A Phase 3, Randomized, Clinical Study in HIV-1-Infected Heavily Treatment-Experienced Participants Evaluating the Antiretroviral Activity of Blinded Islatravir (ISL), Doravirine (DOR), and Doravirine/Islatravir (DOR/ISL), Each Compared to Placebo, and the Antiretroviral Activity, Safety, and Tolerability of Open-Label DOR/ISL
Phase: PHASE3
Conditions: HIV-1 Infection
Sponsor: Merck Sharp & Dohme LLC

Official Protocol Title:
NCT number:                NCT04233216
Document Date:           26-Sep-2022
A Phase 3, Randomized, Clinical Study in HIV-1-
Infected Heavily Treatment-Experienced Participants 
Evaluating the Antiretroviral Activity of Blinded Islatravir 
(ISL), Doravirine (DOR), and Doravirine/Islatravir (DOR/
ISL), Each Compared to Placebo, and the Antiretroviral 
Activity, Safety, and Tolerability of Open-Label DOR/ISL

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, Clinical Study in HIV-1-Infected Heavily 
Treatment-Experienced Participants Evaluating the Antiretroviral Activity of Blinded 
Islatravir (ISL), Doravirine (DOR), and Doravirine/Islatravir (DOR/ISL), Each Compared to 
Placebo, and the Antiretroviral Activity, Safety, and Tolerability of Open-Label DOR/ISL
Protocol Number: 019-09
Compound Number: MK-8591A
Sponsor Name:
Merck Sharp & Dohme LLC
(hereafter referred to as the Sponsor or MSD)
Legal Registered Address:
126 East Lincoln Avenue
P.O. Box 2000
Rahway, NJ 07065 USA
Regulatory Agency Identifying Number(s):
IND
134,036
EudraCT
2019-000588-26
Approval Date: 26 September 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 09
26-SEP-2022
Merck Sharp & Dohme Corp. underwent an entity name and address change to 
Merck Sharp & Dohme LLC, Rahway, NJ, USA. This conversion resulted only 
in an entity name change and update to the address.
Amendment 08
20-JAN-2022
Given the findings of decreases in CD4+ T-cell and total lymphocyte counts in 
clinical studies evaluating ISL, the protocol is being amended to increase the 
frequency of monitoring of CD4+ T-cell and total lymphocyte counts and to 
specify the management of participants who meet protocol-defined decreases 
in CD4+ T-cell and/or total lymphocyte counts. 
Amendment 07
07-DEC-2021
To increase frequency of monitoring of CD4+ T-cell counts and lymphocyte 
counts and add criteria for management of participants 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 07 were not implemented at 
clinical sites. Amendment 08 supersedes Amendment 07.
Amendment 06
08-JUN-2021
Modified inclusion criteria to clearly characterize the HTE study population as 
individuals with no more than 2 fully active antiretroviral drugs across all 
approved antiretroviral classes.
Amendment 05
17-MAY-2021
Modified inclusion criteria for triple-class resistance and number of active 
ART at study entry. Increased safety monitoring for participants who become 
pregnant and continue study intervention. Increased safety data collection for 
infants born to participants who become pregnant.
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Document
Date of Issue
Overall Rationale
Amendment 04
16-MAR-2021
A country-specific amendment for Russia. As required by the Russian Ministry 
of Health, if a participant becomes pregnant (has a positive serum pregnancy 
test), study intervention must be discontinued.
Amendment 03
29-OCT-2020
Extend Part 2 of the study from 48 weeks to 96 weeks of open-label 
intervention with DOR/ISL + OBT, permit continued administration of study 
intervention in participants who become pregnant, add a discontinuation 
criterion if a participant chooses to breastfeed, and add a Per-Protocol analysis 
to the SAP.
Amendment 02
12-MAY-2020
Allow participants to rescreen following consultation with the Sponsor. The 
lower age limit of 12 years was removed. 
Amendment 01
10-MAR-2020
Assessment of fasting lipid and glucose profiles were added to the protocol to 
comply with the DHHS “Guidelines For the Use of Antiretroviral Agents in 
Adult and Adolescents with HIV.” 
Original Protocol
18-NOV-2019
Not applicable.
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PROTOCOL AMENDMENT SUMMARY OF CHANGES
Amendment: 09
Overall Rationale for the Amendments:
Sponsor underwent an entity name change and update to the address.
Summary of Changes Table:
Section # and Name
Description of Change 
Brief Rationale 
Title Page 
Section 10.1.1 Code of 
Conduct for Clinical Trials
Throughout
Sponsor entity name and address change.
Merck Sharp & Dohme Corp. underwent an entity name 
and address change to Merck Sharp & Dohme LLC, 
Rahway, NJ, USA. This conversion resulted only in an 
entity name change and update to the address.
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Table of Contents
DOCUMENT HISTORY ........................................................................................................3
PROTOCOL AMENDMENT SUMMARY OF CHANGES...............................................5
1
PROTOCOL SUMMARY ............................................................................................15
1.1
Synopsis.................................................................................................................15
1.2
Schema ..................................................................................................................20
1.3
Schedule of Activities (SoA)................................................................................22
1.3.1
Schedule of Activities..................................................................................22
1.3.2
Schedule of Activities – Viremia Confirmation and End of Treatment  
(All Participants Except Those With Specified Decreases in CD4+ T-
cell and/or Total Lymphocyte Counts) ........................................................32
1.3.3
Schedule of Activities for Participants Whose Pregnancy or Postpartum 
Visit(s) Extends Beyond Week 97...............................................................35
1.3.4
Schedule of Activities – Participants With Specified Decreases in CD4+ 
T-cell Counts and/or Total Lymphocyte Counts .........................................37
2
INTRODUCTION..........................................................................................................40
2.1
Study Rationale....................................................................................................40
2.2
Background ..........................................................................................................40
2.2.1
Islatravir.......................................................................................................40
2.2.2
Doravirine ....................................................................................................41
2.2.3
Doravirine/Islatravir.....................................................................................41
2.2.4
Information on Other Study-related Therapy ..............................................42
2.3
Benefit/Risk Assessment......................................................................................42
3
HYPOTHESES, OBJECTIVES, AND ENDPOINTS................................................43
4
STUDY DESIGN............................................................................................................47
4.1
Overall Design......................................................................................................47
4.2
Scientific Rationale for Study Design.................................................................48
4.2.1
Rationale for Endpoints ...............................................................................49
4.2.1.1
Efficacy Endpoints.............................................................................49
4.2.1.1.1
HIV-1 RNA Measurements .....................................................49
4.2.1.2
Patient-reported Outcomes.................................................................49
4.2.1.3
Safety Endpoints................................................................................50
4.2.1.4
Laboratory Markers ...........................................................................50
4.2.1.5
Pharmacokinetic Endpoints ...............................................................50
4.2.1.6
Planned Exploratory Biomarker Research.........................................50
4.2.1.6.1
Planned Genetic Analysis ........................................................50
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4.2.1.7
Future Biomedical Research..............................................................51
4.2.2
Rationale for the Use of Comparator/Placebo .............................................51
4.2.3
Rationale for the Selected Participant Population .......................................51
4.2.4
Rationale for Collecting Race and Ethnicity Data.......................................52
4.2.5
Rationale for Collecting Gender Identity Data ............................................52
4.2.6
Rationale for Infant Safety Data Collection.................................................53
4.2.7
Rationale for Continuing Study Intervention During Pregnancy ................53
4.3
Justification for Dose...........................................................................................53
4.4
Beginning and End of Study Definition .............................................................54
4.4.1
Clinical Criteria for Early Study Termination .............................................55
5
STUDY POPULATION ................................................................................................55
5.1
Inclusion Criteria.................................................................................................55
5.2
Exclusion Criteria................................................................................................57
5.3
Lifestyle Considerations......................................................................................59
5.4
Screen Failures.....................................................................................................59
5.5
Participant Replacement Strategy......................................................................59
6
STUDY INTERVENTION............................................................................................59
6.1
Study Intervention(s) Administered...................................................................59
6.2
Preparation/Handling/Storage/Accountability .................................................62
6.2.1
Dose Preparation..........................................................................................62
6.2.2
Handling, Storage, and Accountability........................................................62
6.3
Measures to Minimize Bias: Randomization and Blinding..............................63
6.3.1
Intervention Assignment..............................................................................63
6.3.2
Stratification.................................................................................................63
6.3.3
Blinding........................................................................................................63
6.4
Study Intervention Compliance..........................................................................64
6.5
Concomitant Therapy..........................................................................................64
6.5.1
Rescue Medications and Supportive Care ...................................................66
6.6
Dose Modification (Escalation/Titration/Other)...............................................66
6.7
Intervention After the End of the Study............................................................66
6.8
Clinical Supplies Disclosure................................................................................66
7
DISCONTINUATION OF STUDY INTERVENTION AND PARTICIPANT 
WITHDRAWAL............................................................................................................67
7.1
Discontinuation of Study Intervention...............................................................67
7.2
Participant Withdrawal From the Study...........................................................68
7.3
Lost to Follow-up .................................................................................................68
8
STUDY ASSESSMENTS AND PROCEDURES........................................................68
8.1
Administrative and General Procedures ...........................................................69
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8.1.1
Informed Consent/Assent.............................................................................69
8.1.1.1
General Informed Consent/Assent.....................................................69
8.1.1.2
Consent/Assent and Collection of Specimens for Future 
Biomedical Research .........................................................................70
8.1.1.3
Consent/Assent for Postnatal Infant Safety Data Collection 
Through One Year of Age .................................................................70
8.1.1.4
Consent/Assent for Continuation of Study Intervention During 
Pregnancy...........................................................................................70
8.1.2
Inclusion/Exclusion Criteria ........................................................................71
8.1.3
Participant Identification Card.....................................................................71
8.1.4
Medical History ...........................................................................................71
8.1.5
Prior and Concomitant Medications Review...............................................71
8.1.5.1
Prior Medications...............................................................................71
8.1.5.2
Concomitant Medications..................................................................71
8.1.6
Assignment of Screening Number...............................................................72
8.1.7
Assignment of Treatment/Randomization Number.....................................72
8.1.8
Study Intervention Administration ..............................................................72
8.1.8.1
Timing of Dose Administration.........................................................72
8.1.9
Discontinuation and Withdrawal .................................................................73
8.1.9.1
Withdrawal From Future Biomedical Research ................................73
8.1.10
Participant Blinding/Unblinding..................................................................74
8.1.11
Calibration of Equipment.............................................................................74
8.1.12
Administration of Patient Questionnaires....................................................75
8.2
Efficacy Assessments ...........................................................................................75
8.2.1
HIV-1 RNA..................................................................................................75
8.2.2
Management of Study Participants with Viremia........................................75
8.2.2.1
Viremia Confirmation........................................................................75
8.2.2.2
Viral Drug Resistance Testing...........................................................76
8.2.3
T- and B- Lymphocyte and Natural Killer Cell Profile (TBNK).................76
8.3
Safety Assessments...............................................................................................76
8.3.1
Physical Examinations.................................................................................76
8.3.2
Vital Signs....................................................................................................77
8.3.3
Electrocardiograms ......................................................................................77
8.3.4
Confirmation of Menarche, Contraception, and Pregnancy Testing ...........77
8.3.5
Clinical Safety Laboratory Assessments .....................................................78
8.3.6
HBV Assessments........................................................................................78
8.3.7
Tobacco and Alcohol Assessments..............................................................78
8.4
Adverse Events (AEs), Serious Adverse Events (SAEs), and Other 
Reportable Safety Events ....................................................................................78
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8.4.1
Time Period and Frequency for Collecting AE, SAE, and Other 
Reportable Safety Event Information ..........................................................79
8.4.2
Method of Detecting AEs, SAEs, and Other Reportable Safety Events......81
8.4.3
Follow-up of AE, SAE, and Other Reportable Safety Event Information...81
8.4.4
Regulatory Reporting Requirements for SAE .............................................81
8.4.5
Pregnancy and Exposure During Breastfeeding ..........................................82
8.4.6
Disease-related Events and/or Disease-related Outcomes Not Qualifying 
as AEs or SAEs............................................................................................82
8.4.7
Events of Clinical Interest (ECIs)................................................................82
8.5
Treatment of Overdose........................................................................................83
8.6
Pharmacokinetics.................................................................................................83
8.6.1
Blood Collection for Plasma ISL and DOR.................................................83
8.7
Pharmacodynamics..............................................................................................84
8.8
Biomarkers ...........................................................................................................84
8.8.1
Planned Genetic Analysis Sample Collection..............................................84
8.8.2
Inflammation................................................................................................84
8.8.3
Fasting Lipid and Metabolic Profiles...........................................................85
8.9
Future Biomedical Research Sample Collection...............................................85
8.10
Health Economics Medical Resource Utilization and Health Economics.......85
8.11
Visit Requirements...............................................................................................85
8.11.1
Screening/Rescreening.................................................................................85
8.11.2
Run-in Period...............................................................................................86
8.11.3
Treatment Period..........................................................................................87
8.11.3.1
Fasting................................................................................................87
8.11.3.2
Double-blind (Part 1).........................................................................87
8.11.3.3
Open-label (Part 2).............................................................................87
8.11.3.4
Optional Nurse Visits and Telephone Visits......................................87
8.11.3.5
End of Study Week 97 Visit ..............................................................88
8.11.4
Participants Who Discontinue Study Intervention.......................................88
8.11.4.1
Early Discontinuation of Treatment...................................................89
8.11.4.2
End of Treatment Follow-Up Visit....................................................89
8.11.5
Viremia Confirmation..................................................................................89
8.11.6
Management of Participants with Decreases in CD4+ T-cell Counts 
and/or Total Lymphocyte Counts ................................................................89
8.11.6.1
Participants Whose CD4+ T-cell Count and/or Total Lymphocyte 
Count Decreases Meet Criteria for Events of Clinical Interest 
While on Study Intervention..............................................................89
8.11.6.2
Participants Discontinued from Study Intervention Due to
Decreased CD4+ T-cell Count and/or Total Lymphocyte Count......90
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8.11.6.3
Participants Discontinued from Study Intervention For Other 
Reasons AND Have Decreases in CD4+ T-cell Count and/or 
Total Lymphocyte Count...................................................................90
8.11.7
Clinical Management of Participants Who Become Pregnant.....................90
8.11.7.1
Continuing Study Intervention...........................................................91
8.11.7.2
Discontinuing Study Intervention......................................................92
8.11.7.3
Participants Who Choose to Breastfeed.............................................92
8.11.7.4
Infant Safety Data Collection.............................................................92
8.11.7.4.1
Schedule of Activities: Infant Safety Data Collection.............93
9
STATISTICAL ANALYSIS PLAN .............................................................................93
9.1
Statistical Analysis Plan Summary.....................................................................93
9.2
Responsibility for Analyses/In-house Blinding .................................................96
9.3
Hypotheses/Estimation ........................................................................................96
9.4
Analysis Endpoints...............................................................................................96
9.4.1
Efficacy/Pharmacokinetics Endpoints .........................................................96
9.4.1.1
Primary Efficacy Endpoint ................................................................96
9.4.1.2
Secondary Efficacy Endpoints...........................................................97
9.4.1.3
Pharmacokinetics Endpoints..............................................................98
9.4.2
Safety Endpoints..........................................................................................98
9.4.3
Patient-reported Outcome Endpoints...........................................................99
9.5
Analysis Populations............................................................................................99
9.5.1
Efficacy Analysis Populations.....................................................................99
9.5.1.1
Full Analysis Set................................................................................99
9.5.1.2
Per-protocol Analysis Set ..................................................................99
9.5.1.3
Resistance Analysis Subset..............................................................100
9.5.2
Safety Analysis Population........................................................................100
9.6
Statistical Methods.............................................................................................100
9.6.1
Statistical Methods for Efficacy Analyses.................................................100
9.6.2
Statistical Methods for Safety Analyses ....................................................107
9.6.3
Summaries of Baseline Characteristics, Demographic, and other 
Analyses.....................................................................................................108
9.6.3.1
Demographic and Baseline Characteristics .....................................108
9.7
Interim Analyses ................................................................................................108
9.7.1
Safety Monitoring......................................................................................109
9.7.2
Futility Monitoring.....................................................................................109
9.7.3
Interim Analysis for Potential Marketing Authorization Application.......110
9.7.4
Interim Analysis for Testing the Primary Hypothesis ...............................110
9.8
Multiplicity .........................................................................................................111
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9.9
Sample Size and Power Calculations ...............................................................111
9.9.1
Sample Size and Power for Efficacy Analyses..........................................111
9.9.1.1
Futility Criteria and Superiority Testing..........................................111
9.9.1.2
Evaluation of the Primary Hypotheses ............................................112
9.9.2
Sample Size and Power for Safety Analyses .............................................113
9.10
Subgroup Analyses.............................................................................................115
9.11
Compliance (Medication Adherence)...............................................................115
9.12
Extent of Exposure.............................................................................................116
10
SUPPORTING DOCUMENTATION AND OPERATIONAL 
CONSIDERATIONS...................................................................................................117
10.1
Appendix 1: Regulatory, Ethical, and Study Oversight Considerations......117
10.1.1
Code of Conduct for Clinical Trials...........................................................117
10.1.2
Financial Disclosure...................................................................................119
10.1.3
Data Protection...........................................................................................119
10.1.3.1
Confidentiality of Data ....................................................................120
10.1.3.2
Confidentiality of Participant Records.............................................120
10.1.3.3
Confidentiality of IRB/IEC Information..........................................120
10.1.4
Committees Structure.................................................................................120
10.1.4.1
Scientific Advisory Committee (SAC)............................................120
10.1.4.2
Executive Oversight Committee......................................................121
10.1.4.3
External Data Monitoring Committee .............................................121
10.1.5
Publication Policy......................................................................................121
10.1.6
Compliance with Study Registration and Results Posting Requirements .121
10.1.7
Compliance with Law, Audit, and Debarment ..........................................122
10.1.8
Data Quality Assurance .............................................................................122
10.1.9
Source Documents .....................................................................................123
10.1.10
Study and Site Closure...............................................................................124
10.2
Appendix 2: Clinical Laboratory Tests............................................................125
10.3
Appendix 3: Adverse Events: Definitions and Procedures for Recording, 
Evaluating, Follow-up, and Reporting.............................................................132
10.3.1
Definition of AE ........................................................................................132
10.3.2
Definition of SAE ......................................................................................133
10.3.3
Additional Events Reported.......................................................................134
10.3.4
Recording AE and SAE .............................................................................134
10.3.5
Reporting of AEs, SAEs, and Other Reportable Safety Events to the 
Sponsor ......................................................................................................138
10.4
Appendix 4: Device Events, Adverse Device Events, and Medical Device 
Incidents: Definitions, Collection, and Documentation..................................139
10.5
Appendix 5: Contraceptive Guidance..............................................................140
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10.5.1
Definitions..................................................................................................140
10.5.2
Contraception Requirements......................................................................142
10.6
Appendix 6: Collection and Management of Specimens for Future 
Biomedical Research..........................................................................................143
10.7
Appendix 7: Country-specific Requirements..................................................148
10.7.1
Country-specific Request for Russia .........................................................148
10.7.2
Country-specific Request for Australia .....................................................148
10.7.3
Country-specific Request for Germany .....................................................148
10.7.4
Country-specific Request for Ukraine .......................................................148
10.8
Appendix 8: Calculation of Creatinine Clearance..........................................149
10.9
Appendix 9: Abbreviations ...............................................................................150
11
REFERENCES.............................................................................................................153
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LIST OF TABLES
Table 1
Laboratory Exclusion Criteria....................................................................58
Table 2
Study Interventions....................................................................................60
Table 3
Prohibited Therapies ..................................................................................65
Table 4
Reporting Time Periods and Time Frames for Adverse Events and 
Other Reportable Safety Events.................................................................80
Table 5
Collection of Population PK Samples........................................................83
Table 6
Collection of Population PK Samples During Pregnancy and 
Postpartum .................................................................................................92
Table 7
Definitions of Study Time Points ............................................................101
Table 8
Analysis Strategy for Key Efficacy Variables.........................................106
Table 9
Analysis Strategy for Safety Parameters..................................................108
Table 10
Futility Boundary That Would Trigger Ad Hoc eDMC Review 
Corresponding to Current Possible Sample Size in DOR/ISL Group .....110
Table 11
Probability of Meeting Futility Criteria and the Overall Study Power 
for Various Underlying True Response Rates Assuming the Response 
Rate is 3% or 10% for Placebo Recipients ..............................................112
Table 12
Power (%) to Establish Superiority† Under Various Response Rate 
Assumptions (20 DOR/ISL Recipients and 20 Placebo Recipients) .......113
Table 13
Probability of Observing At Least One Event in a Treatment Group for 
a Given Sample Size and a Variety of Underlying AE Incidence Rates .113
Table 14
Estimate of Incidence of AEs and 95% Upper Confidence Bound 
Based on Hypothetical Numbers of Participants with AEs .....................114
Table 15
Protocol-required Laboratory Assessments.............................................125
Table 16
Blood Volume by Visit............................................................................129
Table 17
Blood Volumes: Participants Whose Pregnancy or Postpartum Visit(s) 
Extends Beyond Week 97........................................................................131
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LIST OF FIGURES
Figure 1
Study Schema and Treatment Plan ............................................................20
Figure 2
HIV-1 RNA Study Entry Eligibility Schema.............................................21
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1
PROTOCOL SUMMARY
1.1
Synopsis
Protocol Title: A Phase 3, Randomized, Clinical Study in HIV-1-Infected Heavily 
Treatment-Experienced Participants Evaluating the Antiretroviral Activity of Blinded 
Islatravir (ISL), Doravirine (DOR), and Doravirine/Islatravir (DOR/ISL), Each Compared to 
Placebo, and the Antiretroviral Activity, Safety, and Tolerability of Open-Label DOR/ISL
Short Title: DOR/ISL in heavily treatment-experienced participants
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:
The following objectives will be evaluated in HTE adult participants and in pediatric 
participants weighing ≥35 kg with pre-study HIV-1 RNA ≥500 copies/mL and currently on 
failing ART. 
Primary Objectives
Primary Endpoints

To evaluate the antiretroviral activity of 
DOR/ISL compared to placebo, each given in 
combination with failing ART as assessed by the 
percentage of participants achieving ≥0.5 log10 
decrease in HIV-1 RNA from study baseline 
(Day 1) to Day 8 (Part 1).
Hypothesis: The percentage of participants receiving 
DOR/ISL and achieving ≥0.5 log10 decrease in 
HIV-1 RNA from study baseline (Day 1) to Day 8 is 
superior to placebo, each given in combination with 
failing ART.

HIV-1 RNA

To evaluate the safety and tolerability of 
DOR/ISL as assessed by review of the 
accumulated safety data through Week 25 and 
Week 49.

AEs

AEs leading to discontinuation 
of study intervention
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Primary Objectives
Primary Endpoints
Secondary Objectives
Secondary Endpoints

To evaluate the safety and tolerability of 
DOR/ISL as assessed by review of the 
accumulated safety data through Week 97.

AEs

AEs leading to discontinuation 
of study intervention

To evaluate the antiretroviral activity of ISL and 
DOR, each compared to placebo, when each is 
given in combination with failing ART, as 
assessed by the percentage of participants 
achieving ≥0.5 log10 decrease in HIV-1 RNA 
from study baseline (Day 1) to Day 8 (Part 1).

HIV-1 RNA

To further evaluate the antiretroviral activity of 
DOR/ISL, ISL, and DOR each compared to 
placebo, when each is given in combination with 
failing ART (Part 1) as assessed by:
-
mean change in HIV-1 RNA from study 
baseline (Day 1) to Day 8
-
percentage of participants achieving ≥1.0 
log10 decrease in HIV-1 RNA from study 
baseline (Day 1) to Day 8

HIV-1 RNA

To further evaluate the antiretroviral activity of 
DOR/ISL compared to ISL and DOR, when each 
is given in combination with failing ART (Part 
1) as assessed by:
-
percentage of participants achieving ≥0.5 
log10 decrease in HIV-1 RNA from study 
baseline (Day 1) to Day 8
-
mean change in HIV-1 RNA from study 
baseline (Day 1) to Day 8
-
percentage of participants achieving ≥1.0 
log10 decrease in HIV-1 RNA from study 
baseline (Day 1) to Day 8

HIV-1 RNA
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Primary Objectives
Primary Endpoints

To evaluate the antiretroviral activity of 
DOR/ISL + OBT in Part 2 as assessed by the 
following at Week 25, Week 49, and Week 97 
compared to study baseline (Day 1) and Part 2 
baseline (Day 8):
-
percentage of participants achieving ≥0.5 
log10 decrease in HIV-1 RNA
-
percentage of participants achieving ≥1.0 
log10 decrease in HIV-1 RNA
-
mean change in HIV-1 RNA
-
percentage of participants achieving HIV-1 
RNA <200 copies/mL
-
percentage of participants achieving HIV-1 
RNA <50 copies/mL
-
percentage of participants achieving HIV-1 
RNA <40 copies/mL

HIV-1 RNA

To evaluate the development of viral drug 
resistance to DOR, ISL, or components of OBT 
through the study duration (Part 1 and Part 2).

Viral resistance-associated 
substitutions

To evaluate the impact of study baseline (Day 1) 
antiviral resistance on virologic outcome at 
Week 25, Week 49, and Week 97 (Part 2).

Viral resistance-associated 
substitutions

HIV-1 RNA

To evaluate the change in CD4+ T-cell counts 
from both study baseline (Day 1) and Part 2 
baseline (Day 8) at Week 25, Week 49, and 
Week 97 (Part 2).

CD4+ T-cell count
Overall Design:
Study Phase
Phase 3
Primary Purpose
Treatment
Indication
HIV-1 infection
Population
HTE adult participants and pediatric participants weighing 
≥35 kg currently on failing ART with pre-study HIV-1
RNA ≥500 copies/mL
Study Type
Interventional
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Intervention Model
Parallel followed by single-group
This is a multi-site study.
Type of Control
Placebo control (Part 1 only)
Study Blinding
Double-blind double-dummy (Part 1) followed by 
unblinded open-label (Part 2)
Masking
Sponsor (Part 1 only)
Investigator (Part 1 only)
Participant (Part 1 only)
Estimated Duration of Study
The Sponsor estimates that the study will require 
approximately 3 years from the time the first participant 
(or their legally acceptable representative) provides 
documented informed consent/assent until the last 
participant’s last study-related contact.
Number of Participants:
Approximately 100 participants will be randomized.  
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Intervention Groups and Duration:
Interven-
tion 
Groups
Intervention 
Group Name
Drug
Dose 
Strength
Dose 
Frequency
Route of 
Administration
Treatment 
Period
Use
Double-Blind Period (Part 1)
Group 1
ISL + ART
0.75 mg
QD
Oral
Day 1 to 
Day 7
Experimental
Group 2
DOR + 
ART
100 mg
QD
Oral
Day 1 to 
Day 7
Experimental
Group 3
DOR/ISL + 
ART
100 mg 
DOR/0.75 mg
ISL
QD
Oral
Day 1 to 
Day 7
Experimental
Group 4
Placebo + 
ART
0 mg
QD
Oral
Day 1 to 
Day 7
Placebo 
comparison
Open-Label Period (Part 2)
Open-Label
DOR/ISL + 
OBT
100 mg 
DOR/0.75 mg
ISL
QD
Oral
Day 8 
through 
Week 97a
Experimental
Abbreviations: ART=antiretroviral therapy; DOR=doravirine; ISL=islatravir; OBT=optimized background 
therapy; QD=once daily.
The Sponsor will not provide ART during Part 1 or OBT during Part 2. Participants will provide their own 
medications.
a
For participants who are pregnant at the last regularly scheduled study visit (Week 97), study intervention will 
be dispensed at Week 97. In addition, their visit schedule will be extended through the duration of the 
pregnancy and study intervention will be dispensed at Weeks 109, 121, and 133, as applicable.
Total 
Number
5
Duration of 
Participa-
tion
Each participant will participate in the study for approximately 112 weeks
from the time the participant provides documented informed consent/assent
through the final contact. After a screening period of up to 60 days and a 
Run-in Period prior to randomization, each participant will receive assigned 
double-blind intervention for 7 days in Part 1 and open-label intervention for 
approximately 96 weeks in Part 2. Participants who discontinue study 
intervention or who become pregnant will be followed as described in the 
protocol.
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Study Governance Committees:
Steering Committee
No
Executive Oversight Committee
Yes
Data Monitoring Committee
Yes
Clinical Adjudication Committee
No
Scientific Advisory Committee
Yes
Study governance considerations are outlined in Appendix 1.
Study Accepts Healthy Volunteers: No
A list of abbreviations used in this document can be found in Appendix 9.
1.2
Schema
The study design is depicted in Figure 1.
Figure 1
Study Schema and Treatment Plan
ART=antiretroviral therapy; DOR=doravirine; HIV-1=Human Immunodeficiency Virus Type 1; ISL=islatravir; 
n=number of participants per group; OBT=optimized background therapy; QD=once daily; RNA=ribonucleic 
acid.
*HIV-1 RNA testing will be repeated during the Run-in Period to confirm eligibility for randomization (defined 
as HIV-1 RNA ≥500 copies/mL). Participants with ≥500 copies/mL on confirmation testing but with ≥0.5 log10
decline in HIV-1 RNA from the Screening Visit (Visit 1) will have an additional HIV-1 RNA confirmation test 
within 7 to 14 days. Participants with a further decline in HIV-1 RNA ≥0.3 log10 compared to the previous 
confirmation test will be excluded from the study.
Note: Participants are treated with open-label DOR/ISL + OBT for 96 weeks in Part 2.
08BJ8V

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Figure 2
HIV-1 RNA Study Entry Eligibility Schema
HIV-1=Human Immunodeficiency Virus Type 1; RNA=ribonucleic acid.
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1.3
Schedule of Activities (SoA)
1.3.1
Schedule of Activities
Study 
Period
Screening/Run-In Period
Intervention
Notes
Screening
HIV-1 
Confirmation 
Visitc
Repeat HIV-1 
Confirmation 
Visitd
Double-blind 
(Part 1)
Open-label 
(Part 2)
Visit 3 is an additional HIV-1 
RNA confirmation test for 
participants with 500 
copies/mL on confirmation 
testing but with 0.5 log10
decline in HIV-1 RNA from 
the Screening Visit (Visit 1)
Visit 
Number
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
Each visit should be 
calculated from date of 
Randomization (Day 1). A 
visiting nurse may be used for 
visits after randomization per 
Section 8.11.3.4.
Scheduled 
Day/Week
Screen
NA
NA
Day 1 
(Fasting) 
Day 8
(Fasting)
TW3
TW7
TW13
TW19
TW25
TW37
TW49
(Fasting)
TW61
TW73 
(Fasting)
TW85
TW97 
(Fasting)
Visit Window
≤60 daysa
≤10 days 
prior to
Day 1
7-14 days 
after 
Visit 2
NA
+3 days
±7 days
Adherence to the visit window 
is critical for study 
intervention resupply. 
Randomization of eligible 
participants must occur within 
10 days of Visit 2 (or Visit 3, 
if required).
Administrative Procedures
Informed 
Consent/Assent
X
Informed 
Consent/Assent 
for Future 
Biomedical 
Research
X
Informed 
Consent/Assent
for Study 
Intervention 
During 
Pregnancy
<-------------------------------------X------------------------------------>
Obtain upon confirmation of 
pregnancy if participant wants 
to continue receiving study 
intervention.
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Study 
Period
Screening/Run-In Period
Intervention
Notes
Screening
HIV-1 
Confirmation 
Visitc
Repeat HIV-1 
Confirmation 
Visitd
Double-blind 
(Part 1)
Open-label 
(Part 2)
Visit 3 is an additional HIV-1 
RNA confirmation test for 
participants with 500 
copies/mL on confirmation 
testing but with 0.5 log10
decline in HIV-1 RNA from 
the Screening Visit (Visit 1)
Visit 
Number
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
Each visit should be 
calculated from date of 
Randomization (Day 1). A 
visiting nurse may be used for 
visits after randomization per 
Section 8.11.3.4.
Scheduled 
Day/Week
Screen
NA
NA
Day 1 
(Fasting) 
Day 8
(Fasting)
TW3
TW7
TW13
TW19
TW25
TW37
TW49
(Fasting)
TW61
TW73 
(Fasting)
TW85
TW97 
(Fasting)
Visit Window
≤60 daysa
≤10 days 
prior to
Day 1
7-14 days 
after 
Visit 2
NA
+3 days
±7 days
Adherence to the visit window 
is critical for study 
intervention resupply. 
Randomization of eligible 
participants must occur within 
10 days of Visit 2 (or Visit 3, 
if required).
Collect and enter 
data from 
prenatal provider
<-------------------------------------X------------------------------------>
For female participants who 
become pregnant and consent 
to continue DOR/ISL, obtain 
relevant prenatal clinical & 
laboratory data to monitor the 
safety of the mother & fetus 
per Section 8.11.7.
Inclusion/Exclus
ion Criteria
X
X
X
X
Review prior to randomization 
on Day 1 to confirm no 
changes in eligibility.
Participant 
Identification 
Card
X
X
At the time of randomization, 
site personnel will add the 
randomization number to the 
participant identification card.
Medical History
X
Prior/
Concomitant 
Medication 
Review
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Register study 
visit in IRT
X
X
X
X
X
X
X
X
X
X
X
X
X
X
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Study 
Period
Screening/Run-In Period
Intervention
Notes
Screening
HIV-1 
Confirmation 
Visitc
Repeat HIV-1 
Confirmation 
Visitd
Double-blind 
(Part 1)
Open-label 
(Part 2)
Visit 3 is an additional HIV-1 
RNA confirmation test for 
participants with 500 
copies/mL on confirmation 
testing but with 0.5 log10
decline in HIV-1 RNA from 
the Screening Visit (Visit 1)
Visit 
Number
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
Each visit should be 
calculated from date of 
Randomization (Day 1). A 
visiting nurse may be used for 
visits after randomization per 
Section 8.11.3.4.
Scheduled 
Day/Week
Screen
NA
NA
Day 1 
(Fasting) 
Day 8
(Fasting)
TW3
TW7
TW13
TW19
TW25
TW37
TW49
(Fasting)
TW61
TW73 
(Fasting)
TW85
TW97 
(Fasting)
Visit Window
≤60 daysa
≤10 days 
prior to
Day 1
7-14 days 
after 
Visit 2
NA
+3 days
±7 days
Adherence to the visit window 
is critical for study 
intervention resupply. 
Randomization of eligible 
participants must occur within 
10 days of Visit 2 (or Visit 3, 
if required).
Intervention 
Randomization
X
All procedures should be 
completed prior to dose on 
Day 1.
Randomization should occur 
within 10 days of 
confirmation of HIV-1 RNA 
eligibility.
Dispense study 
intervention 
using IRT
X
X
X
X
X
X
X
X
X
X
X
X
Dispense DOR/ISL at Week 
97 to any pregnant participant 
whose pregnancy or 
postpartum visit(s) extend 
beyond Week 97. See Section 
1.3.3.
Evaluation to 
receive 
continued study 
intervention
X
See Section 6.7
Study 
intervention 
compliance 
review
X
X
X
X
X
X
X
X
X
X
X
X
Reconcile doses and assess 
study intervention 
compliance.
08BJ8V

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26-SEP-2022
Study 
Period
Screening/Run-In Period
Intervention
Notes
Screening
HIV-1 
Confirmation 
Visitc
Repeat HIV-1 
Confirmation 
Visitd
Double-blind 
(Part 1)
Open-label 
(Part 2)
Visit 3 is an additional HIV-1 
RNA confirmation test for 
participants with 500 
copies/mL on confirmation 
testing but with 0.5 log10
decline in HIV-1 RNA from 
the Screening Visit (Visit 1)
Visit 
Number
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
Each visit should be 
calculated from date of 
Randomization (Day 1). A 
visiting nurse may be used for 
visits after randomization per 
Section 8.11.3.4.
Scheduled 
Day/Week
Screen
NA
NA
Day 1 
(Fasting) 
Day 8
(Fasting)
TW3
TW7
TW13
TW19
TW25
TW37
TW49
(Fasting)
TW61
TW73 
(Fasting)
TW85
TW97 
(Fasting)
Visit Window
≤60 daysa
≤10 days 
prior to
Day 1
7-14 days 
after 
Visit 2
NA
+3 days
±7 days
Adherence to the visit window 
is critical for study 
intervention resupply. 
Randomization of eligible 
participants must occur within 
10 days of Visit 2 (or Visit 3, 
if required).
ART/OBT 
compliance 
review
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Completion of 
participant 
questionnaire 
(FAHI)
X
X
X
X
Administered to participants 
≥18 years of age at the time of 
consent and prior to being 
seen by investigator and 
discussions about medical 
conditions or test results.
Efficacy/Immunogenicity Procedures
Plasma HIV-1 
RNA 
Quantification 
(Real Time 
PCR) 
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
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 8.11.6 and Section 
1.3.4.
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Study 
Period
Screening/Run-In Period
Intervention
Notes
Screening
HIV-1 
Confirmation 
Visitc
Repeat HIV-1 
Confirmation 
Visitd
Double-blind 
(Part 1)
Open-label 
(Part 2)
Visit 3 is an additional HIV-1 
RNA confirmation test for 
participants with 500 
copies/mL on confirmation 
testing but with 0.5 log10
decline in HIV-1 RNA from 
the Screening Visit (Visit 1)
Visit 
Number
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
Each visit should be 
calculated from date of 
Randomization (Day 1). A 
visiting nurse may be used for 
visits after randomization per 
Section 8.11.3.4.
Scheduled 
Day/Week
Screen
NA
NA
Day 1 
(Fasting) 
Day 8
(Fasting)
TW3
TW7
TW13
TW19
TW25
TW37
TW49
(Fasting)
TW61
TW73 
(Fasting)
TW85
TW97 
(Fasting)
Visit Window
≤60 daysa
≤10 days 
prior to
Day 1
7-14 days 
after 
Visit 2
NA
+3 days
±7 days
Adherence to the visit window 
is critical for study 
intervention resupply. 
Randomization of eligible 
participants must occur within 
10 days of Visit 2 (or Visit 3, 
if required).
Blood (plasma) 
for HIV-1 drug 
resistance
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Testing performed via central 
laboratory at Screening, Day 
1, Day 8, and thereafter on 
samples with HIV-1 RNA 
≥200 copies/mL for 
participants who never 
suppressed at Week 25, Week 
49, and Week 97 and those 
that were collected either to 
confirm viremia after 
suppression (VL<50 
copies/mL) or at 
discontinuation.
08BJ8V

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Study 
Period
Screening/Run-In Period
Intervention
Notes
Screening
HIV-1 
Confirmation 
Visitc
Repeat HIV-1 
Confirmation 
Visitd
Double-blind 
(Part 1)
Open-label 
(Part 2)
Visit 3 is an additional HIV-1 
RNA confirmation test for 
participants with 500 
copies/mL on confirmation 
testing but with 0.5 log10
decline in HIV-1 RNA from 
the Screening Visit (Visit 1)
Visit 
Number
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
Each visit should be 
calculated from date of 
Randomization (Day 1). A 
visiting nurse may be used for 
visits after randomization per 
Section 8.11.3.4.
Scheduled 
Day/Week
Screen
NA
NA
Day 1 
(Fasting) 
Day 8
(Fasting)
TW3
TW7
TW13
TW19
TW25
TW37
TW49
(Fasting)
TW61
TW73 
(Fasting)
TW85
TW97 
(Fasting)
Visit Window
≤60 daysa
≤10 days 
prior to
Day 1
7-14 days 
after 
Visit 2
NA
+3 days
±7 days
Adherence to the visit window 
is critical for study 
intervention resupply. 
Randomization of eligible 
participants must occur within 
10 days of Visit 2 (or Visit 3, 
if required).
Whole Blood for 
Proviral DNA 
Resistance 
Testing
X
X
X
X
Testing to be performed via 
central laboratory at a) 
Screening Visit for all 
participants and b) on
postrandomization samples
with HIV-1 RNA ≥200 
copies/mL at Week 25, Week 
49, and Week 97 and samples
collected either to confirm 
viremia after suppression (VL 
<50 copies/mL) or at 
discontinuation.
Safety Procedures
Full physical 
examination
X
Height
X
X
X
Weight
X
X
X
X
X
X
X
X
Directed 
physical 
examination
X
X
X
X
X
X
X
X
X
X
X
X
X
Vital Signs
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Includes pulse, bp, temp, and 
rr.
12-lead ECG
X
May be read locally.
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Study 
Period
Screening/Run-In Period
Intervention
Notes
Screening
HIV-1 
Confirmation 
Visitc
Repeat HIV-1 
Confirmation 
Visitd
Double-blind 
(Part 1)
Open-label 
(Part 2)
Visit 3 is an additional HIV-1 
RNA confirmation test for 
participants with 500 
copies/mL on confirmation 
testing but with 0.5 log10
decline in HIV-1 RNA from 
the Screening Visit (Visit 1)
Visit 
Number
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
Each visit should be 
calculated from date of 
Randomization (Day 1). A 
visiting nurse may be used for 
visits after randomization per 
Section 8.11.3.4.
Scheduled 
Day/Week
Screen
NA
NA
Day 1 
(Fasting) 
Day 8
(Fasting)
TW3
TW7
TW13
TW19
TW25
TW37
TW49
(Fasting)
TW61
TW73 
(Fasting)
TW85
TW97 
(Fasting)
Visit Window
≤60 daysa
≤10 days 
prior to
Day 1
7-14 days 
after 
Visit 2
NA
+3 days
±7 days
Adherence to the visit window 
is critical for study 
intervention resupply. 
Randomization of eligible 
participants must occur within 
10 days of Visit 2 (or Visit 3, 
if required).
Confirmation of 
menarche status 
(females only)
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Not required once menarche 
has been confirmed.
Contraception 
Use 
Confirmation 
(WOCBP only)
X
X
X
X
X
X
X
X
X
X
X
X
X
To be done per local 
guidelines.
Serum 
Pregnancy Test 
(β-hCG; 
WOCBP only)
X
Urine Pregnancy 
Test (WOCBP 
only)
X
X
X
X
X
X
X
X
X
X
X
X
X
Confirm with serum test if 
urine test is positive. If 
confirmatory serum test is
positive, participants will be 
managed per Section 8.11.7
and safety of her infant 
collected per Section 
8.11.7.4.1.
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Study 
Period
Screening/Run-In Period
Intervention
Notes
Screening
HIV-1 
Confirmation 
Visitc
Repeat HIV-1 
Confirmation 
Visitd
Double-blind 
(Part 1)
Open-label 
(Part 2)
Visit 3 is an additional HIV-1 
RNA confirmation test for 
participants with 500 
copies/mL on confirmation 
testing but with 0.5 log10
decline in HIV-1 RNA from 
the Screening Visit (Visit 1)
Visit 
Number
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
Each visit should be 
calculated from date of 
Randomization (Day 1). A 
visiting nurse may be used for 
visits after randomization per 
Section 8.11.3.4.
Scheduled 
Day/Week
Screen
NA
NA
Day 1 
(Fasting) 
Day 8
(Fasting)
TW3
TW7
TW13
TW19
TW25
TW37
TW49
(Fasting)
TW61
TW73 
(Fasting)
TW85
TW97 
(Fasting)
Visit Window
≤60 daysa
≤10 days 
prior to
Day 1
7-14 days 
after 
Visit 2
NA
+3 days
±7 days
Adherence to the visit window 
is critical for study 
intervention resupply. 
Randomization of eligible 
participants must occur within 
10 days of Visit 2 (or Visit 3, 
if required).
Hepatitis 
Serology 
(HBsAg, 
HBsAb, Anti-
HBc, HCV Ab)
X
X
Participants who do not 
demonstrate immunity to 
HBV should be encouraged to 
be vaccinated against HBV.
HBV DNA
X
X
HCV RNA
X
X
HIV-1 & -2 
Serology
X
Hematology
X
X
X
X
X
X
X
X
X
X
X
Decreases in total lymphocyte 
counts that meet ECI criteria 
should be managed per 
Section 8.11.6 and Section 
1.3.4.
PT/INR
X
Urinalysis
X
X
X
X
X
X
X
X
X
X
X
Fasting 
Lipid/Glucose
X
X
X
X
X
If abnormal profile at Day 8, 
repeat the abnormal test at 
TW 25
Chemistry
X
X
X
X
X
X
X
X
X
X
X
Review of 
Adverse Events
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
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Study 
Period
Screening/Run-In Period
Intervention
Notes
Screening
HIV-1 
Confirmation 
Visitc
Repeat HIV-1 
Confirmation 
Visitd
Double-blind 
(Part 1)
Open-label 
(Part 2)
Visit 3 is an additional HIV-1 
RNA confirmation test for 
participants with 500 
copies/mL on confirmation 
testing but with 0.5 log10
decline in HIV-1 RNA from 
the Screening Visit (Visit 1)
Visit 
Number
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
Each visit should be 
calculated from date of 
Randomization (Day 1). A 
visiting nurse may be used for 
visits after randomization per 
Section 8.11.3.4.
Scheduled 
Day/Week
Screen
NA
NA
Day 1 
(Fasting) 
Day 8
(Fasting)
TW3
TW7
TW13
TW19
TW25
TW37
TW49
(Fasting)
TW61
TW73 
(Fasting)
TW85
TW97 
(Fasting)
Visit Window
≤60 daysa
≤10 days 
prior to
Day 1
7-14 days 
after 
Visit 2
NA
+3 days
±7 days
Adherence to the visit window 
is critical for study 
intervention resupply. 
Randomization of eligible 
participants must occur within 
10 days of Visit 2 (or Visit 3, 
if required).
Pharmacokinetics
Blood (plasma) 
for DOR and 
ISL PK
X
X
X
X
X
X
X
At Weeks 25 and 49, a 
predose and postdose sample 
will be taken.
Blood (plasma) 
for 
Investigational 
PK
X
X
Analysis triggered by Sponsor 
as needed.
Blood (Plasma) 
for DOR and 
ISL PK in 
Pregnant 
Participants
<---------------------------------------X----------------------------------->
Collected during the 1st, 2nd, & 
3rd trimesters & postpartum 
per Section 8.11.7.1.
Biomarkers
Blood for 
Genetic 
Analysisb
X
Whole Blood for 
Future 
Biomedical 
Research
X
X
X
X
Optional participation; 
requires FBR consent. 
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Study 
Period
Screening/Run-In Period
Intervention
Notes
Screening
HIV-1 
Confirmation 
Visitc
Repeat HIV-1 
Confirmation 
Visitd
Double-blind 
(Part 1)
Open-label 
(Part 2)
Visit 3 is an additional HIV-1 
RNA confirmation test for 
participants with 500 
copies/mL on confirmation 
testing but with 0.5 log10
decline in HIV-1 RNA from 
the Screening Visit (Visit 1)
Visit 
Number
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
Each visit should be 
calculated from date of 
Randomization (Day 1). A 
visiting nurse may be used for 
visits after randomization per 
Section 8.11.3.4.
Scheduled 
Day/Week
Screen
NA
NA
Day 1 
(Fasting) 
Day 8
(Fasting)
TW3
TW7
TW13
TW19
TW25
TW37
TW49
(Fasting)
TW61
TW73 
(Fasting)
TW85
TW97 
(Fasting)
Visit Window
≤60 daysa
≤10 days 
prior to
Day 1
7-14 days 
after 
Visit 2
NA
+3 days
±7 days
Adherence to the visit window 
is critical for study 
intervention resupply. 
Randomization of eligible 
participants must occur within 
10 days of Visit 2 (or Visit 3, 
if required).
Blood for 
Inflammatory 
Markers
X
X
X
X
Anti-HBc=hepatitis B core antibody; ART=antiretroviral therapy; β-hcg-beta human chorionic gonadotropin; bp=blood pressure; D/C=discontinuation; DNA=deoxyribonucleic acid; DOR=doravirine; 
ECG=electrocardiogram; ECI=Events of Clinical Interest; FAHI=Functional Assessment of HIV Infection; FBR=Future Biomedical Research; F/U=follow-up; HBsAb=hepatitis B surface antibody; 
HBsAg=hepatitis B surface antigen; HBV=hepatitis B virus; HCV=hepatitis C virus; HIV=human immunodeficiency virus; HIV-1=human immunodeficiency virus Type 1; INR=international 
normalized ratio; IRT=Interactive Response Technology; ISL=islatravir; NA=not applicable; OBT=optimized background therapy; PCR=polymerase chain reaction; PK=pharmacokinetic; 
PT=prothrombin time; RNA=ribonucleic acid; rr=respiratory rate; temp=body temperature; TBNK=T- and B-lymphocyte and natural killer cell profile; TW=treatment week; VL=viral load; 
WOCBP=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 60 
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.
c
Following confirmation of eligibility at Screening, a repeat HIV-1 RNA test will be performed to confirm HIV-1 RNA eligibility for randomization (HIV-1 RNA ≥500 copies/mL with a <0.5 
log10 decline from the Screening Visit [Visit 1]). If there is ≥0.5 log10 decline from the Screening Visit, a repeat confirmation test is required (see footnote d below).
d
The Repeat HIV-1 Confirmation Visit is only for those participants with HIV-1 RNA ≥500 copies/mL at Visit 2 AND with a ≥0.5 log10 decline in HIV-1 RNA from the Screening Visit; these 
participants will be required to return to the site for a Repeat HIV-1 RNA Confirmation Visit (Visit 3). At Visit 3, in order to be eligible for randomization, participants must have HIV-1 RNA 
≥500 copies/mL and a <0.3 log10 decline in HIV-1 RNA from the previous result at Visit 2.
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1.3.2
Schedule of Activities – Viremia Confirmation and End of Treatment
(All Participants Except Those With Specified Decreases in CD4+ T-cell and/or Total Lymphocyte Counts)
Study Period
Viremia Confirmation
End of Treatment
Notes
Visit Number
Unscheduled
Unscheduled
The End of Treatment Follow-up visit 
should also be performed for participants 
who will not continue study intervention 
after Week 97.
Scheduled Day/Week
Viremia Confirmation
Early Discontinuation of 
Treatment
End of Treatment
Follow-up
Visit Window
Within ~1 month of 
HIV-1 Initial Viremia
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.
ART/OBT compliance review
X
X
Completion of Participant 
Questionnaire (FAHI)
X
Administered to participants ≥18 years 
of age at the time of consent and prior to 
being seen by investigator and 
discussions about medical conditions or 
test results.
Efficacy Procedures
Plasma HIV-1 RNA 
Quantification (Real Time PCR)
X
X
X
CD4+ T-cell Count/
TBNK Panel
X
Participants with decreases in CD4+ 
T-cell count >10% from average 
baseline valuea or who meet relevant 
ECI criteria at the Early Discontinuation 
of Treatment visit should be managed 
per Section 8.11.6 and Section 1.3.4.
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Study Period
Viremia Confirmation
End of Treatment
Notes
Visit Number
Unscheduled
Unscheduled
The End of Treatment Follow-up visit 
should also be performed for participants 
who will not continue study intervention 
after Week 97.
Scheduled Day/Week
Viremia Confirmation
Early Discontinuation of 
Treatment
End of Treatment
Follow-up
Visit Window
Within ~1 month of 
HIV-1 Initial Viremia
NA
42 (+7) days after the 
end of treatment
Blood (plasma) for HIV-1 Drug 
Resistance Testing
X
X
X
Testing performed on samples with HIV-
1 RNA ≥200 copies/mL that were 
collected either to confirm viremia after 
suppression (VL <50 copies/mL) or at 
discontinuation.
Whole Blood for Proviral DNA 
Resistance Testing
X
X
X
Testing performed on samples with HIV-
1 RNA ≥200 copies/mL that were 
collected either to confirm viremia after 
suppression (VL <50 copies/mL) or at 
discontinuation.
Blood (Plasma) for 
Investigational PK
X
X
X
Analysis triggered by Sponsor as 
needed.
Safety Procedures
Directed Physical Examination 
X
X
Vital Signs 
X
X
Includes weight, pulse, bp, temp, and rr.
Confirmation of Menarche 
Status (Females Only)
X
X
X
Not required once menarche has been 
confirmed.
Contraception Use Confirmation 
(WOCBP Only)
X
X
X
To be done per local guidelines.
Urine Pregnancy Test (WOCBP 
Only)
X
X
Confirm with serum test if positive. If 
serum test is positive, participants will 
be managed per Section 8.11.7 and 
safety of her infant collected per Section 
8.11.7.4.1.
Chemistry
X
X
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Study Period
Viremia Confirmation
End of Treatment
Notes
Visit Number
Unscheduled
Unscheduled
The End of Treatment Follow-up visit 
should also be performed for participants 
who will not continue study intervention 
after Week 97.
Scheduled Day/Week
Viremia Confirmation
Early Discontinuation of 
Treatment
End of Treatment
Follow-up
Visit Window
Within ~1 month of 
HIV-1 Initial Viremia
NA
42 (+7) days after the 
end of treatment
Hematology
X
Participants with decreases in total
lymphocyte counts >10% from average 
baseline valuea or who meet relevant 
ECI criteria at the Early Discontinuation 
of Treatment visit should be managed 
per Section 8.11.6 and Section 1.3.4.
Urinalysis
X
X
Review of Adverse Events
X
X
X
Biomarkers
Whole Blood for Future 
Biomedical Research
X
X
If FBR sample was collected at viremia 
confirmation, it is not necessary to 
collect another sample at Early 
Discontinuation visit.
ART=antiretroviral therapy; β-hcg=beta human chorionic gonadotropin; bp=blood pressure; DOR=doravirine; ECI=Events of Clinical Interest; 
FAHI=Functional Assessment of HIV Infection; FBR=Future Biomedical Research; HIV=human immunodeficiency virus; HIV-1=human immunodeficiency
virus Type 1; IRT=Interactive Response Technology; NA=not applicable; OBT=optimized background therapy; PCR=polymerase chain reaction; 
PK=pharmacokinetic; RNA=ribonucleic acid; rr=respiratory rate; TBNK=T- and B-lymphocyte and natural killer cell profile; temp=body temperature; 
VL=viral load; WOCBP=a woman/women of childbearing potential.
a. The average baseline value is defined as the average value between screening (within 60 days prior to the first dose of study intervention) and Day 1.
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1.3.3
Schedule of Activities for Participants Whose Pregnancy or Postpartum Visit(s) Extends Beyond Week 97
Visit Number
17
18
19
20
Notes
Scheduled Week
109
121
133
145
For any participant who is pregnant at the last regularly 
scheduled study visit (TW97) and consents to continue
DOR/ISL, the visit schedule will be extended through the 
duration of the pregnancy 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.
Visit Window
± 7 days
Administrative Procedures
Collect and enter data from prenatal care provider
<-------------------------------X----------------------------->
For female participants who become pregnant and consent 
to continue DOR/ISL, obtain relevant prenatal clinical & 
laboratory data to monitor the safety of the mother & fetus 
per Section 8.11.7
Register Study Visit in IRT
X
X
X
X
Dispense DOR/ISL Using IRT
X
X
X
Study intervention compliance review
X
X
X
X
Reconcile doses and assess study intervention compliance.
OBT compliance review
X
X
X
X
Prior and Concomitant Medications Review
X
X
X
X
Evaluation to receive continued study intervention
X
X
X
X
At the end of pregnancy, continued access to DOR/ISL will 
be offered per Section 6.7.
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 8.11.6 and Section 1.3.4
Blood (plasma) for HIV-1 drug resistance
X
X
X
X
Testing performed via central laboratory at Screening and 
thereafter on samples for participants who never suppressed 
(HIV-1 RNA ≥200 copies/mL) and those that were 
collected either to confirm viremia after suppression (VL
<50 copies/mL) or at discontinuation.
Whole Blood for Proviral DNA Resistance Testing
X
X
X
X
Testing performed via central laboratory on samples for 
participants who never suppressed (HIV-1 RNA ≥200 
copies/mL) and those that were collected either to confirm 
viremia after suppression (VL <50 copies/mL) or at 
discontinuation.
Safety Procedures
Weight
X
X
X
X
Directed Physical Examination
X
X
X
X
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Visit Number
17
18
19
20
Notes
Scheduled Week
109
121
133
145
For any participant who is pregnant at the last regularly 
scheduled study visit (TW97) and consents to continue
DOR/ISL, the visit schedule will be extended through the 
duration of the pregnancy 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.
Visit Window
± 7 days
Vital Signs
X
X
X
X
Chemistry
X
X
X
X
Hematology
X
X
X
X
Decreases in total lymphocyte counts that meet ECI criteria 
should be managed per Section 8.11.6 and Section 1.3.4
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, & 3rd trimesters & postpartum 
per Section 8.11.7.1.
Biomarkers
Whole Blood for Future Biomedical Research
X
X
X
X
Optional participation; requires FBR consent.
DNA=deoxyribonucleic acid; DOR=doravirine; ECI=Events of Clinical Interest; HIV=human immunodeficiency virus; IRT=Interactive Response Technology; ISL=islatravir; 
OBT=optimized background therapy; PCR=polymerase chain reaction; PK=pharmacokinetic; RNA=ribonucleic acid; TBNK=T- and B-lymphocyte and natural killer cell 
profile; VL=viral load.
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1.3.4
Schedule of Activities – 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
Notes
Visit Number
Unscheduled
Unscheduled
Unscheduled
Scheduled Day/Week
CD4+ T-cell and/or 
Total Lymphocyte 
Confirmation
Early Discontinuation 
of Treatment
End of Treatment 
Follow-up
CD4+ T-cell and/or 
Total Lymphocyte 
Monitoring
See Sections 8.1.9 and 
8.11.6 for details 
regarding 
discontinuation and 
monitoring.
Visit Window
Within 3-4 weeks of 
initial decrease
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 assess 
study intervention 
compliance.
ART/OBT Compliance
Review
X
Completion of Participant
Questionnaire (FAHI)
X
Administered to 
participants ≥18 years of 
age prior to being seen by 
investigator and 
discussions about medical 
conditions or test results.
Efficacy Procedures
Plasma HIV-1 RNA 
Quantification (Real Time 
PCR)
X
X
CD4+ T-cell Count/TBNK 
Panel
X
X
X
X
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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
Notes
Visit Number
Unscheduled
Unscheduled
Unscheduled
Scheduled Day/Week
CD4+ T-cell and/or 
Total Lymphocyte 
Confirmation
Early Discontinuation 
of Treatment
End of Treatment 
Follow-up
CD4+ T-cell and/or 
Total Lymphocyte 
Monitoring
See Sections 8.1.9 and 
8.11.6 for details 
regarding 
discontinuation and 
monitoring.
Visit Window
Within 3-4 weeks of 
initial decrease
NA
42 (+ 7) days after 
discontinuing 
study intervention
Every 4 weeks (7 
days)
Blood (plasma) for HIV-1
Drug Resistance Testing
X
X
Analysis of samples 
collected at End of 
Treatment visits triggered 
by Sponsor as needed.
Whole Blood for Proviral
DNA Resistance Testing
X
X
Testing performed on 
samples with HIV-1 RNA 
≥200 copies/mL that were 
collected either to confirm 
viremia after suppression 
(VL <50 copies/mL) or at 
discontinuation.
Safety Procedures
Directed Physical 
Examination 
X
X
Vital Signs 
X
X
Includes weight, pulse, bp, 
temp, and rr.
Confirmation of Menarche 
Status (Females Only)
X
X
Not required once 
menarche has been 
confirmed.
Contraceptive Use 
Confirmation (WOCBP 
Only)
X
X
To be performed per local 
guidelines.
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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
Notes
Visit Number
Unscheduled
Unscheduled
Unscheduled
Scheduled Day/Week
CD4+ T-cell and/or 
Total Lymphocyte 
Confirmation
Early Discontinuation 
of Treatment
End of Treatment 
Follow-up
CD4+ T-cell and/or 
Total Lymphocyte 
Monitoring
See Sections 8.1.9 and 
8.11.6 for details 
regarding 
discontinuation and 
monitoring.
Visit Window
Within 3-4 weeks of 
initial decrease
NA
42 (+ 7) days after 
discontinuing 
study intervention
Every 4 weeks (7 
days)
Urine Pregnancy Test 
(WOCBP Only)
X
X
Confirm with serum test if 
positive. If serum test is 
positive, participants will 
be managed per Section 
8.11.7 and safety of her 
infant collected per Section 
8.11.7.4.1.
Chemistry
X
X
Hematology
X
X
X
X
Urinalysis
X
X
Review of Adverse Events
X
X
X
X
Pharmacokinetics
Blood (Plasma) for 
Investigational PK
X
X
Analysis triggered by 
Sponsor as needed.
Biomarkers
Whole Blood for Future 
Biomedical Research
X
ART=antiretroviral therapy; bp=blood pressure; FAHI=Functional Assessment of HIV Infection; FBR=Future Biomedical Research; HIV=human 
immunodeficiency virus; IRT=Interactive Response Technology; NA=not applicable; OBT=optimized background therapy; PCR=polymerase chain reaction; 
PK=pharmacokinetic; RNA=ribonucleic acid; rr=respiratory rate; TBNK=T- and B-lymphocyte and natural killer cell profile; temp=body temperature; 
WOCBP=a woman/women of childbearing potential.
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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 pediatric participants
35 kg.
2.1
Study Rationale
Heavily treatment-experienced (HTE) individuals are a small but important population of 
patients with HIV-1. These individuals have exhausted all or nearly all antiretroviral options 
for constructing a viable HIV treatment regimen primarily because of extensive multidrug 
resistance but also because of drug intolerance, lack of access to key drugs, or 
unacceptability to the participant (eg, parenteral agents). There is consequently an unmet 
medical need in this population for better treatment options. Preliminary data suggest ISL
may be useful in this population and the purpose of the P019 study is to evaluate the safety 
and efficacy of DOR/ISL in the HTE population.
The HTE population in this clinical study is defined by the following characteristics: 1) HIV 
heavily treatment-experienced, 2) failing their current antiretroviral regimen, 3) drug 
resistance to antiretrovirals belonging to at least 3 antiretroviral classes, 4) inability to 
construct a fully suppressive regimen with available ARTs, and 5) having no more than 
2 fully active antiretroviral agents remaining to construct a viable regimen. 
DOR/ISL has the potential to be an agent for the treatment of HIV-1 infection in the HTE 
population 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 DDI profiles observed to date.
2.2
Background
Refer to the IBs/approved labeling for detailed background information on DOR and ISL.
2.2.1
Islatravir
ISL is the first member of a new class of antiretroviral agents, known as NRTTIs, that block 
HIV-1 reverse transcriptase by novel mechanisms of action. It is an inactive nucleoside 
analog that is converted to the pharmacologically active triphosphate (ISL-TP) form via 
endogenous intracellular kinases. It acts through multiple mechanisms, including immediate 
chain termination by blocking translocation and delayed chain termination by preventing 
nucleotide excision [Michailidis E 2014].
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 
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also exhibits potent in vitro activity against the most prevalent NRTI resistance mutations, 
including M184V.
2.2.2
Doravirine
DOR, a potent NNRTI with demonstrated efficacy and good tolerability, was first approved 
for the treatment of HIV-1 infection by the FDA and EMA in 2018. 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 including
K103N, Y181C, G190A, and E138K.
2.2.3
Doravirine/Islatravir
DOR/ISL is an FDC containing DOR (100 mg) and ISL (0.75 mg), administered as a single
tablet QD. DOR and ISL represent 2 distinct classes of antiretrovirals that inhibit reverse 
transcription by different mechanisms. Based on the profiles of each of these drugs and data 
available to date, the combination DOR/ISL is expected to be well tolerated and highly 
efficacious with a high barrier to resistance. The combination has demonstrated additive 
antiretroviral activity in vitro and has suppressed emergence of resistance at clinically
relevant concentrations.
The combination of DOR and ISL (administered as single entities, DOR+ISL) is being 
evaluated in an ongoing randomized Phase 2 study (MK-8591 Protocol 011) in 
approximately 90 treatment-naïve adult participants with HIV-1. Participants were initially 
assigned to receive either DOR+ISL and 3TC or an FDC of DOR, 3TC, and TDF 
(DOR/3TC/TDF). 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 was comparable to those who received the 3-drug regimen of 
DOR/3TC/TDF. The majority of participants maintained virologic suppression through Week 
144. None of the participants with protocol-defined virologic failure rebounded above the 
clinically relevant HIV-1 RNA >200 copies/mL cutoff. As such, no participant met the 
criteria for resistance testing. DOR+ISL, administered with 3TC or alone as a 2-drug 
regimen, had a favorable safety and tolerability profile through Week 96, comparable to that 
of DOR/3TC/TDF. Mean changes from baseline in CD4+ T-cell count were comparable for 
DOR/3TC/TDF and each dose of ISL as a 3-drug regimen (at Week 24) or a 2-drug regimen 
(at Weeks 48, 96, 144).
In addition to this study, the clinical development program of DOR/ISL includes ongoing 
studies in treatment-naïve adults (Protocol 020), virologically suppressed adults (Protocol 
017 and Protocol 018), and participants <18 years of age and weighing 35 kg
(Protocol 028).
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2.2.4
Information on Other Study-related Therapy
ART continued at baseline and OBT will be administered at the approved marketed dose. 
Refer to local labeling for detailed information on baseline ART and OBT.
2.3
Benefit/Risk Assessment
Although it cannot be guaranteed that participants in clinical studies will directly benefit 
from treatment during participation, as clinical studies are designed to provide information 
about the safety and effectiveness of an investigational medicine, the totality of available 
nonclinical and clinical data supports continued evaluation of DOR/ISL in Phase 3 clinical 
studies. 
The comprehensive nonclinical safety evaluations of DOR (an approved NNRTI) and ISL 
(an investigational NRTTI) as mono-entities have not revealed toxicities of concern for daily 
dosing. Nonclinical developmental and reproductive toxicity studies did not identify any 
clinically relevant concerns that would preclude continued dosing of DOR/ISL in participants 
who become pregnant during the study. Both mono-entities are differentiated by a high 
barrier to resistance in vitro with DOR exhibiting potent activity against the most prevalent 
NNRTI-resistant mutations (eg, K103N, Y181C, G190A, and E138K) and ISL against 
common NRTI-resistant mutations (eg, M184V and TAMs). Both may be administered 
without regard to food, have a low potential for DDIs, and have favorable PK and tolerability 
profiles.
High potency against wild-type and resistant variants of HIV-1 virus and a long half-life 
make ISL a suitable candidate for development for the treatment of HIV-1 infection. Across 
the clinical development program, ISL administered alone or with DOR was generally well-
tolerated. 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. ISL+DOR (as a 2-drug regimen) maintained virologic suppression of HIV-1 RNA 
24 and 48 weeks after switching from the 3-drug regimen and through Week 144. In 2
ongoing Phase 3 studies evaluating DOR/ISL 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 the 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 (Protocol 017) and BIC/FTC/TAF
(Protocol 018), 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 (Protocol 017 
and Protocol 018). At the doses administered for daily treatment, DOR/ISL has been well-
tolerated and associated with low rates of drug-related AEs.
Downward trends of total lymphocytes counts and 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 
and CD4+ T-cell counts from baseline were observed in the ISL 20 mg + MK-8507 treatment 
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arms at Week 12 and Week 24. Decreases from baseline in total lymphocyte counts were 
observed in all dosing arms of ISL+MK-8507 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 lymphocytes observed in the 60 mg 
arm (the dose being evaluated in Phase 3 PrEP studies) and a 36% decrease in total 
lymphocytes observed in the 120 mg arm. In this population of HIV-1 uninfected 
participants, mean decreases were in the normal range and there was no increase in clinical 
AEs related to infection. Dosing of oral ISL 60 mg QM has been discontinued in PrEP 
clinical studies.
In an interim analysis for each of the Phase 3 studies studying DOR/ISL 100 mg/0.75 mg for 
HIV-1 treatment (Protocol 017 and Protocol 018), there were mean decreases from baseline 
in total lymphocyte counts at Week 48 of 10.6% and 8.5%, respectively, in the DOR/ISL 
groups compared with mean increases of 2.27% and 3.46% 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 increase of 8.7% in the baseline ART group 
(Protocol 017) and 12.8% in the BIC/FTC/TAF group (Protocol 018). These decreases in 
CD4+ T-cell and total lymphocyte counts have not been associated with an increased
incidence of infection or other AEs. The clinical impact of these laboratory changes over the 
long term is unknown, and the Sponsor is assessing the reversibility of the reductions in 
CD4+ T-cell and total lymphocyte counts. To mitigate the risk, increased monitoring of 
CD4+ T-cell and total lymphocyte counts and strict stopping rules have been added to 
DOR/ISL studies. At this time, the data review support continuation of the Phase 3 clinical 
studies for the DOR/ISL 100 mg/0.75 mg daily HIV-1 treatment program. With regard to this 
Phase 3 study in the HTE population, review of the available data and benefit/risk assessment 
support continuing DOR/ISL 100 mg/0.75 mg daily treatment in this important population of 
patients with multi-drug resistant HIV, who have exhausted all or nearly all antiretroviral 
options for constructing a viable HIV treatment regimen.
Additional details regarding specific benefits and risks for participants in this clinical study 
may be found in the accompanying IBs and informed consent/assent documents.
3
HYPOTHESES, OBJECTIVES, AND ENDPOINTS
Hypotheses are aligned with objectives in the Objectives and Endpoints table. 
The following objectives will be evaluated in HTE adult participants and in pediatric 
participants weighing ≥35 kg with pre-study HIV-1 RNA ≥500 copies/mL and currently on 
failing ART. 
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Objectives
Endpoints
Primary

To evaluate the antiretroviral activity of DOR/ISL
compared to placebo, each given in combination 
with failing ART as assessed by the percentage of 
participants achieving ≥0.5 log10 decrease in 
HIV-1 RNA from study baseline (Day 1) to Day 8
(Part 1).
Hypothesis: The percentage of participants 
receiving DOR/ISL and achieving ≥0.5 log10
decrease in HIV-1 RNA from study baseline 
(Day 1) to Day 8 is superior to placebo, each 
given in combination with failing ART.

HIV-1 RNA

To evaluate the safety and tolerability of 
DOR/ISL as assessed by review of the 
accumulated safety data through Week 25 and 
Week 49.

AEs

AEs leading to discontinuation
of study intervention
Secondary

To evaluate the safety and tolerability of 
DOR/ISL as assessed by review of the 
accumulated safety data through Week 97.

AEs

AEs leading to discontinuation 
of study intervention

To evaluate the antiretroviral activity of ISL and 
DOR, each compared to placebo, when each is 
given in combination with failing ART, as 
assessed by the percentage of participants 
achieving ≥0.5 log10 decrease in HIV-1 RNA from 
study baseline (Day 1) to Day 8 (Part 1).

HIV-1 RNA

To further evaluate the antiretroviral activity of 
DOR/ISL, ISL, and DOR each compared to 
placebo, when each is given in combination with 
failing ART (Part 1) as assessed by:
-
mean change in HIV-1 RNA from study 
baseline (Day 1) to Day 8
-
percentage of participants achieving ≥1.0 log10
decrease in HIV-1 RNA from study baseline 
(Day 1) to Day 8

HIV-1 RNA
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Objectives
Endpoints

To further evaluate the antiretroviral activity of 
DOR/ISL compared to ISL and DOR, when each 
is given in combination with failing ART (Part 1) 
as assessed by:
-
percentage of participants achieving ≥0.5 
log10 decrease in HIV-1 RNA from study 
baseline (Day 1) to Day 8
-
mean change in HIV-1 RNA from study 
baseline (Day 1) to Day 8
-
percentage of participants achieving ≥1.0 log10
decrease in HIV-1 RNA from study baseline 
(Day 1) to Day 8

HIV-1 RNA

To evaluate the antiretroviral activity of DOR/ISL
+ OBT in Part 2 as assessed by the following at 
Week 25, Week 49, and Week 97 compared to 
study baseline (Day 1) and Part 2 baseline (Day 
8):
-
percentage of participants achieving ≥0.5 
log10 decrease in HIV-1 RNA
-
percentage of participants achieving ≥1.0 
log10 decrease in HIV-1 RNA
-
mean change in HIV-1 RNA
-
percentage of participants achieving HIV-1 
RNA <200 copies/mL
-
percentage of participants achieving HIV-1 
RNA <50 copies/mL
-
percentage of participants achieving HIV-1 
RNA <40 copies/mL

HIV-1 RNA

To evaluate the development of viral drug 
resistance to DOR, ISL, or components of OBT 
through the study duration (Part 1 and Part 2).

Viral resistance-associated 
substitutions

To evaluate the impact of study baseline (Day 1)
antiviral resistance on virologic outcome at 
Week 25, Week 49, and Week 97 (Part 2).

Viral resistance-associated 
substitutions

HIV-1 RNA
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Objectives
Endpoints

To evaluate the change in CD4+ T-cell counts
from both study baseline (Day 1) and Part 2 
baseline (Day 8) at Week 25, Week 49, and 
Week 97 (Part 2).

CD4+ T-cell count
Tertiary/Exploratory

To evaluate the impact of study baseline (Day 1) 
resistance on primary efficacy (Day 8) (Part 1):
-
NRTI resistance on ISL antiviral activity
-
NNRTI resistance on DOR antiviral activity

Viral resistance-associated 
substitutions

HIV-1 RNA

To evaluate the impact of DOR/ISL + OBT on 
inflammation as measured by the mean change 
from study baseline (Day 1) to Week 25, 
Week 49, and Week 97 (Part 2) in laboratory 
markers.

Inflammatory markers

To describe PROs related to HIV disease-specific 
QoL assessed at study baseline (Day 1), Week 25, 
Week 49, and Week 97 (Part 2) for participants 
≥18 years of age who received DOR/ISL + OBT.

FAHI questionnaire: Total 
score and individual subscale 
scores

To evaluate the PK of ISL and DOR, when each is 
given in combination with failing ART (Part 1).

PK values, such as AUC, 
Cmax, and C24

To evaluate the PK of ISL and DOR, when given 
in combination with OBT (Part 2).

PK values, such as AUC, 
Cmax, and C24

To explore the relationship between genetic 
variation and response to the treatment(s) 
administered, and mechanisms of disease. 
Variation across the human genome may be 
analyzed for association with clinical data 
collected in this study.

Germline genetic variation
The success of the study is determined by successfully confirming the primary efficacy 
hypothesis that DOR/ISL is superior to placebo.
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4
STUDY DESIGN
4.1
Overall Design
This is a Phase 3, randomized, multi-site study in HTE participants infected with HIV-1 
currently on failing ART for HIV-1 infection. Following Screening, eligible participants will 
enter a Run-in Period on current failing baseline ART prior to randomization. Part 1 is a 
7-day double-blind period of QD therapy, where the investigational agent (ISL 0.75 mg,
DOR 100 mg, or DOR/ISL [100 mg/0.75 mg]) or placebo is added to the participant’s 
current failing ART. In Part 2, all participants receive open-label DOR/ISL
(100 mg/0.75 mg) added to OBT through Week 97. The study schema is shown in Figure 1.
Run-in Period: The Run-in Period will start immediately after Screening and end at 
randomization. During this time, participants will continue their failing ART regimen. 
Following confirmation of eligibility at the Screening Visit (Visit 1) (test results anticipated 
to take approximately 30 to 45 days), a repeat measurement for HIV-1 RNA will be 
performed at Visit 2 to confirm HIV-1 RNA eligibility for randomization (HIV-1 RNA
≥500 copies/mL with a <0.5 log10 decline in HIV-1 RNA from Visit 1). Participants with 
HIV-1 RNA ≥500 copies/mL and a ≥0.5 log10 decline in HIV-1 RNA from Visit 1 must 
return to the site 7 to 14 days after Visit 2 for a Repeat HIV-1 RNA confirmation visit 
(Visit 3). In order to be eligible for randomization, participants must have HIV-1 RNA 
≥500 copies/mL and a <0.3 log10 decline in HIV-1 RNA from the previous result at Visit 2
(Figure 2). Randomization of eligible participants must occur within 10 days of Visit 2 (or 
Visit 3, if required).
Participants must have 2 HIV-1 RNA measurements ≥500 copies/mL to participate in this 
study: The first measurement at the Screening Visit and the second measurement taken no 
sooner than 7 days after the first measurement, but ≤10 days prior to randomization.
Double-blind Period, Part 1 (Day 1 to Day 7): Participants will be randomized in a 1:2:1:1 
ratio into 1 of 4 treatment groups (Figure 1). The overall goal for this study is to randomize 
150 participants; however, a minimum sample size of 100 randomized participants is the 
target for the planned analyses (40 participants randomized into the DOR treatment group 
and 20 participants randomized into each of the other treatment groups):

Group 1 (n ~20): ISL QD + failing baseline ART

Group 2 (n ~40): DOR QD + failing baseline ART

Group 3 (n ~20): DOR/ISL QD + failing baseline ART

Group 4 (n ~20): Placebo QD + failing baseline ART
Randomization will be stratified by age and within the adult strata, the existence of M184V 
or I substitutions at baseline (see Section 6.3.2).
Baseline ART will not be provided by the Sponsor.
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Open-label Period, Part 2 (Day 8 to Week 97): Following the 7-day double-blind treatment 
period, all participants will be treated with DOR/ISL and OBT from Day 8 through Week 97
(with the opportunity to continue DOR/ISL after Week 97; Section 6.7). OBT options will be 
driven by historic and baseline resistance as well as drug safety and tolerability, drug access,
and acceptability to the participant. In cases where the failing regimen cannot be optimized, 
participants will continue their failing regimen plus DOR/ISL. OBT will consist of approved 
and licensed ARTs and will not be provided by the Sponsor.
Participants with confirmed viremia (defined as having 2 consecutive confirmed HIV-1 RNA 
≥200 copies/mL [at least 4 weeks apart] after achieving HIV-1 RNA <50 copies/mL) or who 
discontinued study intervention with HIV-1 RNA ≥200 copies/mL, or who never suppressed 
(<50 copies/mL) at Week 25, Week 49, and Week 97 with HIV-1 RNA >200 copies/mL, will 
be assessed for development of viral drug resistance.
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 study design is based on the schema suggested in the regulatory guidance document
[Food and Drug Administration (CDER) 2015] for a study population with multidrug 
resistant HIV-1 infection failing their current ART, when the study intervention is expected 
to offer antiretroviral activity. The P019 study design is a modification of the above schema 
that reflects the use of a combination agent (DOR/ISL) rather than a single new study 
intervention.
After the Screening Visit, there is a Run-in Period before randomization occurs. After at least 
7 days during this period, repeat HIV-1 RNA testing is performed to exclude responders due 
to possible improved adherence to their ongoing “failing” ART after enrolling in the clinical 
study. The efficacy analysis (Part 1) will occur after 7 days of functional monotherapy or 
FDC DOR/ISL and will compare ISL, DOR, or FDC DOR/ISL added to failing baseline 
ART to placebo. The DOR arm is over-weighted 2:1 to reflect the heterogeneity of resistant 
mutants typically associated with NNRTI resistance. It is expected that the higher number of 
participants may allow for the determination of DOR activity over a range of IC50 values
and evaluation of the impact and the clinical relevance of NNRTI mutations on DOR 
activity.
The primary safety evaluation and virologic follow-up will occur after 24 weeks of study 
intervention (24 weeks of open-label DOR/ISL with an optimized background regimen) to 
allow for an adequate assessment of safety and a longer observation period for virologic 
rebound or durability.
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4.2.1
Rationale for Endpoints
4.2.1.1
Efficacy Endpoints
4.2.1.1.1
HIV-1 RNA Measurements
The primary efficacy endpoint in this study is the percentage of participants achieving 
≥0.5 log10 decrease in HIV-1 RNA from study baseline (Day 1) to Day 8, a well-established 
endpoint for evaluation of efficacy in the HTE population and aligned with regulatory
guidance [Food and Drug Administration (CDER) 2015]. The antiretroviral activity of ISL
and DOR will be further evaluated through the secondary efficacy endpoints, the percentage 
of participants achieving ≥1.0 log10 decrease and the mean change in HIV-1 RNA from study 
baseline (Day 1) to Day 8.
Similar assessments of the antiretroviral activity of DOR/ISL + OBT at Week 25, Week 49, 
and Week 97 will be performed, along with evaluation of the percentage of participants 
achieving HIV-1 RNA <200 copies/mL, <50 copies/mL, and <40 copies/mL.
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.
In individuals with no remaining suppressive ART options, decreases in HIV-1 RNA, even if 
detectable at >50 copies/mL, have been correlated with improved mortality and outcomes.
An HIV-1 RNA level of <200 copies/mL allows for patient monitoring to reduce the risk of 
developing viral drug resistance and to detect potential treatment failure in a timely manner. 
It also accounts for isolated detectable HIV-1 RNA after virologic suppression followed by a 
return to virologic suppression (ie, ‘virologic blip’) that may not be clinically meaningful.
4.2.1.2
Patient-reported Outcomes
PROs can provide unique information on the impact of HIV disease and its treatment from 
the patients’ perspective as some domains are difficult to observe or are subjective and best 
collected through patient report. HTE patients have limited treatment options including 
complex regimens that are associated with adverse effects and consequently impaired
HRQoL. PRO data may help clinicians and patients in making informed decision on 
appropriate combination ART. PROs, including HRQoL data, have been increasingly 
considered in drug benefit assessment and reimbursement decision-making by HTA 
authorities. HTA agencies in many countries recommend patient perspectives data and QoL
measurement as part of their drug benefit evaluations.
The study will include the Functional Assessment of Human Immunodeficiency Virus 
Infection (FAHI) for participants ≥18 years of age at the time of consent. The FAHI is a self-
administered 47-item questionnaire designed to capture the effects of HIV infection and 
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treatment-related symptoms on physical, emotional, functional, social, and global well-being 
as well as cognitive functioning.
4.2.1.3
Safety Endpoints
Safety evaluations will include physical examinations (including vital signs) and laboratory 
tests (eg, hematology, chemistry, fasting lipid/glucose, and urinalysis) performed per the SoA 
(Section 1.3). AEs will be evaluated at each visit and assessed according to the guidelines in 
Section 8.4 and Appendix 3. Participants may be asked to return for unscheduled visits to 
perform additional safety monitoring.
4.2.1.4
Laboratory Markers
The study will assess changes in inflammation after treatment with DOR/ISL + OBT. 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]. The following laboratory markers will be measured: 

IL-6

D-dimer

sCD-163

hs-CRP
4.2.1.5
Pharmacokinetic Endpoints
PK samples collected from all participants as described in the SoA and Section 8.6.1 will be 
used to evaluate PK concentrations of ISL and DOR in Part 1 and Part 2, and as appropriate, 
PK-efficacy, PK-pharmacodynamic, and PK-AE relationships of DOR/ISL. PK values such 
as AUC, Cmax, and C24 will be explored.
4.2.1.6
Planned Exploratory Biomarker Research
4.2.1.6.1
Planned Genetic Analysis
Genetic variation may impact a participant’s response to therapy, susceptibility to, severity, 
and progression of disease. Variable response to therapy may be due to genetic determinants 
that impact drug absorption, distribution, metabolism, and excretion; mechanism of action of 
the drug; disease etiology; and/or molecular subtype of the disease being treated. Therefore, 
where local regulations and IRB/IEC allow, a sample will be collected for DNA analysis 
from consenting participants.
DNA samples may be used for research related to the study intervention(s), the disease under 
study, or related diseases. They may also be used to develop tests/assays including diagnostic 
tests related to the disease under study, related diseases, and study intervention(s). Genetic 
research may consist of the analysis of 1 or more candidate genes, the analysis of genetic 
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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.
4.2.2
Rationale for the Use of Comparator/Placebo
In alignment with regulatory guidance [Food and Drug Administration (CDER) 2015], Part 1
of this study consists of a brief period (7 days) of functional monotherapy (ie, each 
component of DOR/ISL), and the FDC DOR/ISL, or placebo added to the participant’s 
current failing ART. Given a non-inferiority comparison is not feasible in this population, to 
evaluate the efficacy of each component of DOR/ISL, the antiretroviral activity of ISL and 
DOR at Day 8 are each compared to placebo. The functional monotherapy period is limited 
to 7 days to minimize the risk for development of resistance to ISL or DOR or additional 
resistance to the baseline ART.
The uncontrolled (open-label) study design beyond the primary 7-day comparison is deemed 
appropriate as the modest loss of certainty interpreting study results is outweighed by the 
unmet medical need in this population and the potential to decrease further development of 
resistance to the background regimen from this type of study design.
4.2.3
Rationale for the Selected Participant Population
The rationale for the participant population selected for this study is as follows:

HTE Participants: There is an unmet medical need for new treatments in patients with 
documented baseline resistance to multiple drug classes, who are experiencing an 
ongoing inability to suppress viral replication on their current regimen and have few if 
any remaining options to construct a fully suppressive regimen. 
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Patients with multidrug resistant HIV-1 are at risk of serious illness and death, leading to 
an urgent need for new antiviral drugs that are active against multidrug resistant virus. In 
addition to a broad pharmacologic distribution and a long intracellular half-life, ISL has a 
high IQ (Ctrough/IC50) and the potential to be active against common NRTI-resistant 
variants (eg, M184I/V, K65R, L74V, Q151M, 69ins). DOR is a potent NNRTI that 
retains in vitro activity against HIV-1 variants harboring the most common NNRTI 
resistance mutations (eg, K103N, G190A, Y181C, and E138A/K). Therefore, the FDC of 
ISL and DOR has the desired properties to meet a critical unmet medical need in this 
population.

Enrollment of Pediatric Participants: The nonclinical data for DOR/ISL, and its 
individual components (ISL and DOR), and clinical studies of DOR + ISL conducted to 
date in adults with and without HIV-1 infection, have not demonstrated significant safety 
concerns that would preclude evaluation in pediatric participants <18 years of age). 
Pediatric participants (weighing ≥35 kg) are predicted to have similar plasma ISL and 
intracellular ISL-TP concentrations to the adults studied in Phase 2 and no dose 
adjustment is necessary in this age group. The use of a weight limit for pediatric
participants is in alignment with WHO pediatric HIV guidance [World Health 
Organization 2007] to administer antiretrovirals using a weight-band dosing approach.
4.2.4
Rationale for Collecting Race and Ethnicity Data
The differential effect on the safety and efficacy based on any demographic parameter, 
including race or ethnicity cannot be predicted when evaluating a new investigational drug. 
Therefore, it is important to collect race and ethnicity data along with other 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 outcome and 
toxicity.
4.2.5
Rationale for Collecting Gender Identity Data
Transgender people, defined as those whose gender identities and/or expressions differ from 
the sex assigned to them at birth, have a high prevalence and incidence of HIV infection 
globally [Poteat, T., et al 2016]. Specifically, transgender women have an increased risk of 
HIV infection attributed to challenges associated with coping with psychosocial issues such 
as discrimination, stigmatization, and marginalization [Centers for Disease Control and 
Prevention 2019] [Department of HIV/AIDS 2015]. When considering HIV treatment, the 
WHO considers transgender people to be a separate key population because of their specific 
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health needs and high vulnerability [Department of HIV/AIDS 2015]. Data will be collected 
in this study to assess clinical outcomes in the transgender population.
4.2.6
Rationale for Infant Safety Data Collection
Follow-up through 1-year of age for infants born to participants who become pregnant while 
receiving study intervention provides the ability to monitor growth and development as well
as potential adverse effects that may be associated with prenatal drug exposure. Growth 
parameters (ie, length, weight, and head circumference) within normal range at 
approximately 1-year of age are key noninvasive indicators that a serious congenital 
malformation caused by in utero drug exposure is unlikely.
4.2.7
Rationale for Continuing Study Intervention During Pregnancy
The US Department of Health and Human Services guidelines currently advise that women 
who become pregnant while receiving ART for HIV should continue their regimen provided 
it is safe, well tolerated, and effective at virologic suppression since altering the regimen 
could cause an increase in viral load [Panel on Treatment of Pregnant Women with HIV 
Infection and Prev 2018]. Nonclinical developmental and reproductive toxicology studies did 
not identify any teratogenicity or other clinically relevant concerns that would preclude 
continued dosing of DOR/ISL in participants who become pregnant and 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 8.11.7).
There are no clinical data currently available to support breastfeeding by participants who are 
receiving DOR/ISL.
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 at the 
end of Day 1 after a single dose of 0.75 mg 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 QD doses, with an IQ of 5. Steady-state concentrations at 
later timepoints will produce even higher IQs, as there is additional accumulation of ISL-TP. 
These simulations support the selection of 0.75 mg ISL as the dose to be studied as 
monotherapy (in Part 1) and in combination with 100 mg DOR in Part 1 and Part 2.
In the 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 3-drug comparator 
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DOR/3TC/TDF, as demonstrated by the primary efficacy endpoint, the proportion of 
participants with HIV-1 RNA <50 copies/mL, at both Week 24 and Week 48. Overall, no 
ISL dose-response for efficacy was observed. Graphical analysis of steady-state ISL-TP 
trough concentrations and viral load at Week 48 from 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. 
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. In addition, a 0.75 mg QD dose of ISL in 
combination with 100 mg QD DOR is predicted to provide concentrations sufficient to cover 
mutant virus strains anticipated in an HTE patient population.
Pediatric participants (weighing ≥35 kg) are predicted to have similar plasma ISL and 
intracellular ISL-TP concentrations to the adults studied in Protocol 011, and no dose 
adjustment is necessary in this age group (Section 4.2.3).
DOR will be administered at the approved dose of 100 mg. This dose has been studied in 
Phase 1 to 3 clinical studies in treatment-naïve and virologically suppressed participants with 
HIV-1 and was selected based on 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. Of note, among 32 participants in MK-1439A 
Protocols 024 and 030 infected with HIV-1 harboring the NNRTI resistance mutations
K103N, Y181C, and/or G190A at study entry, all achieved virologic suppression following 
48 weeks of treatment with DOR/3TC/TDF (24 of these 32 participants had been 
virologically suppressed on PI or InSTI regimens and 8 had been TN). DOR is also expected 
to have antiviral activity against other prevalent NNRTI-associated reverse transcriptase
substitutions including L100I, E138K, H221Y, and P225H when dosed at 100 mg daily.
The DOR dose selection for adolescents was based on a physiologically based PK model that 
indicated that the 100 mg DOR tablet once daily can be safely and effectively administered 
in the adolescent population ranging from 12 to 18 years of age, and this dose is currently 
being studied in MK-1439 Protocol 027.
Therefore, 100 mg DOR has been selected to be studied in monotherapy (in Part 1) and in 
combination with 0.75 mg ISL in Part 1 and Part 2.
In summary, a 0.75 mg dose of ISL in combination with 100 mg DOR is predicted to provide 
concentrations that will demonstrate potent activity against both wild-type virus and most 
common NRTI- and NNRTI-resistance-associated variants.
4.4
Beginning and End of Study Definition
The overall study begins when the first participant (or their legally acceptable representative) 
provides documented informed consent/assent. The overall study ends when the last 
participant completes the last study-related contact, withdraws from the study, or is lost to 
follow-up (ie, the participant is unable to be contacted by the investigator).
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4.4.1
Clinical Criteria for Early Study Termination
The clinical study may be terminated early if the extent (incidence and/or severity) of 
emerging effects/clinical endpoints is such that the risk/benefit ratio to the study population 
as a whole is unacceptable. In addition, further recruitment in the study or at (a) particular 
study site(s) may be stopped due to insufficient compliance with the protocol, Good Clinical 
Practice (GCP), and/or other applicable regulatory requirements, procedure-related problems 
or the number of discontinuations for administrative reasons is too high.
Blinded data for participants who fail to achieve ≥0.5 log10 decline in HIV-1 RNA at the end 
of Part 1 will be communicated to an external unblinded statistician on an ongoing basis to 
perform the futility assessment. If the futility boundary is met, early study termination may 
be considered (Section 9.7).
5
STUDY POPULATION
HTE adult participants and pediatric participants weighing ≥35 kg with HIV-1 who are 
currently on failing 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.
5.1
Inclusion Criteria
A participant will be eligible for inclusion in the study if the participant:
Type of Participant and Disease Characteristics
1. Is HIV-1 positive with plasma HIV-1 RNA ≥500 copies/mL at the Screening Visit and 
confirmed upon repeat testing (Visit 2 [or Visit 3 if required]) during the Run-in Period.
In addition, the log change in HIV-1 RNA must meet 1 of the following criteria at a 
confirmation visit:
-
<0.5 log10 decline in HIV-1 RNA from the Screening Visit (Visit 1) to the 
Confirmation visit (Visit 2)
OR
-
If ≥0.5 log10 decline in HIV-1 RNA at Visit 2, another confirmation test is required 
(Visit 3). In this case, there must be <0.3 log10 decline in HIV-1 RNA from Visit 2
Note: HIV-1 RNA ≥500 copies/mL must be confirmed within 10 days prior to 
randomization.
Note: Repeat HIV-1 RNA Confirmation Visit (Visit 3) to occur 7 to 14 days following 
Visit 2.
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2. Has been receiving the same baseline ART for ≥3 months prior to signing the Informed 
Consent Form/Assent Form.
3. Has at least triple-class resistance (must include NRTI, NNRTI, and resistance to either 
PI or InSTI) based on any of the following: (a) central laboratory based resistance testing 
at the Screening Visit, (b) central laboratory based proviral DNA resistance testing at the 
Screening Visit, or (c) historical resistance testing within 12 months of Screening.
Resistance to at least 2 antiretroviral agents in a particular class denotes class resistance.
Note: For purposes of determining NRTI class resistance, resistance to FTC 
(emtricitabine) and 3TC (lamivudine), resistance associated with MI84V/I substitution 
must include 1 additional NRTI resistance substitution.
4. Has ≤2 fully active antiretroviral drugs remaining, among all antiretroviral classes, that 
can be effectively combined to form a viable regimen based on resistance, tolerability, 
safety, drug access, or acceptability to participant.
Demographics
5. Is male or female, adult (≥18 years of age) or pediatric participants (weighing ≥35 kg and 
<18 years of age), at the time of signing the informed consent/assent (the Screening 
Visit).
Contraception/Pregnancy

A female participant is eligible to participate if she is not pregnant or breastfeeding, and 
at least one of the following conditions applies:
-
Is not a woman of childbearing potential (WOCBP).
OR
-
Is a WOCBP and using an acceptable contraceptive method, or be abstinent from 
heterosexual intercourse as their preferred and usual lifestyle (abstinent on a long 
term and persistent basis), as described in Appendix 5 during the intervention period 
and for at least 6 weeks, corresponding to the time needed to eliminate any study 
intervention(s) (eg, 5 terminal half-lives) after the last dose of study intervention. The 
investigator should evaluate the potential for contraceptive method failure (ie, 
noncompliance, recently initiated) in relationship to the first dose of study 
intervention.
-
A WOCBP must have a negative highly sensitive pregnancy test ([urine or serum] as 
required by local regulations) within 24 hours before the first dose of study 
intervention.

If a urine test cannot be confirmed as negative (eg, an ambiguous result), a serum 
pregnancy test is required. In such cases, the participant must be excluded from 
participation if the serum pregnancy result is positive.
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-
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/Assent
6. The participant (or legally acceptable representative) has provided documented informed 
consent/assent for the study. The participant may also provide consent/assent for future 
biomedical research. However, the participant may participate in the main study without 
participating in future biomedical research.
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 HBV co-infection (defined as HBsAg-positive or HBV DNA positive) and is not 
currently being treated for HBV.
Note: Participants coinfected with HBV who are currently taking oral antiviral treatment 
for hepatitis B (eg, tenofovir, entecavir, telbivudine, adefovir, lamivudine, etc.) are
eligible for enrollment and should remain on the same treatment for their HBV 
throughout the study.
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 or current evidence of any condition (including active TB co-infection), 
therapy, laboratory abnormality, or other circumstance (including drug or alcohol abuse 
or dependence) that might, in the opinion of the investigator, confound the results of the 
study or interfere with study participation for the full study duration.
Prior/Concomitant Therapy
5. Is taking or is anticipated to require any of the prohibited therapies outlined in Section 6.5 
from the Screening Visit and throughout the study treatment period. (See Table 3
footnote for special considerations in Part 2 of the study.)
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6. Is taking DOR as part of his/her current failing antiretroviral regimen.
7. Is taking EFV, etravirine, or nevirapine.
Note: Although expected to be rare, these drugs are excluded because of the potential for 
decreased DOR concentrations when administered with DOR or DOR/ISL).  (See Table 3
footnote for more information.)
Prior/Concurrent Clinical Study Experience
8. Is currently participating in or has participated in an interventional clinical study with an 
investigational compound or device from the Screening Visit through the study treatment 
period.
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.
Diagnostic Assessments
9. Has exclusionary laboratory values at the Screening Visit as listed in Table 1 below.
Table 1
Laboratory Exclusion Criteria
Laboratory Assessment
Exclusionary Values
AST SGOT
>5 × ULN
ALT SGPT
>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 SGPT=alanine aminotransferase; AST SGOT=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 60-day screening window.
Other Exclusions
10. 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 treatment. Consistent with the 
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recommendations for contraceptive use, it is recommended that all female participants 
refrain from egg donation for 6 weeks following their last dose of study treatment.
Note: Donation of sperm should follow local guidelines for HIV-positive individuals.
5.3
Lifestyle Considerations
There are no lifestyle restrictions for ISL and DOR. Refer to approved labeling for any 
lifestyle restrictions with administration of ART and OBT.
5.4
Screen Failures
Screen failures are defined as participants who consent/assent to participate in the clinical 
study, but are not subsequently randomized in the study. A minimal set of screen failure 
information is required to ensure transparent reporting of screen failure participants to meet 
the 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 interventions to be used in this study are outlined in Table 2.
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Table 2
Study Interventions
Arm Name
Arm Type
Intervention 
Name
Type
Dose 
Formulation
Unit Dose 
Strength(s)
Dosage Level(s)
Route of 
Administration
Treatment Period
Use
IMP/
NIMP
Sourcing
All Groups 
(Group 1, 
2, 3, 4)
N/A
Baseline ART 
regimena
Drug
Per Approved 
Product Label
Per Approved 
Product Label
Per Approved 
Product Label
Per Approved 
Product Label
Run-in Period 
through Part 1 
Day 7
Background 
Treatment
NIMP
Local
country 
level 
Sourcing b
Group 1
Experimental
ISL
Drug
Capsule
0.75 mg
0.75 mg QD
Oral
Part 1: Day 1 to 
Day 7 (blinded)
Experimental
IMP
Provided 
centrally by 
Sponsor
Group 1
Experimental
DOR Placebo
Drug
Tablet
0 mg
0 mg QD
Oral
Part 1: Day 1 to
Day 7 (blinded)
Placebo
IMP
Provided 
centrally by 
Sponsor
Group 1
Experimental
DOR/ISL 
Placebo
Drug
Tablet
0 mg
0 mg QD
Oral
Part 1: Day 1 to 
Day 7 (blinded)
Placebo
IMP
Provided 
centrally by 
Sponsor
Group 2
Experimental
DOR
Drug
Tablet
100 mg
100 mg QD
Oral
Part 1: Day 1 to 
Day 7 (blinded)
Experimental
IMP
Provided 
centrally by 
Sponsor
Group 2
Experimental
ISL Placebo
Drug
Capsule
0 mg
0 mg QD
Oral
Part 1: Day 1 to 
Day 7 (blinded)
Placebo
IMP
Provided 
centrally by 
Sponsor
Group 2
Experimental
DOR/ISL 
Placebo
Drug
Tablet
0 mg
0 mg QD
Oral
Part 1: Day 1 to 
Day 7 (blinded)
Placebo
IMP
Provided 
centrally by 
Sponsor
Group 3
Experimental
DOR/ISL
Drug
Tablet
100 mg 
DOR/0.75 mg 
ISL
100 mg/0.75 mg 
QD
Oral
Part 1: Day 1 to
Day 7 (blinded)
Experimental
IMP
Provided 
centrally by 
Sponsor
Group 3
Experimental
DOR Placebo
Drug
Tablet
0 mg
0 mg QD
Oral
Part 1: Day 1 to 
Day 7 (blinded)
Placebo
IMP
Provided 
centrally by 
Sponsor
Group 3
Experimental
ISL Placebo
Drug
Capsule
0 mg
0 mg QD
Oral
Part 1: Day 1 to 
Day 7 (blinded)
Placebo
IMP
Provided 
centrally by 
Sponsor
Group 4
Placebo 
Comparator
ISL Placebo
Drug
Capsule
0 mg
0 mg QD
Oral
Part 1: Day 1 to 
Day 7 (blinded)
Placebo
IMP
Provided 
centrally by 
Sponsor
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Arm Name
Arm Type
Intervention 
Name
Type
Dose 
Formulation
Unit Dose 
Strength(s)
Dosage Level(s)
Route of 
Administration
Treatment Period
Use
IMP/
NIMP
Sourcing
Group 4
Placebo 
Comparator
DOR Placebo
Drug
Tablet
0 mg
0 mg QD
Oral
Part 1: Day 1 to 
Day 7 (blinded)
Placebo
IMP
Provided 
centrally by 
Sponsor
Group 4
Placebo 
Comparator
DOR/ISL 
Placebo
Drug
Tablet
0 mg
0 mg QD
Oral
Part 1: Day 1 to 
Day 7 (blinded)
Placebo
IMP
Provided 
centrally by 
Sponsor
All Groups 
(Group 1, 
2, 3, 4)
Experimental
DOR/ISL
Drug
Tablet
100 mg 
DOR/0.75 mg 
ISL
100 mg/0.75 mg 
QD
Oral
Part 2: Day 8 to 
Week 97 (open-
label)c
Experimental
IMP
Provided 
centrally by 
Sponsor
All Groups 
(Group 1, 
2, 3, 4
N/A
Optimized 
Background 
Treatmenta
Drug
Per Approved 
Product Label
Per Approved 
Product Label
Per Approved 
Product Label
Per Approved 
Product Label
Part 2: Day 8 to 
Week 97 (open-
label)
Background 
Treatment
NIMP
Local 
country 
level 
sourcingb
ART=antiretroviral therapy; CCR5=chemokine receptor type 5; DOR=doravirine; InSTI=integrase strand transfer inhibitor; ISL=islatravir; NNRTI=non-nucleoside reverse transcriptase inhibitor; 
NRTI=nucleoside reverse transcriptase inhibitor; OBT=optimized background therapy; PK=pharmacokinetic; QD=once daily.
a
Allowed drug classes include NRTIs, NNRTIs, protease inhibitors, InSTIs, fusion inhibitors, CCR5 antagonists, and postattachment inhibitor.
b
The Sponsor will not provide ART during Part 1 or OBT during Part 2. Participants will provide their own medications.
c
For participants who are pregnant at the last regularly scheduled study visit (Week 97), study intervention will be dispensed at Week 97. In addition, their visit schedule will be extended through 
the duration of the pregnancy and study intervention will be dispensed at Weeks 109, 121, and 133, as applicable.
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 of the definition of IMP/NIMP may exist. In these circumstances, local legislation is followed.
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All supplies indicated in Table 2 will be provided per the "Sourcing" column depending upon 
local country operational requirements. If local sourcing, every attempt should be made to 
source these supplies from a single lot/batch number.
Refer to Section 8.1.8 for details regarding administration of the study intervention.
All placebos were created by the Sponsor to match the active product.
6.2
Preparation/Handling/Storage/Accountability
6.2.1
Dose Preparation
There are no specific calculations or evaluations required to be performed in order to 
administer the proper dose to each participant. The rationale for selection of doses to be used 
in this study is provided in Section 4.3.
6.2.2
Handling, Storage, and Accountability
The investigator or designee must confirm appropriate temperature conditions have been 
maintained during transit for all study intervention received, and any discrepancies are 
reported and resolved before use of the study intervention.
Only participants enrolled in the study may receive study intervention, and only authorized 
site staff may supply or administer study intervention. All study interventions must be stored 
in a secure, environmentally controlled, and monitored (manual or automated) area in 
accordance with the labeled storage conditions with access limited to the investigator and 
authorized site staff.
The investigator, institution, or the head of the medical institution (where applicable) is 
responsible for study intervention accountability, reconciliation, and record maintenance (ie, 
receipt, reconciliation, and final disposition records).
For all study sites, the local country Sponsor personnel or designee will provide appropriate 
documentation that must be completed for drug accountability and return, or local discard 
and destruction if appropriate. Where local discard and destruction is appropriate, the 
investigator is responsible for ensuring that a local discard/destruction procedure is 
documented.
The study site is responsible for recording the lot number, manufacturer, and expiry date for 
any locally purchased product (if applicable) as per local guidelines unless otherwise 
instructed by the Sponsor.
The investigator shall take responsibility for and shall take all steps to maintain appropriate 
records and ensure appropriate supply, storage, handling, distribution, and usage of study 
interventions in accordance with the protocol and any applicable laws and regulations.
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6.3
Measures to Minimize Bias: Randomization and Blinding
6.3.1
Intervention Assignment
Intervention randomization will occur centrally using an IRT system. There are 4 blinded 
study intervention arms in Part 1. Participants will be assigned randomly in a 1:2:1:1 ratio to 
ISL, DOR, DOR/ISL, or placebo, respectively. In Part 2, there is 1 open-label study 
intervention arm; all eligible participants will receive DOR/ISL + OBT.
6.3.2
Stratification
Intervention randomization will be stratified according to the following factors:

Stratum 1: Adults (≥18 years of age) with M184V or I substitutions.
-
At least 73 participants will be enrolled into this Stratum.

Stratum 2: Adults (≥18 years of age) without M184V or I substitutions.

Stratum 3: Pediatric participants (<18 years of age).
-
Pediatric participants will not be stratified by M184V or I substitutions as few 
participants <18 years of age are expected to be enrolled into the study.
Stratification factors help ensure that the blinded treatment arms in Part 1 will be well 
balanced across the treatment groups within each stratum and the study results will not be 
confounded by age of the participant or by the existence of M184V or I substitutions at 
baseline.
6.3.3
Blinding
In Part 1 of this study, a double-blinding technique with in-house blinding will be used. 
DOR, ISL, DOR/ISL, and placebo will be packaged identically so that the blind is 
maintained. The participant, the investigator, and Sponsor personnel or delegate(s) who are 
involved in the study intervention administration or clinical evaluation of the participants are 
unaware of the intervention assignments.
Clinical site personnel and participants will remain blinded to Part 1 treatment through 
Week 97 while Sponsor personnel will remain blinded until the end of Part 1. Sponsor 
personnel involved in performing and reviewing results of the Part 1 analysis will be 
unblinded after the Part 1 database lock.
Part 2 of this study is open-label; therefore, the Sponsor, investigator, and participant will 
know the intervention administered.
To allow timely completion of population PK modeling, restricted early (before database 
lock) unblinding of PK data may be requested. No personnel directly associated with study 
conduct will be unblinded. Before granting select personnel access to unblinded PK data, an 
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official memo detailing unblinding procedures will be generated per Sponsor SOP. This 
memo will list the names of the personnel who will have access to unblinded PK data before 
database lock.
6.4
Study Intervention Compliance
Participants should be instructed to bring their medication, whether clinical supplies provided 
by the Sponsor or ART/OBT provided by study participants, to their visits. At each visit, the 
number of tablets or capsules remaining will be counted, reviewed, and recorded. For any 
ART/OBT that is received via injection or infusion, the participant will provide information 
regarding dosing via a conversation with site personnel. 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 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 or vaccinations specifically prohibited in the exclusion criteria are not allowed 
during time periods specified by this protocol for that medication or vaccination. If there is a 
clinical indication for any medications or vaccinations 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 or vaccination 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.
In instances where the local product circular for DOR is more restrictive with regards to 
prohibited (ie, contraindicated or not recommended) therapies, the local product circular 
supersedes this section.
Prior and concomitant therapies listed in Table 3 are not permitted from the Screening Visit 
and throughout the study treatment period. See footnote in Table 3 for certain exceptions and 
considerations for Part 2 of the study.
This list of prohibited therapies in Table 3 is not comprehensive, and the investigator should 
use his/her medical judgment when assessing a participant’s prior and concomitant 
therapy(ies). The Sponsor Clinical Director or designee should be contacted if there are any 
questions about a therapy not in Table 3 or regarding potential drug interactions with a 
specific treatment that the participant may be receiving or planning to receive.
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Table 3
Prohibited Therapies
Strong and moderate CYP3A 
inducers
Including, but not limited to:
Carbamazepine
Oxcarbazepine
Phenobarbital
Phenytoin
Enzalutamide
Rifabutin
Rifampin
Rifapentine
Mitotane
St. John’s Wort
Herbal remedies
Modafinil
Bosentan
Nafcillin
Non-Study ART
Use of antiretrovirals other than as components of the 
baseline ART (Run-in Period and Part 1) or OBT (Part 2)
is not allowed, except for treatment of ongoing HBV 
infection.
Immunosuppressive therapies
Immune therapy agents, immune modulators or other 
systemic immunosuppressive therapy, including interferon-
based treatment for hepatitis
Time-limited courses of corticosteroids (eg, for asthma 
exacerbation) are permitted.
Investigational agents
All non-study investigational agents including devices. 
Note: For participants with no fully active agents to 
construct optimized background therapy in Part 2 of the 
study, consideration will be given to allow use of 1 
investigational agent, on a case-by-case basis, but this 
must first be approved by the study Clinical Director.
Additional prohibited therapies 
based on baseline ART (Part 1) or 
OBT (Part 2)
Refer to the approved local label(s)
Additional prohibited therapies 
based on ISL
Pentostatin
ART=antiretroviral therapy; CYP3A=cytochrome P450 3A; DOR=doravirine; HBV=hepatitis B Virus; 
ISL=islatravir; OBT=optimized background therapy.
Note: Efavirenz, etravirine, and nevirapine may lead to decreased DOR concentrations when taken 
concomitantly with DOR. If use of these agents is considered essential for constructing the OBT in Part 2,
investigators should first discuss this with the Sponsor’s Clinical Director. Similarly, if use of a moderate 
CYP3A inducer or immunosuppressive agent is considered essential in Part 2 of the study, this should first 
be discussed with the Sponsor’s Clinical Director.
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6.5.1
Rescue Medications and Supportive Care
No rescue or supportive medications are specified for use in this study.
6.6
Dose Modification (Escalation/Titration/Other)
No dose modification of ISL, DOR, or DOR/ISL (during Part 1) or DOR/ISL (during Part 2) 
is allowed during the study.
6.7
Intervention After the End of the Study
At the end of Week 97, provided development of DOR/ISL continues, all eligible 
participants will be given the option to continue receiving study intervention without 
interruption (eg, as part of a rollover study) until it becomes locally available. Eligible 
participants are those who have completed the last scheduled study visit and are considered 
by the investigator to derive clinical benefit from continued administration of DOR/ISL.
Participants who complete the Week 97 visit who do not consent to participate in the rollover 
study should also have an End of Treatment Follow-up visit.
Participants who choose to participate in the rollover study who have decreases in CD4+ T-
cell and/or total lymphocyte counts that meet ECI criteria (Section 8.4.7) at Week 97 should 
have a confirmation visit in this study (per Section 8.11.6 and Section 1.3.4). The 
confirmatory CD4+ T-cell count and/or total lymphocyte count will be followed in this 
study, and the participant will be concurrently enrolled in the rollover study.

Upon repeat testing, if discontinuation criteria (Section 7.1) are confirmed, participation 
in the rollover study will be stopped. The participant will be followed monthly in this 
study until 2 values (12 weeks apart) for the CD4+ T-cell and total lymphocyte counts are 
not decreased by >10% of the average baseline value (Section 8.11.6).

Upon repeat testing, if discontinuation criteria (Section 7.1) are not confirmed, the 
participant will continue to participate in the rollover study only.
Participants who decline participation in the rollover study whose Week 97 visit shows 
decreases in CD4+ T-cell and/or total lymphocyte counts should be managed per Section 
8.11.6.3.
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 for Part 1 of this 
study. The emergency unblinding call center should only be used in cases of emergency (see 
Section 8.1.10). In the event that the emergency unblinding call center is not available for a 
given site in this study, the central electronic 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.
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In Part 1 of the study (Day 1 to Day 7), all study supplies will be double-blinded; therefore, 
the participant, the study site personnel, the Sponsor and/or designee will be blinded. After 
Day 7, DOR/ISL will be provided as open-label supplies (Part 2). Study treatment (name, 
strength, or potency) is included in the label text.
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 1.3 and Section 
8.11.4.
Participants may discontinue study intervention at any time for any reason or be discontinued 
from the study intervention at the discretion of the investigator should any untoward effect 
occur. In addition, a participant may be discontinued from study intervention by the 
investigator or the Sponsor if study intervention is inappropriate, the study plan is violated, or 
for administrative and/or other safety reasons. Specific details regarding procedures to be 
performed at study intervention discontinuation are provided in Section 8.1.9 and Section 
8.11.4.
A participant must be discontinued from study intervention but continue to be monitored per 
Section 8.11.4 for any of the following reasons:

The participant or participant’s legally acceptable representative requests to discontinue 
study intervention.

The participant has a medical condition or personal circumstance (for pregnancy, see
Section 8.11.7) which, in the opinion of the investigator and/or Sponsor, placed 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 is considered by the investigator to no longer derive clinical benefit from 
continued administration of DOR/ISL.

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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
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.
A participant must be discontinued from study intervention if the following criteria are met
but continue to be monitored per Section 8.11.6:

A ≥30% reduction from average baseline value* in CD4+ T-cell count OR in total
lymphocyte count on 2 consecutive measurements taken 3 to 4 weeks apart.
*Note: The average baseline value is defined as the average value between screening 
(within 60 days prior to the first dose of study intervention) and Day 1.
7.2
Participant Withdrawal From the Study
A participant must be withdrawn from the study if the participant or participant’s legally 
acceptable representative withdraws consent from the study.
If a participant withdraws from the study, they will no longer receive study intervention or be 
followed at scheduled protocol visits. 
Specific details regarding procedures to be performed at the time of withdrawal from the 
study, as well as specific details regarding withdrawal from future biomedical research, are 
outlined in Section 8.1.9. The procedures to be performed should a participant repeatedly fail 
to return for scheduled visits and/or if the study site is unable to contact the participant are 
outlined in Section 7.3.
7.3
Lost to Follow-up
If a participant fails to return to the clinic for a required study visit and/or if the site is unable 
to contact the participant, the following procedures are to be performed:
The site must attempt to contact the participant and reschedule the missed visit. If the 
participant is contacted, the participant should be counseled on the importance of maintaining 
the protocol-specified visit schedule.
The investigator or designee must make every effort to regain contact with the participant at 
each missed visit (eg, telephone calls and/or a certified letter to the participant’s last known 
mailing address or locally equivalent methods). These contact attempts should be 
documented in the participant’s medical record.
8
STUDY ASSESSMENTS AND PROCEDURES

Study procedures and their timing are summarized in the SoA. 

Adherence to the study design requirements, including those specified in the SoA, is 
essential and required for study conduct.
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
The investigator is responsible for ensuring that procedures are conducted by 
appropriately qualified (by education, training, and experience) staff. Delegation of study 
site personnel responsibilities will be documented in the Investigator Trial File Binder (or 
equivalent).

All study-related medical decisions must be made by an investigator who is a qualified 
physician.

All screening evaluations must be completed and reviewed to confirm that potential 
participants meet all eligibility criteria. The investigator will maintain a screening log to 
record details of all participants screened and to confirm eligibility or record reasons for 
screening failure, as applicable.

Additional evaluations/testing may be deemed necessary by the investigator and or the 
Sponsor for reasons related to participant safety. In some cases, such evaluation/testing 
may be potentially sensitive in nature (eg, HIV, Hepatitis C), and thus local regulations 
may require that additional informed consent, and assent if applicable, 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 full duration of the study is 
provided in Appendix 2.
Repeat or unscheduled samples may be taken for safety reasons or for technical issues with 
the samples.
8.1
Administrative and General Procedures
8.1.1
Informed Consent/Assent
The investigator or medically qualified designee (consistent with local requirements) must 
obtain documented informed consent, and assent if applicable, from each potential 
participant or their legally acceptable representative prior to participating in this clinical 
study or future biomedical research. If there are changes to the participant’s status during the 
study (eg, health or age of majority requirements), the investigator or medically qualified 
designee must ensure the appropriate documented informed consent/assent is in place.
8.1.1.1
General Informed Consent/Assent
Informed consent/assent given by the participant or their legally acceptable representative 
must be documented on a consent form. The form must include the study protocol number, 
study protocol title, dated signature, and agreement of the participant (or his/her legally 
acceptable representative) and agreement of the person conducting the consent/assent
discussion.
A copy of the signed and dated informed consent/assent form should be given to the 
participant (or their legally acceptable representative) before participation in the study.
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The initial informed consent/assent form, any subsequent revised informed consent/assent 
form, and any written information provided to the participant must receive the Institutional 
Review Board/Independent Ethics Committee’s (IRB/IEC’s) approval/favorable opinion in 
advance of use. The participant or his/her legally acceptable representative should be 
informed in a timely manner if new information becomes available that may be relevant to 
the participant’s willingness to continue participation in the study. The communication of 
this information will be provided and documented via a revised consent/assent form or 
addendum to the original consent/assent form that captures the participant’s or the 
participant’s legally acceptable representative’s dated signature.
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. The assent, as applicable will adhere to IRB/IEC requirements, 
applicable laws and regulations and Sponsor requirements.
8.1.1.2
Consent/Assent and Collection of Specimens for Future Biomedical 
Research
The investigator or medically qualified designee will explain the future biomedical research 
consent/assent to the participant, or the participant's legally acceptable representative, answer 
all of his/her questions, and obtain documented informed consent/assent before performing 
any procedure related to future biomedical research. A copy of the informed consent/assent
will be given to the participant before performing any procedure related to future biomedical 
research.
8.1.1.3
Consent/Assent for Postnatal Infant Safety Data Collection Through One 
Year of Age
The investigator or medically qualified designee will explain the consent/assent for infant 
safety data collection to the participant, or the participant’s legally acceptable representative, 
answer all questions, and obtain documented informed consent/assent before collecting any 
data related to infant safety. A copy of the informed consent/assent will be given to the 
participant.
8.1.1.4
Consent/Assent for Continuation of Study Intervention During Pregnancy
Upon learning that a participant is pregnant, the investigator or medically qualified designee 
and the participant will discuss the potential benefits and risks of continuing (or 
discontinuing) study intervention (Section 8.11.7). A separate consent/assent is required to 
continue study intervention in participants who become pregnant. The investigator or 
medically qualified designee will explain the consent/assent to the participant, or the 
participant’s legally acceptable representative, answer all questions, and obtain documented 
informed consent/assent before continuing study intervention. A copy of the informed 
consent/assent will be given to the participant.
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8.1.2
Inclusion/Exclusion Criteria
All inclusion and exclusion criteria will be reviewed by the investigator, who is a qualified 
physician, to ensure that the participant qualifies for the study.
8.1.3
Participant Identification Card
All participants will be given a participant identification card identifying them as participants 
in a research study. The card will contain study site contact information (including direct 
telephone numbers) to be used in the event of an emergency. The investigator or qualified 
designee will provide the participant with a participant identification card immediately after 
the participant provides documented informed consent/assent. At the time of intervention
randomization, site personnel will add the treatment/randomization number to the participant 
identification card.
The participant identification card also contains contact information for the emergency 
unblinding call center so that a healthcare provider can obtain information about study 
intervention in emergency situations where the investigator is not available. 
8.1.4
Medical History
A medical history will be obtained by the investigator or qualified designee at the Screening 
Visit. 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 as relevant.
8.1.5
Prior and Concomitant Medications Review
8.1.5.1
Prior Medications
The investigator or qualified designee will review prior medication use and record prior 
medication taken by the participant since the Screening Visit through first dose of study 
intervention.
All prior ARTs taken by the participant from the initiation of treatment (if available) will be 
recorded before the first dose of study intervention.
8.1.5.2
Concomitant Medications
The investigator or qualified designee will record medication, if any, taken by the participant 
during the study.
The ART/OBT taken by the participant during the study will be recorded by the investigator 
or qualified designee.
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8.1.6
Assignment of Screening Number
All consented participants will be given a unique screening number that will be used to 
identify the participant for all procedures that occur 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 rescreened will retain the original screening number assigned at the 
initial Screening Visit. Specific details on the screening/rescreening visit requirements are 
provided in Section 8.11.1.
8.1.7
Assignment of Treatment/Randomization Number
All eligible participants will be randomly allocated and will receive a 
treatment/randomization number at the randomization visit (Day 1). The 
treatment/randomization number identifies the participant for all procedures occurring after 
treatment randomization. Once a treatment/randomization number is assigned to a 
participant, it can never be reassigned to another participant.
A single participant cannot be assigned more than 1 treatment/randomization number.
8.1.8
Study Intervention Administration
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 1.3.1).
The first dose of double-blind study intervention will be administered at the study site at the 
randomization visit (Day 1). Subsequent dosing will be performed once daily by the 
participant (ie, unsupervised at his/her home) at approximately the same time each day.
8.1.8.1
Timing of Dose Administration
All study interventions should be administered QD at approximately the same time each day 
without regard to food. The tablets or capsules from each container of study intervention 
should be taken together.
During the double-blind treatment period (Part 1), all participants will take 1 tablet or capsule
from each of the 3 containers QD with their failing ART.
During the open-label treatment period (Part 2), all participants will receive open-label 
DOR/ISL and will take 1 tablet each day with OBT. If more than 1 bottle is dispensed, the 
participant is instructed to use all of the medication in a single bottle before opening another 
bottle. 
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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.
If a participant misses a dose of baseline ART (during Part 1) or OBT (during Part 2), 
guidance in the approved label(s) should be followed.
8.1.9
Discontinuation and Withdrawal
Participants who discontinue study intervention prior to completion of the treatment period 
should have an Early Discontinuation visit performed per the SoA (Section 1.3) and be 
encouraged to continue to be followed as outlined in Section 8.11.4. Participants who 
discontinue study intervention for decreases in CD4+ T-cell counts and/or total lymphocyte 
counts or who discontinue study intervention for any other reason and are noted to have a 
>10% decrease from average baseline value in their CD4+ T-cell and/or total lymphocyte 
counts or have decreases in CD4+ T-cell and/or total lymphocyte counts that meet ECI 
criteria at the Early Discontinuation of Treatment Visit should be managed per Section 8.11.6
until the counts recover.
When a participant withdraws from participation in the study, all applicable activities 
scheduled for the Early Discontinuation visit should be performed (at the time of 
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 and participants should 
attend the End of Treatment Follow-up visit approximately 6 weeks after discontinuing study 
intervention.
8.1.9.1
Withdrawal From Future Biomedical Research
A participant’s consent for Future Biomedical Research may be withdrawn by the participant 
or the participant’s legally acceptable representative (as appropriate). 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.
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In the event that the medical records for the main study are no longer available (eg, if the 
investigator is no longer required by regulatory authorities to retain the main study records) 
or the specimens have been completely anonymized, there will no longer be a link between 
the participant’s personal information and their specimens. In this situation, the request for 
specimen withdrawal cannot be processed.
8.1.10
Participant Blinding/Unblinding
STUDY INTERVENTION IDENTIFICATION INFORMATION IS TO BE UNMASKED 
ONLY IF NECESSARY FOR THE WELFARE OF THE PARTICIPANT. EVERY 
EFFORT SHOULD BE MADE NOT TO UNBLIND.
For emergency situations where the investigator or medically qualified designee (consistent 
with local requirements) needs to identify the intervention used by a participant and/or the 
dosage administered, he/she will contact the emergency unblinding call center by telephone 
and make a request for emergency unblinding. As requested by the investigator or medically 
qualified designee, the emergency unblinding call center will provide the information to 
him/her promptly and report unblinding to the Sponsor. Prior to contacting the emergency 
unblinding call center to request unblinding of a participant’s intervention assignment, the 
investigator who is a qualified physician should make reasonable attempts to enter the 
intensity of the AEs observed, the relation to study intervention, the reason thereof, etc., in 
the medical chart. If it is not possible to record this assessment in the chart prior to the 
unblinding, the unblinding should not be delayed.
In the event that unblinding has occurred, the circumstances around the unblinding (eg, date, 
reason, and person performing the unblinding) must be documented promptly, and the 
Sponsor Clinical Director notified as soon as possible.
Once an emergency unblinding has taken place, the principal investigator, site personnel, and 
Sponsor personnel are unblinded so that appropriate follow-up medical care can be provided 
to the participant.
Additionally, the investigator or medically qualified designee must go into the IRT system 
and perform the unblind in the IRT system to update drug disposition. In the event that the 
emergency unblinding call center is not available for a given site in this study, the IRT 
system should be used for emergency unblinding in the event that this is required for 
participant safety.
8.1.11
Calibration of Equipment
The investigator or qualified designee has the responsibility to ensure that any device or 
instrument used for a clinical evaluation/test during a clinical study that provides information 
about inclusion/exclusion criteria and/or safety or efficacy parameters shall be suitably 
calibrated and/or maintained to ensure that the data obtained are reliable and/or reproducible. 
Documentation of equipment calibration must be retained as source documentation at the 
study site.
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8.1.12
Administration of Patient Questionnaires
Adult participants (≥18 years at the time of consent) will complete the FAHI at Day 1, 
Week 25, Week 49, Week 97, and/or the Early Discontinuation visit. Participants are to 
complete the questionnaire on their own at the site on paper during the appropriate study visit 
(see SoA, Section 1.3) prior to being seen by the investigator, receiving study intervention, 
discussing any medical conditions with the study personnel, or receiving any medical results. 
The questionnaire will not be administered to participants if native language translation is not 
available.  
The participant responses to the questionnaire will be entered into the appropriate eCRF by 
site staff according to data entry guidelines.
8.2
Efficacy Assessments
The primary efficacy measurement is HIV-1 RNA. Additional efficacy measurements 
include CD4+ T-cell counts, viral resistance testing, and proviral DNA resistance testing. 
Blood will be collected as indicated in the SoA (Section 1.3).
8.2.1
HIV-1 RNA
Plasma HIV-1 RNA quantification will be performed at the central laboratory using an 
Abbott Real Time PCR assay with a lower limit of detection of 40 copies/mL.  
8.2.2
Management of Study Participants with Viremia
When viremia (HIV-1 RNA ≥200 copies/mL after participant has achieved HIV-1 RNA of 
<50 copies/mL) is detected, the investigator should query the participant regarding adherence 
to study therapy, intercurrent illness, or recent immunization. All cases of viremia must be 
confirmed, and the participant should continue to take the assigned dosage of study 
intervention while awaiting confirmation.
HTE patients may derive clinical benefit from declining HIV-1 RNA levels even if complete 
viral suppression is not achieved. Participants with HIV-1 RNA ≥200 copies/mL during the 
open-label treatment period (Part 2) who are considered by the investigator to derive clinical 
benefit may continue treatment with DOR/ISL.
8.2.2.1
Viremia Confirmation
Confirmation of viremia requires 2 consecutive plasma HIV-1 RNA results of ≥200 
copies/mL after a participant previously achieved HIV-1 RNA of <50 copies/mL. The second 
sample collected at a “Viremia Confirmation” visit at least 4 weeks from the date of the 
initial sample. This timeframe may be extended if study intervention is interrupted for one 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 without interruption;
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
Immunization: Redraw approximately 4 weeks following any immunization, during 
which time the participant should continue to receive the assigned dosage of study 
intervention without interruption;

Toxicity management, noncompliance, or other reason: Redraw 2 to 4 weeks 
following resuming the assigned dosage of study intervention.
8.2.2.2
Viral Drug Resistance Testing
Phenotypic and genotypic HIV-1 drug resistance testing will be performed on plasma 
samples per the SoA (Section 1.3) to determine resistance to ISL, DOR, and other ARTs. 
Samples collected at Day 1 (baseline), Day 8, and samples with HIV-1 RNA ≥200 copies/mL 
for participants who never suppressed at Week 25, Week 49, and Week 97 and those that 
were collected either to confirm viremia or at discontinuation will be sent for genotypic and 
phenotypic resistance testing.
Whole blood samples for proviral DNA resistance testing will be collected and analyzed at 
Screening for all participants. In addition, postrandomization samples for proviral DNA 
resistance testing will be collected per the SoA (Section 1.3). Postrandomization whole blood 
samples in participants with plasma HIV-1 RNA ≥200 copies/mL at Week 25, Week 49, and 
Week 97 and those that were collected either to confirm viremia or at discontinuation will be 
analyzed for proviral DNA resistance testing.
All viral resistance testing will be performed by the central laboratory.
8.2.3
T- and B- Lymphocyte and Natural Killer Cell Profile (TBNK)
A TBNK Panel, including CD4+ T cell count, will be performed at the central laboratory
(Appendix 2). Refer to Section 8.11.6 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.
8.3.1
Physical Examinations
A complete physical examination will be conducted at the randomization visit (Day 1) by an 
investigator or medically qualified designee (consistent with local requirements) as per 
institutional standard. The complete physical examination will include examination of body 
systems (including, but not limited to, general appearance, skin, neck, eyes, ears, nose, throat, 
breast, lungs, heart, abdomen, back, lymph nodes, extremities, and nervous system).
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A directed physical examination will be conducted as indicated in the SoA (Section 1.3) by 
an investigator or medically qualified designee (consistent with local requirements) per 
institutional standard, 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. This does not preclude examination of any of the 
body system as clinically indicated.
Height and weight will also be measured and recorded at the visits specified in the SoA 
(Section 1.3). Height measurements are recommended to be taken by use of a stadiometer, 
however not required.
Investigators should pay special attention to clinical signs related to previous serious 
illnesses.
8.3.2
Vital Signs
Vital signs will be measured after approximately 5-10 minutes of rest and will include 
temperature, pulse, respiratory rate, and systolic and diastolic blood pressure.
Note: Oral temperatures are preferred, but not required. 
8.3.3
Electrocardiograms
A single 12-lead ECG will be obtained and reviewed by an investigator or medically 
qualified designee (consistent with local requirements) as outlined in the SoA (see Section 
1.3.1) using an ECG machine that automatically calculates the heart rate and measures PR,
QRS, QT, and QTc intervals. 
8.3.4
Confirmation of Menarche, Contraception, and Pregnancy Testing
To determine if a participant is of child bearing potential, female participants should be asked 
to confirm their menarche status. Once menarche has been established and recorded in source 
documents, a participant is considered a WOCBP, and is 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 the use of 
contraception since the prior visit, according to Contraceptive Guidance in Appendix 5. 
Confirmation should be noted in source documents at each visit.
Urine pregnancy test kits will be provided by the central laboratory, and routine testing will 
be performed by the local laboratory. In the event of a positive urine pregnancy test result, 
serum pregnancy testing must be performed by the central laboratory. If a participant 
becomes pregnant, refer to Section 8.11.7.
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8.3.5
Clinical Safety Laboratory Assessments
Refer to Appendix 2 for the list of clinical laboratory tests to be performed and to the SoA for 
the timing and frequency.

The investigator or medically qualified designee (consistent with local requirements) 
must review the laboratory report, document this review, and record any clinically 
relevant changes occurring during the study in the AE section of the 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: Management of decreases in CD4+ T-cell and/or total lymphocyte counts is 
described in Section 8.11.6.
8.3.6
HBV Assessments
Participants who become HBsAg or HBV DNA positive after study entry may be allowed to 
continue study treatment if deemed medically appropriate upon consultation with the 
Sponsor.
8.3.7
Tobacco and Alcohol Assessments
Participants’ use of tobacco and alcohol will be obtained and recorded at Week 97.
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.
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Adverse events, SAEs, and other reportable safety events will be reported by the participant
(or, when appropriate, by a caregiver, surrogate, or the participant's legally authorized 
representative).
The investigator and any designees are responsible for detecting, documenting, and reporting 
events that meet the definition of an AE or SAE as well as other reportable safety events. 
Investigators remain responsible for following up AEs, SAEs, and other reportable safety 
events for outcome according to Section 8.4.3.
The investigator, who is a qualified physician, will assess events that meet the definition of 
an AE or SAE as well as other reportable safety events with respect to seriousness, 
intensity/toxicity and causality.
8.4.1
Time Period and Frequency for Collecting AE, SAE, and Other Reportable 
Safety Event Information
All AEs, SAEs, and other reportable safety events that occur after the participant provides 
documented informed consent but before intervention randomization must be reported by the 
investigator if the participant is receiving placebo run-in or other run-in treatment, if the 
event causes the participant to be excluded from the study, or is the result of a protocol-
specified intervention, including but not limited to washout or discontinuation of usual 
therapy, diet, or a procedure.
From the time of intervention randomization through study duration, all AEs, SAEs, and 
other reportable safety events must be reported by the investigator.
Additionally, any SAE brought to the attention of an investigator at any time outside of the 
time period specified in the previous paragraph must be reported immediately to the Sponsor 
if the event is considered related to study intervention. 
For infants born to participants who become pregnant and consent to infant safety data 
collection, SAEs (including perinatal HIV-1 infection) occurring through 1 year of age must 
be reported by the investigator to the Sponsor within 24 hours of learning of the event.
Investigators are not obligated to actively seek AEs or SAEs or other reportable safety events 
in former study participants. However, if the investigator learns of any SAE, including a 
death, at any time after a participant has been discharged from the study, and he/she 
considers the event to be reasonably related to the study intervention or study participation, 
the investigator must promptly notify the Sponsor.
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.
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For participants who continue in a rollover study, the collection requirements of AEs, SAEs, 
and other reportable safety events in this protocol are amended as follows:

AEs, SAEs, and other reportable safety events will be collected and recorded through the 
last study visit in this protocol.

Pregnancy outcome and infant SAEs will be captured in this protocol, if pregnancy 
exposure is reported in this protocol.

The last collection of nonserious AEs (including cancer that does not meet serious 
criteria) will be at the last study visit in this protocol.
Note: All new SAEs (including those considered related to study intervention) and other 
new reportable safety events (including pregnancy exposure) that occur after the last 
study visit will be collected in the rollover study.
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
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Type of Event
Reporting Time 
Period:
Consent to 
Randomization/ 
Allocation
Reporting Time 
Period:
Randomization/ 
Allocation through 
Protocol-specified 
Follow-up Period
Reporting Time Period:
After the Protocol-
specified Follow-up 
Period
Time Frame 
to Report 
Event and 
Follow-up 
Information 
to Sponsor:
Event of Clinical Interest 
(do not require regulatory 
reporting)
Report if:
- due to 
intervention
- causes exclusion
Report
- non-DILI ECIs and 
those not requiring 
regulatory reporting
Not required
Within 5 
calendar days 
of learning of 
event
Cancer
Report if:
- due to 
intervention
- causes exclusion
Report all
Not required
Within 5 
calendar days 
of learning of 
event
Overdose
Report if:
- receiving placebo 
run-in or other run-
in medication 
Report all
Not required
Within 5 
calendar days 
of learning of 
event
8.4.2
Method of Detecting AEs, SAEs, and Other Reportable Safety Events
Care will be taken not to introduce bias when detecting AEs and/or SAEs and other 
reportable safety events. Open-ended and nonleading verbal questioning of the participant is 
the preferred method to inquire about AE occurrence.
8.4.3
Follow-up of AE, SAE, and Other Reportable Safety Event Information
After the initial AE/SAE report, the investigator is required to proactively follow each 
participant at subsequent visits/contacts. All AEs, SAEs, and other reportable safety events,
including pregnancy and exposure during breastfeeding, events of clinical interest (ECIs), 
cancer, and overdose will be followed until resolution, stabilization, until the event is 
otherwise explained, or the participant is lost to follow-up (as defined in Section 7.3). In 
addition, the investigator will make every attempt to follow all nonserious AEs that occur in
randomized participants for outcome. Further information on follow-up procedures is given 
in Appendix 3.
8.4.4
Regulatory Reporting Requirements for SAE
Prompt notification (within 24 hours) by the investigator to the Sponsor of SAE is essential 
so that legal obligations and ethical responsibilities towards the safety of participants and the 
safety of a study intervention under clinical investigation are met.
The Sponsor has a legal responsibility to notify both the local regulatory authority and other 
regulatory agencies about the safety of a study intervention under clinical investigation. The 
Sponsor will comply wth 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.
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An investigator who receives an investigator safety report describing an SAE or other 
specific safety information (eg, summary or listing of SAE) from the Sponsor will file it 
along with the IB and will notify the IRB/IEC, if appropriate according to local requirements.
8.4.5
Pregnancy and Exposure During Breastfeeding
Although pregnancy and infant exposure during breastfeeding are not considered AEs, any 
pregnancy or infant exposure during breastfeeding in a participant (spontaneously reported to 
the investigator or their designee) that occurs during the study are reportable to the Sponsor.
All reported pregnancies must be followed to the completion/termination of the pregnancy. 
Pregnancy outcomes of spontaneous abortion, missed abortion, benign hydatidiform mole, 
blighted ovum, fetal death, intrauterine death, miscarriage, and stillbirth must be reported as 
serious events (Important Medical Events). If the pregnancy continues to term, the outcome 
(health of infant) must also be reported.
For infants born to participants who become pregnant and consent to infant safety data 
collection, SAEs (including perinatal HIV-1 infection) occurring through 1 year of age must 
be reported by the investigator to the Sponsor within 24 hours of learning of the event.
8.4.6
Disease-related Events and/or Disease-related Outcomes Not Qualifying as 
AEs or SAEs
This section is not applicable to the study.
8.4.7
Events of Clinical Interest (ECIs)
Selected nonserious and SAEs are also known as ECIs and must be reported to the Sponsor.
Events of clinical interest for this study include:

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).

A ≥30% decrease from average baseline** values of CD4+ T-cell count or total
lymphocyte count values while on study intervention. 
** The average baseline value is defined as the average value between screening (within 
60 days prior to the first dose of study intervention) and Day 1.
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Note: The first on-treatment value that meets the above CD4+ T-cell or total lymphocyte 
criteria should be reported as an ECI. See Section 8.11.6 for further guidance on the 
management of participants meeting CD4+ T-cell or total lymphocyte criteria.
8.5
Treatment of Overdose
In this study, an overdose is any dose higher than the prescribed dose of study intervention.
No specific information is available on the treatment of overdose. 
Decisions regarding dose interruptions will be made by the investigator in consultation with 
the Sponsor Clinical Director based on the clinical evaluation of the participant.
8.6
Pharmacokinetics
8.6.1
Blood Collection for Plasma ISL and DOR
Venous blood samples will be collected for measurement of ISL and DOR. Sample 
collection, storage, and shipment instructions for plasma samples will be provided in the 
operations/laboratory manual.
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. 
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.
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 8.11.7.1.
Table 5
Collection of Population PK Samples
Study Visit
Time relative to dose
Day 1
Predose
Day 8
Sample collected irrespective of time of dose (time of last dose and 
time of PK sample collection must be documented), but prior to 
initiation of open-label DOR/ISL + OBT (Part 2)
Week 3
Sample collected irrespective of time of dose (time of last dose and 
time of PK sample collection must be documented)
Week 13
Sample collected irrespective of time of dose (time of last dose and 
time of PK sample collection must be documented)
Week 25
Sample to be collected predose and within 0.5 and 2 hours postdose*
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Study Visit
Time relative to dose
Week 37
Sample collected irrespective of time of dose (time of last dose and 
time of PK sample collection must be documented)
Week 49
Sample to be collected predose and within 0.5 and 2 hours postdose*
*
For participants who take their study intervention during the day, samples should be collected predose 
and postdose. For participants who take their study intervention in the evening, only a postdose sample 
should be collected the following day irrespective of time of dose (time of last dose and time of PK 
sample collection must be documented).
8.7
Pharmacodynamics
Pharmacodynamic parameters will not be evaluated in this study.
8.8
Biomarkers
8.8.1
Planned Genetic Analysis Sample Collection
The planned genetic analysis sample should be drawn for planned analysis of the association 
between genetic variants in DNA and drug response. This sample will not be collected at the 
site if there is either a local law or regulation prohibiting collection, or if the IRB/IEC does 
not approve the collection of the sample for these purposes. If the sample is collected, 
leftover extracted DNA will be stored for future biomedical research if the participant 
provides documented informed consent for future biomedical research. If the planned genetic 
analysis is not approved, but future biomedical research is approved and consent is given, 
this sample will be collected for the purpose of future biomedical research.
Sample collection, storage, and shipment instructions for Planned Genetic Analysis samples 
will be provided in the operations/laboratory manual.
8.8.2
Inflammation
Blood samples will be collected to evaluate the inflammatory and thrombotic response as 
measured by the following laboratory markers as indicated in the SoA (Section 1.3).

IL-6

D-dimer

sCD-163

hs-CRP
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8.8.3
Fasting Lipid and Metabolic Profiles
Participants will be asked to fast for at least 8 hours prior to Day 1 (Visit 4) and Day 8 
(Visit 5) where blood will be taken to measure glucose, HDL-C, TGs, TC, and non-HDL-C.
Participants with normal fasting lipid and metabolic profiles will repeat measurements at 
Week 49 (Visit 12), Week 73 (Visit 14), and Week 97 (Visit 16). Participants with abnormal 
measurements at Day 8 will also have repeat testing at Week 25 (Visit 10).
8.9
Future Biomedical Research Sample Collection
If the participant provides documented informed consent for FBR, 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 instruction for whole blood FBR samples will be 
provided in the operations/laboratory manual. Refer to the SoA (Section 1.3) for timing of 
sample collection.
8.10
Health Economics Medical Resource Utilization and Health Economics
Medical Resource Utilization and Health Economics are not evaluated in this study.
8.11
Visit Requirements
Visit requirements are outlined in Section 1.3. Specific procedure-related details are provided 
in Section 8.
8.11.1
Screening/Rescreening
Screening
Approximately 60 days 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 within 10 days after confirmatory HIV-1 RNA result has been obtained 
and all other eligibility criteria have been met.
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 60-day screening window.
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Rescreening
Since HTE participants have few or no options for an effective treatment, it is necessary to 
consider the circumstances where a participant may not meet eligibility criteria at the current 
time, but due to the progression of their HIV-1 disease, they may qualify at a later time (eg, a 
participant not having a high enough HIV-1 RNA at Screening or a participant not having 
NRTI or NNRTI resistance on the screening resistance test). Participants may be allowed to 
rescreen following consultation with the Sponsor. Once a participant has started the 
rescreening process, a new screening period (ie, an additional 60-day window) will begin, 
during which time screening procedures may be repeated.
The following assessments must be repeated for participants who are rescreened:

Vital signs, weight, and directed physical examination

Review medical history and prior/concomitant medications for new information

All laboratory assessments (includes serum hCG pregnancy testing for WOCBP)

HIV-1 drug resistance testing will be repeated only if determined to be required

Review of AEs
Documented informed consent/assent provided during the original screening period should 
be reviewed with the participant and 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).
8.11.2
Run-in Period
The Run-in Period begins immediately after Screening and ends at randomization. This 
period is designed to allow detection of participants who are failing their baseline regimen 
due to nonadherence. HIV-1 RNA testing will be repeated at Visit 2 to confirm study 
eligibility (HIV-1 RNA ≥500 copies/mL with a <0.5 log10 decline in HIV-1 RNA from Visit 
1). Participants at Visit 2 who have HIV-1 RNA ≥500 copies/mL and a ≥0.5 log10 decline 
from Visit 1, must return to the site 7 to 14 days after Visit 2 for a Repeat HIV-1 RNA 
confirmation visit (Visit 3). In order to be eligible for randomization, participants must have 
HIV-1 RNA ≥500 copies/mL and a <0.3 log10 decline in HIV-1 RNA from the previous 
result at Visit 2. Participants should be instructed to maintain strict adherence to their 
baseline ART regimen during this Run-in Period.
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8.11.3
Treatment Period
8.11.3.1
Fasting
Visits at Day 1 (Visit 4), Day 8 (Visit 5), Week 49 (Visit 12), Week 73 (Visit 14), and Week 
97 (Visit 16) 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. 
Participants may need to fast at the Week 25 (Visit 10) visit as well depending on the 
outcome of the fasting lipid profile and fasting glucose measurement at Day 8 (see 
Section 8.8.3).
8.11.3.2
Double-blind (Part 1)
All procedures should be completed prior to intervention randomization as per the SoA 
(Section 1.3.1). Randomization should occur within 10 days after confirmation of HIV-1 
RNA eligibility. Participants who are eligible will enter the 7-day double-blind treatment 
period (Part 1). Participants will continue on their failing ART during Part 1 and should be 
instructed to maintain strict adherence to both their failing ART and to the study intervention 
during this period.
The Visit at Day 1 requires 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 this visit and to confirm with participants 
their fasting status in the appropriate source documentation.
8.11.3.3
Open-label (Part 2)
Participants who complete the 7-day double-blind treatment period (Part 1) will continue to 
the open-label treatment period (Part 2). Participants will take OBT along with open-label 
DOR/ISL for 96 weeks. 
8.11.3.4
Optional Nurse Visits and Telephone Visits
A visiting nurse service may be used (if locally available and approved for use) at any visit 
after a participant is randomized. If a visiting nurse service is used for any visit, the 
investigator should contact the participant by phone on the same day as the nurse visit, or as 
soon as possible to perform an investigator AE assessment. Refer to the nursing manual for 
additional details.
For visits conducted by the visiting nurse, whole blood for proviral DNA resistance and FBR 
samples (for those participants who consent to FBR) 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 proviral DNA resistance and FBR, when 
possible. If an unscheduled visit for collection of whole blood for proviral DNA resistance 
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testing and FBR is not possible, the sample should be drawn at the next scheduled visit at the 
site.
8.11.3.5
End of Study Week 97 Visit
Week 97 represents the end of this study.
Participants will be given 2 options at the Week 97 visit:
1. End participation in this study and resume locally available treatment of their choice. 
These participants should have an End of Treatment Follow-up visit approximately 42 
(+ 7) days (6 weeks) after the last dose of study intervention.
2. Provide documented consent to participate in the rollover study. The rollover study will 
provide open-label DOR/ISL to participants.
Participants who are pregnant at Week 97 will be managed per Section 8.11.7.
Management of participants with decreased CD4+ T-cell counts and/or total lymphocyte 
counts is as follows:

See Section 6.7 for management of participants entering the rollover study who have 
CD4+ T-cell count and/or total lymphocyte count decreases that meet ECI criteria at 
their last study visit in this study (ie, rollover enrollment visit).

Participants not participating in the rollover study who have decreases in CD4+ T-cell 
and/or total lymphocyte counts that meet ECI criteria or are decreased by >10% of 
their average baseline value require additional follow-up monitoring of CD4+ T-cell 
and lymphocyte counts per Section 6.7 and Section 8.11.6.
8.11.4
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 8.11.4.1) 
and an End of Treatment Follow-up visit (Section 8.11.4.2) conducted. After the visit 
procedures are completed, the participant will be withdrawn from the study and managed for 
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 8.11.6.

If participants discontinue study intervention for other reasons and the CD4+ T-cell 
counts and/or total lymphocyte counts at Early Discontinuation of Treatment visit are 
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decreased by >10% of their average baseline value, additional monitoring is required per 
Section 8.11.6.
8.11.4.1
Early Discontinuation of Treatment
Participants that discontinue treatment early for any reason should have an Early 
Discontinuation of Treatment visit as outlined in Section 1.3.2. If early discontinuation 
occurs during the timeframe of a scheduled study visit, the assessments for the Early 
Discontinuation of Treatment visit should be conducted.
8.11.4.2
End of Treatment Follow-Up Visit
Participants who discontinue study intervention at any time prior to the Week 97 visit for any 
reason(s) and participants who will not continue study intervention after Week 97 will have 
an End of Treatment Follow-up visit in the clinic approximately 42 days after the last dose of 
study intervention. Assessments for this visit are outlined in Section 1.3.2. Participants who 
complete the Week 97 visit who do not consent to participate in the rollover study should 
also have an End of Treatment Follow-up visit.
Participants discontinuing study intervention with specified decreases in CD4+ T-cell and/or 
total lymphocyte counts will be followed monthly for monitoring of CD4+ T-cell and/or total 
lymphocyte counts per Section 8.11.6.
8.11.5
Viremia Confirmation
If a participant meets the criteria for viremia (see Section 8.2.2), a Viremia Confirmation 
visit must be conducted at least 4 weeks of the initial HIV-1 viremia. 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 from the viremia confirmation visit must be collected.
8.11.6
Management of Participants with Decreases in CD4+ T-cell Counts and/or 
Total Lymphocyte Counts
Management of participants with decreases in CD4+ T-cell counts and/or total lymphocyte 
counts is explained below.
8.11.6.1
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 counts and/or total lymphocyte counts meet 
ECI criteria (Section 8.4.7) must have a confirmation visit in 3 to 4 weeks*. 
Upon repeat testing at the confirmation visit (Section 1.3.4), if the discontinuation criteria are 
met (Section 7.1), participants must be discontinued from study intervention and managed 
per Section 8.11.6.2.
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8.11.6.2
Participants Discontinued from Study Intervention Due to Decreased CD4+ 
T-cell Count and/or Total Lymphocyte Count
After discontinuation from study intervention, participants will be managed for treatment of 
HIV-1 per local standard of care.
Participants discontinued from study intervention due to specified decreases in CD4+ T-cell 
and/or total lymphocyte counts should undergo assessments as specified for the Early 
Discontinuation of Treatment Visit and the End of Treatment Follow-up Visit (Section 
1.3.4). 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.
8.11.6.3
Participants Discontinued from Study Intervention For Other Reasons 
AND Have Decreases in CD4+ T-cell Count and/or Total Lymphocyte 
Count
Participants who discontinue study intervention for any other reason or decline participation 
into the rollover study who are found to have decreases in CD4+ T-cell and/or total 
lymphocyte counts >10% of average baseline values, or that meet ECI criteria at the Early 
Discontinuation of Treatment Visit should undergo assessments specified at the End of 
Treatment Follow-up at Day 42 (Section 1.3.5).

If the decrease of >10% of average baseline is confirmed at this visit, participants should 
continue to 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.

If the decrease of >10% of average baseline is not confirmed at this visit, then no further 
follow-up for CD4+ T cell and/or total lymphocyte counts is required. 
8.11.7
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.”
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 8.11.7.4,

Her intended breastfeeding status (Section 8.11.7.3),
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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).
8.11.7.1
Continuing Study Intervention
Participants who become pregnant and consent to continue study intervention 
(Section 8.1.1.4) should complete all remaining protocol-specified visits and procedures per 
the regular schedule in the SoA (Section 1.3.1). 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]). 
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 (TW 97), their
visit schedule will be extended through the duration of the pregnancy to allow assessments 
through each trimester and postpartum (Section 1.3.3). At the completion of the pregnancy, 
continued access to DOR/ISL will be offered per Section 6.7. 
For participants who continue DOR/ISL, PK samples will be collected at their scheduled visit 
during the 1st, 2nd, and 3rd trimesters and postpartum to evaluate DOR and ISL concentration
levels per Table 6. These samples will be used to characterize the PK profile of DOR/ISL 
during pregnancy.
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Table 6
Collection of Population PK Samples During Pregnancy and Postpartum
Study Visit
Time Relative to Dose
1st Trimestera
Predose
2nd Trimester
Predose AND 
0.5 to 2 hours AND 4 to 6 hours postdose
3rd Trimester
Predose AND 
0.5 to 2 hours AND 4 to 6 hours postdose
Postpartumb
Predose
PK=pharmacokinetic.
a
Collected in the 1st trimester at a scheduled visit when a participant reports gravid status.
b
The first visit after delivery; ~12 weeks after the 3rd trimester visit and ≤8 weeks after delivery. 
8.11.7.2
Discontinuing Study Intervention
Participants who become pregnant and discontinue study intervention should have an Early 
Discontinuation of Treatment visit per the SoA (Section 1.3.2). 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  42 (+7) days after 
the last dose of study intervention (Section 1.3.2).
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 ART.
8.11.7.3
Participants Who Choose to Breastfeed
If a participant chooses to breastfeed, she should discontinue study intervention before 
initiating breastfeeding (Section 7.1) and be followed in the study per Section 8.11.7.2. The 
investigator (or local HIV care provider, if not the study site) should make every effort to 
develop a new treatment plan (per local guidelines) within sufficient time prior to delivery to 
minimize the likelihood of a gap in ART.
8.11.7.4
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 8.11.7.4.1 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.
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Infant safety data collection will be captured in this study, if exposure during pregnancy is 
reported in this study.
8.11.7.4.1
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; 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 hypothesis, or 
the statistical methods related to this hypothesis, then the protocol will be amended 
(consistent with ICH Guideline E-9). Changes to exploratory or other nonconfirmatory 
analyses made after the protocol has been finalized, but prior to final database lock, will be 
documented in an sSAP and referenced in the CSR for the study. Post hoc exploratory 
analyses will be clearly identified in the CSR.
9.1
Statistical Analysis Plan Summary
Key elements of the SAP are summarized below; the comprehensive plan is provided in 
Section 9.2 to Section 9.12.  
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Study Design 
Overview
A Phase 3, Randomized, Clinical Study in HIV-1-Infected Heavily Treatment-
Experienced Participants Evaluating the Antiretroviral Activity of Blinded Islatravir 
(ISL), Doravirine (DOR), and Doravirine/Islatravir (DOR/ISL), Each Compared to 
Placebo, and the Antiretroviral Activity, Safety, and Tolerability of Open-Label 
DOR/ISL.
Treatment
Assignment
Run-in Period: Participants will continue to take their current failing baseline ART.
Part 1: Participants will be randomized in a 1:2:1:1 ratio into 1 of 4 treatment groups
stratified by factors in Section 6.3.2. The goal is to randomize 150 participants; 
however, a minimum of 100 randomized participants is targeted for the planned 
analyses.
Group 1 (n ~20): ISL QD + failing baseline ART
Group 2 (n ~40): DOR QD + failing baseline ART
Group 3 (n ~20): DOR/ISL QD + failing baseline ART
Group 4 (n ~20): Placebo QD + failing baseline ART
Part 2: All participants will be treated with DOR/ISL and OBT for 96 weeks (with 
the opportunity to continue DOR/ISL after Week 97). OBT options will be driven by 
historic and baseline resistance as well as safety and tolerability considerations. 
Analysis 
Populations
Efficacy: FAS, Per-Protocol Analysis Set, and Resistance Analysis Subset
Safety: APaT
Primary 
Endpoint(s)
Percentage of participants achieving ≥0.5 log10 decrease in HIV-1 RNA from 
study baseline (Day 1) to Day 8 in the DOR/ISL group
Number of participants experiencing AEs and discontinuing study intervention
due to AEs through Week 25 and Week 49.
Key Secondary 
Endpoints
Percentage of participants achieving ≥0.5 log10 decrease in HIV-1 RNA from 
study baseline (Day 1) to Day 8 in the ISL group and DOR group
Percentage of participants achieving ≥0.5 log10 decrease in HIV-1 RNA from 
study baseline (Day 1) and Part 2 baseline (Day 8) to Week 25, Week 49, and 
Week 97
Percentage of participants achieving ≥1.0 log10 decrease in HIV-1 RNA from 
study baseline (Day 1) to Day 8, Week 25, Week 49, and Week 97, and from Part 
2 baseline (Day 8) to Week 25, Week 49, and Week 97
Percentage of participants with HIV-1 RNA <200 copies/mL, <50 copies/mL, and 
<40 copies/mL at Week 25, Week 49, and Week 97
Mean change in HIV-1 RNA from study baseline (Day 1) to Day 8, Week 25,
Week 49, and Week 97 and from Part 2 baseline (Day 8) to Week 25, Week 49, 
and Week 97
Mean change in CD4+ T-cell count from study baseline (Day 1) and Part 2 
baseline (Day 8) to Week 25, Week 49, and Week 97
Viral resistance-associated substitutions
Number of participants experiencing AEs and discontinuing study intervention 
due to AEs through Week 97.
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Statistical Methods 
for Key Efficacy/
Immunogenicity/ 
Pharmacokinetic 
Analyses
To evaluate the primary efficacy hypothesis, superiority of DOR/ISL compared to 
placebo with respect to the percentage of participants achieving ≥0.5 log10 decrease 
in HIV-1 RNA from study baseline (Day 1) to Day 8 will be calculated using the 
stratified Miettinen and Nurminen method with CMH weights (stratified by 
stratification factors in Section 6.3.2). Superiority will be concluded if the lower 
bound of the multiplicity-adjusted 95% CI for the difference is greater than 0. 
To assess the secondary efficacy objective regarding the treatment effect of ISL and 
DOR each compared to placebo with respect to the percentage of participants 
achieving ≥0.5 log10 decrease in HIV-1 RNA from study baseline (Day 1) to Day 8, 
the stratified Miettinen and Nurminen method with CMH weights will be used to 
estimate the nominal 95% CI for the difference. Similar methodology will be used to 
estimate all other between-group differences and the associated nominal 95% CIs 
with respect to the percentage of participants achieving ≥0.5 log10 decrease and ≥1.0 
log10 decrease in HIV-1 RNA from baseline to the analysis time points of interest.
For participants with HIV-1 RNA <200 copies/mL, those with HIV-1 RNA <50 
copies/mL, and those with HIV-1 RNA <40 copies/mL at Week 25, Week 49, and 
Week 97, the relevant percentages will be tabulated, and the within-group nominal 
95% CIs will be presented using the Clopper Pearson method.
Statistical Methods 
for Key Safety 
Analyses
Safety and tolerability will be assessed by clinical review of all relevant parameters. 
Of primary interest will be a descriptive summary of the safety and tolerability of 
DOR/ISL. Safety summaries will be presented by treatment group through Day 8; in 
addition, a pooled summary will be presented for data collected through Week 25 and 
Week 49. The Clopper Pearson method will be used to compute within-group 
nominal 95% CIs for selected binary parameters. CIs for change from baseline 
parameters will be computed based on the t-distribution.
Interim Analyses
Three types of interim analyses are planned in this study.
Periodic reviews of safety and efficacy data (conducted by an independent, 
unblinded eDMC).
Futility assessment. HIV-1 RNA at the end of Part 1 will be tracked and provided 
to an external unblinded statistician to perform the futility assessment. Details on 
futility boundaries are presented in Section 9.7.2. If any of the futility boundaries 
are met, an ad hoc eDMC review will be triggered and the eDMC may recommend 
the study be stopped; the eDMC will review the totality of the available data at the 
time of this ad hoc interim analysis before making such a recommendation.
Analysis for testing the primary efficacy hypothesis. This analysis will be 
conducted by Sponsor at the end of Part 1. Results will be shared with the eDMC.
Multiplicity
For statistical rigor, a small amount of alpha (α=0.00001) will be set aside for the 
futility assessment and each eDMC evaluation. The Type I error rate for testing the 
primary hypothesis at Day 8 will be adjusted depending on the number of eDMC
reviews conducted prior to completion of the testing of the primary hypothesis.
Sample Size and 
Power 
The study power to establish superiority under various assumptions is presented in 
Section 9.9.1.
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9.2
Responsibility for Analyses/In-house Blinding
The statistical analysis of the data obtained from this study will be the responsibility of the 
Clinical Biostatistics department of the Sponsor. 
Part 1 of this study (Day 1 through Day 8) will be conducted as a double-blind study under 
in-house blinding procedures. The official, final database for Part 1 will not be unblinded 
until medical/scientific review has been performed, protocol deviations have been identified, 
and data have been declared final and complete for Part 1. The clinical database and all 
Sponsor personnel will become unblinded to Part 1 intervention assignment at the time of the 
Part 1 analysis, although study participants and site personnel will remain blinded until 
Week 97. Part 2 of this study (Day 8 through Week 97) will be conducted as an open-label
study. Results of Part 2 will be presented in the CSR along with results of Part 1.
PK data may be unblinded earlier for the purpose of preparing a population PK model. A 
separate team from the Sponsor 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 
PK analysis. Interim data or results will not be shared with the Sponsor protocol team before 
unblinding of the Sponsor.
The Clinical Biostatistics department will generate the randomized allocation schedule(s) for 
study intervention assignment. Randomization will be implemented via an IRT.
Blinding issues related to the planned interim analyses are described in Section 9.7.
9.3
Hypotheses/Estimation
Objectives and hypothesis 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. 
9.4.1
Efficacy/Pharmacokinetics Endpoints
9.4.1.1
Primary Efficacy Endpoint
An initial description of efficacy measures is provided in Section 4.
Percentage of participants with ≥0.5 log10 decrease in HIV-1 RNA from study baseline
(Day 1) to Day 8 in the DOR/ISL group
The Abbott RealTime PCR assay with a reliable lower limit of quantification of 
40 copies/mL will be used to measure the HIV-1 RNA level in blood samples obtained at 
each visit. The evaluation of the primary efficacy objective (including the primary efficacy 
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hypothesis) will be based on the percentage of participants with ≥0.5 log10 decrease in HIV-1 
RNA from study baseline (Day 1) to Day 8 in the DOR/ISL group.  
9.4.1.2
Secondary Efficacy Endpoints
Percentage of participants with ≥0.5 log10 decrease in HIV-1 RNA from study baseline 
(Day 1) to Day 8 in the ISL group and DOR group
Percentage of participants with ≥0.5 log10 decrease in HIV-1 RNA from study baseline
(Day 1) and Part 2 baseline (Day 8) to Week 25, Week 49, and Week 97
Percentage of participants with ≥1.0 log10 decrease in HIV-1 RNA from study baseline
(Day 1) to Day 8, Week 25, Week 49, and Week 97 and from Part 2 baseline (Day 8) to 
Week 25, Week 49, and Week 97
Percentage of participants with HIV-1 RNA <200 copies/mL, <50 copies/mL, and 
<40 copies/mL at Week 25, Week 49, and Week 97
Antiretroviral activity will also be assessed on the basis of the percentage of participants with 
HIV-1 RNA <200 copies/mL, <50 copies/mL, and <40 copies/mL. These endpoints will be 
estimated at each time point at which HIV-1 RNA is measured, with primary interest at 
Week 25, Week 49, and Week 97 to support the secondary objectives.
Change in HIV-1 RNA from study baseline (Day 1) to Day 8, Week 25, Week 49, and 
Week 97 and from Part 2 baseline (Day 8) to Week 25, Week 49, and Week 97
For calculations of change from baseline in HIV-1 RNA, both study baseline (Day 1) and the 
Part 2 baseline (Day 8) HIV-1 RNA measurements will be used. In the rare event when 
baseline data are missing, the last measurement within the screening window will be used as 
the study baseline (Day 1) when available, and the last measurement in Part 1 prior to Day 8 
intervention will be used as Part 2 baseline (Day 8) when available. These rules will also 
apply to define the baseline measurements for calculation of change from baseline in CD4+ 
T-cell count, and for other laboratory tests.
Change in CD4 + T-cell Count from study baseline (Day 1) and Part 2 baseline (Day 8)
at Week 25, Week 49, and Week 97
Change in CD4+ T-cell count from baseline will be estimated at each time point at which 
CD4+ T-cell count is collected. A secondary objective will assess the change in CD4+ T-cell 
count from study baseline (Day 1) and Part 2 baseline (Day 8) baseline at Week 25,
Week 49, and Week 97.
Viral resistance-associated substitutions
Participants who meet the definition of confirmed viremia (defined as having 2 consecutive 
confirmed HIV-1 RNA ≥200 copies/mL [at least 4 weeks apart] after achieving HIV-1 RNA 
<50 copies/mL), or who discontinue study intervention with HIV-1 RNA ≥200 copies/mL, or 
who never suppressed (<50 copies/mL) at Week 25, Week 49, and Week 97 with HIV-1 
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RNA >200 copies/mL, 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 summarize the number of participants who have resistance-
associated substitutions associated with each study intervention and will be summarized with 
primary interest at Day 8, Week 25, Week 49, and Week 97.
9.4.1.3
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 DOR, and as appropriate, 
PK-efficacy, PK-pharmacodynamic, and PK-AE relationships of ISL or DOR. 
9.4.2
Safety Endpoints
An initial description of safety measures is provided in Section 4.
Adverse Events
The following clinical and laboratory adverse events 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 
nondrug-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 study baseline (Day 1) or 
Part 2 baseline (Day 8) and postrandomized 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 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.
These PDLC summaries will be performed for the following:

Day 1 (study baseline) to Day 8 (end of blinded treatment period)

Day 1 (study baseline) to Week 25

Day 1 (study baseline) to Week 49

Day 1 (study baseline) to Week 97
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
Day 8 (Part 2 baseline) to Week 25

Day 8 (Part 2 baseline) to Week 49

Day 8 (Part 2 baseline) to Week 97
Measures of Inflammation
Change from baseline in IL-6, D-dimer, sCD-163, and hs-CRP from study baseline (Day 1) 
to Week 25, Week 49, and Week 97 will be analyzed. 
9.4.3
Patient-reported Outcome Endpoints
An initial description of patient-reported outcome measures is provided in Section 4.2.1.2 of 
the protocol.  
Patient-reported outcomes from each questionnaire at Day 1, Week 25, Week 49, and Week 
97 will be summarized for participants ≥18 years of age at the time of consent in each 
treatment group. A total FAHI score and score for individual subscales (physical, emotional, 
functional, social, and global well-being as well as cognitive functioning) will be 
summarized.
9.5
Analysis Populations
9.5.1
Efficacy Analysis Populations
Details on the approach to handling missing data for efficacy analyses are provided in 
Section 9.6.1.
9.5.1.1
Full Analysis Set
The FAS will serve as the primary population for the analysis of efficacy data in this study. 
The FAS population consists of all randomized participants who:

Receive at least 1 dose of study intervention

Have baseline data for those analyses that require baseline data
Participants will be included in the treatment group to which they are randomized for the 
analyses of efficacy data using the FAS population. 
9.5.1.2
Per-protocol Analysis Set 
The secondary analysis set for the efficacy analyses is defined as the PP analysis set, which 
will include all participants in the FAS who have not committed any major protocol 
violations that could impact the assessment of efficacy. Participants will be grouped 
according to the treatment to which they are randomized.
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Participants who are nonadherent to study intervention (ie, participants with a study 
intervention compliance rate <95%) or who become pregnant will be excluded from the PP 
analysis set.
The additional criteria resulting in exclusion from the PP analysis set will be provided in the 
sSAP and will be identified prior to unblinding and completion of Part 1.
The composition of the PP analysis set will vary by the analysis timepoint, based on the 
number of participants who satisfy the PP criteria at that timepoint.
9.5.1.3
Resistance Analysis Subset
The resistance analysis subset will include all participants in the FAS with confirmed HIV-1 
RNA ≥400 copies/mL and any participant for whom available genotypic or phenotypic data 
show evidence of resistance irrespective of viral load.  
9.5.2
Safety Analysis Population
The APaT population will be used for the analysis of safety data in this study. The APaT 
population consists of all randomized participants who received at least 1 dose of study 
intervention. Participants will be included in the treatment group corresponding to the study 
intervention they actually received for the analysis of safety data using the APaT population. 
For most participants, this will be the treatment group to which they are randomized. 
Participants who take incorrect study intervention for the entire treatment period will be 
included in the treatment group corresponding to the study intervention actually received.  
At least 1 laboratory or vital sign measurement obtained subsequent to at least 1 dose of 
study intervention is required for inclusion in the analysis of each specific parameter. To 
assess change from baseline, a baseline measurement is also required.  
Details on the approach to handling missing data for safety analyses are provided in 
Section 9.6.2.
9.6
Statistical Methods
This section describes the statistical methods that address the primary and secondary 
objectives. Methods related to PK analysis and modeling will be described in a separate 
modeling and simulation plan authored by the department of Quantitative Pharmacology and 
Pharmacometrics (QP2). Methods related to other exploratory objectives will be described in 
the sSAP.
9.6.1
Statistical Methods for Efficacy Analyses
Time Window
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 are presented in Table 7. The last available on-treatment measurement 
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within a window will be used for analyses at a specific time point, unless otherwise specified. 
Results from additional time points beyond Week 97 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.
Table 7
Definitions of Study Time Points
Treatment 
Phase
Treatment 
Period
Visit
Day-Range Rules
Target Daya
Pretreatment
Screening
Day 1b
≤1
1
Treatment
Part 1
Day 8‡
≥2 and ≤14
8
Part 2
Week 3
≥15 and ≤35
22
Week 7
≥36 and ≤70
50
Week 13
≥71 and ≤112
92
Week 19
≥113 and ≤154
134
Week 25
≥155 and ≤217
176
Week 37
≥218 and ≤301
260
Week 49
≥302 and ≤385
344
Week 61
≥385 and ≤469
428
Week 73
≥470 and ≤553
512
Week 85
≥554 and ≤637
596
Week 97
≥638 and ≤721
680
a
Relative days and target days are computed from the first day of study intervention. Participants have to complete 
Day 8 assessment before entering study Part 2; Day 8 window will not overlap with start of OBT.
b
Day 1 is also referred to as the Study Baseline. Day 8 is also referred to as the Part 2 Baseline.
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.
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Three approaches will be used to handle missing values. The primary approach for the 
analysis of binary efficacy endpoints (eg, assessing percentage of participants with ≥0.5 log10
or a ≥1.0 log10 decrease in HIV-1 RNA from baseline; assessing the percentages of 
participants with HIV-1 RNA <200 copies/mL, <50 copies/mL, and <40 copies/mL) is the 
FDA “snapshot” algorithm [Food and Drug Administration (CDER) 2015]. Under this 
approach, the binary outcomes will be defined according to the following categories:

Success: depending on the analysis and endpoint, success could mean ≥0.5 log10 
decrease in HIV-1 RNA from baseline; ≥1.0 log10 decrease in HIV-1 RNA from 
baseline; HIV-1 RNA <200 copies/mL, <50 copies/mL, or <40 copies/mL. This category 
includes participants who have the last available on-treatment HIV-1 RNA measurement 
meeting the success criteria within the time point of interest analysis window specified in 
Table 7.

Failure: depending on the analysis and endpoint, failure could mean <0.5 log10 decrease 
in HIV-1 RNA from baseline; <1.0 log10 decrease in HIV-1 RNA from baseline; HIV-1 
RNA ≥200 copies/mL, ≥50 copies/mL, or ≥40 copies/mL. This category includes the 
following participants:
1) Those whose last available on-treatment HIV-1 RNA fails to meet the success criteria 
within the time point of interest analysis window specified in Table 7
2) Those who do not have on-treatment HIV-1 RNA data in the time point of interest 
analysis window and 

Who discontinue study intervention prior to or in the time point of interest 
analysis window due to lack of efficacy, or

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 
whose last available on-treatment HIV-1 RNA fails to meet the success criteria.

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 virologic data
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 or AE/Death (ie, lost to follow-up, 
noncompliance with study intervention, physician decision, protocol deviation, 
withdrawal by participant, etc.) and have the last available on-treatment HIV-1 RNA
meeting the success criteria. 
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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 of this window will be classified as “on study intervention, but missing data 
in window” regardless of the HIV-1 RNA results.
In Part 2 of the study, any changes to the OBT regimen due to lack of efficacy will be 
imputed as failure using the FDA snapshot approach. For participants who become pregnant 
during the study, modification of the OBT will not be imputed as failure unless the change 
was due to lack of efficacy. Additionally, changes to the OBT regimen due to delayed drug 
sourcing or other extraneous circumstances will not be imputed as failure.
For the primary evaluation of superiority based on those with a ≥0.5 log10 decrease in HIV-1 
RNA, the parameter for evaluation is the number of participants classified as “success” 
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 a ≥1.0 log10 decrease in HIV-1 RNA from baseline and the percentage of 
participants with HIV-1 RNA <200 copies/mL, <50 copies/mL, and <40 copies/mL in 
accordance with the relevant secondary endpoints. It is noted that those classified as having 
no data in the specified analysis window will contribute to the denominator (as these 
participants are included in the FAS), but are effectively treated as failures under this 
approach as they do not contribute to the numerator.  
A second approach, the missing data treated as treatment failure (M=F) approach, will be 
performed as a sensitivity analysis. Under this approach, participants who 1) have at least one 
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 
meeting the success criterion for the endpoint will be classified as “success” at the time point 
of interest, 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 
meeting the success criterion will be classified as “success” at the time point of interest. 
Participants with other reasons for missing data will be classified as a “failure” at the time 
point of interest. 
A third approach, the Observed Failure (OF) approach will also be performed as a sensitivity 
analysis for these efficacy endpoints. 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 at the time of study 
intervention 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 if both the immediately preceding and immediately subsequent on-treatment HIV-1 
RNA measurements meet the success criterion; all other intermittent missing results will be 
imputed as failures.
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In accordance with the FDA snapshot algorithm and to provide a full picture of virologic 
outcomes at Day 8, Week 25, Week 49, and Week 97, participants will be classified as either 
“success”, “failure”, or as having “no virologic data within the time window”. Participants 
with no virologic data within the time window will be further classified by reason:  1) 
discontinued study intervention due to AE or death, 2) discontinued study intervention for 
other reasons (includes withdrawal of consent, loss to follow-up, moved, etc.), or 3) on study 
intervention, but missing data in window.
Percentage of participants achieving ≥0.5 log10 or ≥1.0 log10 decrease in HIV-1 RNA 
from study baseline (Day 1) and Part 2 baseline (Day 8)
For the evaluation of the primary hypothesis, superiority of DOR/ISL compared to placebo
with respect to the percentage of participants achieving ≥0.5 log10 decrease in HIV-1 RNA
from study baseline (Day 1) to Day 8 will be calculated using the Miettinen and Nurminen 
method with CMH weights (stratified by the factors specified in Section 6.3.2). Superiority 
will be concluded if the lower bound of the multiplicity-adjusted 95% CI for the difference 
(DOR/ISL minus placebo) is greater than 0.
To assess the secondary objective regarding estimation of the treatment effect of ISL
monotherapy and DOR monotherapy compared to placebo with respect to the percentage of 
participants achieving ≥0.5 log10 decrease in HIV-1 RNA from study baseline (Day 1) to 
Day 8, the Miettinen and Nurminen method with CMH weights will also be used to estimate 
the nominal 95% CI for the treatment difference (ISL minus placebo, DOR minus placebo). 
Similar methodology will be used to estimate between-group differences and the associated 
nominal 95% CIs for the percentage of participants achieving ≥0.5 log10 decrease from Part 2 
baseline (Day 8) to Week 25, Week 49, and Week 97, as well as for the percentage of 
participants achieving ≥1.0 log10 decrease from study baseline (Day 1) to Day 8, Week 25, 
Week 49, and Week 97, and from Part 2 baseline (Day 8) to Week 25, Week 49, and Week 
97.
It is noted that the enrollment into Stratum 2 and Stratum 3 (as defined in Section 6.3.2) are 
likely to be low. If there are fewer than 5 participants randomized into one of these strata 
(which would be a complete randomization block), Strata 2 and 3 will be combined for the 
purposes of conducting all stratified analyses. If after combining Strata 2 and 3 there are still 
<2 participants in a treatment group, the unstratified Miettinen and Nurminen method would 
be used instead for that analysis.
Percentages of participants with HIV-1 RNA <200 copies/mL, <50 copies/mL, and 
<40 copies/mL
For the secondary endpoints associated with Week 25, Week 49, and Week 97, the relevant 
percentages will be tabulated and the within-group 95% CIs will be presented using the 
Clopper Pearson method. Since all participants will have received DOR/ISL, these results 
will also be pooled across the original treatment groups at Week 25, Week 49, and Week 97.
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Mean change in HIV-1 RNA from study baseline (Day 1) and Part 2 baseline (Day 8)
Change in HIV-1 RNA from study baseline (Day 1) to Day 8, Week 25, Week 49, and Week 
97, and from Part 2 baseline (Day 8) to Week 25, Week 49, and Week 97, will be 
summarized by treatment groups. The treatment differences in change in HIV-1 RNA from 
baseline will be estimated between treatment groups using ANCOVA models. 
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 one postbaseline 
measurement within the time point of interest analysis window specified in Table 7 in order 
to be included in the analyses of the mean change from baseline in HIV-RNA. Supportive 
analyses will also be provided using the LOCF method to account for missing data.
Mean change in CD4+ T-cell count from study baseline (Day 1) and Part 2 baseline
(Day 8) to Week 25, Week 49, and Week 97
Change from baseline in CD4+ T-cell count will be summarized at each time point at which 
CD4+ T-cell count is collected with primary interests at Week 25, Week 49, and Week 97.
Descriptive statistics will be provided including point estimates and corresponding 
confidence intervals based on the t-distribution. Change from baseline in CD4+ T-cell count 
will be summarized by Part 1 treatment group as well as pooled across groups. 
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 one postbaseline 
measurement within the time point of interest analysis window specified in Table 7 in order 
to be included in the analyses of the mean change from baseline in CD4+ T-cell count. 
Supportive analyses will also be provided using the baseline observation carried forward 
(BOCF) method to account for missing data.
Viral resistance-associated substitutions
The number of participants in the resistant analysis subset with genotypic and/or phenotypic 
resistance to each study intervention will be summarized for each treatment group with 
primary interests at Day 1, Day 8, Week 25, Week 49, and Week 97.
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 acute 
infection/reactivation of HBV or pregnancy 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, such 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.
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Participants Who Become Pregnant or Choose to Breastfeed
Efficacy assessments in participants who become pregnant and discontinue study 
intervention or choose to breastfeed will be censored from that point forward and will be 
handled in the primary efficacy analyses following the FDA snapshot algorithm classification 
rules.
Table 8 summarizes the key efficacy analyses of the study.
Table 8
Analysis Strategy for Key Efficacy Variables
Endpoint/Variable 
(Description, Time Point)
Primary vs. 
Supportive 
Approach
Statistical Methoda
Analysis 
Population
Missing 
Data 
Approach
Percentage of participants 
achieving ≥0.5 log10 decrease 
in HIV-1 RNA from study 
baseline (Day 1) to Day 8, 
Week 25, Week 49, and Week 
97, and from Part 2 baseline 
(Day 8) to Week 25, Week 49, 
and Week 97
P
M&N method with CMH 
weights
FAS
Snapshot b
S
M&N method with CMH 
weights
FAS
M=F
S
M&N method with CMH 
weights
PP
OF
Percentage of participants 
achieving ≥1.0 log10 decrease 
in HIV-1 RNA from study 
baseline (Day 1) to Day 8, 
Week 25, Week 49, and Week 
97, and from Part 2 baseline 
(Day 8) to Week 25, Week 49, 
and Week 97
P
M&N method with CMH 
weights
FAS
Snapshot b
S
M&N method with CMH 
weights
FAS
M=F
S
M&N method with CMH 
weights
PP
OF
Percentage of Participants with 
HIV-1 RNA <200 copies/mL,
those with HIV-1 RNA <50 
copies/mL, and those with 
HIV-1 RNA <40 copies/mL at 
Week 25, Week 49, and Week 
97
P
Clopper Pearson
FAS
Snapshot b
S
Clopper Pearson
FAS
M=F
S
Clopper Pearson
PP
OF
Change in HIV-1 RNA from 
study baseline (Day 1) to Day 
8, Week 25, Week 49, and 
Week 97, and from Part 2 
baseline (Day 8) to Week 25,
Week 49, and Week 97
P
ANCOVA
FAS
DAO
S
ANCOVA
FAS
LOCF
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Endpoint/Variable 
(Description, Time Point)
Primary vs. 
Supportive 
Approach
Statistical Methoda
Analysis 
Population
Missing 
Data 
Approach
Change in CD4+ T-cell count 
from study baseline (Day 1) 
and Part 2 baseline (Day 8) to 
Week 25, Week 49, and Week 
97
P
Within-group summaries 
using the t-distribution
FAS
DAO
S
Within-group summaries 
using the t-distribution
FAS
BOCF
ANCOVA=analysis of covariance; BOCF=Baseline Observation Carried Forward; CMH=Cochran-Mantel-Haenszel; 
DAO=Data as Observed; FAS=Full Analysis Set; HIV-1=human immunodeficiency virus Type 1; LOCF=Last 
Observation Carried Forward; M=F=Missing=Failure; OF=Observed Failure; P=Primary approach; PP=Per-Protocol 
Analysis Set; RNA=ribonucleic acid; S=Supportive approach.
a
The Miettinen and Nurminen method with CMH weights will be stratified by stratification factors specified in Section 
6.3.2 
b
Number of participants that meet the endpoint clinical response criteria over total FAS population. 
9.6.2
Statistical Methods for Safety Analyses
Safety and tolerability will be assessed by clinical review of all relevant parameters including 
AEs, laboratory values, and vital signs.
Of primary interest will be a descriptive summary of the safety and tolerability of DOR/ISL. 
Upon the completion of Part 1, safety data from Day 1 through Day 8 will be summarized by 
treatment group. At Week 25, Week 49, and Week 97, safety data will be summarized by 
treatment group as well as pooled across treatment groups; the safety data from Day 8 in the 
placebo group and the safety data from Day 1 in all other treatment groups will be pooled for 
these summaries. A summary of the analysis strategy for the safety parameters is provided in
Table 9. The Clopper Pearson method will be used to compute within-group 95% CIs for 
selected binary parameters. Confidence intervals for change from baseline parameters will be 
computed using the t-distribution.
Missing values 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. Baseline measurements are defined as either the Day 1 value (study baseline) 
or Day 8 value (Part 2 baseline) for each participant, depending on the analysis/summary. In 
the rare event when study baseline data are missing, the value obtained at the most recent 
Screening Visit will be used as the Day 1 baseline. If no pretreatment result is available, that 
participant will not be included in the summary. Similarly, if no Day 8 value is available, that 
participant will not be included in summaries involving the Part 2 baseline. 
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. 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 Parameters
Within-Group 
95% CIa
Descriptive 
Statistics

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 

The percentage of participants with a cardiac SAE

Specific AEs (preferred terms), SOCs, or PDLCs occurring with an 
incidence ≥10% in one of the groups

Change from baseline in markers of inflammation
X
X

Specific AEs (preferred terms), SOCs, or PDLCs occurring with an 
incidence <10% in all groups

Change from baseline in laboratory measurements and vital signs
X
AE(s)=adverse event(s); CI=confidence interval; PDLC=Predefined Limit of Change; SAE=serious adverse event; 
SOC=System Organ Class; X=results will be provided.
a 95% CIs will be calculated using the Clopper Pearson method for binary parameters and the t-distribution for change 
from baseline measures.
9.6.3
Summaries of Baseline Characteristics, Demographic, and other Analyses
9.6.3.1
Demographic and Baseline Characteristics
The comparability of the treatment groups for each relevant demographic and baseline 
characteristic will be assessed by the use of tables and/or graphs. No statistical hypothesis 
tests will be performed on these characteristics. The number and percentage of participants 
screened and randomized and the primary reasons for screening failure and discontinuation 
will be displayed. Demographic variables (eg, age, gender, race, region, etc.), baseline 
characteristics (eg, prior ART class exposure, known resistance [both phenotypic and 
genotypic] to all drugs in class), 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
There are possibly 4 types of analysis that will be performed at interim time points 
(Section 9.7.1 to Section 9.7.4). Study enrollment is likely to be ongoing at the time of some 
interim analyses. Blinding to Part 1 treatment assignment will be maintained at all 
investigational sites.  
An eDMC will serve as the primary reviewer of the results of the interim analyses of the 
study and may make recommendations for discontinuation of the study or protocol 
modifications to an executive committee of the Sponsor. If the eDMC recommends 
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modifications to the design of the protocol or discontinuation of the study, this executive 
committee (and potentially other limited Sponsor personnel) may be unblinded to results at 
the treatment level in order to act on these recommendations. The extent to which individuals 
are unblinded with respect to results of interim analyses will be documented by the unblinded 
statistician. Additional logistical details will be provided in the eDMC Charter.
Treatment-level results from the interim analyses will be provided to the eDMC by the 
external unblinded statistician until the Sponsor is unblinded at the time of the Part 1 
analysis. Prior to final study unblinding, 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 after the interim analyses. 
Following the unblinding of the Sponsor after Part 1 analysis, the responsibility for providing 
subsequent interim analysis results to the eDMC may transfer to unblinded Sponsor 
personnel.
9.7.1
Safety Monitoring
A periodic review of safety and efficacy data will be conducted by an independent, 
unblinded, eDMC. A description of the structure and function of the eDMC, along with the 
timing and content of the review, will be outlined in the DMC charter. 
9.7.2
Futility Monitoring
HIV-1 RNA at Day 8 (the end of Part 1) will be tracked and provided to an unblinded 
statistician on an ongoing basis to perform futility assessment. Table 10 lists the futility 
boundaries corresponding to each possible sample size in the DOR/ISL group. For example, 
based on the futility boundary with a sample size of up to and including 20, if 12 or more 
participants who receive DOR/ISL in the double-blind treatment period (Part 1) fail to 
achieve ≥0.5 log10 decline in HIV-1 RNA at the end of Part 1, an eDMC review will be 
triggered. This futility criterion corresponds to an OF rate of 60%. If such a futility analysis 
is triggered, the results will be shared with the eDMC who will make recommendations for 
discontinuation of the study or protocol modifications to the study Executive Oversight 
Committee (EOC). The Sponsor will not be informed if an eDMC review is triggered due to 
meeting the futility boundaries.
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Table 10
Futility Boundary That Would Trigger Ad Hoc eDMC Review Corresponding to 
Current Possible Sample Size in DOR/ISL Group
Current Sample Size 
in DOR/ISL Group
Futility Boundary 
(Number of Participants 
with <0.5 log10 Decline in 
HIV-1 RNA at Day 8)
Observed Failure 
Rate (<0.5 log10
Decline in HIV-1 
RNA)
Observed Rate with 
≥0.5 log10 Decline in 
HIV-1 RNA
≤20
12
≥60.0%
≤40.0%
21
12
57.1%
42.9%
22
13
59.1%
40.9%
23
13
56.5%
43.5%
24
14
58.3%
41.7%
25
14
56.0%
44.0%
26
15
57.7%
42.3%
27
15
55.6%
44.4%
28
16
57.1%
42.9%
29
16
55.2%
44.8%
30
17
56.7%
43.3%
DOR=doravirine; HIV-1=human immunodeficiency virus Type 1; ISL=islatravir; RNA=ribonucleic acid.
9.7.3
Interim Analysis for Potential Marketing Authorization Application
Prior to the formal unblinded IA in Section 9.7.4, a blinded interim data summary may be 
conducted to support any potential marketing authorization application of DOR/ISL. In such 
an event, blinded efficacy and safety summaries from Part 1 will be presented along with 
open-label efficacy and safety summaries from Part 2. This analysis will be prepared by the 
blinded team of the Sponsor.
9.7.4
Interim Analysis for Testing the Primary Hypothesis
An analysis will be conducted to test the primary efficacy hypothesis after all participants 
have completed Part 1. This will be the formal evaluation of the primary efficacy hypothesis
and the Sponsor will become unblinded at that time. The analysis of Part 1 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. Following the unblinding of the Sponsor after Part 1, the 
responsibility for providing subsequent interim analysis results to the eDMC may transfer to 
unblinded Sponsor personnel.
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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, 
safety, and tolerability. There is no intention of stopping the study due to positive efficacy at 
any of these reviews. Nevertheless, since unblinded summaries of HIV-1 RNA values may 
be included in these reviews, a small amount of alpha (α=0.00001) will be allocated for each 
of these looks, purely for statistical rigor. An allowance will be made such that a total of up 
to 5 of these unblinded eDMC reports (including the futility assessment if the eDMC review 
is triggered) may be presented prior to the evaluation of the primary efficacy hypothesis
(DOR/ISL vs. placebo) at Day 8.
9.9
Sample Size and Power Calculations
9.9.1
Sample Size and Power for Efficacy Analyses
9.9.1.1
Futility Criteria and Superiority Testing
All the calculations in this section are conservatively based on a sample size of 20 in the 
DOR/ISL group. As the sample size may be larger, these calculations are expected to 
represent the minimum power.  
As described in Section 9.8, the alpha level used in the final analysis (corresponding to the 
multiplicity-adjusted 95% CI) will account for the actual number of eDMC evaluations 
conducted in the study. For the purposes of the power calculations, 5 eDMC evaluations are 
assumed, leaving α=0.02495 (one-sided) available for the final analysis of the Part 1 
hypothesis.
The power calculations shown in Table 11 incorporate the futility stopping rule. Based on the 
futility rule, the study may stop if 12 or more out of 20 participants who receive DOR/ISL in
the double-blind treatment period (Part 1) fail to achieve ≥0.5 log10 decline in HIV-1 RNA at 
the end of Part 1. Table 11 displays the probability of this study meeting the stopping rule,
and the overall power to demonstrate superiority of DOR/ISL compared to placebo under a 
variety of response assumptions. For example, if the true response rate for DOR/ISL
recipients in Part 1 is 80%, there is a 0.01% chance of meeting the futility rule. In addition, if 
the true response rate for the placebo recipients is 3%, the probability of demonstrating
superiority of DOR/ISL compared to placebo at Day 8 is >99.9%.
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Table 11
Probability of Meeting Futility Criteria and the Overall Study Power for Various 
Underlying True Response Rates Assuming the Response Rate is 3% or 10% for Placebo 
Recipients
True Response Rate 
for Placebo 
Recipients (N=20)
True Response 
Rate for DOR/ISL
Recipients (N=20)
Probability of Meeting 
Futility Criteriaa
Probability Of Demonstrating 
Superiority Of DOR/ISL Over 
Placebo At Day 8b
3%
30%
88.7%
7.3%
40%
59.6%
33.9%
50%
25.1%
71.3%
60%
5.6%
93.6%
70%
0.5%
99.4%
80%
0.01%
>99.9%
90%
<0.001%
≥99.9%
10%
30%
88.7%
3.9%
40%
59.6%
24.1%
50%
25.1%
60.9%
60%
5.6%
89.1%
70%
0.5%
98.7%
80%
0.01%
>99.9%
90%
<0.001%
≥99.9%
DOR=doravirine; HIV-1=human immunodeficiency virus Type 1; ISL=islatravir; RNA=ribonucleic acid.
a Calculated using the binomial distribution. Under the minimum sample size of 20, the cutoff for futility is 12 
participants, meaning if 12 or more out of 20 participants who receive DOR/ISL in the double-blind treatment period 
(Part 1) fail to achieve ≥0.5 log10 decline in HIV-1 RNA at the end of Part 1, the study may be stopped.
b Overall power to demonstrate superiority of DOR/ISL compared to placebo are calculated based on one-sided 
α=0.02495.
9.9.1.2
Evaluation of the Primary Hypotheses
This section provides further description of the power calculations for the primary analysis of 
superiority of DOR/ISL over placebo. In contrast to the power shown in Table 11, the power 
calculations shown in Table 12 do not account for the futility analysis and instead assume the 
futility criteria are not met. 
The study power of demonstrating superiority of DOR/ISL over placebo under various 
assumptions is presented in Table 12, with assumed true response rates ranging from 70% to 
90% for DOR/ISL and rates from 3% to 25% for placebo. For example, if the true rate of 
DOR/ISL participants achieving a ≥0.5 log10 decrease in HIV-1 RNA is 83%, and the 
corresponding true rate in placebo recipients is 3%, this study has >99.9% power to 
demonstrate superiority of DOR/ISL over placebo.
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Table 12
Power (%) to Establish Superiority† Under Various Response Rate Assumptions 
(20 DOR/ISL Recipients and 20 Placebo Recipients)
True Response Rate for 
Placebo Recipients
True Response Rate for DOR/ISL Recipients
70%
78%
83%
88%
90%
3%
>99.9%
>99.9%
>99.9%
>99.9%
>99.9%
10%
99.2%
>99.9%
>99.9%
>99.9%
>99.9%
20%
92%
98.2%
99.5%
>99.9%
>99.9%
25%
84%
95%
98.3%
99.6%
99.8%
DOR=doravirine; ISL=islatravir.
† Overall power to demonstrate superiority of DOR/ISL compared to placebo is calculated based on one-sided α=0.02495.
9.9.2
Sample Size and Power for Safety Analyses
A summary of the probability of observing at least one AE for a given incidence rate is 
summarized in Table 13 for a variety of underlying AE incidence rates. For example, in a 
treatment group with 20 participants (such as Group 1 in the double-blind treatment period 
[Part 1]), if the underlying incidence of a particular AE is 10%, there is a 87.8% chance of 
observing at least 1 participant with that particular AE among 20 participants receiving 
DOR/ISL through Day 8.
Table 13
Probability of Observing At Least One Event in a Treatment Group for a Given 
Sample Size and a Variety of Underlying AE Incidence Rates
Underlying AE 
Incidence Rate
Probability of Observing 
At Least One Event in a 
Treatment Group of Size 
N=20
Probability of Observing 
At Least One Event in a 
Treatment Group of Size 
N=40
Probability of Observing 
At Least One Event in a 
Treatment Group of Size 
N=100
0.1%
2.0%
3.9%
9.5%
0.5%
9.5%
18.2%
39.4%
1.0%
18.2%
33.1%
63.4%
3.0%
45.6%
70.4%
95.2%
5.0%
64.2%
87.1%
99.4%
10.0%
87.8%
98.5%
>99.99%
AE=adverse event.
The estimate and associated upper bound of the 95% CI for the underlying percentage of 
participants with an AE given various hypothetical observed number of participants with the 
AE are provided in Table 14 for treatment groups of varying size. These calculations are 
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based on the exact binomial method proposed by Clopper and Pearson [Clopper, C. J. and 
Pearson, E. S. 1934].  
Table 14
Estimate of Incidence of AEs and 95% Upper Confidence Bound Based on 
Hypothetical Numbers of Participants with AEs
Sample Size
Hypothetical Number 
of Participants with 
Adverse Event
Observed AE Incidence 
Rate
95% CI Upper 
Bounda
20
0
0%
13.9%
1
5%
24.8%
2
10%
31.7%
3
15%
37.9%
4
20%
43.7%
5
25%
49.1%
40
0
0%
7.2%
1
2.5%
13.2%
2
5%
16.9%
4
10%
23.7%
8
20%
35.6%
12
30%
46.5%
15
37.5%
54.2%
100
0
0%
2.9%
1
1%
5.4%
2
2%
7.0%
4
4%
9.9%
8
8%
15.2%
12
12%
20.0%
15
15%
23.5%
20
20%
29.2%
AE=adverse event; CI=confidence interval
a Based on the two-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 one-sided (α=0.05 all in the upper tail).  
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9.10
Subgroup Analyses
To assess the consistency of the treatment effect 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 will be calculated within each category of 
the following classification variables:

Age group (<18, ≥18 years of age)

Sex at birth

Gender identity

Race (White, Black, Asian, Other) 

Region (North America, South America, Europe, Asia, Africa, etc.) 

Ethnicity (Hispanic/Latino, not Hispanic/Latino)

Randomization stratum

Number of fully active and available drugs in the OBT

Baseline CD4+ T-cell count category (50 to <200 cells/mm3, <50 cells/mm3)

Baseline HIV-1 RNA (≤100,000, >100,000 copies/mL)

Baseline NNRTI mutations

Baseline NRTI mutations
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 medication CRF page, the number of tablets or capsules
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 or capsule 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 date of the scheduled 
Week 97 visit for those participants who are on study intervention for the entire study period. 
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For participants who discontinue study intervention early (ie, prior to completion of the study 
at Week 97), 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, percent compliance will then 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 therapy for all randomized and treated participants will be 
summarized. The number of participants exposed to each intervention for defined periods of 
time will be listed, along with a summary of the mean (range) duration participants were 
exposed to each intervention. 
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10
SUPPORTING DOCUMENTATION AND OPERATIONAL 
CONSIDERATIONS
10.1
Appendix 1: Regulatory, Ethical, and Study Oversight Considerations
10.1.1
Code of Conduct for Clinical Trials
Merck Sharp & Dohme LLC, Rahway, NJ, USA (MSD)
Code of Conduct for Interventional Clinical Trials
I. Introduction
A. Purpose
MSD, through its subsidiaries, conducts clinical trials worldwide to evaluate the safety and effectiveness of our 
products. As such, we are committed to designing, implementing, conducting, analyzing, and reporting these trials 
in compliance with the highest ethical and scientific standards. Protection of participants in clinical trials is the 
overriding concern in the design and conduct of clinical trials. In all cases, MSD clinical trials will be conducted 
in compliance with local and/or national regulations, and International Council for Harmonisation Good Clinical 
Practice (ICH-GCP), and also in accordance with the ethical principles that have their origin in the Declaration of 
Helsinki.
B. Scope
Highest ethical and scientific standards shall be endorsed for all clinical interventional investigations sponsored by 
MSD irrespective of the party (parties) employed for their execution (e.g., contract research organizations, 
collaborative research efforts). This Code is not intended to apply to trials that are observational in nature, or 
which are retrospective. Further, this Code does not apply to investigator-initiated trials, which are not under the 
full control of MSD.
II. Scientific Issues
A. Trial Conduct
1. Trial Design
Except for pilot or estimation trials, clinical trial protocols will be hypothesis-driven to assess safety, efficacy 
and/or pharmacokinetic or pharmacodynamic indices of MSD or comparator products. Alternatively, MSD
may conduct outcomes research trials, trials to assess or validate various endpoint measures, or trials to 
determine patient preferences, etc.
The design (i.e., participant population, duration, statistical power) must be adequate to address the specific
purpose of the trial. Participants must meet protocol entry criteria to be enrolled in the trial. 
2. Site Selection
MSD selects investigative sites based on medical expertise, access to appropriate participants, adequacy of 
facilities and staff, previous performance in clinical trials, as well as budgetary considerations. Prior to trial 
initiation, sites are evaluated by MSD personnel (or individuals acting on behalf of MSD) to assess the ability 
to successfully conduct the trial.
3. Site Monitoring/Scientific Integrity
Investigative trial sites are monitored to assess compliance with the trial protocol and Good Clinical Practice
(GCP). MSD reviews clinical data for accuracy, completeness, and consistency. Data are verified versus 
source documentation according to standard operating procedures. Per MSD policies and procedures, if fraud, 
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scientific/research misconduct or serious GCP-non-compliance is suspected, the issues are investigated. 
When necessary, the clinical site will be closed, the responsible regulatory authorities and ethics review 
committees notified.
B. Publication and Authorship
Regardless of trial outcome, MSD commits to publish the primary and secondary results of its registered trials of 
marketed products in which treatment is assigned, according to the pre-specified plans for data analysis. To the 
extent scientifically appropriate, MSD seeks to publish the results of other analyses it conducts that are important 
to patients, physicians, and payers. Some early phase or pilot trials are intended to be hypothesis-generating rather 
than hypothesis testing; in such cases, publication of results may not be appropriate since the trial may be 
underpowered and the analyses complicated by statistical issues such as multiplicity.
MSD’s policy on authorship is consistent with the recommendations published by the International Committee of 
Medical Journal Editors (ICMJE). In summary, authorship should reflect significant contribution to the design and 
conduct of the trial, performance or interpretation of the analysis, and/or writing of the manuscript. All named 
authors must be able to defend the trial results and conclusions. MSD funding of a trial will be acknowledged in 
publications.
III. Participant Protection
A. Regulatory Authority and Ethics Committee Review (Institutional Review Board [IRB]/Independent Ethics 
Committee [IEC])
All protocols and protocol amendments will be submitted by MSD for regulatory authority 
acceptance/authorization prior to implementation of the trial or amendment, in compliance with local and/or 
national regulations.
The protocol, protocol amendment(s), informed consent form, investigator’s brochure, and other relevant trial 
documents must be reviewed and approved by an IRB/IEC before being implemented at each site, in compliance 
with local and/or national regulations. Changes to the protocol that are required urgently to eliminate an 
immediate hazard and to protect participant safety may be enacted in anticipation of ethics committee approval.  
MSD will inform regulatory authorities of such new measures to protect participant safety, in compliance with 
local and/or national regulations.
B. Safety
The guiding principle in decision-making in clinical trials is that participant welfare is of primary importance. 
Potential participants will be informed of the risks and benefits of, as well as alternatives to, trial participation. At 
a minimum, trial designs will take into account the local standard of care.
All participation in MSD clinical trials is voluntary. Participants enter the trial only after informed consent is 
obtained. Participants may withdraw from an MSD trial at any time, without any influence on their access to, or 
receipt of, medical care that may otherwise be available to them.
C. Confidentiality
MSD is committed to safeguarding participant confidentiality, to the greatest extent possible. Unless required by 
law, only the investigator, Sponsor (or individuals acting on behalf of MSD), ethics committee, and/or regulatory 
authorities will have access to confidential medical records that might identify the participant by name.
D. Genomic Research
Genomic research will only be conducted in accordance with a protocol and informed consent authorized by an 
ethics committee.
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IV. Financial Considerations
A. Payments to Investigators
Clinical trials are time- and labor-intensive. It is MSD’s policy to compensate investigators (or the sponsoring 
institution) in a fair manner for the work performed in support of MSD trials. MSD does not pay incentives to 
enroll participants in its trials. However, when enrollment is particularly challenging, additional payments may be 
made to compensate for the time spent in extra recruiting efforts.
MSD does not pay for participant referrals. However, MSD may compensate referring physicians for time spent 
on chart review and medical evaluation to identify potentially eligible participants.
B. Clinical Research Funding
Informed consent forms will disclose that the trial is sponsored by MSD, and that the investigator or sponsoring 
institution is being paid or provided a grant for performing the trial. However, the local ethics committee may 
wish to alter the wording of the disclosure statement to be consistent with financial practices at that institution. As 
noted above, all publications resulting from MSD trials will indicate MSD as a source of funding.
C. Funding for Travel and Other Requests
Funding of travel by investigators and support staff (e.g., to scientific meetings, investigator meetings, etc.) will be 
consistent with local guidelines and practices.
V. Investigator Commitment
Investigators will be expected to review MSD’s Code of Conduct as an appendix to the trial protocol, and in signing the 
protocol, agree to support these ethical and scientific standards.
10.1.2
Financial Disclosure
Financial Disclosure requirements are outlined in the US Food and Drug Administration 
Regulations, Financial Disclosure by Clinical Investigators (21 CFR Part 54). It is the 
Sponsor's responsibility to determine, based on these regulations, whether a request for 
Financial Disclosure information is required. It is the investigator's/subinvestigator's 
responsibility to comply with any such request.
The investigator/subinvestigator(s) agree, if requested by the Sponsor in accordance with 21 
CFR Part 54, to provide his/her financial interests in and/or arrangements with the Sponsor to 
allow for the submission of complete and accurate certification and disclosure statements. 
The investigator/subinvestigator(s) further agree to provide this information on a 
Certification/Disclosure Form, commonly known as a financial disclosure form, provided by 
the Sponsor. The investigator/subinvestigator(s) also consent to the transmission of this 
information to the Sponsor in the United States for these purposes. This may involve the 
transmission of information to countries that do not have laws protecting personal data.
10.1.3
Data Protection
Participants will be assigned a unique identifier by the Sponsor. Any participant records or 
datasets that are transferred to the Sponsor will contain the identifier only; participant names 
or any information that would make the participant identifiable will not be transferred.
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The participant must be informed that his/her personal study-related data will be used by the 
Sponsor in accordance with local data protection law. The level of disclosure must also be 
explained to the participant. 
The participant must be informed that his/her medical records may be examined by Clinical 
Quality Assurance auditors or other authorized personnel appointed by the Sponsor, by 
appropriate IRB/IEC members, and by inspectors from regulatory authorities.
10.1.3.1
Confidentiality of Data
By signing this protocol, the investigator affirms to the Sponsor that information furnished to 
the investigator by the Sponsor will be maintained in confidence, and such information will 
be divulged to the IRB, IEC, or similar or expert committee; affiliated institution and 
employees, only under an appropriate understanding of confidentiality with such board or 
committee, affiliated institution and employees. Data generated by this study will be 
considered confidential by the investigator, except to the extent that it is included in a 
publication as provided in the Publications section of this protocol.
10.1.3.2
Confidentiality of Participant Records
By signing this protocol, the investigator agrees that the Sponsor (or Sponsor representative), 
IRB/IEC, or regulatory authority representatives may consult and/or copy study documents to 
verify worksheet/CRF data. By signing the consent form, the participant agrees to this 
process. If study documents will be photocopied during the process of verifying 
worksheet/CRF information, the participant will be identified by unique code only; full 
names/initials will be masked prior to transmission to the Sponsor.
By signing this protocol, the investigator agrees to treat all participant data used and 
disclosed in connection with this study in accordance with all applicable privacy laws, rules 
and regulations.
10.1.3.3
Confidentiality of IRB/IEC Information
The Sponsor is required to record the name and address of each IRB/IEC that reviews and 
approves this study. The Sponsor is also required to document that each IRB/IEC meets 
regulatory and ICH GCP requirements by requesting and maintaining records of the names 
and qualifications of the IRB/IEC members and to make these records available for 
regulatory agency review upon request by those agencies.
10.1.4
Committees Structure
10.1.4.1
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.
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10.1.4.2
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.
10.1.4.3
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 
Analyses]) 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.
10.1.5
Publication Policy
The results of this study may be published or presented at scientific meetings. The Sponsor 
will comply with the requirements for publication of study results. In accordance with 
standard editorial and ethical practice, the Sponsor will generally support publication of 
multicenter studies only in their entirety and not as individual site data. In this case, a 
coordinating investigator will be designated by mutual agreement.
If publication activity is not directed by the Sponsor, the investigator agrees to submit all 
manuscripts or abstracts to the Sponsor before submission. This allows the Sponsor to protect
proprietary information and to provide comments.
Authorship will be determined by mutual agreement and in line with International Committee 
of Medical Journal Editors authorship requirements.
10.1.6
Compliance with Study Registration and Results Posting Requirements
Under the terms of the Food and Drug Administration Amendments Act (FDAAA) of 2007 
and the European Medicines Agency (EMA) clinical trial Directive 2001/20/EC, the Sponsor 
of the study is solely responsible for determining whether the study and its results are subject
to the requirements for submission to http://www.clinicaltrials.gov, 
www.clinicaltrialsregister.eu or other local registries. MSD, as Sponsor of this study, will 
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review this protocol and submit the information necessary to fulfill these requirements. MSD 
entries are not limited to FDAAA or the EMA clinical trial directive mandated trials. 
Information posted will allow participants to identify potentially appropriate studies for their 
disease conditions and pursue participation by calling a central contact number for further 
information on appropriate study locations and study site contact information.
By signing this protocol, the investigator acknowledges that the statutory obligations under 
FDAAA, the EMA clinical trials directive, or other locally mandated registries are that of the 
Sponsor and agrees not to submit any information about this study or its results to those 
registries.
10.1.7
Compliance with Law, Audit, and Debarment
By signing this protocol, the investigator agrees to conduct the study in an efficient and 
diligent manner and in conformance with this protocol; generally accepted standards of GCP
(eg, International Conference on Harmonization of Technical Requirements for Registration 
of Pharmaceuticals for Human Use GCP: Consolidated Guideline and other generally 
accepted standards of GCP); and all applicable federal, state and local laws, rules and 
regulations relating to the conduct of the clinical study.
The Code of Conduct, a collection of goals and considerations that govern the ethical and 
scientific conduct of clinical investigations sponsored by MSD, is provided in this appendix 
under the Code of Conduct for Clinical Studies.
The investigator agrees not to seek reimbursement from participants, their insurance 
providers, or from government programs for procedures included as part of the study 
reimbursed to the investigator by the Sponsor.
The investigator will promptly inform the Sponsor of any regulatory authority inspection 
conducted for this study.
The investigator agrees to provide the Sponsor with relevant information from inspection 
observations/findings to allow the Sponsor to assist in responding to any citations resulting 
from regulatory authority inspection and will provide the Sponsor with a copy of the 
proposed response for consultation before submission to the regulatory authority. 
Persons debarred from conducting or working on clinical studies by any court or regulatory 
authority will not be allowed to conduct or work on this Sponsor’s studies. The investigator 
will immediately disclose in writing to the Sponsor if any person who is involved in 
conducting the study is debarred or if any proceeding for debarment is pending or, to the best 
of the investigator’s knowledge, threatened.
10.1.8
Data Quality Assurance
All participant data relating to the study will be recorded on printed or electronic CRF unless 
transmitted to the Sponsor or designee electronically (eg, laboratory data). The investigator 
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or qualified designee is responsible for verifying that data entries are accurate and correct by 
physically or electronically signing the CRF.
Detailed information regarding Data Management procedures for this protocol will be 
provided separately.
The investigator must maintain accurate documentation (source data) that supports the 
information entered in the CRF.
The investigator must permit study-related monitoring, audits, IRB/IEC review, and 
regulatory agency inspections and provide direct access to source data documents.
Study documentation will be promptly and fully disclosed to the Sponsor by the investigator 
upon request and also shall be made available at the study site upon request for inspection, 
copying, review, and audit at reasonable times by representatives of the Sponsor or any 
regulatory authorities. The investigator agrees to promptly take any reasonable steps that are 
requested by the Sponsor or any regulatory authorities as a result of an audit or inspection to 
cure deficiencies in the study documentation and worksheets/CRFs.
The Sponsor or designee is responsible for the data management of this study including 
quality checking of the data.
Study monitors will perform ongoing source data review and verification to confirm that data 
entered into the CRF by authorized site personnel are accurate, complete, and verifiable from 
source documents; that the safety and rights of participants are being protected; and that the 
study is being conducted in accordance with the currently approved protocol and any other 
study agreements, ICH GCP, and all applicable regulatory requirements.
Records and documents, including participants' documented informed consent pertaining to 
the conduct of this study must be retained by the investigator for 15 years after study 
completion unless local regulations or institutional policies require a longer retention period. 
No records may be destroyed during the retention period without the written approval of the 
Sponsor. No records may be transferred to another location or party without written 
notification to the Sponsor.
10.1.9
Source Documents
Source documents provide evidence for the existence of the participant and substantiate the 
integrity of the data collected. The investigator/institution should maintain adequate and 
accurate source documents and study records that include all pertinent observations on each 
of the site’s participants. Source documents and data should be attributable, legible, 
contemporaneous, original, accurate, and complete. Changes to source data should be 
traceable, should not obscure the original entry, and should be explained if necessary (eg, via 
an audit trail). Source documents are filed at the investigator’s site.
Data reported on the CRF or entered in the eCRF that are transcribed from source documents 
must be consistent with the source documents or the discrepancies must be explained. The 
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investigator/institution may need to request previous medical records or transfer records, 
depending on the study. Also, current medical records must be available.
10.1.10
Study and Site Closure
The Sponsor or its designee may stop the study or study site participation in the study for 
medical, safety, regulatory, administrative, or other reasons consistent with applicable laws, 
regulations, and GCP.
In the event the Sponsor prematurely terminates a particular study site, the Sponsor or 
designee will promptly notify that study site’s IRB/IEC as specified by applicable regulatory 
requirement(s).
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10.2
Appendix 2: Clinical Laboratory Tests

The tests detailed in Table 15 will be performed by the central laboratory.

Local laboratory results are only required in the event that the central laboratory results 
are not available in time for either study intervention administration and/or response 
evaluation. If a local sample is required, it is important that the sample for central 
analysis is obtained at the same time. Additionally, if the local laboratory results are used 
to make either a study intervention decision or response evaluation, the results must be
entered into the CRF.

Protocol-specific requirements for inclusion or exclusion of participants are detailed in 
Section 5 of the protocol.

Additional tests may be performed at any time during the study as determined necessary 
by the investigator or required by local regulations.
-
Pregnancy testing:
-
Pregnancy testing requirements for study inclusion are described in Section 5.1.
-
Additional serum or urine pregnancy tests may be performed, as determined 
necessary by the investigator or required by local regulation, to establish the absence 
of pregnancy at any time during the subject's participation in the study.
Table 15
Protocol-required Laboratory Assessments
Laboratory Assessments
Parameters
Hematology
Platelet Count 
Red blood cell (RBC) Count
Hemoglobin
Hematocrit
RBC Indices:

Mean corpuscular volume (MCV)

Mean corpuscular hemoglobin (MCH)

MCH concentration

Red cell distribution width (RDW)
White blood cell (WBC) count with Differential (%; absolute):

Neutrophils, total

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 panel includes:
CD3+ Percent
CD3+ Value/Absolute Count
CD3+CD4+ Percent
CD3+CD4+ Value/Absolute Count
CD3+CD8+ Percent
CD3+CD8+ Value/Absolute Count
CD3-CD19+ Percent
CD3-CD19+ Value/Absolute Count
CD16+CD56+ Percent
CD16+CD56+ Value/Absolute Count
CD3+CD4+CD8+ Percent
CD3+CD4+CD8+ Value/Absolute Count
CD4/CD8 Ratio
Coagulation
Prothrombin time/International normalized ratio (INR)
Chemistry
(nonfasting)
Alanine Aminotransferase (ALT)
Albumin
Alkaline Phosphatase
Amylase
Aspartate Aminotransferase (AST)
Bicarbonate
Blood Urea Nitrogen (BUN)
Calcium
Chloride
Creatinine
Creatine Kinase
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 visit (fasting for at 
least 8h)
Glucose [fasting]
High-density lipoprotein (HDL-C)
Low-density lipoprotein (LDL-C)
Triglycerides (TGs)
Total Cholesterol (TC)
Non-HDL-C
Renal Function
Creatinine clearance will be measured by Cockcroft-Gault (see Appendix 8) 
and estimated glomerular filtration rate (eGFR) by Modification of Diet in 
Renal Disease (MDRD) equation
Routine Urinalysis
Blood
Bilirubin
Glucose
Ketones
Leukocytes
Nitrite
pH
Protein
Specific gravity
Urobilinogen
Pregnancy Testing
Serum β human chorionic gonadotropin (β hCG) test (as needed for 
WOCBP)
Urine β human chorionic gonadotropin (β hCG) test (as needed for 
WOCBP)
Hepatitis Serology (at 
Screening)
Hepatitis B virus surface antigen (HBsAg)
Hepatitis B virus (HBV) surface antibody
Anti-HBc (hepatitis B core antibody)
HBV DNA 
Hepatitis C antibody plasma
HCV RNA (hepatitis C virus quantitative test)
HIV-1 Serology
HIV-1/-2 antigen/antibody screen
Virology
HIV-1 viral RNA quantification (Real time polymerase chain reaction 
[PCR])
HIV-1 drug resistance
Proviral DNA Resistance Testing (GenoSure Archive)
Inflammatory Markers
D-dimer
IL-6
Soluble CD163
hs-CRP
PK
ISL
DOR
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The investigator (or medically qualified designee) must document their review of each 
laboratory safety report.
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Table 16
Blood Volume by Visit
Study Period
Screening
HIV-1 RNA 
Confirmation
Repeat
HIV-1 RNA 
Confirmationa
Intervention
End of Treatment
Double-
Blind 
(Part 1)
Open-Label
(Part 2)
Viremia 
Confirmation
CD4+ T-cell / 
Lymphocyte 
Confirmation
Early D/C of 
Treatment
CD4+ T-cell / 
Lymphocyte 
Monitoringd
End of
Treatment F/U
Scheduled 
Day/Week
Screen
≤10 days prior 
to Day 1
7-14 days after 
Visit 2
Day 1 
(Fasting)
Day 8 
(Fasting)
TW3
TW7
Unscheduled
TW19
TW25
TW37
TW49 
(Fasting)
TW61
TW73 
(Fasting)
TW85
TW97 
(Fasting)
Unscheduled
Unscheduled
Unscheduled
Unscheduled
Unscheduled
Blood Parameter
Approximate Blood Volume (mL)
Hematology
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
Chemistry 
(includes serum 
pregnancy at 
Screening and 
Early 
Discontinuation)
6
6
6
6
6
6
6
6
6
6
6
6
6
Renal Function
NA; eGFR 
by MDRD 
equation
Serum Pregnancy 
Test (β-hCG; 
WOCBP only)
Included 
in 
Chemistry
Fasting 
Lipids/Glucose
Included 
in 
Chemistry
PT/INR
2.7
HIV-1/2 and 
hepatitis serologyb
6
HBV DNA
6
6
HCV RNA
6
6
HIV-1 viral RNA 
Quantification 
(Real Time PCR)
6
6
6
6
6
6
6
6
6
6
6
6
6
6
6
6
6
6
6
HIV Confirmation 
Geenius
1
CD4+ T-cell 
count/TBNK Panel
4
4
4
4
4
4
4
4
4
4
4
4
4
4
4
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Study Period
Screening
HIV-1 RNA 
Confirmation
Repeat
HIV-1 RNA 
Confirmationa
Intervention
End of Treatment
Double-
Blind 
(Part 1)
Open-Label
(Part 2)
Viremia 
Confirmation
CD4+ T-cell / 
Lymphocyte 
Confirmation
Early D/C of 
Treatment
CD4+ T-cell / 
Lymphocyte 
Monitoringd
End of
Treatment F/U
Scheduled 
Day/Week
Screen
≤10 days prior 
to Day 1
7-14 days after 
Visit 2
Day 1 
(Fasting)
Day 8 
(Fasting)
TW3
TW7
Unscheduled
TW19
TW25
TW37
TW49 
(Fasting)
TW61
TW73 
(Fasting)
TW85
TW97 
(Fasting)
Unscheduled
Unscheduled
Unscheduled
Unscheduled
Unscheduled
HIV-1 drug 
resistance
16
16
16
16
16
16
16
16
16
16
16
16
16
16
16
16
16
Whole blood for 
Proviral DNA 
resistance testing
3
3
3
3
3
3
3
Blood (plasma) for 
ISL and DOR PK
4
4
4
4
8
4
8
Blood (plasma) for 
Investigational PK
4
4
4
4
4
Blood (Plasma) for 
DOR and ISL PK 
During Pregnancy
<--------------------------------------Xc------------------------------------>
Genetic Analysis
8.5
FBR
8
8
8
8
8
8
Inflammatory 
Markers
10.7
10.7
10.7
10.7
Total Blood 
Volume per Visit
58.7
6
6
65.2
38
26
26
38
26
63.7
38
75.7
34
34
34
55.7
37
6
49
6
41
anti-HBc=hepatitis B core antibody; DNA=deoxyribonucleic acid; DOR=doravirine; eGFR=estimated glomerular filtration rate; FBR=future biomedical research; HBsAg=hepatitis B surface antigen; 
HBV=hepatitis B virus; HIV-1=human immunodeficiency virus-1; INR=international normalized ratio; ISL=islatravir; MDRD=Modification of Diet in Renal Disease; NA=Not Applicable; 
PCR=polymerase chain reaction; PK=pharmacokinetic(s) PT=prothrombin time; RNA=ribonucleic acid; TBNK=T- and B-lymphocyte and natural killer cell profile; WOCBP=women of childbearing 
potential.
a The Repeat HIV-1 Confirmation Visit is only for those participants with HIV-1 RNA ≥500 copies/mL at Visit 2 AND with a ≥0.5 log10 decline in HIV-1 RNA from the Screening Visit; these 
participants will be required to return to the site for a Repeat HIV-1 RNA Confirmation Visit (Visit 3). At Visit 3, in order to be eligible for randomization, participants must have HIV-1 RNA ≥500 
copies/mL and a <0.3 log10 decline in HIV-1 RNA from the previous result at Visit 2.
b HIV-1/2 and hepatitis serology includes: HBsAg, HBsAb, anti-HBc total, HCV Ab, and HIV-1/2 antigen/antibody test. 
c PK samples collected during pregnancy per Section 8.11.7.1. 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.
d Blood volumes collected at the CD4+ T-cell Count/Lymphocyte Count Monitoring Visit represent single monthly monitoring visits.
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The assessments in Table 17 are for any participant who is pregnant at the last regularly 
scheduled study visit (ie, Week 97) and whose visit schedule will be extended through the 
duration of the pregnancy to allow assessments through each trimester and postpartum.
Table 17
Blood Volumes: Participants Whose Pregnancy or Postpartum Visit(s) Extends 
Beyond Week 97
Visit Number
17
18
19
20
Scheduled Week
Week 109
Week 121
Week 133
Week 145
Blood Parameter
Approximate Blood Volume (mL)
Plasma HIV-1 RNA Quantification (Real Time PCR)
6
6
6
6
CD4+ T-cell Count/TBNK panel
4
4
4
4
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
Total Blood Volume per Visit (mL)a
53
53
53
53
DOR=doravirine; FBR=future biomedical research; HIV-1=human immunodeficiency virus Type 1; ISL=islatravir; 
PCR=polymerase chain reaction; PK=pharmacokinetic(s); RNA=ribonucleic acid; TBNK=T- and B-lymphocyte and 
natural killer cell profile.
a PK samples collected during pregnancy will be collected per Section 8.11.7.1. During the 1st trimester and postpartum 
study visits, 4 mL of blood will be collected for PK sampling. During the 2nd and 3rd trimester study visits, 12 mL of 
blood will be collected for PK sampling.
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10.3
Appendix 3: Adverse Events: Definitions and Procedures for Recording, 
Evaluating, Follow-up, and Reporting
10.3.1
Definition of AE
AE definition

An AE is any untoward medical occurrence in a clinical study participant, temporally 
associated with the use of study intervention, whether or not considered related to the 
study intervention.

NOTE: An AE can therefore be any unfavorable and unintended sign (including an 
abnormal laboratory finding), symptom, or disease (new or exacerbated) temporally 
associated with the use of a study intervention.

NOTE: For purposes of AE definition, study intervention (also referred to as Sponsor’s 
product) includes any pharmaceutical product, biological product, vaccine, diagnostic 
agent, or protocol specified procedure whether investigational or marketed (including 
placebo, active comparator product, or run-in intervention), manufactured by, licensed 
by, provided by, or distributed by the Sponsor for human use in this study.
Events meeting the AE definition

Any abnormal laboratory test results (hematology, clinical chemistry, or urinalysis) or 
other safety assessments (eg, ECG, radiological scans, vital signs measurements), 
including those that worsen from baseline, considered clinically significant in the medical 
and scientific judgment of the investigator.

Exacerbation of a chronic or intermittent pre-existing condition including either an 
increase in frequency and/or intensity of the condition.

New conditions detected or diagnosed after study intervention administration even 
though it may have been present before the start of the study.

Signs, symptoms, or the clinical sequelae of a suspected drug-drug interaction.

Signs, symptoms, or the clinical sequelae of a suspected overdose of either study 
intervention or a concomitant medication.

For all reports of overdose (whether accidental or intentional) with an associated AE, the 
AE term should reflect the clinical symptoms or abnormal test result. An overdose 
without any associated clinical symptoms or abnormal laboratory results is reported using 
the terminology “accidental or intentional overdose without adverse effect.”

Any new cancer or progression of existing cancer.
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Events NOT meeting the AE definition

Medical or surgical procedure (eg, endoscopy, appendectomy): the condition that leads to 
the procedure is the AE.

Situations in which an untoward medical occurrence did not occur (social and/or 
convenience admission to a hospital).

Anticipated day-to-day fluctuations of pre-existing disease(s) or condition(s) present or 
detected at the start of the study that do not worsen.

Surgery planned prior to informed consent to treat a pre-existing condition that has not 
worsened.

Refer to Section 8.4.6 for protocol-specific exceptions.
10.3.2
Definition of SAE
If an event is not an AE per definition above, then it cannot be an SAE even if serious 
conditions are met.
An SAE is defined as any untoward medical occurrence that, at any dose:
a. Results in death
b. Is life-threatening
-
The term “life-threatening” in the definition of “serious” refers to an event in which 
the participant was at risk of death at the time of the event. It does not refer to an 
event, which hypothetically might have caused death, if it were more severe.
c.
Requires inpatient hospitalization or prolongation of existing hospitalization
-
Hospitalization is defined as an inpatient admission, regardless of length of stay, even 
if the hospitalization is a precautionary measure for continued observation. (Note: 
Hospitalization for an elective procedure to treat a pre-existing condition that has not 
worsened is not an SAE.) A pre-existing condition is a clinical condition that is 
diagnosed prior to the use of an MSD product and is documented in the participant’s 
medical history.
d. Results in persistent or significant disability/incapacity
-
The term disability means a substantial disruption of a person’s ability to conduct 
normal life functions.
-
This definition is not intended to include experiences of relatively minor medical 
significance such as uncomplicated headache, nausea, vomiting, diarrhea, influenza, 
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and accidental trauma (eg, sprained ankle) that may interfere with or prevent 
everyday life functions but do not constitute a substantial disruption.
e.
Is a congenital anomaly/birth defect
-
In offspring of participant taking the product regardless of time to diagnosis.
f.
Other important medical events
-
Medical or scientific judgment should be exercised in deciding whether SAE 
reporting is appropriate in other situations such as important medical events that may 
not be immediately life-threatening or result in death or hospitalization but may 
jeopardize the participant or may require medical or surgical intervention to prevent 1 
of the other outcomes listed in the above definition. These events should usually be 
considered serious.
-
Examples of such events include invasive or malignant cancers, intensive treatment in 
an emergency room or at home for allergic bronchospasm, blood dyscrasias or 
convulsions that do not result in hospitalization, or development of drug dependency 
or drug abuse.
10.3.3
Additional Events Reported
Additional events that require reporting
In addition to the above criteria, AEs meeting either of the below criteria, although not 
serious per ICH definition, are reportable to the Sponsor.

Is a cancer

Is associated with an overdose 
10.3.4
Recording AE and SAE
AE and SAE recording

When an AE/SAE occurs, it is the responsibility of the investigator to review all 
documentation (eg, hospital progress notes, laboratory, and diagnostics reports) related to 
the event.

The investigator will record all relevant AE/SAE information on the AE 
CRFs/worksheets at each examination.

It is not acceptable for the investigator to send photocopies of the participant’s medical 
records to the Sponsor in lieu of completion of the AE CRF page.

There may be instances when copies of medical records for certain cases are requested by 
the Sponsor. In this case, all participant identifiers, with the exception of the participant 
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number, will be blinded on the copies of the medical records before submission to the 
Sponsor.

The investigator will attempt to establish a diagnosis of the event based on signs, 
symptoms, and/or other clinical information. In such cases, the diagnosis (not the 
individual signs/symptoms) will be documented as the AE/SAE.
Assessment of intensity/toxicity

An event is defined as “serious” when it meets at least 1 of the predefined outcomes as 
described in the definition of an SAE, not when it is rated as severe.

The investigator will make an assessment of intensity for each AE and SAE (and other 
reportable safety event) by recording the grade according to the NIH DAIDS Table for 
Grading the Severity of Adult and Pediatric Adverse Events, version 2.1. Any AE which 
changes DAIDS grade over the course of a given episode will have each change of grade 
recorded on the AE CRFs/worksheets.
-
Grade 1 Mild event: Mild symptoms causing no or minimal interference with usual 
social and functional activities with intervention not indicated.
-
Grade 2 Moderate event: Moderate symptoms causing greater than minimal 
interference with usual social and functional activities with intervention indicated.
-
Grade 3 Severe event: Severe symptoms causing inability to perform usual social and 
functional activities with intervention or hospitalization indicated.
-
Grade 4 Potentially life-threatening event: Potentially life-threatening symptoms 
causing inability to perform basic self-care 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 Sponsor’s product cause the AE?

The determination of the likelihood that the Sponsor’s product caused the AE will be 
provided by an investigator who is a qualified physician. The investigator’s signed/dated 
initials on the source document or worksheet that supports the causality noted on the AE 
form, ensures that a medically qualified assessment of causality was done. This initialed 
document must be retained for the required regulatory time frame. The criteria below are 
intended as reference guidelines to assist the investigator in assessing the likelihood of a 
relationship between the test product and the AE based upon the available information.

The following components are to be used to assess the relationship between the 
Sponsor’s product and the AE; the greater the correlation with the components and 
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their respective elements (in number and/or intensity), the more likely the Sponsor’s 
product caused the AE:
-
Exposure: Is there evidence that the participant was actually exposed to the 
Sponsor’s product such as: reliable history, acceptable compliance assessment (pill 
count, diary, etc.), expected pharmacologic effect, or measurement of drug/metabolite 
in bodily specimen?
-
Time Course: Did the AE follow in a reasonable temporal sequence from 
administration of the Sponsor’s product? Is the time of onset of the AE compatible 
with a drug-induced effect (applies to studies with investigational medicinal product)?
-
Likely Cause: Is the AE not reasonably explained by another etiology such as 
underlying disease, other drug(s)/vaccine(s), or other host or environmental factors.
-
Dechallenge: Was the Sponsor’s product discontinued or dose/exposure/frequency 
reduced?
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 Sponsor’s product; 
(3) the study is a single-dose drug study; or (4) Sponsor’s product(s) is/are only used 1 
time.)
-
Rechallenge: Was the participant re-exposed to the Sponsor’s product in this study?
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) Sponsor’s product(s) is/are 
used only 1 time.)
NOTE: IF A RECHALLENGE IS PLANNED FOR AN AE THAT WAS SERIOUS AND 
MAY HAVE BEEN CAUSED BY THE SPONSOR’S PRODUCT, OR IF RE-EXPOSURE 
TO THE SPONSOR’S PRODUCT POSES ADDITIONAL POTENTIAL SIGNIFICANT 
RISK TO THE PARTICIPANT THEN THE RECHALLENGE MUST BE APPROVED IN 
ADVANCE BY THE SPONSOR CLINICAL DIRECTOR, AND IF REQUIRED, THE 
IRB/IEC.
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-
Consistency with study intervention profile: Is the clinical/pathological 
presentation of the AE consistent with previous knowledge regarding the Sponsor’s 
product or drug class pharmacology or toxicology?
-
The assessment of relationship will be reported on the case report forms/worksheets 
by an investigator who is a qualified physician according to his/her best clinical 
judgment, including consideration of the above elements.
-
Use the following scale of criteria as guidance (not all criteria must be present to be 
indicative of a Sponsor’s product relationship).
-
Yes, there is a reasonable possibility of Sponsor’s product relationship:
o
There is evidence of exposure to the Sponsor’s product. The temporal sequence of 
the AE onset relative to the administration of the Sponsor’s product is reasonable. 
The AE is more likely explained by the Sponsor’s product than by another cause.
-
No, there is not a reasonable possibility of Sponsor’s product relationship:
o
Participant did not receive the Sponsor’s product OR temporal sequence of the 
AE onset relative to administration of the Sponsor’s product is not reasonable OR 
the AE is more likely explained by another cause than the Sponsor’s product. 
(Also entered for a participant with overdose without an associated AE.)

For each AE/SAE, the investigator must document in the medical notes that he/she has 
reviewed the AE/SAE and has provided an assessment of causality.

There may be situations in which an SAE has occurred and the investigator has minimal 
information to include in the initial report to the Sponsor. However, it is very important 
that the investigator always make an assessment of causality for every event before the 
initial transmission of the SAE data to the Sponsor.

The investigator may change his/her opinion of causality in light of follow-up 
information and send an SAE follow-up report with the updated causality assessment.

The causality assessment is 1 of the criteria used when determining regulatory reporting 
requirements.
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.
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
The investigator will submit any updated SAE data to the Sponsor within 24 hours of 
receipt of the information.
10.3.5
Reporting of AEs, SAEs, and Other Reportable Safety Events to the Sponsor
AE, SAE, and other reportable safety event reporting to Sponsor via electronic data 
collection tool

The primary mechanism for reporting to the Sponsor will be the 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.
o
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
10.5.1
Definitions 
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. 
o
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.
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:
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Transgender women (assigned male gender at birth and transitioning toward femaleness).

Premenarchal

Premenopausal female with 1 of the following:
-
Documented hysterectomy
-
Documented bilateral salpingectomy
-
Documented bilateral oophorectomy
For individuals with permanent infertility due to an alternate medical cause other than the 
above (eg, Mullerian agenesis, androgen insensitivity), investigator discretion should be 
applied to determining study entry.
Note: Documentation can come from the site personnel’s review of the participant’s medical 
records, medical examination, or medical history interview.

Postmenopausal female
-
A postmenopausal state is defined as no menses for 12 months without an alternative 
medical cause.
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.
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10.5.2
Contraception Requirements
Female Participants
Contraceptives allowed during the study includea:
Highly Effective Contraceptive Methods That Have Low User Dependencyb
Failure rate of <1% per year when used consistently and correctly.

Progestogen- only contraceptive implantc

IUSd

Non-hormonal IUD

Bilateral tubal occlusion

Azoospermic partner (vasectomized or secondary to medical cause)
This is a highly effective contraception method provided that the partner is the sole male sexual partner of the WOCBP 
and the absence of sperm has been confirmed. If not, an additional highly effective method of contraception should be 
used. A spermatogenesis cycle is approximately 90 days.
Note: Documentation of azoospermia can come from the site personnel’s review of the participant’s medical records, 
medical examination, or medical history interview.
Highly Effective Contraceptive Methods That Are User Dependentb
Failure rate of <1% per year when used consistently and correctly.
-
Combined (estrogen- and progestogen- containing) hormonal contraceptionc

Oral

Intravaginal

Transdermal

Injectable
-
Progestogen-only hormonal contraceptionc

Oral

Injectable
Sexual Abstinence

Sexual abstinence is considered a highly effective method only if defined as refraining from heterosexual intercourse 
during the entire period of risk associated with the study intervention. The reliability of sexual abstinence needs to be 
evaluated in relation to the duration of the study and the preferred and usual lifestyle of the participant.
Acceptable Contraceptive Methods
Failure rate of >1% per year when used consistently and correctly.

Progesterone-only hormonal contraception where inhibition of ovulation is not the primary mode of action

Male or female condom with or without spermicide

Cervical cap, diaphragm, or sponge with spermicide

A combination of male condom with either cervical cap, diaphragm, or sponge with spermicide (double barrier 
methods)e
a.
Contraceptive use by men or women should be consistent with local regulations regarding the use of 
contraceptive methods for participants of clinical studies.
b.
Typical use failure rates are higher than perfect-use failure rates (ie, when used consistently and correctly).
c.
If locally required, in accordance with CTFG guidelines, acceptable contraceptive implants are limited to those 
which inhibit ovulation. 
d.
IUS is a progestin releasing IUD.
e.
A combination of male condom with either cap, diaphragm, or sponge with spermicide are considered 
acceptable, but not highly effective, birth control methods. 
Note: The following are not acceptable methods of contraception:
-
Periodic abstinence (calendar, symptothermal, post-ovulation methods), withdrawal (coitus interruptus), 
spermicides only, and LAM.
-
Male and female condom should not be used together (due to risk of failure with friction).
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10.6
Appendix 6: Collection and Management of Specimens for Future Biomedical 
Research
1. Definitions
a.
Biomarker: A biological molecule found in blood, other body fluids, or tissues that is
a sign of a normal or abnormal process or of a condition or disease. A biomarker may
be used to see how well the body responds to a treatment for a disease or condition.1
b. Pharmacogenomics: The investigation of variations of DNA and RNA characteristics 
as related to drug/vaccine response.2
c.
Pharmacogenetics: A subset of pharmacogenomics, pharmacogenetics is the influence 
of variations in DNA sequence on drug/vaccine response.2
d. DNA: Deoxyribonucleic acid.
e.
RNA: Ribonucleic acid.
2. Scope of Future Biomedical Research
The specimens consented and/or collected in this study as outlined in Section 8.9 will be 
used in various experiments to understand:
o
The biology of how drugs/vaccines work
o
Biomarkers responsible for how a drug/vaccine enters and is removed by the body
o
Other pathways drugs/vaccines may interact with
o
The biology of disease
The specimen(s) may be used for future assay development and/or drug/vaccine 
development.
It is now well recognized that information obtained from studying and testing clinical 
specimens offers unique opportunities to enhance our understanding of how individuals 
respond to drugs/vaccines, enhance our understanding of human disease and ultimately 
improve public health through development of novel treatments targeted to populations 
with the greatest need. All specimens will be used by the Sponsor or those working for or 
with the Sponsor.
3. Summary of Procedures for Future Biomedical Research.
a.
Participants for Enrollment
All participants enrolled in the clinical study will be considered for enrollment in 
future biomedical research
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b. Informed Consent
Informed consent for specimens (ie, DNA, RNA, protein, etc.) will be obtained 
during Screening for protocol enrollment from all participants or legal guardians, at a 
study visit by the investigator or his or her designate. Informed consent for future 
biomedical research should be presented to the participants on the visit designated in 
the SoA. If delayed, present consent at next possible Participant Visit. Consent forms 
signed by the participant will be kept at the clinical study site under secure storage for 
regulatory reasons.
A template of each study site’s approved informed consent will be stored in the 
Sponsor’s clinical document repository.
c.
eCRF Documentation for Future Biomedical Research Specimens
Documentation of participant consent for future biomedical research will be captured 
in the eCRFs. Any specimens for which such an informed consent cannot be verified 
will be destroyed.
d. Future Biomedical Research Specimen(s)
Collection of specimens for future biomedical research will be performed as outlined 
in the SoA. In general, if additional blood specimens are being collected for future 
biomedical research, these will usually be obtained at a time when the participant is 
having blood drawn for other study purposes.
4. Confidential Participant Information for Future Biomedical Research
In order to optimize the research that can be conducted with future biomedical research 
specimens, it is critical to link participant’ clinical information with future test results. In 
fact little or no research can be conducted without connecting the clinical study data to 
the specimen. The clinical data allow specific analyses to be conducted. Knowing 
participant characteristics like gender, age, medical history and intervention outcomes are 
critical to understanding clinical context of analytical results.
To maintain privacy of information collected from specimens obtained for future 
biomedical research, the Sponsor has developed secure policies and procedures. All 
specimens will be single-coded per ICH E15 guidelines as described below.
At the clinical study site, unique codes will be placed on the future biomedical research 
specimens. This code is a random number which does not contain any personally 
identifying information embedded within it. The link (or key) between participant 
identifiers and this unique code will be held at the study site. No personal identifiers will 
appear on the specimen tube.
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5. Biorepository Specimen Usage
Specimens obtained for the Sponsor will be used for analyses using good scientific 
practices. Analyses utilizing the future biomedical research specimens may be performed 
by the Sponsor, or an additional third party (eg, a university investigator) designated by 
the Sponsor. The investigator conducting the analysis will follow the Sponsor’s privacy 
and confidentiality requirements. Any contracted third party analyses will conform to the 
specific scope of analysis outlined in future biomedical research protocol and consent. 
Future biomedical research specimens remaining with the third party after specific 
analysis is performed will be reported to the Sponsor.
6. Withdrawal From Future Biomedical Research
Participants may withdraw their consent for future biomedical research and ask that their 
biospecimens not be used for future biomedical research. Participants may withdraw 
consent at any time by contacting the investigator for the main study. If medical records 
for the main study are still available, the investigator will contact the Sponsor using the 
designated mailbox (clinical.specimen.management@MSD.com). Subsequently, the 
participant’s specimens will be flagged in the biorepository and restricted to main study 
use only. If specimens were collected from study participants specifically for future 
biomedical research, these specimens will be removed from the biorepository and 
destroyed. Documentation will be sent to the investigator confirming withdrawal and/or 
destruction, if applicable. It is the responsibility of the investigator to inform the 
participant of completion of the withdrawal and/or destruction, if applicable. Any 
analyses in progress at the time of request for withdrawal/destruction or already 
performed prior to the request being received by the Sponsor will continue to be used as 
part of the overall research study data and results. No new analyses would be generated 
after the request is received.
In the event that the medical records for the main study are no longer available (eg, if the 
investigator is no longer required by regulatory authorities to retain the main study 
records) or the specimens have been completely anonymized, there will no longer be a 
link between the participant’s personal information and their specimens. In this situation, 
the request for withdrawal of consent and/or destruction cannot be processed.
7. Retention of Specimens
Future biomedical research specimens will be stored in the biorepository for potential 
analysis for up to 20 years from the end of the main study. Specimens may be stored for 
longer if a regulatory or governmental authority has active questions that are being 
answered. In this special circumstance, specimens will be stored until these questions 
have been adequately addressed.
Specimens from the study site will be shipped to a central laboratory and then shipped to 
the Sponsor-designated biorepository. If a central laboratory is not utilized in a particular 
study, the study site will ship directly to the Sponsor-designated biorepository. The 
specimens will be stored under strict supervision in a limited access facility which 
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operates to assure the integrity of the specimens. Specimens will be destroyed according 
to Sponsor policies and procedures and this destruction will be documented in the 
biorepository database.
8. Data Security
Databases containing specimen information and test results are accessible only to the 
authorized Sponsor representatives and the designated study administrator research 
personnel and/or collaborators. Database user authentication is highly secure, and is 
accomplished using network security policies and practices based on international 
standards to protect against unauthorized access.
9. Reporting of Future Biomedical Research Data to Participants
No information obtained from exploratory laboratory studies will be reported to the 
participant, family, or physicians. Principle reasons not to inform or return results to the 
participant include: Lack of relevance to participant health, limitations of predictive 
capability, and concerns regarding misinterpretation.
If important research findings are discovered, the Sponsor may publish results, present 
results in national meetings, and make results accessible on a public website in order to 
rapidly report this information to doctors and participants. Participants will not be 
identified by name in any published reports about this study or in any other scientific 
publication or presentation.
10. Future Biomedical Research Study Population
Every effort will be made to recruit all participants diagnosed and treated on Sponsor 
clinical studies for future biomedical research.
11. Risks Versus Benefits of Future Biomedical Research
For future biomedical research, risks to the participant have been minimized and are 
described in the future biomedical research informed consent.
The Sponsor has developed strict security, policies, and procedures to address participant 
data privacy concerns. Data privacy risks are largely limited to rare situations involving 
possible breach of confidentiality. In this highly unlikely situation, there is risk that the 
information, like all medical information, may be misused.
12. Questions
Any questions related to the future biomedical research should be emailed directly to 
clinical.specimen.management@MSD.com.
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13. References
1. National Cancer Institute [Internet]: Available from 
https://www.cancer.gov/publications/dictionaries/cancer-terms?cdrid=45618
2. International Council for Harmonisation of Technical Requirements for Pharmaceuticals 
for Human Use [Internet]: E15: Definitions for Genomic Biomarkers, 
Pharmacogenomics, Pharmacogenetics, Genomic Data and Sample Coding Categories. 
Available from http://www.ich.org/products/guidelines/efficacy/efficacy-
single/article/definitions-for-genomic-biomarkers-pharmacogenomics-pharmacogenetics-
genomic-data-and-sample-cod.html 
3. Industry Pharmacogenomics Working Group [Internet]: Understanding the Intent, Scope 
and Public Health Benefits of Exploratory Biomarker Research: A Guide for IRBs/IECs 
and Investigational Site Staff. Available at http://i-pwg.org/ 
4. Industry Pharmacogenomics Working Group [Internet]: Pharmacogenomics 
Informational Brochure for IRBs/IECs and Investigational Site Staff. Available at http://i-
pwg.org/
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10.7
Appendix 7: Country-specific Requirements
10.7.1
Country-specific Request for Russia
In Russia, only adult (≥18 years of age) participants will be enrolled in this study.
In Russia, if a participant becomes pregnant (has a positive serum pregnancy test), study 
intervention must be discontinued and the participant’s HIV-1 infection and treatment should 
be managed per local standard-of-care. Therefore, the following sections of the protocol are 
not applicable:

Section 4.2.7: Rationale for Continuing Study Intervention During Pregnancy

Section 8.1.1.4: Consent/Assent for Continuation of Study Intervention During 
Pregnancy

Section 8.11.7.1: Continuing Study Intervention
10.7.2
Country-specific Request for Australia
In Australia, only adult (≥18 years of age) participants will be enrolled in this study.
10.7.3
Country-specific Request for Germany
In Germany, only adult (≥18 years of age) participants will be enrolled in this study.
10.7.4
Country-specific Request for Ukraine
In Ukraine, only adult (≥18 years of age) participants will be enrolled in this study.
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10.8
Appendix 8: Calculation of Creatinine Clearance
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)
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10.9
Appendix 9: Abbreviations
Abbreviation
Expanded Term
3TC
Lamivudine
AE
adverse event 
AIDS
Acquired Immune Deficiency Syndrome
ALT
alanine aminotransferase
ANCOVA
analysis of covariance
APaT
All Participants as Treated
ART
antiretroviral therapy
AST
aspartate aminotransferase
AUC
area under the curve
BOCF
baseline observation carried forward
C24
concentration after 24 hours
CI
confidence interval
Cmax
maximum (peak) observed drug plasma concentration
CMH
Cochran-Mantel-Haenszel
CONSORT
Consolidated Standards of Reporting Trials
CRCL
creatinine clearance
CRF
Case Report Form 
CSR
Clinical Study Report
eCTA
exploratory Clinical Trial Application
CTCAE
Common Terminology Criteria for Adverse Events
CTFG
Clinical Trial Facilitation Group 
Ctrough
lowest concentration reached by a drug before the next dose is administered
DAIDS
The Division of AIDS
DAO
data as observed
DDI
drug-drug interaction
DHHS
US Department of Health and Human Services
DMC
Data Monitoring Committee
DOR
Doravirine
DNA
deoxyribonucleic acid 
ECG
electrocardiogram 
ECI
event of clinical interest
eCRF
electronic Case Report Form
EDC
electronic data collection 
eDMC
External Data Monitoring Committee
EE
ethinyl estradiol
EFV
Efavirenz
EMA
European Medicines Agency
EOC
Executive Oversight Committee 
FAHI
Functional Assessment of Human Immunodeficiency Virus Infection
FAS
Full Analysis Set
FBR
Future Biomedical Research
FDA
Food and Drug Administration
FDC
Fixed-Dose Combination
FSH
follicle stimulating hormone 
FTC
emtricitabine
GCP
Good Clinical Practice 
HBsAG
Hepatitis B surface antigen
HBV
Hepatitis B Virus
HCV
Hepatitis C Virus
HDL-C
High-density lipoprotein cholesterol
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Abbreviation
Expanded Term
HIV
Human Immunodeficiency Virus
HIV-1
Human Immunodeficiency Virus Type 1
HIV-2
Human Immunodeficiency Virus Type 2
HRQoL
health-related quality of life
hs-CRP
High Sensitivity C-Reactive Protein
HTA
Health Technology Assessment
HTE
Heavily Treatment-Experienced
IB
Investigator’s Brochure 
IC50
concentration of drug needed to inhibit 50% of viral growth
ICF
Informed Consent Form 
ICH
International Council for Harmonisation of Technical Requirements for 
Pharmaceuticals for Human Use
IEC
Independent Ethics Committee
IL-6
interleukin-6
INR
international normalized ratio
InSTI
integrase strand transfer inhibitor
IQ
inhibitory quotient
IRB
Institutional Review Board 
IRT
interactive response technology
ISL
Islatravir
IUD
intrauterine device
IUS
intrauterine hormone-releasing system
LNG
Levonorgestrel
LOCF
last observation carried forward
NNRTI
non-nucleoside reverse transcriptase inhibitor
Non-HDL-C
nonhigh-density lipoprotein cholesterol
NRTI
nucleoside reverse transcriptase inhibitor
NRTTI
nucleoside reverse transcriptase translocation inhibitor
OBT
Optimized Background Therapy
OF
Observed Failure
PCR
polymerase chain reaction
PDLC
predefined limit of change 
PI
protease inhibitor
PK
pharmacokinetic
PP
per-protocol
PrEP
preexposure prophylaxis
PROs
patient-reported outcomes
QD
once daily
QoL
quality of life
QW
once weekly
RNA
ribonucleic acid
SAC
Scientific Advisory Committee
SAE
serious adverse event 
SAP
statistical analysis plan
sCD-163
soluble CD-163
SoA
schedule of activities
SOP
Standard Operating Procedure
sSAP
supplemental statistical analysis plan
SUSARs
suspected unexpected serious adverse reactions
TAMs
thymidine analog mutations
TB
tuberculosis
TBNK
T- and B- Lymphocyte and Natural Killer Cell Profile
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Abbreviation
Expanded Term
TC
total cholesterol
TDF
tenofovir disoproxil fumarate
TG
Triglycerides
TN
treatment-naïve
TP
Triphosphate
TW
treatment week
ULN
upper limit of normal
VL
viral load
WHO
World Health Organization
WOCBP
woman/women of childbearing potential 
WONCB
woman/women of nonchildbearing potential 
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11
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