 2, and 3
Study Period
Screening
Intervention
Scheduled Day/Week
Screening
Day 1
Week 2
Week 4
Week 8
Week 12
Week 16
Week 24
Week 36
Week 48
Week 60
Week 72
Week 84
Week 96
Week 100c
Week 108
Week 120
Week 132
Week 144
Blood Parameter
Approximate Blood Volume (mL)
Plasma HIV-1 RNA 
Quantification (Real 
Time PCR)
6
6
6
6
6
6
6
6
6
6
6
6
6
6
6
6
6
6
6
CD4+ T-cell 
Count/TBNK Panel
6
6
6
6
6
6
6
6
6
6
Plasma for HIV Viral 
Drug Resistance Testing 
12
12
12
12
12
12
12
12
12
12
12
12
12
12
12
12
12
12
HIV-1 & 2 and 
Hepatitisa Serology
6
HIV-1 confirmation 
(Geenius)
1
HBsAga,b
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
HBV DNAa
6
6
6
6
6
6
6
6
6
6
6
6
6
6
6
6
6
6
6
Chemistry (Includes 
Serum Pregnancy at 
Screening)
6
6
6
6
6
6
6
6
6
6
6
6
6
6
6
6
6
6
6
Hematology
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
Fasting Lipids
2
2
2
2
2
2
2
2
PT/INR
2.7
Plasma fluoride
4
4
4
4
4
4
4
4
4
4
4
4
4
4
4
Serum PTH
2
2
2
Blood (Plasma) for ISL 
and MK-8507 PK
4
8
4
4
8
8
4
4
4
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Study Period
Screening
Intervention
Scheduled Day/Week
Screening
Day 1
Week 2
Week 4
Week 8
Week 12
Week 16
Week 24
Week 36
Week 48
Week 60
Week 72
Week 84
Week 96
Week 100c
Week 108
Week 120
Week 132
Week 144
Blood Parameter
Approximate Blood Volume (mL)
Blood (Plasma) for 
Investigational PK 
4
4
4
4
4
4
Blood for Genetic 
Analysis
8.5
Whole Blood for FBR
8
8
8
8
8
Total Blood Volume 
per Visit (mL)
36
69
38
44
42
44
42
64
48
64
42
50
42
58
38
38
50
38
58
anti-HBc=Hepatitis B core antibody; CD4+=CD4-positive; DNA=deoxyribonucleic acid; FBR=future biomedical research; HBsAg=Hepatitis B surface antigen; 
HBV=Hepatitis B virus; HIV=human immunodeficiency virus; HIV-1=human immunodeficiency virus, Type 1; INR=international normalized ratio; ISL=islatravir; 
PCR=polymerase chain reaction; PK=pharmacokinetic(s); PT=prothrombin time; PTH; parathyroid hormone; RNA=ribonucleic acid; TBNK=T- and B- Lymphocyte and 
Natural Killer Cell. 
a. All participants will be screened for HBsAg, Hepatitis B surface antibody, anti-HBc, and HBV DNA. Participants that are anti-HBc positive, but HBV DNA negative, will 
have HBsAg and HBV DNA monitored for the duration of the study.
b. HBsAg is tested as part of the HIV-1 & 2 and Hepatitis Serology sample at Screening.
c. Week 100 is only for participants in Group 4.
Note: Approximately 1025 mL of blood will be collected during the study.
CCI
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Table 19
Blood Volumes – Unscheduled Visits
Study Period
Viremia 
Confirmation
Skeletal 
Fluorosis 
Evaluation
Early 
Discontinuation 
of Treatment
End of Treatment 
Follow-Up
Scheduled Day/Week
Unscheduled
Unscheduled
Unscheduled
Unscheduled
Blood Parameter
Approximate Blood Volume (mL)
Plasma HIV-1 RNA 
Quantification (Real 
Time PCR)
6
6
6
CD4+ T-cell 
Count/TBNK Panel
6
6
Plasma for HIV Viral 
Drug Resistance 
Testing 
12a
12a
12
Chemistry
(Includes Serum 
Pregnancy at Early 
Discontinuation of 
Treatment and End of 
Treatment Follow-up 
visits)
6
6
Hematology
2
2
Plasma fluoride
4
4
Blood (Plasma) for 
Investigational PK 
4
4
4
4
Whole Blood for FBR
8
8
Total Blood Volume 
per Visit (mL)
30
8
48
36
CD4+=CD4-positive; FBR=future biomedical research; HIV=human immunodeficiency virus; HIV-1=human 
immunodeficiency virus Type 1; PCR=polymerase chain reaction; PK=pharmacokinetics; RNA=ribonucleic acid; 
TBNK=T- and B- Lymphocyte and Natural Killer Cell.
a. If HIV drug resistance sample is collected at Viremia Confirmation visit, it is not necessary to collect another sample 
at Early Discontinuation of Treatment visit.
Note: Approximately 1025 mL of blood will be collected during the study.
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Note: As of Amendment 013-02, Table 20 outlines the blood volume collection for the remainder of the study per the SoA in 
Section 1.3.3. Table 18 and Table 19 are no longer applicable.
Table 20
Blood Volumes – Amendment 02
Study Period
Early Discontinuation 
of Treatment
Unblinded Safety Monitoring (Groups 1, 2, and 3 Only)
End of Treatment 
Telephone Contact 
(42 days after last dose)
Scheduled Day/Week
Week 20
Week 24
Week 28
Week 32
Week 36
Week 40
Week 44
Week 48
Week 52
Week 56
Week 60
Week 72
Week 84
Blood Parameter
Approximate Blood Volume (mL)
Plasma HIV-1 RNA Quantification
6
6
6
6
CD4+ T-cell Count/TBNK Panel
6
6
6
6
6
6
6
6
6
6
6
6
6
6
HBsAg
2
HBV DNA
6
Chemistry 
6
6
6
6
6
Hematology
2
2
2
2
2
2
2
2
2
2
2
2
2
2
Blood ISL & MK-8507 Plasma PK
4
4
4
4
4
4
4
4
4
4
4
4
0.12
Total Blood Volume per Visit (mL)
32.1
12
12
12
12
24
12
12
24
12
12
24
8
14
0
CD4+=CD4-positive; DNA=deoxyribonucleic acid; HBsAg=Hepatitis B surface antigen; HBV=Hepatitis B virus; HIV-1=human immunodeficiency virus, Type 1;
ISL=islatravir; PK=pharmacokinetic(s); RNA=ribonucleic acid; TBNK=T- and B- Lymphocyte and Natural Killer Cell. 
Note: For participants in Groups 1-3, approximately 222.1 mL of blood will be collected during the remainder of the study (Early Discontinuation of Treatment visit and 
Unblinded Safety Monitoring period). For participants in Group 4, approximately 32.1 mL of blood will be collected during the remainder of the study (Early Discontinuation 
of Treatment visit and End of Treatment Telephone Contact).
Note: As of Amendment 013-03, Table 21 outlines the blood volume collection for the Long-term Unblinded Safety Monitoring
of the study per the SoA in Section 1.3.4.
CCI
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Table 21
Blood Volumes – Amendment 03
Study Period
Long-term Unblinded Safety Monitoring:
(Groups 1, 2, and 3 Only) a
Scheduled Day/Week
Unscheduled
Blood Parameter
Approximate Blood Volume (mL)
CD4+ T-cell Count/TBNK Panel
6
Chemistry 
6
Hematology
2
Total Blood Volume per Visit (mL)
14
CD4+=CD4-positive; TBNK=T- and B- Lymphocyte and Natural Killer Cell. 
a.
Long-term Unblinded Safety Monitoring as outlined in Section 1.3.4 is required for participants in Groups 1-3 of whom total lymphocyte and CD4+ T-cell counts have not 
recovered within 10% of baseline during the initial 12-months of follow-up. Participants in Groups 1-3 will continue to be followed up every 12 weeks ±7 days until total 
lymphocyte and CD4+ T-cell criteria for recovery are met.
b.
Approximately 14 mL of blood will be collected at each visit every 12 weeks ±7 days during the long-term Unblinded Safety Monitoring period of the study until total 
lymphocyte and CD4+ T-cell criteria for recovery are met. The total volume of blood collected during the long-term safety monitoring period will vary depending on the 
number of visits required to meet the recovery criteria for total lymphocyte and CD4+ T-cell counts.
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10.3
Appendix 3: Adverse Events: Definitions and Procedures for Recording, 
Evaluating, Follow-up, and Reporting
10.3.1
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.

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.
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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.
10.3.2
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.
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, 
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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.
10.3.3
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
10.3.4
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 
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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. 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.
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 
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their respective elements (in number and/or intensity), the more likely the Sponsor’s 
product caused the AE:
-
Exposure: Is there evidence that the participant was actually exposed to the 
Sponsor’s product such as: reliable history, acceptable compliance assessment (pill 
count, diary, etc.), expected pharmacologic effect, or measurement of 
drug/metabolite in bodily specimen?
-
Time Course: Did the AE follow in a reasonable temporal sequence from 
administration of the Sponsor’s product? Is the time of onset of the AE compatible 
with a drug-induced effect (applies to studies with investigational medicinal 
product)?
-
Likely Cause: Is the AE not reasonably explained by another etiology such as 
underlying disease, other drug(s)/vaccine(s), or other host or environmental factors.
-
Dechallenge: Was the Sponsor’s product discontinued or dose/exposure/frequency 
reduced?
◦
If yes, did the AE resolve or improve?
◦
If yes, this is a positive dechallenge.
◦
If no, this is a negative dechallenge.
(Note: This criterion is not applicable if: (1) the AE resulted in death or permanent 
disability; (2) the AE resolved/improved despite continuation of the Sponsor’s 
product; (3) the study is a single-dose drug study; or (4) Sponsor’s product(s) is/are 
only used 1 time.)
-
Rechallenge: Was the participant re-exposed to the Sponsor’s product in this 
study?
◦
If yes, did the AE recur or worsen?
◦
If yes, this is a positive rechallenge.
◦
If no, this is a negative rechallenge.
(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 
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ADVANCE BY THE SPONSOR CLINICAL DIRECTOR, AND IF REQUIRED, THE 
IRB/IEC.

Consistency with study intervention profile: Is the clinical/pathological presentation of 
the AE consistent with previous knowledge regarding the Sponsor’s product or drug class 
pharmacology or toxicology?

The assessment of relationship will be reported on the case report forms/worksheets by 
an investigator who is a qualified physician according to his/her best clinical judgment, 
including consideration of the above elements.

Use the following scale of criteria as guidance (not all criteria must be present to be 
indicative of a Sponsor’s product relationship).
-
Yes, there is a reasonable possibility of Sponsor’s product relationship:
◦
There is evidence of exposure to the Sponsor’s product. The temporal sequence 
of the AE onset relative to the administration of the Sponsor’s product is 
reasonable. The AE is more likely explained by the Sponsor’s product than by 
another cause.
-
No, there is not a reasonable possibility of Sponsor’s product relationship:
◦
Participant did not receive the Sponsor’s product OR temporal sequence of the 
AE onset relative to administration of the Sponsor’s product is not reasonable 
OR the AE is more likely explained by another cause than the Sponsor’s 
product. (Also entered for a participant with overdose without an associated 
AE.)

For each AE/SAE, the investigator must document in the medical notes that he/she has 
reviewed the AE/SAE and has provided an assessment of causality.

There may be situations in which an SAE has occurred and the investigator has minimal 
information to include in the initial report to the Sponsor. However, it is very important 
that the investigator always make an assessment of causality for every event before the 
initial transmission of the SAE data to the Sponsor.

The investigator may change his/her opinion of causality in light of follow-up 
information and send an SAE follow-up report with the updated causality assessment.

The causality assessment is 1 of the criteria used when determining regulatory reporting 
requirements.
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Follow-up of AE and SAE

The investigator is obligated to perform or arrange for the conduct of supplemental 
measurements and/or evaluations as medically indicated or as requested by Sponsor to 
elucidate the nature and/or causality of the AE or SAE as fully as possible. This may 
include additional laboratory tests or investigations, histopathological examinations, or 
consultation with other health care professionals.

New or updated information will be recorded in the CRF.

The investigator will submit any updated SAE data to the Sponsor within 24 hours of 
receipt of the information.
10.3.5
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
Not applicable.
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10.5
Appendix 5: Contraceptive Guidance
10.5.1
Definitions
Women of Childbearing Potential (WOCBP)
A woman (including a transgender male who is assigned female sex at birth) is considered 
fertile following menarche and until becoming postmenopausal unless permanently sterile 
(see below):
If fertility is unclear (eg, amenorrhea in adolescents or athletes) and a menstrual cycle cannot 
be confirmed before first dose of study intervention, additional evaluation should be 
considered.
Women in the following categories are not considered WOCBP:

Transgender Women (assigned male sex at birth)

Premenarchal

Premenopausal female with 1 of the following:
-
Documented hysterectomy
-
Documented bilateral salpingectomy
-
Documented bilateral oophorectomy
For individuals with permanent infertility due to an alternate medical cause other than the 
above (eg, Mullerian agenesis, androgen insensitivity), investigator discretion should be 
applied to determining study entry.
Note: Documentation can come from the site personnel’s review of the participant’s 
medical records, medical examination, or medical history interview.

Postmenopausal female
-
A postmenopausal state is defined as no menses for 12 months without an 
alternative medical cause.
◦
A high FSH level in the postmenopausal range may be used to confirm a 
postmenopausal state in women not using hormonal contraception or HRT. 
However, in the absence of 12 months of amenorrhea, confirmation with two 
FSH measurements in the postmenopausal range is required.
-
Females on HRT and whose menopausal status is in doubt will be required to use 
one of the nonhormonal highly effective contraception methods if they wish to 
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continue their HRT during the study. Otherwise, they must discontinue HRT to 
allow confirmation of postmenopausal status before study enrollment.
Women of Nonchildbearing Potential (WONCBP)
Women in the following categories are considered WONCBP:

Premenopausal female with 1 of the following:
-
Documented hysterectomy
-
Documented bilateral salpingectomy
-
Documented bilateral oophorectomy
For individuals with permanent infertility due to an alternate medical cause other than the 
above (eg, Mullerian agenesis, androgen insensitivity), investigator discretion should be 
applied to determining study entry.
Note: Documentation can come from the site personnel’s review of the participant’s 
medical records, medical examination, or medical history interview.
•
Postmenopausal female
-
A postmenopausal state is defined as no menses for 12 months without an 
alternative medical cause. 
◦
A high FSH level in the postmenopausal range may be used to confirm a 
postmenopausal state in women not using hormonal contraception or HRT. 
However, in the absence of 12 months of amenorrhea, confirmation with two 
FSH measurements in the postmenopausal range is required. 
-
Females on HRT and whose menopausal status is in doubt must discontinue HRT to 
allow confirmation of postmenopausal status before study enrollment.
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10.5.2
Contraception Requirements
Contraceptives allowed during the study includea:
Highly Effective Contraceptive Methods That Have Low User Dependencyb
Failure rate of <1% per year when used consistently and correctly.
•
Progestogen-only subdermal contraceptive implantc
•
IUSd
•
Non-hormonal IUD
•
Bilateral tubal occlusion
•
Azoospermic partner (vasectomized or secondary to medical cause)
This is a highly effective contraception method provided that the partner is the sole male sexual partner of 
the WOCBP and the absence of sperm has been confirmed. If not, an additional highly effective method of 
contraception should be used. A spermatogenesis cycle is approximately 90 days.
Note: Documentation of azoospermia can come from the site personnel’s review of the participant’s 
medical records, medical examination, or medical history interview. 
Highly Effective Contraceptive Methods That Are User Dependentb
Failure rate of <1% per year when used consistently and correctly.
•
Combined (estrogen- and progestogen- containing) hormonal contraceptionc
- Oral
- Intravaginal
- Transdermal
- Injectable
•
Progestogen-only hormonal contraceptionc
- Oral
- Injectable
Sexual Abstinence
•
Sexual abstinence is considered a highly effective method only if defined as refraining from heterosexual 
intercourse during the entire period of risk associated with the study intervention. The reliability of sexual 
abstinence needs to be evaluated in relation to the duration of the study and the preferred and usual lifestyle 
of the participant.
a   Contraceptive use by men or women should be consistent with local regulations regarding the use of 
contraceptive methods for participants of clinical studies.
b   Typical use failure rates are higher than perfect-use failure rates (ie, when used consistently and correctly).
c   If locally required, in accordance with CTFG guidelines, acceptable contraceptive implants are limited to 
those which inhibit ovulation.
d   IUS is a progestin releasing IUD.
Note: The following are not acceptable methods of contraception:
-  Periodic abstinence (calendar, symptothermal, post-ovulation methods), withdrawal (coitus 
interruptus), spermicides only, and LAM.
-  Male condom with cap, diaphragm, or sponge with spermicide.
-  Male and female condom should not be used together (due to risk of failure with friction).
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10.6
Appendix 6: Collection and Management of Specimens for Future Biomedical 
Research
1.  Definitions
a.   Biomarker: A biological molecule found in blood, other body fluids, or tissues that is a 
sign of a normal or abnormal process or of a condition or disease. A biomarker may be 
used to see how well the body responds to a treatment for a disease or condition.1
b   Pharmacogenomics: The investigation of variations of DNA and RNA characteristics as 
related to drug/vaccine response.2
c.   Pharmacogenetics: A subset of pharmacogenomics, pharmacogenetics is the influence of 
variations in DNA sequence on drug/vaccine response.2
d.   DNA: Deoxyribonucleic acid.
e.   RNA: Ribonucleic acid.
2.  Scope of Future Biomedical Research
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 Research
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 Research
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 Usage
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 Research
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 Specimens
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 Security
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 Participants
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 Population
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 Research
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 Requirement for France
 

 
CCI
CCI
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10.8
Appendix 8: Calculation of Creatinine Clearance
Cockcroft-Gault equations:

If male:

If female:
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10.9
Appendix 9: Abbreviations
Abbreviation
Expanded Term
3TC
lamivudine
ADA
anti-drug antibodies
ADL
activities of daily living  
AE
adverse event 
AIDS
Acquired Immune Deficiency Syndrome
ANCOVA
analysis of covariance
APaT
All-Participants-as-Treated
AR
adverse reaction
ART
anti-retroviral therapy
ATP
adenosine triphosphate
AUC
area under the concentration-time curve 
hCG
human chorionic gonadotropin
BIC
bictegravir
BID
twice daily
BMI
body mass index
BP
blood pressure
C168
Concentration at 168 hours postdose
CAC
Clinical Adjudication Committee
CD4+
CD4-positive
CG
Cockcroft-Gault
CI
confidence interval
CNS
central nervous system
CONSORT
Consolidated Standards of Reporting Trials
CL
clearance
Cmax
maximum (peak) observed drug concentration
CrCl
creatinine clearance
CR
complete response
CRF
Case Report Form 
CRU
clinical research unit
CSR
Clinical Study Report
CT
computed tomography
CTCAE
Common Terminology Criteria for Adverse Events
CTCAE 5.0
Common Terminology Criteria for Adverse Events, Version 5.0
CTFG
Clinical Trial Facilitation Group 
DAIDS
Division of AIDS
DAO
data-as-observed
DDIs
drug-drug interactions
DEXA
Dual X-ray Absorptiometry
DILI
drug-induced liver injury
DMC
Data Monitoring Committee 
DNA
deoxyribonucleic acid 
DOR
doravirine
ECG
electrocardiogram 
ECI
event of clinical interest
eCRF
electronic Case Report Form
eCTA
exploratory Clinical Trial Application
ECOG
Eastern Cooperative Oncology Group
eDMC
external Data Monitoring Committee
EFV
efavirenz
eGFR
estimated glomerular filtration rate
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Abbreviation
Expanded Term
ELISA
enzyme-linked immunosorbent assay
EMA
European Medicines Agency
EOC
Executive Oversight Committee 
ePROs
electronic patient-reported outcomes
FDAAA
Food and Drug Administration Amendments Act
FAS
Full Analysis Set
FBR
future biomedical research
FSH
follicle stimulating hormone 
FTC
Emtricitabine
GCP
Good Clinical Practice 
GI
Gastrointestinal
HAT-QoL
HIV/AIDS-Targeted Quality of Life
HBsAg
Hepatitis B surface antigen
HBV
Hepatitis B virus
hCG
human chorionic gonadotropin
HCV
Hepatitis C virus
HIV
human immunodeficiency virus 
HIV-1
human immunodeficiency virus type 1
HIV-2
human immunodeficiency virus type 2
HIVTSQs
HIV Treatment Satisfaction Questionnaire, status version
HR
heart rate
HRQoL
health-related quality of life
HRT
hormone replacement therapy
IB
Investigator’s Brochure 
IC50
half-maximal inhibitory concentration 
ICF
Informed Consent Form
ICH
International Council on Harmonisation of Technical Requirements for 
Pharmaceuticals of Human Use
iCRO
imaging CRO
IEC
Independent Ethics Committee
IND
Investigational New Drug 
INR
international normalized ratio
InSTI
integrase strand transfer inhibitor
IQ
inhibitory quotient
IRB
Institutional Review Board
iRECIST
Response Evaluation Criteria in Solid Tumors 1.1 for immune-based therapeutics
IRT
interactive response technology
ISL
Islatravir (MK-8591)
ISL-TP
triphosphate form of islatravir
IUD
intrauterine device
IUS
intrauterine hormone-releasing system
IV
intravenous
IVRS
interactive voice response system
IWRS
integrated web response system
LLOQ
lower limit of quantification
LOCF
last observation carried forward
MDRD
Modification of Diet in Renal Disease
MedDRA
Medical Dictionary for Regulatory Activities
NCI
National Cancer Institute
NCS
not clinically significant
NDA
New Drug Application 
NK
Natural killer
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Abbreviation
Expanded Term
NNRTI
nonnucleoside reverse transcriptase inhibitor
NRTI
nucleoside analog reverse transcriptase inhibitor
NRTTI
nucleoside reverse transcriptase translocation inhibitor
OF
observed failure
PBMC
peripheral blood mononuclear cell
PD
pharmacodynamic
PI
protease inhibitor
PK
pharmacokinetic
PP
per-protocol
PR
partial response
PRO
patient-reported outcome
QD
Once daily
QW
Once weekly
QOL
quality of life
QP2
department of quantitative pharmacology and pharmacometrics
RNA
ribonucleic acid
SAC
Scientific Advisory Committee
SAE
serious adverse event 
SAP
Statistical Analysis Plan
SoA
schedule of activities
sSAP
supplemental Statistical Analysis Plan
SUSAR
suspected unexpected serious adverse reaction
TAF
tenofovir alafenamide
TBNK
T- and B- Lymphocyte and Natural Killer Cell
TDF
tenofovir disoproxil fumarate 
US
United States
VDM
viral dynamics model
WHO
World Health Organization
WOCBP
woman/women of childbearing potential 
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11
REFERENCES
[AIDS info 2017]
AIDS info. Guidelines for the use of antiretroviral 
agents in HIV-1-Infected adults and adolescents 
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