Clinical trial NCT04233879
Conditions: HIV-1 Infection
Sponsor: Merck Sharp & Dohme LLC
Start date: 2020-02-28; Completion date: 2025-01-29
Enrollment: 599 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This is a phase 3, randomized, controlled, double-blind, multisite clinical study of a once-daily fixed dose combination (FDC) of 100 mg doravirine/0.75 mg islatravir (DOR/ISL \[also known as MK-8591A\]) in treatment-naïve participants with human immunodeficiency virus type-1 (HIV-1) infection. The primary objectives are to evaluate the antiretroviral activity, safety, and tolerability of DOR/ISL compared to bictegravir/emtricitabine/tenofovir alafenamide (BIC/FTC/TAF). The primary hypothesis is that DOR/ISL is noninferior or superior to BIC/FTC/TAF treatment based on the percentage of participants with HIV-1 ribonucleic acid (RNA) \<50 copies/mL at Week 48.

Detailed description:
Double-blind treatment with the assigned intervention occurs from Day 1 to Week 96, followed by an open-label portion up to Week 144. Participants who benefit from treatment in the opinion of the Investigator may continue their assigned intervention up to Week 168 (or until they have the option to enroll in a DOR/ISL 100 mg/0.25 mg study, whichever is sooner).

Arms: arm 1: Treatment-naïve participants with HIV-1 receive blinded DOR/ISL and placebo to BIC/FTC/TAF once daily (QD) from Day 1 to Week 96, and open-label DOR/ISL up to Week 144. Participants who are benefitting from treatment are then eligible to continue on open-label DOR/ISL up to Week 168. arm 2: Treatment-naïve participants with HIV-1 receive blinded BIC/FTC/TAF and placebo to DOR/ISL QD from Day 1 to Week 96, and open-label BIC/FTC/TAF up to Week 144. Participants who are benefitting from treatment are then eligible to continue on open-label BIC/FTC/TAF up to Week 168.
Interventions: intervention 1: DOR/ISL intervention 2: BIC/FTC/TAF intervention 3: Placebo to BIC/FTC/TAF intervention 4: Placebo to DOR/ISL
Intervention descriptions: intervention 1: 100 mg DOR/0.75 mg ISL FDC tablet taken once daily by mouth. intervention 2: BIC/FTC/TAF 50/200/25 mg FDC tablet taken once daily by mouth. intervention 3: Placebo tablet matched to BIC/FTC/TAF taken by mouth. intervention 4: Placebo tablet matched to DOR/ISL taken by mouth.

Protocol documents:
Prot_SAP_000.pdf: 
Official Protocol Title:
NCT number:
NCT04233879
Document Date:            12-Oct-2022
A Phase 3 Randomized, Active-Controlled,
Double-Blind Clinical Study to Evaluate the
Antiretroviral Activity, Safety, and Tolerability of
Doravirine/Islatravir Once-Daily in HIV-1
Infected Treatment-Naïve Participants


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 the Antiretroviral Activity, Safety, and Tolerability of Doravirine/Islatravir Once-
Daily in HIV-1 Infected Treatment-Naïve Participants
Protocol Number: 020-05
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
134,036
EudraCT
2019-000590-23
Approval Date: 12 October 2022
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Sponsor Signatory
Typed Name:
Title:
Date
Protocol-specific Sponsor contact information can be found in the Investigator Study
File Binder (or equivalent).
Investigator Signatory
I agree to conduct this clinical study in accordance with the design outlined in this protocol 
and to abide by all provisions of this protocol.
Typed Name:
Title:
Date
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DOCUMENT HISTORY
Document
Date of Issue
Overall Rationale
Amendment 05
12-OCT-2022
This protocol was amended to allow 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 the participant has 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 04
26-JAN-2022
The protocol was amended to: (1) 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, given the findings of decreases in CD4+ T-cell and total 
lymphocyte counts in clinical studies evaluating ISL and (2) to update the timing 
of when the Sponsor will be unblinded to individual participants' treatment 
assignments.
Protocol Amendment 03
09-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 03 were not implemented at clinical 
sites. Amendment 04 supersedes amendment 03.
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Document
Date of Issue
Overall Rationale
Protocol Amendment 02
28-MAY-2021
The protocol was amended to: (1) extend study intervention (open-label) from 96 
weeks to 144 weeks for all participants; (2) provide an option for Group 2 to 
receive open-label DOR/ISL from Week 144 to Week 156; (3) offer the option to 
continue study intervention for participants who become pregnant; and (4) add a 
discontinuation criterion if a participant chooses to breastfeed.
Protocol Amendment 01
11-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.
Original Protocol
05-NOV-2019
Not applicable.
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PROTOCOL AMENDMENT SUMMARY OF CHANGES
Amendment: 05
Overall Rationale for the Amendments:
This protocol was amended to allow 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 the participant has 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.
Summary of Changes Table:
Section # and Name
Description of Change 
Brief Rationale 
1.1 Synopsis 
1.2 Schema
1.3.2 Schedule of Activities – Week 108 
Through Week 168 Open-label 
Intervention, Including Study Extension 
1.3.3 Schedule of Activities – Viremia 
Confirmation and End of Treatment
1.3.4 Schedule of Activities for 
Participants Whose Pregnancy or 
Postpartum Visit(s) Extends Beyond Week 
168
4.1 Overall Design
4.2 Scientific Rationale for Study Design
Relevant text across multiple sections was 
updated to reflect the following key 
changes:

Group 2 participants will continue 
receiving BIC/FTC/TAF and not 
switch to DOR/ISL 100 mg/0.75 mg at 
Week 144. 

An extension of up to 24 weeks has 
been added following Week 144 (visits 
at Week 156 and Week 168) has been 
added; participants who enter the study 
extension may continue assigned study 
intervention through Week 168.

Given the findings of decreases in 
CD4+ T-cell and total lymphocyte 
counts in clinical studies evaluating 
ISL, participants who are not already 
on a DOR/ISL regimen (ie, Group 2
receiving BIC/FTC/TAF) will not be 
given an option to switch to DOR/ISL 
100 mg/0.75 mg in the study.

To allow participants to continue 
assigned study intervention for an 
extended duration of up to 24 weeks 
(Week 168) until they have the option 
to enroll in a DOR/ISL (100 mg/0.25 
mg) study or transition to commercial 
ART, whichever is sooner.
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Section # and Name
Description of Change 
Brief Rationale 
6.1 Study Intervention(s) Administered
6.3.3 Blinding
7.1 Discontinuation of Study Intervention
8.1.1.5 Consent to Participate in the Study 
Extension
8.3.6 HBV Assessments
8.4.7 Events of Clinical Interest
8.11.2.1 Fasting
8.11.2.3 Week 144 Visit
8.11.3.2 End of Treatment Follow-up Visit
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
8.11.5.3 Participants Discontinued from 
Study Intervention for Other Reasons And 
Have Decreases in CD4+ T-cell and/or 
Total Lymphocyte Counts
8.11.6.1 Continuing Study Intervention
9.4.1.1 Efficacy Endpoints
9.4.2 Safety Endpoints
9.5.2 Safety Analysis Population
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Section # and Name
Description of Change 
Brief Rationale 
9.6.1 Statistical Methods for Efficacy 
Analysis
9.6.2 Statistical Methods for Safety 
Analyses
9.11 Compliance (Medication Adherence)
10.2 Appendix 2: Clinical Laboratory 
Tests (Table 17 and Table 18)
6.7 Intervention After the End of the Study
8.4.1 Time Period and Frequency for 
Collecting AE, SAE, and Other Reportable 
Safety Event Information

DOR/ISL 100 mg/0.75 mg rollover 
study was removed and an option to  
enroll in a DOR/ISL 100 mg/0.25 mg 
study (where available) was added.

Collection of safety events in the
rollover study was removed.

DOR/ISL 100 mg/0.75 mg is not 
available at the end of the study.

Instructions for the rollover study are 
not applicable.
4.1 Study Design
The following sentence was added to this 
section:

Participants receiving assigned study 
intervention may be eligible to enroll 
in a DOR/ISL 100 mg/0.25 mg study 
(when and where available) or to 
transition to commercially available 
ART (see Section 6.7).
Added to clarify that participants do not 
need to reach Week 144 or enter the 
study extension in order to enroll in a 
DOR/ISL 100 mg/0.25 study (when it 
becomes available) or transition to 
commercially available ART.
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Section # and Name
Description of Change 
Brief Rationale 
6.3.3 Blinding
The following sentence was added to this 
section:

The investigator and participant may 
become unblinded by the Sponsor 
(after the Week 48 database lock) to 
facilitate decisions regarding the 
option to enroll the participant in a 
DOR/ISL 100 mg/0.25 mg study 
(where available) or transition to 
commercially available ART.
Unblinding may be necessary for 
participants who have not yet reached 
Week 96 to allow investigators and their 
participants to determine future treatment 
options.
1.3.3 Schedule of Activities – Viremia 
Confirmation and End of Treatment (All 
Participants Except Those with Specified 
Decreases in CD4+ T-cell/Lymphocyte 
counts)
Note for blood (Plasma) for DOR and ISL 
PK was updated.
PK sampling is not needed if participant 
is known to be receiving BIC/FTC/TAF.
1.3.4 Schedule of Activities for 
Participants Whose Pregnancy or 
Postpartum Visit(s) Extends Beyond Week 
168
8.11.6.1 Continuing Study Intervention
Pregnancy visit scheduling was updated 
and the text was updated with instructions 
for the End of Treatment Follow-up Visit 
in pregnant participants.
Revised for clarity.
2.2.1 Pharmaceutical and Therapeutic 
Background
2.3 Benefit/Risk Assessment
Updated text with more recent data from 
the ISL clinical development program.
To account for new safety and efficacy 
information from the ISL clinical 
development program that is relevant to 
the participants in this ongoing study.
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Section # and Name
Description of Change 
Brief Rationale 
8.11.6.1 Continuing Study Intervention
Table 6 was revised.
Revised to specify the time of PK 
sampling, dependent upon the time of 
dose of study intervention (daytime dose 
versus evening dose).
Title Page
Section 10.1.1 Code of Conduct for 
Clinical Trials
Throughout
Sponsor entity name and address change.
Merck Sharp & Dohme underwent an 
entity name and address change to Merck 
Sharp & Dohme LLC, Rahway, NJ, 
USA. This conversion resulted only in an 
entity name change and update to the 
address.
10.3.1 Definitions of Medication Error, 
Misuse, and Abuse
Added section.
Per Regulation (EU) No 536/2014 of the 
European Parliament and of the Council.
10.7.2 Country-specific Request for Japan
Statement about the use of BIC/FTC/TAF 
in Japan has been added.
Added per recent PMDA regulation 
changes.
Throughout Document
Minor administrative, formatting, 
grammatical, and typographical changes 
were made throughout the document.
To ensure clarity and accurate 
interpretation of the intent of the 
protocol.
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Table of Contents
DOCUMENT HISTORY ........................................................................................................3
PROTOCOL AMENDMENT SUMMARY OF CHANGES...............................................5
1
PROTOCOL SUMMARY ............................................................................................19
1.1
Synopsis.................................................................................................................19
1.2
Schema ..................................................................................................................24
1.3
Schedule of Activities (SoA)................................................................................25
Schedule of Activities – Screening Through Week 96 (Blinded 
Intervention).................................................................................................25
Schedule of Activities – Week 108 Through Week 168 Open-label 
Intervention, Including Study Extension .....................................................32
Schedule of Activities – Viremia Confirmation and End of Treatment 
(End of Treatment for all Participants Except Those with Specified 
Decreases in CD4+ T-cell/Total Lymphocyte Counts) ...............................37
Schedule of Activities for Participants Whose Pregnancy or Postpartum 
Visit(s) Extends Beyond Week 168.............................................................40
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
Pharmaceutical and Therapeutic Background .............................................46
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
Rationale for Endpoints ...............................................................................56
4.2.1.1
Efficacy Endpoints.............................................................................56
4.2.1.1.1
HIV-1 RNA Measurement.......................................................56
4.2.1.1.2
Definition of Clinically Significant Confirmed Viremia.........56
4.2.1.2
Safety Endpoints................................................................................57
4.2.1.3
Weight, Laboratory, and Radiological Markers ................................57
4.2.1.4
Pharmacokinetic Endpoints ...............................................................58
4.2.1.5
Patient-Reported Outcomes ...............................................................58
4.2.1.6
Planned Exploratory Biomarker Research.........................................58
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4.2.1.6.1
Planned Genetic Analysis ........................................................58
4.2.1.7
Future Biomedical Research..............................................................59
Rationale for the Use of Comparator/Placebo .............................................59
Rationale for the Selected Participant Population .......................................59
Rationale for Collecting Race and Ethnicity ...............................................60
Rationale for Collecting Gender Identity Data ............................................60
Rationale for Infant Safety Data Collection.................................................60
Rationale for Continuing Study Intervention During Pregnancy ................60
4.3
Justification for Dose...........................................................................................61
4.4
Beginning and End of Study Definition .............................................................62
Clinical Criteria for Early Study Termination .............................................62
5
STUDY POPULATION ................................................................................................62
5.1
Inclusion Criteria.................................................................................................63
5.2
Exclusion Criteria................................................................................................64
5.3
Lifestyle Considerations......................................................................................67
5.4
Screen Failures.....................................................................................................67
5.5
Participant Replacement Strategy......................................................................67
6
STUDY INTERVENTION............................................................................................67
6.1
Study Intervention(s) Administered...................................................................67
6.2
Preparation/Handling/Storage/Accountability .................................................69
Dose Preparation..........................................................................................69
Handling, Storage, and Accountability........................................................69
6.3
Measures to Minimize Bias: Randomization and Blinding..............................70
Intervention Assignment..............................................................................70
Stratification.................................................................................................70
Blinding........................................................................................................70
6.4
Study Intervention Compliance..........................................................................71
6.5
Concomitant Therapy..........................................................................................71
Rescue Medications and Supportive Care ...................................................72
6.6
Dose Modification (Escalation/Titration/Other)...............................................72
6.7
Intervention After the End of the Study............................................................73
6.8
Clinical Supplies Disclosure................................................................................73
6.9
Standard Policies..................................................................................................73
7
DISCONTINUATION OF STUDY INTERVENTION AND PARTICIPANT 
WITHDRAWAL............................................................................................................74
7.1
Discontinuation of Study Intervention...............................................................74
7.2
Participant Withdrawal From the Study...........................................................76
7.3
Lost to Follow-up .................................................................................................76
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8
STUDY ASSESSMENTS AND PROCEDURES........................................................76
8.1
Administrative and General Procedures ...........................................................77
Informed Consent.........................................................................................77
8.1.1.1
General Informed Consent.................................................................77
8.1.1.2
Consent and Collection of Specimens for Future Biomedical 
Research.............................................................................................78
8.1.1.3
Consent for Postnatal Infant Safety Data Collection Through One 
Year of Age........................................................................................78
8.1.1.4
Consent for Continuation of Study Intervention During 
Pregnancy...........................................................................................78
8.1.1.5
Consent to Participate in the Study Extension...................................78
Inclusion/Exclusion Criteria ........................................................................78
Participant Identification Card.....................................................................78
Medical History ...........................................................................................79
Prior and Concomitant Medications Review...............................................79
8.1.5.1
Prior Medications...............................................................................79
8.1.5.2
Concomitant Medications..................................................................79
Assignment of Screening Number...............................................................79
Assignment of Treatment/Randomization Number.....................................79
Study Intervention Administration ..............................................................80
8.1.8.1
Timing of Dose Administration.........................................................80
Discontinuation and Withdrawal .................................................................80
8.1.9.1
Withdrawal From Future Biomedical Research ................................81
Participant Blinding/Unblinding..................................................................81
Calibration of Equipment.............................................................................82
Administration of Participant Questionnaires..............................................82
8.2
Efficacy Assessments ...........................................................................................82
HIV-1 RNA..................................................................................................82
Management of Study Participants with Viremia........................................82
8.2.2.1
Viremia Confirmation........................................................................83
8.2.2.2
Participants with Clinically Significant Viremia (≥200 
copies/mL) .........................................................................................83
8.2.2.3
Participants with Low-level Viremia (≥50 and <200 copies/mL) .....83
8.2.2.4
Viral Drug Resistance Testing...........................................................84
T- and B-Lymphocyte and Natural Killer Cell Profile (TBNK)..................84
8.3
Safety Assessments...............................................................................................84
Physical Examinations.................................................................................84
8.3.1.1
Weight................................................................................................85
Vital Signs....................................................................................................85
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Electrocardiograms ......................................................................................85
Confirmation of Contraception and Pregnancy Testing ..............................85
Clinical Safety Laboratory Assessments .....................................................86
HBV Assessments........................................................................................86
Tobacco and Alcohol Assessments..............................................................87
8.4
Adverse Events (AEs), Serious Adverse Events (SAEs), and Other 
Reportable Safety Events ....................................................................................87
Time Period and Frequency for Collecting AE, SAE, and Other 
Reportable Safety Event Information ..........................................................87
Method of Detecting AEs, SAEs, and Other Reportable Safety Events......89
Follow-up of AE, SAE, and Other Reportable Safety Event Information...89
Regulatory Reporting Requirements for SAE .............................................89
Pregnancy and Exposure During Breastfeeding ..........................................89
Disease-related Events and/or Disease-related Outcomes Not Qualifying 
as AEs or SAEs............................................................................................90
Events of Clinical Interest (ECIs)................................................................90
8.5
Treatment of Overdose........................................................................................91
8.6
Pharmacokinetics.................................................................................................91
Blood Collection for Plasma ISL.................................................................91
8.7
Pharmacodynamics..............................................................................................92
8.8
Biomarkers ...........................................................................................................92
Planned Genetic Analysis Sample Collection..............................................92
Inflammation................................................................................................92
Renal Function.............................................................................................92
Fasting Lipid and Metabolic Profiles...........................................................92
Waist and Hip Measurements......................................................................93
DEXA Assessments.....................................................................................93
8.9
Future Biomedical Research Sample Collection...............................................94
8.10
Health Economics Medical Resource Utilization and Health Economics.......94
8.11
Visit Requirements...............................................................................................94
Screening/Rescreening.................................................................................94
Treatment Period..........................................................................................95
8.11.2.1
Fasting................................................................................................95
8.11.2.2
Optional Nurse Visits and Telephone Visits......................................95
8.11.2.3
Week 144 Visit ..................................................................................96
Participants Who Discontinue Study Intervention.......................................96
8.11.3.1
Early Discontinuation of Treatment...................................................96
8.11.3.2
End of Treatment Follow-up Visit.....................................................97
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Viremia Confirmation..................................................................................97
Management of Participants with Specified Decreases in CD4+ T-cell 
Count and/or Total Lymphocyte Count.......................................................97
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..............................................................97
8.11.5.2
Participants Discontinued from Study Intervention Due to 
Decreased CD4+ T-cell Count and/or Total Lymphocyte Count......98
8.11.5.3
Participants Discontinued from Study Intervention for Other 
Reasons And Have Decreases in CD4+ T-cell and/or Total 
Lymphocyte Counts...........................................................................99
Clinical Management of Participants Who Become Pregnant.....................99
8.11.6.1
Continuing Study Intervention.........................................................100
8.11.6.2
Discontinuing Study Intervention for Pregnancy ............................101
8.11.6.3
Participants Who Choose to Breastfeed...........................................101
8.11.6.4
Infant Safety Data Collection...........................................................102
8.11.6.4.1
Schedule of Activities: Infant Safety Data Collection...........102
9
STATISTICAL ANALYSIS PLAN ...........................................................................102
9.1
Statistical Analysis Plan Summary...................................................................103
9.2
Responsibility for Analyses/In-house Blinding ...............................................105
9.3
Hypotheses/Estimation ......................................................................................105
9.4
Analysis Endpoints.............................................................................................105
Efficacy/Pharmacokinetics Endpoints .......................................................105
9.4.1.1
Efficacy Endpoints...........................................................................105
9.4.1.2
Pharmacokinetics Endpoints............................................................107
Safety Endpoints........................................................................................107
Patient-reported Outcome Endpoints.........................................................108
9.5
Analysis Populations..........................................................................................108
Efficacy Analysis Populations...................................................................108
9.5.1.1
Sentinel Cohort ................................................................................108
9.5.1.2
Full Analysis Set..............................................................................108
9.5.1.3
Per-Protocol Analysis Set ................................................................109
9.5.1.4
Resistance Analysis Subset..............................................................109
Safety Analysis Population........................................................................109
9.6
Statistical Methods.............................................................................................109
Statistical Methods for Efficacy Analyses.................................................110
Statistical Methods for Safety Analyses ....................................................116
Summaries of Baseline Characteristics, Demographic, and Other 
Analyses.....................................................................................................119
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9.6.3.1
Demographic and Baseline Characteristics .....................................119
9.7
Interim Analyses ................................................................................................119
9.8
Multiplicity .........................................................................................................121
9.9
Sample Size and Power Calculations ...............................................................123
Sample Size and Power Calculations for Efficacy Analyses.....................123
Sample Size and Power for Safety Analyses .............................................129
9.9.2.1
Evaluation of Adverse Events..........................................................129
9.9.2.2
Evaluation of Change in Weight......................................................131
9.10
Subgroup Analyses.............................................................................................133
9.11
Compliance (Medication Adherence)...............................................................133
9.12
Extent of Exposure.............................................................................................134
10
SUPPORTING DOCUMENTATION AND OPERATIONAL 
CONSIDERATIONS...................................................................................................135
10.1
Appendix 1: Regulatory, Ethical, and Study Oversight Considerations......135
Code of Conduct for Clinical Trials...........................................................135
Financial Disclosure...................................................................................137
Data Protection...........................................................................................138
10.1.3.1
Confidentiality of Data ....................................................................138
10.1.3.2
Confidentiality of Participant Records.............................................138
10.1.3.3
Confidentiality of IRB/IEC Information..........................................138
Committees Structure.................................................................................139
10.1.4.1
Executive Oversight Committee......................................................139
10.1.4.2
External Data Monitoring Committee .............................................139
10.1.4.3
Scientific Advisory Committee (SAC)............................................139
Publication Policy......................................................................................139
Compliance with Study Registration and Results Posting Requirements .140
Compliance with Law, Audit, and Debarment ..........................................140
Data Quality Assurance .............................................................................141
Source Documents .....................................................................................141
Study and Site Closure...............................................................................142
10.2
Appendix 2: Clinical Laboratory Tests............................................................143
10.3
Appendix 3: Adverse Events: Definitions and Procedures for Recording, 
Evaluating, Follow-up, and Reporting.............................................................151
Definitions of Medication Error, Misuse, and Abuse................................151
Definition of AE ........................................................................................151
Definition of SAE ......................................................................................152
Additional Events Reported.......................................................................154
Recording AE and SAE .............................................................................154
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Reporting of AEs, SAEs, and Other Reportable Safety Events to the 
Sponsor ......................................................................................................158
10.4
Appendix 4: Device Events, Adverse Device Events, and Medical Device 
Incidents: Definitions, Collection, and Documentation..................................159
10.5
Appendix 5: Contraceptive Guidance..............................................................160
Definitions..................................................................................................160
Contraception Requirements......................................................................162
10.6
Appendix 6: Collection and Management of Specimens for Future 
Biomedical Research..........................................................................................163
10.7
Appendix 7: Country-specific Requirements..................................................168
Country-specific Request for Germany .....................................................168
Country-specific Request for Japan...........................................................168
10.8
Appendix 8: Calculation of Creatinine Clearance and eGFR .......................169
10.9
Appendix 9: Abbreviations ...............................................................................170
11
REFERENCES.............................................................................................................173
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LIST OF TABLES
Table 1
Laboratory Exclusion Criteria..........................................................................66
Table 2
Study Interventions..........................................................................................68
Table 3
Prohibited Therapies ........................................................................................72
Table 4
Reporting Time Periods and Time Frames for Adverse Events and Other 
Reportable Safety Events.................................................................................88
Table 5
Collection of Population PK Samples..............................................................91
Table 6
Collection of Population PK Samples During Pregnancy and Postpartum ...101
Table 7
Definitions of Study Time Points ..................................................................110
Table 8
Analysis Strategy for Key Efficacy Variables...............................................116
Table 9
Analysis Strategy for Safety Parameters........................................................119
Table 10
Summary of Assumptions and Overall Study Power Assuming 60 
Participants in the Sentinel Cohort and 680 Participants Overall..................124
Table 11
Power to Establish Superiority at Week 48/96 Under Various Response 
Rate Assumptions (Assuming All Prior Hypothesis Tests Reach Statistical 
Significance) (340 Participants Per Group)...................................................128
Table 12
Power to Establish Noninferiority at Week 96 Under Various Response 
Rate Assumptions (340 Participants per Group) ...........................................129
Table 13
Estimate of Incidence of AEs and 95% Upper Confidence Bound Based 
on Hypothetical Numbers of Participants with AEs (340 Participants Per 
Group)............................................................................................................130
Table 14
Difference in Incidence of AEs (Group 1 Minus Group 2) That Can Be 
Ruled Out with 340 Participants in Each Group............................................130
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............................................................................................131
Table 16
Protocol-required Laboratory Assessments...................................................143
Table 17
Blood Volumes ..............................................................................................147
Table 18
Blood Volumes: Participants Whose Pregnancy or Postpartum Visit(s) 
Extends Beyond Week 168............................................................................150
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LIST OF FIGURES
Figure 1
Study Schema and Treatment Plan ..................................................................24
Figure 2
Estimated Power to Declare Noninferiority of DOR/ISL to BIC/FTC/TAF 
at Week 48 Assuming 30 Enrolled and Evaluable Participants in Group 1 
in the Sentinel Cohort and 680 Participants Overall......................................126
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1
PROTOCOL SUMMARY
1.1
Synopsis
Protocol Title: A Phase 3 Randomized, Active-Controlled, Double-Blind Clinical Study to
Evaluate the Antiretroviral Activity, Safety, and Tolerability of Doravirine/Islatravir Once-
Daily in HIV-1 Infected Treatment-Naïve Participants
Short Title: Randomized, double-blind, safety, efficacy Doravirine/Islatravir in Tx naïve
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 who are infected 
with HIV-1 and naïve to antiretroviral therapy.
Primary Objectives
Primary Endpoints
- To evaluate the antiretroviral activity of 
DOR/ISL compared to 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 noninferior to 
BIC/FTC/TAF as measured by the percentage of 
participants with HIV-1 RNA <50 copies/mL at 
Week 48. A margin of 10 percentage points is 
used to define noninferiority.
- 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 
DOR/ISL compared to 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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Secondary Objectives
Secondary Endpoints
- To evaluate the antiretroviral activity of 
DOR/ISL compared to 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 noninferior to 
BIC/FTC/TAF as measured by the percentage of 
participants with HIV-1 RNA <50 copies/mL at 
Week 96. A margin of 10 percentage points is 
used to define noninferiority.
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 of 
DOR/ISL compared to 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 <200 copies/mL
- HIV-1 RNA
- To evaluate the immunologic effect of 
DOR/ISL as measured by the 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 in participants who receive DOR/ISL 
and in those who receive BIC/FTC/TAF
- Viral resistance-associated 
substitutions
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- To evaluate the effect of DOR/ISL compared to 
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-1 infection
Population
Participants ≥18 years of age with HIV-1 who are naïve to 
antiretroviral therapy
Study Type
Interventional
Intervention Model
Parallel
This is a multi-site study.
Type of Control
Placebo with active control
Study Blinding
Double-blind
Masking
Sponsor (through Week 48)
Investigator (through Week 96)
Participants or Subjects (through Week 96)
Estimated Duration of Study
The Sponsor estimates that the study will require 
approximately 5 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 680 participants will be randomized.
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Intervention Groups and Duration:
Intervention 
Groups
Inter-
vention 
Group 
Name
Drug
Dose Strength
Dose 
Frequency
Route of 
Administration
Treatment 
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 2a
BIC/FTC/TAF
50/ 200/ 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/ISL=fixed dose combination of doravirine and islatravir, also known as MK-8591A; 
FTC=emtricitabine; 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
Participants 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 period of up to 45 days, each participant will 
receive assigned blinded intervention for approximately 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.
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.
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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/ISL=fixed dose combination of doravirine and islatravir, also known as MK-8591A; 
FTC=emtricitabine; N=total number of participants in the study; n=number of participants per group;
TAF=tenofovir alafenamide.
Note: Randomization will occur at Day 1.
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 extension 
(Section 8.11.2.3).
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1.3
Schedule of Activities (SoA)
Schedule of Activities – Screening Through Week 96 (Blinded Intervention)
Study Period
Screen
Blinded Intervention
Notes
Visit Number
1
2
3
4
5
6
7
8
9
10
11
12
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
Screening
Day 1
(Fasting)
4
8
16
24
(Fasting)
36
48
(Fasting)
60
72
84
96
(Fasting)
Visit Window
≤45 daysa
NA
±7 days
Group 1 and Group 2
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 for 
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 Section
8.11.6.
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Study Period
Screen
Blinded Intervention
Notes
Visit Number
1
2
3
4
5
6
7
8
9
10
11
12
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
Screening
Day 1
(Fasting)
4
8
16
24
(Fasting)
36
48
(Fasting)
60
72
84
96
(Fasting)
Visit Window
≤45 daysa
NA
±7 days
Group 1 and Group 2
Administration of 
EQ-5D-5L and 
HIV-SI Participant 
Questionnaires
X
X
X
X
X
Administer before being seen by 
investigator and discussing 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 time of randomization, site personnel 
will add randomization number to 
participant identification card.
Medical History
X
Prior/Concomitant 
Medication Review
X
X
X
X
X
X
X
X
X
X
X
X
Register Study Visit 
in IRT
X
X
X
X
X
X
X
X
X
X
X
X
Intervention 
Randomization
X
All procedures should be completed prior 
to dose on Day 1.
Dispense Study 
Intervention Using 
IRT
X
X
X
X
X
X
X
X
X
X
X
At Week 96 open-label study intervention 
will be dispensed.
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Study Period
Screen
Blinded Intervention
Notes
Visit Number
1
2
3
4
5
6
7
8
9
10
11
12
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
Screening
Day 1
(Fasting)
4
8
16
24
(Fasting)
36
48
(Fasting)
60
72
84
96
(Fasting)
Visit Window
≤45 daysa
NA
±7 days
Group 1 and Group 2
Study Intervention 
Compliance Review
X
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
X
CD4+ T-cell 
Count/TBNK Panel
X
X
X
X
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.
Blood (Plasma) for 
HIV-1 Drug 
Resistance
X
Blood (Plasma) for 
HIV-1 Drug 
Resistance – Backup
X
X
X
X
X
X
X
X
X
X
X
X
Backup samples will be used if needed.
Safety Procedures
Full Physical 
Examination
X
Height
X
Weight
X
X
X
X
X
X
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Study Period
Screen
Blinded Intervention
Notes
Visit Number
1
2
3
4
5
6
7
8
9
10
11
12
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
Screening
Day 1
(Fasting)
4
8
16
24
(Fasting)
36
48
(Fasting)
60
72
84
96
(Fasting)
Visit Window
≤45 daysa
NA
±7 days
Group 1 and Group 2
Directed Physical 
Examination
X
X
X
X
X
X
X
X
X
X
X
Vital Signs
X
X
X
X
X
X
X
X
X
X
X
X
Includes pulse, blood pressure, body 
temperature, and respiratory rate.
12-Lead ECG
X
May be performed up to 7 days prior to 
dose on Day 1 after all other eligibility 
criteria are confirmed.
Contraception Use 
Confirmation
(WOCBP only)
X
X
X
X
X
X
X
X
X
X
X
Serum Pregnancy 
Test 
(hCG; WOCBP 
only)
X
Urine Pregnancy 
Test
(WOCBP only)
X
X
X
X
X
X
X
X
X
X
X
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 and HIV-2 
Serology
X
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Study Period
Screen
Blinded Intervention
Notes
Visit Number
1
2
3
4
5
6
7
8
9
10
11
12
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
Screening
Day 1
(Fasting)
4
8
16
24
(Fasting)
36
48
(Fasting)
60
72
84
96
(Fasting)
Visit Window
≤45 daysa
NA
±7 days
Group 1 and Group 2
Hepatitis Serology
X
Participants who do not demonstrate 
immunity to HBV should be encouraged 
to be vaccinated against HBV.
HBV DNA
X
Chemistry
X
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
X
Decreases in total lymphocyte count that 
meet ECI criteria should be managed per 
Section 1.3.5 and Section 8.11.5.
PT/INR
X
Urinalysis
X
X
X
X
X
Review of Adverse 
Events
X
X
X
X
X
X
X
X
X
X
X
X
Pharmacokinetics
Blood (Plasma) for 
ISL PK
X
X
X
X
X
X
At Week 4, a predose and postdose 
sample will be taken. 
Blood (Plasma) for 
Investigational ISL 
PK 
X
X
X
X
X
Analysis will be triggered by Sponsor as 
needed.
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Study Period
Screen
Blinded Intervention
Notes
Visit Number
1
2
3
4
5
6
7
8
9
10
11
12
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
Screening
Day 1
(Fasting)
4
8
16
24
(Fasting)
36
48
(Fasting)
60
72
84
96
(Fasting)
Visit Window
≤45 daysa
NA
±7 days
Group 1 and Group 2
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. Only applicable for women 
receiving DOR/ISL.
Biomarkers
Blood for Genetic 
Analysisb
X
Whole Blood for 
Future Biomedical 
Research
X
X
X
X
Requires FBR consent.
Blood for 
Inflammatory 
Markers
X
X
X
X
Blood and Urine for 
Renal Markers
X
X
X
X
Waist and Hip 
Measurements
X
X
X
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Study Period
Screen
Blinded Intervention
Notes
Visit Number
1
2
3
4
5
6
7
8
9
10
11
12
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
Screening
Day 1
(Fasting)
4
8
16
24
(Fasting)
36
48
(Fasting)
60
72
84
96
(Fasting)
Visit Window
≤45 daysa
NA
±7 days
Group 1 and Group 2
DEXA Scan
(only where 
permitted by local 
law)
X
X
X
Perform after all eligibility criteria are 
confirmed and up to 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 scans should not be performed on 
pregnant participants.
CD4+=CD4 positive; DEXA=dual-energy x-ray absorptiometry; DNA=deoxyribonucleic acid; DOR= doravirine; ECG=electrocardiogram; EQ-5D-5L=EuroQol Five-
Dimensional Descriptive System, Five Level Version; HBV=hepatitis B virus; hCG= human chorionic gonadotropin; HCV=hepatitis C virus; HIV=human immunodeficiency 
virus; HIV-1=human immunodeficiency virus type 1; HIV-2= human immunodeficiency virus type 2; HIV-SI=Human Immunodeficiency Virus Symptom Index; 
INR=international normalized ratio; IRT=interactive response technology; ISL=islatravir; NA=not applicable; PCR=polymerase chain reaction; PK=pharmacokinetic; 
PT=prothrombin time; RNA=ribonucleic acid; TBNK=T and B lymphocyte and natural killer cells; WOCBP=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, a 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 (or their legally acceptable representative) provides documented informed consent for future 
biomedical research. 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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Schedule of Activities – Week 108 Through Week 168 Open-label Intervention, Including Study Extension
Study Period
Open-label Intervention
Notes
Visit Number
13
14
15
16
17
18
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 Week
108
120
(Fasting)
132
144
(Fasting)
Week 156*
Week 168*
(Fasting)
*Week 156 and Week 168 are part of the 
study extension
Visit Window
±7 days
Group 1 and Group 2
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.
Dispense Study 
Intervention 
Using IRT
X
X
X
X
X
Study intervention should only be dispensed 
at Week 144 and Week 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.
08BBK7


PRODUCT: MK-8591A  
33
PROTOCOL/AMENDMENT NO.: 020-05
MK-8591A-020-05 FINAL PROTOCOL
12-OCT-2022
Study Period
Open-label Intervention
Notes
Visit Number
13
14
15
16
17
18
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 Week
108
120
(Fasting)
132
144
(Fasting)
Week 156*
Week 168*
(Fasting)
*Week 156 and Week 168 are part of the 
study extension
Visit Window
±7 days
Group 1 and Group 2
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.
Collect and enter 
data from prenatal 
care provider for
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 Section 
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.
08BBK7


PRODUCT: MK-8591A  
34
PROTOCOL/AMENDMENT NO.: 020-05
MK-8591A-020-05 FINAL PROTOCOL
12-OCT-2022
Study Period
Open-label Intervention
Notes
Visit Number
13
14
15
16
17
18
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 Week
108
120
(Fasting)
132
144
(Fasting)
Week 156*
Week 168*
(Fasting)
*Week 156 and Week 168 are part of the 
study extension
Visit Window
±7 days
Group 1 and Group 2
Blood (Plasma) 
for HIV-1 Drug 
Resistance
X
X
X
X
X
X
Backup samples will be used if needed.
Safety Procedures
Directed Physical 
Examination
X
X
X
X
X
X
Weight
X
X
X
X
Vital Signs
X
X
X
X
X
X
Includes pulse, blood pressure, body 
temperature, and respiratory rate.
Contraception 
Use Confirmation
(WOCBP only)
X
X
X
X
X
X
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 
infant collected per Section 8.11.6.4.1.
Chemistry
X
X
X
X
X
X
Fasting is required at Week 120, Week 144, 
and Week 168.
Hematology
X
X
X
X
X
X
Decreases in total lymphocyte count that 
meet ECI criteria should be managed per 
Section 1.3.5 and Section 8.11.5.
08BBK7


PRODUCT: MK-8591A  
35
PROTOCOL/AMENDMENT NO.: 020-05
MK-8591A-020-05 FINAL PROTOCOL
12-OCT-2022
Study Period
Open-label Intervention
Notes
Visit Number
13
14
15
16
17
18
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 Week
108
120
(Fasting)
132
144
(Fasting)
Week 156*
Week 168*
(Fasting)
*Week 156 and Week 168 are part of the 
study extension
Visit Window
±7 days
Group 1 and Group 2
Urinalysis
X
X
X
Review of 
Adverse Events
X
X
X
X
X
X
Pharmacokinetics
Blood (Plasma) 
for Investigational 
ISL PK
X
Group 1 (DOR/ISL) only. Analysis triggered 
by Sponsor as needed
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
Requires FBR consent.
Blood for 
Inflammatory 
Markers
X
Blood and Urine 
for Renal Markers
X
Waist and Hip 
Measurements
X
08BBK7


PRODUCT: MK-8591A  
36
PROTOCOL/AMENDMENT NO.: 020-05
MK-8591A-020-05 FINAL PROTOCOL
12-OCT-2022
Study Period
Open-label Intervention
Notes
Visit Number
13
14
15
16
17
18
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 Week
108
120
(Fasting)
132
144
(Fasting)
Week 156*
Week 168*
(Fasting)
*Week 156 and Week 168 are part of the 
study extension
Visit Window
±7 days
Group 1 and Group 2
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. DEXA 
should not be performed on pregnant 
participants.
anti-HBc=hepatitis B core antibody; CD4+=CD4 positive; DEXA=dual-energy x-ray absorptiometry; DNA=deoxyribonucleic acid; DOR=doravirine; FBR=future biomedical 
research; HBsAg=hepatitis B surface antigen; HBV=hepatitis B virus; HIV=human immunodeficiency virus; HIV-1=human immunodeficiency virus type 1; IRT=interactive 
response technology; ISL=islatravir; NA=not applicable; PCR=polymerase chain reaction; PK=pharmacokinetic; RNA=ribonucleic acid; TBNK=T and B lymphocyte and 
natural killer cells; WOCBP=woman/women of childbearing potential.
08BBK7


PRODUCT: MK-8591A  
37
PROTOCOL/AMENDMENT NO.: 020-05
MK-8591A-020-05 FINAL PROTOCOL
12-OCT-2022
Schedule of Activities – Viremia Confirmation and End of Treatment
(End of Treatment for 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 continuing 
DOR/ISL in a new 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 assess study 
intervention compliance.
Administration of EQ-5D-5L and 
HIV-SI Participant Questionnaires
X
Administer before being seen by 
investigator and discussing medical 
conditions or test results.
Not to be collected if participant 
discontinues study intervention after 
Week 96.
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 the average 
baseline valuec or who meet relevant ECI 
criteria at the Early Discontinuation of 
Treatment visit should be managed per 
Section 1.3.5 and Section 8.11.5.
08BBK7


PRODUCT: MK-8591A  
38
PROTOCOL/AMENDMENT NO.: 020-05
MK-8591A-020-05 FINAL PROTOCOL
12-OCT-2022
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 continuing 
DOR/ISL in a new studyb.
Visit Window
Within 2 to 4 weeks of 
HIV-1 Viremia
(≥50 copies/mL)
NA
42 (+7) days after the
end of treatment
Blood (Plasma) for HIV-1 Drug 
Resistance
X
X
X
If HIV-1 Drug Resistance sample is 
collected at the Viremia Confirmation 
visit, it is not necessary to collect another 
sample at Early Discontinuation of 
Treatment visit. Analysis of samples 
collected at Viremia Confirmation and 
End of Treatment Follow-up visits will be
triggered by Sponsor as needed.
Safety Procedures 
Full Physical Examination
X
X
Weight
X
X
Vital Signs 
X
X
Includes pulse, blood pressure, body 
temperature, respiratory rate.
Contraception Use Confirmation
(WOCBP only)
X
X
X
Serum Pregnancy Test
(WOCBP only)
X
X
If serum test is positive, participant will 
be managed per Section 8.11.6 and safety 
of infant collected per Section 8.11.6.4.1.
Chemistry
X
Hematology
X
Participants with decreases in total 
lymphocyte count >10% from the average 
baseline valuec at the Early 
Discontinuation of Treatment visit should 
be managed per Section 1.3.5 and Section 
8.11.5
Urinalysis
X
Review of Adverse Events
X
X
X
08BBK7


PRODUCT: MK-8591A  
39
PROTOCOL/AMENDMENT NO.: 020-05
MK-8591A-020-05 FINAL PROTOCOL
12-OCT-2022
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 continuing 
DOR/ISL in a new studyb.
Visit Window
Within 2 to 4 weeks of 
HIV-1 Viremia
(≥50 copies/mL)
NA
42 (+7) days after the
end of treatment
Pharmacokinetics
Blood (Plasma) for Investigational 
ISL PK
X
X
X
Analysis will be triggered by Sponsor as 
needed. Do not collect if participant is 
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 is collected at the Viremia 
Confirmation visit, it is not necessary to 
collect another sample at Early 
Discontinuation of Treatment visit.
CD4+=CD4 positive; EQ-5D-5L=EuroQol Five-Dimensional Descriptive System, Five Level Version; FBR=future biomedical research; HIV= human immunodeficiency virus; 
HIV-1=human immunodeficiency virus type 1; HIV-SI=Human Immunodeficiency Virus Symptom Index; IRT=interactive response technology; ISL= islatravir; NA=not 
applicable; PCR=polymerase chain reaction; PK=pharmacokinetics; RNA=ribonucleic acid; TBNK=T and B lymphocyte and natural killer cells; WOCBP=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 for CD4+ T-cell count and total lymphocyte count is defined as the average of the screening (within 45 days prior to the first dose of study 
intervention) and Day 1 values through Week 48. After Week 48, the baseline resets to the Week 48 value only if the Week 48 value is greater than the average baseline 
value. If there are ≥2 values at Week 48, then use the most recent value. 
08BBK7


PRODUCT: MK-8591A  
40
PROTOCOL/AMENDMENT NO.: 020-05
MK-8591A-020-05 FINAL PROTOCOL
12-OCT-2022
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
(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 assessments 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
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-1 Viral Drug Resistance 
Testing 
X
X
X
X
Backup samples, will be used if needed
08BBK7


PRODUCT: MK-8591A  
41
PROTOCOL/AMENDMENT NO.: 020-05
MK-8591A-020-05 FINAL PROTOCOL
12-OCT-2022
Visit Number
Unscheduled
Notes
Scheduled Week
Pregnancy 1
(Week 180)
Pregnancy 2
(Week 192)
Pregnancy 3
(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 assessments 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
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.
Chemistry
X
X
X
X
Hematology
X
X
X
X
Decreases in total lymphocyte count 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. Only 
applicable for women receiving DOR/ISL
Biomarkers
Whole Blood for Future Biomedical 
Research
X
X
X
X
Optional participation; requires FBR consent
anti-HBc=hepatitis B core antibody; CD4+=CD4 positive; DNA=deoxyribonucleic acid; DOR=doravirine; FBR=future biomedical research; HBsAg=hepatitis B surface 
antigen; HBV=hepatitis B virus; HIV=human immunodeficiency virus; HIV-1= human immunodeficiency virus type 1; IRT=Interactive Response Technology; ISL=islatravir; 
PCR=polymerase chain reaction; PK=pharmacokinetic; RNA=ribonucleic acid; TBNK=T and B lymphocyte and natural killer cells.
08BBK7


PRODUCT: MK-8591A  
42
PROTOCOL/AMENDMENT NO.: 020-05
MK-8591A-020-05 FINAL PROTOCOL
12-OCT-2022
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 Count 
and/or Total Lymphocyte 
Count Confirmation
Early 
Discontinuation 
of Treatment
End of Treatment 
Follow-up
CD4+ T-cell Count and/or 
Total Lymphocyte Count
Monitoring
See Sections 8.1.9 and 8.11.5 
for details regarding 
discontinuation and 
monitoring.
If specified decreases in CD4+ 
T-cell counts and/or total 
lymphocyte counts are 
confirmed, then the participant 
should be unblinded (if 
applicable) to determine the 
need for additional 
monitoring. Only those 
receiving 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 within 10 to 14 weeks
(ie, at the next routine study 
visit).
NA
42 (+7) days after 
discontinuing study 
intervention
Every 4 weeks (±7 days)
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.
08BBK7


PRODUCT: MK-8591A  
43
PROTOCOL/AMENDMENT NO.: 020-05
MK-8591A-020-05 FINAL PROTOCOL
12-OCT-2022
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 Count 
and/or Total Lymphocyte 
Count Confirmation
Early 
Discontinuation 
of Treatment
End of Treatment 
Follow-up
CD4+ T-cell Count and/or 
Total Lymphocyte Count
Monitoring
See Sections 8.1.9 and 8.11.5 
for details regarding 
discontinuation and 
monitoring.
If specified decreases in CD4+ 
T-cell counts and/or total 
lymphocyte counts are 
confirmed, then the participant 
should be unblinded (if 
applicable) to determine the 
need for additional 
monitoring. Only those 
receiving 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 within 10 to 14 weeks
(ie, at the next routine study 
visit).
NA
42 (+7) days after 
discontinuing study 
intervention
Every 4 weeks (±7 days)
Administration of 
EQ-5D-5L and 
HIV-SI 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 study 
intervention after Week 96.
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
Blood (Plasma) for 
HIV-1 Viral Drug 
Resistance Testing
X
X
Analysis of samples collected 
at End of Treatment Follow-
up visits triggered by Sponsor 
as needed.
08BBK7


PRODUCT: MK-8591A  
44
PROTOCOL/AMENDMENT NO.: 020-05
MK-8591A-020-05 FINAL PROTOCOL
12-OCT-2022
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 Count 
and/or Total Lymphocyte 
Count Confirmation
Early 
Discontinuation 
of Treatment
End of Treatment 
Follow-up
CD4+ T-cell Count and/or 
Total Lymphocyte Count
Monitoring
See Sections 8.1.9 and 8.11.5 
for details regarding 
discontinuation and 
monitoring.
If specified decreases in CD4+ 
T-cell counts and/or total 
lymphocyte counts are 
confirmed, then the participant 
should be unblinded (if 
applicable) to determine the 
need for additional 
monitoring. Only those 
receiving 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 within 10 to 14 weeks
(ie, at the next routine study 
visit).
NA
42 (+7) days after 
discontinuing study 
intervention
Every 4 weeks (±7 days)
Safety Procedures
Full Physical 
Examination 
X
X
Vital Signs 
X
X
Includes weight, pulse, blood 
pressure, temperature, and 
respiratory rate.
Contraception Use 
Confirmation 
(WOCBP Only)
X
X
Serum Pregnancy 
Test 
(WOCBP Only)
X
X
If serum test is positiv, 
participants will be managed 
per Section 8.11.6 and safety 
of her infant collected per 
Section 8.11.6.4.1.
Chemistry
X
Hematology
X
X
X
(DOR/ISL Only)
X
08BBK7


PRODUCT: MK-8591A  
45
PROTOCOL/AMENDMENT NO.: 020-05
MK-8591A-020-05 FINAL PROTOCOL
12-OCT-2022
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 Count 
and/or Total Lymphocyte 
Count Confirmation
Early 
Discontinuation 
of Treatment
End of Treatment 
Follow-up
CD4+ T-cell Count and/or 
Total Lymphocyte Count
Monitoring
See Sections 8.1.9 and 8.11.5 
for details regarding 
discontinuation and 
monitoring.
If specified decreases in CD4+ 
T-cell counts and/or total 
lymphocyte counts are 
confirmed, then the participant 
should be unblinded (if 
applicable) to determine the 
need for additional 
monitoring. Only those 
receiving 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 within 10 to 14 weeks
(ie, at the next routine study 
visit).
NA
42 (+7) days after 
discontinuing study 
intervention
Every 4 weeks (±7 days)
Urinalysis
X
Review of Adverse 
Events
X
X
X
X
Pharmacokinetics
Blood (Plasma) for 
Investigational ISL 
PK
X
X
PK analysis triggered by 
Sponsor as needed. No PK 
sampling after Week 144 visit. 
PK sampling not needed if 
participant is known to be in 
Group 2 (BIC/FTC/TAF).
Biomarkers
Whole Blood for 
Future Biomedical 
Research
X
CD4+=CD4 positive; EQ-5D-5L=EuroQol Five-Dimensional descriptive system, five level version; FBR=future biomedical research; HIV=human immunodeficiency virus; 
HIV-SI=Human Immunodeficiency Virus Symptom Index; IRT=Interactive Response Technology; NA=not applicable; PCR=polymerase chain reaction; 
PK=pharmacokinetics; RNA=ribonucleic acid; TBNK=T and B lymphocyte and natural killer cells; WOCBP=woman/women of childbearing potential.
08BBK7


PRODUCT:  MK-8591A  
46
PROTOCOL/AMENDMENT NO.:  020-05
MK-8591A-020-05 FINAL PROTOCOL
12-OCT-2022
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 lifelong treatment, the 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 an 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 one of the components having a relatively high barrier to resistance.
DOR/ISL has the potential for use in the treatment of HIV-1 infection in TN patients 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.
Pharmaceutical and Therapeutic Background
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. ISL is an inactive nucleoside 
analogue that is converted to the pharmacologically active triphosphate (ISL-TP) form via 
endogenous intracellular kinases. It acts through multiple mechanisms, including immediate 
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chain termination by blocking translocation and delayed chain termination by preventing 
nucleotide excision [Michailidis E 2014].
ISL is differentiated from other HIV-1 antiretrovirals by its high potency, long intracellular 
half-life, and favorable drug resistance profile. ISL (at the proposed dose of 0.75 mg QD) 
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-associated 
substitutions, including M184V and TAMs.
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 the EMA in 2018. DOR is differentiated 
from other NNRTIs by its distinct resistance profile, low likelihood of selection for viral 
resistance in vivo, and low potential for DDIs. DOR 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 TN 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 (MK-1439A Protocol 024).
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 Protocol 011) in ~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 tolerability profile through Week 96, comparable 
to that of DOR/3TC/TDF.
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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/ISL 100 mg/0.75 mg included studies in treatment-naïve adults (P020), virologically 
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 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.
Information on Other Study-related Therapy
BIC/FTC/TAF is approved for the treatment of HIV-1 infection in patients naïve to ART.
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-resistance-associated substitutions (eg, K103N, Y181C, G190A, and E138K) and 
ISL against common NRTI-resistance-associated substitutions (eg, M184V and TAMs). Both 
may be administered without regard to food, have a low potential for DDIs, and have 
favorable PK, safety, 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 Protocol 011), ISL+DOR+3TC (as a 3-drug regimen) 
achieved virological suppression in most (>90%) of treatment-naïve participants by Week 24. 
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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 Phase 3 studies evaluating DOR/ISL 100 mg/0.75 mg for daily 
treatment of HIV-1 in virologically suppressed participants (MK-8591A Protocol 017 and 
MK-8591A Protocol 018), approximately 95% of 658 participants enrolled in the DOR/ISL 
arm completed 48 weeks of treatment in both studies. In Protocol 017 and Protocol 018, 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 and 
BIC/FTC/TAF groups, respectively, at Week 48. To date, no viral resistance to either 
component of DOR/ISL has been shown in the Phase 2 (Protocol 011) and Phase 3 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 Protocol 013) 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 total lymphocyte counts 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 total lymphocyte counts 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 Protocol 013 has been 
discontinued.
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 
Protocol 016), there was a 21% mean decrease in total lymphocyte counts observed in the 
60 mg arm (the dose being evaluated in Phase 3 PrEP studies) and a 36% decrease in total
lymphocyte counts 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 Protocol 016. 
Dosing of oral ISL 60 mg QM has been discontinued in PrEP clinical studies.
Interim analyses of Protocol 017 and Protocol 018 studying 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%, respectively, in the DOR/ISL groups compared with mean 
increases of 2.3% and 3.5% in the comparator arms. In the same studies, DOR/ISL treated 
participants had a mean change in CD4+ T-cell counts of -0.7% and 0.9%, compared with an 
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increase of 8.7% in the baseline ART group and 12.8% in the BIC/FTC/TAF group. These 
decreases in CD4+ T-cell and lymphocyte counts have not been associated with an increased 
incidence of infection or other AEs. 
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 0.25 mg 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 100 mg/0.25 mg for daily treatment of HIV-1.
The Sponsor is assessing the reversibility of the reductions in CD4+ T-cell and total
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 mg and 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 total lymphocyte counts and strict study intervention 
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/0.75 mg QD in virologically suppressed adults (Protocol 017 and Protocol 
018) 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 IBs 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 who are infected 
with HIV-1 and naïve to antiretroviral therapy.
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Objectives
Endpoints
Primary

To evaluate the antiretroviral activity of 
DOR/ISL compared to 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 
noninferior to BIC/FTC/TAF as 
measured by the percentage of 
participants with HIV-1 RNA <50 
copies/mL at Week 48. A margin of 10 
percentage points is used to define 
noninferiority.
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 
DOR/ISL compared to 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

To evaluate the antiretroviral activity of 
DOR/ISL compared to 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 
noninferior to BIC/FTC/TAF as 
measured by the percentage of 
participants with HIV-1 RNA <50 
copies/mL at Week 96. A margin of 10 
percentage points is used to define 
noninferiority.
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
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Objectives
Endpoints

To evaluate the antiretroviral activity of 
DOR/ISL compared to 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 <200 copies/mL

HIV-1 RNA

To evaluate the immunologic effect of 
DOR/ISL as measured by the 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 in participants who 
receive DOR/ISL and in those who 
receive BIC/FTC/TAF

Viral resistance-associated 
substitutions

To evaluate the effect of DOR/ISL 
compared to 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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Objectives
Endpoints
Tertiary/Exploratory

To evaluate the effect of DOR/ISL 
compared to BIC/FTC/TAF on fasting 
lipid and metabolic profiles, renal 
function, inflammation, and body 
composition, as measured by the mean 
change from baseline to Week 48, Week 
96, and Week 144 in laboratory and 
radiological markers

Weight and laboratory and radiological 
markers

To evaluate the pharmacokinetics of ISL
when administered as a component of 
DOR/ISL

Pharmacokinetic values, such as area 
under the curve, maximum (peak) 
observed drug plasma concentration, 
and concentration after 24 hours 

To describe patient-reported outcomes 
related to health-related quality of life 
and self-reported HIV symptoms for 
participants who receive DOR/ISL 
compared to BIC/FTC/TAF at Weeks 48
and 96

EQ-5D-5L and HIV-SI

To explore the antiretroviral activity of 
DOR/ISL compared to BIC/FTC/TAF as 
assessed by time to loss of virologic 
response at Week 48, Week 96, and 
Week 144

Time to loss of virologic response 

To explore the relationship between 
genetic variation and response to the 
treatment(s) administered, and 
mechanism of disease. Variation across 
the human genome may be analyzed for 
association with clinical data collected in 
this study

Germline genetic variation and 
association to clinical data collection in 
this study
Success of this study is predicated only upon establishing noninferiority 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).
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4
STUDY DESIGN
4.1
Overall Design
This is a Phase 3, randomized, active-controlled, multisite, double-blind, double-dummy 
clinical study to evaluate the antiretroviral activity, safety, and tolerability of DOR/ISL QD 
in TN participants with HIV-1. The active control selected for this study is the 3-drug 
combination of BIC/FTC/TAF QD with demonstrated antiretroviral activity against HIV-1 in 
TN patients.
A total of approximately 680 participants will be randomized (stratified by screening HIV-1 
RNA level [≤100,000 copies/mL, >100,000 copies/mL] and screening CD4+ T-cell count 
[<200 cells/mm3, ≥200 cells/mm3]) in a 1:1 ratio into 1 of 2 treatment groups (Figure 1):
Group 1 (n = approximately 340): DOR/ISL (taken with matching placebo to 
BIC/FTC/TAF) on Day 1 through Week 96 (double-blind period); and DOR/ISL (taken 
without matching placebo to BIC/FTC/TAF) from Week 96 through Week 144 (open-label 
period).
Group 2 (n = approximately 340): BIC/FTC/TAF (taken with matching placebo to 
DOR/ISL) on Day 1 through Week 96 (double-blind period); BIC/FTC/TAF (taken without 
matching placebo to DOR/ISL) from Week 96 through Week 144 (open-label period).
Participants will receive blinded oral therapy for 96 weeks. The participant and the clinical 
site personnel will be unblinded to the participant’s study intervention assignment at the 
Week 96 visit. Sponsor personnel will be unblinded to each participant’s study intervention 
assignment at the earlier of the Week 96 visit or the Week 48 database lock. Safety and 
efficacy laboratory results, including HIV-1 RNA, will remain unmasked throughout the 
study. Viral resistance data will remain masked to the Sponsor until the Week 48 database 
lock.
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.
Participants receiving assigned study intervention may be eligible to enroll in a DOR/ISL 
100 mg/0.25 mg study (when and where available) or to transition to commercially available 
ART (see Section 6.7).
The first 60 participants enrolled and evaluable at the Week 24 time point will be identified 
as the Sentinel Cohort. An interim analysis (which will hereafter be referred to as the 
“Sentinel Cohort Week 24 interim analysis”) will be conducted by an external unblinded 
statistician once the Sentinel Cohort completes the Week 24 visit; all available efficacy and 
safety data for all participants enrolled by that time will be submitted to an independent 
eDMC for review. A futility assessment will also be conducted at this interim analysis using 
Week 24 data from the 30 participants in the Sentinel Cohort that received DOR/ISL
(Section 9.7). Decisions regarding study continuation will be made based on the eDMC 
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review of the Sentinel Cohort Week 24 interim analysis results, and in consultation with the
Sponsor.
Enrollment will be capped at a total of 180 participants prior to the availability of the 
Sentinel Cohort Week 24 interim analysis results. All participants enrolled prior to the 
availability of these results must have screening HIV-1 RNA level ≤100,000 copies/mL. 
Following the Sentinel Cohort Week 24 interim analysis, participants with HIV-1 RNA level 
>100,000 copies/mL may be enrolled.
In addition to the Sentinel Cohort Week 24 interim analysis, the eDMC will also review 
accumulating efficacy and safety data at regular intervals throughout the study duration and 
when either of the following occur (as assessed by the external unblinded statistician):

In the Sentinel Cohort (prior to completion of the Sentinel Cohort Week 24 interim 
analysis): 
>3 participants in the DOR/ISL treatment group meet the definition for confirmed 
virologic rebound or incomplete virologic response (Section 4.2.1.1.2).

Overall (following enrollment of the Sentinel Cohort): 
>10% of participants in the DOR/ISL treatment group meet the definition for confirmed 
virologic rebound or incomplete virologic response (Section 4.2.1.1.2).
The eDMC will recommend steps to ensure the safety of study participants and the integrity 
of the study (see Appendix 1).
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.
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, noninferiority study design is consistent with regulatory 
guidance [Food and Drug Administration (CDER) 2015] and is considered appropriate for a 
study population with HIV-1 who are naïve to antiretroviral therapy. Inconsistencies in 
virologic efficacy, emergence of resistance, and loss of tolerability or safety may be detected 
in TN patients prior to 48 weeks, 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, reduce participant 
pill burden, and study simplification. The study extension allows participants who continue 
to benefit from study intervention (as determined by the investigator) to continue their 
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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.
Rationale for Endpoints
4.2.1.1
Efficacy Endpoints
4.2.1.1.1
HIV-1 RNA Measurement
Plasma HIV-1 RNA <50 copies/mL is a well-established, clinically meaningful endpoint and 
is the primary efficacy endpoint in this study. 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 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 after achieving HIV-1 RNA <50 copies/mL at any time during the study,
or as

Incomplete Virologic Response: Two consecutive (2 to 4 weeks apart) occurrences of 
HIV-1 RNA ≥200 copies/mL at or after Week 24 in the absence of previous suppression
of HIV-1 RNA to <50 copies/mL
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 DHHS 
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 
results 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.
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An HIV-1 RNA level of ≥50 copies/mL following suppression of HIV-1 RNA to <50 
copies/mL at any time during the study or at or after Week 24 in the absence of previous 
suppression to <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 (hematology, chemistry, and urinalysis) performed per the SoA in 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 changes from baseline in weight, laboratory, and radiological 
markers between DOR/ISL and BIC/FTC/TAF to evaluate the impact of DOR/ISL as per the 
SoA on the following:
Weight
Compared with other antiretrovirals, use of integrase inhibitors in patients with HIV-1 has 
been associated with greater increases in body weight [Hill, A., et al 2019]. Thus, the mean 
change in weight will be measured (Section 8.8.5).
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).
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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 (Sections 8.8.5 and 8.8.6).
4.2.1.4
Pharmacokinetic Endpoints
PK samples collected from all participants as described in the SoA (Section 1.3) 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 patient’s 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 informed decision-
making on appropriate ART regimens. HTA authorities in many countries recommend 
patient perspective 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.
The study will include 2 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.
4.2.1.6
Planned Exploratory Biomarker Research
4.2.1.6.1
Planned Genetic Analysis
Genetic variation may impact a participant’s response to therapy, susceptibility to, severity, 
and progression of disease. Variable response to therapy may be due to genetic determinants 
that impact drug absorption, distribution, metabolism, and excretion; mechanism of action of 
the drug; disease etiology; and/or molecular subtype of the disease being treated. Therefore, 
where local regulations and IRB/IEC allow, a sample will be collected for DNA analysis 
from consenting participants.
DNA samples may be used for research related to the study intervention(s), the disease under 
study, or related diseases. They may also be used to develop tests/assays including diagnostic 
tests related to the disease under study, related diseases, and study intervention(s). Genetic 
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research may consist of the analysis of 1 or more candidate genes, the analysis of genetic 
markers throughout the genome, or analysis of the entire genome. Analysis may be 
conducted if it is hypothesized that this may help further understand the clinical data.
The samples may be analyzed as part of a multi-study assessment of genetic factors involved 
in the response to understand study disease or related conditions.
4.2.1.7
Future Biomedical Research
The Sponsor will conduct future biomedical research on specimens for which consent was 
provided during this study. This research may include genetic analyses (DNA), gene 
expression profiling (RNA), proteomics, metabolomics (serum, plasma), and/or the 
measurement of other analytes, depending on which specimens are consented for future 
biomedical research.
Such research is for biomarker testing to address emergent questions not described elsewhere 
in the protocol (as part of the main study) and will only be conducted on specimens from 
appropriately consented participants. The objective of collecting/retaining specimens for 
future biomedical research is to explore and identify biomarkers that inform the scientific 
understanding of diseases and/or their therapeutic treatments. The overarching goal is to use 
such information to develop safer, more effective drugs/vaccines, and/or to ensure that 
participants receive the correct dose of the correct drug/vaccine at the correct time. The 
details of future biomedical research are presented in Appendix 6.
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 for use in TN patients and is recommended by DHHS 
guidelines as a preferred first-line treatment for HIV-1 infection in most TN adults [Panel on 
Antiretroviral Guidelines for Adults and Adolescents 2018].
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.
Rationale for the Selected Participant Population
The rationale for the participant population selected for this study is as follows:

Antiretroviral TN Participants: The current paradigm of lifelong treatment for HIV 
creates the desire for safe, simple regimens. While the standard of care has been a 3-drug 
regimen for the treatment of HIV, there is growing interest in 2-drug regimens for a TN 
population. This study is designed to evaluate the antiretroviral efficacy and safety of 
DOR/ISL QD compared to the 3-drug regimen of BIC/FTC/TAF QD in TN participants 
using a randomized, double-blind, active-controlled noninferiority design. The 
combination of DOR+ISL is being studied in HIV-1 infected antiretroviral TN adult 
participants in a randomized Phase 2 multicenter study (MK-8591 Protocol 011). At 
Week 24, all ISL treatment groups demonstrated potent antiretroviral activity comparable 
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to DOR/3TC/TDF as demonstrated by the primary efficacy endpoint, the proportion of 
participants with HIV-1 RNA <50 copies/mL.
Rationale for Collecting Race and Ethnicity
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 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 one 
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 United States, 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 outcomes and toxicity.
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.
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.
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 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 
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not identify any teratogenicity or other clinically relevant concerns that would preclude
continued dosing of DOR/ISL in participants who become pregnant and 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). For participants who become pregnant on BIC/FTC/TAF see 
Section 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
IQ (Ctrough/IC50) is the ratio of drug exposure to viral susceptibility. In a Phase 1b proof of 
concept study (MK-8591 Protocol 003), 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 time points 
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 in TN 
participants with HIV-1.
In a Phase 2 clinical study (MK-8591 Protocol 011), 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 proportion 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 Protocol 011 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. MK-8591 Protocol 011 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 TN and virologically suppressed participants with HIV-1 and 
was selected based upon favorable efficacy, safety, tolerability, and metabolic profiles as 
confirmed in the Phase 3 clinical studies ([Orkin, C., et al 2018] [Molina, J. M., et al 2018]
and MK-1439A Protocol 024). Participants harboring NNRTI resistance-associated 
substitutions RT K103N or G190A were evaluated in MK-8591 Protocol 030, a Phase 2 trial 
evaluating TN participants with transmitted NNRTI drug resistance. Of the 8 participants 
treated with DOR/3TC/TDF who completed Week 48, all had HIV-1 RNA <50 copies/mL at 
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Week 48. In MK-8591 Protocol 024, a Phase 3 trial in virologically suppressed adults, 24 
participants had NNRTI resistance-associated substitutions RT K103N, Y181C, and/or 
G190A. All 24 participants maintained virologic suppression after switching to 
DOR/3TC/TDF.
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 
HIV-1 virus and most common NRTI- and NNRTI-resistant variants.
4.4
Beginning and End of Study Definition
The overall study ends when the last participant completes the last study-related contact, 
withdraws consent, or is lost to follow-up (Section 7.3 ie, the participant is unable to be 
contacted by the investigator).
Clinical Criteria for Early Study Termination
The clinical study may be terminated early if the extent (incidence and/or severity) of 
emerging effects/clinical endpoints is such that the risk/benefit ratio to the study population 
as a whole is unacceptable. In addition, further recruitment in the study or at (a) particular 
study site(s) may be stopped due to insufficient compliance with the protocol, GCP, and/or 
other applicable regulatory requirements, procedure-related problems or the number of 
discontinuations for administrative reasons is too high.
Early study termination may also be considered if the Sentinel Cohort meets the futility 
criteria as assessed at the Sentinel Cohort Week 24 interim analysis or after review of 
accumulating efficacy and safety data by the eDMC (Section 9.7).
5
STUDY POPULATION
Participants with HIV-1 ≥18 years of age who are naïve to ART will be enrolled in this 
study.
Prospective approval of protocol deviations to recruitment and enrollment criteria, also 
known as protocol waivers or exemptions, is not permitted.
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5.1
Inclusion Criteria
A participant is eligible for inclusion in the study if the participant meets all of the following 
criteria:
Type of Participant and Disease Characteristics
1. Is HIV-1 positive with plasma HIV-1 RNA ≥500 copies/mL at screening.
Note: A single repeat of the plasma HIV-1 RNA screening test by the central laboratory 
will be allowed, provided results are available within the 45-day screening window.
Note: Participants enrolled prior to the availability of the Sentinel Cohort Week 24 
interim analysis results must have HIV-1 RNA ≤100,000 copies/mL at screening.
2. Is naïve to ART defined as having received ≤10 days of prior therapy with any 
antiretroviral agent following a diagnosis of HIV-1 infection including prevention of 
mother-to-child transmission up to 1 month prior to screening.
Note: The use of any PrEP or PEP prior to diagnosis of HIV-1 infection is permissible up 
to 1 month prior to screening.
Demographics
3. Is male or female ≥18 years of age inclusive at the time of signing 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.
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
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.
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 infection 
(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 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.
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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. Has been treated for a viral infection other than HIV-1, such as hepatitis B, with an agent 
that is active against HIV-1, including, but not limited to, the following: adefovir, TDF, 
TAF, FTC, or 3TC.
7. Is taking or is anticipated to require systemic immunosuppressive therapy, immune 
modulators, or any of the prohibited therapies outlined in Section 6.5 from 45 days prior 
to Day 1 through the study intervention period.
Note: Time-limited courses of corticosteroids (eg, for asthma exacerbation) will be 
allowed.
Prior/Concurrent Clinical Study Experience
8. Is currently participating in or has participated in a clinical study with an investigational 
compound or device from 45 days prior to Day 1 through the study intervention period.
Note: BIC/FTC/TAF is not considered as investigational in countries where it has 
received health authority approvals, regardless of commercial availability.
Note: Concurrent participation in observational or noninterventional studies may be 
permitted and should be discussed with the Sponsor prior to enrollment and through the 
study duration.
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Diagnostic Assessments
9. Has a documented or known virologic resistance to any approved HIV-1 reverse 
transcriptase inhibitor, or any study intervention, as demonstrated by any of the following 
resistance substitutions (according to the 2017 IAS-USA drug resistance mutations list)
[Wensing, A. M., et al 2017]:
a.
FTC: K65R/E/N or M184I/V
b. TAF: K65R/E/N or K70E
c.
Multi-NRTI resistance substitutions: T69insert, Q151M, or 3 or more of thymidine 
analogue-associated mutations (M41L, D67N, K70R, L210W, T215F/Y, K219E/Q).
d. DOR resistance substitutions: V106A/M, V108I, Y188L, H221Y, P225H, F227C/L, 
M230I/L, L234I, P236L, or Y318F.
Note: This exclusionary list is for the purpose of this study and includes major (or 
primary) resistance substitutions, but not substitutions that are minor and found as 
naturally occurring polymorphisms.
Note: Resistance testing will be performed by the central laboratory as part of the 
screening assessments. However, if resistance testing results obtained from a local 
laboratory ≤90 days prior to the screening visit date are available prior to the 
availability of the central laboratory screening resistance results, the local results can be 
used to determine participant eligibility.
10. Has exclusionary laboratory values within 45 days prior to Day 1 as listed in Table 1:
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.
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.
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Other Exclusions
11. Is female and is expecting to conceive or donate eggs at any time during the study.
Note: Investigators should provide appropriate guidance to female participants 
regarding egg donation after completion of the study intervention. Consistent with the 
recommendations for contraceptive use, it is recommended that all female participants 
refrain from egg donation for 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 from the study will 
not be replaced.
6
STUDY INTERVENTION
Study intervention is defined as any investigational intervention(s), marketed product(s), 
placebo, or medical device(s) intended to be administered to a study participant according to 
the study protocol.
Clinical supplies (study intervention[s] provided by the Sponsor) will be packaged to support 
enrollment where possible (eg, not applicable in the case where multiple lots or batches may 
be required due to the length of the study, etc.). Clinical supplies will be affixed with a 
clinical label in accordance with regulatory requirements.
6.1
Study Intervention(s) Administered
The study intervention(s) to be used in this study are outlined in Table 2. Country-specific 
differences are noted in Appendix 7.
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Table 2
Study Interventions
Arm 
Name
Arm Type
Intervention 
Name
Type
Dose 
Formula-
tion
Unit Dose 
Strength(s)
Dosage 
Level(s)
Route of 
Admin-
istration
Regimen/
Treatment 
Period
Use
IMP/
NIMP/
Sourcing
Group 1
Experimental
DOR/ISL
Drug
Tablet
100 mg/
0.75 mg
100 mg/
0.75 mg QD
Oral
Day 1 to 
Week 168 a,c
Test Product
IMP
Provided 
centrally 
by the 
Sponsor
Group 1
Experimental
Placebo to 
BIC/FTC/TAF
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
Drug
Tablet
50/200/25 mg
50/200/
25 mg QD
Oral
Day 1 to 
Week 168 b,c
Comparator
IMP
Provided 
centrally 
by the 
Sponsor
Group 2
Active 
Comparator
Placebo to 
DOR/ISL
Drug
Tablet
0 mg
0 mg QD
Oral
Day 1 to 
Week 96
Placebo
IMP
Provided 
centrally 
by the 
Sponsor
BIC=bictegravir; DOR/ISL=fixed dose combination of doravirine and islatravir, also known as MK-8591 A; FTC=emtricitabine; QD=once-daily; TAF=tenofovir alafenamide.
Definition of Investigational Medicinal Product (IMP) and Non-Investigational Medicinal Product (NIMP) is based on guidance issued by the European Commission. Regional 
and/or country differences in 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 at Week 144 may continue their assigned study intervention 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
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.
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
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 (DOR/ISL and placebo to BIC/FTC/TAF) and Group 2 (BIC/FTC/TAF 
and placebo to DOR/ISL), respectively.
Stratification
Intervention randomization will be stratified according to the following factors:

Screening HIV-1 RNA level (≤100,000 copies/mL, >100,000 copies/mL)

Screening CD4+ T-cell count (<200 cells/mm3, ≥200 cells/mm3) 
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.
Sponsor personnel involved in performing and reviewing results of the Week 48 analysis will 
be unblinded to all participants’ study intervention assignments at the time of the Week 48 
database lock. However, it is noted that participants who reach Week 96 (and are dispensed 
open-label study intervention) prior to the Week 48 database lock will have already been 
unblinded to the Sponsor.
As described in Section 4, at Week 96 all clinical site personnel and participants will be 
unblinded and participants will continue to receive their assigned study intervention open-
label through Week 144 (and up to Week 168 if participating in the study extension). 
The investigator and participant may become unblinded by the Sponsor (after the Week 48 
database lock) to facilitate decisions regarding the option to enroll the participant in a 
DOR/ISL 100 mg/0.25 mg study (where available) or transition to commercially available 
ART.
To allow timely completion of population PK modeling, restricted early (before database 
lock) unblinding of PK data may be requested. Before granting select study 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.
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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 
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. 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 intervention 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’s Clinical Director or designee should be contacted if 
there are any questions about a therapy not listed or regarding potential DDIs with a specific 
treatment that the participant may plan to receive.
In instances where the local product circular for DOR or BIC/FTC/TAF is more restrictive 
with regards to prohibited (ie, contraindicated or not recommended) therapies, the local 
product circular supersedes this section. Concomitant medications will be monitored for the 
duration of the study and once a participant is unblinded, local product circular should be 
followed for participants on BIC/FTC/TAF.
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
Nonstudy ART
All nonstudy antiretrovirals (with the exception of
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 nonstudy investigational agents including devices
Antiarrhythmics
Dofetilide
Additional prohibited therapies 
based on ISL
Pentostatin
ART=antiretroviral therapy; CYP3A=cytochrome P450 3A; ISL=islatravir.
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 a randomized study 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 product to provide the 
following advice:
“You have participated in a study conducted by the Sponsor. This letter is to advise you that 
you were among those who received a look-alike tablet created by the Sponsor to resemble 
the drug BIKTARVY 50/200/25 mg (BICTEGRAVIR/EMTRICITABINE/TENOFOVIR 
ALAFENAMIDE) as much as possible. You did not receive the active drug 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 chooses to breastfeed.
Note: Study intervention can continue until breastfeeding is initiated.

The participant has confirmed HIV-1 virologic rebound or incomplete virologic response 
as defined in Section 4.2.1.1.2.

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.

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].
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A participant must be discontinued from study intervention for any of the following reasons
(those receiving DOR/ISL must continue to be monitored per Section 8.11.5):

CD4+ T-cell count:
o
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
o
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
o
For all participants with an average baseline* CD4+ T-cell count ≥200 cells/mm3 (as 
well as participants with an average baseline CD4+ T-cell count <200 cells/mm3 who 
have increases in CD4+ T-cell count to ≥200 cells/mm3 for 2 consecutive 
measurements approximately 12 weeks apart), a CD4+ T-cell count decrease to
<200 cells/mm3 on 2 consecutive measurements taken 3 to 4 weeks apart.

Total lymphocyte count:
o
For participants with an average baseline* total lymphocyte count ≥1×109 cells/L

A ≥30% reduction from average baseline* total lymphocyte count AND a 
decrease in total lymphocyte count to <1×109 cells/L on 2 consecutive 
measurements taken 3 to 4 weeks apart
OR

A ≥30% reduction from average baseline* total lymphocyte count on 2 
consecutive measurements taken 10 to 14 weeks apart.
o
For participants with an average baseline* total lymphocyte count <1×109 cells/L, a 
≥30% reduction from average baseline* total lymphocyte count on 2 consecutive 
measurements taken 3 to 4 weeks apart.
**Note: The average baseline value for CD4+ T-cell count and total lymphocyte 
count is defined as the average of the screening (within 45 days prior to the first dose 
of study intervention) and Day 1 values through Week 48. After Week 48, the 
baseline resets to the Week 48 value only if the Week 48 value is greater than the 
average baseline value. If there are ≥2 values at Week 48, then use the most recent 
value.
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7.2
Participant Withdrawal From the Study
A participant must be withdrawn from the study if the participant withdraws consent from the 
study.
If a participant withdraws from the study, they will no longer receive study intervention or be 
followed at scheduled protocol visits.
Specific details regarding procedures to be performed at the time of withdrawal from the 
study, as well as specific details regarding withdrawal from future biomedical research, are 
outlined in Section 8.1.9. The procedures to be performed should a participant repeatedly fail 
to return for scheduled visits and/or if the study site is unable to contact the participant are 
outlined in Section 7.3.
7.3
Lost to Follow-up
If a participant fails to return to the clinic for a required study visit and/or if the site is unable 
to contact the participant, the following procedures are to be performed:

The site must attempt to contact the participant and reschedule the missed visit. If the 
participant is contacted, the participant should be counseled on the importance of 
maintaining the protocol-specified visit schedule.

The investigator or designee must make every effort to regain contact with the participant 
at each missed visit (eg, telephone calls and/or a certified letter to the participant’s last 
known mailing address or locally equivalent methods). These contact attempts should be 
documented in the participant’s medical record.
8
STUDY ASSESSMENTS AND PROCEDURES

Study procedures and their timing are summarized in the SoA.

Adherence to the study design requirements, including those specified in the SoA, is 
essential and required for study conduct.

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.
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
Additional evaluations/testing may be deemed necessary by the investigator and or the 
Sponsor for reasons related to participant safety. In some cases, such evaluation/testing 
may be potentially sensitive in nature (eg, HIV, Hepatitis C), and thus local regulations 
may require that additional informed consent be obtained from the participant. In these 
cases, such evaluations/testing will be performed in accordance with those regulations.
The amount of blood collected from each participant over the 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
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.
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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 
his/her 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.
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 
their legally acceptable representative, answer all 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 Study Extension
The investigator or medically qualified designee will explain the consent to participate in 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.
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.
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.
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.
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 the first dose of study intervention.
All prior HIV medication use, regardless of timing, including PrEP, must be recorded.
8.1.5.2
Concomitant Medications
The investigator or qualified designee will record medication, if any, taken by the participant 
during the study.
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.
Assignment of Treatment/Randomization Number
All eligible participants will be randomly allocated and will receive a 
treatment/randomization number. The treatment/randomization number identifies the 
participant for all procedures occurring after treatment randomization. Once a 
treatment/randomization number is assigned to a participant, it can never be re-assigned to 
another participant.
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A single participant cannot be assigned more than 1 treatment/randomization number.
Study Intervention Administration
Study intervention will be provided as per Table 2 (Section 6.1) and dispensed through the 
IRT system at visits indicated in the SoA (Section 1.3).
8.1.8.1
Timing of Dose Administration
The first dose of study intervention will be administered at the study site on Day 1.
Following Day 1, all study interventions will be taken together QD by the participant (ie, 
unsupervised at their home) at approximately the same time each day without regard to food.
Participants will take 2 tablets of blinded study intervention (1 tablet from each of 2 
containers: [1] Bottle A: DOR/ISL or placebo to DOR/ISL, and [2] Bottle B: BIC/FTC/TAF 
or placebo to BIC/FTC/TAF). If more than 1 Bottle A is dispensed at a time, the participant 
is instructed to use all of the study intervention in 1 Bottle A before opening another Bottle 
A.
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.
Discontinuation and Withdrawal
Participants who discontinue study intervention prior to completion of the treatment period
should have an Early Discontinuation visit performed per SoA (Section 1.3) and be 
encouraged to continue to be followed as outlined in Section 8.11.3.
When a participant withdraws from participation in the study, all applicable activities 
scheduled for the Early Discontinuation of Treatment visit should be performed (at the time 
of withdrawal). Any AEs that are present at the time of withdrawal should be followed in 
accordance with the safety requirements outlined in Section 8.4.
Participants who discontinue study intervention due to decreases in CD4+ T-cell count and/or 
total lymphocyte counts, or those who discontinue for any other reason and have decreases in 
CD4+ T-cell and/or total lymphocyte counts >10% of the average baseline values or that
meet ECI criteria at the Early Discontinuation of Treatment visit should be managed per 
Section 8.11.5.
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8.1.9.1
Withdrawal From Future Biomedical Research
A participant’s consent for Future Biomedical Research may be withdrawn by the 
participant. A participant’s consent may be withdrawn 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.
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 are 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.
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.
Administration of Participant Questionnaires
Participants will complete 2 PRO questionnaires at Day 1, Week 4, Week 16, Week 48, 
Week 96, and/or the Early Discontinuation of Treatment visit. Participants are to complete 
the questionnaires on their own at the site on paper during the appropriate study visit (per
SoA in Section 1.3) prior to being seen by the investigator, discussing any medical conditions 
with the study personnel, or receiving any medical results. The questionnaires should not be 
administered to participants who are illiterate, who are unable to complete questionnaires 
unassisted, or for whom native language translations of the questionnaires are unavailable.
The participant responses to questionnaires will be entered into the appropriate eCRF by site 
staff according to data entry guidelines.
8.2
Efficacy Assessments
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.
Management of Study Participants with Viremia
When viremia (HIV-1 RNA ≥50 copies/mL) is detected (Section 4.2.1.1.2) following 
suppression of HIV-1 RNA to <50 copies/mL at any time during the study or at or after 
Week 24 in the absence of previous suppression to <50 copies/mL, 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 
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 (following suppression to 
<50 copies/mL or at or after Week 24 in the absence of previous suppression to <50 
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 1.3.2 and 8.11.3) 
and the participant managed by the investigator per local standard of care.
8.2.2.3
Participants with Low-level Viremia (≥50 and <200 copies/mL)
Study participants with confirmed HIV-1 RNA of ≥50 and <200 copies/mL should continue 
study intervention and all regularly scheduled study visits during which HIV-1 RNA levels 
will be monitored per the 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.
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8.2.2.4
Viral Drug Resistance Testing
Participants with confirmed virologic rebound or incomplete virologic response (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. Samples with HIV-1 RNA ≥200 copies/mL that were collected either to confirm 
viremia or at discontinuation will be sent for genotypic and phenotypic resistance testing.
Samples will be collected for genotypic and phenotypic HIV-1 Drug Resistance testing per 
the SoA (Section 1.3) and used to assess resistance-associated substitutions as applicable 
during the study.
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 
(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 Appendix 2.
Planned time points for all safety assessments are provided in the SoA.
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.
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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.
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.
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 first dose of study 
intervention on Day 1 as outlined in the SoA (see Section 1.3.1). 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.
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 the SoA to verbally confirm their use of 
contraception since the prior visit, according to the Contraceptive Guidance in Appendix 5.
Confirmation should be noted in the source documents for each visit.
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 7.1. If a participant becomes pregnant, refer to Section 
8.11.6.
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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.

All protocol-required laboratory assessments, as defined in Appendix 2, must be 
conducted in accordance with the laboratory manual and the SoA.

If laboratory values from nonprotocol-specified laboratory assessments performed at the 
institution’s local laboratory require a change in study participant management or are 
considered clinically significant by the investigator (eg, SAE or AE or dose 
modification), then the results must be recorded in the appropriate CRF (eg, SLAB).

For any laboratory tests with values considered clinically significantly abnormal during 
participation in the study or within 42 days after the last dose of study intervention, every 
attempt should be made to perform repeat assessments until the values return to normal or 
baseline or if a new baseline is established as determined by the investigator.
Note: Decreases in CD4+ T-cell and/or total lymphocyte counts should be managed per 
Section 8.11.5.
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. Investigators should 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.
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Tobacco and Alcohol Assessments
Information on tobacco and alcohol use by participants will be collected and recorded at 
Weeks 48, 96, and 144.
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 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.
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 
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death, at any time after a participant has been discharged from the study, and he/she 
considers the event to be reasonably related to the study intervention or study participation, 
the investigator must promptly notify the Sponsor.
All initial and follow-up AEs, SAEs, and other reportable safety events will be recorded and 
reported to the Sponsor or designee within the time frames as indicated in Table 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
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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.
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.
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.
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.
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For infants born to participants who become pregnant and consent to infant safety data 
collection, SAEs occurring (including perinatal HIV-1 infection) through 1 year of age must 
be reported by the investigator to the Sponsor within 24 hours of learning of the event.
Disease-related Events and/or Disease-related Outcomes Not Qualifying as 
AEs or SAEs
This section is not applicable to the study.
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 2 consecutive 
measurements approximately 12 weeks apart while on study intervention.  
**Note: The average baseline value for CD4+ T-cell count and total lymphocyte count is 
defined as the average of the screening (within 45 days prior to the first dose of study 
intervention) and Day 1 values through Week 48. After Week 48, the baseline resets to 
the Week 48 value only if the Week 48 value is greater than the average baseline value. If 
there are ≥2 values at Week 48, then use the most recent value.
See Section 8.11.5 for further details on the management of participants with specified
decreases in CD4+ T-cell and/or total lymphocyte counts.
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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.
8.6
Pharmacokinetics
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 operations/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 that routinely take their study intervention during the day, a predose and 
postdose sample will be taken at the Week 4 visit (Table 5). Participants that 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 in 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 8
Sample collected irrespective of time of dose 
(time of last dose and time of PK sample collection must be documented)
Week 16
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.
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8.7
Pharmacodynamics
Pharmacodynamic parameters will not be evaluated in this study.
8.8
Biomarkers
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.
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
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
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.
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Participants with diabetes mellitus (type 1 or 2) or insulin resistance are not required to have 
the blood draw for insulin testing.
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).
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 BICR; 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 prior to 
DEXA imaging.
DEXA scans should not be performed on pregnant participants.
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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
•
Leftover main study plasma from HIV drug resistance samples
•
Whole blood for FBR
Sample collection, storage, and shipment instructions for whole blood FBR samples will be 
provided in the operations/laboratory manual. Refer to the SoA (Section 1.3) for timing of 
sample collections.
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.
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 following 
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 may be repeated.
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The following assessments must be repeated for participants who are rescreened:
•
Vital signs, weight, and directed physical examination
•
Review medical history and prior/concomitant medications for new information
•
All laboratory assessments (includes serum hCG pregnancy testing for WOCBP), with 
the exception of HIV-1 Drug Resistance testing
•
Review of AEs
If the informed consent form has been updated, participants should be reconsented prior to 
rescreening. If no updates have been made, documented informed consent obtained during 
the original screening period should be reviewed with the participant and a verbal reconsent 
to continue in the study should be documented.
If a participant had a Day 1 ECG during the original screening period, it should be repeated 
(at the Day 1 visit or within 7 days prior).
If a participant had a baseline Day 1 DEXA scan during the original screening period and 
>30 days have elapsed, the Day 1 DEXA should be repeated. If <30 days have elapsed since 
the DEXA, it is not necessary to repeat the Day 1 DEXA scan during rescreening.
Treatment Period
All procedures and their timing should be completed as per the 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 to 4 
weeks from the scheduled visit for collection of whole blood for FBR, when possible. If an 
unscheduled visit for collection of whole blood for FBR is not possible, the sample should be 
drawn at the next scheduled visit at the site.
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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:
1. End participation in the clinical study and resume commercial treatment of their choice. 
These participants should have an End of Treatment Follow-up Visit approximately 42 
days (+7 days) after the last dose of study intervention.
2. Provide documented consent to participate in the study extension to continue assigned 
study intervention for a maximum of 24 additional weeks.
3. 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. 
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.

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 due to other reasons 
and the CD4+ T-cell count and/or total lymphocyte count at the Early Discontinuation of 
Treatment visit is >10% lower than the average baseline value or meets ECI criteria, then 
additional monitoring is required per Section 8.11.5.
8.11.3.1
Early Discontinuation of Treatment
Participants who discontinue study intervention 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.
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8.11.3.2
End of Treatment Follow-up Visit
Participants who discontinue study intervention at any time for any reasons(s) will have a 
safety follow-up visit in-clinic approximately 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 intervention 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 who discontinue DOR/ISL with specified decreases in CD4+ T-cell and/or total 
lymphocyte counts will be followed monthly for monitoring of CD4+ T-cell and total
lymphocyte count recovery, as per Section 8.11.5.
Viremia Confirmation
If a participant has a viral load of ≥50 copies/mL following suppression of HIV-1 RNA to 
<50 copies/mL at any time during the study or at or after Week 24 in the absence of previous 
suppression, a Viremia Confirmation visit must be conducted within 2 to 4 weeks of the 
initial HIV-1 viremia (see Section 1.3.3 and 4.2.1.1). If a scheduled visit is to occur within 
the timeframe that a participant would return for a Viremia Confirmation visit, the 
assessments for the scheduled visit should be conducted, and the HIV viral drug resistance 
sample must be collected.
Management of Participants with Specified Decreases in CD4+ T-cell Count 
and/or Total Lymphocyte Count
Management of participants with specified 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 meet ECI criteria (Section 8.4.7) must 
have a confirmation visit in 3 to 4 weeks. Participants whose decreases in total lymphocytes 
meet ECI criteria should have a confirmation visit in 3 to 4 weeks, except for those with an 
average baseline* total lymphocyte count ≥1×109 cells/L that does not decline to 
<1×109 cells/L, in which case the confirmation visit should be conducted in 10 to 14 weeks.
* The average baseline value for CD4+ T-cell count and total lymphocyte count is defined as 
the average of the screening (within 45 days prior to the first dose of study intervention) and 
Day 1 values through Week 48. After Week 48, the baseline resets to the Week 48 value only 
if the Week 48 value is greater than the average baseline value. If there are ≥2 values at 
Week 48, then use the most recent value.
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If the discontinuation criteria are met (Section 7.1), the participant must be discontinued from 
study intervention 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 the 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 due to specified decreases in CD4+ T-cell and/or total lymphocyte 
counts should be unblinded (if applicable) and managed as noted below:

Participants who were receiving 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). Participants will then be monitored monthly until 2 values 12 weeks apart 
of CD4+ T-cell counts and total lymphocyte counts are not decreased by >10% of the 
average baseline value. Participants discontinued due to confirmed CD4+ T-cell count 
<200 cells/mm3 need to be followed monthly until the CD4+ T-cell count is ≥200 
cells/mm3 on 2 visits 12 weeks apart.

Participants who were receiving BIC/FTC/TAF who discontinue study intervention due 
to decreases in CD4+ T-cell count or total lymphocyte count will be managed per 
Section 8.11.3 and will not require further monitoring after their End of Treatment 
Follow-up visit (Section 1.3.3).
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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 who are found to have 
decreases in CD4+ T-cell and/or total lymphocyte counts >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 should undergo assessments specified at the 
End of Treatment Follow-up visit (Section 1.3.5).  
o
If the decrease(s) of >10% of average baseline and/or a decrease in CD4+ T-cell 
count to <200 cells/mm3 is confirmed at this visit, participants should be monitored 
monthly until 2 values 12 weeks apart of CD4+ T-cell counts and total lymphocyte 
counts are not decreased by >10% of the average baseline value and the CD4+ T-cell 
count has recovered to ≥200 cells/mm3 . 
o
If the decrease(s) of >10% of average baseline and/or a decrease in CD4+ T-cell 
count 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 should have their End of Treatment 
Follow-up visit after study intervention is discontinued (Section 1.3.3) and no further 
monitoring is needed.

Participants who are enrolling directly into a DOR/ISL 100 mg/0.25 mg study will be 
managed per their study’s guidelines.
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 
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)
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
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

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 the last dose of 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 
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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 
time. In addition, these participants will have an End of Treatment Follow-up Visit in-clinic 
approximately 42 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.
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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-1
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
---------------------------X----------------------------
HIV=human immunodeficiency virus; N/A=not applicable; 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 nonconfirmatory analyses made after the protocol has been finalized, but prior to final 
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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 
the Antiretroviral Activity, Safety, and Tolerability of DOR/ISL Once-Daily in HIV-
1 Infected Treatment-Naïve Participants.
Treatment
Assignment
This study will enroll approximately 680 TN participants with HIV-1 infection.
Participants will be randomized (stratified by screening HIV-1 RNA level [≤100,000 
copies/mL, >100,000 copies/mL] and screening CD4+ T-cell count [<200 cells/mm3, 
≥200 cells/mm3]) in a 1:1 ratio to DOR/ISL QD (Group 1) or the 3-drug combination 
of BIC/FTC/TAF QD (Group 2). Clinical site personnel and participants will remain 
blinded through Week 96, while 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
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 <200 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. Viral resistance-associated substitutions
5. Change from baseline in weight at Week 48, Week 96, and Week 144
6. General safety and tolerability through study duration
Statistical Methods 
for Key Efficacy 
Analyses
The primary objective and hypothesis will be assessed using a 2-sided multiplicity-
adjusted 95% CI for the difference between treatment groups (DOR/ISL minus 
BIC/FTC/TAF) in the percentage of participants with HIV-1 RNA <50 copies/mL at 
Week 48. The CI will be based on the stratified Miettinen and Nurminen method
[Miettinen, O. and Nurminen, M. 1985] with Cochran-Mantel-Haenszel weights 
(stratified by screening HIV-1 RNA level [≤100,000 copies/mL, >100,000 
copies/mL] and screening CD4+ T-cell count [<200 cells/mm3, ≥200 cells/mm3]).
Noninferiority at Week 48 will be concluded if the lower bound of the CI is greater 
than -10 percentage points.
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Statistical Methods 
for Key Safety 
Analyses
Point estimates and 2-sided nominal 95% CIs will be provided using the unstratified
Miettinen and Nurminen method [Miettinen, O. and Nurminen, M. 1985] for the 
difference between treatment groups (DOR/ISL minus BIC/FTC/TAF) 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 nondrug-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 (DOR/ISL minus 
BIC/FTC/TAF) for the change from baseline in weight at Weeks 48 and 96.
Interim Analyses
The following interim analyses and data summaries are planned. Details are provided 
in Section 9.7.
Interim analysis once the Sentinel Cohort completes Week 24: An interim analysis
(hereafter referred to as the “Sentinel Cohort Week 24 interim analysis”) will be 
performed once the Sentinel Cohort has completed the 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. Additionally, a futility assessment will be conducted 
based on the Sentinel Cohort data. If 7 or more participants in Group 1 (out of 30
enrolled and evaluable participants) fail to achieve HIV-1 RNA <200 copies/mL 
at Week 24, the eDMC may recommend the study be stopped; the eDMC will 
review the totality of the available data at the time of the Sentinel Cohort Week 24 
interim analysis before making such a recommendation.
Primary efficacy and safety analyses conducted at the Week 48 interim time point 
(will be conducted by the Sponsor and results shared with the eDMC).
Continuous safety and efficacy monitoring throughout the study: The eDMC will 
review accumulating safety and efficacy data at regular intervals throughout the 
study duration.
Multiplicity
For statistical rigor, a small amount of alpha (α=0.00001) will be set aside for the 
Sentinel Cohort Week 24 interim analysis and each additional eDMC evaluation. An 
allowance will be made such that a total of up to 5 of these unblinded eDMC reports
may be presented prior to the evaluation of the primary noninferiority efficacy 
hypothesis at Week 48. A subset of the efficacy hypotheses listed in Section 3 will be 
tested in a sequential order specified in Section 9.8 at a 1-sided 2.5% Type 1 error 
rate adjusted for the number of eDMC reports. Testing will stop with the first of these 
tests failing to reach statistical significance; in this way, the overall 1-sided 2.5% 
Type 1 error rate is strongly controlled among these hypotheses. Additional details
are provided in Section 9.8.
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 680 participants to be randomized in a 1:1 ratio to Group 
1 or Group 2. The rate of participants in Group 1 in the Sentinel Cohort with Week 
24 HIV-1 RNA <200 copies/mL is assumed to be 90%, and the rate of participants in 
both Group 1 and Group 2 with Week 48 HIV-1 RNA <50 copies/mL is assumed to 
be 82%. Under these assumptions, there is a 97.7% chance of continuing the study 
after the futility assessment on the Sentinel Cohort Week 24 data and a 90% chance 
of declaring noninferiority between groups at Week 48.
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.
The Week 48 database lock will occur once all participants have completed the Week 48 visit 
assessments, and data from Day 1 through Week 48 will be analyzed. The database lock will 
not occur until medical/scientific review has been performed, protocol deviations have been 
identified, and data have been declared final and complete. Sponsor personnel directly 
involved in the analysis and reporting associated with the Week 48 CSR will be unblinded to 
each participant’s study intervention assignment at the earlier of the Week 96 visit or the 
time of the Week 48 database lock.
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 
population 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 at the Week 48 database lock.
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.
Efficacy/Pharmacokinetics Endpoints
9.4.1.1
Efficacy Endpoints
An initial description of efficacy measures is provided in Section 4.
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Percentage of Participants with HIV-1 RNA <50 copies/mL, Percentage of Participants 
with HIV-1 RNA <40 copies/mL, and Percentage of Participants with HIV-1 RNA <200
copies/mL at Week 48
The Abbott Real-Time 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 <40 copies/mL and the percentage of participants with HIV-1 
RNA <200 copies/mL at Week 48.
Percentage of Participants with HIV-1 RNA <50 copies/mL, Percentage of Participants 
with HIV-1 RNA <40 copies/mL, and Percentage of Participants with HIV-1 RNA <200
copies/mL at Week 96 and Week 144
Secondary objectives will assess the percentage of participants with HIV-1 RNA <50 
copies/mL, the percentage of participants with HIV-1 RNA <40 copies/mL, and the 
percentage of participants with HIV-1 RNA <200 copies/mL at 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 time point 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 or incomplete virologic response 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 or incomplete virologic 
response (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 resistance associated with each study intervention and will 
be summarized with primary interest at Week 48, Week 96, and Week 144.
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Time to Loss of Virologic Response
TLOVR will be assessed at Week 48, Week 96, and Week 144.
For participants who achieve HIV-1 RNA <50 copies/mL and subsequently have 2 
consecutive HIV-1 RNA values (measured at least 2 weeks apart) ≥50 copies/mL, TLOVR is 
the time between the date of the initial HIV-1 RNA suppression to <50 copies/mL and the 
date of the first of the 2 consecutive HIV-1 RNA values ≥50 copies/mL.
For participants who achieve and sustain HIV-1 RNA <50 copies/mL, TLOVR is censored at 
the time of the last available measurement. For participants who do not achieve an HIV-1 
RNA value <50 copies/mL, TLOVR is 0 weeks.
9.4.1.2
Pharmacokinetics Endpoints
PK samples collected from all participants as described in the SoA (Section 1.3) 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.
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.
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.
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Change from baseline in weight will be summarized at each time point 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.
Patient-reported Outcome Endpoints
An initial description of patient-reported outcome measures is provided in Section 4.2.1.5.
Patient-reported outcomes from each questionnaire at Day 1 and Weeks 4, 16, 48, and 96 will 
be summarized for each treatment group.
9.5
Analysis Populations
Efficacy Analysis Populations
9.5.1.1
Sentinel Cohort
The first 30 participants enrolled and evaluable at the Week 24 time point in each treatment 
group will be identified as the Sentinel Cohort (60 total). To be considered “enrolled and 
evaluable” at Week 24, participants must be randomized in the study and 1) have at least one 
on-treatment HIV-1 RNA measurement in the Week 24 analysis window (Table 7) or 2) 
discontinue study intervention prior to or within the Week 24 analysis window due to lack of 
efficacy. Participants who do not meet these criteria will not be eligible for inclusion in the 
Sentinel Cohort population. The external unblinded statistician will monitor participant status 
throughout the trial to identify the first 30 participants in each treatment group (by date of 
study intervention discontinuation due to lack of efficacy or the date of clinically significant 
confirmed viremia/date of the Week 24 HIV-1 RNA measurement) who meet the 
requirements for inclusion in the Sentinel Cohort.
9.5.1.2
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.
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9.5.1.3
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.
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 (Section 6.5).

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 the Week 48 database lock.
The composition of the PP analysis set will vary by the analysis time point, based on the 
number of participants who satisfy the PP criteria at that time point.
9.5.1.4
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.
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 
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Pharmacology and Pharmacometrics (QP2). Methods related to exploratory objectives will 
be described in the sSAP.
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 
be used for all analyses by time point (with the exception of DEXA assessments). The last 
available on-treatment measurement within a window will be used for analyses at a specific 
time point, unless otherwise specified. Results from additional time points 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 ≤42
29
Week 8
≥43 and ≤84
57
Week 16
≥85 and ≤140
113
Week 24
≥141 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
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. 
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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;

Nonintermittent 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”;

Nonintermittent 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 AE/death and have 
the last available on-treatment HIV-1 RNA measurement ≥50 copies/mL.
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
No Virologic Data in Specified Analysis Time Window: this includes participants who 
do not have on-treatment HIV-1 RNA data in the 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.
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 and AE/death (ie, lost to follow-up, 
noncompliance with study intervention, physician decision, protocol deviation, 
withdrawal by participant, etc.) and have the last available on-treatment HIV-1 RNA
measurement <50 copies/mL.
3) On study 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 noninferiority 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. Similar logic will also be used to define the 
percentage of participants with HIV-1 RNA <40 copies/mL and the percentage of 
participants with HIV-1 RNA <200 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 time point 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 time point 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” (HIV-1 RNA <50 copies/mL) at the time point of interest. 
Participants with other reasons for missing data will be classified as a virologic failure (HIV-
1 RNA ≥50 copies/mL) at the time point of interest.
A third approach, the OF approach, will also be performed as a sensitivity analysis for the 
percentage of participants achieving HIV-1 RNA <50 copies/mL. Under this approach, 
participants with nonintermittent missing data who prematurely discontinue study 
intervention due to lack of efficacy or who discontinue study intervention for other reasons 
and are failures (HIV-1 RNA ≥50 copies/mL) at the time of study intervention
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discontinuation are considered as failures at time points 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 time points. Participants with intermittent missing data will be considered as 
successes (HIV-1 RNA <50 copies/mL) if both the immediately preceding and immediately 
subsequent on-treatment HIV-1 RNA measurements are <50 copies/mL; all other intermittent 
missing results will be imputed as failures.
The same supportive approaches as described above will similarly be used for the analysis of 
the percentage of participants achieving HIV-1 RNA <40 copies/mL and the percentage of 
participants achieving HIV-1 RNA <200 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 time point 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 
i) discontinued study intervention due to an AE or death, ii) discontinued study intervention
for other reasons (includes withdrawal of consent, loss to follow-up, move, etc.), or iii) on
study intervention but missing data in window.
Noninferiority of DOR/ISL compared to BIC/FTC/TAF with respect to the percentage of 
participants with HIV-1 RNA <50 copies/mL at Week 48 and at Week 96 will be calculated 
using the stratified Miettinen and Nurminen method with CMH weights (stratified by 
screening HIV-1 RNA level [≤100,000 copies/mL, >100,000 copies/mL] and screening 
CD4+ T-cell count [<200 cells/mm3, ≥200 cells/mm3]) [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 10 percentage points is used to define the noninferiority of DOR/ISL 
compared to BIC/FTC/TAF; noninferiority will be concluded if the lower bound of the 2-
sided multiplicity-adjusted 95% CI for the difference in the percentage of participants with 
HIV-1 RNA <50 copies/mL (DOR/ISL minus BIC/FTC/TAF) is greater than -10 percentage 
points. A noninferiority margin of 10 percentage points is clinically reasonable because it 
preserves a large portion of the treatment effect, which is expected to be >80%. The 
supportive analyses using the M=F and OF approaches (as defined above) will also be 
presented.
Superiority of DOR/ISL compared to BIC/FTC/TAF 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 stratified Miettinen and Nurminen method with CMH weights [Miettinen, O. and 
Nurminen, M. 1985]. For the evaluation of the efficacy superiority hypotheses at Weeks 48
and 96, superiority will be concluded if the lower bound of the 2-sided multiplicity-adjusted 
95% CI for the difference in the percentage of participants with HIV-1 RNA <50 copies/mL 
(DOR/ISL minus BIC/FTC/TAF) is greater than 0 percentage points.
For the summary of virologic response over time, the difference in percentages between
treatment groups at each time point through Week 144 will also be estimated and the 
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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 <200 copies/mL
The percentage of participants achieving HIV-1 RNA <40 copies/mL and the percentage of 
participants achieving HIV-1 RNA <200 copies/mL will be summarized by treatment group 
at each time point, with primary interest at Week 48, Week 96, and Week 144 by comparing 
Group 1 and Group 2. For each time point of interest, the difference in percentages between
treatment groups and the associated 2-sided nominal 95% CI will be calculated using the 
stratified Miettinen and Nurminen method with CMH weights (stratified by screening HIV-1 
RNA level [≤100,000 copies/mL, >100,000 copies/mL] and screening CD4+ T-cell count 
[<200 cells/mm3, ≥200 cells/mm3]) [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 
time point 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 time point through Week 144 will be estimated using an ANCOVA model adjusted 
by baseline CD4+ T-cell count, stratum, and treatment group. 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 postbaseline measurement within the 
analysis window specified in Table 7 for the time point of interest to be included in the 
analyses of the mean change from baseline in CD4+ T-cell count by time point. Supportive 
analyses will also be provided using the BOCF and LOCF methods to account for missing 
data.
Clinically Significant Confirmed Viremia
The number of participants with confirmed virologic rebound or incomplete virologic 
response, 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 Week 48, Week 96, and Week 144.
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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 not related to efficacy (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 according to the FDA snapshot algorithm classification rules.
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 who choose to breastfeed will be censored from the time of study intervention 
discontinuation forward and will be handled in the primary efficacy analyses according to 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.
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Table 8
Analysis Strategy for Key Efficacy Variables
Endpoint/Variable 
(Description, Time Point)
Primary vs. 
Supportive 
Approach
Statistical Methoda
Analysis 
Population
Missing 
Data 
Approach
Primary Hypothesis
Percentage of participants with 
HIV-1 RNA <50 copies/mL at 
Week 48 
P
M&N with CMH weights
FAS
Snapshotb
S
M&N with CMH weights
FAS
M=F
S
M&N with CMH weights
PP
OF
Secondary Objectives
Percentage of participants with 
HIV-1 RNA <50 copies/mL at 
Week 96 and Week 144
P
M&N with CMH weights
FAS
Snapshotb
S
M&N with CMH weights
FAS
M=F
S
M&N with CMH weights
PP
OF
Percentage of participants with 
HIV-1 RNA <40 copies/mL and 
percentage of participants with 
HIV-1 RNA <200 copies/mL at 
Week 48, Week 96, and 
Week 144
P
M&N with CMH weights
FAS
Snapshotb
S
M&N with CMH weights
FAS
M=F
S
M&N with CMH weights
PP
OF
Change from baseline in CD4+ T-
cell count at Week 48, Week 96, 
and Week 144
P
ANCOVA
FAS
DAO
S
ANCOVA
FAS
BOCF
S
ANCOVA
FAS
LOCF
ANCOVA=analysis of covariance; BOCF=Baseline Observation Carried Forward; CMH=Cochran-Mantel-Haenszel; 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.
a The Miettinen and Nurminen method with CMH weights will be stratified by screening HIV-1 RNA level (≤100,000 copies/mL, 
>100,000 copies/mL) and screening CD4+ T-cell count (<200 cells/mm3, ≥200 cells/mm3) [Miettinen, O. and Nurminen, M. 1985].
b Number of participants who meet the endpoint clinical response criteria over total FAS population. 
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. For analyses of safety by time point, the same analysis 
windows as specified in Table 7 will be used, unless otherwise specified.
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. Adverse events 
(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” endpoints 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 with 2-sided nominal 95% confidence 
intervals provided for between-treatment differences in the percentage of participants with 
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events via the unstratified 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 nondrug-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 of DOR/ISL on 
weight compared to that of BIC/FTC/TAF at Weeks 48 and 96, the treatment difference in 
the change from baseline will be estimated between the treatment groups using ANCOVA 
models adjusted by baseline weight, sex at birth, race, stratum, and treatment group.
Superiority of DOR/ISL to BIC/FTC/TAF will be concluded if the upper bound of the 2-
sided multiplicity-adjusted 95% CI for the estimate of the treatment group difference 
(DOR/ISL minus BIC/FTC/TAF) is less than 0. P-values for the 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 1 or 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 pre-specified as Tier 2 endpoints, summary statistics for baseline, on-
treatment, and change from baseline values will be provided by treatment group in table 
format.
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For 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 or 156 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: one 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 nondrug-related]
leading to discontinuation of study intervention, and AE(s) 
leading to death
Specific AEs (preferred terms), SOCs, or PDLCs occurring 
with an incidence ≥4 participants in either treatment group
The percentage of participants with a cardiac SAE
Change from baseline in select laboratory and radiological 
markers of fasting lipid profiles, renal function, 
inflammation, and body compositiona
Change from baseline to Weeks 48, 96, and 144 in body 
weighta,b
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; SAE=serious adverse event; 
SOC=System Organ Class.
a For participants who become pregnant, data collected after the estimated date of conception will be excluded.
b 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.
c Includes only those endpoints not already pre-specified as Tier-2 endpoints.
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 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 any interim analyses. Blinding to 
treatment assignment will be maintained at all investigational sites until Week 96.
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An external Data Monitoring Committee 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 interim analyses will be 
documented by the external unblinded statistician. Additional logistical details will be 
provided in the eDMC Charter.
Once participants in the Sentinel Cohort (defined in Section 9.5.1.1) have completed the 
Week 24 visit, an interim analysis (referred to as the “Sentinel Cohort Week 24 interim 
analysis”) will be conducted by the external unblinded statistician and reviewed by the
eDMC. All available efficacy and safety data for all participants enrolled by that time will be 
reviewed at this interim analysis. Additionally, a futility assessment will be performed based 
on the Sentinel Cohort data. Due to potential differences in the viral decline profiles of the 
compounds under study, the futility assessment will be based only on participants who 
receive DOR/ISL. If 7 or more participants (out of 30 enrolled and evaluable Group 1 
participants in the Sentinel Cohort) fail to achieve HIV-1 RNA <200 copies/mL at Week 24, 
the eDMC may recommend the study be stopped; the eDMC will review the totality of the 
available data at the time of the Sentinel Cohort Week 24 interim analysis before making 
such a recommendation.
The endpoint of <200 copies/mL for the futility assessment was selected in recognition that 
the time profile for viral suppression to <50 copies/mL may differ between the treatment 
groups and that participants with high viral loads at baseline (eg, >50,000 copies/mL) may be 
enrolled in the study. Such participants may not be able to achieve suppression to <50 
copies/mL (the primary efficacy endpoint) by the Week 24 time point, but achieving an HIV-
1 RNA level <200 copies/mL by Week 24 is clinically meaningful as it indicates that 
participants have declining viral loads.
A possibility exists that unblinded data from the Sentinel Cohort Week 24 interim analysis 
may ultimately be submitted to regulatory authorities prior to the Week 48 database lock
when the Sponsor becomes unblinded to all participants’ study intervention assignments. In 
that event, 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 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 team at the Sponsor.
The eDMC will also be convened in the event that the listed efficacy criteria for either the 
Sentinel Cohort prior to completion of the Sentinel Cohort Week 24 interim analysis or for 
the complete study population after enrollment of the Sentinel Cohort are met, as assessed by 
the external unblinded statistician (see Section 4.1 for the listed efficacy criteria).
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 
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eDMC. The eDMC will recommend steps to ensure the safety of study participants and the 
integrity of the trial.
An interim data summary may be conducted to support any potential marketing authorization 
application of DOR/ISL. In such an event, efficacy and/or safety summaries will be prepared 
by the Sponsor.
An analysis will be conducted to test the primary noninferiority efficacy hypothesis once all 
participants have completed the Week 48 visit assessments. This will be the formal 
evaluation of the primary noninferiority efficacy hypothesis, and the Sponsor will become 
unblinded to all participants’ study intervention assignments 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.
Treatment-level results from all unblinded 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 deviations, or data validation efforts.
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 Sentinel Cohort Week 24 interim analysis data) may 
be presented prior to the evaluation of the primary noninferiority efficacy hypothesis at Week 
48. If further eDMC reviews occur between the evaluation of the primary noninferiority 
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.
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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:
1) Primary efficacy hypothesis (H1) testing noninferiority of HIV-1 RNA <50 copies/mL 
between Group 1 and Group 2 at Week 48.
2) Secondary efficacy hypothesis (H4) testing superiority of HIV-1 RNA <50 copies/mL 
between Group 1 and Group 2 at Week 96.
3) 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 noninferiority 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 1% 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 1.5% 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* ≤1% + 1.5% = 2.5% [Maurer, 
W., et al 2011].
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9.9
Sample Size and Power Calculations
Sample Size and Power Calculations for Efficacy Analyses
The probability of passing the futility assessment based on the Week 24 Sentinel Cohort data 
and the overall study power to demonstrate noninferiority at Week 48 under a variety of 
assumptions is presented in Table 10.
The power calculations shown in Table 10 incorporate the futility assessment stopping rule 
based on a continuation of the study if at least 24 participants (out of 30 enrolled and
evaluable Group 1 participants in the Sentinel Cohort) achieve HIV-1 RNA <200 copies/mL 
at Week 24. Given the threshold of 24 out of 30, there is a high probability the study will 
continue if the rate of HIV-1 RNA <200 copies/mL at Week 24 is high (eg, with a rate of 
90%, the estimated probability of continuing the study is 97.7%—see “Baseline Case” in 
Table 10). Conversely, if the rate of HIV-1 RNA <200 copies/mL at Week 24 is low, then the 
probability of continuing the study is low given the threshold of 24 out of 30 participants (eg, 
with a rate of 70%, the estimated probability of continuing the study is 15.6%—see “Low 
Efficacy Case” in Table 10).
The “Baseline Case” summarized in Table 10 is the most likely scenario. In this case, the rate 
of participants in Group 1 in the Sentinel Cohort with Week 24 HIV-1 RNA <200 copies/mL 
is assumed to be 90%, and the rate of participants in both Group 1 and Group 2 with Week 
48 HIV-1 RNA <50 copies/mL is assumed to be 82%. Under these assumptions, there is a 
97.7% chance of continuing the study after the futility assessment and a 90% chance of 
declaring noninferiority between groups at Week 48.
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Table 10
Summary of Assumptions and Overall Study Power Assuming 60 Participants in 
the Sentinel Cohort and 680 Participants Overall
Parameter
Baseline Case
More 
Conservative 
Case
Less 
Conservative 
Case
Low Efficacy 
Case
High Efficacy 
Case
Assumptionsa
% with Week 24 HIV-1 RNA <200 
copies/mL
90%
88%
93%
70%
93%
% with Week 48 HIV-1 RNA <50 
copies/mL if Week 24 HIV-1 RNA 
<200 copies/mL
90%
90%
93%
90%
93%
% with Week 48 HIV-1 RNA <50 
copies/mL if Week 24 HIV-1 RNA 
≥200 copies/mL
10%
6.67%
7.29%
66.67%
50.14%
% with Week 48 HIV-1 RNA <50 
copies/mL (Group 1)
82%
80%
87%
83%
90%
% with Week 48 HIV-1 RNA <50 
copies/mL (Group 2)
82%
80%
87%
83%
90%
Study Power
Probability of Passing Futility 
Assessmentb
97.73%
94.32%
99.72%
15.55%
99.72%
Overall Study Power to Establish 
Noninferiority at Week 48c
90.01%
84.99%
96.91%
14.69%
98.73%
HIV=human immunodeficiency virus; RNA=ribonucleic acid.
a Assumptions for calculating power are based on experience with MK-1439A Protocol 018 and Protocol 020 and MK-
8591 Protocol 011. Specifically, pooled results for MK-1439A in a TN population showed a rate <200 copies/mL at 
Week 24 of 90.6%, a rate <50 copies/mL at Week 48 among those with <200 copies/mL at Week 24 of 92%, a rate <50 
copies/mL at Week 48 among those with ≥200 copies/mL at Week 24 of 7.1%, and an overall rate of <50 copies/mL at 
Week 48 of 84.1%.
b The cutoff for futility is 7 participants, ie, if 7 or more participants (out of 30 enrolled and evaluable Group 1 
participants in the Sentinel Cohort) are observed to have HIV-1 RNA ≥200 copies/mL at Week 24, the study may be 
stopped. Values presented are based on simulation. The corresponding exact values based on the binomial distribution 
are 97.42%, 93.94%, 99.60%, 15.95%, and 99.60% for the Baseline Case, More Conservative Case, Less Conservative 
Case, Low Efficacy Case, and High Efficacy Case, respectively.
c Calculated via simulation to evaluate first whether the futility criteria were met and if not, evaluate noninferiority 
between groups using the unstratified Miettinen and Nurminen method [Miettinen, O. and Nurminen, M. 
1985]. Noninferiority margin was 10 percentage points and Type 1 error was 0.02495 (1-sided).
To supplement the cases presented in Table 10, Figure 2 displays the estimated power to 
declare noninferiority of DOR/ISL to BIC/FTC/TAF at Week 48 under a broader range of 
potential scenarios. All scenarios in Figure 2 assume 30 enrolled and evaluable participants 
in Group 1 in the Sentinel Cohort with a cutoff for futility of 7 (ie, the underlying simulation 
assumes that the study is stopped at the Sentinel Cohort Week 24 interim analysis if 7 or 
more participants in Group 1 in the Sentinel Cohort fail to achieve HIV-1 RNA <200 
copies/mL at Week 24), 340 participants each in Group 1 and Group 2, a 1-sided Type 1
error of 0.02495, and a noninferiority margin of 10%. The power achieved for each scenario 
was estimated using 10,000 simulations.
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To generate the graphs, the percentage of participants with Week 48 HIV-1 RNA <50 
copies/mL in the DOR/ISL group was assumed to be 80%, 82.5%, 85%, 87.5%, or 90%, as 
indicated on the x-axis. For each of these quantities, the corresponding percentage of 
participants with Week 48 HIV-1 RNA <50 copies/mL in the BIC/FTC/TAF group ranges 
between ±2% the value assumed in the DOR/ISL group (in increments of 1%). For example, 
when the percentage of participants with Week 48 HIV-1 RNA <50 copies/mL in the 
DOR/ISL group is assumed to be 80%, power is estimated for the 5 cases in which the 
percentage of participants with Week 48 HIV-1 RNA <50 copies/mL in the BIC/FTC/TAF
group is 78%, 79%, 80%, 81%, and 82%. Additionally, for each scenario the rate of HIV-1 
RNA <50 copies/mL at Week 48 in Group 1 for participants who achieved HIV-1 RNA <200 
copies/mL at Week 24 is assumed to be 5 percent greater than the overall rate of HIV-1 RNA 
<50 copies/mL at Week 48 in Group 1 (ie, for Group 1, P[<50 copies/mL at Week 48|<200 
copies/mL at Week 24] = P[<50 copies/mL at Week 48] + 0.05). The value of 5 percent was 
selected for illustrative purposes only and, as such, is not representative of all possible cases 
that could be produced via the simulation. Each of the 4 graphs in Figure 2 assumes a distinct 
value for the percentage of participants in Group 1 in the Sentinel Cohort with HIV-1 RNA 
<200 copies/mL at Week 24 (values displayed are for 85%, 87.5%, 90%, and 92.5%), as 
indicated in the panel titles; these percentages correspond to estimated probabilities of 
passing the futility assessment of 84.77%, 93.19%, 97.73%, and 99.56%, respectively.
The legend at the bottom of Figure 2 indicates the difference in the percentage of participants 
with Week 48 HIV-1 RNA <50 copies/mL in terms of DOR/ISL minus BIC/FTC/TAF (eg, a 
treatment difference of 2% in the legend indicates that the percentage of participants with 
Week 48 HIV-1 RNA <50 copies/mL is 2% higher in the DOR/ISL group than the 
BIC/FTC/TAF group).
To illustrate the use of Figure 2, consider the first panel where the probability of having HIV-
1 RNA <200 copies/mL at Week 24 in Group 1 in the Sentinel Cohort is 85%. When the 
probability of HIV-1 RNA <50 copies/mL at Week 48 in the DOR/ISL group is 90% and the 
probability of HIV-1 RNA <50 copies/mL at Week 48 in the BIC/FTC/TAF group is 88% 
(corresponding to a treatment difference of DOR/ISL minus BIC/FTC/TAF equal to 2%), the 
estimated power to declare DOR/ISL noninferior to BIC/FTC/TAF is approximately 84.7%; 
this value is comprised of 1) an 84.77% chance of passing the futility assessment as a result 
of the assumption that 85% of participants in Group 1 in the Sentinel Cohort would have
Week 24 HIV-1 RNA <200 copies/mL, and 2) a 99.93% chance that, having passed the 
futility assessment, noninferiority would be concluded at Week 48, driven by the assumed 
2% treatment difference [DOR/ISL=90% minus BIC/FTC/TAF=88%] in the percentage of 
participants with Week 48 HIV-1 RNA <50 copies/mL.
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Figure 2
Estimated Power to Declare Noninferiority of DOR/ISL to BIC/FTC/TAF at 
Week 48 Assuming 30 Enrolled and Evaluable Participants in Group 1 in the Sentinel Cohort 
and 680 Participants Overall
(Figure Continued on Next Page)
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Figure 2 Continued
Estimated Power to Declare Noninferiority of DOR/ISL to 
BIC/FTC/TAF at Week 48 Assuming 30 Enrolled and Evaluable Participants in Group 1 in 
the Sentinel Cohort and 680 Participants Overall
Table 11 summarizes the power to declare DOR/ISL superior to BIC/FTC/TAF with regard 
to the percentage of participants with HIV-1 RNA <50 copies/mL at Week 48/96 under 
various assumptions for the response rate in each treatment group. For example, if the 
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percentage of participants with Week 48/96 HIV-1 RNA <50 copies/mL is assumed to be 
96% in the DOR/ISL group and 90% in the BIC/FTC/TAF group, then this study will have
approximately 88.5% power to declare DOR/ISL superior to BIC/FTC/TAF at Week 48/96.
Table 11
Power to Establish Superiority at Week 48/96 Under Various Response Rate 
Assumptions (Assuming All Prior Hypothesis Tests Reach Statistical Significance) (340 
Participants Per Group)
Group 1: True Rate of 
HIV-1 RNA <50 
copies/mL at Week 48/96
Group 2: True Rate of 
HIV-1 RNA <50 
copies/mL at Week 48/96
Probability of Demonstrating 
Superiority at Week 48/96
92%
90%
14.56%
94%
90%
49.21%
96%
90%
88.45%
87%
85%
11.17%
90%
85%
50.98%
93%
85%
92.54%
CI=confidence interval; eDMC=external Data Monitoring Committee; HIV=human immunodeficiency virus.
Note: Values are computed assuming that all prior hypotheses in the testing hierarchy (see Section 9.8) reach statistical 
significance.
Note: To establish superiority, the lower bound of the 2-sided multiplicity-adjusted 95% CI must be greater than 0 
percentage points for Group 1 minus Group 2. The 95% CI used for the power calculations is based on the unstratified
Miettinen and Nurminen method [Miettinen, O. and Nurminen, M. 1985], and power was estimated via 10,000 
simulations for each scenario. 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.
Table 12 summarizes the power to declare DOR/ISL noninferior to BIC/FTC/TAF with 
regard to the percentage of participants with HIV-1 RNA <50 copies/mL at Week 96 under 
various assumptions for the response rate in Group 2 and the underlying difference in 
response rates between treatment groups. For example, if the true rate of HIV-1 RNA 
<50 copies/mL in the BIC/FTC/TAF group at Week 96 is 90% and the true rate in the 
DOR/ISL group is 91% (ie, a true difference in response rates of 1%), then this study has 
approximately 99.8% power to declare DOR/ISL noninferior to BIC/FTC/TAF at Week 96. 
If the true rate of HIV-1 RNA <50 copies/mL at Week 96 is 80% in both treatment groups,
then this study has approximately 90.1% power to declare DOR/ISL noninferior to 
BIC/FTC/TAF at Week 96.
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Table 12
Power to Establish Noninferiority at Week 96 Under Various Response Rate 
Assumptions (340 Participants per Group)
Group 2: True 
Rate of HIV-1 
RNA <50 
copies/mL at 
Week 96
True Difference in Week 96 Response Rates (Group 1 Minus Group 2)
2%
1%
0%
-1%
-2%
90%
99.97%
99.76%
99.05%
96.54%
90.50%
85%
99.38%
98.04%
95.09%
89.09%
80.63%
80%
97.90%
94.87%
90.12%
82.25%
72.45%
75%
95.41%
91.16%
85.16%
76.55%
66.15%
70%
92.83%
88.35%
81.32%
72.13%
61.44%
CI=confidence interval; eDMC=external Data Monitoring Committee; HIV=human immunodeficiency virus.
Note: Noninferiority margin=10%. To establish noninferiority, the lower bound of the 2-sided multiplicity-adjusted 95% 
CI must be greater than -10 percentage points for Group 1 minus Group 2. The 95% CI used for the power calculations is 
based on the unstratified Miettinen & Nurminen method [Miettinen, O. and Nurminen, M. 1985]. The 1-sided Type 1 
error is 0.02493, which adjusts for an assumed 7 eDMC reports between Day 1 and Week 96 (5 reports assumed between 
Day 1 and Week 48 and 2 reports assumed between Week 48 and Week 96). Power was assessed via 10,000 simulations 
for each scenario.
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 96.7% chance of observing at 
least 1 AE among 340 participants in a treatment group. If no AE of that type is observed 
among the 340 participants in a treatment group, this study will provide 97.5% confidence 
that the underlying percentage of participants with that particular AE is <1.08% (1 out of 
every 92 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 numbers 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 (340 Participants Per Group)
Hypothetical Number of 
Participants with Adverse Event
Estimate of Incidence
95% Upper Confidence 
Bounda
0
0.0%
0.9%
5
1.5%
3.4%
10
2.9%
5.3%
15
4.4%
7.2%
20
5.9%
8.9%
25
7.4%
10.7%
30
8.8%
12.4%
AE=adverse event; CI=confidence interval.
a Based on the 2-tailed exact confidence interval for a binomial proportion [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 (DOR/ISL minus BIC/FTC/TAF) 
that can be ruled out with different power levels and 95% confidence when there are 340
participants in each group. The underlying incidence of the AE is assumed to be the same for 
the two 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 9.2 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 340 Participants in Each Group
Target 
Power
Underlying AE Incidence Rate
1%
5%
10%
20%
30%
40%
50%
80%
3.5
5.8
7.4
9.2
10.2
10.7
10.7
85%
3.9
6.3
7.9
9.9
11.0
11.4
11.4
90%
4.3
6.9
8.7
10.8
11.9
12.4
12.3
95%
5.1
7.8
9.8
12.1
13.3
13.7
13.6
AE=adverse event; CI=confidence interval.
Note: Values represent 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 the DOR/ISL and BIC/FTC/TAF treatment groups 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 272, then this 
study will provide 90% power to detect a difference at least as large as 2.37 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* = 0.00995
Power
n = 295 Participants per Groupa
Standard Deviation of Change in Weight From Baselineb
4 kg
5 kg
6 kg
80%
1.05
1.31
1.57
85%
1.11
1.39
1.67
90%
1.19
1.49
1.79
If Week 48 Hypothesis (H5) is Rejected, Week 96 Hypothesis (H6) is Tested at α1*+α2* = 0.02493
Power
n = 272 Participants per Groupa
Standard Deviation of Change in Weight From Baselineb
8 kg
10 kg
12 kg
80%
1.93
2.41
2.89
85%
2.06
2.57
3.09
90%
2.23
2.79
3.34
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If Week 48 Hypothesis (H5) is Retained, Week 96 Hypothesis (H6) is Tested at α2* = 0.01498
Power
n = 272 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%
2.20
2.76
3.31
90%
2.37
2.97
3.56
If Week 48 Hypothesis (H5) is Retained and Week 96 Hypothesis (H6) is Rejected, Week 48 
Hypothesis (H5) is Retested at α2* = 0.01498
Power
n = 295 Participants per Groupa
Standard Deviation of Change in Weight From Baselineb
4 kg
5 kg
6 kg
80%
0.99
1.24
1.49
85%
1.06
1.32
1.59
90%
1.14
1.42
1.71
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 13% at Week 48 and 20% at Week 96 was assumed in the calculations based on data from MK-1439A-021. As such, 
the number of participants per group is assumed to be 295 at Week 48 and 272 at Week 96.
b Values of the standard deviation of change in weight from baseline are based on experience with MK-8591 Protocol 
011. 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*=1% 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*=1.5% 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 unadjusted for stratification factors) for the primary endpoint of HIV-1 RNA <50 
copies/mL and the secondary endpoint of HIV-1 RNA <40 copies/mL (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)

Baseline CD4+ T-cell count category (<200 cells/mm3, ≥200 cells/mm3)

Screening HIV-1 RNA (≤100,000 copies/mL, >100,000 copies/mL)

Baseline HIV-1 RNA (≤100,000 copies/mL, >100,000 copies/mL)

Baseline HIV-1 RNA (≤500,000 copies/mL, >500,000 copies/mL)

HIV-1 subtype
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 
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(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.
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
Code of Conduct for Clinical Trials
Merck Sharp & Dohme LLC, Rahway, NJ, USA (MSD)
Code of Conduct for Interventional Clinical Trials
I. Introduction
A. Purpose
MSD, through its subsidiaries, conducts clinical trials worldwide to evaluate the safety and effectiveness of our 
products. As such, we are committed to designing, implementing, conducting, analyzing, and reporting these trials 
in compliance with the highest ethical and scientific standards. Protection of participants in clinical trials is the 
overriding concern in the design and conduct of clinical trials. In all cases, MSD clinical trials will be conducted 
in compliance with local and/or national regulations (including all applicable data protection laws and 
regulations), and International Council for Harmonisation Good Clinical Practice (ICH-GCP), and also in 
accordance with the ethical principles that have their origin in the Declaration of Helsinki.
B. Scope
Highest ethical and scientific standards shall be endorsed for all clinical interventional investigations sponsored by 
MSD irrespective of the party (parties) employed for their execution (e.g., contract research organizations, 
collaborative research efforts). This Code is not intended to apply to trials that are observational in nature, or 
which are retrospective. Further, this Code does not apply to investigator-initiated trials, which are not under the 
full control of MSD.
II. Scientific Issues
A. Trial Conduct
1. Trial Design
Except for pilot or estimation trials, clinical trial protocols will be hypothesis-driven to assess safety, efficacy 
and/or pharmacokinetic or pharmacodynamic indices of MSD or comparator products. Alternatively, MSD
may conduct outcomes research trials, trials to assess or validate various endpoint measures, or trials to 
determine patient preferences, etc.
The design (i.e., participant population, duration, statistical power) must be adequate to address the specific
purpose of the trial and shall respect the data protection rights of all participants, trial site staff and, where 
applicable, third parties. All trial protocols are and will be assessed for the need and capability to enroll 
underrepresented groups. Participants must meet protocol entry criteria to be enrolled in the trial. 
2. Site Selection
MSD’s clinical trials are conducted globally in many different countries and in diverse populations, including 
people of varying age, race, ethnicity, gender, and accounting for other potential disease related factors. MSD 
selects investigative sites based on medical expertise, access to appropriate participants, adequacy of facilities 
and staff, previous performance in clinical trials, as well as budgetary considerations. Prior to trial initiation, 
sites are evaluated by MSD personnel (or individuals acting on behalf of MSD) to assess the ability to 
successfully conduct the trial.
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Where appropriate, and in accordance with regulatory authority guidance, MSD will make concerted efforts 
to raise awareness of clinical trial opportunities in various communities. MSD will seek to engage 
underrepresented groups and those disproportionately impacted by the disease under study. MSD will support 
clinical trial investigators to enroll underrepresented groups and expand access to those who will ultimately 
use the products under investigation.
3. Site Monitoring/Scientific Integrity
Investigative trial sites are monitored to assess compliance with the trial protocol and Good Clinical Practice 
(GCP). MSD reviews clinical data for accuracy, completeness, and consistency. Data are verified versus 
source documentation according to standard operating procedures. Per MSD policies and procedures, if 
potential fraud, scientific/research misconduct, privacy incidents/breaches or Clinical Trial-related 
Significant Quality Issues are reported, such matters are investigated. When necessary, appropriate corrective 
and/or preventative actions are defined and regulatory authorities and/or ethics review committees are 
notified.
B. Publication and Authorship
Regardless of trial outcome, MSD commits to publish the primary and secondary results of its registered trials of 
marketed products in which treatment is assigned, according to the pre-specified plans for data analysis. To the 
extent scientifically appropriate, MSD seeks to publish the results of other analyses it conducts that are important 
to patients, physicians, and payers. Some early phase or pilot trials are intended to be hypothesis-generating rather 
than hypothesis testing; in such cases, publication of results may not be appropriate since the trial may be 
underpowered and the analyses complicated by statistical issues such as multiplicity.
MSD’s policy on authorship is consistent with the recommendations published by the International Committee of 
Medical Journal Editors (ICMJE). In summary, authorship should reflect significant contribution to the design and 
conduct of the trial, performance or interpretation of the analysis, and/or writing of the manuscript. All named 
authors must be able to defend the trial results and conclusions. MSD funding of a trial will be acknowledged in 
publications.
III. Participant Protection
A. Regulatory Authority and Ethics Committee Review (Institutional Review Board [IRB]/Independent Ethics 
Committee [IEC])
All protocols and protocol amendments will be submitted by MSD for regulatory authority 
acceptance/authorization prior to implementation of the trial or amendment, in compliance with local and/or 
national regulations.
The protocol, protocol amendment(s), informed consent form, investigator’s brochure, and other relevant trial 
documents must be reviewed and approved by an IRB/IEC before being implemented at each site, in compliance 
with local and/or national regulations. Changes to the protocol that are required urgently to eliminate an 
immediate hazard and to protect participant safety may be enacted in anticipation of ethics committee approval. 
MSD will inform regulatory authorities of such new measures to protect participant safety, in compliance with 
local and/or national regulations.
B. Safety
The guiding principle in decision-making in clinical trials is that participant welfare is of primary importance. 
Potential participants will be informed of the risks and benefits of, as well as alternatives to, trial participation. At 
a minimum, trial designs will take into account the local standard of care.
All participation in MSD clinical trials is voluntary. Participants enter the trial only after informed consent is 
obtained. Participants may withdraw from an MSD trial at any time, without any influence on their access to, or 
receipt of, medical care that may otherwise be available to them.
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C. Confidentiality
MSD is committed to safeguarding participant confidentiality, to the greatest extent possible, as well as all 
applicable data protection rights. Unless required by law, only the investigator, Sponsor (or individuals acting on 
behalf of MSD), ethics committee, and/or regulatory authorities will have access to confidential medical records 
that might identify the participant by name.
D. Genomic Research
Genomic research will only be conducted in accordance with a protocol and informed consent authorized by an 
ethics committee.
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.
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 
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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.
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.
The participant must be informed that his/her personal study-related data will be used by the 
Sponsor in accordance with local data protection law. The level of disclosure must also be 
explained to the participant. 
The participant must be informed that his/her medical records may be examined by Clinical 
Quality Assurance auditors or other authorized personnel appointed by the Sponsor, by 
appropriate IRB/IEC members, and by inspectors from regulatory authorities.
10.1.3.1
Confidentiality of Data
By signing this protocol, the investigator affirms to the Sponsor that information furnished to 
the investigator by the Sponsor will be maintained in confidence, and such information will 
be divulged to the IRB, IEC, or similar or expert committee, affiliated institution and 
employees, only under an appropriate understanding of confidentiality with such board or 
committee, affiliated institution and employees. Data generated by this study will be 
considered confidential by the investigator, except to the extent that it is included in a 
publication as provided in the Publications section of this protocol.
10.1.3.2
Confidentiality of Participant Records
By signing this protocol, the investigator agrees that the Sponsor (or Sponsor representative), 
IRB/IEC, or regulatory authority representatives may consult and/or copy study documents to 
verify worksheet/CRF data. By signing the consent form, the participant agrees to this 
process. If study documents will be photocopied during the process of verifying 
worksheet/CRF information, the participant will be identified by unique code only; full 
names/initials will be masked prior to transmission to the Sponsor.
By signing this protocol, the investigator agrees to treat all participant data used and 
disclosed in connection with this study in accordance with all applicable privacy laws, rules 
and regulations.
10.1.3.3
Confidentiality of IRB/IEC Information
The Sponsor is required to record the name and address of each IRB/IEC that reviews and 
approves this study. The Sponsor is also required to document that each IRB/IEC meets 
regulatory and ICH GCP requirements by requesting and maintaining records of the names 
and qualifications of the IRB/IEC members and to make these records available for 
regulatory agency review upon request by those agencies.
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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.
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.
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.
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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, 
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.
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 
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conducting the study is debarred or if any proceeding for debarment is pending or, to the best 
of the investigator’s knowledge, threatened.
Data Quality Assurance
All participant data relating to the study will be recorded on printed or electronic CRF unless 
transmitted to the Sponsor or designee electronically (eg, laboratory data). The investigator 
or qualified designee is responsible for verifying that data entries are accurate and correct by 
physically or electronically signing the CRF.
Detailed information regarding Data Management procedures for this protocol will be 
provided separately.
The investigator must maintain accurate documentation (source data) that supports the 
information entered in the CRF.
The investigator must permit study-related monitoring, audits, IRB/IEC review, and 
regulatory agency inspections and provide direct access to source data documents.
Study documentation will be promptly and fully disclosed to the Sponsor by the investigator 
upon request and also shall be made available at the study site upon request for inspection, 
copying, review, and audit at reasonable times by representatives of the Sponsor or any 
regulatory authorities. The investigator agrees to promptly take any reasonable steps that are 
requested by the Sponsor or any regulatory authorities as a result of an audit or inspection to 
cure deficiencies in the study documentation and worksheets/CRFs.
The Sponsor or designee is responsible for the data management of this study including 
quality checking of the data.
Study monitors will perform ongoing source data review and verification to confirm that data 
entered into the CRF by authorized site personnel are accurate, complete, and verifiable from 
source documents; that the safety and rights of participants are being protected; and that the 
study is being conducted in accordance with the currently approved protocol and any other 
study agreements, ICH GCP, and all applicable regulatory requirements.
Records and documents, including participants’ documented informed consent, pertaining to 
the conduct of this study must be retained by the investigator for 15 years after study 
completion unless local regulations or institutional policies require a longer retention period. 
No records may be destroyed during the retention period without the written approval of the 
Sponsor. No records may be transferred to another location or party without written 
notification to the Sponsor.
Source Documents
Source documents provide evidence for the existence of the participant and substantiate the 
integrity of the data collected. The investigator/institution should maintain adequate and 
accurate source documents and study records that include all pertinent observations on each 
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of the site’s participants. Source documents and data should be attributable, legible, 
contemporaneous, original, accurate, and complete. Changes to source data should be 
traceable, should not obscure the original entry, and should be explained if necessary (eg, via 
an audit trail). Source documents are filed at the investigator’s site.
Data reported on the CRF or entered in the eCRF that are transcribed from source documents 
must be consistent with the source documents or the discrepancies must be explained. The 
investigator/institution may need to request previous medical records or transfer records, 
depending on the study. Also, current medical records must be available.
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.

Any laboratory tests related to study endpoints (eg, HIV-1 RNA and CD4+ T-cell 
enumeration) must be performed by the central laboratory.

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 Count
Hemoglobin
Hematocrit
RBC Indices:

MCV

MCH

MCH Concentration

Red Cell Distribution Width (RDW)
WBC Count with Differential:

Neutrophils

Lymphocytes

Monocytes

Eosinophils

Basophils
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Laboratory Assessments
Parameters
CD4+ T-cell count/TBNK panel
T-cell, B-cell, and natural killer cell profile that includes but is 
not limited to the following:
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
Coagulation
Prothrombin Time/INR
Chemistry (nonfasting)
Alanine Aminotransferase (ALT)
Albumin
Alkaline Phosphatase
Amylase
Aspartate Aminotransferase (AST)
Bicarbonate
Blood Urea Nitrogen (BUN)
Calcium
Chloride
Creatine Kinase
Creatinine
Creatinine Clearance
eGFR (by MDRD calculation)
Glucose (nonfasting)
Lipase
Magnesium
Phosphorous
Potassium
Sodium
Total Bilirubin

Direct Bilirubin

Indirect Bilirubin
Total Protein
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Laboratory Assessments
Parameters
Additional Chemistry at Fasting Visits 
(fasting for at least 8 hours)
Glucose (fasting)
High-Density Lipoprotein Cholesterol (HDL-C)
Low-Density Lipoprotein Cholesterol (LDL-C)
Non-High-Density Lipoprotein Cholesterol (non-HDL-C)
Total Cholesterol (TC)
Triglycerides (TGs)
Insulin a
HOMA-IR (calculation)
Routine Urinalysis
Blood
Bilirubin
Glucose
Ketones
Leukocytes
Nitrite
pH
Protein
Specific Gravity
Urobilinogen
Pregnancy Testing
Serum human chorionic gonadotropin (hCG) test (as needed for 
WOCBP)
Urine human chorionic gonadotropin (hCG) test (as needed for 
WOCBP)
Blood for Renal Biomarkers
Cystatin – C
Urine for Renal Biomarkers
Albumin
Protein
Beta-2-microglobulin/creatinine ratio (B-2 M/Cr)
Retinol Binding Protein/creatinine ratio (RBP/Cr)
Hepatitis Serology
Hepatitis B Virus Surface Antigen
Hepatitis B Virus Surface Antibody
Anti-HBc
HBV DNA
Hepatitis C Antibody (if positive perform plasma Hepatitis C 
Virus quantitative test)
HIV-1 and HIV-2 Serology
HIV-1 and HIV-2 Antibody Test
HIV Confirmation
Virology
HIV-1 Viral RNA Quantification (Real-time PCR)
HIV-1 Drug Resistance
Inflammatory Markers
D-dimer
hs-CRP
IL-6
Soluble CD163
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Laboratory Assessments
Parameters
PK
ISL PK
Blood for Genetic Analysis
Whole Blood for FBR
Blood (plasma) for backup HIV-1 Drug Resistance testing as needed
Blood (plasma) for investigational ISL PK testing as needed
a
Participants with diabetes mellitus (type 1 or type 2) or insulin resistance are not required to have the 
blood draw for insulin testing.
The investigator (or medically qualified designee) must document their review of each 
laboratory safety report.
Table 17 summarizes the blood volumes collected for laboratory assessments.
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Table 17
Blood Volumes
Study Period
Screening
Group 1 and Group 2
Viremia Confir-
mation
CD4+ T-cell
/Lymphocyte
Confirmation
Early Discon of 
Treatment
CD4+ T-cell
/Lymphocyte
Monitoringe
End of Treatment 
Follow-up
Scheduled 
Day/Week
Screening
Day 1
Week 4
Week 8
Week 16
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
6
CD4+ T-cell 
Count/TBNK Panel
6
6
6
6
6
6
6
6
6
6
6
6
6
6
6
6
6
6
6
6
6f
Blood (Plasma) for 
HIV-1 Drug 
Resistance
6
12
12c
12
Blood (Plasma) for 
HIV-1 Drug 
Resistance –
Backup
6
12
12
12
12
12
12
12
12
12
12
12
12
12
12
12
12
12
12
12
12
HIV Serology and 
Hepatitis Serologya
6
HIV Confirmation
1
HBV DNA
6
Plasma Hepatitis C 
Virus PCR 
Quantitative Test 
(only performed if 
antibody positive)
6
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Study Period
Screening
Group 1 and Group 2
Viremia Confir-
mation
CD4+ T-cell
/Lymphocyte
Confirmation
Early Discon of 
Treatment
CD4+ T-cell
/Lymphocyte
Monitoringe
End of Treatment 
Follow-up
Scheduled 
Day/Week
Screening
Day 1
Week 4
Week 8
Week 16
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)
Serum Pregnancy 
(hCG; WOCBP 
only)
2
2
Chemistry (includes 
Serum Pregnancy at 
Screening)
6
6
6
6
6
6
6
6
6
6
6
6
6
6
6
6
6
6
6
Hematology
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2g
PT/INR
2.7
Blood (Plasma) for 
ISL PK
4
8
4
4
4
4
Blood (Plasma) for 
Investigational ISL 
PK
4
4
4
4
4
4
4
4
4
Blood (Plasma) for 
DOR and ISL PK
in Pregnant Women 
Only
<--------------------------------------------------Xb---------------------------------------------------->
Blood for Genetic 
Analysis
8.5
Whole Blood for 
FBR
8
8
8
8
8
8
8c
Inflammatory 
Markers
7.7
7.7
7.7
7.7
7.7
Cystatin-C
2
2
2
2
2
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Study Period
Screening
Group 1 and Group 2
Viremia Confir-
mation
CD4+ T-cell
/Lymphocyte
Confirmation
Early Discon of 
Treatment
CD4+ T-cell
/Lymphocyte
Monitoringe
End of Treatment 
Follow-up
Scheduled 
Day/Week
Screening
Day 1
Week 4
Week 8
Week 16
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)
Fasting Insulind
1
1
1
1
1
1
Total Blood 
Volume per Visit
53.7
63.2
34
36
36
54.7
36
54.7
36
36
36
54.7
36
37
36
58.7
36
36
42
8
58
12
44
hCG=human chorionic gonadotropin; FBR=future biomedical research; HBV=hepatitis B virus; HCV=hepatitis C virus; HIV-1=human immunodeficiency virus; HIV-1=human 
immunodeficiency virus type 1; INR=international normalized ratio; PCR=polymerase chain reaction; PK=pharmacokinetic; PT=prothrombin time; RNA=ribonucleic acid; 
TBNK=T and B lymphocyte and natural killer cells; WOCBP= woman/women of childbearing potential.
a At screening visit, HIV-1 and HIV-2 screen, and HBV and HCV testing are performed from same 6 mL sample, with the exception of HBV DNA testing, which requires a separate 
sample. Plasma hepatitis C virus PCR quantitative test (performed if hepatitis C virus antibody is positive) requires 6 mL of whole blood.
b 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.
c If sample is collected at Viremia Confirmation visit, it is not necessary to collect another sample at the Early Discontinuation of Treatment visit.
d Participants with diabetes mellitus (type 1 or type 2) or insulin resistance are not required to have the blood draw for insulin testing.
e Blood volumes collected at the CD4+ T-cell Count/Absolute Lymphocyte Count Monitoring Visit represent single monthly monitoring visits.
f
CD4+ T-cell count and hematology samples to be collected only for participants with specified decreases in CD4+ T-cell counts and/or absolute lymphocyte counts per Section 1.3.5.
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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.
Table 18
Blood Volumes: Participants Whose Pregnancy or Postpartum Visit(s) Extends 
Beyond Week 168
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/TBNK Panel
6
6
6
6
Plasma for HIV Viral Drug Resistance Testing 
15
15
15
15
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
55
55
55
55
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; TBNK=T and B lymphocyte and natural killer cells.
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
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 nontherapeutic 
effect.
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, 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.
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
Exacerbation of a chronic or intermittent pre-existing condition including either an 
increase in frequency and/or intensity of the condition.

New conditions detected or diagnosed after study intervention administration even 
though it may have been present before the start of the study.

Signs, symptoms, or the clinical sequelae of a suspected drug-drug interaction.

Signs, symptoms, or the clinical sequelae of a suspected overdose of either study 
intervention or a concomitant medication.

For all reports of overdose (whether accidental or intentional) with an associated AE, the 
AE term should reflect the clinical symptoms or abnormal test result. An overdose 
without any associated clinical symptoms or abnormal laboratory results is reported using 
the terminology “accidental or intentional overdose without adverse effect.”

Any new cancer or progression of existing cancer.
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.
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.
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An SAE is defined as any untoward medical occurrence that, at any dose:
a. Results in death
b. Is life-threatening

The term “life-threatening” in the definition of “serious” refers to an event in which 
the participant was at risk of death at the time of the event. It does not refer to an 
event, which hypothetically might have caused death, if it were more severe.
c.
Requires inpatient hospitalization or prolongation of existing hospitalization

Hospitalization is defined as an inpatient admission, regardless of length of stay, even 
if the hospitalization is a precautionary measure for continued observation. (Note: 
Hospitalization for an elective procedure to treat a pre-existing condition that has not 
worsened is not an SAE. A pre-existing condition is a clinical condition that is 
diagnosed prior to the use of an MSD product and is documented in the participant’s 
medical history.
d. Results in persistent or significant disability/incapacity

The term disability means a substantial disruption of a person’s ability to conduct 
normal life functions.

This definition is not intended to include experiences of relatively minor medical 
significance such as uncomplicated headache, nausea, vomiting, diarrhea, influenza, 
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.
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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
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.
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
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 funtions with intervention indicated to 
prevent permanent impairment, persistent disability, or death.
-
Grade 5 Death: Deaths related to an AE.
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)?
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-
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?
o
If yes, did the AE resolve or improve?
o
If yes, this is a positive dechallenge.
o
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?
o
If yes, did the AE recur or worsen?
o
If yes, this is a positive rechallenge.
o
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.
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
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:
o
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:
o
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.

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.
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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).
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
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.
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
Postmenopausal female
-
A postmenopausal state is defined as no menses for 12 months without an alternative 
medical cause.
o
A high follicle stimulating hormone (FSH) level in the postmenopausal range may 
be used to confirm a postmenopausal state in women not using hormonal 
contraception or hormone replacement therapy (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 
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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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,d

IUSc, d, e

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 drugs/vaccines may interact with

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.
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3. Summary of Procedures for Future Biomedical Research3, 4
a.
Participants for Enrollment
All participants enrolled in the clinical study will be considered for enrollment in 
future biomedical research
b. Informed Consent
Informed consent for specimens (ie, DNA, RNA, protein, etc.) will be obtained 
during screening for protocol enrollment from all participants or legal guardians, at a 
study visit by the investigator or his or her designate. Informed consent for future 
biomedical research should be presented to the participants on the visit designated in 
the SoA. If delayed, present consent at next possible Participant Visit. Consent forms 
signed by the participant will be kept at the clinical study site under secure storage for 
regulatory reasons.
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 
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identifying information embedded within it. The link (or key) between participant 
identifiers and this unique code will be held at the study site. No personal identifiers will 
appear on the specimen tube.
5. Biorepository Specimen Usage3, 4
Specimens obtained for the Sponsor will be used for analyses using good scientific 
practices. Analyses utilizing the future biomedical research specimens may be performed 
by the Sponsor, or an additional third party (eg, a university investigator) designated by 
the Sponsor. The investigator conducting the analysis will follow the Sponsor’s privacy 
and confidentiality requirements. Any contracted third party analyses will conform to the 
specific scope of analysis outlined in future biomedical research protocol and consent. 
Future biomedical research specimens remaining with the third party after specific 
analysis is performed will be reported to the Sponsor.
6. Withdrawal From Future Biomedical Research3, 4
Participants may withdraw their consent for future biomedical research and ask that their 
biospecimens not be used for future biomedical research. Participants may withdraw 
consent at any time by contacting the investigator for the main study. If medical records 
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.
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Specimens from the study site will be shipped to a central laboratory and then shipped to 
the Sponsor-designated biorepository. If a central laboratory is not utilized in a particular 
study, the study site will ship directly to the Sponsor-designated biorepository. The 
specimens will be stored under strict supervision in a limited access facility which 
operates to assure the integrity of the specimens. Specimens will be destroyed according 
to Sponsor policies and procedures and this destruction will be documented in the 
biorepository database.
8. Data Security3, 4
Databases containing specimen information and test results are accessible only to the 
authorized Sponsor representatives and the designated study administrator research 
personnel and/or collaborators. Database user authentication is highly secure, and is 
accomplished using network security policies and practices based on international 
standards to protect against unauthorized access.
9. Reporting of Future Biomedical Research Data to Participants3, 4
No information obtained from exploratory laboratory studies will be reported to the 
participant, family, or physicians. Principle reasons not to inform or return results to the 
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 Conference on Harmonization [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
Country-specific Request for Germany
Participants that 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.
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.
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10.8
Appendix 8: Calculation of Creatinine Clearance and eGFR
Cockcroft-Gault equations

If male:
CrCL (mL/min) = (140-age [y]) × weight [kg])
72 × serum creatinine (mg/dL)

If female:
CrCL (mL/min) = (140-age [y]) × weight [kg]) × 0.85
72 × serum creatinine (mg/dL)
Modification of Diet in Renal Disease Study (MDRD) equation
eGFR (mL/min/1.73 m2) = 175 x (SCr)-1.154 x (age)-0.203 x 0.742 [if female] x 1.212 [if 
African American]

Note:eGFR = estimated glomerular filtration rate

SCr = standardized serum creatinine

age = years
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10.9
Appendix 9: Abbreviations
Abbreviation
Expanded Term
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
BICR
blinded independent central review
BMD
bone mineral density
BMI
body mass index
BOCF
baseline observation carried forward
bp
blood pressure
C24
concentration after 24 hours
CD4+
CD4-positive
cART
combination antiretroviral therapy
CI
confidence interval
Cmax
maximum (peak) observed drug concentration
CMH
Cochran-Mantel-Haenszel
CONSORT
Consolidated Standards of Reporting Trials
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
CYP3A
CYP3A=cytochrome P450 3A
DAIDS
The Division of AIDS
DAO
Data-As-Observed
DDI
drug-drug interaction
DEXA
dual-energy X-ray absorptiometry
DHHS
Department of Health and Human Services
DILI
drug-induced liver injury
DMC
Data Monitoring Committee 
DNA
deoxyribonucleic acid 
DOR
doravirine
DTG
dolutegravir
ECG
electrocardiogram 
ECI
event of clinical interest
eCRF
electronic Case Report Form
EDC
electronic data collection 
eDMC
external Data Monitoring Committee
EFV
efavirenz
eGFR
estimated glomerular filtration rate
EMA
European Medicines Agency
EOC
Executive Oversight Committee 
EQ-5D-5L
EuroQol Five-Dimensional descriptive system, five level version
EU
European Union
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Abbreviation
Expanded Term
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 
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
hCG
human chorionic gonadotropin
HDL-C
high-density lipoprotein cholesterol
HIV
human immunodeficiency virus
HIV-1
human immunodeficiency virus type 1
HIV SDM
Human Immunodeficiency Virus Symptom Distress Module
HIV-SI
Human Immunodeficiency Virus Symptom Index
HOMA-IR
homeostatic model assessment-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 Harmonization
ICMJE
International Committee of Medical Journal Editors
IEC
Independent Ethics Committee
IL-6
interleukin-6
IMP
Investigational Medicinal Product
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
LDL-C
low-density lipoprotein cholesterol
LNG/EE
levonorgestrel/ethinyl estradiol
LOCF
last observation carried forward
M=F
missing equal to failure
M&N
Miettinen and Nurminen
MCH
mean corpuscular hemoglobin
MCV
mean corpuscular volume
NA
not applicable
NIMP
Non-Investigational Medicinal Product
NK
Natural killer
NNRTI
non-nucleoside reverse transcriptase inhibitor
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Abbreviation
Expanded Term
Non-HDL-C
non-high-density lipoprotein cholesterol
NRTI
nucleoside analog reverse transcriptase inhibitor
NRTTI
nucleoside reverse transcriptase translocation inhibitor
OF
Observed Failure
P
primary approach
PCL
protocol clarification letter
PCR
polymerase chain reaction
PDLC
predefined limit of change
PEP
postexposure prophylaxis
PI
protease inhibitor
PK
pharmacokinetic(s)
PMDA
Pharmaceuticals and Medical Devices Agency
PP
Per-Protocol
PrEP
pre-exposure prophylaxis 
PRO
patient-reported outcomes
PT
prothrombin time
QD
once-daily
QM
once-monthly
QW
once-weekly
RAP
Resistance Analysis Population
RNA
ribonucleic acid
rr
respiratory rate
S
supportive approach
SAC
Scientific Advisory Committee
SAE
serious adverse event 
sCD-163
soluble CD-163
SCr
standardized serum creatinine
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 analogue mutations
TBNK
T and B lymphocyte and natural killer cells
TC
total cholesterol
TDF
tenofovir disoproxil fumarate
temp
body temperature
TG
triglycerides
TLOVR
Time to Loss of Virologic Response
TN
treatment-naïve
TP
triphosphate
ULN
upper limit of normal
US
United States
WOCBP
woman/women of childbearing potential 
WONCBP
Woman/women of nonchildbearing potential
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11
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