A Phase 3, Randomized, Active-Controlled, Double-Blind Clinical Study to Evaluate a Switch to Doravirine/Islatravir (DOR/ISL) Once-Daily in Participants With HIV-1 Virologically Suppressed on Bictegravir/Emtricitabine/Tenofovir Alafenamide (BIC/FTC/TAF)
Phase: PHASE3
Conditions: HIV Infection
Sponsor: Merck Sharp & Dohme LLC

Official Protocol Title: 
NCT number: 
NCT04223791 
Document Date: 
25-Mar-2024
A Phase 3, Randomized, Active-Controlled, Double-Blind Clinical 
Study to Evaluate a Switch to Doravirine/Islatravir (DOR/ISL) 
Once-Daily in Participants With HIV-1 Virologically Suppressed on 
Bictegravir/Emtricitabine/Tenofovir Alafenamide (BIC/FTC/TAF)

PRODUCT: MK-8591A  
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Title Page
THIS PROTOCOL AMENDMENT AND ALL OF THE INFORMATION RELATING 
TO IT ARE CONFIDENTIAL AND PROPRIETARY PROPERTY OF MERCK 
SHARP & DOHME LLC, RAHWAY, NJ, USA (MSD).
Protocol Title: A Phase 3, Randomized, Active-Controlled, Double-Blind Clinical Study to 
Evaluate a Switch to Doravirine/Islatravir (DOR/ISL) Once-Daily in Participants With HIV-
1 Virologically Suppressed on Bictegravir/Emtricitabine/Tenofovir Alafenamide 
(BIC/FTC/TAF)
Protocol Number: 018-09
Compound Number: MK-8591A
Sponsor Name:
Merck Sharp & Dohme LLC
(hereafter referred to as the Sponsor or MSD)
Legal Registered Address:
126 East Lincoln Avenue
P.O. Box 2000
Rahway, NJ 07065 USA
Regulatory Agency Identifying Number(s):
IND
134036
EudraCT
2019-000587-23
Approval Date: 25 March 2024
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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 09
25-MAR-2024
The protocol was amended to revise the post-treatment management of participants 
with specific decreases in CD4+ T-cell or total lymphocyte counts. The recovery 
criteria were revised to account for normal physiologic variability in CD4+ T-cell or 
total lymphocyte counts and the frequency of monitoring was updated to minimize 
the burden on study participants.
Amendment 08
12-OCT-2022
This protocol was amended to allow Group 1/Group 2 participants who continue to 
benefit (as determined by the investigator) from their assigned study intervention to 
continue their assigned study intervention through a study extension after Week 144. 
This extension will continue for up to 24 additional weeks (up to maximum Week 
168) or until participants have the option to enroll in a DOR/ISL 100-mg/0.25-mg 
study; whichever is sooner. Participants choosing not to enroll in a DOR/ISL 100 
mg/0.25 mg study, will transition to commercially available ART as soon as possible. 
Amendment 07
31-MAR-2022
Given the findings of decreases in CD4+ T-cell and total lymphocyte counts in 
clinical studies evaluating ISL, the protocol is being amended to include 2 optional 
substudies to be conducted at selected sites in the United States: (1) A plasma/PBMC 
PK substudy to measure ISL in plasma and ISL-TP in PBMCs to evaluate steady-
state levels in participants living with HIV, with long-term dosing of ISL; and (2) An 
investigational research substudy to collect PBMCs to assess lymphocyte 
immunophenotyping and the functionality of the lymphocyte subpopulations.
Amendment 06
20-JAN-2022
Given the findings of decreases in CD4+ T-cell and total lymphocyte counts in 
clinical studies evaluating ISL, the protocol is being amended to increase the 
frequency of monitoring of CD4+ T-cell and total lymphocyte counts and to specify 
the management of participants who meet protocol-defined decreases in CD4+ T-cell 
and/or total lymphocyte counts.
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Document
Date of Issue
Overall Rationale
Amendment 05
07-DEC-2021
To increase frequency of monitoring of CD4+ T-cell counts and lymphocyte counts, 
and to add discontinuation criteria in response to findings of decreases in CD4+ T-
cell counts (in studies of participants with HIV) and lymphocytes (in studies of 
participants with or without HIV) in ISL clinical studies.
Note: The changes made in Amendment 05 were not implemented at clinical sites. 
Amendment 06 supersedes Amendment 05.
Amendment 04
16-JUL-2021
As required by the Germany Health Authority (BfArM), the protocol is amended for 
Germany; if a participant becomes pregnant (has a positive serum pregnancy test), 
she must discontinue from study intervention. Additionally, Germany will not allow 
legally acceptable representatives to provide consent on behalf of the study 
participant.
Amendment 03
05-APR-2021
The protocol was amended to: (1) extend study intervention, open-label, from 
96 weeks to 144 weeks for all participants, (2) add option for Group 2 to receive 
open-label DOR/ISL from Week 144 to Week 156 (a 12-week safety monitoring 
period before being offered enrollment in DOR/ISL rollover study), (3) offer the 
option to continue study intervention for participants who become pregnant, (4) add a 
discontinuation criterion if a participant chooses to breastfeed.
Amendment 02
07-MAY-2020
The protocol was amended to: (1) update the hypothesis testing strategy in the 
statistical analysis plan, (2) update the prohibited concomitant therapies, and 
(3) allow participants to rescreen one time following approval from the Sponsor.
Amendment 01
15-JAN-2020
At the request of Health Canada, the protocol is amended for Canada to indicate that 
participants who become HBsAg or HBV DNA positive after randomization must be 
discontinued from study intervention.
Original Protocol
24-OCT-2019
Not applicable
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PROTOCOL AMENDMENT SUMMARY OF CHANGES
Amendment: 09
Overall Rationale for the Amendment:
The protocol was amended to revise the post-treatment management of participants with specific decreases in CD4+ T-cell or total 
lymphocyte counts. The recovery criteria were revised to account for normal physiologic variability in CD4+ T-cell or total 
lymphocyte counts and the frequency of monitoring was updated to minimize the burden on study participants.
Summary of Changes Table
Section Number and Name
Description of Change
Brief Rationale
Primary Reason for Amendment
Section 8.11.5.2, Participants Discontinued from 
Study Intervention Due to Decreased CD4+ T-cell 
Count and/or Total Lymphocyte Count
Revised the post-treatment management of participants 
by reducing post-treatment lymphocyte monitoring 
frequency (from monthly to approximately every 10 to 
14 weeks) and by updating the criteria to stop 
monitoring for Group 1 participants who discontinued 
DOR/ISL.
This amendment provides an update to 
the strategy for post treatment 
monitoring. CD4+ T-cell and total 
lymphocyte counts exhibit significant 
normal physiologic variability 
independent of ISL, such that the 
original criteria to stop monitoring are 
challenging to satisfy even long after 
DOR/ISL is stopped. Given this 
information, the frequency of 
monitoring may be decreased to 
minimize participant burden and it is no 
longer required to continue monitoring 
until CD4+ T-cell and total lymphocyte 
values are within 10% of baseline.
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Section Number and Name
Description of Change
Brief Rationale
Additional Changes
Section 1.3.5, Schedule of Activities for 
Participants With Specified Decreases in CD4+ T-
cell Counts and/or Total Lymphocyte Counts
Reduced the post-treatment lymphocyte monitoring 
frequency from monthly to approximately every 10 to
14 weeks.
Refer to Section 8.11.5.2 rationale. 
Section 8.11.3.2, End of Treatment Follow-up
Visit
Removed the requirement for monthly monitoring.
Refer to Section 8.11.5.2 rationale.
Section 8.11.5.3, Participants Discontinued from 
Study Intervention for Other Reasons And Have 
Decreases in CD4+ T-cell and/or Total 
Lymphocyte Counts
Removed monitoring details to refer to Section 8.11.5.2
Refer to Section 8.11.5.2 rationale.
Section 10.10, Appendix 10.10: Summary of 
Protocol Clarification Letters
Added Appendix 10.
To incorporate a summary of protocol 
clarification letters that were implemented 
at sites. No text was incorporated into this 
protocol amendment because it is not 
relevant to study conduct at this time.
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Table of Contents
DOCUMENT HISTORY ........................................................................................................3
PROTOCOL AMENDMENT SUMMARY OF CHANGES...............................................5
1
PROTOCOL SUMMARY ............................................................................................16
1.1
Synopsis.................................................................................................................16
1.2
Schema ..................................................................................................................21
1.3
Schedule of Activities (SoA)................................................................................22
1.3.1
Schedule of Activities – Screening Through Week 96 – Blinded 
Intervention..................................................................................................22
1.3.2
Schedule of Activities – Week 108 Through Week 168 – Open-label 
Intervention, Including Study Extension .....................................................27
1.3.3
Schedule of Activities – Viremia Confirmation and End of Treatment 
(All Participants Except Those With Specified Decreases in CD4+ T-
cell/Total Lymphocyte Counts) ...................................................................34
1.3.4
Schedule of Activities for Participants Whose Pregnancy or Postpartum 
Visit(s) Extends Beyond Week 168.............................................................39
1.3.5
Schedule of Activities for Participants With Specified Decreases in 
CD4+ T-cell Counts and/or Total Lymphocyte Counts...............................42
2
INTRODUCTION..........................................................................................................46
2.1
Study Rationale....................................................................................................46
2.2
Background ..........................................................................................................46
2.2.1
Islatravir.......................................................................................................46
2.2.2
Doravirine ....................................................................................................47
2.2.3
Doravirine/Islatravir.....................................................................................47
2.2.4
Information on Other Study-related Therapy ..............................................48
2.3
Benefit/Risk Assessment......................................................................................48
3
HYPOTHESES, OBJECTIVES, AND ENDPOINTS................................................50
4
STUDY DESIGN............................................................................................................54
4.1
Overall Design......................................................................................................54
4.2
Scientific Rationale for Study Design.................................................................55
4.2.1
Rationale for Endpoints ...............................................................................55
4.2.1.1
Efficacy Endpoints.............................................................................55
4.2.1.1.1
HIV-1 RNA Measurements .....................................................55
4.2.1.1.2
Definition of Clinically Significant Confirmed Viremia.........56
4.2.1.2
Safety Endpoints................................................................................56
4.2.1.3
Weight, Laboratory, and Radiological Markers ................................56
4.2.1.4
Pharmacokinetic Endpoints ...............................................................57
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4.2.1.5
Patient-reported Outcomes.................................................................57
4.2.1.6
Planned Exploratory Biomarker Research.........................................58
4.2.1.6.1
Planned Genetic Analysis ........................................................58
4.2.1.7
Future Biomedical Research..............................................................58
4.2.2
Rationale for the Use of Comparator/Placebo .............................................59
4.2.3
Rationale for the Selected Participant Population .......................................59
4.2.4
Rationale for Collecting Race and Ethnicity Data.......................................60
4.2.5
Rationale for Collecting Gender Identity Data ............................................60
4.2.6
Rationale for Infant Safety Data Collection.................................................60
4.2.7
Rationale for Continuing Study Intervention During Pregnancy ................61
4.3
Justification for Dose...........................................................................................61
4.4
Beginning and End of Study Definition .............................................................62
4.4.1
Clinical Criteria for Early Study Termination .............................................62
5
STUDY POPULATION ................................................................................................62
5.1
Inclusion Criteria.................................................................................................62
5.2
Exclusion Criteria................................................................................................64
5.3
Lifestyle Considerations......................................................................................66
5.4
Screen Failures.....................................................................................................66
5.5
Participant Replacement Strategy......................................................................66
6
STUDY INTERVENTION............................................................................................66
6.1
Study Intervention(s) Administered...................................................................66
6.2
Preparation/Handling/Storage/Accountability .................................................68
6.2.1
Dose Preparation..........................................................................................68
6.2.2
Handling, Storage, and Accountability........................................................68
6.3
Measures to Minimize Bias: Randomization and Blinding..............................69
6.3.1
Intervention Assignment..............................................................................69
6.3.2
Stratification.................................................................................................69
6.3.3
Blinding........................................................................................................69
6.4
Study Intervention Compliance..........................................................................69
6.5
Concomitant Therapy..........................................................................................70
6.5.1
Rescue Medications and Supportive Care ...................................................71
6.6
Dose Modification (Escalation/Titration/Other)...............................................71
6.7
Intervention After the End of the Study............................................................72
6.8
Clinical Supplies Disclosure................................................................................72
6.9
Standard Policies..................................................................................................72
7
DISCONTINUATION OF STUDY INTERVENTION AND PARTICIPANT 
WITHDRAWAL............................................................................................................73
7.1
Discontinuation of Study Intervention...............................................................73
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7.2
Participant Withdrawal From the Study...........................................................74
7.3
Lost to Follow-up .................................................................................................75
8
STUDY ASSESSMENTS AND PROCEDURES........................................................75
8.1
Administrative and General Procedures ...........................................................76
8.1.1
Informed Consent.........................................................................................76
8.1.1.1
General Informed Consent.................................................................76
8.1.1.2
Consent and Collection of Specimens for Future Biomedical 
Research.............................................................................................76
8.1.1.3
Consent for Postnatal Infant Safety Data Collection Through One 
Year of Age........................................................................................77
8.1.1.4
Consent for Continuation of Study Intervention During 
Pregnancy...........................................................................................77
8.1.1.5
Consent to Participate in the Optional Plasma/PBMC PK 
Substudy (Applicable Only to the United States)..............................77
8.1.1.6
Consent to Participate in the Optional Investigational Research 
Substudy (Applicable Only to the United States)..............................77
8.1.1.7
Consent to Participate in the Study Extension...................................77
8.1.2
Inclusion/Exclusion Criteria ........................................................................77
8.1.3
Participant Identification Card.....................................................................77
8.1.4
Medical History ...........................................................................................78
8.1.5
Prior and Concomitant Medications Review...............................................78
8.1.5.1
Prior Medications...............................................................................78
8.1.5.2
Concomitant Medications..................................................................78
8.1.6
Assignment of Screening Number...............................................................78
8.1.7
Assignment of Treatment/Randomization Number.....................................78
8.1.8
Study Intervention Administration ..............................................................79
8.1.8.1
Timing of Dose Administration.........................................................79
8.1.9
Discontinuation and Withdrawal .................................................................79
8.1.9.1
Withdrawal From Future Biomedical Research ................................80
8.1.10
Participant Blinding/Unblinding..................................................................80
8.1.11
Calibration of Equipment.............................................................................81
8.1.12
Administration of Patient Questionnaires....................................................81
8.2
Efficacy Assessments ...........................................................................................81
8.2.1
HIV-1 RNA..................................................................................................81
8.2.2
Management of Study Participants With Viremia.......................................81
8.2.2.1
Viremia Confirmation........................................................................82
8.2.2.2
Participants With Clinically Significant Viremia 
(≥200 copies/mL)...............................................................................82
8.2.2.3
Participants With Low-level Viremia (≥50 and <200 copies/mL) ....82
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8.2.2.4
Viral Drug Resistance Testing...........................................................82
8.2.3
T- and B- Lymphocyte and Natural Killer Cell Profile (TBNK).................83
8.3
Safety Assessments...............................................................................................83
8.3.1
Physical Examinations.................................................................................83
8.3.1.1
Weight................................................................................................83
8.3.2
Vital Signs....................................................................................................84
8.3.3
Electrocardiograms ......................................................................................84
8.3.4
Confirmation of Contraception and Pregnancy Testing ..............................84
8.3.5
Clinical Safety Laboratory Assessments .....................................................84
8.3.6
HBV Assessments........................................................................................85
8.3.7
Tobacco and Alcohol Assessments..............................................................85
8.4
Adverse Events (AEs), Serious Adverse Events (SAEs), and Other 
Reportable Safety Events ....................................................................................86
8.4.1
Time Period and Frequency for Collecting AE, SAE, and Other 
Reportable Safety Event Information ..........................................................86
8.4.2
Method of Detecting AEs, SAEs, and Other Reportable Safety Events......87
8.4.3
Follow-up of AE, SAE, and Other Reportable Safety Event Information...88
8.4.4
Regulatory Reporting Requirements for SAE .............................................88
8.4.5
Pregnancy and Exposure During Breastfeeding ..........................................88
8.4.6
Disease-related Events and/or Disease-related Outcomes Not Qualifying 
as AEs or SAEs............................................................................................89
8.4.7
Events of Clinical Interest (ECIs)................................................................89
8.5
Treatment of Overdose........................................................................................89
8.6
Pharmacokinetics.................................................................................................90
8.6.1
Blood Collection for Plasma ISL.................................................................90
8.7
Pharmacodynamics..............................................................................................90
8.8
Biomarkers ...........................................................................................................91
8.8.1
Planned Genetic Analysis Sample Collection..............................................91
8.8.2
Inflammation................................................................................................91
8.8.3
Renal Function.............................................................................................91
8.8.4
Fasting Lipid and Metabolic Profiles...........................................................91
8.8.5
Waist and Hip Measurements......................................................................92
8.8.6
DEXA Assessments.....................................................................................92
8.9
Future Biomedical Research Sample Collection...............................................92
8.10
Health Economics Medical Resource Utilization and Health Economics.......93
8.11
Visit Requirements...............................................................................................93
8.11.1
Screening/Rescreening.................................................................................93
8.11.2
Treatment Period..........................................................................................94
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8.11.2.1
Fasting................................................................................................94
8.11.2.2
Optional Nurse Visits and Telephone Visits......................................94
8.11.2.3
Week 144 Visit ..................................................................................94
8.11.3
Participants Who Discontinue Study Intervention.......................................95
8.11.3.1
Early Discontinuation of Treatment...................................................95
8.11.3.2
End of Treatment Follow-up Visit.....................................................95
8.11.4
Viremia Confirmation..................................................................................95
8.11.5
Management of Participants with Decreases in CD4+ T-cell Counts 
and/or Total Lymphocyte Counts ................................................................96
8.11.5.1
Participants Whose CD4+ T-cell Count and/or Total Lymphocyte 
Count Decreases Meet Criteria for Events of Clinical Interest 
While on Study Intervention..............................................................96
8.11.5.2
Participants Discontinued from Study Intervention Due to 
Decreased CD4+ T-cell Count and/or Total Lymphocyte Count......96
8.11.5.3
Participants Discontinued from Study Intervention for Other 
Reasons And Have Decreases in CD4+ T-cell and/or Total 
Lymphocyte Counts...........................................................................97
8.11.6
Clinical Management of Participants Who Become Pregnant.....................97
8.11.6.1
Continuing Study Intervention...........................................................98
8.11.6.2
Discontinuing Study Intervention for Pregnancy ..............................99
8.11.6.3
Participants Who Choose to Breastfeed...........................................100
8.11.6.4
Infant Safety Data Collection...........................................................100
8.11.6.4.1
Schedule of Activities: Infant Safety Data Collection...........100
9
STATISTICAL ANALYSIS PLAN ...........................................................................101
9.1
Statistical Analysis Plan Summary...................................................................101
9.2
Responsibility for Analyses/In-house Blinding ...............................................104
9.3
Hypotheses/Estimation ......................................................................................104
9.4
Analysis Endpoints.............................................................................................104
9.4.1
Efficacy/Pharmacokinetics Endpoints .......................................................105
9.4.1.1
Efficacy Endpoints...........................................................................105
9.4.1.2
Pharmacokinetic Endpoint...............................................................106
9.4.2
Safety Endpoints........................................................................................106
9.4.3
Patient-reported Outcome Endpoints.........................................................107
9.5
Analysis Populations..........................................................................................107
9.5.1
Efficacy Analysis Populations...................................................................107
9.5.1.1
Full Analysis Set..............................................................................107
9.5.1.2
Per-Protocol Analysis Set ................................................................107
9.5.1.3
Resistance Analysis Subset..............................................................108
9.5.2
Safety Analysis Population........................................................................108
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9.6
Statistical Methods.............................................................................................108
9.6.1
Statistical Methods for Efficacy Analyses.................................................108
9.6.2
Statistical Methods for Safety Analyses ....................................................115
9.6.3
Summaries of Baseline Characteristics, Demographic, and Other 
Analyses.....................................................................................................117
9.6.3.1
Demographic and Baseline Characteristics .....................................117
9.7
Interim Analyses ................................................................................................117
9.8
Multiplicity .........................................................................................................119
9.9
Sample Size and Power Calculations ...............................................................120
9.9.1
Sample Size and Power for Efficacy Analyses..........................................120
9.9.1.1
Futility Criteria.................................................................................120
9.9.1.2
Evaluation of Non-inferiority and Superiority Hypotheses.............121
9.9.2
Sample Size and Power for Safety Analyses .............................................123
9.9.2.1
Evaluation of Adverse Events..........................................................123
9.9.2.2
Evaluation of Change in Weight......................................................125
9.10
Subgroup Analyses.............................................................................................127
9.11
Compliance (Medication Adherence)...............................................................127
9.12
Extent of Exposure.............................................................................................128
10
SUPPORTING DOCUMENTATION AND OPERATIONAL 
CONSIDERATIONS...................................................................................................129
10.1
Appendix 1: Regulatory, Ethical, and Study Oversight Considerations......129
10.1.1
Code of Conduct for Clinical Trials...........................................................129
10.1.2
Financial Disclosure...................................................................................131
10.1.3
Data Protection...........................................................................................131
10.1.3.1
Confidentiality of Data ....................................................................132
10.1.3.2
Confidentiality of Participant Records.............................................132
10.1.3.3
Confidentiality of IRB/IEC Information..........................................132
10.1.4
Committees Structure.................................................................................132
10.1.4.1
Executive Oversight Committee......................................................132
10.1.4.2
External Data Monitoring Committee .............................................133
10.1.4.3
Scientific Advisory Committee (SAC)............................................133
10.1.5
Publication Policy......................................................................................133
10.1.6
Compliance with Study Registration and Results Posting Requirements .133
10.1.7
Compliance with Law, Audit, and Debarment ..........................................134
10.1.8
Data Quality Assurance .............................................................................134
10.1.9
Source Documents .....................................................................................135
10.1.10
Study and Site Closure...............................................................................136
10.2
Appendix 2: Clinical Laboratory Tests............................................................137
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10.3
Appendix 3: Adverse Events: Definitions and Procedures for Recording, 
Evaluating, Follow-up, and Reporting.............................................................144
10.3.1
Definitions of Medication Error, Misuse, and Abuse................................144
10.3.2
Definition of AE ........................................................................................144
10.3.3
Definition of SAE ......................................................................................145
10.3.4
Additional Events Reported.......................................................................146
10.3.5
Recording AE and SAE .............................................................................147
10.3.6
Reporting of AEs, SAEs, and Other Reportable Safety Events to the 
Sponsor ......................................................................................................150
10.4
Appendix 4: Device Events, Adverse Device Events, and Medical Device 
Incidents: Definitions, Collection, and Documentation..................................152
10.5
Appendix 5: Contraceptive Guidance..............................................................153
10.5.1
Definitions..................................................................................................153
10.5.2
Contraception Requirements......................................................................155
10.6
Appendix 6: Collection and Management of Specimens for Future 
Biomedical Research..........................................................................................156
10.7
Appendix 7: Country-specific Requirements..................................................161
10.7.1
Country-specific Request for Germany .....................................................161
10.7.2
Country-specific Request for Canada ........................................................161
10.7.3
Country-specific Request for Japan...........................................................162
10.7.4
Country-specific Request for the United States.........................................162
10.7.4.1
Plasma/PBMC PK Substudy............................................................162
10.7.4.1.1
Consent to Participate in the Optional Plasma/PBMC PK 
Substudy.................................................................................162
10.7.4.1.2
Plasma/PBMC PK Substudy Procedures...............................163
10.7.4.2
Investigational Research Substudy ..................................................163
10.7.4.2.1
Consent to Participate in the Optional Investigational 
Research Substudy.................................................................164
10.7.4.2.2
Investigational Research Substudy Procedures .....................164
10.8
Appendix 8: Calculation of Creatinine Clearance..........................................166
10.9
Appendix 9: Abbreviations ...............................................................................167
10.10 Appendix 10: Summary of Protocol Clarification Letters.............................170
11
REFERENCES.............................................................................................................171
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LIST OF TABLES
Table 1
Laboratory Exclusion Criteria........................................................................65
Table 2
Study Interventions.........................................................................................67
Table 3
Prohibited Therapies.......................................................................................71
Table 4
Reporting Time Periods and Time Frames for Adverse Events and Other 
Reportable Safety Events ...............................................................................87
Table 5
Collection of Population PK Samples............................................................90
Table 6
Collection of Population PK Samples During Pregnancy and Postpartum....99
Table 7
Definitions of Study Time Points.................................................................109
Table 8
Analysis Strategy for Key Efficacy Variables .............................................114
Table 9
Analysis Strategy for Safety Parameters......................................................117
Table 10
Probability of Passing the Interim Analysis and the Overall Study Power 
for Various Underlying True Response Rates Assuming Futility Assessed 
at 40% Enrollment........................................................................................121
Table 11
Power (%) to Establish Non-Inferiority at Week 48/96 Under Various 
Response Rate Assumptions (289 Participants per Group)..........................122
Table 12
Power (%) to Establish Superiority at Week 48/96 Under Various 
Response Rate Assumptions (Assuming All Prior Hypothesis Tests 
Reach Statistical Significance) (289 Participants per Group)......................123
Table 13
Estimate of Incidence of AEs and 95% Upper Confidence Bound Based 
on Hypothetical Numbers of Participants with AEs (289 Participants per 
Group) ..........................................................................................................124
Table 14
Difference in Incidence of AEs (Group 1 minus Group 2) That Can Be 
Ruled Out With 289 Participants in Each Group. ........................................124
Table 15
Hypothetical Minimal Treatment Differences in the Change From 
Baseline in Body Weight That Can Be Detected With Given Power at 
Weeks 48 and 96 ..........................................................................................125
Table 16
Protocol-required Laboratory Assessments..................................................137
Table 17
Blood Volumes.............................................................................................140
Table 18
Blood Volumes: Participants Whose Pregnancy or Postpartum Visit(s) 
Extends Beyond Week 168 ..........................................................................143
Table 19
Schedule of Activities for Participants in the Plasma/PBMC PK Substudy163
Table 20
Blood Volumes: Plasma/PBMC PK Substudy.............................................163
Table 21
Schedule of Activities for Participants in the Investigational Research 
Substudy.......................................................................................................164
Table 22
Blood Volumes: Investigational Research Substudy ...................................165
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LIST OF FIGURES
Figure 1
Study Schema and Treatment Plan.................................................................21
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1
PROTOCOL SUMMARY
1.1
Synopsis
Protocol Title: A Phase 3, Randomized, Active-Controlled, Double-Blind Clinical Study to 
Evaluate a Switch to Doravirine/Islatravir (DOR/ISL) Once-Daily in Participants With HIV-
1 Virologically Suppressed on Bictegravir/Emtricitabine/Tenofovir Alafenamide 
(BIC/FTC/TAF)
Short Title: DOR/ISL Blinded Label Switch
Acronym: Not applicable
MK-8591A (hereafter referred to as DOR/ISL) is a novel 2-drug FDC of DOR and ISL.
Hypotheses, Objectives, and Endpoints:
Hypotheses are aligned with objectives in the Objectives and Endpoints table.
The following objectives will be evaluated in participants ≥18 years of age with HIV-1 who 
have been virologically suppressed for ≥3 months on BIC/FTC/TAF.
Primary Objectives
Primary Endpoints
- To evaluate the antiretroviral activity 
following switch to DOR/ISL compared to 
continued treatment with BIC/FTC/TAF 
as assessed by the percentage of 
participants with HIV-1 RNA 
≥50 copies/mL at Week 48.
- Hypothesis (H1): DOR/ISL is non-inferior 
to BIC/FTC/TAF as measured by the 
percentage of participants with HIV-1 
RNA ≥50 copies/mL at Week 48. A 
margin of 4 percentage points is used to 
define non-inferiority.
- If non-inferiority of HIV-1 RNA ≥50 
copies/mL at Week 48 and superiority of 
HIV-1 RNA ≥50 copies/mL at Week 96 
are met:
- Hypothesis (H2): DOR/ISL is superior to 
BIC/FTC/TAF as measured by the 
percentage of participants with HIV-1 
RNA ≥50 copies/mL at Week 48.
- HIV-1 RNA
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- To evaluate the safety and tolerability of 
switch to DOR/ISL compared to 
continued treatment with BIC/FTC/TAF 
as assessed by review of the accumulated 
safety data through Week 48.
- Adverse events
- Adverse events leading to discontinuation 
of study intervention
Secondary Objectives
Secondary Endpoints
- To evaluate the antiretroviral activity 
following switch to DOR/ISL compared to 
continued treatment with BIC/FTC/TAF 
as assessed by the percentage of 
participants with HIV-1 RNA 
≥50 copies/mL at Week 96 and Week 144.
- Hypothesis (H3): DOR/ISL is non-inferior 
to BIC/FTC/TAF as measured by the 
percentage of participants with HIV-1 
RNA ≥50 copies/mL at Week 96. A 
margin of 4 percentage points is used to 
define non-inferiority.
- If non-inferiority of HIV-1 RNA ≥50 
copies/mL at Week 48 is met:
- Hypothesis (H4): DOR/ISL is superior to 
BIC/FTC/TAF as measured by the 
percentage of participants with HIV-1 
RNA ≥50 copies/mL at Week 96.
- HIV-1 RNA
- To evaluate the antiretroviral activity 
following switch to DOR/ISL compared to 
continued treatment with BIC/FTC/TAF 
as assessed by the percentage of 
participants with the following at Week 
48, Week 96 and Week 144:
- HIV-1 RNA <40 copies/mL
- HIV-1 RNA <50 copies/mL
- HIV-1 RNA
- To evaluate the immunologic effect of 
switch to DOR/ISL compared to 
continued treatment with BIC/FTC/TAF 
as measured by change from baseline in 
CD4+ T-cell count at Week 48, Week 96, 
and Week 144.
- CD4+ T-cell count
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- To evaluate the development of viral drug 
resistance to any study intervention in 
participants who switch to DOR/ISL and 
participants who continue treatment with 
BIC/FTC/TAF.
- Viral resistance-associated substitutions
- To evaluate the effect of switch to 
DOR/ISL compared to continued 
treatment with BIC/FTC/TAF on weight, 
as measured by the mean change from 
baseline to Week 48, Week 96, and Week 
144.
- Hypothesis (H5): DOR/ISL is superior to 
BIC/FTC/TAF as measured by lower 
mean increase from baseline in body 
weight at Week 48.
- Hypothesis (H6): DOR/ISL is superior to 
BIC/FTC/TAF as measured by lower 
mean increase from baseline in body 
weight at Week 96.
- Weight
- To evaluate the safety and tolerability of 
DOR/ISL compared to BIC/FTC/TAF as 
assessed by review of the accumulated 
safety data through study duration.
- Adverse events
- Adverse events leading to discontinuation 
of study intervention
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Overall Design:
Study Phase
Phase 3
Primary Purpose
Treatment
Indication
HIV infection
Population
Participants ≥18 years of age with HIV-1 who have been 
virologically suppressed for ≥3 months on BIC/FTC/TAF
Study Type
Interventional
Intervention Model
Parallel
This is a multi-site study.
Type of Control
Active control
Study Blinding
Double-blind
Masking
Participant or Subject
Sponsor
Investigator
Estimated Duration of Study
The Sponsor estimates that the study will require 
approximately 4 years from the time the first participant 
(or their legally acceptable representative) provides 
documented informed consent until the last participant’s 
last study-related contact.
Number of Participants:
Approximately 578 participants will be randomized.
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Intervention Groups and Duration:
Intervention 
Groups
Interven-
tion 
Group 
Name
Drug
Dose Strength
Dose 
Frequency
Route of 
Adminis-
tration
Treat-
ment 
Period
Use
Group 1
DOR/ISL
100 mg/0.75 mg
qd
Oral
Day 1 
to 
Week 
168a
Test 
product
Placebo to 
BIC/FTC/
TAF
0 mg
qd
Oral
Day 1 
to 
Week 
96
Placebo
Group 2
BIC/FTC/TAF
50 mg/200 mg/
25 mg
qd
Oral
Day 1 
to 
Week 
168a
Comparator
Placebo to 
DOR/ISL
0 mg
qd
Oral
Day 1 
to 
Week 
96
Placebo
BIC=bictegravir; DOR=doravirine; FTC=emtricitabine; ISL=islatravir; qd=once-daily; 
TAF=tenofovir alafenamide.
a Participants who consent to the study extension beginning after Week 144 may continue their 
assigned study intervention up to Week 168 if needed.
Total 
Number
2
Duration of 
Participation
Each participant will participate in the study for approximately 3.5 years
from the time the participant provides documented informed consent 
through the final contact. After a screening phase of up to 45 days, each 
participant will receive blinded intervention for 96 weeks and open-label 
intervention through Week 144. Participants may then participate in an 
open-label 24-week extension (up to Week 168). Participants who 
discontinue study intervention or who become pregnant will be followed as 
described in the protocol.
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Study Governance 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.
1.2
Schema
The study design is depicted in Figure 1.
Figure 1
Study Schema and Treatment Plan
BIC=bictegravir; DOR=doravirine; FTC=emtricitabine; ISL=islatravir; N=total number of participants in the 
study; n=number of participants per group; TAF=tenofovir alafenamide.
a
Participants are expected to enroll as soon as possible after eligibility is confirmed. In cases of unexpected 
delays in receiving repeat screening laboratory results, a screening period of up to 45 days is allowed.
b
At the end of Week 144, eligible participants will be offered the option to continue their assigned study 
intervention for up to 24 additional weeks (up to Week 168) during the open-label study extension (Section
8.11.2.3).
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1.3
Schedule of Activities (SoA)
1.3.1
Schedule of Activities – Screening Through Week 96 – Blinded Intervention
Study Period
Screen
Intervention (Blinded)
Notes
Group 1 and Group 2
Visit Number
1
2
3
4
5
6
7
8
9
10
11
Scheduled Day/Week
Screening
Day 1 
(Fasting)
Week 4
Week 12
Week 24 
(Fasting)
Week 36
Week 48 
(Fasting)
Week 60
Week 72
Week 84
Week 96 
(Fasting)
Each visit should be calculated from date of 
Day 1. A visiting nurse may be utilized for 
visits after randomization per 
Section 8.11.2.2.
Visit Window
≤45 
daysa
NA
±7 days
To ensure timely study intervention resupply.
Administrative Procedures
Informed Consent
X
Informed Consent for Future 
Biomedical Research
X
Informed Consent for Study 
Intervention During 
Pregnancy
<------------------------------X------------------------------>
Obtain upon confirmation of pregnancy if 
study intervention will be continued.
Collect and enter data from 
prenatal care provider in 
pregnant participants
<------------------------------X------------------------------>
The investigator (or designee) is responsible 
for obtaining relevant clinical and laboratory 
data from the obstetric care provider to 
monitor the safety and well-being of the 
mother and fetus. See 8.11.6.
Administration of EQ-5D-5L, 
HIV-SI/SDM, and HIVTSQ 
Patient Questionnaires
X
X
X
X
X
Administered prior to being seen by 
investigator and discussions about medical 
conditions or test results. 
Inclusion/Exclusion Criteria
X
X
Review prior to randomization on Day 1 to 
confirm no 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.
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Study Period
Screen
Intervention (Blinded)
Notes
Group 1 and Group 2
Visit Number
1
2
3
4
5
6
7
8
9
10
11
Scheduled Day/Week
Screening
Day 1 
(Fasting)
Week 4
Week 12
Week 24 
(Fasting)
Week 36
Week 48 
(Fasting)
Week 60
Week 72
Week 84
Week 96 
(Fasting)
Each visit should be calculated from date of 
Day 1. A visiting nurse may be utilized for 
visits after randomization per 
Section 8.11.2.2.
Visit Window
≤45 
daysa
NA
±7 days
To ensure timely study intervention resupply.
Medical History 
X
Prior and Concomitant 
Medications Review
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
Intervention Randomization 
X
All procedures should be completed prior to 
dose on Day 1.
Unblind using IRT
X
Dispense Study Intervention 
Using IRT
X
X
X
X
X
X
X
X
X
Study Intervention 
Compliance Review
X
X
X
X
X
X
X
X
X
Reconcile doses and assess study intervention 
compliance.
Efficacy Procedures
Plasma HIV-1 RNA 
Quantification (Real Time 
PCR)
X
X
X
X
X
X
X
X
X
X
X
CD4+ T-cell Count/
TBNK Panel
X
X
X
X
X
X
X
Decreases in CD4+ T-cell count that meet 
ECI criteria should be managed per Section 
1.3.5 and Section 8.11.5.
Plasma for HIV Viral Drug 
Resistance Testing 
X
X
X
X
X
X
X
X
X
X
Back-up samples; will be used if needed.
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Study Period
Screen
Intervention (Blinded)
Notes
Group 1 and Group 2
Visit Number
1
2
3
4
5
6
7
8
9
10
11
Scheduled Day/Week
Screening
Day 1 
(Fasting)
Week 4
Week 12
Week 24 
(Fasting)
Week 36
Week 48 
(Fasting)
Week 60
Week 72
Week 84
Week 96 
(Fasting)
Each visit should be calculated from date of 
Day 1. A visiting nurse may be utilized for 
visits after randomization per 
Section 8.11.2.2.
Visit Window
≤45 
daysa
NA
±7 days
To ensure timely study intervention resupply.
Safety Procedures
Full Physical Examination 
X
Height
X
Weight
X
X
X
X
X
X
Directed Physical 
Examination
X
X
X
X
X
X
X
X
X
X
Vital Signs 
X
X
X
X
X
X
X
X
X
X
X
Includes pulse, blood pressure, temperature, 
and respiratory rate.
12-Lead ECG
X
May be performed up to 7 days prior to Day 1 
after all other eligibility criteria are confirmed.
Contraceptive Use 
Confirmation (WOCBP 
Only)
X
X
X
X
X
X
X
X
X
X
Serum Pregnancy Test
(β-hCG; WOCBP Only)
X
Urine Pregnancy Test 
(WOCBP Only)
X
X
X
X
X
X
X
X
X
X
Confirm with serum test if urine test is 
positive. If serum positive, participants will be 
managed per Section 8.11.6 and safety of her 
infant collected per Section 8.11.6.4.1.
HIV-1 & -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
All participants at screening, only anti-HBc 
positive participants thereafter. 
HBV DNA
X
X
X
X
X
X
X
X
X
X
X
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Study Period
Screen
Intervention (Blinded)
Notes
Group 1 and Group 2
Visit Number
1
2
3
4
5
6
7
8
9
10
11
Scheduled Day/Week
Screening
Day 1 
(Fasting)
Week 4
Week 12
Week 24 
(Fasting)
Week 36
Week 48 
(Fasting)
Week 60
Week 72
Week 84
Week 96 
(Fasting)
Each visit should be calculated from date of 
Day 1. A visiting nurse may be utilized for 
visits after randomization per 
Section 8.11.2.2.
Visit Window
≤45 
daysa
NA
±7 days
To ensure timely study intervention resupply.
Chemistry
X
X
X
X
X
X
X
X
X
X
X
Fasting is required at Day 1 and Weeks 24, 48 
and 96.
Hematology
X
X
X
X
X
X
X
X
X
X
X
Decreases in total lymphocyte counts that 
meet ECI criteria should be managed per 
Section 1.3.5 and Section 8.11.5.
PT/INR
X
Test to be performed only in participants 
infected with HCV.
Urinalysis
X
X
X
X
X
Review of Adverse Events
X
X
X
X
X
X
X
X
X
X
X
Pharmacokinetics
Blood (Plasma) for ISL PK 
X
X
X
X
X
At Week 4, a predose and postdose sample 
will be taken. 
Blood (Plasma) for 
Investigational PK
X
X
X
X
X
Analysis triggered by Sponsor as needed. Not 
collected for pregnant participants.
Blood (Plasma) for DOR and 
ISL PK in Pregnant 
Participants
<------------------------------X------------------------------>
Collected during the 1st, 2nd, and 3rd trimesters 
and postpartum per Section 8.11.6.1.
Biomarkers
Blood for Genetic Analysisb
X
Whole Blood for Future 
Biomedical Research
X
X
X
X
Optional participation; requires FBR consent.
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Study Period
Screen
Intervention (Blinded)
Notes
Group 1 and Group 2
Visit Number
1
2
3
4
5
6
7
8
9
10
11
Scheduled Day/Week
Screening
Day 1 
(Fasting)
Week 4
Week 12
Week 24 
(Fasting)
Week 36
Week 48 
(Fasting)
Week 60
Week 72
Week 84
Week 96 
(Fasting)
Each visit should be calculated from date of 
Day 1. A visiting nurse may be utilized for 
visits after randomization per 
Section 8.11.2.2.
Visit Window
≤45 
daysa
NA
±7 days
To ensure timely study intervention resupply.
DEXA Scan
(Only Where Permitted by 
Local Law)
X
X
X
Perform after all eligibility criteria are 
confirmed and within 14 days after Day 1. At 
Weeks 48 and 96, scans may be performed ± 
14 days of the scheduled visit. May require 
additional planning/scheduling. DEXA should 
not be performed on pregnant participants.
Waist and Hip Measurements
X
X
X
Blood and Urine for Renal 
Markers
X
X
X
X
Blood for Inflammatory 
Markers
X
X
X
X
anti-HBc=hepatitis B core antibody; β-hCG=beta human chorionic gonadotropin; bp=blood pressure; DEXA=Dual X-ray Absorptiometry; DNA=deoxyribonucleic acid;
ECG=electrocardiogram; EQ-5D-5L=EuroQol five-dimensional descriptive system, five-level version; FBR=future biomedical research; HBsAg=hepatitis B surface antigen;
HBV=hepatitis B virus; HCV=hepatitis C virus; HIV=human immunodeficiency virus; HIV-SI/SDM=Human Immunodeficiency Virus Symptom Index/Symptom Distress
Module; HIVTSQ=Human Immunodeficiency Virus Treatment Satisfaction Questionnaire; INR=international normalized ratio; IRT=Interactive Response Technology; 
NA=not applicable; PCR=polymerase chain reaction; PK=pharmacokinetic; PT=prothrombin time; RNA=ribonucleic acid; rr=respiratory rate; TBNK= T- and B- Lymphocyte 
and Natural Killer Cell Profile; temp=body temperature; WOCBP=a woman/women of childbearing potential.
a
Participants are expected to enroll as soon as possible after eligibility is confirmed. In cases of unexpected delays in receiving repeat screening laboratory results, screening 
period of up to 45 days is allowed.
b
This 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 that 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 the future biomedical research consent. If the planned genetic analyses are not 
approved, but future biomedical research is approved and consent is given, this sample will be collected for the purpose of future biomedical research.
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1.3.2
Schedule of Activities – Week 108 Through Week 168 – Open-label Intervention, Including Study Extension
Study Period
Intervention
(Open-label)
Notes
Visit Number
12
13
14
15
16
17
Each visit should be 
calculated from date of 
Visit 2, Day 1. A visiting 
nurse service may be utilized 
for visits after randomization 
(if locally available and 
approved for use).
Scheduled 
Day/Week
Week 108
Week 120
(Fasting)
Week 132
Week 144
(Fasting)
Week 156
Week 168
(Fasting)
Week 156 and Week 168 are 
part of study extension.
Visit Window
±7 days
Administrative Procedures
Prior / 
Concomitant 
Medication 
Review
X
X
X
X
X
X
Register Study 
Visit in IRT
X
X
X
X
X
X
Informed 
Consent for 
Study 
Extension
<-----------------------------------------X----------------------------------------->
Participants who do not 
consent to the study 
extension will have an End 
of Treatment Follow-up 
visit in 42 (+7) days and 
complete their study 
participation
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Study Period
Intervention
(Open-label)
Notes
Visit Number
12
13
14
15
16
17
Each visit should be 
calculated from date of 
Visit 2, Day 1. A visiting 
nurse service may be utilized 
for visits after randomization 
(if locally available and 
approved for use).
Scheduled 
Day/Week
Week 108
Week 120
(Fasting)
Week 132
Week 144
(Fasting)
Week 156
Week 168
(Fasting)
Week 156 and Week 168 are 
part of study extension.
Visit Window
±7 days
Dispense 
Study 
Intervention 
using IRT
X
X
X
X
X
Study intervention should 
only be dispensed at Week 
144 and 156 if the participant 
consents to the 24-week 
study extension or is pregnant 
and consents to continue 
study intervention during 
pregnancy. See Section 1.3.4 
for pregnant participants
continuing treatment beyond 
Week 168.
Study 
Intervention 
Compliance 
Review
X
X
X
X
X
X
Reconcile doses and assess 
study intervention 
compliance.
Informed 
Consent for 
Study 
Intervention 
During 
Pregnancy
<-----------------------------------------X----------------------------------------->
Obtain upon confirmation of 
pregnancy if study 
intervention will be 
continued.
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Study Period
Intervention
(Open-label)
Notes
Visit Number
12
13
14
15
16
17
Each visit should be 
calculated from date of 
Visit 2, Day 1. A visiting 
nurse service may be utilized 
for visits after randomization 
(if locally available and 
approved for use).
Scheduled 
Day/Week
Week 108
Week 120
(Fasting)
Week 132
Week 144
(Fasting)
Week 156
Week 168
(Fasting)
Week 156 and Week 168 are 
part of study extension.
Visit Window
±7 days
Collect and 
enter data 
from prenatal 
care provider 
in pregnant 
participants
<-----------------------------------------X----------------------------------------->
The investigator (or 
designee) is responsible for 
obtaining relevant clinical 
and laboratory data from the 
obstetric care provider to 
monitor the safety and well-
being of the mother and fetus. 
See 8.11.6.
Efficacy Procedures
Plasma HIV-1
RNA 
Quantification 
(Real Time 
PCR)
X
X
X
X
X
X
CD4+ T-cell 
Count/TBNK 
Panel
X
X
X
X
X
X
Decreases in CD4+ T-cell 
count that meet ECI criteria 
should be managed per 
Section 1.3.5 and Section 
8.11.5.
Blood 
(Plasma) for 
HIV-1 Drug 
Resistance 
X
X
X
X
X
X
Back-up samples, will be 
used if needed
Safety Procedures
Weight
X
X
X
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PRODUCT: MK-8591A  
30
PROTOCOL/AMENDMENT NO.: 018-09
MK-8591A-018-09 FINAL PROTOCOL
25-MAR-2024
Study Period
Intervention
(Open-label)
Notes
Visit Number
12
13
14
15
16
17
Each visit should be 
calculated from date of 
Visit 2, Day 1. A visiting 
nurse service may be utilized 
for visits after randomization 
(if locally available and 
approved for use).
Scheduled 
Day/Week
Week 108
Week 120
(Fasting)
Week 132
Week 144
(Fasting)
Week 156
Week 168
(Fasting)
Week 156 and Week 168 are 
part of study extension.
Visit Window
±7 days
Directed 
Physical 
Examination
X
X
X
X
X
X
Vital Signs
X
X
X
X
X
X
Includes pulse, blood 
pressure, temperature, and 
respiratory rate.
Contraception 
Use 
Confirmation
(WOCBP 
only)
X
X
X
X
X
X
Not applicable during 
ongoing pregnancy
Urine 
Pregnancy 
Test
(WOCBP 
only)
X
X
X
X
X
X
Confirm with serum test if 
urine test is positive. If serum 
positive, participants will be 
managed per Section 8.11.6 
and safety of her infant 
collected per Section 
8.11.6.4.1.
HBsAg 
X
X
X
X
X
Participants who are anti-
HBc positive at screening
HBV DNA
X
X
X
X
X
Chemistry
X
X
X
X
X
X
Fasting is required at 
Week 120 and 144, and 
Week 168.
08J270

PRODUCT: MK-8591A  
31
PROTOCOL/AMENDMENT NO.: 018-09
MK-8591A-018-09 FINAL PROTOCOL
25-MAR-2024
Study Period
Intervention
(Open-label)
Notes
Visit Number
12
13
14
15
16
17
Each visit should be 
calculated from date of 
Visit 2, Day 1. A visiting 
nurse service may be utilized 
for visits after randomization 
(if locally available and 
approved for use).
Scheduled 
Day/Week
Week 108
Week 120
(Fasting)
Week 132
Week 144
(Fasting)
Week 156
Week 168
(Fasting)
Week 156 and Week 168 are 
part of study extension.
Visit Window
±7 days
Hematology
X
X
X
X
X
X
Decreases in total 
lymphocyte counts should be 
managed according to 
Section 1.3.5 and Section 
8.11.5.
Urinalysis
X
X
X
Review of 
Adverse 
Events
X
X
X
X
X
X
08J270

PRODUCT: MK-8591A  
32
PROTOCOL/AMENDMENT NO.: 018-09
MK-8591A-018-09 FINAL PROTOCOL
25-MAR-2024
Study Period
Intervention
(Open-label)
Notes
Visit Number
12
13
14
15
16
17
Each visit should be 
calculated from date of 
Visit 2, Day 1. A visiting 
nurse service may be utilized 
for visits after randomization 
(if locally available and 
approved for use).
Scheduled 
Day/Week
Week 108
Week 120
(Fasting)
Week 132
Week 144
(Fasting)
Week 156
Week 168
(Fasting)
Week 156 and Week 168 are 
part of study extension.
Visit Window
±7 days
Pharmacokinetics
Blood 
(Plasma) for 
Investigational 
PK
X
Group 1 (DOR/ISL) only.
Analysis triggered by 
Sponsor as needed. Not 
collected for pregnant 
participants
Blood 
(Plasma) for 
DOR and ISL 
PK in 
Pregnant 
Participants 
Only
<-----------------------------------------X----------------------------------------->
Group 1 (DOR/ISL) only.
PK samples will be collected 
during the 1st, 2nd, and 3rd
trimesters and postpartum per 
Section 8.11.6.1.
Biomarkers
Whole Blood 
for Future 
Biomedical 
Research
X
Optional participation; 
requires FBR consent.
Blood for 
Inflammatory 
Markers
X
Blood and 
Urine for 
Renal Markers
X
08J270

PRODUCT: MK-8591A  
33
PROTOCOL/AMENDMENT NO.: 018-09
MK-8591A-018-09 FINAL PROTOCOL
25-MAR-2024
Study Period
Intervention
(Open-label)
Notes
Visit Number
12
13
14
15
16
17
Each visit should be 
calculated from date of 
Visit 2, Day 1. A visiting 
nurse service may be utilized 
for visits after randomization 
(if locally available and 
approved for use).
Scheduled 
Day/Week
Week 108
Week 120
(Fasting)
Week 132
Week 144
(Fasting)
Week 156
Week 168
(Fasting)
Week 156 and Week 168 are 
part of study extension.
Visit Window
±7 days
Waist and Hip 
Measurements
X
DEXA Scan
(only where 
permitted by 
local law)
X
At Week 144, scans may be 
performed ±14 days of the 
scheduled visit. May require 
additional planning/
scheduling. Participants who 
become pregnant will not 
have DEXA Scans
DEXA=dual-energy X-ray absorptiometry; HIV=human immunodeficiency virus; HIV-1=human immunodeficiency virus type 1; IRT=interactive response 
technology; ISL=islatravir; NA=not applicable; PCR=polymerase chain reaction; RNA=ribonucleic acid; TBNK= T- and B- Lymphocyte and Natural Killer 
Cell Profile; WOCBP=woman/women of childbearing potential.
08J270

PRODUCT: MK-8591A  
34
PROTOCOL/AMENDMENT NO.: 018-09
MK-8591A-018-09 FINAL PROTOCOL
25-MAR-2024
1.3.3
Schedule of Activities – Viremia Confirmation and End of Treatment
(All Participants Except Those With Specified Decreases in CD4+ T-cell/Total Lymphocyte Counts)
Study Period
Viremia Confirmation
End of Treatment
Notes
Visit Number
Unscheduled
Unscheduled
Scheduled 
Day/Week
Viremia Confirmation
Early Discontinuation of 
Treatmenta
End of Treatment 
Follow-up
The End of Treatment 
Follow-up visit should 
also be performed for all 
participants except those 
enrolling immediately in a
DOR/ISL 100-mg/0.25-
mg studyb.
Visit Window
Within 2 to 4 Weeks of HIV-1 Viremia 
(≥50 copies/mL)
NA
42 (+7) days after the end 
of treatment
Administrative Procedures
Prior and 
Concomitant 
Medications 
Review
X
X
X
Register Study 
Visit in IRT
X
X
Study 
Intervention 
Compliance 
Review 
X
X
Reconcile doses and study 
intervention compliance.
Administration 
of EQ-5D-5L, 
HIV-SI/SDM, 
and HIVTSQ 
Patient 
Questionnaires
X
Administered prior to 
being seen by investigator 
and discussions about 
medical conditions or test 
results.
Not to be collected if 
participant discontinues 
treatment after Week 96.
08J270

PRODUCT: MK-8591A  
35
PROTOCOL/AMENDMENT NO.: 018-09
MK-8591A-018-09 FINAL PROTOCOL
25-MAR-2024
Study Period
Viremia Confirmation
End of Treatment
Notes
Visit Number
Unscheduled
Unscheduled
Scheduled 
Day/Week
Viremia Confirmation
Early Discontinuation of 
Treatmenta
End of Treatment 
Follow-up
The End of Treatment 
Follow-up visit should 
also be performed for all 
participants except those 
enrolling immediately in a
DOR/ISL 100-mg/0.25-
mg studyb.
Visit Window
Within 2 to 4 Weeks of HIV-1 Viremia 
(≥50 copies/mL)
NA
42 (+7) days after the end 
of treatment
Efficacy Procedures
Plasma HIV-1 
RNA 
Quantification 
(Real Time 
PCR)
X
X
X
CD4+ T-cell 
Count/TBNK 
Panel
X
Participants with 
decreases in CD4+ T-
cell count >10% from 
average baseline 
valuec or who meet 
ECI criteria at the 
Early Discontinuation
of Treatment visit 
should be managed 
per Section 8.11.5 and 
Section 1.3.5.
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 
End of Treatment visits 
triggered by Sponsor as 
needed.
08J270

PRODUCT: MK-8591A  
36
PROTOCOL/AMENDMENT NO.: 018-09
MK-8591A-018-09 FINAL PROTOCOL
25-MAR-2024
Study Period
Viremia Confirmation
End of Treatment
Notes
Visit Number
Unscheduled
Unscheduled
Scheduled 
Day/Week
Viremia Confirmation
Early Discontinuation of 
Treatmenta
End of Treatment 
Follow-up
The End of Treatment 
Follow-up visit should 
also be performed for all 
participants except those 
enrolling immediately in a
DOR/ISL 100-mg/0.25-
mg studyb.
Visit Window
Within 2 to 4 Weeks of HIV-1 Viremia 
(≥50 copies/mL)
NA
42 (+7) days after the end 
of treatment
Safety Procedures
Full Physical 
Examination 
X
X
Vital Signs 
X
X
Includes weight, pulse, 
blood pressure, 
temperature, and 
respiratory rate.
Contraceptive 
Use 
Confirmation 
(WOCBP 
Only)
X
X
X
Serum 
Pregnancy 
Test 
(WOCBP 
Only)
X
X
If serum test is positive, 
participants will be 
managed per Section 
8.11.6 and safety of her 
infant collected per 
Section 8.11.6.4.1.
Chemistry
X
08J270

PRODUCT: MK-8591A  
37
PROTOCOL/AMENDMENT NO.: 018-09
MK-8591A-018-09 FINAL PROTOCOL
25-MAR-2024
Study Period
Viremia Confirmation
End of Treatment
Notes
Visit Number
Unscheduled
Unscheduled
Scheduled 
Day/Week
Viremia Confirmation
Early Discontinuation of 
Treatmenta
End of Treatment 
Follow-up
The End of Treatment 
Follow-up visit should 
also be performed for all 
participants except those 
enrolling immediately in a
DOR/ISL 100-mg/0.25-
mg studyb.
Visit Window
Within 2 to 4 Weeks of HIV-1 Viremia 
(≥50 copies/mL)
NA
42 (+7) days after the end 
of treatment
Hematology
X
Participants with 
decreases in total 
lymphocyte counts >10%
from average baseline 
valuec or who meet ECI 
criteria at the Early 
Discontinuation of 
Treatment Visit should be 
managed per Section 
8.11.5 and Section 1.3.5.
Urinalysis
X
Review of 
Adverse 
Events
X
X
X
Pharmacokinetics
Blood 
(Plasma) for 
Investigational 
PK
X
X
X
Analysis triggered by 
Sponsor as needed. Do not 
collect if participant 
known to be in Group 2 
(BIC/FTC/TAF) at time of 
visit.
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. 
08J270

PRODUCT: MK-8591A  
38
PROTOCOL/AMENDMENT NO.: 018-09
MK-8591A-018-09 FINAL PROTOCOL
25-MAR-2024
Study Period
Viremia Confirmation
End of Treatment
Notes
Visit Number
Unscheduled
Unscheduled
Scheduled 
Day/Week
Viremia Confirmation
Early Discontinuation of 
Treatmenta
End of Treatment 
Follow-up
The End of Treatment 
Follow-up visit should 
also be performed for all 
participants except those 
enrolling immediately in a
DOR/ISL 100-mg/0.25-
mg studyb.
Visit Window
Within 2 to 4 Weeks of HIV-1 Viremia 
(≥50 copies/mL)
NA
42 (+7) days after the end 
of treatment
bp=blood pressure; EQ-5D-5L=EuroQol five-dimensional descriptive system, five-level version; FBR=future biomedical research; HIV=human 
immunodeficiency virus; HIV-SI/SDM=Human Immunodeficiency Virus Symptom Index/Symptom Distress Module; HIVTSQ=Human Immunodeficiency 
Virus Treatment Satisfaction Questionnaire; IRT=Interactive Response Technology; NA=not applicable; PCR=polymerase chain reaction; 
PK=pharmacokinetic; RNA=ribonucleic acid; rr=respiratory rate; TBNK= T- and B- Lymphocyte and Natural Killer Cell Profile; temp=body temperature; 
WOCBP=a woman/women of childbearing potential.
a Early Discontinuation of Treatment visit applies to any participant who discontinues study intervention prior to Week 144 or prior to Week 168 for those 
participants who continue in the study extension.
b For women who become pregnant, see Section 8.11.6 for instructions on discontinuation and end of treatment follow-up.
c The average baseline value is defined as the average value between screening (within 45 days prior to the first dose of study intervention) and Day 1.
08J270

PRODUCT: MK-8591A  
39
PROTOCOL/AMENDMENT NO.: 018-09
MK-8591A-018-09 FINAL PROTOCOL
25-MAR-2024
1.3.4
Schedule of Activities for Participants Whose Pregnancy or Postpartum Visit(s) Extends Beyond Week 168
Visit Number
Unscheduled
Notes
Scheduled Week
Pregnancy 1
(Week 180)
Pregnancy 2
(Week 192)
Pregnancy 3
(Week 204)
Pregnancy 4
(Week 216)
For any participant who is 
pregnant at the last study visit
and consents to continue study 
intervention, the visit schedule 
will be extended to allow 
assessment through each 
trimester and postpartum. 
Extension visits will only be 
performed through pregnancy &
a single postpartum timepoint, as 
applicable for each participant.
Each pregnancy visit will be 12 
weeks apart
The End of Treatment Follow-up 
Visit should also be performed 
approximately 42 days (+7 days) 
after the last dose of study 
intervention (See Section 1.3.3).
Visit Window
± 7 days
Administrative Procedures
Prior and Concomitant Medications Review
X
X
X
X
Register Study Visit in IRT
X
X
X
X
Dispense Study Intervention Using IRT
X
X
X
Study intervention dispensation 
will stop at the first visit 
postpartum.
Evaluation to Receive Continued Study 
Intervention
X
X
X
X
Following pregnancy completion, 
options for future treatment are 
managed per Section 6.7.
Study Intervention Compliance Review
X
X
X
X
Reconcile doses and study 
intervention compliance
Collect and enter data from prenatal care 
provider
<-----------------------------------------X-------------------------------------->
Obtain relevant prenatal clinical 
& laboratory data to monitor the 
safety of the mother & fetus per 
Section 8.11.6
08J270

PRODUCT: MK-8591A  
40
PROTOCOL/AMENDMENT NO.: 018-09
MK-8591A-018-09 FINAL PROTOCOL
25-MAR-2024
Visit Number
Unscheduled
Notes
Scheduled Week
Pregnancy 1
(Week 180)
Pregnancy 2
(Week 192)
Pregnancy 3
(Week 204)
Pregnancy 4
(Week 216)
For any participant who is 
pregnant at the last study visit
and consents to continue study 
intervention, the visit schedule 
will be extended to allow 
assessment through each 
trimester and postpartum. 
Extension visits will only be 
performed through pregnancy &
a single postpartum timepoint, as 
applicable for each participant.
Each pregnancy visit will be 12 
weeks apart
The End of Treatment Follow-up 
Visit should also be performed 
approximately 42 days (+7 days) 
after the last dose of study 
intervention (See Section 1.3.3).
Visit Window
± 7 days
Efficacy Procedures
Plasma HIV-1 RNA Quantification (Real 
Time PCR)
X
X
X
X
CD4+ T-cell Count/TBNK Panel
X
X
X
X
Decreases in CD4+ T-cell count 
that meet ECI criteria should be 
managed per Section 1.3.5 and 
Section 8.11.5.
Plasma for HIV Viral Drug Resistance 
Testing 
X
X
X
X
Back-up samples, will be used if 
needed
Safety Procedures
Weight
X
X
X
X
Directed Physical Examination
X
X
X
X
Vital Signs
X
X
X
X
Includes pulse, blood pressure, 
temperature, and respiratory rate
HBsAg
X
X
X
X
Participants who are anti-HBc 
positive at screening 
HBV DNA
X
X
X
X
Chemistry
X
X
X
X
08J270

PRODUCT: MK-8591A  
41
PROTOCOL/AMENDMENT NO.: 018-09
MK-8591A-018-09 FINAL PROTOCOL
25-MAR-2024
Visit Number
Unscheduled
Notes
Scheduled Week
Pregnancy 1
(Week 180)
Pregnancy 2
(Week 192)
Pregnancy 3
(Week 204)
Pregnancy 4
(Week 216)
For any participant who is 
pregnant at the last study visit
and consents to continue study 
intervention, the visit schedule 
will be extended to allow 
assessment through each 
trimester and postpartum. 
Extension visits will only be 
performed through pregnancy &
a single postpartum timepoint, as 
applicable for each participant.
Each pregnancy visit will be 12 
weeks apart
The End of Treatment Follow-up 
Visit should also be performed 
approximately 42 days (+7 days) 
after the last dose of study 
intervention (See Section 1.3.3).
Visit Window
± 7 days
Hematology
X
X
X
X
Decreases in total lymphocyte
counts that meet ECI criteria 
should be managed per Section 
1.3.5 and Section 8.11.5.
Urinalysis
X
X
X
X
Review of Adverse Events
X
X
X
X
Pharmacokinetics
Blood (Plasma) for DOR and ISL PK
X
X
X
X
Collected during the 1st, 2nd, and 
3rd trimesters and postpartum per 
Section 8.11.6.1. Not needed if 
participant in Group 2 
(BIC/FTC/TAF).
Biomarkers
Whole Blood for Future Biomedical 
Research
X
X
X
X
Optional participation; requires 
FBR consent
DNA=deoxyribonucleic acid; DOR=doravirine; HBsAg=hepatitis B surface antigen; HBV=hepatitis B virus; HIV=human immunodeficiency virus; 
IRT=Interactive Response Technology; ISL=islatravir; PCR=polymerase chain reaction; PK=pharmacokinetic; RNA=ribonucleic acid; TBNK= T- and B-
Lymphocyte and Natural Killer Cell Profile.
08J270

PRODUCT: MK-8591A  
42
PROTOCOL/AMENDMENT NO.: 018-09
MK-8591A-018-09 FINAL PROTOCOL
25-MAR-2024
1.3.5
Schedule of Activities for Participants With Specified Decreases in CD4+ T-cell Counts and/or Total Lymphocyte 
Counts
Study Period
CD4+ T-cell Count 
and/or Total 
Lymphocyte Count
Confirmation
End of Treatment
CD4+ T-cell Count and/or 
Total Lymphocyte Count 
Monitoring
DOR/ISL Only
Notes
Visit Number
Unscheduled
Unscheduled
Unscheduled
Scheduled Day/Week
CD4+ T-cell and/or Total 
Lymphocyte Confirmation
Early Discontinuation 
of Treatment
End of Treatment 
Follow-up
CD4+ T-cell and/or Total 
Lymphocyte Monitoring
See Sections 8.1.9 and 8.11.5 
for details regarding 
discontinuation and 
monitoring.
If specified decreases to 
CD4+ T-cell count and/or 
lymphocyte count are 
confirmed, the participant 
should be discontinued from 
treatment and unblinded (if 
applicable) to determine need 
for additional monitoring.
Only those treated with 
DOR/ISL require additional 
monitoring.
Visit Window
Within 3-4 weeks* of 
initial decrease
*Note: if total lymphocyte
count remains ≥1 x 109
cells/L, confirmation of 
decreased lymphocytes is 
due in 10 to 14 weeks (ie,
at the next routine study 
visit).
NA
42 (+7) days after 
discontinuing study 
intervention
Approximately every 10-14
weeks
Administrative Procedures
Prior and Concomitant 
Medications Review
X
X
X
X
Register Study Visit in IRT
X
X
X
Study Intervention 
Compliance Review 
X
Reconcile doses and study 
intervention compliance.
Administration of EQ-5D-5L, 
HIV-SI/SDM, and HIVTSQ 
Patient Questionnaires 
X
Administered prior to being 
seen by investigator and 
discussions about medical 
conditions or test results.
Not to be collected if 
participant discontinues 
treatment after Week 96.
08J270

PRODUCT: MK-8591A  
43
PROTOCOL/AMENDMENT NO.: 018-09
MK-8591A-018-09 FINAL PROTOCOL
25-MAR-2024
Study Period
CD4+ T-cell Count 
and/or Total 
Lymphocyte Count
Confirmation
End of Treatment
CD4+ T-cell Count and/or 
Total Lymphocyte Count 
Monitoring
DOR/ISL Only
Notes
Visit Number
Unscheduled
Unscheduled
Unscheduled
Scheduled Day/Week
CD4+ T-cell and/or Total 
Lymphocyte Confirmation
Early Discontinuation 
of Treatment
End of Treatment 
Follow-up
CD4+ T-cell and/or Total 
Lymphocyte Monitoring
See Sections 8.1.9 and 8.11.5 
for details regarding 
discontinuation and 
monitoring.
If specified decreases to 
CD4+ T-cell count and/or 
lymphocyte count are 
confirmed, the participant 
should be discontinued from 
treatment and unblinded (if 
applicable) to determine need 
for additional monitoring.
Only those treated with 
DOR/ISL require additional 
monitoring.
Visit Window
Within 3-4 weeks* of 
initial decrease
*Note: if total lymphocyte
count remains ≥1 x 109
cells/L, confirmation of 
decreased lymphocytes is 
due in 10 to 14 weeks (ie,
at the next routine study 
visit).
NA
42 (+7) days after 
discontinuing study 
intervention
Approximately every 10-14
weeks
Efficacy Procedures
Plasma HIV-1 RNA 
Quantification (Real Time 
PCR)
X
X
CD4+ T-cell Count/
TBNK Panel
X
X
X
(DOR/ISL Only)
X
Plasma for HIV Viral Drug 
Resistance Testing
X
X
Analysis of samples collected 
at End of Treatment visits will 
be triggered by Sponsor, as 
needed.
Safety Procedures
Full Physical Examination 
X
X
Vital Signs 
X
X
Includes weight, pulse, blood 
pressure, temperature, and 
respiratory rate.
Contraceptive Use 
Confirmation (WOCBP Only)
X
X
08J270

PRODUCT: MK-8591A  
44
PROTOCOL/AMENDMENT NO.: 018-09
MK-8591A-018-09 FINAL PROTOCOL
25-MAR-2024
Study Period
CD4+ T-cell Count 
and/or Total 
Lymphocyte Count
Confirmation
End of Treatment
CD4+ T-cell Count and/or 
Total Lymphocyte Count 
Monitoring
DOR/ISL Only
Notes
Visit Number
Unscheduled
Unscheduled
Unscheduled
Scheduled Day/Week
CD4+ T-cell and/or Total 
Lymphocyte Confirmation
Early Discontinuation 
of Treatment
End of Treatment 
Follow-up
CD4+ T-cell and/or Total 
Lymphocyte Monitoring
See Sections 8.1.9 and 8.11.5 
for details regarding 
discontinuation and 
monitoring.
If specified decreases to 
CD4+ T-cell count and/or 
lymphocyte count are 
confirmed, the participant 
should be discontinued from 
treatment and unblinded (if 
applicable) to determine need 
for additional monitoring.
Only those treated with 
DOR/ISL require additional 
monitoring.
Visit Window
Within 3-4 weeks* of 
initial decrease
*Note: if total lymphocyte
count remains ≥1 x 109
cells/L, confirmation of 
decreased lymphocytes is 
due in 10 to 14 weeks (ie,
at the next routine study 
visit).
NA
42 (+7) days after 
discontinuing study 
intervention
Approximately every 10-14
weeks
Serum Pregnancy Test 
(WOCBP Only)
X
X
If serum test is positive, 
participants will be managed 
per Section 8.11.6 and Section 
8.11.6.2 safety of her infant 
collected per Section 
8.11.6.4.1.
Chemistry
X
Hematology
X
X
X
(DOR/ISL Only)
X
Urinalysis
X
Review of Adverse Events
X
X
X
X
08J270

PRODUCT: MK-8591A  
45
PROTOCOL/AMENDMENT NO.: 018-09
MK-8591A-018-09 FINAL PROTOCOL
25-MAR-2024
Study Period
CD4+ T-cell Count 
and/or Total 
Lymphocyte Count
Confirmation
End of Treatment
CD4+ T-cell Count and/or 
Total Lymphocyte Count 
Monitoring
DOR/ISL Only
Notes
Visit Number
Unscheduled
Unscheduled
Unscheduled
Scheduled Day/Week
CD4+ T-cell and/or Total 
Lymphocyte Confirmation
Early Discontinuation 
of Treatment
End of Treatment 
Follow-up
CD4+ T-cell and/or Total 
Lymphocyte Monitoring
See Sections 8.1.9 and 8.11.5 
for details regarding 
discontinuation and 
monitoring.
If specified decreases to 
CD4+ T-cell count and/or 
lymphocyte count are 
confirmed, the participant 
should be discontinued from 
treatment and unblinded (if 
applicable) to determine need 
for additional monitoring.
Only those treated with 
DOR/ISL require additional 
monitoring.
Visit Window
Within 3-4 weeks* of 
initial decrease
*Note: if total lymphocyte
count remains ≥1 x 109
cells/L, confirmation of 
decreased lymphocytes is 
due in 10 to 14 weeks (ie,
at the next routine study 
visit).
NA
42 (+7) days after 
discontinuing study 
intervention
Approximately every 10-14
weeks
Pharmacokinetics
Blood (Plasma) for 
Investigational PK
X
X
No PK sampling after Week 
144 visit. PK sampling is not 
needed if participant is known 
to be in Group 2 (BIC/FTC/
TAF). PK analysis triggered 
by Sponsor as needed.
Biomarkers
Whole Blood for Future 
Biomedical Research
X
bp=blood pressure; FBR=future biomedical research; HIV=human immunodeficiency virus; HIV-SI/SDM=Human Immunodeficiency Virus Symptom Index/Symptom Distress 
Module; HIVTSQ=Human Immunodeficiency Virus Treatment Satisfaction Questionnaire; IRT=Interactive Response Technology; NA=not applicable; PCR=polymerase chain 
reaction; PK=pharmacokinetic; RNA=ribonucleic acid; rr=respiratory rate; TBNK= T- and B- Lymphocyte and Natural Killer Cell Profile; temp=body temperature; WOCBP=a 
woman/women of childbearing potential.
08J270

PRODUCT: MK-8591A  
46
PROTOCOL/AMENDMENT NO.: 018-09
MK-8591A-018-09 FINAL PROTOCOL
25-MAR-2024
2
INTRODUCTION
DOR/ISL (also known as MK-8591A or MK-8591/DOR) is a novel 2-drug FDC of DOR (a 
recently approved NNRTI) and ISL (a first-in-class investigational NRTTI). DOR/ISL is
being developed for qd treatment of HIV-1 infection in adults and adolescents.
2.1
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 long-term treatment, long-term 
tolerability and safety of antiretrovirals have become increasingly important considerations.
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) [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 lifelong daily treatment is 
associated with a need for simpler and safer regimens, with reduced long-term drug 
exposure. Furthermore, as the population living with HIV ages, there is increasing concern 
for the risks of long-term toxicity and DDIs with respect to comorbid conditions (ie,
neuropsychiatric, cardiovascular).
There is accumulating evidence that simplified 2-drug regimens can achieve efficacy 
comparable to that of 3-drug regimens, better tolerability, and improve 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.
DOR/ISL has the potential to be an agent for the treatment of HIV-1 infection in the switch 
setting due to its potent antiretroviral activity (including activity against common NRTI- and 
NNRTI-resistant variants) by multiple mechanisms of action, lack of food requirements, and 
favorable tolerability and DDI profiles observed to date.
2.2
Background
Refer to the IBs/approved labeling for detailed background information on DOR and ISL.
2.2.1
Islatravir
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 
analog that is converted to the pharmacologically-active triphosphate (ISL-TP) form via 
endogenous intracellular kinases. It acts through multiple mechanisms, including immediate 
chain termination by blocking translocation and delayed chain termination by preventing 
nucleotide excision [Michailidis E 2014].
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ISL is differentiated from other HIV-1 antiretrovirals by its high potency, long half-life, and 
favorable drug resistance profile. At the proposed dose of 0.75 mg qd, ISL achieves higher 
steady-state IQs (the ratio of drug exposure to viral susceptibility [Ctrough/IC50]) against wild-
type HIV-1 than any NRTI currently approved for treatment. It also exhibits potent activity 
against the most prevalent NRTI resistance mutations, including M184V.
2.2.2
Doravirine
DOR, a potent NNRTI with demonstrated efficacy and good tolerability, was first approved 
for the treatment of HIV-1 infection by the FDA and EMA in 2018. It is differentiated from 
other NNRTIs by its distinct resistance profile, low likelihood of selection for viral resistance 
in vivo, and low potential for DDIs. It exhibits potent activity against both wild-type HIV-1 
virus and frequently-transmitted NNRTI-resistant variants (eg, K103N, Y181C, G190A, and 
E138K). The safety and efficacy profiles of DOR have been well characterized in Phase 3 
clinical studies conducted in treatment-naïve adult participants [Orkin, C., et al 2018] 
[Molina, J. M., et al 2018] and in virologically suppressed adult participants switching from a 
stable antiretroviral regimen [CSR P024MK1439A ].
2.2.3
Doravirine/Islatravir
DOR/ISL is an FDC containing DOR (100 mg) and ISL (0.75 mg), administered as a single 
tablet qd. DOR and ISL represent 2 distinct classes of antiretrovirals that inhibit reverse 
transcription by different mechanisms. Based on the profiles of each of these drugs and data 
available to date, the combination DOR/ISL is expected to be well tolerated and highly 
efficacious, with a high barrier to resistance. The combination has demonstrated additive 
antiretroviral activity in vitro and has suppressed emergence of resistance at clinically
relevant concentrations.
The combination of DOR and ISL (administered as single entities, DOR + ISL) was
evaluated in a randomized Phase 2 study (MK-8591 P011) in approximately 90 treatment-
naïve adult participants with HIV-1. Participants were initially assigned to receive either 
DOR + ISL and 3TC or an FDC of DOR, 3TC, and TDF (DOR/3TC/TDF). Three doses of 
ISL were tested: 0.25 mg, 0.75 mg, and 2.25 mg. Participants receiving DOR + ISL + 3TC 
who achieved HIV-1 RNA <50 copies/mL at Week 20 (or later) discontinued 3TC at their 
next study visit (most were able to discontinue 3TC at Week 24) while continuing DOR + 
ISL. At Weeks 48 and 96, the percentage of participants with HIV-1 RNA <50 copies/mL 
among those who received the 2-drug regimen of DOR + ISL in all dose groups was 
comparable to those who received the 3-drug regimen of DOR/3TC/TDF. The majority of 
participants maintained virologic suppression through Week 144. None of the participants 
with protocol-defined virologic failure rebounded above the clinically relevant HIV-1 RNA 
>200 copies/mL cutoff. As such, no participant met the criteria for resistance testing. DOR + 
ISL, administered with 3TC or alone as a 2-drug regimen, had a favorable safety and 
tolerability profile through Week 96, comparable to that of DOR/3TC/TDF. 
The 0.75 mg dose of ISL (in combination with DOR 100 mg) was initially selected for 
further development for the daily treatment program. The clinical development program of 
DOR/ISL100mg/0.75 mg included studies in treatment-naïve adults (P020), virologically 
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suppressed adults (P017 and P018), and heavily treatment-experienced participants (P019)
and participants <18 years of age and weighing ≥35 kg (P028).
Due to findings of decreases in CD4+ T-cell and lymphocyte counts in the ISL 0.75 mg 
development program, a post hoc analysis was conducted of P011 data (See IB for details). 
Dose-dependent changes from baseline in total lymphocyte and CD4+ T-cell counts were 
observed for the different ISL dose groups. Lymphocytes, CD4+ T-cells, CD8+ T-cells, B-
cells, and natural killer (NK) cells in ISL 0.25 mg + DOR 100 mg qd (±3TC) participants 
increased (as would be expected in a treatment-naïve population) and were comparable to
results in those receiving DOR/3TC/TDF.
Based on this Phase 2 data and PK modeling, the ISL 0.25-mg dose is expected to maintain 
treatment efficacy against HIV-1 without lowering CD4+ T-cell and total lymphocyte counts. 
Where available, participants currently enrolled in this study may be given the option to join 
a new DOR/ISL 100-mg/0.25-mg study.
2.2.4
Information on Other Study-related Therapy
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
Although 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 effectiveness of an investigational medicine, the totality of available 
nonclinical and clinical data supports continued evaluation of DOR/ISL in Phase 3 clinical
studies.
The comprehensive nonclinical safety evaluations of DOR (an approved NNRTI) and ISL 
(an investigational NRTTI) as mono-entities have not revealed toxicities of concern for daily 
dosing. Nonclinical developmental and reproductive toxicity studies did not identify any 
clinically relevant concerns that would preclude continued dosing of DOR/ISL in participants 
who become pregnant during the study. Both mono-entities are differentiated by a high 
barrier to resistance in vitro with DOR exhibiting potent activity against the most prevalent 
NNRTI-resistant mutations (eg, K103N, Y181C, G190A, and E138K) and ISL against 
common NRTI-resistant mutations (eg, M184V and TAMs). Both may be administered 
without regard to food, have a low potential for DDIs, and have favorable PK and tolerability 
profiles.
High potency against wild-type and resistant variants of HIV-1 virus and a long half-life 
make ISL a suitable candidate for development for the treatment of HIV-1 infection. In the 
dose-ranging study (MK-8591 P011), ISL+DOR+3TC (as a 3-drug regimen) achieved 
virological suppression in most (>90%) treatment-naïve participants by Week 24. ISL+DOR 
(as a 2-drug regimen) maintained virologic suppression of HIV-1 RNA at all doses tested 24 
and 48 weeks after switching from the 3-drug regimen and through Week 144. In 2 ongoing 
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Phase 3 studies evaluating DOR/ISL 100 mg/0.75 mg for daily treatment of HIV-1 in 
virologically suppressed participants (MK-8591A P017 and MK-8591A P018),
approximately 95% of 658 participants enrolled in the DOR/ISL arm completed 48 weeks of
treatment in both studies. In P017 and P018, the percentage of participants with HIV-1 RNA 
≥50 copies/mL was <1% for the DOR/ISL group and a high percentage of participants 
(>93% to 95%) in the DOR/ISL group maintained virologic suppression (HIV-1 RNA <50 
copies/mL) comparable to baseline ART (P017) and BIC/FTC/TAF (P018) at Week 48. To 
date, no viral resistance to either component of DOR/ISL has been shown in the Phase 2 
(P011) and Phase 3 (P017 and P018) studies involving approximately 1096 treatment-naïve
and switch participants with HIV-1 treated with DOR/ISL. At the doses administered for 
daily treatment (ie, 100-mg DOR + 0.25, 0.75, or 2.25 mg ISL), DOR/ISL has been well
tolerated and associated with low rates of drug-related AEs.
Exposure-dependent decreases in total lymphocyte counts and lymphocyte subsets including
CD4+ T-cell counts were observed in studies with ISL alone or in combination with other 
antiviral agents. In a Phase 2 study (MK-8591 P013) for once weekly HIV-1 treatment, 
decreases in total lymphocyte, CD4+ T-cell, CD8+ T-cell, and B-cell counts from baseline 
were observed in the ISL 20 mg + MK-8507 treatment arms at Week 12 and Week 24. 
Decreases from baseline in lymphocyte count were observed in all dosing arms of ISL + 
MK-8507 QW starting at Week 8 with further decreases continuing through Week 24. 
Twenty of 58 participants on ISL + MK-8507 had a decrease in lymphocyte count of >30% 
(of whom 9 had a >50% reduction) by Week 24. These reductions were more pronounced in 
the 2 higher MK-8507 dose arms (200 and 400 mg), potentially indicating a dose-response 
relationship. Dosing of ISL+MK-8507 in P013 has been stopped.
In the Phase 2 randomized, double-blind, placebo-controlled study evaluating 60 mg and 
120 mg of ISL monthly for PrEP in participants at low-risk of HIV-1 infection (MK-8591
P016), there was a 21% mean decrease in total lymphocytes observed in the 60 mg arm (the 
dose being evaluated in Phase 3 PrEP studies) and a 36% decrease in total lymphocytes 
observed in the 120 mg arm. In this population of HIV-1 uninfected participants, the mean 
decreases were in the normal range and there was no increase in clinical AEs related to 
infection. Lymphocyte subsets were not measured in P016. Dosing of oral ISL 60 mg QM 
has been stopped in PrEP clinical studies. 
Interim analyses of this study and P017 evaluating DOR/ISL 100 mg/0.75 mg daily for 
HIV-1 treatment in a virologically suppressed population indicates that mean total 
lymphocyte count decreases in the DOR/ ISL group reached a nadir at Week 48 and then 
stabilized through Week 84 (see IB for details). After a switch from various baseline ART 
regimens, including BIC/FTC/TAF, the mean decreases from baseline in lymphocyte counts 
at Week 48 were 10.6% and 8.5% in the DOR/ISL groups (in P017 and P018, respectively)
compared with mean increases from baseline of 2.27% and 3.46% in the comparator arms (in 
P017 and P018, respectively). In the same studies, DOR/ISL-treated participants had mean 
changes from baseline at Week 48 in CD4+ T-cell count of -0.7% (P017) and +0.9% (P018)
compared with mean increases of 8.7% in the baseline ART group (P017) and 12.8% in the 
BIC/FTC/TAF group (P018). The decreases in CD4+ T-cell counts and lymphocyte counts 
have not been associated with an increased incidence of infection or other AEs. 
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Overall, the evaluation of data from across the ISL clinical programs to date suggests that the 
decrease in mean total lymphocyte and lymphocyte subset counts is ISL dose-dependent with 
lower doses less likely to cause decreases. In the dose-ranging phase of P011 (Part 1 and 
Part 2 through Week 72), the 0.25mg dose of ISL with DOR ± 3TC achieved and maintained 
high rates of virologic suppression. Participants who received ISL 0.25 mg qd had changes in 
total lymphocyte and CD4+ T-cell counts comparable to those observed for participants in 
the DOR/3TC/TDF comparator group. The results of modeling analyses of ISL exposure-
effect predict no meaningful decreases in total lymphocyte or CD4+ T-cell counts with the 
0.25-mg daily dose (see Section 4.3). For these reasons, the Sponsor is initiating new studies 
of DOR/ISL 100mg/0.25 mg for daily treatment of HIV-1.
The Sponsor is assessing the reversibility of the reductions in CD4+ T-cell and lymphocyte 
counts. A return toward baseline in lymphocyte and lymphocyte subset counts has been 
observed across the ISL clinical development program. The most robust data on recovery of 
the lymphocyte counts available at this point is from the studies involving administration of 
ISL QW (20 mg) and QM (60 to 120 mg) for PrEP where a full recovery was not observed 
by 24 weeks after stopping 60 mg ISL monthly. 
To mitigate the risk of decreases in total lymphocyte and CD4+ T-cell counts, increased 
monitoring of CD4+ T-cell and lymphocyte counts and strict treatment discontinuation rules 
were added to DOR/ISL studies. As these rules requiring treatment discontinuation for 
specified decreases in total lymphocyte counts and/or CD4+ T-cell counts went into effect 
more recently, data on recovery to baseline following discontinuation of DOR/ISL 100 
mg/0.75mg qd in virologically suppressed adults (P017 and P018) is not yet available. At this 
time, the data review supports continuation of DOR/ ISL 100 mg/0.75 mg in participants who 
continue to receive benefit and have not met discontinuation criteria until they can be 
enrolled in a DOR/ISL 100 mg/0.25 mg study (where available) or transitioned to 
commercially available ART.
Additional details regarding specific benefits and risks for participants in this clinical study 
may be found in the accompanying IB and informed consent documents.
3
HYPOTHESES, OBJECTIVES, AND ENDPOINTS
Hypotheses are aligned with objectives in the Objectives and Endpoints table.
The following objectives will be evaluated in participants ≥18 years of age with HIV-1 who 
have been virologically suppressed for ≥3 months on BIC/FTC/TAF.
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Objectives
Endpoints
Primary

To evaluate the antiretroviral activity following
switch to DOR/ISL compared to continued 
treatment with BIC/FTC/TAF as assessed by the 
percentage of participants with HIV-1 RNA 
≥50 copies/mL at Week 48.
•
Hypothesis (H1): DOR/ISL is non-inferior to 
BIC/FTC/TAF as measured by the percentage of 
participants with HIV-1 RNA ≥50 copies/mL at 
Week 48. A margin of 4 percentage points is used 
to define non-inferiority.
•
If non-inferiority of HIV-1 RNA ≥50 copies/mL at 
Week 48 and superiority of HIV-1 RNA ≥50 
copies/mL at Week 96 are met:
•
Hypothesis (H2): DOR/ISL is superior to 
BIC/FTC/TAF as measured by the percentage of 
participants with HIV-1 RNA ≥50 copies/mL at 
Week 48.
•
HIV-1 RNA
•
To evaluate the safety and tolerability of switch to 
DOR/ISL compared to continued treatment with 
BIC/FTC/TAF as assessed by review of the 
accumulated safety data through Week 48.
•
Adverse events
•
Adverse events leading to 
discontinuation of study 
intervention
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Objectives
Endpoints
Secondary
•
To evaluate the antiretroviral activity following
switch to DOR/ISL compared to continued 
treatment with BIC/FTC/TAF as assessed by the 
percentage of participants with HIV-1 RNA 
≥50 copies/mL at Week 96 and Week 144.
•
Hypothesis (H3): DOR/ISL is non-inferior to 
BIC/FTC/TAF as measured by the percentage of 
participants with HIV-1 RNA ≥50 copies/mL at 
Week 96. A margin of 4 percentage points is used 
to define non-inferiority.
•
If non-inferiority of HIV-1 RNA ≥50 copies/mL at 
Week 48 is met:
•
Hypothesis (H4): DOR/ISL is superior to 
BIC/FTC/TAF as measured by the percentage of 
participants with HIV-1 RNA ≥50 copies/mL at 
Week 96.
•
HIV-1 RNA
•
To evaluate the antiretroviral activity following
switch to DOR/ISL compared to continued 
treatment with BIC/FTC/TAF as assessed by the 
percentage of participants with the following at 
Week 48, Week 96 and Week 144:
-
HIV-1 RNA <40 copies/mL
-
HIV-1 RNA <50 copies/mL
•
HIV-1 RNA
•
To evaluate the immunologic effect of switch to 
DOR/ISL compared to continued treatment with 
BIC/FTC/TAF as measured by change from 
baseline in CD4+ T-cell count at Week 48, 
Week 96, and Week 144.
•
CD4+ T-cell count
•
To evaluate the development of viral drug 
resistance to any study intervention in participants 
who switch to DOR/ISL and participants who 
continue treatment with BIC/FTC/TAF.
•
Viral resistance-associated 
substitutions
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Objectives
Endpoints
•
To evaluate the effect of switch to DOR/ISL 
compared to continued treatment with 
BIC/FTC/TAF on weight, as measured by the mean 
change from baseline to Week 48, Week 96, and 
Week 144.
•
Hypothesis (H5): DOR/ISL is superior to 
BIC/FTC/TAF as measured by lower mean increase 
from baseline in body weight at Week 48.
•
Hypothesis (H6): DOR/ISL is superior to 
BIC/FTC/TAF as measured by lower mean increase 
from baseline in body weight at Week 96.
•
Weight
•
To evaluate the safety and tolerability of DOR/ISL 
compared to BIC/FTC/TAF as assessed by review 
of the accumulated safety data through study 
duration.
•
Adverse events
•
Adverse events leading to 
discontinuation of study 
intervention
Tertiary/Exploratory
•
To evaluate the effect on fasting lipid and metabolic 
profiles, renal function, inflammation, and body 
composition following switch to DOR/ISL
compared to continued treatment with 
BIC/FTC/TAF as measured by the mean change in 
laboratory and radiological markers from baseline 
at Week 48, Week 96 and Week 144.
•
Laboratory and radiological 
markers
•
To evaluate the pharmacokinetics of ISL, when 
administered as a component of DOR/ISL.
•
Pharmacokinetic values, 
such as AUC, Cmax, and 
C24
•
To describe PROs related to HRQoL, self-reported 
HIV symptoms, and treatment satisfaction of switch 
to DOR/ISL compared to continued treatment with 
BIC/FTC/TAF at Week 48 and Week 96.
•
HRQoL, HIV symptom 
burden, and treatment 
satisfaction
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Objectives
Endpoints
•
To explore the antiretroviral activity following
switch to DOR/ISL compared to continued 
treatment with BIC/FTC/TAF as assessed by time 
to loss of virologic response at Week 48 and
Week 96.
•
Time to loss of virologic 
response 
•
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 this study.
•
Germline genetic variation
Success of this study is predicated only on establishing non-inferiority of DOR/ISL to 
BIC/FTC/TAF with respect to the percentage of participants with HIV-1 RNA 
≥50 copies/mL at Week 48 (ie, establishing statistical significance of H1).
4
STUDY DESIGN
4.1
Overall Design
This is a Phase 3, randomized, active-controlled, multi-site, double-blind, double-dummy 
study to evaluate a switch from BIC/FTC/TAF qd to DOR/ISL qd in participants with HIV-1 
who have been virologically suppressed on BIC/FTC/TAF for ≥3 months with no history of 
treatment failure.
A total of approximately 578 participants will be randomized in a 1:1 ratio into 1 of 
2 treatment groups (Figure 1):
•
Group 1 (n = approximately 289): Switch from BIC/FTC/TAF to DOR/ISL on Day 1
(taken with matching placebo to BIC/FTC/TAF through Week 96).
•
Group 2 (n = approximately 289): Continue BIC/FTC/TAF (taken with matching 
placebo to DOR/ISL through Week 96).
Clinical site personnel and participants will remain blinded through Week 96 while Sponsor 
personnel will remain blinded through Week 48. Safety and efficacy laboratory results, 
including HIV-1 RNA, will remain unmasked throughout the study. At Week 96, all 
participants and site personnel will be unblinded and participants will continue to receive 
their assigned study intervention open-label through Week 144. All participants who reach 
Week 144 will be considered to have completed the base study. At Week 144, participants
may be offered the option to continue study intervention up to Week 168 in the study 
extension. 
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Any 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 to the Sponsor through Week 48 and 
to site personnel and participants through Week 96.
Participant safety will be monitored by an independent eDMC through periodic review of 
safety and efficacy data (received from an unblinded independent statistician) throughout the 
study (Appendix 1). When 40% of target enrollment have completed Week 24, including
visit assessments, an interim analysis (which will hereafter be referred to as the “Week 24 
interim analysis”) to assess futility based on Week 24 data is planned (Section 9.7).
Specific procedures to be performed during the study, as well as their prescribed times and 
associated visit windows, are outlined in the SoA in Section 1.3. Details of each procedure 
are provided in Section 8.
4.2
Scientific Rationale for Study Design
The randomized active-controlled non-inferiority study design is consistent with FDA 
regulatory guidance [Food and Drug Administration (CDER) 2015] and is considered 
appropriate for a treatment-experienced study population that is switching from another 
stable ART regimen with HIV RNA <50 copies/mL. Small differences in virologic efficacy, 
emergence of resistance, and loss of tolerability or safety may be detected prior to 48 weeks
of treatment, particularly for therapies with largely comparable characteristics. Thus, aligned 
with regulatory guidance [Food and Drug Administration (CDER) 2015], the primary 
efficacy analysis will occur after 48 weeks of treatment with DOR/ISL or BIC/FTC/TAF. 
Blinded study intervention will continue through Week 96 and participants’ originally 
assigned therapy will be continued open-label from Week 96 to Week 144 to enable a longer-
term comparison between the 2 treatment groups. The study extension allows participants 
who continue to benefit from study medication (as determined by the investigator) to 
continue their assigned treatment for up to 24 additional weeks when needed until the 
participant is able to enroll in a DOR/ISL 100-mg/ 0.25-mg study (where available, see 
Section 6.7) or transition to commercially available ART therapy.
4.2.1
Rationale for Endpoints
4.2.1.1
Efficacy Endpoints
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.
Clinical studies of antiretroviral agents in multiple drug classes have demonstrated that 
virologic suppression of HIV-1 RNA to <50 copies/mL reflects a clinically relevant standard 
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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 secondary efficacy endpoint of plasma HIV-1 RNA <40 copies/mL corresponds to the 
lower limit of quantification 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 <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
Safety evaluations will include physical examinations (including vital signs) and laboratory 
tests (eg, hematology, chemistry, and urinalysis) performed per SoA (Section 1.3). AEs will 
be evaluated at each visit and assessed according to the guidelines in Section 8.4 and 
Appendix 3. Participants may be asked to return for unscheduled visits to perform additional 
safety monitoring.
4.2.1.3
Weight, Laboratory, and Radiological Markers
The study will evaluate weight, laboratory, and radiological markers as changes from 
baseline in the treatment arms to evaluate the impact of DOR/ISL as per the SoA 
(Section 1.3):
Weight
Compared with other antiretroviral classes, use of integrase inhibitors in patients with HIV-1 
has been associated with greater increases in body weight [Hill, A., et al 2019]. The mean 
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change in body weight will be compared between participants who switch to DOR/ISL and 
participants who continue taking BIC/FTC/TAF.
Inflammation
Causes of persistent inflammation and thrombotic activity in patients with HIV-1 remain 
topics of debate and ongoing research [Baker, J. V., et al 2011] [Knudsen, T. B., et al 2016] 
[Wang, H., et al 2016]; thus, key indicators of inflammation will be measured (Section 
8.8.2).
Renal Function
Decreases in renal function have been noted with the use of certain NRTIs [U.S. Prescribing 
Information 2019]; thus, key indicators of renal function will be measured (Section 8.8.3).
Fasting Lipid and Metabolic Profiles
Some antiretrovirals have been associated with lipid abnormalities [U.S. Prescribing 
Information 2017]; thus, key indicators of fasting lipid profiles will be measured (Section 
8.8.4).
Insulin resistance has been reported with certain antiretroviral therapies [Carr, A., et al 1998]. 
It is associated with metabolic complications including diabetes, cardiovascular disease, fatty 
liver and weight gain [Vazquez-Carrera, M. 2016]. Fasting insulin and glucose will be 
measured to calculate HOMA-IR (Section 8.8.4).
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 8.8.6).
4.2.1.4
Pharmacokinetic Endpoints
PK samples collected from all participants as described in the SoA and Section 8.6 will be 
used to evaluate PK concentrations of ISL, and as appropriate, PK-efficacy, PK-
pharmacodynamic, and PK-AE relationships of ISL. PK values such as AUC, Cmax, and 
C24 will be explored.
4.2.1.5
Patient-reported Outcomes
PROs can provide unique information on the impact of HIV infection and its treatment from 
the patients’ perspective as some domains are difficult to observe or are subjective and best 
collected through patient report. HIV infection and its treatment can impair HRQoL. 
Symptom burden associated with HIV treatment has decreased with improvements in ART 
regimens but persists despite viral suppression and immunologic recovery. In conjunction 
with efficacy and safety, PRO data may help clinicians and patients in making informed 
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decisions on appropriate ART regimens. HTA authorities in many countries recommend 
patient perspectives data and HRQoL measurement as part of their drug benefit evaluations. 
HRQoL data is used to estimate health utility scores, which inform cost-effectiveness model 
analysis.
This study will include 3 self-administered PRO questionnaires. The EQ-5D-5L, a generic 
HRQoL questionnaire, will provide a simple descriptive profile and index value for health 
status used to compute health utilities for health economic analyses. The HIV-SI (also known 
as HIV SDM) is a 20-item HIV disease-specific questionnaire designed to assess the 
prevalence and burden of adverse effects associated with ART regimens. The HIVTSQ is a 
10-item instrument used to measure satisfaction with medications for people with HIV 
infection. The status version (HIVTSQs) will be used to evaluate treatment satisfaction over 
time.
4.2.1.6
Planned Exploratory Biomarker Research
4.2.1.6.1
Planned Genetic Analysis
Genetic variation may impact a participant’s response to therapy, susceptibility to, severity, 
and progression of disease. Variable response to therapy may be due to genetic determinants 
that impact drug absorption, distribution, metabolism, and excretion; mechanism of action of 
the drug; disease etiology; and/or molecular subtype of the disease being treated. Therefore, 
where local regulations and IRB/IEC allow, a sample will be collected for DNA analysis 
from consenting participants.
DNA samples may be used for research related to the study intervention(s), the disease under 
study, or related diseases. They may also be used to develop tests/assays including diagnostic 
tests related to the disease under study, related diseases, and study intervention(s). Genetic 
research may consist of the analysis of 1 or more candidate genes, the analysis of genetic 
markers throughout the genome, or analysis of the entire genome. Analysis may be 
conducted if it is hypothesized that this may help further understand the clinical data.
The samples may be analyzed as part of a multi-study assessment of genetic factors involved 
in the response to understand study disease or related conditions.
4.2.1.7
Future Biomedical Research
The Sponsor will conduct future biomedical research on specimens for which consent 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 
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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
The recently 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 infected with HIV-1
[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 DOR/ISL 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 DOR/ISL by maintaining double-blind, double-dummy therapy through Week 96.
4.2.3
Rationale for the Selected Participant Population
The rationale for the participant population selected for this study is as follows:
Participants Switching ART Regimens: Although many ART regimens are associated with
a high likelihood of achieving and maintaining undetectable HIV-1 RNA levels, globally, 
while 70% of all persons living with HIV know their HIV status, only 44% are virologically 
suppressed [Joint United Nations Programme on HIV/AIDS 2017]. Drug-associated adverse 
effects and toxicities, food requirements, high pill burdens, and/or dosing frequency and 
DDIs with concomitant medications are among the reasons that may contribute to lack of 
adherence to prescribed ART regimens. These are the same motivators for patients and 
prescribers to consider switching components of an antiretroviral regimen even in the setting 
of viral suppression before failure can occur.
Furthermore, given the aging of the population with HIV, it is anticipated that switches will 
become even more common in the setting of ongoing concerns for the risks of long-term 
toxicity, DDIs, and comorbid conditions (ie, neuropsychiatric, cardiovascular).
Participants With Virological Suppression for ≥3 Months: With increasing prevalence of 
early treatment initiation, increasing life expectancy for those who are infected with HIV-1,
and decreasing incidence rates of new HIV-1 infections in many parts of the world, an 
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important population in need of improved treatment regimens are those who are already 
virologically suppressed. Data from the ongoing Phase 2 study (MK-8591A P011)
demonstrate that after receiving at least 3 months of the 3-drug regimen of DOR + ISL +
3TC, almost all participants with HIV-1 RNA <50 copies/mL maintained virologic 
suppression on a 2-drug regimen of DOR + ISL through an additional 24 weeks. Based on 
the results of the Phase 2 study, enrollment in this study will be open to those who have 
demonstrated stable suppression with an HIV-1 RNA <50 copies/mL for ≥3 months.
4.2.4
Rationale for Collecting Race and Ethnicity Data
The differential effect on the safety and efficacy based on any demographic parameter, 
including race or ethnicity, cannot be predicted when evaluating a new investigational drug. 
Therefore, it is important to collect race and ethnicity data to ensure that there is not a 
differential effect based on these parameters and to gain assurance the results observed in the 
clinical study will be representative of the drug’s use in a broader patient population. As an 
example, non-Caucasian females and males were found to have higher plasma concentrations 
of EFV (an NNRTI) than their Caucasian counterparts, indicating an increased risk of EFV-
induced toxicity in non-Caucasian patients [Burger, D., et al 2005]. As another example, 
among the population with HIV in the US, those of African heritage have been found to be 
less likely to maintain virologic suppression compared to other groups, and the factors 
contributing to this remain to be elucidated [Weintrob, A. C., et al 2009] [Ribaudo, H. J., et 
al 2013]. Thus, subgroup analyses on race and ethnicity will be performed to better 
understand how these parameters may influence clinical outcome and toxicity.
4.2.5
Rationale for Collecting 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.
4.2.6
Rationale for Infant Safety Data Collection
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.
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4.2.7
Rationale for Continuing Study Intervention During Pregnancy
The US Department of Health and Human Services guidelines currently advise that women 
who become pregnant while receiving ART for HIV infection should continue their regimen 
provided it is safe, well tolerated, and effective at virologic suppression since altering the 
regimen could cause an increase in viral load [Panel on Treatment of Pregnant Women with 
HIV Infection and Prev 2018]. Nonclinical developmental and reproductive toxicology 
studies did not identify any teratogenicity or other clinically relevant concerns, that would 
preclude continued dosing of DOR/ISL in participants who become pregnant and who 
consent to continue study intervention (where allowed by local regulations, health 
authorities, and ethics committees and as appropriate based on available data/local standard-
of-care guidelines) (Sections 8.1.1.4 and 8.11.6).
There are no clinical data currently available to support breastfeeding by participants who are 
receiving DOR/ISL or BIC/FTC/TAF.
4.3
Justification for Dose
Inhibitory quotient (Ctrough/IC50) is the ratio of drug exposure to viral susceptibility. In a 
Phase 1b proof of concept study (MK-8591 P003), single doses as low as 0.5 mg ISL showed 
robust antiretroviral activity at 7 days postdose; this low single-dose provided an IQ 
threshold of 5 for wild-type HIV-1 virus. Simulations suggest the ISL-TP concentrations 
achieved after a single-dose of 0.75 mg ISL provide IQs of 21 and 4 for wild-type and 
M184V virus, respectively. After 7 daily doses of 0.75 mg ISL, IQs increase to 113 for wild-
type virus and 23 for M184V/I virus. Antiretroviral activity against the exceedingly rare 
69ins + M184I/V mutant virus (the NRTI mutant with the highest potency reduction for ISL) 
is expected to be achieved after 7 daily doses, with an IQ of 5. Steady-state concentrations at 
later timepoints will produce even higher IQs, as there is additional accumulation of ISL-TP. 
These simulations support the selection of 0.75 mg ISL in combination with 100 mg DOR to 
maintain virologic suppression in participants who switch from a stable ART regimen, 
BIC/FTC/TAF, at baseline.
In the Phase 2 clinical study (MK-8591 P011), 3 daily doses of ISL (0.25, 0.75, and 2.25 mg)
were evaluated in combination with DOR (100 mg) + 3TC for 24 weeks and subsequently 
with DOR alone through Week 48. All 3 doses of ISL with DOR ± 3TC demonstrated potent 
antiretroviral activity comparable with the comparator, DOR/3TC/TDF, as demonstrated by 
the primary efficacy endpoint: the percentage of participants with HIV-1 RNA 
<50 copies/mL at both Weeks 24 and 48. Overall, no ISL dose-response for efficacy was 
observed. Graphical analysis of steady-state ISL-TP trough concentrations and response at 
Week 48 from MK-8591 P011 showed no trends in exposure-response. The totality of these 
efficacy data supports the conclusion that the dose range studied (0.25 to 2.25 mg daily) is on 
the plateau of the dose-response curve. P011 also demonstrated that all doses of ISL studied, 
when administered with DOR + 3TC or DOR alone, had a favorable safety and tolerability 
profile through Week 48, comparable with that of DOR/3TC/TDF.
DOR will be administered at the approved dose of 100 mg. This dose has been studied in 
Phase 1 to 3 clinical studies in treatment-naïve and virologically suppressed participants with 
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HIV-1 and was selected based upon favorable efficacy, safety, tolerability, and metabolic 
profiles, as confirmed in Phase 3 clinical studies [Orkin, C., et al 2018] [Molina, J. M., et al 
2018] [CSR P024MK1439A ]. Of note, among 32 participants in MK-1439A Protocols 024 
and 030 infected with HIV-1 harboring the NNRTI resistance mutations K103N, Y181C, 
and/or G190A at study entry, all achieved virologic suppression following 48 weeks of 
treatment with DOR/3TC/TDF (24 of 32 participants had been virologically suppressed on PI 
or InSTI regimens and 8 had been treatment-naïve).
In summary, a 0.75-mg dose of ISL in combination with 100 mg DOR is predicted to provide
concentrations that will demonstrate potent antiretroviral activity against both wild-type virus 
and most common NRTI- and NNRTI-resistant variants.
4.4
Beginning and End of Study Definition
The overall study begins when the first participant (or their legally acceptable representative) 
provides documented informed consent. The overall study ends when the last participant 
completes the last study-related contact, withdraws consent, or is lost to follow-up (ie, the 
participant is unable to be contacted by the investigator).
4.4.1
Clinical Criteria for Early Study Termination
The clinical study may be terminated early if the extent (incidence and/or severity) of 
emerging effects/clinical endpoints is such that the risk/benefit ratio to the study population 
as a whole is unacceptable. In addition, further recruitment in the study or at (a) particular 
study site(s) may be stopped due to insufficient compliance with the protocol, Good Clinical 
Practice (GCP), and/or other applicable regulatory requirements, procedure-related problems 
or the number of discontinuations for administrative reasons is too high.
Early study termination will also be considered if futility criteria are met at the Week 24 
interim analysis (Section 9.7).
5
STUDY POPULATION
Participants ≥18 years of age with HIV-1 who have been virologically suppressed for 
≥3 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.
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.
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2. Has been receiving BIC/FTC/TAF therapy with documented viral suppression (HIV-1 
RNA <50 copies/mL) for ≥3 months prior to signing informed consent and has no history 
of prior virologic treatment failure on any past or current regimen.
Note: A non-clinically significant HIV-1 RNA result above the limit of quantification (ie, 
transient detectable viremia) during the 3 months prior to screening is acceptable.
Note: Previous regimen switches for tolerability, side effects, dosing convenience, or cost 
are permitted if they occurred >3 months prior to signing informed consent.
Demographics
3. Is male or female, at least 18 years of age at the time of signing the informed consent.
Contraception/Pregnancy
4. 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 woman of childbearing potential (WOCBP)
OR
•
Is a WOCBP and using an acceptable contraceptive method, 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 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.
Informed Consent
5. The participant (or legally acceptable representative) has provided documented informed 
consent for the study. The participant may also provide consent for future biomedical 
research. However, the participant may participate in the main study without participating 
in future biomedical research.
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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 an active diagnosis of hepatitis due to any cause, including active HBV coinfection 
(defined as HBsAg-positive or HBV DNA positive).
Note: Past HBV infection or previous HBV vaccination (defined as HBsAg negative and 
positive for antibody against HBsAg) is not an exclusion criterion.
Note: Participants who do not demonstrate immunity to HBV are encouraged to be 
vaccinated against HBV.
Note: Chronic HCV infection (detectable HCV RNA) and treatment with direct-acting 
antiviral therapies are not exclusionary, provided the participant has stable liver function 
tests and no significant hepatic synthetic dysfunction. Hepatic synthetic dysfunction is
defined as a serum albumin <2.8 g/dL or an INR >1.7 in the absence of another 
explanation for the abnormal laboratory value.
4. Has a history of malignancy ≤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.
5. Has a history or current evidence of any condition (including active tuberculosis 
infection), therapy, laboratory abnormality or other circumstance (including drug or 
alcohol use or dependence) that might, in the opinion of the investigator, confound the 
results of the study or interfere with the participant’s participation for the full duration of 
the study, such that it is not in the best interest of the participant to participate.
Prior/Concomitant Therapy
6. 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.
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Prior/Concurrent Clinical Study Experience
7. 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 non-interventional studies may be 
permitted and should be discussed with the Sponsor prior to enrollment and through 
study duration.
Diagnostic Assessments
8. Has a documented or known virologic resistance to DOR, as demonstrated by any of the 
following DOR resistance substitutions in reverse transcriptase:
V106A/M, V108I, Y188L, H221Y, P225H, F227C/L, M230I/L, L234I, P236L, or 
Y318F.
Note: Participants who do not have documentation of resistance testing may enroll.
9. 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
>3 × ULN
AST 
>5 × ULN
ALT 
>5 × ULN
Hemoglobin
<9.0 g/dL (female) or <10.0 g/dL (male)
Calculated Crcl
≤30 mL/min based on the Cockcroft-Gault 
equation (Appendix 8).
ALT=alanine aminotransferase; AST=aspartate aminotransferase; Crcl=creatinine clearance; ULN=upper 
limit of normal.
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Other Exclusions
10. 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.
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 
Consolidated Standards of Reporting Trials (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 consent will not be 
replaced.
6
STUDY INTERVENTION
Study intervention is defined as any investigational intervention(s), marketed product(s), 
placebo, or medical device(s) intended to be administered to a study participant according to 
the study protocol.
Clinical supplies (study interventions provided by the Sponsor) will be packaged to support 
enrollment. Clinical supplies will be affixed with a clinical label in accordance with 
regulatory requirements.
6.1
Study Intervention(s) Administered
The study interventions to be used in this study are outlined in Table 2. Country specific 
differences are noted in Appendix 7. 
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Table 2
Study Interventions
Arm 
Name
Arm Type
Intervention
Name
Type
Dose 
Form-
ulation
Unit Dose 
Strength(s)
Dosage 
Level(s)
Route of 
Adminis-
tration
Treatment 
Period
Use
IMP/
NIMP
Sourcing
Group 1
Experimental
DOR/ISL 
(blinded)
Drug
Tablet
100 mg/
0.75 mg
100 mg/
0.75 mg 
qd
Oral
Day 1 to 
Week 96 
Test 
product
IMP
Provided 
centrally by 
the Sponsor
Group 1
Experimental
Placebo to 
BIC/FTC/TAF 
(blinded)
Drug
Tablet
0 mg
0 mg qd
Oral
Day 1 to 
Week 96
Placebo
IMP
Provided 
centrally by 
the Sponsor
Group 2
Active 
Comparator
BIC/FTC/TAF 
(blinded)
Drug
Tablet
50 mg/
200 mg/
25 mg
50 mg/
200 mg/
25 mg 
qd
Oral
Day 1 to 
Week 96
Comparator
IMP
Provided 
centrally by 
the Sponsor
Group 2
Active 
Comparator
Placebo to 
DOR/ISL 
(blinded)
Drug
Tablet
0 mg
0 mg qd
Oral
Day 1 to 
Week 96
Placebo
IMP
Provided 
centrally by 
the Sponsor
Group 1
Experimental
DOR/ISL 
(open-label)
Drug
Tablet
100 mg/
0.75 mg
100 mg/
0.75 mg 
qd
Oral
Week 96 to 
Week 168a,c
Test 
product
IMP
Provided 
centrally by 
the Sponsor
Group 2
Active 
Comparator
BIC/FTC/TAF 
(open-label)
Drug
Tablet
50 mg/
200 mg/
25 mg
50 mg/
200 mg/
25 mg 
qd
Oral
Week 96 to 
Week 168b,c
Comparator
IMP
Provided 
centrally by 
the Sponsor
BIC=bictegravir; DOR=doravirine; FTC=emtricitabine; ISL=islatravir; qd=once-daily; TAF=tenofovir alafenamide.
Definition Investigational Medicinal Product (IMP) and Non-Investigational Medicinal Product (NIMP) is based on guidance issued by the European 
Commission. Regional and/or Country differences of the definition of IMP/NIMP may exist. In these circumstances, local legislation is followed.
a If a participant in Group 1 is pregnant at their last routine study visit, they will continue to receive DOR/ISL for the duration of their pregnancy. Study 
intervention will be provided centrally by the Sponsor.
b If a participant in Group 2 is pregnant at their last routine study visit, the investigator should refer to local product circular and local guidelines to determine if 
BIC/FTC/TAF treatment can be continued. If the decision is made for the participant to continue to receive BIC/FTC/TAF, study intervention will be provided 
centrally by the Sponsor for the duration of their pregnancy.
c Participants who consent to the study extension may continue their assigned study medication up to Week 168 if needed.
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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.
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
Intervention randomization will occur centrally using an interactive response technology 
(IRT) system. There are 2 study intervention arms. Participants will be assigned randomly in 
a 1:1 ratio to Group 1 or Group 2, respectively.
6.3.2
Stratification
No stratification based on age, sex, or other characteristics will be used in this study.
6.3.3
Blinding
A double-blinding technique with in-house blinding will be used. DOR/ISL and 
BIC/FTC/TAF will be packaged identically relative to their matching placebos so that blind 
is maintained. The participant, the investigator, and Sponsor personnel or delegate(s) who are 
involved in the study intervention administration or clinical evaluation of the participants are 
unaware of the intervention assignments.
Clinical site personnel and participants will remain blinded through Week 96 while all 
Sponsor personnel will remain blinded through Week 48. Sponsor personnel involved in 
performing and reviewing results of the Week 48 analysis will be unblinded after the 
Week 48 database lock.
As described in Section 4, at Week 96 all clinical site personnel and participants will be 
unblinded and will continue to receive their assigned study intervention open-label through 
Week 144 (and to maximum of Week 168 if participating in the study extension). 
To allow timely completion of population PK modeling, restricted early (before database 
lock) unblinding of PK data may be requested. No personnel directly associated with study 
conduct will be unblinded before the database lock at Week 48. Before granting select 
personnel access to unblinded PK data, an official memo detailing unblinding procedures 
will be generated per Sponsor SOP. This memo will list the names of the personnel who will 
have access to unblinded PK data before database lock.
6.4
Study Intervention Compliance
Participants should be instructed to bring the study intervention bottles to their visits. At each 
visit, the number of tablets remaining in the study packaging will be counted, reviewed, and 
recorded. 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. Participants should be reminded of the importance of 
taking their study intervention as instructed for the entire duration of the study.
Decisions to temporarily withhold study intervention 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 7 consecutive days or longer require 
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consultation between the investigator and the Sponsor and written documentation of the 
collaborative decision on participant management.
6.5
Concomitant Therapy
Medications specifically prohibited in the exclusion criteria are not allowed during time 
periods specified by this protocol for that medication or vaccination. If there is a clinical 
indication for any medications specifically prohibited, discontinuation from study 
intervention may be required. The investigator should discuss any questions regarding this 
with the Sponsor Clinical Director. The final decision on any supportive therapy rests with 
the investigator and/or the participant’s primary physician. However, the decision to continue 
the participant on study intervention requires the mutual agreement of the investigator, the 
Sponsor, and the participant.
Prior and concomitant therapies listed in Table 3 are not permitted from 45 days prior to 
Day 1 through the study treatment period. 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 Clinical Director or designee should be contacted if there are any 
questions about a therapy not on the list below or regarding potential DDI interactions with a 
specific treatment that the participant may plan to receive.
In instances where the local product circular for DOR or BIC/FTC/TAF is more restrictive 
with regard to prohibited (ie, contraindicated or not recommended) therapy(ies), the local 
product circular supersedes this section.
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. Refer to the local product circular for BIC/FTC/TAF for additional information.
For participants taking medications or oral supplements containing polyvalent cations (eg, 
Mg, Al, Ca, Fe), study intervention should be taken either 2 hours before or 6 hours after 
taking any polyvalent cation containing medicine.
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Table 3
Prohibited Therapies
Strong and moderate CYP3A 
inducers
Including, but not limited to:
Carbamazepine
Oxcarbazepine
Phenobarbital
Phenytoin
Enzalutamide
Rifabutin
Rifampin
Rifapentine
Mitotane
St. John’s Wort
Herbal remedies
Modafinil
Bosentan
Nafcillin
Non-study ART
All non-study antiretrovirals (with the exception of
baseline ART during the screening period and 
intrapartum treatment [eg, IV AZT] in the case of 
pregnancy)
Immunosuppressive 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 non-study investigational agents including 
devices
Antiarrhythmics
Dofetilide
Additional prohibited therapies 
based on ISL
Pentostatin
ART=antiretroviral therapy; CYP3A=cytochrome P450 3A; ISL=islatravir.
6.5.1
Rescue Medications and Supportive Care
No rescue or supportive medications are specified for use in this study.
6.6
Dose Modification (Escalation/Titration/Other)
No dose modification of DOR/ISL or BIC/FTC/TAF is allowed during the study.
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6.7
Intervention After the End of the Study
The following options are available upon study completion: 
Group 1 participants (DOR ISL 100 mg/0.75 mg) may be eligible to enroll in an open-label 
study of DOR/ISL 100 mg/0.25 mg, where available. Participants who are not eligible or do 
not consent to continued participation in the DOR/ISL investigational program should be 
transitioned to commercially available ART. Group 1 participants receiving DOR/ISL 100
mg/0.75 mg with decreases in CD4+ T-cell count and/or lymphocyte count should be 
managed per Section 8.11.5.3. 
Group 2 participants (BIC/FTC/TAF) may be eligible to enroll in randomized studies of a 
switch to DOR/ISL 100 mg/0.25 mg, where available. Participants who are not eligible or do 
not consent to continued participation in the DOR/ISL investigational program should be 
transitioned to commercially available ART.
6.8
Clinical Supplies Disclosure
The emergency unblinding call center will use the intervention/randomization schedule for 
the study to unblind participants and to unmask study intervention identity. The emergency 
unblinding call center should only be used in cases of emergency (see Section 8.1.10). 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 Week 96 while Sponsor 
personnel will remain blinded through Week 48. 
6.9
Standard Policies
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 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. You did not receive the active 
drug/vaccine BIKTARVY 50/200/25 mg (BICTEGRAVIR/EMTRICITABINE/
TENOFOVIR ALAFENAMIDE) as manufactured by Gilead Sciences, Inc.”
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7
DISCONTINUATION OF STUDY INTERVENTION AND PARTICIPANT 
WITHDRAWAL
7.1
Discontinuation of Study Intervention
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 requests to discontinue study intervention.
•
The participant has a medical condition or personal circumstance (for pregnancy, see
Section 8.11.6), which in the opinion of the investigator and/or Sponsor, places 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.
Occurrence of any Category C conditions included in the CDC 1993 Revised 
Classification System for HIV Infection and Expanded Surveillance Case Definition for 
AIDS Among Adolescents and Adults [Centers for Disease Control (CDC) 1992].
•
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 chooses to breastfeed.
Note: Study intervention can continue until breastfeeding is initiated.
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A participant must be discontinued from study intervention and managed per Section 8.11.5
if any of the following criteria are met:
1. Discontinuation criteria for CD4+ T-cell count:
a.
For participants with an average baseline* CD4+ T-cell count ≥500 cells/mm3, a 
≥30% reduction from average baseline in CD4+ T-cell count AND a CD4+ T-cell 
count decrease to <500 cells/mm3 on 2 consecutive measurements taken 3 to 4 weeks 
apart
OR
b. For participants with an average baseline* CD4+ T-cell count <500 cells/mm3, a 
≥30% reduction from average baseline in CD4+ T-cell count on 2 consecutive 
measurements taken 3 to 4 weeks apart
OR
c.
For all participants with an average baseline* CD4+ T-cell count ≥200 cells/mm3
(including participants with an average baseline CD4+ T-cell counts <200 cells/mm3
who have increases in CD4+ T-cell count to ≥200 cells/mm3 for 3 consecutive 
months), a CD4+ T-cell count decrease to <200 cells/mm3 on 2 consecutive 
measurements taken 3 to 4 weeks apart
2. Discontinuation criteria for total lymphocyte count:
For participants with an average baseline* total lymphocyte count ≥1 x 109 cells/L:
a ≥30% reduction from average baseline* total lymphocyte count AND a decrease in total 
lymphocyte count to <1 x 109 cells/L on 2 consecutive measurements taken 3 to 4 weeks 
apart
OR
a ≥30% reduction from average baseline* total lymphocyte count with total lymphocyte 
count remaining ≥1 x 109 cells/L on 2 consecutive measurements taken 10 to 14 weeks 
apart.
For participants with an average baseline* total lymphocyte count <1 x 109 cells/L, a ≥30% 
reduction from average baseline* total lymphocyte count on 2 consecutive measurements 
taken 3 to 4 weeks apart.
* Average baseline is defined as the average value between screening (within 45 days prior 
to the first dose of study intervention) and Day 1.
7.2
Participant Withdrawal From the Study
A participant must be withdrawn from the study if the participant withdraws consent from the 
study.
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If a participant withdraws from the study, they will no longer receive study intervention or be 
followed at scheduled protocol visits.
Specific details regarding procedures to be performed at the time of withdrawal from the 
study, as well as specific details regarding withdrawal from future biomedical research, are 
outlined in Section 8.1.9. The procedures to be performed should a participant repeatedly fail 
to return for scheduled visits and/or if the study site is unable to contact the participant are 
outlined in Section 7.3.
7.3
Lost to Follow-up
If a participant fails to return to the clinic for a required study visit and/or if the site is unable 
to contact the participant, the following procedures are to be performed:
The site must attempt to contact the participant and reschedule the missed visit. If the 
participant is contacted, the participant should be counseled on the importance of 
maintaining the protocol-specified visit schedule.

The investigator or designee must make every effort to regain contact with the participant 
at each missed visit (eg, telephone calls and/or a certified letter to the participant’s last 
known mailing address or locally equivalent methods). These contact attempts should be 
documented in the participant’s medical record.
8
STUDY ASSESSMENTS AND PROCEDURES

Study procedures and their timing are summarized in the SoA.
•
Adherence to the study design requirements, including those specified in the SoA, is 
essential and required for study conduct.
•
The investigator is responsible for ensuring that procedures are conducted by 
appropriately qualified (by education, training, and experience) staff. Delegation of study 
site personnel responsibilities will be documented in the Investigator Trial File Binder (or 
equivalent).
•
All study-related medical decisions must be made by an investigator who is a qualified 
physician.
•
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.
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The amount of blood collected from each participant over the full duration of the study is 
provided in Table 17 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 informed consent from each potential participant (or their legally 
acceptable representative) prior to participating in this clinical study or future biomedical 
research. If there are changes to the participant’s status during the study (eg, health or age of 
majority requirements), the investigator or medically qualified designee must ensure the 
appropriate documented informed consent is in place.
8.1.1.1
General Informed Consent
•
Informed consent given by the participant or their legally acceptable representative must 
be documented on a consent form. The form must include the trial protocol number, trial 
protocol title, dated signature, and /agreement of the participant (or his/her legally 
acceptable representative) and of the person conducting the consent discussion.
•
A copy of the signed and dated informed consent form should be given to the participant 
(or their legally acceptable representative) before participation in the study.
•
The initial ICF, any subsequent revised ICF, and any written information provided to the 
participant must receive the IRB/IEC’s approval/favorable opinion in advance of use. The 
participant 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 or 
the participant’s legally acceptable representative’s dated signature.
•
Specifics about the study and the study population are to be included in the study 
informed consent form. 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
The investigator or medically qualified designee will explain the future biomedical research 
consent to the participant, or the participant’s legally acceptable representative, answer all of 
their questions, and obtain documented informed consent before performing any procedure 
related to future biomedical research. A copy of the informed consent will be given to the 
participant before performing any procedure related to future biomedical research.
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8.1.1.3
Consent for Postnatal Infant Safety Data Collection Through One Year of 
Age
The investigator or medically qualified designee will explain the infant safety data collection
consent to the participant, or the participant’s legally acceptable representative, answer all 
questions, and obtain documented informed consent before collecting any data related to 
infant safety. A copy of the informed consent will be given to the participant.
8.1.1.4
Consent for Continuation of Study Intervention During Pregnancy
Upon learning that a participant is pregnant and following unblinding, the investigator or 
medically qualified designee and the participant will discuss the potential benefits and risks 
of continuing (or discontinuing) study intervention (Section 8.11.6). A separate consent is 
required to continue study intervention in participants who become pregnant. The 
investigator or medically qualified designee will explain the consent to the participant, or the 
participant’s legally acceptable representative, answer all of their questions, and obtain 
documented informed consent before continuing study intervention. A copy of the informed 
consent will be given to the participant.
8.1.1.5
Consent to Participate in the Optional Plasma/PBMC PK Substudy
(Applicable Only to the United States)
See Section 10.7.4.1.1.
8.1.1.6
Consent to Participate in the Optional Investigational Research Substudy
(Applicable Only to the United States)
See Section 10.7.4.2.1.
8.1.1.7
Consent to Participate in the Study Extension
The investigator or medically qualified designee will explain the study extension to the 
participant, or the participant’s legally acceptable representative, answer all questions, and 
obtain documented informed consent before participating in the study extension. A copy of 
the informed consent will be given to the participant (see Section 8.11.2.3).
8.1.2
Inclusion/Exclusion Criteria
All inclusion and exclusion criteria will be reviewed by the investigator, who is a qualified 
physician, to ensure that the participant qualifies for the study.
8.1.3
Participant Identification Card
All participants will be given a participant identification card identifying them as participants 
in a research study. The card will contain study site contact information (including direct 
telephone numbers) to be used in the event of an emergency. The investigator or qualified 
designee will provide the participant with a participant identification card immediately after 
the participant provides documented informed consent. At the time of intervention
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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 
smoking 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 and record prior 
medication taken by the participant within 45 days before 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.
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 
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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
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 within 24 hours of randomization.
8.1.8.1
Timing of Dose Administration
From Day 1 to Week 96, participants will take (unsupervised at their home) 2 tablets of 
blinded study intervention qd at the same time each day (1 tablet from each of 2 containers
taken together; (1) Bottle A: DOR/ISL or matching placebo, and (2) Bottle B: BIC/FTC/TAF 
or matching placebo). Study intervention will be taken without regard to food. If more than 1
bottle A is dispensed, the participant is instructed to use all of the medication in 1 Bottle A 
before opening another Bottle A. From Week 96 through the end of study, participants will 
take 1 tablet of open-label study intervention qd at the same time each day.
If a participant misses a dose of any of the study interventions, 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 of Treatment visit performed per SoA (Section 1.3) 
and be encouraged to continue to be followed as outlined in Section 8.11.3.
Participants who discontinue study intervention due to decreases in CD4+ T-cell counts 
and/or total lymphocyte counts or who discontinue for any other reason and are found to 
have decreases in CD4+ T-cell count and/or total lymphocyte count of >10% of the average 
baseline value or that meet ECI criteria at the Early Discontinuation of Treatment Visit 
should be unblinded (if applicable), and those treated with DOR/ISL should be managed per
Section 8.11.5 until their counts recover.
When a participant withdraws from participation in the study, all applicable activities 
scheduled for the Early Discontinuation of Treatment visit should be performed (at the time 
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of withdrawal). Any AEs that are present at the time of withdrawal should be followed in 
accordance with the safety requirements outlined in Section 8.4.
8.1.9.1
Withdrawal From Future Biomedical Research
Participants may withdraw their consent 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
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.
Once an emergency unblinding has taken place, the principal investigator, site personnel, and 
Sponsor personnel may be unblinded so that appropriate follow-up medical care can be 
provided to the participant.
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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 Patient Questionnaires
Participants will complete 3 PRO questionnaires at Day 1, Week 4, Week 12, Week 48, and 
Week 96 and/or at the Early Discontinuation of Treatment visit (if at or before Week 96).
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.
The participant responses to questionnaires will be entered into the appropriate eCRF by site 
staff according to data entry guidelines.
8.2
Efficacy Assessments
8.2.1
HIV-1 RNA
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
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.
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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 of Treatment and End of Treatment Follow-up visit 
procedures should be completed (Sections 1.3.3 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 confirmed HIV-1 RNA ≥200 copies/mL at any time during the study will 
be assessed for development of viral drug resistance.
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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 Profile (TBNK)
A TBNK panel, including CD4+ T-cell count, will be performed at the central laboratory (see 
Table 16 in Appendix 2). Refer to Section 8.11.5 for guidance on management of participants 
with decreased CD4+ T-cell counts and/or decreased total lymphocyte counts.
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, 
including approximate blood volumes drawn/collected by visit and by sample type per 
participant, can be found in Table 17 in Appendix 2.
Planned time points for all safety assessments are provided in the SoA.
8.3.1
Physical Examinations
A complete physical examination will be conducted by an investigator or medically qualified 
designee (consistent with local requirements) as per institutional standard. 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).
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. 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). 
Participants should remove their shoes and wear a single layer of clothing at each 
measurement.
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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
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 
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 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 8.11.6.
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 case report form 
(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.
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
All protocol-required laboratory assessments, as defined in Table 16 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.

Management of decreases in CD4+ T-cell and/or total lymphocyte counts is described in
Section 8.11.5.
8.3.6
HBV Assessments
Participants coinfected with HIV-1 and HBV who discontinue an antiretroviral medication 
that also has activity against HBV (3TC, FTC, TAF, or TDF) may experience an acute 
exacerbation of HBV. Therefore, participants who have evidence of past HBV exposure 
(anti-HBc positive) and who meet enrollment criteria will be closely monitored during the 
study.
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).
Participants who are confirmed to be HBsAg or HBV DNA positive after randomization will 
be unblinded and be managed by the investigator per local standard-of-care and/or referred 
for management of their HBV infection. Participants may be allowed to continue study 
intervention if deemed medically appropriate upon consultation with the Sponsor.
8.3.7
Tobacco and Alcohol Assessments
Participants’ use of tobacco and alcohol will be obtained and recorded at Weeks 48, 96 and 
144.
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8.4
Adverse Events (AEs), Serious Adverse Events (SAEs), 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 participant provides 
documented informed consent 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 and consent to infant safety data 
collection, SAEs (including perinatal HIV-1 infection) occurring through 1 year of age must 
be reported by the investigator to the Sponsor within 24 hours of learning of the event.
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.
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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 4.
Table 4
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:
Nonserious 
Adverse Event 
(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
Serious Adverse 
Event (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:
- due to intervention
- causes exclusion
Report all
Previously reported – Follow 
to completion/termination; 
report outcome
Within 24 hours of 
learning of event
Event of Clinical 
Interest (require 
regulatory 
reporting)
Report if:
- due to intervention
- causes exclusion
Report
- Potential drug-induced 
liver injury (DILI)
- Require regulatory 
reporting
Not required
Within 24 hours of 
learning of event
Event of Clinical 
Interest (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
Overdose
Report if:
- receiving placebo 
run-in or other run-in 
medication 
Report all
Not required
Within 5 calendar 
days of learning of 
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.
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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, events of clinical interest (ECIs), 
cancer, and overdose will be followed until resolution, stabilization, until the event is 
otherwise explained, or the participant is lost to follow-up (as defined in Section 7.3). In 
addition, the investigator will make every attempt to follow all nonserious AEs that occur in
randomized participants for outcome. Further information on follow-up procedures is given 
in Appendix 3.
8.4.4
Regulatory Reporting Requirements for SAE
Prompt notification (within 24 hours) by the investigator to the Sponsor of SAE is essential 
so that legal obligations and ethical responsibilities towards the safety of participants and the 
safety of a study intervention under clinical investigation are met.
The Sponsor has a legal responsibility to notify both the local regulatory authority and other 
regulatory agencies about the safety of a study intervention under clinical investigation. The 
Sponsor will comply with country-specific regulatory requirements and global laws and 
regulations relating to safety reporting to regulatory authorities, IRB/IECs, and investigators.
Investigator safety reports must be prepared for suspected unexpected serious adverse 
reactions (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 and consent to infant safety data 
collection, SAEs (including perinatal HIV-1 infection) occurring through 1 year of age must 
be reported by the investigator to the Sponsor within 24 hours of learning of the event.
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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 (ECIs)
Selected nonserious and SAEs are also known as ECIs and must be reported to the Sponsor.
Events of clinical interest for this study include:
1. An elevated AST or ALT lab value that is greater than or equal to 3X the upper limit of 
normal and an elevated total bilirubin lab value that is greater than or equal to 2X the 
upper limit of normal and, at the same time, an alkaline phosphatase lab value that is less 
than 2X the upper limit of normal, as determined by way of protocol-specified laboratory 
testing or unscheduled laboratory testing.*
*Note: These criteria are based upon available regulatory guidance documents. The 
purpose of the criteria is to specify a threshold of abnormal hepatic tests that may require 
an additional evaluation for an underlying etiology. The study site guidance for 
assessment and follow-up of these criteria can be found in the Investigator Study File 
Binder (or equivalent).
2. A ≥30% reduction from average baseline** in CD4+ T-cell count or total lymphocyte 
count while on study intervention.
3. A CD4+ T-cell count of <200 cells/mm3 while on study intervention from either (a) 
participants whose average baseline** CD4+ T-cell count was ≥200 cells/mm3 or (b) 
participants whose CD4+ T-cell count increased to ≥200 cells/mm3 for 3 consecutive 
months while on study intervention.
**Note: The average baseline value for CD4+ T-cell count and total lymphocyte count is 
defined as the average value between screening (within 45 days prior to the first dose of 
study intervention) and Day 1. The first on-treatment value that reaches the above CD4+ T-
cell or total lymphocyte criteria should be reported as an ECI. See Section 8.11.5 for further 
guidance on the management of participants meeting CD4+ T-cell and total lymphocyte 
criteria.
8.5
Treatment of Overdose
In this study, an overdose is any dose higher than the prescribed dose of study intervention.
No specific information is available on the treatment of overdose.
Decisions regarding dose interruptions will be made by the investigator in consultation with 
the Sponsor Clinical Director based on the clinical evaluation of the participant.
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8.6
Pharmacokinetics
8.6.1
Blood Collection for Plasma ISL
Venous blood samples will be collected for measurement of ISL. 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.
Population PK samples will be collected from all participants as outlined in Table 5. The 
time of the doses of study interventions taken prior to the sample collection will be verbally 
reported to study staff by the participant and recorded in the appropriate source 
documentation.
For participants who routinely take their study intervention during the day, a predose and 
postdose sample will be taken at the Week 4 visit Table 5. Participants who routinely take 
their study intervention in the evening should continue to do so, and only 1 sample will be 
taken at the Week 4 visit irrespective of time of the last dose.
For participants who become pregnant and consent to continue DOR/ISL, PK samples will be 
collected to evaluate DOR and ISL concentration levels per Table 6 Section 8.11.6.1.
Table 5
Collection of Population PK Samples
Study Visit
Time Relative to Dose
Day 1
Predose
Week 4
Predose and within 0.5 to 2 hours postdose
Week 12
Sample collected irrespective of time of dose (time of last dose and 
time of PK sample collection must be documented)
Week 24
Sample collected irrespective of time of dose (time of last dose and 
time of PK sample collection must be documented)
Week 48
Sample collected irrespective of time of dose (time of last dose and 
time of PK sample collection must be documented)
PK=pharmacokinetic.
8.7
Pharmacodynamics
Pharmacodynamic parameters will not be evaluated in this study.
See Section 10.7.4.2 for the additional investigational research substudy (applicable only to 
the United States).
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8.8
Biomarkers
8.8.1
Planned Genetic Analysis Sample Collection
The planned genetic analysis sample should be drawn for planned analysis of the association 
between genetic variants in DNA and drug response. This sample will not be collected at the 
site if there is either a local law or regulation prohibiting collection, or if the IRB/IEC does 
not approve the collection of the sample for these purposes. If the sample is collected, 
leftover extracted DNA will be stored for future biomedical research if the participant 
provides documented informed consent for future biomedical research. 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
Inflammation
Blood samples will be collected to evaluate the inflammatory and thrombotic response as 
measured by the following laboratory markers as indicated in the SoA (Section 1.3):
•
IL-6
•
D-dimer
•
sCD-163
•
hs-CRP
8.8.3
Renal Function
Urine and blood samples will be collected to evaluate renal function as measured by key 
indicators, such as the following potential analytes and calculations:
•
Urine: albumin, protein, beta-2-microglobulin/creatinine ratio, and retinol binding 
protein/creatinine ratio
•
Serum: cystatin-C and creatinine clearance
8.8.4
Fasting Lipid and Metabolic Profiles
Participants will be asked to fast for at least 8 hours prior to visits where blood will be taken 
to measure insulin, glucose, HDL-C, LDL-C, TGs, TC, and non-HDL-C. HOMA-IR will be 
calculated.
Participants with diabetes mellitus (type 1 or type 2) or insulin resistance are not required to 
have the blood draw for insulin testing.
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8.8.5
Waist and Hip Measurements
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).
8.8.6
DEXA Assessments
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
(Appendix 7, 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).
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.
DEXA should not be performed on pregnant participants.
8.9
Future Biomedical Research Sample Collection
If the participant provides documented informed consent for future biomedical research, 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
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•
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
Health Economics Medical Resource Utilization and Health Economics
Medical Resource Utilization and Health Economics are not evaluated in this study.
8.11
Visit Requirements
Visit requirements are outlined in Section 1.3. Specific procedure-related details are provided 
in Section 8.
8.11.1
Screening/Rescreening
Screening
Prior to randomization, potential participants will be evaluated to determine that they fulfill 
the entry requirements as set forth in Section 5. Participants are expected to enroll as soon as 
possible after eligibility is confirmed. In cases of unexpected delays in receiving repeat 
screening laboratory results, a screening period of up to 45 days is allowed.
Rescreening
If the screening window has been exceeded, participants are allowed to rescreen one 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 β-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, documented informed consent 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).
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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 <3 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 ≥3 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
Visits at Day 1, Week 24, Week 48, Week 96, Week 120, Week 144 and Week 168 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.
8.11.2.2
Optional Nurse Visits and Telephone Visits
A visiting nurse service may be utilized (if locally available and approved for use) at any 
visit after a participant is randomized. If a visiting nurse service is utilized 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 2-4 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.
8.11.2.3
Week 144 Visit
Week 144 represents the end of the base study. Participants will be given the following
options at the Week 144 visit:

End participation in this study and resume locally available treatment of their choice. 
These participants should have an End of Treatment Follow-up Visit 42 days (+7 
days) after the last dose of study intervention.

Provide documented consent to participate in the study extension to continue study 
intervention for a maximum of 24 additional weeks. 
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
Enroll in a new study of DOR/ISL 100 mg/0.25 mg (where available).
Participants who are pregnant at Week 144 will be managed per Section 8.11.6.
8.11.3
Participants Who Discontinue Study Intervention
A participant must be discontinued from study intervention but continue to be monitored for 
any of the reasons listed in Section 7.1.
When it is determined that discontinuation from study intervention is appropriate, the 
participant should have both an Early Discontinuation of Treatment visit (Section 8.11.3.1) 
and an End of Treatment Follow-up visit (Section 8.11.3.2) conducted. After the visit 
procedures are completed, the participant will be withdrawn from the study and managed for 
the treatment of HIV-1 per local standard of care.

Guidance for management of participants who discontinue study intervention due to 
confirmed decreased CD4+ T-cell counts and/or decreased total lymphocyte counts is 
provided in Section 8.11.5.

If participants receiving DOR/ISL discontinue study intervention for other reasons 
and the CD4+ T-cell count and/or total lymphocyte count at the Early Discontinuation 
of Treatment visit is decreased by >10% of their average baseline value or meets ECI 
criteria, additional monitoring is required per Section 8.11.5.
8.11.3.1
Early Discontinuation of Treatment
Participants who discontinue treatment early for any reason should have an Early 
Discontinuation of Treatment visit as outlined in Section 1.3.3. If early discontinuation 
occurs during the timeframe of a scheduled study visit, the assessments for the Early 
Discontinuation of Treatment visit should be conducted.
8.11.3.2
End of Treatment Follow-up Visit
Participants who discontinue study intervention at any time for any reason(s) will have a 
safety follow-up visit in-clinic 42 days (+7 days) after the last dose of study intervention.
Assessments for this End of Treatment Follow-up visit are outlined in Section 1.3.3.
Participants ending study treatment should have an End of Treatment follow-up visit unless 
enrolling in a new study within the DOR/ ISL 100 mg/ 0.25 mg program.
Participants discontinuing DOR/ISL with specified decreases in CD4+ T-cell and/or total 
lymphocyte counts will be followed for monitoring of CD4+ T-cell and total lymphocyte 
counts recovery as per Section 8.11.5.
8.11.4
Viremia Confirmation
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 
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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
Management of Participants with Decreases in CD4+ T-cell Counts and/or 
Total Lymphocyte Counts
Management of participants with decreases in CD4+ T-cell count and/or total lymphocyte 
count is explained below.
8.11.5.1
Participants Whose CD4+ T-cell Count and/or Total Lymphocyte Count
Decreases Meet Criteria for Events of Clinical Interest While on Study 
Intervention
Participants whose decreases in CD4+ T-cell count and/or total lymphocyte count meet ECI 
criteria (Section 8.4.7) must have a confirmation visit in 3 to 4 weeks*.
*Note Exception:
Participants with an average baseline total lymphocyte count
≥1 x 109 cells/L and a ≥30% reduction from average baseline with the 
count remaining ≥1 x 109 cells/L, should have a confirmation visit in 10 
to 14 weeks (or earlier if applicable).
Upon repeat testing at the confirmation visit (Section 1.3.5), the participant must be 
discontinued from study intervention if the discontinuation criteria are met (Section 7.1) and 
unblinded (if applicable). If receiving DOR/ISL, the participant must be managed per Section 
8.11.5.2.
Upon repeat testing at the confirmation visit (Section 1.3.5), if the ECI criteria are confirmed 
but the values do not meet discontinuation criteria, the Sponsor must be consulted. 
Treatment may be continued with approval from Sponsor.
8.11.5.2
Participants Discontinued from Study Intervention Due to Decreased CD4+ 
T-cell Count and/or Total Lymphocyte Count
After discontinuation from study intervention, participants will be managed for treatment of 
HIV-1 per local standard-of-care.
Participants discontinued from study intervention due to specified decreases in CD4+ T-cell 
and/or total lymphocyte counts should be unblinded (if applicable) and followed as noted 
below:
Participants who received DOR/ISL should undergo assessments as specified under the Early 
Discontinuation of Treatment visit and the End of Treatment Follow-up visit (Section 1.3.5). 
CD4+ T-cell counts and total lymphocyte counts will be monitored until 2 values 
approximately 10 to 14 weeks apart are within 30% of the average baseline value. If 
additional test results are available within this timeframe, no more than 1 value should show 
a decrease of ≥30% of average baseline. 
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Participants who have previously met the above recovery criterion after discontinuing 
DOR/ISL no longer require monitoring regardless of test results from the most recent visit.
If after ≥24 months following discontinuation of DOR/ISL, a participant has not met the 
above recovery criterion, and their CD4+ T-cell count or total lymphocyte values have 
increased since discontinuation, then the Sponsor may be consulted to discuss whether 
monitoring may be stopped (based on the participant’s clinical status and the trajectory of 
laboratory test results).
Participants who were receiving BIC/FTC/TAF who discontinue study intervention due to 
decreases in CD4+ T-cell counts or total lymphocyte counts should have an Early 
Discontinuation of Treatment visit (Section 8.11.3.1) and an End of Treatment Follow-up 
visit (Section 8.11.3.2) and no further monitoring is needed; see also Section 1.3.3.
8.11.5.3
Participants Discontinued from Study Intervention for Other Reasons And
Have Decreases in CD4+ T-cell and/or Total Lymphocyte Counts
Participants who discontinue study intervention for any other reason and are found to have 
decreases in CD4+ T-cell and/or total lymphocyte counts of >10% of the average baseline 
values or that meet ECI criteria at the Early Discontinuation of Treatment Visit should be 
unblinded (if applicable) to determine their follow-up as noted below:
Participants who were receiving DOR/ISL and choosing not to enroll directly in one of the 
DOR/ISL 100 mg/0.25 mg studies, should undergo assessments specified at the End of 
Treatment Follow-up visit at Day 42 (Section 1.3.5).  
If the decrease(s) of >10% of average baseline or a decrease in CD4+ T-cell counts to <200 
cells/mm3 is confirmed at this visit, participants should continue to be monitored according to 
the criteria specified in Section 8.11.5.2.
If the decrease(s) of >10% of average baseline or a decrease in CD4+ T-cell counts to <200 
cells/mm3 is not confirmed at this visit, then no further follow-up for CD4+ T-cell or total 
lymphocyte counts is required.
Participants who were receiving BIC/FTC/TAF and choosing not to enroll directly in one of 
the DOR/ISL 100 mg/0.25 mg studies, should have an End of Treatment Follow-up visit per 
Section 8.11.3.2 (and Section 1.3.3) and no further monitoring is needed.
Participants who are enrolling directly in a DOR/ISL 100 mg/0.25 mg study will be managed 
per their study’s guidelines.
8.11.6
Clinical Management of Participants Who Become Pregnant
If a participant becomes pregnant (confirmed by a positive serum pregnancy test), the 
investigator should refer her to a local provider for appropriate obstetric (prenatal) care per 
local standard of care. All pregnancies must be followed to completion or termination of the 
pregnancy by the investigator per Section 8.4.5. Severity assessment of AEs that are 
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pregnancy-related complications should follow guidance provided as part of the DAIDS table 
version 2.1 “Addendum 1: Female Genital Grading Table for Use in Microbicide Studies,” 
particularly the section “Complications of Pregnancy.”
If a participant’s study intervention is blinded, the study intervention assignment must be 
unblinded by the investigator (Section 8.1.10).
The site will discuss with the participant:

Joining a pregnancy registry (the Antiretroviral Pregnancy Registry), which collects 
information about the outcome of the pregnancy

Consenting to infant safety data collection per Sections 8.1.1.3 and 8.11.6.4

Her intended breastfeeding status (Section 8.11.6.3)

Appropriateness of continuing study intervention based on available data and local 
standard-of care guidelines (where allowed by local regulations, health authorities, 
and ethics committees)
8.11.6.1
Continuing Study Intervention
Participants who become pregnant and consent to continue their assigned study intervention 
(Section 8.1.1.4) should complete all remaining protocol-specified visits and procedures 
(with the exception of DEXA scans) per the regular schedule in the SoA (Section 1.3.1 and
1.3.2). As the SoA specifies study visits at least every 12 weeks, participants will have a 
study visit approximately during each trimester and postpartum (ie, the first visit after 
delivery [~12 weeks after the 3rd trimester visit and ≤8 weeks after delivery]).
For participants receiving BIC/FTC/TAF, the investigator should refer to local product 
circular and local guidelines to determine if treatment may be continued. The participant will 
continue with the protocol-specified visits per the SoA (with the exception of DEXA and PK 
collection) per the schedules in the SoA (Section 1.3) for the duration of their pregnancy. The 
participant’s prenatal care should be coordinated between the investigator and the local 
obstetric care provider. The investigator (or designee) is responsible for obtaining relevant 
clinical and laboratory data from the obstetric care provider to monitor the safety and well-
being of the mother and fetus. Relevant data obtained by the site should be entered into the 
appropriate CRF and source documentation. The participant’s medical records will be 
collected and reviewed by the study site for:
Clinical safety laboratory assessments

Plasma HIV-1 RNA level

Results of Week 20 to 22 or second trimester ultrasound(s) providing gestational age 
and anatomic survey
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
Any complications associated with the pregnancy

Outcome of pregnancy

Information that could indicate congenital abnormalities
For participants who are pregnant at the last regularly scheduled study visit, their visit 
schedule will be extended through the duration of the pregnancy to allow assessments 
through each trimester and postpartum (Section 1.3.4). Their End of Treatment Follow-up 
visit should be performed approximately 42 days (+7 days) after stopping study intervention
(Section 1.3.4). Following pregnancy completion, options for future treatment are managed 
per Section 6.7.
For participants who continue DOR/ISL, PK samples will be collected at their scheduled visit 
during the 1st, 2nd, and 3rd trimesters and postpartum to evaluate DOR and ISL concentration 
levels per Table 6. These samples will be used to characterize the PK profile of DOR/ISL 
during pregnancy. Participants who do not learn of their pregnancy until the 2nd trimester will 
not have a 1st trimester PK sample.
Table 6
Collection of Population PK Samples During Pregnancy and Postpartum
Study Visit
Time Relative to Dosea
If participant routinely takes 
study intervention during the 
day, collect:
If participant routinely takes study 
intervention in the evening, collect:
1st Trimesterb
Predose
irrespective of time of last dose
2nd Trimester
Predose AND 0.5 to 2 hours 
AND 4 to 6 hours postdose
only 1 sample, irrespective of time 
of last dose
3rd Trimester
Predose AND 0.5 to 2 hours 
AND 4 to 6 hours postdose
only 1 sample, irrespective of time 
of last dose
Postpartumc
Predose
irrespective of time of last dose
PK=pharmacokinetic.
a
Time of last dose and time of PK sample collection must be documented for all samples
b
Collected in the 1st trimester at a scheduled visit when a participant reports gravid status. (May not be 
collected if a participant does not learn of their pregnancy until after the 1st trimester.)
c
The first visit after delivery; ~12 weeks after the 3rd trimester visit and ≤8 weeks after delivery. 
8.11.6.2
Discontinuing Study Intervention for Pregnancy
Participants who become pregnant and discontinue their assigned study intervention should 
have an Early Discontinuation of Treatment visit per the SoA (Section 1.3.3). If the decision 
to discontinue study intervention occurs during the timeframe of a scheduled study visit, the 
assessments for the Early Discontinuation of Treatment visit should be conducted at that 
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time. In addition, these participants will have an End of Treatment Follow-up visit in-clinic 
42 days (+7 days) after the last dose of study intervention (Section 1.3.3). 
The investigator (or local HIV care provider, if not the study site) should develop a new 
treatment plan per local standard-of-care before discontinuing study intervention to minimize 
the risk of a gap in combination ART.
8.11.6.3
Participants Who Choose to Breastfeed
If a participant chooses to breastfeed, they should discontinue study intervention before 
initiating breastfeeding (Section 7.1) and be followed in the study per Section 8.11.6.2. The 
investigator (or local HIV care provider, if not the study site) should make every effort to 
develop a new treatment plan (per local guidance) within sufficient time prior to delivery to 
minimize the likelihood of a gap in ART.
8.11.6.4
Infant Safety Data Collection
For participants who become pregnant while receiving study intervention, or within 42 days 
after the last dose of study intervention, the data in Section 8.11.6.4.1 should be obtained by 
the site and entered into the appropriate CRF and source documentation. In addition, study 
staff should obtain results from any ultrasounds performed per local standard-of-care.
Infant SAEs, including perinatal HIV-1 infection, 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.
Infant safety data collection will be captured in this study, if exposure during pregnancy is 
reported in this study.
8.11.6.4.1
Schedule of Activities: Infant Safety Data Collection
Timepoint
At Birtha
1-Year After Birtha,b
Visit Name
N/A
Infant Follow-up
Administrative and Safety Procedures
Infant informed consent 
Xc
Gestational age at birth
X
Apgar score
X
Length
X
X
Weight
X
X
Head Circumference
X
X
Directed pediatric examination
X
Concomitant medications reviewd
X
X
Review Infant SAEse
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Timepoint
At Birtha
1-Year After Birtha,b
Visit Name
N/A
Infant Follow-up
HIV=human immunodeficiency virus; SAE=serious adverse event.
a Data to be collected and entered at the site within 12 weeks of each timepoint.
b If a participant withdraws from the study, data from 1 year after birth should be collected at the time of withdrawal.
c Consent for infant safety data collection can be obtained from the mother at any time following confirmation of 
pregnancy.
d Concomitant medications taken by the infant (for SAEs or HIV postpartum prophylaxis).
e Collect SAEs, including any congenital anomalies and HIV infection in the infant, per Section 8.4.1 and review at 
participant’s regularly scheduled study visits.
9
STATISTICAL ANALYSIS PLAN
This section outlines the statistical analysis strategy and procedures for the study. If, after the 
study has begun, but prior to final database lock, changes are made to primary and/or key 
secondary hypotheses, or the statistical methods related to those hypotheses, then the 
protocol will be amended (consistent with ICH Guideline E9). Changes to exploratory or 
other non-confirmatory analyses made after the protocol has been finalized, but prior to final 
database lock, will be documented in an sSAP and referenced in the CSR for the study. Post 
hoc exploratory analyses will be clearly identified in the CSR.
9.1
Statistical Analysis Plan Summary
Key elements of the statistical analysis plan are summarized below; the comprehensive plan 
is provided in Sections 9.2 through 9.12.
Study Design Overview
A Phase 3, Randomized, Active-Controlled, Double-Blind Clinical Study to 
Evaluate a Switch to Doravirine/Islatravir (DOR/ISL) Once-Daily in 
Participants With HIV-1 Virologically Suppressed on 
Bictegravir/Emtricitabine/Tenofovir Alafenamide (BIC/FTC/TAF)
Treatment Assignment
This study will enroll approximately 578 evaluable participants with HIV-1 
who have been virologically suppressed on BIC/FTC/TAF for ≥3 months. 
Participants will be randomized in a 1:1 ratio to switch to DOR/ISL on Day 1 
(Group 1) or continue treatment with BIC/FTC/TAF (Group 2) with matching 
placebo through Week 96. Clinical site personnel and study participants will 
remain blinded through Week 96 while the clinical database and all Sponsor 
personnel will remain blinded through Week 48.
Analysis Populations
Efficacy: FAS, PP, and Resistance Analysis Subset
Safety: APaT
Primary Endpoint(s)
1. Percentage of participants with HIV-1 RNA ≥50 copies/mL at Week 48
2. Number of participants experiencing AEs, and discontinuing study 
intervention due to AEs
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Key Secondary 
Endpoints
1.
Percentage of participants with HIV-1 RNA ≥50 copies/mL at Week 96 and 
Week 144
2.
Percentage of participants with HIV-1 RNA <40 and <50 copies/mL at 
Week 48, Week 96 and Week 144
3.
Change from baseline in CD4+T-cell count at Week 48, Week 96 and 
Week 144
4.
Change from baseline in weight at Week 48, Week 96 and Week 144
5.
Viral resistance-associated substitutions
6.
General safety and tolerability through study duration
Statistical Methods for 
Key 
Efficacy/Immunogenicity/ 
Pharmacokinetic 
Analyses
The primary objective and hypothesis will be assessed using a 2-sided 
multiplicity-adjusted 95% CI for the difference between treatment groups 
(Group 1 minus Group 2) in the percentage of participants with HIV-1 RNA 
≥50 copies/mL at Week 48. The CI will be based on the unstratified Miettinen 
and Nurminen method [Miettinen, O. and Nurminen, M. 1985], an 
unconditional, asymptotic method.
The FAS, which is defined as all randomized participants who take at least 1 
dose of study intervention, will serve as the primary analysis population for 
this study. The FDA ‘snapshot’ algorithm will be used as the primary approach 
to analysis; missing data at the primary timepoint will be imputed as an HIV-1 
RNA result ≥50 copies/mL for those who discontinue study intervention prior 
to the Week 48 analysis window due to lack of efficacy, or who discontinue 
study intervention prior to the Week 48 analysis window due to a reason other 
than lack of efficacy and have the last available on-treatment HIV-1 RNA 
result ≥50 copies/mL.
Statistical Methods for 
Key Safety Analyses
Point estimates and 2-sided nominal 95% CIs will be provided using the 
Miettinen and Nurminen method [Miettinen, O. and Nurminen, M. 1985] for 
the difference between treatment groups (Group 1 minus Group 2) for the 
following:
-
The percentage of participants in the broad AE categories (ie, Tier-2 
events) consisting of the percentage of participants with any AE, with a 
drug-related AE, with an SAE, with a Grade 3 to 4 AE, with an AE that 
is both drug-related and serious, with an AE that is both Grade 3 to 4 and 
drug-related, who discontinued study intervention due to a drug-related 
and non-drug-related AE, and with AE(s) leading to death.
-
Specific AEs (preferred terms), SOCs, or PDLCs occurring with an 
incidence ≥4 participants in either treatment group.
-
The percentage of participants with a cardiac SAE.
Point estimates and 2-sided multiplicity-adjusted 95% CIs will be provided 
using ANCOVA models for the difference between treatment groups (Group 1 
minus Group 2) for the change from baseline in weight at Weeks 48 and 96.
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Interim Analyses
The following interim analyses and data summaries are planned. Details are 
provided in Section 9.7.
-
Week 24 interim analysis: An interim analysis to assess futility will be 
performed by an external unblinded statistician when 40% of participants 
have completed Week 24 assessments. All available efficacy and safety 
data for all participants enrolled by that time will be reviewed. Treatment 
level results will be provided by an external unblinded statistician to the 
eDMC. If the upper bound of the 2-sided multiplicity-adjusted 95% CI 
for the treatment difference (Group 1 minus Group 2) in the percentage
of participants with Week 24 HIV-1 RNA ≥200 copies/mL is greater 
than 8 percentage points and excludes 0, consideration may be given to 
stop the study.
-
Week 48 efficacy and safety analyses (to be conducted by the Sponsor 
and results shared with the eDMC).
-
Periodic efficacy and safety reviews (eDMC reviews) to be performed 
every 4 to 6 months or as specified in the eDMC charter.
Multiplicity
For statistical rigor, a small amount of alpha (α = 0.00001) will be set aside for 
the futility assessment and each additional eDMC evaluation. An allowance 
will be made such that a total of up to 5 of the unblinded eDMC reports 
(including the Week 24 interim analysis) may be presented prior to the 
evaluation of the primary efficacy hypotheses at Week 48. If further eDMC 
reviews occur between the evaluation of the primary efficacy hypothesis at 
Week 48 and the evaluation of the secondary hypotheses at Week 96, further 
reduction in the alpha of 0.00001 for each eDMC review will be made for the 
Week 96 hypotheses.
The following efficacy hypotheses will be tested sequentially at a 1-sided 2.5% 
Type 1 error rate adjusted for the number of eDMC reports in the following 
order:
-
Primary efficacy hypothesis (H1) testing non-inferiority of HIV-1 RNA 
≥50 copies/mL between Group 1 and Group 2 at Week 48
-
Secondary efficacy hypothesis (H4) testing superiority of HIV-1 RNA 
≥50 copies/mL between Group 1 and Group 2 at Week 96
-
Secondary efficacy hypothesis (H2) testing superiority of HIV-1 RNA 
≥50 copies/mL between Group 1 and Group 2 at Week 48
Testing will stop with the first of these tests failing to reach statistical 
significance and all subsequent tests would not be considered for statistical 
significance. In this way, the overall 1-sided 2.5% Type 1 error rate in testing 
these hypotheses is strongly controlled.
The secondary safety hypotheses, (H5) testing superiority of having lower 
mean increase from baseline in body weight for Group 1 vs. Group 2 at Week 
48 and (H6) testing superiority of having lower mean increase from baseline in 
body weight for Group 1 vs. Group 2 at Week 96, will be tested independently 
of all efficacy hypotheses. The approach for testing these safety hypotheses at 
a strongly controlled 1-sided 2.5% Type 1 error rate adjusted for the number of 
eDMC reports is described in Section 9.8. 
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Sample Size and Power 
The planned sample size is 578 participants to be randomized in a 1:1 ratio to 
either Group 1 or Group 2. The primary hypothesis will be assessed based on 
the percentage of participants with HIV-1 RNA ≥50 copies/mL at Week 48. 
The non-inferiority will be concluded if the upper bound of the 2-sided 
multiplicity-adjusted 95% CI for the difference in the percentage of 
participants with HIV-1 RNA ≥50 copies/mL (Group 1 minus Group 2) is less 
than 4 percentage points. If the true rate of participants with HIV-1 RNA 
≥50 copies/mL at Week 48 is 2% in both groups, this study with 
289 participants per group has 85% power to demonstrate non-inferiority.
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.
Day 1 through Week 48 will be conducted as a double-blind study under in-house blinding 
procedures. The official, final database for Day 1 through Week 48 will not be unblinded 
until medical/scientific review has been performed, protocol deviations have been identified, 
and data have been declared final and complete. The clinical database and Sponsor personnel 
directly involved in the analysis and reporting associated with the Week 48 CSR will become 
unblinded at the time of the Week 48 analysis, although study participants and site personnel 
will remain blinded until Week 96.
PK data may be unblinded early for the purpose of preparing a population PK model. A
separate team from the protocol team will be unblinded for the purpose of preparing the PK 
model. Efficacy and safety data will not be unblinded for the purpose of preparing the PK 
model. Interim data or results will not be shared with the protocol team before unblinding of 
the Sponsor.
The Clinical Biostatistics department will generate the randomized allocation schedule(s) for 
study intervention assignment. Randomization will be implemented via an IRT.
Blinding issues related to the planned interim analyses are described in Section 9.7.
9.3
Hypotheses/Estimation
Objectives and hypotheses of the study are stated in Section 3.
9.4
Analysis Endpoints
Efficacy and safety endpoints 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.
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9.4.1
Efficacy/Pharmacokinetics Endpoints
9.4.1.1
Efficacy Endpoints
An initial description of efficacy measures is provided in Section 4.
Percentage of Participants With HIV-1 RNA ≥50 copies/mL
The Abbott RealTime PCR assay with a reliable lower limit of quantification of 
40 copies/mL will be used to measure the HIV-1 RNA level in blood samples obtained at 
each visit. The primary objective will be assessed based upon the percentage of participants 
with HIV-1 RNA ≥50 copies/mL at Week 48. A secondary objective will assess the 
percentage of participants with HIV-1 RNA ≥50 copies/mL at Week 96 and Week 144.
Percentage of Participants With HIV-1 RNA <40 copies/mL and Percentage of 
Participants With HIV-1 RNA <50 copies/mL
Secondary objectives addressing the antiretroviral activity following a switch to DOR/ISL
will be assessed on the basis of the percentage of participants achieving HIV-1 RNA 
<40 copies/mL at Week 48, Week 96 and Week 144, as well as the percentage of participants
achieving HIV-1 RNA <50 copies/mL at Week 48, Week 96 and Week 144.
Change From Baseline in CD4+ T-cell Count
Change from baseline in CD4+ T-cell count will be estimated at each timepoint at which 
CD4+ T-cell count is collected. A secondary objective will assess the change from baseline 
in CD4+ T-cell count at Week 48, Week 96, and Week 144.
For the analysis of change from baseline in CD4+ T-cell count, 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, when 
available.
Clinically significant Confirmed Viremia
Participants with confirmed virologic rebound as defined in Section 4.2.1.1.2 will be 
identified.
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 will be included in
resistance analyses. In addition, anyone for whom available genotypic or phenotypic data 
show evidence of resistance, irrespective of viral load, will also be included in resistance 
analyses. The resistance analysis will count the number of participants who have evidence of 
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resistance-associated with each study intervention and will be summarized with primary 
interest at Week 48, Week 96 and Week 144.
Time to Loss of Virologic Response
TLOVR will be assessed at Week 48, Week 96 and Week 144.
For participants who have 2 consecutive HIV-1 RNA values (measured at least 2 weeks
apart) ≥50 copies/mL during the study, TLOVR is the time between Day 1 and the date of the 
first of the 2 consecutive HIV-1 RNA values ≥50 copies/mL.
For participants who sustain HIV-1 RNA <50 copies/mL, TLOVR is censored at the time of 
the last available measurement.
9.4.1.2
Pharmacokinetic Endpoint
PK samples collected from all participants as described in the SoA and Section 8.6 will be 
used to evaluate PK concentrations of ISL, and as appropriate, PK-efficacy, PK-
pharmacodynamic, and PK-AE relationships of ISL.
9.4.2
Safety Endpoints
An initial description of safety measures is provided in Section 4.
Adverse Events
The following clinical and laboratory AEs will be summarized: 1) participants with at least 
1 AE; 2) participants with at least 1 drug-related AE; 3) participants with at least 1 SAE; 
4) participants with at least 1 Grade 3 to 4 AE; 5) participants with at least 1 serious and 
drug-related AE; 6) participants with at least 1 AE, which is both Grade 3 to 4 and drug-
related; 7) participants who discontinued study intervention due to a drug-related and non-
drug-related AE; and 8) participants with AE(s) leading to death.
Predefined Limits of Change in Laboratory Parameters
For the summaries of laboratory tests, participants must have both a baseline and post-
randomization 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 or not 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 the 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.
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Weight, Laboratory, and Radiological Markers
The mean change from baseline to Week 48, Week 96 and Week 144 in select weight, 
laboratory, and radiological markers of fasting lipid and metabolic profiles, renal function, 
inflammation, and body composition will be summarized.
Change from baseline in weight will be summarized at each timepoint at which weight is 
collected. A secondary objective will assess the change from baseline in weight at Week 48, 
Week 96, and Week 144.
For analyses of change from baseline in weight, laboratory, and radiological parameters, 
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, when available.
The baseline measurement for analyses of DEXA will be defined in the sSAP.
9.4.3
Patient-reported Outcome Endpoints
An initial description of patient-reported outcome measures is provided in Section 4.2.1.5.
PROs from each questionnaire at Day 1 and Weeks 4, 12, 48, and 96 will be summarized for 
each treatment group.
9.5
Analysis Populations
9.5.1
Efficacy Analysis Populations
9.5.1.1
Full Analysis Set
The FAS will serve as the primary population for the analysis of efficacy data in this study. 
The FAS population consists of all randomized participants who:
Receive at least 1 dose of study intervention
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
Per-Protocol Analysis Set
The secondary analysis set for the efficacy analyses is defined as the PP analysis set, which 
will include all participants in the FAS who have not committed any major protocol 
violations that could impact the assessment of efficacy, including violation of key entry 
criteria. Participants will be grouped according to the treatment to which they are 
randomized.
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Participants meeting any of the following criteria will be excluded from the PP analysis set:
Participants who meet the exclusion criteria for receiving any ongoing prohibited therapies 
listed in Table 3.
Nonadherence to study intervention: participants with <95% drug compliance rate.
Participants who become pregnant.
Any additional criteria resulting in exclusion from the PP analysis set will be provided in the 
sSAP and/or CSR and will be identified prior to unblinding of the Sponsor at Week 48.
The composition of the PP analysis set will vary by the analysis timepoint, based on the 
number of participants who satisfy the PP criteria at that timepoint.
9.5.1.3
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.
At least 1 laboratory or vital sign measurement obtained subsequent to 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.
9.6
Statistical Methods
This section describes the statistical methods that address the primary and secondary 
objectives. Methods related to PK analysis and modeling will be described in a separate 
modeling and simulation plan authored by the department of Quantitative Pharmacology and 
Pharmacometrics. Methods related to exploratory objectives will be described in the sSAP.
9.6.1
Statistical Methods for Efficacy Analyses
Time Windows
Table 7 lists the definition of time windows 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 
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be used for all analyses by timepoint (with the exception of DEXA assessments). 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.
Analysis windows for DEXA measurements will be provided in the sSAP.
Table 7
Definitions of Study Time Points
Treatment 
Phase
Treatment Period
Visit
Day-Range 
Rulesa
Target 
Daya
Pretreatment
Baseline
Day 1
≤1
1
Treatment
Blinded Intervention: 
DOR/ISL or BIC/FTC/TAF
Week 4
≥2 and ≤56
29
Week 12
≥57 and ≤126
85
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
Open-label Intervention: 
DOR/ISL or BIC/FTC/TAF
Week 108
≥715 and ≤798
757
Week 120
≥799 and ≤882
841
Week 132
≥883 and ≤966
925
Week 144
≥967 and ≤1050
1009
Treatment 
Extensionb
Open-label Intervention:
DOR/ISL or BIC/FTC/TAF
Week 156
≥1051 and ≤1134
1093
Week 168
≥1135 and ≤1218
1177
NA=not applicable.
a Relative days and target days are computed from the first day of study intervention.
b The treatment extension phase visits apply only to participants who consent to the 24-week study extension. 
FDA Snapshot Algorithm and 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
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•
Non-intermittent missing values due to premature study intervention discontinuations 
because of treatment-related reasons such as, “clinical adverse experience” 
(regardless of relationship to study intervention), “laboratory adverse experience”
(regardless of relationship to study intervention), and “withdrew based on HIV-1 
RNA results”
•
Non-intermittent missing values due to premature study intervention discontinuations 
because of other reasons which are not related to treatment such as “loss to follow-
up”, “protocol violation”, “participant withdrew consent”, etc.
Three approaches will be used to handle missing values. The primary approach for analysis 
of the percentage of participants with HIV-1 RNA ≥50 copies/mL is the FDA “snapshot” 
algorithm [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 within the time point of interest analysis 
window specified in Table 7.
•
HIV-1 RNA ≥50 copies/mL: this includes participants
1) Who have the last available on-treatment HIV-1 RNA measurement 
≥50 copies/mL within the time point of interest analysis window specified in 
Table 7.
2) Who do not have on-treatment HIV-1 RNA data in the time point of interest 
analysis window and
a) Who discontinue study intervention prior to or in the time point of interest 
analysis window due to lack of efficacy, or
b) Who discontinue study intervention prior to or in the time point of interest 
analysis window due to reasons other than lack of efficacy and have the last 
available on-treatment HIV-1 RNA measurement ≥50 copies/mL.
•
No Virologic Data in Specified Analysis Time Window: this includes participants 
who do not have on-treatment HIV-1 RNA data in the time point of interest analysis 
window because of the following:
1) Discontinued study intervention due to AE or death: this includes participants 
who discontinued study intervention because of an AE or death at any time point 
from Day 1 through the analysis window if this resulted in no on-treatment HIV-1 
RNA measurements during the specified window and have the last available on-
treatment HIV-1 RNA measurement <50 copies/mL. In addition, this category 
will include participants who discontinued study intervention because of an AE or 
death and had no on-treatment HIV-1 RNA measurements during the entirety of 
the study.
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2) Discontinued study intervention for other reasons: this includes participants who 
discontinued study intervention prior to or in the time point of interest analysis 
window due to reasons other than lack of efficacy or AE/death (ie, lost to follow-
up, non-compliance 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. In addition, this category will include 
participants who discontinued study intervention due to reasons other than lack of 
efficacy or AE/death and had no on-treatment HIV-1 RNA measurements during 
the entirety of the study.
3) On study intervention but missing data in window: only data in the predefined 
analysis window can be used for the statistical analysis at a given time point for 
participants remaining on study intervention. Participants with HIV-1 RNA 
results outside this window will be classified as “on study intervention, but 
missing data in window” regardless of the out of window HIV-1 RNA results.
For the primary evaluation of non-inferiority based on those with HIV-1 RNA 
≥50 copies/mL, the parameter for evaluation is the number of participants classified as 
“HIV-1 RNA ≥50 copies/mL” according to the FDA snapshot algorithm defined above, 
divided by the number of participants in the FAS. For the secondary endpoint involving those 
with HIV-1 RNA <50 copies/mL, the parameter for evaluation is the number of participants 
classified as “HIV-1 RNA <50 copies/mL” according to the snapshot algorithm, divided by 
the number of participants in the FAS. Similar logic will also be used to define the 
percentage of participants with HIV-1 RNA <40 copies/mL in accordance with the relevant 
secondary endpoints.
A second approach, the missing data treated as treatment failure (M=F) approach, will be 
performed as a sensitivity analysis for the percentage of participants achieving HIV-1 RNA 
<50 copies/mL. Under this approach, participants who 1) have at least 1 on-treatment HIV-1 
RNA measurement within the timepoint of interest analysis window specified in Table 7 and 
have the last available on-treatment measurement within the window <50 copies/mL, OR 
2) are on study intervention and have no HIV-1 RNA measurements within the timepoint of 
interest analysis window specified in Table 7 and have both the immediately preceding and 
immediately subsequent on-treatment HIV-1 RNA measurements <50 copies/mL, will be 
classified as a virologic “success” at the timepoint of interest. Participants with other reasons 
for missing data will be classified as a virologic failure at the timepoint of interest.
A third 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 
non-intermittent missing data who prematurely discontinue study intervention due to lack of 
efficacy or who discontinue intervention for other reasons and are 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 
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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 supportive approaches as described above will similarly be used for the analysis of 
the percentage of participants achieving HIV-1 RNA <40 copies/mL.
Percentage of Participants With HIV-1 RNA ≥50 copies/mL
The snapshot approach will be used as the primary approach to analysis with respect to the 
percentage of participants with HIV-1 RNA ≥50 copies/mL. The full categorization of 
virologic outcome at a timepoint by the snapshot approach includes 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 intervention due to an AE/death, b) discontinued study
intervention for other reasons (includes withdrawal of consent, loss to follow-up, move, etc.), 
or c) on study intervention, but missing data in window.
Non-inferiority of Group 1 compared to Group 2 with respect to the percentage of 
participants with HIV-1 RNA ≥50 copies/mL at Weeks 48 and 96 will be calculated using
the unstratified method of Miettinen and Nurminen [Miettinen, O. and Nurminen, M. 1985].
For the evaluation of the primary hypothesis at Week 48 and the secondary hypothesis at 
Week 96, a margin of 4 percentage points is used to define the non-inferiority of a switch to 
DOR/ISL at Day 1 compared to the continuation of baseline BIC/FTC/TAF for 48 weeks and 
96 weeks, as appropriate; non-inferiority will be concluded if the upper bound of the 2-sided 
multiplicity-adjusted 95% CI for the difference in the percentage of participants with HIV-1 
RNA ≥50 copies/mL (Group 1 minus Group 2) is less than 4 percentage points. The choice 
of non-inferiority margin is driven by the amount of virologic failure that is clinically 
acceptable; with an anticipated virologic failure rate of approximately 2%, a stringent margin 
of 4 percentage points is clinically acceptable.
Superiority of Group 1 compared to Group 2 with respect to the percentage of participants 
with HIV-1 RNA ≥50 copies/mL at Weeks 48 and 96 will also be calculated using the 
unstratified method of Miettinen and Nurminen [Miettinen, O. and Nurminen, M. 1985]. For 
the evaluation of the efficacy superiority hypotheses, superiority will be concluded if the 
upper bound of the 2-sided multiplicity-adjusted 95% CI for the difference in the percentage
of participants with HIV-1 RNA ≥50 copies/mL (Group 1 minus Group 2) is less than 0 
percentage points.
For the summary of virologic response over time, the difference in percentages between 
treatment groups at each timepoint through Week 144 will also be estimated and the 
associated 2-sided nominal 95% CI will be derived in a similar fashion to that described for 
the primary efficacy analysis.
Percentage of Participants With HIV-1 RNA <40 copies/mL and Percentage of 
Participants With HIV-1 RNA <50 copies/mL
The percentage of participants achieving HIV-1 RNA <40 copies/mL and the percentage of 
participants with HIV-1 RNA <50 copies/mL will be summarized by treatment group at each 
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timepoint, with primary interest at Week 48,Week 96, and Week 144 by comparing Group 1
and Group 2. For each timepoint of interest, the difference in percentages between treatment 
groups and the associated 2-sided nominal 95% CI will be calculated using the unstratified 
Miettinen and Nieminen method [Miettinen, O. and Nurminen, M. 1985]. The supportive 
analyses using the M=F and OF approaches (as defined above) will also be presented.
Change From Baseline in CD4+ T-cell Count
Change from baseline in CD4+ T-cell count will be summarized by treatment group at each 
timepoint at which CD4+ T-cell count is collected, with primary interest at Week 48, Week 
96, and Week 144. The treatment difference in changes from baseline in CD4+ T-cell count 
at each timepoint will be estimated using the ANCOVA model adjusted by baseline CD4+ T-
cell count and treatment group through Week 144. However, these estimates will not be 
subject to an absolute criterion for similarity. The clinical interpretation of treatment 
difference is dependent upon the absolute value at baseline and the magnitude and direction 
of the CD4+ T-cell count changes observed in each treatment arm. 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 post-baseline measurement within the 
timepoint of interest analysis window specified in Table 7 to be included in the analyses of 
the mean change from baseline in CD4+ T-cell count. Supportive analyses will also be 
provided using the LOCF and BOCF methods 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 for each treatment group.
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 for each treatment group with 
primary interest at Weeks 48, 96 and 144.
Unblinding of Participants During the Study
Given the objective nature of the efficacy endpoint HIV-1 RNA, if a participant becomes
unblinded during the study for any reason (eg, due to a safety event, acute 
infection/reactivation of HBV or pregnancy that requires unblinding, or accidental
unblinding), such participants will not be treated as treatment failures in the primary efficacy 
analyses on the FAS population due to the unblinding alone.
If the unblinding is due to HBV acute infection/reactivation that requires discontinuation of 
study intervention or if the clinical management of the HBV requires the addition of a 
concomitant therapy that is also active against HIV-1, efficacy assessments in these 
participants will be censored from that point forward and will be handled in the primary 
efficacy analyses following the FDA snapshot algorithm classification rules.
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In the event of a pregnancy that necessitates unblinding of the treatment regimen to allow 
appropriate clinical management, such participants will not be treated as treatment failures in 
the primary efficacy analyses on the FAS population due to the unblinding alone. Efficacy 
assessments in participants who become pregnant and require discontinuation of study 
intervention or choose to breastfeed will be censored from that point forward and will be 
handled in the primary efficacy analyses following the FDA snapshot algorithm classification 
rules. Results for participants whose pregnancy extends beyond Week 144 will be reported 
separately. Additional details will be provided in the sSAP and/or CSR.
Table 8 summarizes the key efficacy analyses of the study.
Table 8
Analysis Strategy for Key Efficacy Variables
Endpoint/Variable 
(Description, Time Point)
Primary vs 
Supportive 
Approach
Statistical Method
Analysis 
Population
Missing Data 
Approach
Primary Hypothesis
Percentage of participants with 
HIV-1 RNA ≥50 copies/mL at 
Week 48 
P
M&N
FAS
Snapshota
Secondary Objectives
Percentage of participants with 
HIV-1 RNA <40 and 
<50 copies/mL at Week 48 
P
M&N
FAS
Snapshota
S
M&N
FAS
M=F
S
M&N
PP
OF
Percentage of participants with 
HIV-1 RNA ≥50 copies/mL at 
Week 96
P
M&N
FAS
Snapshota
Percentage of participants with 
HIV-1 RNA <40 and 
<50 copies/mL at Week 96 and 
Week 144
P
M&N
FAS
Snapshota
S
M&N
FAS
M=F
S
M&N
PP
OF
Change from baseline in CD4+ 
T-cell counts at Study 
Weeks 48, Week 96, and Week 
144
P
ANCOVA
FAS
DAO
S
ANCOVA
FAS
LOCF
S
ANCOVA
FAS 
BOCF
BOCF=Baseline Observation Carried Forward; DAO=Data-As-Observed; FAS=Full Analysis Set; 
HIV=human immunodeficiency virus; LOCF=Last Observation Carried Forward; M=F=missing equal to 
failure; M&N=Miettinen and Nurminen; OF=Observed Failure; P=Primary approach; PP=Per-protocol; 
RNA=ribonucleic acid; S=Supportive approach; vs=versus.
a Number of participants who meet the endpoint clinical response criteria over total FAS population. 
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9.6.2
Statistical Methods for Safety Analyses
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 (Table 9) at Weeks 48, 96 and 
144. The tiers differ with respect to the analyses that will be performed. AEs (specific terms 
as well as system organ class terms) and events that meet predefined limits of change in 
laboratory and vital signs are either prespecified as “Tier 1” endpoint or will be classified as 
belonging to “Tier 2” or “Tier 3”, based on the number of events observed.
Safety parameters or adverse events of special interest that are identified a priori constitute 
“Tier 1” safety endpoints that will be subject to inferential testing for statistical significance. 
There are no Tier 1 events for this protocol as there are no a priori clinical events of concern 
that have been identified for this study.
Tier 2 parameters will be assessed via point estimates and 2-sided nominal 95% CIs provided 
for between treatment differences (Group 1 minus Group 2) in the percentage of participants 
with Tier 2 events; these analyses will be performed using the Miettinen and Nurminen 
method [Miettinen, O. and Nurminen, M. 1985], an unconditional, asymptotic method.
Membership in Tier 2 requires that at least 4 participants in any treatment group exhibit the 
event. The threshold of at least 4 events 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 events and thus, 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 be regarded as a helpful 
descriptive measure to be used in review, not a formal method for assessing the statistical 
significance of the between group differences in AEs and safety parameters that meet 
predefined limits of change.
In addition to individual events that occur in 4 or more participants in any treatment group, 
the broad categories consisting of the percentage of participants with any AE, with a drug-
related AE, with an SAE, with a Grade 3 to 4 AE, with an AE that is both drug-related and 
serious, with an AE that is both Grade 3 to 4 and drug-related, who discontinued study 
intervention due to a drug-related and non-drug-related AE, and with AE(s) leading to death
will be considered Tier 2 endpoints. The percentage of participants with a cardiac SAE will 
also be considered a Tier 2 endpoint.
The mean change from baseline to Weeks 48, 96 and 144 in body weight will be considered 
Tier 2 events. For the evaluation of the secondary hypotheses of the effect on weight of a 
switch to DOR/ISL at Day 1 compared to the continuation of baseline BIC/FTC/TAF at 
Weeks 48 and 96, the treatment difference in the change from baseline will be estimated 
between treatment groups using ANCOVA models adjusted by baseline weight, sex at birth, 
race, and treatment group. Superiority of having lower mean increase from baseline will be 
concluded if the upper bound of the 2-sided multiplicity-adjusted 95% CI for the estimate of 
the treatment group difference (Group 1 minus Group 2) is less than 0. P-values for the 
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comparisons at Week 48 and Week 96 will also be provided. For participants who become 
pregnant during the study, weight measured after the estimated date of conception will be 
excluded from the analyses. The APaT population will be used for this analysis, and the 
DAO approach will be used to handle missing data. The same statistical model will be used 
to evaluate the between group difference in the change from baseline to Week 144 in body 
weight.
Safety endpoints that are not Tier 2 events are considered Tier 3 events. Only point estimates 
by treatment group will be provided for Tier 3 safety parameters. Safety endpoints collected 
after Week 144 for participants who choose to continue their assigned study intervention 
during the open-label study extension (up to Week 168) are considered Tier 3 events.  
For 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 in table 
format.
For the lipid profile analyses, participants who receive lipid-lowering therapy at baseline will 
be excluded from all lipid-related analyses. Missing lipid data will be handled using the DAO
approach, that is, any participant with a missing value will be excluded from the analysis. For 
participants who initiate lipid-lowering therapy during the study, the last lipid measurement 
before initiating the lipid-lowering therapy will be carried forward. For participants who 
become pregnant, lipid data collected after the estimated date of conception will be 
excluded. The percentages of participants who initiate or modify lipid-lowering therapy prior 
to Week 48, Week 96, and Week 144 will be summarized by treatment group.
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. In the rare event when Day 1 data
are missing, the value obtained at the most recent screening visit will be used as baseline, 
when available. If no baseline result is available, that participant will not be included in the 
summary.
For participants who become pregnant during the study, safety parameters assessed during 
the pregnancy period (estimated date of conception to date of conclusion of the pregnancy) 
may be summarized separately from the primary and secondary safety analyses. For 
continuous measures that are considered to be Tier 2 events, data collected after the 
estimated date of conception will be excluded from the analyses. Data collected for 
participants whose pregnancy or postpartum visit(s) extend beyond Week 144 will be 
reported separately. Infant safety data will be reported separately. Additional details on how 
pregnancy and infant data will be handled in safety analyses will be provided in the sSAP 
and/or CSR.
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Table 9
Analysis Strategy for Safety Parameters
Safety 
Tier
Safety Endpoint
95% CI for 
Treatment 
Difference
Descriptive 
Statistics
Tier 2
The percentage of participants with an AE in each of the 
following categories: 1 or more AE(s); drug-related AE(s), 
serious AE(s), Grade 3 to 4 AE(s), AE(s), which are both 
drug-related and serious, AE(s), which are both Grade 3 to 4
and drug-related, AE(s) [drug-related and non-drug-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 either treatment group
The percentage of participants with a cardiac SAE
Change from baseline to Weeks 48, 96 and 144 in body 
weighta,b
Change from baseline in select laboratory, and radiological 
markers of fasting lipid profiles, renal function, 
inflammation, and body compositionb
X
X
Tier 3
Specific AEs (preferred terms), SOCs, or PDLCs occurring 
with an incidence <4 participants in both treatment groups
Change from baseline in body weight, laboratory 
measurements and vital signsc
X
AE=adverse event; CI=confidence interval; PDLC=predefined limit of change; SOC=System Organ Class.
a Though classified as a Tier 2 event, p-values will be provided for change from baseline to Week 48 and Week 96 in 
body weight to support the evaluation of the corresponding secondary hypotheses.
b For participants who become pregnant, data collected after the estimated date of conception will be excluded.
c Includes only those endpoints not already prespecified as Tier-2 endpoints.
9.6.3
Summaries of Baseline Characteristics, Demographic, and Other Analyses
9.6.3.1
Demographic and Baseline Characteristics
The comparability of the treatment groups for each relevant demographic and baseline 
characteristic will be assessed by the use of tables and/or graphs. No statistical hypothesis 
tests will be performed on these characteristics. The number and percentage of participants 
screened and randomized and the primary reasons for screening failure, and the primary 
reason for discontinuation will be displayed. Demographic variables (eg, age, gender, race, 
region, etc.), baseline characteristics, primary and secondary diagnoses, and prior and 
concomitant therapies will be summarized by treatment either by descriptive statistics or 
categorical tables.
9.7
Interim Analyses
Study enrollment is likely to be ongoing at the time of the interim analyses. Blinding to 
treatment assignment will be maintained at all investigational sites until Week 96.
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An eDMC will serve as the primary reviewer of the results of the interim efficacy and safety 
reviews and may make recommendations for discontinuation of the study or protocol 
modifications to an executive committee of the Sponsor. If the eDMC recommends 
modifications to the design of the protocol or discontinuation of the study, this executive 
committee (and potentially other limited Sponsor personnel) may be unblinded to results at 
the treatment level in order to act on these recommendations. The extent to which individuals 
are unblinded with respect to results of efficacy and safety review will be documented by the 
external unblinded statistician. Additional logistical details will be provided in the eDMC 
charter.
Treatment level results from all interim analyses will be provided to the eDMC by the 
external unblinded statistician. The external unblinded statistician will not be involved in any 
discussions regarding modifications to the protocol, statistical methods, identification of 
protocol violators, or data validation efforts.
Once 40% of target enrollment (n = 232 participants) have completed Week 24, including
visit assessments, the Week 24 interim analysis will be conducted by an external unblinded 
statistician to assess futility. This analysis will be reviewed by the eDMC.
Futility Criteria: If the upper bound of the 2-sided multiplicity-adjusted 95% CI for the 
difference in the percentage of participants with HIV-1 RNA ≥200 copies/mL (Group 1 
minus Group 2) is greater than 8 percentage points and the 95% CI excludes 0, consideration 
may be given to stop the study.
The futility analysis will include all participants in the first 40% of target enrollment. For the 
purpose of the Week 24 interim analysis, those classified as HIV-1 RNA ≥200 copies/mL 
includes participants:
1) Who have the last available on-treatment HIV-1 RNA measurement ≥200 copies/mL 
at the Week 24 visit window specified in Table 7.
If participants do not have confirmed viremia (Section 4.2.1.1.2) at the subsequent 
visit, their virologic outcome will be reassessed for the primary analyses
(Section 9.6.1).
2) Who do not have on-treatment HIV-1 RNA data at Week 24
o
Who discontinue study intervention prior to the Week 24 visit due to lack of 
efficacy or confirmed viremia (Section 4.2.1.1.2), or
o
Who discontinued study intervention prior to the Week 24 visit due to reasons 
other than lack of efficacy and have their last on-treatment HIV-1 RNA 
measurement ≥50 copies/mL
Those participants will be included in the virologic failure rate calculated for the 
purposes of the primary analyses (Section 9.6.1).
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A possibility exists that unblinded data from this interim analysis may ultimately be 
submitted to regulatory authorities prior to Week 48, when the Sponsor becomes unblinded. 
In that event, to preserve the blinding integrity of the trial, an unblinded team at the Sponsor 
will be identified and those working with these unblinded data, working on the submission, 
and responding to regulatory questions would be firewalled from those blinded Sponsor 
personnel still working on the study. A separate data integrity/management plan will be 
developed to further define the roles and access for those on the unblinded and blinded teams 
at the Sponsor.
In addition, the eDMC will review accumulating safety and efficacy data at regular intervals 
throughout the study duration, or modified intervals based on the recommendation of the 
eDMC. The eDMC will recommend steps to ensure the safety of study participants and the 
integrity of the trial.
An analysis will be conducted to test the primary non-inferiority efficacy hypothesis once all 
participants have completed the Week 48 visit assessments. This will be the formal 
evaluation of the primary non-inferiority efficacy hypothesis, and the Sponsor will become 
unblinded at that time. The analysis of the data will be performed by the unblinded team of 
the Sponsor. All available efficacy and safety data will be reviewed at this interim time point. 
Treatment level results from this analysis will also be provided to the eDMC.
If the study is stopped early, the CSR will include all available data up to and including the 
close-out visits. This approach to include all available information is in line with the ICH-E9 
guideline.
9.8
Multiplicity
As noted in Section 9.7, an eDMC will convene at routine intervals to monitor efficacy and 
safety. There is no intention of stopping the study due to positive efficacy at any of these 
reviews. Nevertheless, since unblinded summaries of HIV-1 RNA values may be included in 
these reviews, a small amount of alpha (α=0.00001) will be allocated for each of these looks, 
purely for statistical rigor. An allowance will be made such that a total of up to 5 of these 
unblinded eDMC reports (including the futility assessment once 40% of participants have 
reached Week 24) may be presented prior to the evaluation of the primary non-inferiority
efficacy hypothesis at Week 48. If further eDMC reviews occur between the evaluation of 
the primary non-inferiority efficacy hypothesis at Week 48 and the evaluation of the efficacy
hypotheses tested at Week 96 (ie, (H4) and (H2)), further reduction in the alpha of 0.00001 
for each eDMC review will be made for the hypotheses tested at Week 96.
The following efficacy hypotheses will be tested sequentially at a 1-sided 2.5% Type 1 error 
rate adjusted for the number of eDMC reports in the following order:

Primary efficacy hypothesis (H1) testing non-inferiority of HIV-1 RNA ≥50 copies/mL 
between Group 1 and Group 2 at Week 48.

Secondary efficacy hypothesis (H4) testing superiority of HIV-1 RNA ≥50 copies/mL 
between Group 1 and Group 2 at Week 96.
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
Primary efficacy hypothesis (H2) testing superiority of HIV-1 RNA ≥50 copies/mL 
between Group 1 and Group 2 at Week 48.
Testing will stop with the first of these tests failing to reach statistical significance, and all 
subsequent tests would not be considered for statistical significance. In this way, the overall 
1-sided 2.5% Type 1 error rate in testing these hypotheses is strongly controlled.
It is noted that the last sequential hypothesis to be evaluated concerns efficacy at Week 48 
although it would not be evaluated until the Week 96 analyses are conducted as the second
sequential hypothesis involves a Week 96 endpoint.
The secondary efficacy hypothesis (H3) testing non-inferiority of HIV-1 RNA ≥50 
copies/mL between Group 1 and Group 2 at Week 96 will be tested independently of the 
efficacy hierarchy described above. This hypothesis will be tested at a 1-sided 2.5% Type 1 
error rate adjusted for the number of eDMC reports from Day 1 to Week 96.
The secondary safety hypotheses, (H5) testing superiority of having lower mean increase 
from baseline in body weight for Group 1 vs. Group 2 at Week 48 and (H6) testing 
superiority of having lower mean increase from baseline in body weight for Group 1 vs. 
Group 2 at Week 96, will be tested independently of all aforementioned efficacy hypotheses. 
These hypotheses will be tested using the following rules:
(1) (H5) will be tested at a 1-sided 0.25% Type 1 error rate adjusted for the number of eDMC 
reports from Day 1 to Week 48, denoted by α1*.
(2a) If (H5) is retained (ie, the null hypothesis is not rejected) at Week 48, (H6) will be tested 
at Week 96 at a 1-sided 2.25% Type 1 error rate adjusted for the number of eDMC reports 
from Week 48 to Week 96, denoted by α2*.
(2b) If (H5) is rejected at Week 48, (H6) will be tested at Week 96 at a 1-sided Type 1 error 
rate of α1*+ α2*.
(3) If (H5) is retained at Week 48 and (H6) is rejected at Week 96, (H5) will be retested at 
Week 96 at a 1-sided Type 1 error rate of α2*.
This approach strongly controls the overall 1-sided Type 1 error rate for the safety 
hypotheses (H5) and (H6) to be less than or equal to α1*+ α2* ≤ 0.25% + 2.25% = 2.5% 
[Maurer, W., et al 2011].
9.9
Sample Size and Power Calculations
9.9.1
Sample Size and Power for Efficacy Analyses
9.9.1.1
Futility Criteria
The probability of passing the Week 24 interim analysis and the overall study power to 
demonstrate non-inferiority at Week 48 under a variety of assumptions is presented in 
Table 10.
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The power calculations shown in Table 10 incorporate the Week 24 interim analysis stopping 
rules. The interim analysis for futility will be conducted when 40% of the study enrollment 
(approximately 116 participants per arm) have reached Week 24. The study may stop if the
upper bound of the 2-sided multiplicity-adjusted 95% CI for the difference in the percentage
of participants with HIV-1 RNA ≥200 copies/mL (Group 1 minus Group 2) is greater than 8 
percentage points and the 95% CI excludes 0. Of interest is the likelihood that the study 
would meet the stopping criteria at Week 24 for a variety of assumed Week 24 response rates 
and also whether the non-inferiority criteria at Week 48 would be met.
Table 10
Probability of Passing the Interim Analysis and the Overall Study Power for 
Various Underlying True Response Rates Assuming Futility Assessed at 40% Enrollment
Group 1: True 
Rate for Week 24
| True Rate for 
Week 48
Group 2: True 
Rate for Week 
24 | True Rate 
for Week 48
Probability of 
Passing Interim 
Analysis (40% of 
Enrollment at 
Week 24)
Probability of 
Demonstrating Non-
Inferiority at Week 48 
(Overall Study 
Power)
0.75% | 1.5%
1% | 2%
99.6%
95.4%
1% | 2%
1% | 2%
99.0%
82.8%
1.25% | 2.5%
1% | 2%
97.9%
64.0%
1.5% | 3%
1% | 2%
96.7%
42.2%
1.75% | 3.5%
1% | 2%
95.1%
25.6%
2% | 4%
1% | 2%
93.1%
13.5%
2.5% | 5%
1% | 2%
88.4%
2.8%
HIV=human immunodeficiency virus.
Rate for Week 24 is the percentage of participants at Week 24 with HIV-1 RNA ≥200 copies/mL. Rate for 
Week 48 is the percentage of participants at Week 48 with HIV-1 RNA ≥50 copies/mL.
For example, if the true rate of participants at Week 24 with HIV-1 RNA ≥200 copies/mL is 
1% in both groups, and the true rate of participants at Week 48 with HIV-1 RNA 
≥50 copies/mL is 2% in both groups, there is a 99.0% chance of not meeting the futility 
criteria at Week 24. The overall study power for that scenario is 82.8%.
9.9.1.2
Evaluation of Non-inferiority and Superiority Hypotheses
This section presents a fuller description of the power calculations for the primary analysis of 
non-inferiority at Week 48. In contrast to the power shown in Table 10, the power 
calculations shown here do not account for the futility analysis and instead assume the futility 
criteria are not met and the study continues through Week 48.
As described in Section 9.8, the alpha level used in the final analysis (corresponding to the 
multiplicity-adjusted 95% CI) will account for the actual number of eDMC evaluations 
conducted in the study. For the purposes of the power calculations, 5 eDMC evaluations are
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assumed, leaving α=0.02495 (1-sided) available for the final analysis. Non-inferiority will be 
concluded if the upper bound of the 2-sided multiplicity-adjusted 95% CI for the difference 
in the percentage of participants with HIV-1 RNA ≥50 copies/mL (Group 1 minus Group 2) 
is less than 4 percentage points. The choice of non-inferiority margin is driven by the amount 
of virologic failure that is clinically acceptable; with an anticipated virologic failure rate of 
approximately 1.5% to 2%, a stringent margin of 4 percentage points is clinically acceptable. 
The power calculations are simulated based on an asymptotic method proposed by Miettinen 
and Nurminen [Miettinen, O. and Nurminen, M. 1985] and were carried out using SAS 
version 9.4.
Table 11 summarizes the power for the primary comparison under various assumptions for 
the control response rate and underlying difference in response rate (the percentage of 
participants with HIV-1 RNA ≥50 copies/mL). For example, if the true rates are 1.5% in both 
groups, this study has approximately 91% power to demonstrate non-inferiority. If the true 
rates are 2.0% in both groups, this study has approximately 85% power to demonstrate the 
primary hypothesis that Group 1 is non-inferior to Group 2 at Week 48.
Note that Table 11 can also be used to approximate the power to declare Group 1 non-
inferior to Group 2 with respect to the percentage of participants with HIV-1 RNA ≥50 
copies/mL at Week 96. The estimated power values at Week 96 would differ slightly from 
the Week 48 values presented in Table 11 due to the additional adjustment to the 1-sided 
Type 1 error that would be made for the number of eDMC reports that occur between Week 
48 and Week 96.
Table 11
Power (%) to Establish Non-Inferiority at Week 48/96 Under Various Response 
Rate Assumptions (289 Participants per Group)
True 
Response 
Rate in
Group 2
True Difference in Response Rates (Group 1 Minus Group 2)
-1.0 
Percentage 
Points
-0.5 
Percentage 
Points
0.0 
Percentage 
Points
0.5 
Percentage 
Points
1.0 
Percentage 
Points
1.5%
100
98
91
77
59
2.0%
99
95
85
71
54
2.5%
97
91
80
65
49
3.0%
94
87
74
59
45
3.5%
91
82
69
54
41
CI=confidence interval; eDMC=external Data Monitoring Committee; NI=non-inferiority.
Note: Non-inferiority margin=4%. To establish NI: upper bound of the 2-sided multiplicity-adjusted 95% CI must be <4 
percentage points for Group 1 minus Group 2. The 95% CI is based on the Miettinen & Nurminen method [Miettinen, O. 
and Nurminen, M. 1985]. The 1-sided Type 1 error is 0.02495, which adjusts for an assumed 5 eDMC reports between 
Day 1 and Week 48. If additional eDMC reports occur between Week 48 and Week 96, the 1-sided Type 1 error rate 
would be further adjusted for the assessment of non-inferiority at Week 96. Power was assessed via 10,000 simulations 
for each scenario.
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Table 12 summarizes the power to declare Group 1 superior to Group 2 with regard to the 
percentage of participants with HIV-1 RNA ≥50 copies/mL under various assumptions for 
the response rate in each treatment group. For example, if the percentage of participants with 
Week 48/96 HIV-1 RNA ≥50 copies/mL is assumed to be 0.3% in Group 1 and 2% in Group 
2, then this study will have approximately 51% power to demonstrate superiority.
Table 12
Power (%) to Establish Superiority at Week 48/96 Under Various Response Rate 
Assumptions (Assuming All Prior Hypothesis Tests Reach Statistical Significance) (289 
Participants per Group)
Group 1: True Rate 
for Week 48/96
Group 2: True Rate 
for Week 48/96
Probability of Demonstrating 
Superiority at Week 48/96
0%
2%
83%
0.3%
2%
51%
0.6%
2%
31%
1%
2%
14%
CI=confidence interval; eDMC=external Data Monitoring Committee.
Note: Values are computed assuming that all prior hypotheses in the testing hierarchy (see Section 9.8) reach 
statistical significance.
Note: To establish superiority: upper bound of the 2-sided multiplicity-adjusted 95% CI must be 
<0 percentage points for Group 1 minus Group 2. The 95% CI is based on the Miettinen & Nurminen method 
[Miettinen, O. and Nurminen, M. 1985]. The 1-sided Type 1 error is 0.02495, which adjusts for an assumed 5 
eDMC reports between Day 1 and Week 48. If additional eDMC reports occur between Week 48 and Week 
96, the 1-sided Type 1 error rate would be further adjusted for the assessment of superiority at Week 96.
Power was estimated via 10,000 simulations for each scenario.
9.9.2
Sample Size and Power for Safety Analyses
9.9.2.1
Evaluation of 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 94.5% chance of observing at 
least 1 AE among 289 participants in a treatment group. If no AE of that type is observed 
among the 289 participants in a treatment group, this study will provide 97.5% confidence 
that the underlying percentage of participants with that particular AE is <1.27% (1 out of 
every 78 participants).
The estimate of, and the upper bound of the 2-sided nominal 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 are provided in Table 13. 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 13
Estimate of Incidence of AEs and 95% Upper Confidence Bound Based on 
Hypothetical Numbers of Participants with AEs (289 Participants per Group)
Hypothetical Number of 
Participants With Adverse Event
Estimate of Incidence
95% Upper Confidence 
Bounda
0
0.0%
1.0%
5
1.7%
4.0%
10
3.5%
6.3%
15
5.2%
8.4%
20
6.9%
10.5%
25
8.7%
12.5%
30
10.4%
14.5%
AE=adverse event; CI=confidence interval.
a Based on the 2-tailed exact CI for a binomial proportion (Clopper and Pearson method[Clopper, C. J. and 
Pearson, E. S. 1934]). In the 0 event case, the 95% CI is 1-sided (α=0.05 all in the upper tail). 
Table 14 gives the difference in the incidence of an AE (Group 1 minus Group 2) that can be 
ruled out with different power levels and 95% confidence when there are 289 participants in 
each group. The underlying incidence of the AE is assumed to be the same for the 
2 treatment groups. For example, for a reasonably common AE, which occurs in 20% of 
participants in both groups, the study has 80% power to declare with 95% confidence that the 
true difference between the treatment groups is no more than 10.1 percentage points. The 
calculations are based on an asymptotic method proposed by Miettinen and Nurminen
[Miettinen, O. and Nurminen, M. 1985].
Table 14
Difference in Incidence of AEs (Group 1 minus Group 2) That Can Be Ruled Out 
With 289 Participants in Each Group.
Target 
Power
Underlying AE Incidence Rate
1%
5%
10%
20%
30%
40%
50%
80%
4.0
6.4
8.1
10.1
11.1
11.6
11.6
85%
4.4
6.9
8.7
10.8
11.9
12.4
12.3
90%
4.9
7.6
9.5
11.8
12.9
13.4
13.3
95%
5.8
8.7
10.8
13.2
14.4
14.9
14.8
AE=adverse event; CI=confidence interval.
Note: The upper bound of the 2-sided nominal 95% CI (unstratified Miettinen and Nurminen[Miettinen, O. 
and Nurminen, M. 1985]) for the difference in AE incidences (Group 1 minus Group 2) assuming the 
incidences are the same. 
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9.9.2.2
Evaluation of Change in Weight
Table 15 gives the hypothetical minimal treatment differences in the change from baseline in 
weight that can be detected between Group 1 and Group 2 with given power at Weeks 48 and 
96 assuming varying values of the underlying standard deviation and accounting for potential 
participant dropout. The calculations incorporate the testing strategy specified in Section 9.8,
which allows for the transfer of alpha back and forth between the Week 48 and Week 96 
hypotheses based on whether hypotheses (H5) and (H6) are retained (ie, the null hypothesis 
is not rejected) or rejected. Calculations are performed conditionally, that is, the probability 
that the Week 48 and Week 96 hypotheses are retained or rejected are not estimated or 
accounted for in the power calculations. For example, if the standard deviation of change in 
weight from baseline in both treatment groups at Week 96 is 8 kg and the number of 
participants in each treatment group at Week 96 is 243, then this study will provide 90% 
power to detect a difference at least as large as 2.39 kg at Week 96 assuming that the Week 
48 hypothesis (H5) was retained.
Table 15
Hypothetical Minimal Treatment Differences in the Change From Baseline in 
Body Weight That Can Be Detected With Given Power at Weeks 48 and 96
Week 48 Hypothesis (H5) is Tested at α1* = 0.00245
Power
n = 260 Participants per Groupa
Standard Deviation of Change in Weight From Baselineb
4 kg
5 kg
6 kg
80%
1.29
1.61
1.93
85%
1.36
1.69
2.03
90%
1.44
1.80
2.16
If Week 48 Hypothesis (H5) is Rejected, Week 96 Hypothesis (H6) is Tested at α1*+α2* = 
0.02493
Power
n = 243 Participants per Groupa
Standard Deviation of Change in Weight From Baselineb
8 kg
10 kg
12 kg
80%
2.04
2.55
3.06
85%
2.18
2.72
3.27
90%
2.36
2.95
3.54
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If Week 48 Hypothesis (H5) is Retained, Week 96 Hypothesis (H6) is Tested at α2* = 
0.02248
Power
n = 243 Participants per Groupa
Standard Deviation of Change in Weight From Baselineb
8 kg
10 kg
12 kg
80%
2.07
2.59
3.11
85%
2.21
2.77
3.32
90%
2.39
2.99
3.59
If Week 48 Hypothesis (H5) is Retained and Week 96 Hypothesis (H6) is Rejected, Week 
48 Hypothesis (H5) is Retested at α2* = 0.02248
Power
n = 260 Participants per Groupa
Standard Deviation of Change in Weight From Baselineb
4 kg
5 kg
6 kg
80%
1.00
1.25
1.50
85%
1.07
1.34
1.60
90%
1.16
1.44
1.73
3TC=lamivudine; DOR=doravirine; eDMC=external Data Monitoring Committee; ISL=islatravir; 
TDF=tenofovir disoproxil fumarate.
a The calculations account for potential participant dropout prior to the Week 48 and Week 96 time points. A
dropout rate of 10% at Week 48 and 16% at Week 96 was assumed in the calculations based on data from 
MK-1439A-024. As such, the number of participants per group is assumed to be 260 at Week 48 and 243 at 
Week 96.
b Values of the standard deviation of change in weight from baseline are based on experience with MK-8591
P011. In this study, the standard deviation of change in weight from Day 1 through Week 48 ranged from 
approximately 4.1 kg (DOR/3TC/TDF treatment group) to 5.9 kg (ISL[0.75 mg]+DOR+3TC treatment 
group). Assuming the change in weight from Week 48 through Week 96 would be consistent with the 
observed change in weight from Day 1 through Week 48, the 96-week weight change standard deviations 
range from approximately 8 kg to 12 kg.
α1*=0.25% 1-sided Type 1 error for the Week 48 weight hypothesis (H5) adjusted for an assumed 5 eDMC 
reports between Day 1 and Week 48.
α2*=2.25% 1-sided Type 1 error for the Week 96 weight hypothesis (H6) adjusted for an assumed 2 eDMC 
reports between Week 48 and Week 96.
Note: “Retained” means the corresponding null hypothesis is not rejected.
Note: Calculations are performed conditionally (ie, the probability that the Week 48 and Week 96 hypotheses 
are retained or rejected are not estimated or accounted for in the power calculations).
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9.10
Subgroup Analyses
To determine whether the treatment effect is consistent across various subgroups, the 
estimate of the between group treatment effect (with a nominal 95% Miettinen and Nurminen
CI) for the primary endpoint and the key secondary endpoints (HIV-1 RNA <50 copies/mL 
and HIV-1 RNA <40 copies/mL endpoint to aid in the EU review) will be calculated for the 
following classification variables:
•
Age category (<50 years of age, ≥50 years of age)
•
Sex at birth
•
Gender identity
•
Region (North America, South America, Europe, Asia, Africa, etc.)
•
Race (White, Black, Asian, Other)
•
Ethnicity (Hispanic/Latino, not Hispanic/Latino)
•
Chronic hepatitis C status (HCV-infected, HCV-uninfected)
•
Duration of BIC/FTC/TAF therapy prior to enrollment (≥1 year, <1 year)
The snapshot approach will be used to handle missing values in these subgroup analyses.
9.11
Compliance (Medication Adherence)
In this study, as part of the routine recording of the amount of study intervention taken by 
each participant in the study intervention CRF page, the number of tablets remaining in study 
packaging will be counted and reviewed at regular intervals. These results will be used to 
calculate participant compliance.
For the main analysis of compliance in this study, a day within the study will be considered 
an “On Therapy” day if the participant takes at least 1 tablet from any bottle provided for this 
study.
The “Number of Days Should be on Therapy” is the total number of days from Day 1 to the 
date of the last dose of study intervention for each participant. As such, the “Number of Days 
Should be on Therapy” will be the number of days from Day 1 to the timepoint of interest 
(ie. Week 48, Week 96, or Week 144) for those participants who are on study intervention
for the entire study period of interest. For participants who discontinue study intervention 
prior to or within the study period of interest, the “Number of Days Should be on Therapy” 
will be the number of days from Day 1 to the date of discontinuation of study intervention.
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For each participant and each study period of interest, percent compliance will be calculated 
using the following formula:
Summary statistics will be provided on percent compliance by treatment group for the FAS 
population.
9.12
Extent of Exposure
The extent of exposure to study intervention 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, 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. 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 
source documentation according to standard operating procedures. Per MSD policies and procedures, if fraud, 
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scientific/research misconduct or serious GCP-non-compliance is suspected, the issues are investigated. 
When necessary, the clinical site will be closed, the responsible regulatory authorities and ethics review 
committees 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. Unless required by 
law, only the investigator, Sponsor (or individuals acting on behalf of MSD), ethics committee, and/or regulatory 
authorities will have access to confidential medical records that might identify the participant by name.
D. Genomic Research
Genomic research will only be conducted in accordance with a protocol and informed consent authorized by an 
ethics committee.
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IV. Financial Considerations
A. Payments to Investigators
Clinical trials are time- and labor-intensive. It is MSD’s policy to compensate investigators (or the sponsoring 
institution) in a fair manner for the work performed in support of MSD trials. MSD does not pay incentives to 
enroll participants in its trials. However, when enrollment is particularly challenging, additional payments may be 
made to compensate for the time spent in extra recruiting efforts.
MSD does not pay for participant referrals. However, MSD may compensate referring physicians for time spent 
on chart review and medical evaluation to identify potentially eligible participants.
B. Clinical Research Funding
Informed consent forms will disclose that the trial is sponsored by MSD, and that the investigator or sponsoring 
institution is being paid or provided a grant for performing the trial. However, the local ethics committee may 
wish to alter the wording of the disclosure statement to be consistent with financial practices at that institution. As 
noted above, all publications resulting from MSD trials will indicate MSD as a source of funding.
C. Funding for Travel and Other Requests
Funding of travel by investigators and support staff (e.g., to scientific meetings, investigator meetings, etc.) will be 
consistent with local guidelines and practices.
V. Investigator Commitment
Investigators will be expected to review MSD’s Code of Conduct as an appendix to the trial protocol, and in signing the 
protocol, agree to support these ethical and scientific standards.
10.1.2
Financial Disclosure
Financial Disclosure requirements are outlined in the US Food and Drug Administration 
Regulations, Financial Disclosure by Clinical Investigators (21 CFR Part 54). It is the 
Sponsor's responsibility to determine, based on these regulations, whether a request for 
Financial Disclosure information is required. It is the investigator's/subinvestigator's 
responsibility to comply with any such request.
The investigator/subinvestigator(s) agree, if requested by the Sponsor in accordance with 21 
CFR Part 54, to provide his/her financial interests in and/or arrangements with the Sponsor to 
allow for the submission of complete and accurate certification and disclosure statements. 
The investigator/subinvestigator(s) further agree to provide this information on a 
Certification/Disclosure Form, commonly known as a financial disclosure form, provided by 
the Sponsor. The investigator/subinvestigator(s) also consent to the transmission of this 
information to the Sponsor in the United States for these purposes. This may involve the 
transmission of information to countries that do not have laws protecting personal data.
10.1.3
Data Protection
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.
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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.
10.1.4
Committees Structure
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.
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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.
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 Food and Drug Administration Amendments Act (FDAAA) of 2007 
and the European Medicines Agency (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, 
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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 Conference on Harmonization 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 Studies.
The investigator agrees not to seek reimbursement from participants, their insurance 
providers, or from government programs for procedures included as part of the study 
reimbursed to the investigator by the Sponsor.
The investigator will promptly inform the Sponsor of any regulatory authority inspection 
conducted for this study.
The investigator agrees to provide the Sponsor with relevant information from inspection 
observations/findings to allow the Sponsor to assist in responding to any citations resulting 
from regulatory authority inspection and will provide the Sponsor with a copy of the 
proposed response for consultation before submission to the regulatory authority. 
Persons debarred from conducting or working on clinical studies by any court or regulatory 
authority will not be allowed to conduct or work on this Sponsor’s studies. The investigator 
will immediately disclose in writing to the Sponsor if any person who is involved in 
conducting the study is debarred or if any proceeding for debarment is pending or, to the best 
of the investigator’s knowledge, threatened.
10.1.8
Data Quality Assurance
All participant data relating to the study will be recorded on printed or electronic CRF unless 
transmitted to the Sponsor or designee electronically (eg, laboratory data). The investigator 
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or qualified designee is responsible for verifying that data entries are accurate and correct by 
physically or electronically signing the CRF.
Detailed information regarding Data Management procedures for this protocol will be 
provided separately.
The investigator must maintain accurate documentation (source data) that supports the 
information entered in the CRF.
The investigator must permit study-related monitoring, audits, IRB/IEC review, and 
regulatory agency inspections and provide direct access to source data documents.
Study documentation will be promptly and fully disclosed to the Sponsor by the investigator 
upon request and also shall be made available at the study site upon request for inspection, 
copying, review, and audit at reasonable times by representatives of the Sponsor or any 
regulatory authorities. The investigator agrees to promptly take any reasonable steps that are 
requested by the Sponsor or any regulatory authorities as a result of an audit or inspection to 
cure deficiencies in the study documentation and worksheets/CRFs.
The Sponsor or designee is responsible for the data management of this study including 
quality checking of the data.
Study monitors will perform ongoing source data review and verification to confirm that data 
entered into the CRF by authorized site personnel are accurate, complete, and verifiable from 
source documents; that the safety and rights of participants are being protected; and that the 
study is being conducted in accordance with the currently approved protocol and any other 
study agreements, ICH GCP, and all applicable regulatory requirements.
Records and documents, including participants’ documented informed consent, pertaining to 
the conduct of this study must be retained by the investigator for 15 years after study 
completion unless local regulations or institutional policies require a longer retention period. 
No records may be destroyed during the retention period without the written approval of the 
Sponsor. No records may be transferred to another location or party without written 
notification to the Sponsor.
10.1.9
Source Documents
Source documents provide evidence for the existence of the participant and substantiate the 
integrity of the data collected. The investigator/institution should maintain adequate and 
accurate source documents and study records that include all pertinent observations on each 
of the site’s participants. Source documents and data should be attributable, legible, 
contemporaneous, original, accurate, and complete. Changes to source data should be 
traceable, should not obscure the original entry, and should be explained if necessary (eg, via 
an audit trail). Source documents are filed at the investigator’s site.
Data reported on the CRF or entered in the eCRF that are transcribed from source documents 
must be consistent with the source documents or the discrepancies must be explained. The 
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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 16 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.
Table 16
Protocol-required Laboratory Assessments
Laboratory 
Assessments
Parameters
Hematology
Platelet Count 
RBC Indices:
Mean corpuscular volume 
(MCV)
Mean corpuscular 
hemoglobin (MCH)
MCH concentration
Red Cell Distribution 
Width (RDW)
White Blood Cell (WBC) count 
with Differential:
Neutrophils
Lymphocytes
Monocytes
Eosinophils
Basophils
Red Blood Cell 
(RBC) Count
Hemoglobin
Hematocrit
CD4+ T-cell 
count/TBNK Panel
T-cell, B-cell, and Natural Killer cell profile that includes:
CD3+ Percent 
CD3+ Value/Absolute Count 
CD3+CD4+ Percent 
CD3+CD4+ Value/Absolute Count 
CD3+CD8+ Percent 
CD3+CD8+ Value/Absolute Count 
CD3-CD19+ Percent 
CD3-CD19+ Value/Absolute Count 
CD16+CD56+ Percent 
CD16+CD56+ Value/Absolute Count 
CD3+CD4+CD8+ Percent 
CD3+CD4+CD8+ Value/Absolute Count 
CD4/CD8 Ratio
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Laboratory 
Assessments
Parameters
Coagulation
Prothrombin time / international normalized ratio (INR)
Chemistry
(non-fasting)
Blood Urea 
Nitrogen (BUN)
Potassium
Aspartate 
Aminotransferase
(AST)
Total bilirubin
Direct bilirubin
Indirect bilirubin
Albumin
Bicarbonate
Chloride
Phosphorous
Creatinine
Sodium
Alanine 
Aminotransferase
(ALT)
Total Protein
Glucose [non-
fasting]
Calcium
Alkaline phosphatase
Creatinine Clearance 
Creatine kinase
Lipase
Amylase
Magnesium
Additional chemistry
at fasting visits
(fasting for at least 
8h)
Glucose [fasting]
High-density lipoprotein (HDL-C)
Low-density lipoprotein (LDL-C)
Triglycerides (TGs)
Total Cholesterol (TC)
Non-HDL-C
Insulina
Homeostatic Model Assessment of Insulin Resistance (HOMA-IR) (calculation)
Routine Urinalysis
•
Specific gravity
•
pH, glucose, protein, blood, ketones, bilirubin, urobilinogen, nitrite, leukocytes
Pregnancy testing
•
Serum and urine β human chorionic gonadotropin (β hCG) pregnancy test (for a 
woman/women of childbearing potential [WOCBP])
Urinary analytes
•
Albumin
•
Protein
•
Beta-2-microglobulin/creatinine ratio (B-2 M/Cr)
•
Retinol binding protein/creatinine ratio (RBP/Cr)
Renal function
•
Estimated glomerular filtration rate (eGFR) by Modification of Diet in Renal 
Disease (MDRD) equation
Hepatitis screening 
and monitoringb
•
Hepatitis B virus surface antigen (HBsAg)
•
Hepatitis B virus (HBV) surface antibody
•
Anti-HBc (hepatitis B core antibody)
•
HBV DNA
•
Hepatitis C antibody (if positive perform plasma hepatitis C virus quantitative 
test) (at screening only)
Human 
immunodeficiency 
virus-1 (HIV-1)
serology
•
HIV 1/2 antibody test
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Laboratory 
Assessments
Parameters
Virology
•
HIV-1 viral ribonucleic acid (RNA) quantification (Real time polymerase chain 
reaction [PCR])
•
HIV-1 viral resistance
Inflammatory 
Markers
•
D-dimer
•
Interleukin-6 (IL-6)
•
Soluble CD-163 (sCD-163)
•
High-sensitivity C-reactive protein (hs-CRP)
Blood for Renal 
Biomarkers
•
Cystatin-C
Pharmacokinetics 
(PK)
•
Islatravir (ISL) PK
•
Investigational PK samples will be collected from all participants. Analysis of 
these samples will be triggered by the Sponsor as needed.
•
ISL and DOR PK (Only participants on DOR/ISL who are pregnant)
a Participants with diabetes mellitus (type 1 or type 2) or insulin resistance are not required to have the blood 
draw for insulin testing.
b All participants will be screened for HBsAg, HBV surface antibody, anti-HBc and HBV DNA. Participants 
who 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.
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Table 17
Blood Volumes
Study Period
Screening
Group 1 and 2
Viremia Confirmation
CD4+ T-cell/
Lymphocyte
Confirmation
Early Discon of 
Treatment
CD4+ T-cell/
Lymphocyte
Monitoringa
EoT Follow-Up
Scheduled 
Day/Week
Screening
Day 1
Week 4
Week 12
Week 24
Week 36
Week 48
Week 60
Week 72
Week 84
Week 96
Week 108
Week 120
Week 132
Week 144
Week 156
Week 168
Unscheduled
Unscheduled
Unscheduled
Unscheduled
Unscheduled
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
6
CD4+ T-cell 
Count/TBNK 
Panel
6
6
6
6
6
6
6
6
6
6
6
6
6
6
6
6
Blood (Plasma) 
for HIV-1 Drug 
Resistance 
Testing 
12
12
12
12
12
12
12
12
12
12
12
12
12
12
12
12
12
HIV-1 & -2 and 
Hepatitis 
Screenb
4
4
4
4
4
4
4
4
4
4
4
4
4
4
4
4
4
HIV 
Confirmation 
Geenius
1
HBV DNAc
6
6
6
6
6
6
6
6
6
6
6
6
6
6
6
6
6
Chemistry 
(Includes 
Serum 
Pregnancy at 
Screening and 
Early 
Discontinuation
)
6
6
6
6
6
6
6
6
6
6
6
6
6
6
6
6
6
6
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Study Period
Screening
Group 1 and 2
Viremia Confirmation
CD4+ T-cell/
Lymphocyte
Confirmation
Early Discon of 
Treatment
CD4+ T-cell/
Lymphocyte
Monitoringa
EoT Follow-Up
Scheduled 
Day/Week
Screening
Day 1
Week 4
Week 12
Week 24
Week 36
Week 48
Week 60
Week 72
Week 84
Week 96
Week 108
Week 120
Week 132
Week 144
Week 156
Week 168
Unscheduled
Unscheduled
Unscheduled
Unscheduled
Unscheduled
Blood 
Parameter
Approximate Blood Volume (mL)
Hematology
2
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
Fasting Insulin
1
1
1
1
1
1
PT/INR
2.7
Blood for 
Inflammatory 
Biomarkers
10.7
10.7
10.7
10.7
10.7
Cystatin-C
2
2
2
2
2
PK Blood 
Sample 
Collection (All 
Participants)
4
8
4
4
4
Blood (Plasma) 
for 
Investigational 
PKc
4
4
4
4
4
4
4
4
4
Blood (Plasma) 
for DOR and 
ISL PK During 
Pregnancy d
<--------------------------------------------------Xd---------------------------------------------------->
Blood for 
Genetic 
Analysis
8.5
Whole Blood 
for FBR
8
8
8
8
8
8
8
         
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Study Period
Screening
Group 1 and 2
Viremia Confirmation
CD4+ T-cell/
Lymphocyte
Confirmation
Early Discon of 
Treatment
CD4+ T-cell/
Lymphocyte
Monitoringa
EoT Follow-Up
Scheduled 
Day/Week
Screening
Day 1
Week 4
Week 12
Week 24
Week 36
Week 48
Week 60
Week 72
Week 84
Week 96
Week 108
Week 120
Week 132
Week 144
Week 156
Week 168
Unscheduled
Unscheduled
Unscheduled
Unscheduled
Unscheduled
Blood 
Parameter
Approximate Blood Volume (mL)
Total Blood 
Volume per 
Visit (mL)
33.7
78.2
44
40
63.7
40
69.7
40
46
46
69.7
46
49
46
69.7
30
30
30
8
44
8
22
anti-HBc=hepatitis B core antibody; DNA=deoxyribonucleic acid; FBR=future biomedical research; HBsAg=hepatitis B surface antigen; HBV=hepatitis B virus; HIV-1=human immunodeficiency 
virus-1; INR=international normalized ratio; PCR=polymerase chain reaction; PK=pharmacokinetic(s) PT=prothrombin time; RNA=ribonucleic acid.
a
Blood volumes collected at the CD4+ T-cell count/Lymphocyte count Monitoring Visit represent single monitoring visits.
b
All participants will be screened for HBsAg, HBV surface antibody, anti-HBc and HBV DNA. Participants who are anti-HBc positive, but HBV DNA negative, will have HBsAg and HBV DNA 
monitored for the duration of the study. 
c
Investigational PK samples will be collected from all participants. Analysis of these samples will be triggered by the Sponsor as needed.
d
PK samples collected during pregnancy will be collected per Section 8.11.6.1. During the 1st trimester and postpartum study visits, 4 mL of blood will be collected for PK sampling. During the 2nd 
and 3rd trimester study visits, 12 mL of blood will be collected for PK sampling.
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Table 18
Blood Volumes: Participants Whose Pregnancy or Postpartum Visit(s) Extends Beyond Week 168
The assessments in Table 18 are for any participant who is pregnant at the last scheduled study visit (ie, Week 168) and whose visit 
schedule will be extended through the duration of the pregnancy, to allow assessments through each trimester and postpartum.
Visit Number
Unscheduled
Scheduled Week
Pregnancy 1
(Week 180 )
Pregnancy 2
(Week 192)
Pregnancy 3
(Week 204)
Pregnancy 4
(Week 216)
Blood Parameter
Approximate Blood Volume (mL)
Plasma HIV-1 RNA Quantification (Real Time PCR)
6
6
6
6
CD4+ T-cell Count
6
6
6
6
Plasma for HIV Viral Drug Resistance Testing 
15
15
15
15
HBsAg and DNA
6
6
6
6
Chemistry 
6
6
6
6
Hematology
2
2
2
2
Blood (Plasma) for DOR and ISL PK
-------------------------------Xa-------------------------------
Whole Blood for FBR
8
8
8
8
Approximate Blood Volume per Visit (mL)a
61
61
61
61
DNA=deoxyribonucleic acid; DOR=doravirine; FBR=future biomedical research; HBsAg=hepatitis B surface antigen; HBV=hepatitis B virus; HIV-1=human immunodeficiency virus Type 1; 
ISL=islatravir; PCR=polymerase chain reaction; PK=pharmacokinetic(s); RNA=ribonucleic acid.; mL=milliliter.
a PK samples collected during pregnancy will be collected per Section 8.11.6.1. During the 1st trimester and postpartum study visits, 4 mL of blood will be collected for PK sampling. During the 
2nd and 3rd trimester study visits, 12 mL of blood will be collected for PK sampling.
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10.3
Appendix 3: Adverse Events: Definitions and Procedures for Recording, 
Evaluating, Follow-up, and Reporting
10.3.1
Definitions of Medication Error, Misuse, and Abuse
Medication Error
This is an unintended failure in the drug treatment process that leads to or has the potential to 
lead to harm to the patient.
Misuse
This refers to situations where the medicinal product is intentionally and inappropriately used 
not in accordance with the terms of the product information.
Abuse
This corresponds to the persistent or sporadic, intentional excessive use of a medicinal 
product for a perceived psychological or physiological reward or desired non-therapeutic 
effect.
10.3.2
Definition of AE
AE definition

An AE is any untoward medical occurrence in a clinical study participant, temporally 
associated with the use of study intervention, whether or not considered related to the 
study intervention.

NOTE: An AE can therefore be any unfavorable and unintended sign (including an 
abnormal laboratory finding), symptom, or disease (new or exacerbated) temporally 
associated with the use of a study intervention.

NOTE: For purposes of AE definition, study intervention includes any pharmaceutical 
product, biological product, vaccine, diagnostic agent, medical device, combination 
product, or protocol specified procedure whether investigational or marketed (including 
placebo, active comparator product, or run-in intervention), manufactured by, licensed 
by, provided by, or distributed by the Sponsor for human use in this study.
Events meeting the AE definition

Any abnormal laboratory test results (hematology, clinical chemistry, or urinalysis) or 
other safety assessments (eg, ECG, radiological scans, vital signs measurements), 
including those that worsen from baseline, considered clinically significant in the medical 
and scientific judgment of the investigator.

Exacerbation of a chronic or intermittent pre-existing condition including either an 
increase in frequency and/or intensity of the condition.
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
New conditions detected or diagnosed after study intervention administration even 
though it may have been present before the start of the study.

Signs, symptoms, or the clinical sequelae of a suspected drug-drug interaction.

Signs, symptoms, or the clinical sequelae of a suspected overdose of either study 
intervention or a concomitant medication.

For all reports of overdose (whether accidental or intentional) with an associated AE, the 
AE term should reflect the clinical symptoms or abnormal test result. An overdose 
without any associated clinical symptoms or abnormal laboratory results is reported using 
the terminology “accidental or intentional overdose without adverse effect.”

Any new cancer or progression of existing cancer.
Events NOT meeting the AE definition

Medical or surgical procedure (eg, endoscopy, appendectomy): the condition that leads to 
the procedure is the AE.

Situations in which an untoward medical occurrence did not occur (social and/or 
convenience admission to a hospital).

Anticipated day-to-day fluctuations of pre-existing disease(s) or condition(s) present or 
detected at the start of the study that do not worsen.

Surgery planned prior to informed consent to treat a pre-existing condition that has not 
worsened.

Refer to Section 8.4.6 for protocol-specific exceptions.
10.3.3
Definition of SAE
If an event is not an AE per definition above, then it cannot be an SAE even if serious 
conditions are met.
An SAE is defined as any untoward medical occurrence that, at any dose:
a.
Results in death
b. Is life-threatening

The term “life-threatening” in the definition of “serious” refers to an event in which 
the participant was at risk of death at the time of the event. It does not refer to an 
event, which hypothetically might have caused death, if it were more severe. 
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c. Requires inpatient hospitalization or prolongation of existing hospitalization

Hospitalization is defined as an inpatient admission, regardless of length of stay, even 
if the hospitalization is a precautionary measure for continued observation. (Note: 
Hospitalization for an elective procedure to treat a pre-existing condition that has not 
worsened is not an SAE. A pre-existing condition is a clinical condition that is 
diagnosed prior to the use of an MSD product and is documented in the participant’s 
medical history. 
d. Results in persistent or significant disability/incapacity

The term disability means a substantial disruption of a person’s ability to conduct 
normal life functions. 

This definition is not intended to include experiences of relatively minor medical 
significance such as uncomplicated headache, nausea, vomiting, diarrhea, influenza, 
and accidental trauma (eg, sprained ankle) that may interfere with or prevent 
everyday life functions but do not constitute a substantial disruption. 
e. Is a congenital anomaly/birth defect

In offspring of participant taking the product regardless of time to diagnosis. 
f. Other important medical events

Medical or scientific judgment should be exercised in deciding whether SAE 
reporting is appropriate in other situations such as important medical events that may 
not be immediately life-threatening or result in death or hospitalization but may 
jeopardize the participant or may require medical or surgical intervention to prevent 1 
of the other outcomes listed in the above definition. These events should usually be 
considered serious. 

Examples of such events include invasive or malignant cancers, intensive treatment in 
an emergency room or at home for allergic bronchospasm, blood dyscrasias or 
convulsions that do not result in hospitalization, or development of drug dependency 
or drug abuse.
10.3.4
Additional Events Reported
Additional events that require reporting
In addition to the above criteria, AEs meeting either of the below criteria, although not 
serious per ICH definition, are reportable to the Sponsor.

Is a cancer

Is associated with an overdose
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10.3.5
Recording AE and SAE
AE and SAE recording

When an AE/SAE occurs, it is the responsibility of the investigator to review all 
documentation (eg, hospital progress notes, laboratory, and diagnostics reports) related to 
the event.

The investigator will record all relevant AE/SAE information on the AE 
CRFs/worksheets at each examination.

It is not acceptable for the investigator to send photocopies of the participant’s medical 
records to the Sponsor in lieu of completion of the AE CRF page.

There may be instances when copies of medical records for certain cases are requested by 
the Sponsor. In this case, all participant identifiers, with the exception of the participant 
number, will be blinded on the copies of the medical records before submission to the 
Sponsor.

The investigator will attempt to establish a diagnosis of the event based on signs, 
symptoms, and/or other clinical information. In such cases, the diagnosis (not the 
individual signs/symptoms) will be documented as the AE/SAE.
Assessment of intensity/toxicity

An event is defined as “serious” when it meets at least 1 of the predefined outcomes as 
described in the definition of an SAE, not when it is rated as severe.

The investigator will make an assessment of intensity for each AE and SAE (and other 
reportable safety event) by recording the grade according to the NIH DAIDS Table for 
Grading the Severity of Adult and Pediatric Adverse Events, version 2.1. Any AE which 
changes DAIDS grade over the course of a given episode will have each change of grade 
recorded on the AE CRFs/worksheets.
-
Grade 1 Mild event: Mild symptoms causing no or minimal interference with usual 
social and functional activities with intervention not indicated. 
-
Grade 2 Moderate event: Moderate symptoms causing greater than minimal 
interference with usual social and functional activities with intervention indicated. 
-
Grade 3 Severe event: Severe symptoms causing inability to perform usual social and 
functional activities with intervention or hospitalization indicated. 
-
Grade 4 Potentially life-threatening event: Potentially life-threatening symptoms 
causing inability to perform basic self-care functions with intervention indicated to 
prevent permanent impairment, persistent disability, or death. 
-
Grade 5 Death: Deaths related to an AE.
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Assessment of causality

Did the study intervention cause the AE?

The determination of the likelihood that the study intervention 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 
study intervention and the AE; the greater the correlation with the components and 
their respective elements (in number and/or intensity), the more likely the study 
intervention caused the AE: 
-
Exposure: Is there evidence that the participant was actually exposed to the study 
intervention 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 study intervention? 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 study intervention 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 study 
intervention; (3) the study is a single-dose drug study; or (4) study intervention(s) 
is/are only used 1 time.)
-
Rechallenge: Was the participant re-exposed to the study intervention in this study? 
If yes, did the AE recur or worsen? 
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If yes, this is a positive rechallenge. 
If no, this is a negative rechallenge. 
(Note: This criterion is not applicable if: (1) the initial AE resulted in death or 
permanent disability, or (2) the study is a single-dose drug study; or (3) study 
intervention(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 STUDY INTERVENTION, OR IF RE-
EXPOSURE TO THE STUDY INTERVENTION POSES ADDITIONAL POTENTIAL 
SIGNIFICANT RISK TO THE PARTICIPANT THEN THE RECHALLENGE MUST BE 
APPROVED IN ADVANCE BY THE SPONSOR CLINICAL DIRECTOR, AND IF 
REQUIRED, THE IRB/IEC.

Consistency with study intervention profile: Is the clinical/pathological presentation of 
the AE consistent with previous knowledge regarding the study intervention 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 study intervention relationship). 
-
Yes, there is a reasonable possibility of study intervention relationship: 
There is evidence of exposure to the study intervention. The temporal sequence of 
the AE onset relative to the administration of the study intervention is reasonable. 
The AE is more likely explained by the study intervention than by another cause. 
-
No, there is not a reasonable possibility of study intervention relationship: 

Participant did not receive the study intervention OR temporal sequence of the AE 
onset relative to administration of the study intervention is not reasonable OR the 
AE is more likely explained by another cause than the study intervention. (Also 
entered for a participant with overdose without an associated AE.) 

For each AE/SAE, the investigator must document in the medical notes that he/she has 
reviewed the AE/SAE and has provided an assessment of causality. 

There may be situations in which an SAE has occurred and the investigator has minimal 
information to include in the initial report to the Sponsor. However, it is very important 
that the investigator always make an assessment of causality for every event before the 
initial transmission of the SAE data to the Sponsor. 
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
The investigator may change his/her opinion of causality in light of follow-up 
information and send an SAE follow-up report with the updated causality assessment. 

The causality assessment is 1 of the criteria used when determining regulatory reporting 
requirements.
Follow-up of AE and SAE

The investigator is obligated to perform or arrange for the conduct of supplemental 
measurements and/or evaluations as medically indicated or as requested by Sponsor to 
elucidate the nature and/or causality of the AE or SAE as fully as possible. This may 
include additional laboratory tests or investigations, histopathological examinations, or 
consultation with other health care professionals.

New or updated information will be recorded in the CRF.

The investigator will submit any updated SAE data to the Sponsor within 24 hours of 
receipt of the information.
10.3.6
Reporting of AEs, SAEs, and Other Reportable Safety Events to the Sponsor
AE, SAE, and other reportable safety event reporting to Sponsor via electronic data 
collection tool

The primary mechanism for reporting to the Sponsor will be the electronic data collection 
(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 man who is assigned female gender at birth and is 
transitioning toward maleness) 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 gender at birth and transitioning toward femaleness). 

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 continue 
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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 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. 
Acceptable Contraceptive Methods
Failure rate of >1% per year when used consistently and correctly.

Progesterone-only hormonal contraception where inhibition of ovulation is not the primary mode of action

Male or female condom with or without spermicide

Cervical cap, diaphragm, or sponge with spermicide

A combination of male condom with either cervical cap, diaphragm, or sponge with spermicide (double 
barrier methods)e
a.
Contraceptive use by men or women should be consistent with local regulations regarding the use of 
contraceptive methods for participants of clinical studies.
b.
Typical use failure rates are higher than perfect-use failure rates (ie, when used consistently and correctly).
c.
If locally required, in accordance with CTFG guidelines, acceptable contraceptive implants are limited to 
those which inhibit ovulation.
d.
IUS is a progestin releasing IUD.
e.
A combination of male condom with either cap, diaphragm, or sponge with spermicide are considered 
acceptable, but not highly effective, birth control methods.
Note: The following are not acceptable methods of contraception:
-
Periodic abstinence (calendar, symptothermal, post-ovulation methods), withdrawal (coitus 
interruptus), spermicides only, and LAM.
-
Male and female condom should not be used together (due to risk of failure with friction).
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10.6
Appendix 6: Collection and Management of Specimens for Future Biomedical 
Research
1. Definitions
a. Biomarker: A biological molecule found in blood, other body fluids, or tissues that is a 
sign of a normal or abnormal process or of a condition or disease. A biomarker may be 
used to see how well the body responds to a treatment for a disease or condition.1
b. Pharmacogenomics: The investigation of variations of DNA and RNA characteristics as 
related to drug/vaccine response.2
c. Pharmacogenetics: A subset of pharmacogenomics, pharmacogenetics is the influence of 
variations in DNA sequence on drug/vaccine response.2
d. DNA: Deoxyribonucleic acid.
e. RNA: Ribonucleic acid.
2. Scope of Future Biomedical Research3,4
The specimens consented and/or collected in this study as outlined in Section 8.9 will be 
used in various experiments to understand:

The biology of how drugs/vaccines work

Biomarkers responsible for how a drug/vaccine enters and is removed by the body

Other pathways with which drugs/vaccines may interact

The biology of disease
The specimen(s) may be used for future assay development and/or drug/vaccine 
development.
It is now well recognized that information obtained from studying and testing clinical 
specimens offers unique opportunities to enhance our understanding of how individuals 
respond to drugs/vaccines, enhance our understanding of human disease and ultimately 
improve public health through development of novel treatments targeted to populations 
with the greatest need. All specimens will be used by the Sponsor or those working for or 
with the Sponsor.
3. Summary of Procedures for Future Biomedical Research3,4
a.
Participants for Enrollment
All participants enrolled in the clinical study will be considered for enrollment in 
future biomedical research.
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b.
Informed Consent
Informed consent for specimens (ie, DNA, RNA, protein, etc.) will be obtained 
during screening for protocol enrollment from all participants or legal guardians, at a 
study visit by the investigator or his or her designate. Informed consent for future 
biomedical research should be presented to the participants on the visit designated in 
the SoA. If delayed, present consent at next possible Participant Visit. Consent forms 
signed by the participant will be kept at the clinical study site under secure storage for 
regulatory reasons.
A template of each study site’s approved informed consent will be stored in the 
Sponsor’s clinical document repository.
c.
eCRF Documentation for Future Biomedical Research Specimens
Documentation of participant consent for future biomedical research will be captured 
in the eCRFs. Any specimens for which such an informed consent cannot be verified 
will be destroyed.
d.
Future Biomedical Research Specimen(s)
Collection of specimens for future biomedical research will be performed as outlined 
in the SoA. In general, if additional blood specimens are being collected for future 
biomedical research, these will usually be obtained at a time when the participant is 
having blood drawn for other study purposes.
4. Confidential Participant Information for Future Biomedical Research3,4
In order to optimize the research that can be conducted with future biomedical research 
specimens, it is critical to link participant' 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 gender, age, medical history and intervention outcomes are 
critical to understanding clinical context of analytical results.
To maintain privacy of information collected from specimens obtained for future 
biomedical research, the Sponsor has developed secure policies and procedures. All 
specimens will be single-coded per ICH E15 guidelines as described below.
At the clinical study site, unique codes will be placed on the future biomedical research 
specimens. This code is a random number which does not contain any personally 
identifying information embedded within it. The link (or key) between participant 
identifiers and this unique code will be held at the study site. No personal identifiers will 
appear on the specimen tube.
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5. Biorepository Specimen Usage3,4
Specimens obtained for the Sponsor will be used for analyses using good scientific 
practices. Analyses utilizing the future biomedical research specimens may be performed 
by the Sponsor, or an additional third party (eg, a university investigator) designated by 
the Sponsor. The investigator conducting the analysis will follow the Sponsor’s privacy 
and confidentiality requirements. Any contracted third party analyses will conform to the 
specific scope of analysis outlined in future biomedical research protocol and consent. 
Future biomedical research specimens remaining with the third party after specific 
analysis is performed will be reported to the Sponsor.
6. Withdrawal From Future Biomedical Research3,4
Participants may withdraw their consent for future biomedical research and ask that their 
biospecimens not be used for future biomedical research. Participants may withdraw 
consent at any time by contacting the investigator for the main study. If medical records 
for the main study are still available, the investigator will contact the Sponsor using the 
designated mailbox (clinical.specimen.management@MSD.com). Subsequently, the 
participant's specimens will be flagged in the biorepository and restricted to main study 
use only. If specimens were collected from study participants specifically for future 
biomedical research, these specimens will be removed from the biorepository and 
destroyed. Documentation will be sent to the investigator confirming withdrawal and/or 
destruction, if applicable. It is the responsibility of the investigator to inform the 
participant of completion of the withdrawal and/or destruction, if applicable. Any 
analyses in progress at the time of request for withdrawal/destruction or already 
performed prior to the request being received by the Sponsor will continue to be used as 
part of the overall research study data and results. No new analyses would be generated 
after the request is received.
In the event that the medical records for the main study are no longer available (eg, if the 
investigator is no longer required by regulatory authorities to retain the main study 
records) or the specimens have been completely anonymized, there will no longer be a 
link between the participant’s personal information and their specimens. In this situation, 
the request for withdrawal of consent and/or destruction cannot be processed.
7. Retention of Specimens3,4
Future biomedical research specimens will be stored in the biorepository for potential 
analysis for up to 20 years from the end of the main study. Specimens may be stored for 
longer if a regulatory or governmental authority has active questions that are being 
answered. In this special circumstance, specimens will be stored until these questions 
have been adequately addressed.
Specimens from the study site will be shipped to a central laboratory and then shipped to 
the Sponsor-designated biorepository. If a central laboratory is not utilized in a particular 
study, the study site will ship directly to the Sponsor-designated biorepository. The 
specimens will be stored under strict supervision in a limited access facility which 
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operates to assure the integrity of the specimens. Specimens will be destroyed according 
to Sponsor policies and procedures and this destruction will be documented in the 
biorepository database.
8. Data Security3,4
Databases containing specimen information and test results are accessible only to the 
authorized Sponsor representatives and the designated study administrator research 
personnel and/or collaborators. Database user authentication is highly secure, and is 
accomplished using network security policies and practices based on international 
standards to protect against unauthorized access.
9. Reporting of Future Biomedical Research Data to Participants3,4
No information obtained from exploratory laboratory studies will be reported to the 
participant, family, or physicians. Principle reasons not to inform or return results to the 
participant include: Lack of relevance to participant health, limitations of predictive 
capability, and concerns regarding misinterpretation.
If important research findings are discovered, the Sponsor may publish results, present 
results in national meetings, and make results accessible on a public website in order to 
rapidly report this information to doctors and participants. Participants will not be 
identified by name in any published reports about this study or in any other scientific 
publication or presentation.
10. Future Biomedical Research Study Population3,4
Every effort will be made to recruit all participants diagnosed and treated on Sponsor 
clinical studies for future biomedical research.
11. Risks Versus Benefits of Future Biomedical Research3,4
For future biomedical research, risks to the participant have been minimized and are 
described in the future biomedical research informed consent.
The Sponsor has developed strict security, policies, and procedures to address participant 
data privacy concerns. Data privacy risks are largely limited to rare situations involving 
possible breach of confidentiality. In this highly unlikely situation, there is risk that the 
information, like all medical information, may be misused.
12. Questions
Any questions related to the future biomedical research should be emailed directly to 
clinical.specimen.management@MSD.com.
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13. References
1. National Cancer Institute [Internet]: Available from 
https://www.cancer.gov/publications/dictionaries/cancer-terms?cdrid=45618
2. International Council on Harmonisation [Internet]: E15: Definitions for Genomic 
Biomarkers, Pharmacogenomics, Pharmacogenetics, Genomic Data and Sample 
Coding Categories. Available from 
http://www.ich.org/products/guidelines/efficacy/efficacy-single/article/definitions-
for-genomic-biomarkers-pharmacogenomics-pharmacogenetics-genomic-data-and-
sample-cod.html 
3. Industry Pharmacogenomics Working Group [Internet]: Understanding the Intent, 
Scope and Public Health Benefits of Exploratory Biomarker Research: A Guide for 
IRBs/IECs and Investigational Site Staff. Available at http://i-pwg.org/ 
4. Industry Pharmacogenomics Working Group [Internet]: Pharmacogenomics 
Informational Brochure for IRBs/IECs and Investigational Site Staff. Available at 
http://i-pwg.org/ 
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10.7
Appendix 7: Country-specific Requirements
10.7.1
Country-specific Request for Germany
Participants who enroll in Germany will not have DEXA scans as indicated in the SoA. This 
procedure will be omitted, and participants in Germany will not be included in the applicable 
analyses.
In Germany, if a participant becomes pregnant (has a positive serum pregnancy test), she 
must discontinue from study intervention, and the participant’s HIV-1 infection and 
treatment should be managed per local standard of care. All reported pregnancies must be 
followed to completion or termination so that the outcome of the pregnancy is reported. 
Additionally, pregnant women who discontinue study intervention are encouraged, but not 
required, to consent to postnatal infant safety data collection.
The following protocol sections related to pregnancy remain applicable in Germany:
-
Section 8.1.1.3 Consent for Postnatal Infant Safety Data Collection Through One 
Year of Age
-
Sections 8.4.5 Pregnancy and Exposure During Breastfeeding
-
Section 8.11.6 Clinical Management of Participants Who Become Pregnant
-
Section 8.11.6.2 Discontinuing Study Intervention for Pregnancy 
-
8.11.6.4 Infant Safety Data Collection
-
8.11.6.4.1 Schedule of Activities: Infant Safety Data Collection
The following sections are not applicable in Germany:
-
Section 1.3.4 Schedule of Activities for Participants Whose Pregnancy or Postpartum 
Visits Extend Beyond Week 144 
-
Section 4.2.7 Rationale for Continuing Study Intervention During Pregnancy
-
Section 8.1.1.4 Consent for Continuation of Study Intervention During Pregnancy
-
Section 8.11.6.1 Continuing Study Intervention
-
Section 8.11.6.3 Participants Who Choose to Breastfeed
In addition, consent must be obtained directly from the participant in Germany; the use of a 
legally acceptable representative to obtain consent is not permitted. Participants who cannot 
directly provide informed consent cannot participate in this study.
10.7.2
Country-specific Request for Canada
Participants who become HBsAg or HBV DNA positive after randomization must be 
discontinued from study intervention. This was included in a country-specific amendment 
(MK-8591A-018-01).
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10.7.3
Country-specific Request for Japan
BIC/FTC/TAF taken by participants in Group 2 is not categorized as “product(s) used in the 
clinical trial” in Japan.
10.7.4
Country-specific Request for the United States
Two substudies will be conducted in the United States as described in Section 10.7.4.1 and 
Section 10.7.4.2. 
Participation in the substudies is optional (as described in Section 10.7.4.1.1 and 
Section 10.7.4.2.1, respectively). Eligible participants may opt to enroll in one or both 
substudies.
If a participant is enrolled in both substudies, it is preferable for blood sample collection for 
each substudy to occur at separate visits. The investigator and participant may decide to have 
all samples collected in a single visit.
10.7.4.1
Plasma/PBMC PK Substudy
A plasma/PBMC PK substudy will be conducted at selected sites in the United States to 
measure ISL in plasma and ISL-TP in PBMCs to evaluate steady-state levels in participants
living with HIV, with long-term dosing of ISL. 
Approximately 12 DOR/ISL participants who provide documented informed consent will be 
enrolled in the plasma/PBMC PK substudy. These participants may be enrolled from any of 
the 3 Phase 3 studies (MK-8591A-017, -018, and/or -033). 
Only participants who have completed Week 96 and transitioned to open-label DOR/ISL will 
be eligible to enroll in the plasma/PBMC PK substudy.
The blood samples will be collected from the consented participant 20 to 24 hours after their
previous dose of DOR/ISL Table 19. Site staff will instruct participants to delay the
DOR/ISL dose to be taken on the day of this visit until after the blood samples for the 
substudy are collected. Site staff will record the date and time of the participants’ last dose of 
study intervention and the date and time of each blood sample collection in the appropriate 
eCRF.
Sample collection can occur at a scheduled or unscheduled visit. Site staff must follow the 
operations/laboratory manual for sample collection and handling.
10.7.4.1.1
Consent to Participate in the Optional Plasma/PBMC PK Substudy
The investigator or medically qualified designee will explain the optional plasma/PBMC PK 
substudy to the participant, or the participant’s legally acceptable representative, answer all 
of his/her questions, and obtain documented informed consent before performing any 
procedure related to the plasma/PBMC PK substudy. A copy of the documented informed 
consent will be given to the participant. After documented informed consent is obtained, the 
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participant will have additional blood sample collection performed, as described in 
Section 10.7.4.1.2. 
10.7.4.1.2
Plasma/PBMC PK Substudy Procedures
Participants who provide documented informed consent to participate in the plasma/PBMC 
PK substudy will have the procedures performed as described in Table 19 and Table 20.
Table 19
Schedule of Activities for Participants in the Plasma/PBMC PK Substudy
Study Period
Plasma/PBMC PK Substudy
Notes
Visit Number
Participant’s Next Routine Study Visit 
or Unscheduled
Scheduled Day/Week
Plasma/PBMC PK Substudy
Visit Window
NA
Administrative Procedures
Informed Consent to Participate in the
Optional Plasma/PBMC PK Substudy
X
See Section 10.7.4.1.1.
Pharmacokinetics and Additional Investigational Research
Blood (Plasma) for ISL PK
X
See Section 10.7.4.1.
Blood (PBMC) for ISL-TP PK
X
ISL=islatravir; ISL-TP=islatravir-triphosphate; NA=not applicable; PBMC=peripheral blood mononuclear cells; 
PK=pharmacokinetics.
Table 20
Blood Volumes: Plasma/PBMC PK Substudy
Visit
Participant’s Next Routine Study Visit or 
Unscheduled
Sample Collection Timing
Predose
Blood Parameter
Approximate Blood Volume (mL)
Blood (Plasma) for ISL PK
3
Blood (PBMC) for ISL-TP PK
16
Overall Approximate Blood Volume for the Substudy
19
ISL=islatravir; ISL-TP=islatravir-triphosphate; PBMC=peripheral blood mononuclear cell; PK=pharmacokinetics.
10.7.4.2
Investigational Research Substudy
An investigational research substudy will be conducted at selected sites in the United States 
to collect PBMCs to assess lymphocyte immunophenotyping and the functionality of the
lymphocyte subpopulations.
Participants may provide blood samples for the substudy more than once during the study.
Approximately 12 DOR/ISL participants who provide documented informed consent will be 
enrolled in the investigational research substudy. These participants may be enrolled from 
MK-8591A-018 and/or MK-8591A-033.
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In addition, approximately 6 to 12 BIC/TAF/FTC participants who provide documented 
informed consent will be enrolled in the investigational research substudy. These participants 
will be enrolled only from MK-8591A-018.
Participants will be eligible to enroll in the investigational research substudy irrespective of
the treatment week completed.
The blood sample will be collected from the consented participant irrespective of the timing 
of dosing of DOR/ISL or BIC/TAF/FTC (as applicable) Table 21. Sample collection can 
occur at a scheduled or unscheduled visit. Site staff will record the date and time of each 
blood sample collection in the appropriate eCRF.
Site staff must follow the operations/laboratory manual for sample collection and handling.
10.7.4.2.1
Consent to Participate in the Optional Investigational Research Substudy
The investigator or medically qualified designee will explain the optional investigational 
research substudy to the participant, or the participant’s legally acceptable representative, 
answer all of his/her questions, and obtain documented informed consent before performing 
any procedure related to the investigational research substudy. A copy of the documented 
informed consent will be given to the participant. After documented informed consent is 
obtained, the participant will have an additional blood sample collection as specified in 
Section 10.7.4.2.2.
10.7.4.2.2
Investigational Research Substudy Procedures
Participants who provide documented informed consent to participate in the investigational 
research substudy will have the procedures performed as described in Table 21 and Table 22.
Table 21
Schedule of Activities for Participants in the Investigational Research Substudy
Study Period
Investigational Research Substudy
Notes
Visit Number
Participant’s Next Routine Study Visit 
or Unscheduled
Scheduled Day/Week
Investigational Research Substudy
Visit Window
NA
Administrative Procedures
Informed Consent to Participate in the
Optional Investigational Research Substudy
X
See Section 10.7.4.2.1.
Additional Investigational Research
Blood (PBMC) for Investigational Research
X
See Section 10.7.4.2.
NA=not applicable; PBMC=peripheral blood mononuclear cells.
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Table 22
Blood Volumes: Investigational Research Substudy
Visit
Participant’s Next Routine Study Visit or 
Unscheduled
Sample Collection Timing
Irrespective of timing of prior dose
Blood Parameter
Approximate Blood Volume (mL)
Blood (PBMC) for Investigational Research
30
Overall Approximate Blood Volume for the Substudy
30
PBMC=peripheral blood mononuclear cell.
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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
BfArM
Bundesinstitut für Arzneimittel und Medizinprodukte
β-hCG
Beta human chorionic gonadotropin
3TC
lamivudine
AE
adverse event 
AIDS
acquired immunodeficiency syndrome
ALT
alanine aminotransferase
ANCOVA
analysis of covariance
anti-HBc
hepatitis B core antibody
APaT
All Participants as Treated
ART
antiretroviral therapy
AST
aspartate aminotransferase
AUC
area under the curve
BIC
bictegravir
BMD
bone mineral density
BMI
body mass index
BOCF
baseline observation carried forward
C24
concentration after 24 hours
CD4+
CD4-positive
CI
confidence interval
CONSORT
Consolidated Standards of Reporting Trials
Cmax
maximum (peak) observed drug plasma concentration
CNS
central nervous system 
Crcl
creatinine clearance
CRF
case report form 
CSR
Clinical Study Report
CTFG
Clinical Trial Facilitation Group 
Ctrough
lowest concentration reached by a drug before the next dose is administered
DAIDS
The Division of AIDS
DAO
Data-As-Observed
DDI
drug-drug interaction
DEXA
Dual X-ray Absorptiometry
DMC
Data Monitoring Committee 
DNA
deoxyribonucleic acid 
DOR
doravirine
ECG
electrocardiogram 
ECI
event of clinical interest
eCRF
electronic case report form
EDC
electronic data collection 
EFV
efavirenz
eDMC
external Data Monitoring Committee
EMA
European Medicines Agency
EOC
Executive Oversight Committee 
EQ-5D-5L
EuroQol five-dimensional descriptive system, five-level version
EU
European Union
FAS
Full Analysis Set
FBR
Future Biomedical Research
FDA
Food and Drug Administration
FDAAA
Food and Drug Administration Amendments Act
FDC
fixed dose combination
FSH
follicle stimulating hormone 
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Abbreviation
Expanded Term
FTC
emtricitabine
GCP
Good Clinical Practice 
H
hypothesis
HBc
hepatitis B core
HBsAg
hepatitis B surface antigen
HBV
hepatitis B virus
HCV
hepatitis C virus
HDL-C
high-density lipoprotein cholesterol
HIV
human immunodeficiency virus
HIV SDM
Human Immunodeficiency Virus Symptom Distress Module
HIV-SI
Human Immunodeficiency Virus Symptom Index
HIVTSQ
Human Immunodeficiency Virus Treatment Satisfaction Questionnaire
HOMA-IR
Homeostatic Model Assessment of Insulin Resistance
HRQoL
health-related quality of life
HRT
hormone replacement therapy
hs-CRP
high-sensitivity C-reactive protein
HTA
Health Technology Assessment
IA
Interim Analysis(ses)
IB
Investigator’s Brochure 
IC50
concentration of drug needed to inhibit 50% of viral growth
ICF
Informed Consent Form 
ICH
International Conference on Harmonisation
IEC
Independent Ethics Committee
IL-6
interleukin-6
IND
Investigational New Drug 
INR
international normalized ratio
InSTI
integrase strand transfer inhibitor
IQ
inhibitory quotient
IRB
Institutional Review Board 
IRT
Interactive Response Technology
ISL
islatravir
IUD
intrauterine device
IUS
intrauterine hormone-releasing system
LDL-C
low-density lipoprotein cholesterol
LOCF
last observation carried forward
M=F
missing data treated as treatment failure
NK
natural killer
NNRTI
non-nucleoside reverse transcriptase inhibitor
NRTI
nucleoside analog reverse transcriptase inhibitor
NRTTI
nucleoside reverse transcriptase translocation inhibitor
OF
Observed Failure 
PBMC
peripheral blood mononuclear cell
PCL
Protocol Clarification Letter
PCR
polymerase chain reaction
PDLC
predefined limit of change
PI
protease inhibitor
PK
pharmacokinetic
PP
Per-protocol
PrEP
preexposure prophylaxis
PRO
patient-reported outcome
qd
once-daily
RNA
ribonucleic acid
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Abbreviation
Expanded Term
SAC
Scientific Advisory Committee
SAE
serious adverse event 
sCD-163
soluble CD-163
SoA
schedule of activities
SOC
System Organ Class
SOP
standard operating procedure
sSAP
supplemental statistical analysis plan
SUSAR
suspected unexpected serious adverse reaction
TAF
tenofovir alafenamide
TAMS
thymidine analog mutations
TBNK
T- and B- Lymphocyte and Natural Killer Cell Profile
TC
total cholesterol
TDF
tenofovir disoproxil fumarate
TG
triglyceride
TLOVR
Time to Loss of Virologic Response
TP
triphosphate
US
United States
WHO
World Health Organization
WOCBP
woman/women of childbearing potential 
WONCBP
woman/women of nonchildbearing potential
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10.10 Appendix 10: Summary of Protocol Clarification Letters
Protocol
PCL date
Correction not implemented in a subsequent 
amendment
Impact
P018
04-NOV-2022
Section 10.2: Update to blood volume requirements to 
resolve discrepancies that were noted between the SOA 
(Section 1.3.2), blood volumes on Table 17 (Section 
10.2), and/or the Central Laboratory volume 
requirement for each test. 
In summary,
Week 108, Week 120, Week 132, and Week 144 – Less 
total blood volume is required than depicted in AM08 
Table 17.
Week 156 – Updated from a Total Blood Volume of 30
mL to 42 mL.
Week 168 – Updated from a Total Blood Volume of 30
mL to 36 mL.
HBV DNA references the incorrect footnote. The 
correct footnote is “b.”
Footnote “c” updated to align with SOA (ie, 
Investigational PK samples taken for Group 1 
(DOR/ISL) participants only.
Study conduct.
However, not 
applicable, because
all remaining 
participants are in 
post-treatment 
lymphocyte 
monitoring, and the 
samples are not 
being collected as 
part of the post-
treatment 
lymphocyte 
monitoring.
P018
22-FEB-2023a
Transition 0.75 to 0.25 PCL: Inform sites that additional 
guidance documents will be provided to assist in 
transitioning participants to either the new trials or 
discontinuation from the current trial.  
Study conduct.
DNA=deoxyribonucleic acid; DOR/ISL=doravirine/islatravir; HBV=hepatitis B virus; PCL=protocol 
clarification letter; PK=pharmacokinetics; SOA=summary of activities.
a
Not issued as a PCL but as a memo to sites.
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11
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