Conditions: HIV-1 Infection
Allocation: NA | Intervention model: SINGLE_GROUP
Enrollment: 42
Healthy volunteers: no

Brief summary:
This is a phase 2, single-group, multi-site, open-label study of an islatravir/doravirine (ISL/DOR, MK-8591A) fixed dose combination (FDC) for the treatment of human immunodeficiency virus type 1 (HIV-1) infection in pediatric participants who are virologically suppressed (VS) on antiretroviral therapy (ART) for ≥3 months or are treatment-naive (TN). The primary purposes of the study are 1) to examine the steady-state pharmacokinetics (PK) of ISL in plasma; 2) the steady-state PK of ISL-triphosphate (ISL-TP) in peripheral blood mononuclear cells (PBMCs); and 3) to examine the safety and tolerability of ISL/DOR.

Detailed description:
As of protocol amendment 03 (approved 08-Feb-2022), all participants have been discontinued from study therapy and will be switched to non-study antiretroviral therapy and monitored for safety. The present results cover data obtained through the cut-off date of 30-Mar-2022, and will be updated once monitoring is completed.

Arms:
arm 1: Pediatric participants with HIV-1 infection receive DOR/ISL for 96 weeks.

Interventions: intervention 1: DOR/ISL
Intervention descriptions: intervention 1: 100 mg DOR/0.75 mg ISL FDC tablet taken once daily by mouth.

Protocol document:
Prot_SAP_000.pdf: 
Official Protocol Title: 
NCT number: 
NCT04295772 
Document Date: 
08-Feb-2022
A Phase 2 Clinical Study to Evaluate the Pharmacokinetics, Safety, 
and Efficacy of Doravirine/Islatravir in Pediatric Participants with 
HIV-1 Infection who are Virologically Suppressed or Treatment-
Naïve, are Less Than 18 Years of Age, and Weigh Greater Than or 
Equal to 35 kg


PRODUCT: MK-8591A  
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PROTOCOL/AMENDMENT NO.: 028-03 
MK-8591A-028-03 FINAL PROTOCOL
08-FEB-2022
Title Page
THIS PROTOCOL AMENDMENT AND ALL OF THE INFORMATION RELATING 
TO IT ARE CONFIDENTIAL AND PROPRIETARY PROPERTY OF MERCK 
SHARP & DOHME CORP., A SUBSIDIARY OF MERCK & CO., INC., NJ, U.S.A. 
(MSD).
Protocol Title: A Phase 2 Clinical Study to Evaluate the Pharmacokinetics, Safety, and 
Efficacy of Doravirine/Islatravir in Pediatric Participants with HIV-1 Infection who are 
Virologically Suppressed or Treatment-Naïve, are Less Than 18 Years of Age, and Weigh 
Greater Than or Equal to 35 kg
Protocol Number: 028-03
Compound Number: MK-8591A
Sponsor Name:
Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc.
(hereafter referred to as the Sponsor or MSD)
Legal Registered Address:
One Merck Drive
P.O. Box 100
Whitehouse Station, New Jersey, 08889-0100, U.S.A.
Regulatory Agency Identifying Number(s):
IND
134036
EudraCT
2019-003597-10
Approval Date: 08 February 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
Protocol Amendment 03
08-FEB-2022
The protocol was amended to: (1) discontinue dosing of study intervention in
all participants based on Sponsor’s acceptance of recommendations by the
eDMC for pediatric HIV treatment trials (2) specify plans for detection of and 
follow-up of participants with specified decreases in CD4+ T-cell and/or total 
lymphocyte counts.
Protocol Amendment 02
12-MAR-2021
The protocol was amended to: (1) include an assessment of the palatability of a
split tablet, (2) update inclusion criteria to include only participants who have 
no prior history of treatment failure, (3) add documented M184V/I substitution 
to exclusion criterion 9, and (4) add clarity around safety data collection for 
participants continuing study intervention after the last visit.
Protocol Amendment 01
12-AUG-2020
The protocol was primarily amended to: (1) include a new cohort of 15 
participants who are naïve to ART, (2) adapt the study visit schedule removing 
Week 12 and adding Week 8 and Week 16 visits, (3) remove the 12-year-old 
lower age limit, (4) remove DOR PK assessments, and (5) extend the overall 
duration of the study to a total of 96 weeks.
Original Protocol
09-JAN-2020
Not applicable
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PROTOCOL AMENDMENT SUMMARY OF CHANGES
Amendment: 03
Overall Rationale for the Amendments:
The protocol was amended to: (1) discontinue dosing of study intervention in all participants based on Sponsor’s acceptance of 
recommendations by the eDMC for pediatric HIV treatment trials (2) specify plans for detection and follow-up of participants with 
specified decreases in CD4+ T-cell and/or total lymphocyte counts. 
Summary of Changes Table:
Section # and Name
Description of Change 
Brief Rationale 
1.1 Synopsis 
2.1 Study Rationale
3 Hypotheses, Objectives, and Endpoints
4 Study Design (Sections 4.2, 4.2.1.2, 
4.2.1.3, 4.2.1.4)
4.3 Justification for Dose
6 Study Intervention (Sections 6.1, 6.2,
6.3, 6.4, 6.5, 6.7, 6.8)
7.1 Discontinuation of Study Intervention
8 Study Assessments and Procedures 
(Sections 8.3.5, 8.4.7, 8.6.1, 8.11.3)
9 Statistical Analysis Plan (Sections 9.4.3, 
9.6.1, 9.6.1.1, 9.6.2, 9.6.3, 9.6.4, 9.9, and 
9.10)

Notes were added to multiple 
sections to indicate that study 
intervention administration has 
been discontinued in all 
participants and all participants 
will be switched to non-study 
ART. 

Study endpoints that are no 
longer applicable were noted as 
such.

Duration and details of safety 
follow-up were added where 
relevant.
To make updates consistent with Sponsor’s 
acceptance of the recommendations by the 
eDMC to discontinue study intervention for all 
participants, and to specify plans to monitor 
CD4+ T-cell and total lymphocyte counts.
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Section # and Name
Description of Change 
Brief Rationale 
1.3.2 SoA - Viremia Confirmation and 
End of Treatment

Expanded lymphocyte analysis to 
include B-cells and NK cells.

Changed the laboratory procedure 
name from “CD4+ T cell count”
to “CD4+ T cell count/TBNK
panel”.

Added notes for CD4+ T-cell 
count/TBNK panel testing and 
Hematology assessments to refer 
to Section 8.11.5 and Section 
1.3.3 for participants with 
specified decreases in CD4+ T-
cell and/or total lymphocyte 
counts.

Added random PK sample 
collection to the End of 
Treatment Follow-up Visit. 

Deleted previous notes for HIV 
viral resistance and revised the 
note for PK sample collection.

Given the decreases in total lymphocyte 
count observed in the ISL program, to 
assess for changes in other subpopulations 
of lymphocytes in addition to T-cells.

To clarify that CD4+ T-cell count is part of 
the TBNK panel, which measures different 
T-cell, B-cell, and NK-cell types.

To refer to additional follow-up needed for 
participants with specified decreases in 
CD4+ T-cell and/or total lymphocyte 
counts.

A plasma sample for PK will be collected
at the End of Treatment Follow-up Visit to 
determine whether there is prolonged ISL 
exposure in pediatric participants. 

For clarity
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Section # and Name
Description of Change 
Brief Rationale 
1.3.3 SoA - Participants with Specified 
Decreases in CD4+ T-cell Counts and/or 
Lymphocyte Counts

Added new Schedule of 
Activities

To specify visits and assessments 
associated with confirming and monitoring 
decreases in CD4+ T-cell counts and/ or 
total lymphocyte counts.

To determine whether there is prolonged 
ISL exposure in pediatric participants. 
2.2.3 Doravirine/Islatravir

Updated results for MK-8591 
Protocol 011.

To provide most current information on 
DOR/ISL clinical studies.
2.3 Benefit/Risk Assessment

Updated text based on CD4+ T
cell and total lymphocyte 
findings.

Updated text to state that dosing 
of ISL QM 60 mg in the HIV-1 
PrEP program has been 
discontinued.

Specified DOR/ISL QD doses 
(100 mg/0.75 mg) used in the 
Phase 3 studies (MK-8591A 
Protocol 017 and MK-8591A 
Protocol 018)

To account for new safety and efficacy 
information from the ISL clinical 
development program that is relevant to the 
population in this study.

To provide current status of ISL dosing in 
the PrEP program.

DOR/ISL doses were specified to provide 
context for changes from baseline in CD4+ 
T-cell and/or total lymphocytes
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Section # and Name
Description of Change 
Brief Rationale 
5 Study Population

Clarified that no new participants 
will be enrolled into the study

To align with Sponsor’s acceptance of the 
recommendations by the eDMC to 
discontinue study intervention for all 
participants
5.2 Exclusion Criteria

Updated exclusion criterion #9 
(prior to Sponsor decision to 
discontinue dosing in the study) 
to allow resistance testing results 
from a local laboratory to 
determine participant eligibility, 
if the results were obtained <90 
days prior to Screening Visit 
through Day 1.

To align the protocol text with a Protocol 
Clarification Letter that took effect when 
participant enrollment was ongoing.  
5.2 Exclusion Criteria

The text in parentheses, “(based 
on central laboratory results)”, 
was removed from exclusion 
criterion #10

To align the protocol text with a Protocol 
Clarification Letter that took effect when 
participant enrollment was ongoing. This 
update was made to clarify that central 
laboratory results are not needed for the 
exclusionary laboratory values in Table 1.
Although the exclusion criterion has been 
revised to remove the parenthetical 
statement, any laboratory tests related to 
study endpoints (eg, HIV-1 RNA or CD4+ 
T-cell count) must be performed at the 
central laboratory.
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Section # and Name
Description of Change 
Brief Rationale 
8.2.3 T- and B-Lymphocyte and Natural 
Killer Cell Profile (TBNK)

Updated section title and text to 
reflect TBNK panel (changed 
from “CD4+ T-cell Counts” to 
“T- and B-Lymphocyte and 
Natural Killer Cell Profile 
[TBNK])”.

Revised for clarity and accuracy of 
laboratory test nomenclature. 
8.3.4 Clinical Safety Laboratory 
Assessments

Added note to cross-reference to 
Section 8.11.5 Management of 
Participants with Decreases in 
CD4+ T-cell Counts and/or Total 
Lymphocyte Counts

To clarify additional follow-up needed for 
participants with specified decreases in 
CD4+ T-cell and/or total lymphocyte 
counts.
8.6.1 Blood Collection for Plasma ISL 
measurements

Added PK sample collection at 
the End of Treatment Follow-up 
Visit

Removed footnote in Table 6 for 
the Week 24 visit

To determine whether there is prolonged 
ISL exposure in pediatric participants.

Random samples were no longer taken at 
that visit.
8.11.3.1 Clinical Management of 
Participants Who Become Pregnant

Updated text to include guidance 
for assessment of AEs that are 
pregnancy-related complications

To clarify the reference (within the DAIDS 
table) when assessing AEs that are 
pregnancy-related complications.
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Section # and Name
Description of Change 
Brief Rationale 
8.11.3.2 Early Discontinuation of 
Treatment
8.11.3.3 End of Treatment Follow-up 
Visit

Added guidance that additional 
monitoring after discontinuation 
of DOR/ISL is required for 
participants with specified 
decreases in CD4+ T-cell and/or 
total lymphocyte counts per 
Section 8.11.5.

To clarify management of participants who 
discontinue study intervention and 
emphasize additional requirements to 
monitor decreases in CD4+ T-cell and/or 
total lymphocyte counts for recovery after 
DOR/ISL discontinuation.
8.11.5 Management of Participants with 
Decreases in CD4+ T-cell count Counts 
and/or Total Lymphocyte Counts

New section added to define 
methods for confirming and 
monitoring decreases in CD4+ T-
cell counts and/or total 
lymphocyte counts

To guide the management of participants 
with decreases in CD4+ T-cell counts 
and/or lymphocyte counts.
9 Statistical Analysis Plan

Clarified which analyses will be 
performed based on available 
data and indicated the sections 
that are no longer applicable.

To clarify the statistical analysis plan for 
the study.
10.2 Appendix 2: Clinical Laboratory 
Tests

Added details on TBNK panel to 
Table 13

Added a bullet referencing the 
central laboratory requirements 
for testing study endpoints.

Added Table 15 

Added for completeness; TBNK panel 
measures different T-cell, B-cell, and NK 
cell types.

To improve clarity.

To specify the timing and volume of blood 
collection at Early Discontinuation of 
Treatment, End of Treatment Follow-up 
and Extended Monitoring of CD4+ T-cell 
and/or Total Lymphocyte Count visits 
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Section # and Name
Description of Change 
Brief Rationale 
10.5.2 Contraception Requirements

Added footnote “d” to describe 
IUS

To update standard template language
Throughout as applicable

Minor changes made to correct 
typographical and editorial errors

To provide consistency and/or clarity 
within the document.
Throughout as applicable

Notes were added to indicate 
certain sections of the protocol 
that are no longer applicable due 
to discontinuation of DOR/ISL 
dosing.

For clarity
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Table of Contents
DOCUMENT HISTORY ........................................................................................................3
PROTOCOL AMENDMENT SUMMARY OF CHANGES...............................................4
1
PROTOCOL SUMMARY ............................................................................................19
1.1
Synopsis.................................................................................................................19
1.2
Schema ..................................................................................................................23
1.3
Schedule of Activities...........................................................................................24
1.3.1
Schedule of Activities..................................................................................24
1.3.2
SoA – Viremia Confirmation and End of Treatment...................................29
1.3.3
SoA – Monitoring of Participants with Confirmed Specified Decreases 
in CD4+ T-cell Counts and/or Total Lymphocyte Counts ..........................31
2
INTRODUCTION..........................................................................................................32
2.1
Study Rationale....................................................................................................32
2.2
Background ..........................................................................................................32
2.2.1
Islatravir.......................................................................................................33
2.2.2
Doravirine ....................................................................................................33
2.2.3
Doravirine/Islatravir.....................................................................................33
2.3
Benefit/Risk Assessment......................................................................................34
3
HYPOTHESES, OBJECTIVES, AND ENDPOINTS................................................36
4
STUDY DESIGN............................................................................................................38
4.1
Overall Design......................................................................................................38
4.2
Scientific Rationale for Study Design.................................................................39
4.2.1
Rationale for Endpoints ...............................................................................40
4.2.1.1
Pharmacokinetic Endpoints ...............................................................40
4.2.1.2
Safety Endpoints................................................................................41
4.2.1.3
Efficacy Endpoints.............................................................................41
4.2.1.3.1
Definition of Clinically Significant Confirmed Viremia.........41
4.2.1.4
Palatability and Acceptability Assessment Endpoints.......................42
4.2.1.5
Planned Exploratory Biomarker Research.........................................42
4.2.1.5.1
Planned Genetic Analysis ........................................................42
4.2.1.6
Future Biomedical Research..............................................................43
4.2.2
Rationale for Collecting Race and Ethnicity Data.......................................43
4.2.3
Rationale for Collecting Gender Identity Data ............................................43
4.2.4
Rationale for Collecting Infant Safety Follow-up Data...............................44
4.3
Justification for Dose...........................................................................................44
4.4
Beginning and End of Study Definition .............................................................45
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4.4.1
Clinical Criteria for Early Study Termination .............................................45
5
STUDY POPULATION ................................................................................................46
5.1
Inclusion Criteria.................................................................................................46
5.2
Exclusion Criteria................................................................................................48
5.3
Lifestyle Considerations......................................................................................50
5.4
Screen Failures.....................................................................................................50
5.5
Participant Replacement Strategy......................................................................51
6
STUDY INTERVENTION............................................................................................51
6.1
Study Intervention(s) Administered...................................................................51
6.2
Preparation/Handling/Storage/Accountability .................................................53
6.2.1
Dose Preparation..........................................................................................53
6.2.2
Handling, Storage, and Accountability........................................................53
6.3
Measures to Minimize Bias: Randomization and Blinding..............................54
6.3.1
Intervention Assignment..............................................................................54
6.3.2
Stratification.................................................................................................54
6.3.3
Blinding........................................................................................................54
6.4
Study Intervention Compliance..........................................................................54
6.5
Concomitant Therapy..........................................................................................54
6.5.1
Rescue Medications and Supportive Care ...................................................56
6.6
Dose Modification ................................................................................................56
6.7
Intervention After the End of the Study............................................................56
6.8
Clinical Supplies Disclosure................................................................................57
7
DISCONTINUATION OF STUDY INTERVENTION AND PARTICIPANT 
WITHDRAWAL............................................................................................................57
7.1
Discontinuation of Study Intervention...............................................................57
7.2
Participant Withdrawal From the Study...........................................................58
7.3
Lost to Follow-up .................................................................................................58
8
STUDY ASSESSMENTS AND PROCEDURES........................................................58
8.1
Administrative and General Procedures ...........................................................59
8.1.1
Informed Consent/Assent.............................................................................59
8.1.1.1
General Informed Consent/Assent.....................................................59
8.1.1.2
Consent/Assent for Intensive PK Cohort Blood Sample 
Collection for Plasma and PBMCs ....................................................60
8.1.1.3
Consent for Postnatal Infant Safety Data Collection Through One 
Year of Age........................................................................................60
8.1.1.4
Consent/Assent and Collection of Specimens for Future 
Biomedical Research .........................................................................60
8.1.2
Inclusion/Exclusion Criteria ........................................................................61
8.1.3
Participant Identification Card.....................................................................61
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8.1.4
Medical History ...........................................................................................61
8.1.5
Prior and Concomitant Medications Review...............................................61
8.1.5.1
Prior Medications...............................................................................61
8.1.5.2
Concomitant Medications..................................................................62
8.1.6
Assignment of Screening Number...............................................................62
8.1.7
Assignment of Treatment/Allocation Number.............................................62
8.1.8
Study Intervention Administration ..............................................................62
8.1.8.1
Timing of Dose Administration.........................................................62
8.1.9
Palatability and Acceptability Assessment..................................................64
8.1.10
Discontinuation and Withdrawal .................................................................64
8.1.10.1
Withdrawal From Future Biomedical Research ................................64
8.1.11
Participant Blinding/Unblinding..................................................................65
8.1.12
Calibration of Equipment.............................................................................65
8.1.13
Domiciling ...................................................................................................65
8.2
Efficacy Assessments ...........................................................................................65
8.2.1
HIV-1 RNA Quantification..........................................................................65
8.2.2
Management of Study Participants with Viremia........................................65
8.2.2.1
Viremia Confirmation........................................................................66
8.2.2.2
Participants With Clinically Significant Viremia (≥200 
Copies/mL) ........................................................................................66
8.2.2.3
Participants With Low-Level Viremia (≥50 and <200 Copies/mL)..67
8.2.2.4
Viral Drug Resistance Testing...........................................................67
8.2.3
T- and B-Lymphocyte and Natural Killer Cell (TBNK) Profile..................67
8.3
Safety Assessments...............................................................................................67
8.3.1
Physical Examinations.................................................................................68
8.3.1.1
Weight................................................................................................68
8.3.2
Vital Signs....................................................................................................68
8.3.3
Confirmation of Menarche, Contraception, and Pregnancy Testing ...........68
8.3.4
Clinical Safety Laboratory Assessments .....................................................69
8.3.5
HBV Assessments........................................................................................69
8.3.6
Infant Safety Follow-up Assessments..........................................................70
8.4
Adverse Events, Serious Adverse Events, and Other Reportable Safety 
Events....................................................................................................................71
8.4.1
Time Period and Frequency for Collecting AE, SAE, and Other 
Reportable Safety Event Information ..........................................................71
8.4.2
Method of Detecting AEs, SAEs, and Other Reportable Safety Events......73
8.4.3
Follow-up of AE, SAE, and Other Reportable Safety Event Information...74
8.4.4
Regulatory Reporting Requirements for SAE .............................................74
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8.4.5
Pregnancy and Exposure During Breastfeeding ..........................................74
8.4.6
Disease-related Events and/or Disease-related Outcomes Not Qualifying 
as AEs or SAEs............................................................................................75
8.4.7
Events of Clinical Interest............................................................................75
8.5
Treatment of Overdose........................................................................................75
8.6
Pharmacokinetics.................................................................................................75
8.6.1
Blood Collection for Plasma ISL Measurements.........................................75
8.6.2
Blood Collection for ISL-TP Measurements in PBMCs .............................77
8.7
Pharmacodynamics..............................................................................................78
8.8
Biomarkers ...........................................................................................................78
8.8.1
Planned Genetic Analysis Sample Collection..............................................78
8.9
Future Biomedical Research Sample Collection...............................................78
8.10
Health Economics Medical Resource Utilization and Health Economics.......78
8.11
Visit Requirements...............................................................................................78
8.11.1
Screening/Rescreening.................................................................................79
8.11.2
Treatment Period..........................................................................................79
8.11.2.1
Optional Nurse Visits and Telephone Visits......................................79
8.11.2.2
Day 14 Telephone Call ......................................................................80
8.11.2.3
Fasting................................................................................................80
8.11.3
Participants Who Discontinue Study Intervention.......................................80
8.11.3.1
Participants Who Become Pregnant...................................................80
8.11.3.2
Early Discontinuation of Treatment...................................................81
8.11.3.3
End of Treatment Follow-up Visit.....................................................81
8.11.4
Viremia Confirmation..................................................................................82
8.11.5
Management of Participants with Regards to CD4+ T-Cell Counts 
and/or Total Lymphocyte Counts ................................................................82
9
STATISTICAL ANALYSIS PLAN .............................................................................83
9.1
Statistical Analysis Plan Summary.....................................................................83
9.2
Responsibility for Analyses.................................................................................84
9.3
Hypotheses/Estimation ........................................................................................84
9.4
Analysis Endpoints...............................................................................................84
9.4.1
Pharmacokinetic Endpoints .........................................................................85
9.4.2
Safety Endpoints..........................................................................................85
9.4.3
Efficacy Endpoints.......................................................................................86
9.5
Analysis Populations............................................................................................87
9.5.1
Pharmacokinetic Analysis Population .........................................................87
9.5.2
Safety Analysis Population..........................................................................87
9.5.3
Efficacy Analysis Population.......................................................................87
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9.5.3.1
Full Analysis Set................................................................................87
9.5.3.2
Resistance Analysis Subset................................................................87
9.6
Statistical Methods...............................................................................................88
9.6.1
Pharmacokinetic Analyses...........................................................................88
9.6.1.1
Dose Confirmation.............................................................................88
9.6.2
Safety Analyses............................................................................................89
9.6.3
Efficacy Analyses ........................................................................................90
9.6.4
Palatability and Acceptability Assessment of the Tablet (Whole and 
Split).............................................................................................................95
9.7
Interim Analyses ..................................................................................................95
9.8
Multiplicity ...........................................................................................................95
9.9
Sample Size Calculations.....................................................................................95
9.9.1
Sample Size for PK Analysis.......................................................................95
9.9.2
Sample Size for Safety Analysis..................................................................96
9.9.3
Sample Size for Efficacy Analysis ..............................................................97
9.10
Subgroup Analyses...............................................................................................98
9.11
Compliance (Medication Adherence).................................................................98
9.12
Extent of Exposure...............................................................................................99
10
SUPPORTING DOCUMENTATION AND OPERATIONAL 
CONSIDERATIONS...................................................................................................100
10.1
Appendix 1: Regulatory, Ethical, and Study Oversight Considerations......100
10.1.1
Code of Conduct for Clinical Trials...........................................................100
10.1.2
Financial Disclosure...................................................................................102
10.1.3
Data Protection...........................................................................................102
10.1.3.1
Confidentiality of Data ....................................................................103
10.1.3.2
Confidentiality of Participant Records.............................................103
10.1.3.3
Confidentiality of IRB/IEC Information..........................................103
10.1.4
Committees Structure.................................................................................104
10.1.4.1
Executive Oversight Committee......................................................104
10.1.4.2
External Data Monitoring Committee .............................................104
10.1.5
Publication Policy......................................................................................104
10.1.6
Compliance with Study Registration and Results Posting Requirements .104
10.1.7
Compliance with Law, Audit, and Debarment ..........................................105
10.1.8
Data Quality Assurance .............................................................................106
10.1.9
Source Documents .....................................................................................106
10.1.10
Study and Site Closure...............................................................................107
10.2
Appendix 2: Clinical Laboratory Tests............................................................108
082RKV


PRODUCT: MK-8591A  
16
PROTOCOL/AMENDMENT NO.: 028-03 
MK-8591A-028-03 FINAL PROTOCOL
08-FEB-2022
10.3
Appendix 3: Adverse Events: Definitions and Procedures for Recording, 
Evaluating, Follow-up, and Reporting.............................................................115
10.3.1
Definition of AE ........................................................................................115
10.3.2
Definition of SAE ......................................................................................116
10.3.3
Additional Events Reported.......................................................................117
10.3.4
Recording AE and SAE .............................................................................117
10.3.5
Reporting of AEs, SAEs, and Other Reportable Safety Events to the 
Sponsor ......................................................................................................121
10.4
Appendix 4: Device Events, Adverse Device Events, and Medical Device 
Incidents: Definitions, Collection, and Documentation..................................122
10.5
Appendix 5: Contraceptive Guidance..............................................................123
10.5.1
Definitions..................................................................................................123
10.5.2
Contraception Requirements......................................................................124
10.6
Appendix 6: Collection and Management of Specimens for Future 
Biomedical Research..........................................................................................125
10.7
Appendix 7: Country-specific Requirements..................................................130
10.7.1
Country-specific Requirement for Russia..................................................130
10.8
Appendix 8: Calculation of Estimated Glomerular Filtration Rate .............131
10.9
Appendix 9: Abbreviations ...............................................................................132
11
REFERENCES.............................................................................................................135
082RKV


PRODUCT: MK-8591A  
17
PROTOCOL/AMENDMENT NO.: 028-03 
MK-8591A-028-03 FINAL PROTOCOL
08-FEB-2022
LIST OF TABLES
Table 1
Laboratory Exclusion Criteria........................................................................50
Table 2
Study Interventions.........................................................................................52
Table 3
Prohibited Therapies.......................................................................................55
Table 4
Infant Safety Data Collection Through 1 Year of Age ..................................70
Table 5
Reporting Time Periods and Time Frames for Adverse Events and Other 
Reportable Safety Events ...............................................................................73
Table 6
Plasma Sample Collection Schedule for ISL Concentrations ........................77
Table 7
Analysis Strategy for Safety Parameters........................................................90
Table 8
Definitions of Study Time Points for Analyses..............................................91
Table 9
Analysis Strategy for Key Efficacy Variables ...............................................94
Table 10
Estimate of Incidence of AEs and 95% Upper Confidence Bound Based 
on Hypothetical Numbers of Participants with AEs ......................................96
Table 11
Two-Sided 95% CIs for the Percentage of Participants With HIV-1 RNA 
≥50 copies/mL at Week 24 (FAS)..................................................................97
Table 12
Two-Sided 95% CIs for the Percentage of Participants With HIV-1 RNA 
<50 copies/mL at Week 24 (FAS)..................................................................98
Table 13
Protocol-required Laboratory Assessments..................................................109
Table 14
Estimated Blood Volumes............................................................................111
Table 15
Estimated Blood Volumes for Early Discontinuation of Treatment, End 
of Treatment Follow-up, and Extended Monitoring of CD4+ T-cell and/or 
Lymphocyte Counts .....................................................................................114
082RKV


PRODUCT: MK-8591A  
18
PROTOCOL/AMENDMENT NO.: 028-03 
MK-8591A-028-03 FINAL PROTOCOL
08-FEB-2022
LIST OF FIGURES
Figure 1
Study Schema and Treatment Plan.................................................................23
082RKV


PRODUCT: MK-8591A  
19
PROTOCOL/AMENDMENT NO.: 028-03 
MK-8591A-028-03 FINAL PROTOCOL
08-FEB-2022
1
PROTOCOL SUMMARY
1.1
Synopsis
Protocol Title: A Phase 2 Clinical Study to Evaluate the Pharmacokinetics, Safety, and 
Efficacy of Doravirine/Islatravir in Pediatric Participants with HIV-1 Infection who are 
Virologically Suppressed or Treatment-Naïve, are Less Than 18 Years of Age, and Weigh 
Greater Than or Equal to 35 kg
Short Title: DOR/ISL in Pediatric Participants with HIV-1, Less Than 18 Years of Age and 
Greater Than or Equal to 35 kg
Acronym: Not Applicable
Hypotheses, Objectives, and Endpoints:
Note: As of amendment 028-03, the safety, tolerability, and antiviral activity of 
DOR/ISL will not be evaluated at Weeks 48 and 96 as dosing has been discontinued in 
all participants. Updated analyses are described in Section 9.
There are no hypotheses in this study. The following objectives will be evaluated in pediatric 
participants with HIV-1, who are <18 years of age, weigh ≥35 kg, are treatment-naïve or 
have been virologically suppressed on stable combination ART for ≥3 months.
Primary Objectives
Primary Endpoints
- To evaluate the steady-state plasma 
pharmacokinetic profile of ISL as assessed 
by intensive pharmacokinetic sampling on 
Day 28 in the Intensive PK Cohort
- ISL AUC0-24, Cmax, Tmax, t1/2, CL/F, 
Vz/F
- To evaluate the steady-state intracellular 
pharmacokinetic profile of ISL-triphosphate 
in peripheral blood mononuclear cells on 
Day 28 in the Intensive PK Cohort
- ISL-triphosphate AUC0-24, Cmax, and 
C24
- To evaluate the safety and tolerability of 
DOR/ISL as assessed by review of the 
accumulated safety data through Week 24
- Adverse events
- Adverse events leading to discontinuation 
of study intervention
Secondary Objectives
Secondary Endpoints
- To evaluate the safety and tolerability of 
DOR/ISL as assessed by review of the 
accumulated safety data through study 
duration
- Adverse events
- Adverse events leading to discontinuation 
of study intervention
082RKV


PRODUCT: MK-8591A  
20
PROTOCOL/AMENDMENT NO.: 028-03 
MK-8591A-028-03 FINAL PROTOCOL
08-FEB-2022
- To evaluate the antiretroviral activity of 
DOR/ISL in virologically suppressed and 
treatment-naïve participants, separately, as 
assessed by the percentage of participants 
with the following at Weeks 24, 48, and 96:
Virologically Suppressed Cohort:
- HIV-1 RNA ≥50 copies/mL
- HIV-1 RNA ˂50 copies/mL
Treatment-Naïve Cohort:
- HIV-1 RNA ˂50 copies/mL
- HIV-1 RNA
- To evaluate the immunologic effect of 
DOR/ISL in the Treatment-Naïve and 
Virologically Suppressed Cohorts separately 
as measured by change from baseline in 
CD4+ T-cell count at Weeks 24, 48, and 96
- CD4+ T-cell count
- To evaluate the development of viral drug 
resistance to DOR or ISL in participants who 
receive DOR/ISL
- Viral resistance-associated substitutions
- To evaluate the acceptability and 
palatability of the DOR/ISL tablet (whole 
and split)
- Score on a palatability acceptability 
assessment scale
Overall Design:
Study Phase
Phase 2
Primary Purpose
Treatment
Indication
HIV-1 Infection
Population
Pediatric participants with HIV-1, who are <18 years of 
age, weigh ≥35 kg, are treatment-naïve or have been 
virologically suppressed on stable combination ART for ≥3 
months.
Study Type
Interventional
082RKV


PRODUCT: MK-8591A  
21
PROTOCOL/AMENDMENT NO.: 028-03 
MK-8591A-028-03 FINAL PROTOCOL
08-FEB-2022
Intervention Model
Single Group
Note:  As of Amendment P028-03, all participants will 
have switched to non-study ART.
This is a multi-site study
Type of Control
No treatment control
Study Blinding
Unblinded Open-label
Blinding Roles
No Blinding
Estimated Duration of Study
The Sponsor estimates that the study will require 
approximately 4 years from the time the first participant (or 
legally acceptable representative) provides documented 
informed consent until the last participant’s last study-
related contact.
Number of Participants:
Approximately 45 participants (30 virologically suppressed, 15 treatment-naïve) will be 
enrolled.  As of Amendment 028-03 enrollment was closed with 42 participants enrolled in 
the study (39 virologically suppressed, 3 treatment-naïve).
Intervention Groups and Duration:
Intervention 
Groups
Note:  As of Amendment 028-03, all cohorts have discontinued study 
intervention administration.  All participants will have switched to 
non-study ART.
Intervention 
Group Name
Drug
Dose 
Strength
Dose 
Frequency
Route of 
Admin-
istration
Treatment 
Period
Use
DOR/ISL
DOR/ISL
100 mg / 
0.75 mg
QD
Oral
Day 1 to 
Week 96
Experimental
DOR/ISL=fixed dose combination of doravirine and islatravir, also known as MK-8591A; QD=once
daily
Total 
Number
1
Note:  As of Amendment 028-03, all cohorts have discontinued study 
intervention administration.  All participants will have switched to 
non-study ART.
082RKV


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CCI
5.9


PRODUCT: MK-8591A  
23
PROTOCOL/AMENDMENT NO.: 028-03 
MK-8591A-028-03 FINAL PROTOCOL
08-FEB-2022
1.2
Schema
The study design is depicted in Figure 1.
Figure 1
Study Schema and Treatment Plan
DOR/ISL=fixed dose combination of doravirine and islatravir, also known as MK-8591A; n=number; PBMC=peripheral 
blood mononuclear cell; PK=pharmacokinetic
The visits specified in the Study Schema are not comprehensive. See Section 1.3 Schedule of Activities for additional details
for the scheduled visits, which include the following: Screening, Day 1, Day 14, Day 28, Week 8, Week 16, Week 24, Week 
36, Week 48, Week 60, Week 72, Week 84, and Week 96.
a A screening period of up to 45 days is allowed, but participants are expected to enroll as soon as possible after 
eligibility is confirmed.
b A qualified medical designee will be responsible for a phone call to the participant on Day 14 to collect 
information on the use of concomitant medications and AEs since the prior visit. Medication adherence 
assessment and counseling will also be performed.
c Approximately 10 participants in the Virologically Suppressed Cohort who provide consent for Day 28 
intensive PK sampling (Plasma and PBMC) (at sites that can perform PBMC processing) will comprise the 
Intensive PK Cohort. All participants, including those in the Intensive PK Cohort, will undergo sparse PK 
sampling at prespecified visits during the study.
d At the end of Week 96, there will be a mechanism for all eligible participants to continue receiving study 
intervention without interruption until it becomes commercially accessible.
082RKV


PRODUCT: MK-8591A  
24
PROTOCOL/AMENDMENT NO.: 028-03 
MK-8591A-028-03 FINAL PROTOCOL
08-FEB-2022
1.3
Schedule of Activities
1.3.1
Schedule of Activities
Note:  As of Amendment 028-03, all participants should follow the SoAs in Sections 1.3.2 and 1.3.3.
Study Period
Screen
Treatment Period:
Open-Label DOR/ISL
Notes
Visit Number
1
2
3
4
5
6
7
8
9
10
11
12
13
Each visit should be calculated from 
date of Day 1
Scheduled Day/Week 
Screen
Day 1 
(Fasting)
Day 14 
Phone Call
Day 28
Week 8
Week 16
Week 24
Week 36
Week 48 
(Fasting)
Week 60
Week 72
Week 84
Week 96 
(Fasting)
Visit Window
≤45 
daysa
NA
±4 
days
+14 
days
±7 days
Administrative Procedures
Informed Consent/Assent
X
Informed Consent/Assent for 
Intensive PK Cohort
X
Informed Consent/Assent for FBR
X
Inclusion/Exclusion Criteria
X
X
Review before allocation in IRT on 
Day 1 to confirm eligibility
Participant Identification Card
X
X
At the time of allocation, site will 
add allocation number to 
identification card
Medical History 
X
Prior and Concomitant 
Medications Review
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
Intervention Allocation via IRT
X
Dispense DOR/ISL Using IRT
X
X
X
X
X
X
X
X
X
X
Observed Dosing in-Clinic
X
X
X
X
See Section 8.1.8.1 and 8.6.1 for 
more information (including 
instructions for participants dosing in 
the evening)
082RKV


PRODUCT: MK-8591A  
25
PROTOCOL/AMENDMENT NO.: 028-03 
MK-8591A-028-03 FINAL PROTOCOL
08-FEB-2022
Study Period
Screen
Treatment Period:
Open-Label DOR/ISL
Notes
Visit Number
1
2
3
4
5
6
7
8
9
10
11
12
13
Each visit should be calculated from 
date of Day 1
Scheduled Day/Week 
Screen
Day 1 
(Fasting)
Day 14 
Phone Call
Day 28
Week 8
Week 16
Week 24
Week 36
Week 48 
(Fasting)
Week 60
Week 72
Week 84
Week 96 
(Fasting)
Visit Window
≤45 
daysa
NA
±4 
days
+14 
days
±7 days
Palatability and Acceptability 
Assessment 
X
X
X
Day 1 and Day 28 whole tablet 
assessment. Week 24 assessment for 
split tablet only. See Section 8.1.9.
DOR/ISL Compliance 
Assessment
X
X
X
X
X
X
X
X
X
X
X
Reconcile doses and assess DOR/ISL 
compliance. Day 14 phone call 
should include compliance 
counseling
Evaluation to receive continued 
DOR/ISL
X
See Section 6.7
Efficacy Procedures
Plasma HIV-1 RNA 
Quantification (RealTime PCR)
X
X
X
X
X
X
X
X
X
X
X
X
Day 1 collection must be prior to 
first dose of DOR/ISL.
CD4+ T-cell Count
X
X
X
X
X
Day 1 collection must be prior to 
first dose of DOR/ISL.
Plasma for HIV Viral Drug 
Resistance Testing 
X
X
X
X
X
X
X
X
X
X
X
X
Screening collection is only 
required in Treatment-Naïve 
Cohort (n=15). Day 1 collection 
must be prior to first dose of 
DOR/ISL. 
Safety Procedures
Full Physical Examination
X
X
Directed Physical Examination
X
X
X
X
X
X
X
X
X
X
Day 1 exam must be prior to first 
dose of DOR/ISL
Height
X
X
X
X
X
X
X
X
X
X
X
X
Weight
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
Day 1 vitals must be prior to first 
dose of DOR/ISL. Includes pulse, 
blood pressure, body temperature, 
and respiratory rate.
082RKV


PRODUCT: MK-8591A  
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PROTOCOL/AMENDMENT NO.: 028-03 
MK-8591A-028-03 FINAL PROTOCOL
08-FEB-2022
Study Period
Screen
Treatment Period:
Open-Label DOR/ISL
Notes
Visit Number
1
2
3
4
5
6
7
8
9
10
11
12
13
Each visit should be calculated from 
date of Day 1
Scheduled Day/Week 
Screen
Day 1 
(Fasting)
Day 14 
Phone Call
Day 28
Week 8
Week 16
Week 24
Week 36
Week 48 
(Fasting)
Week 60
Week 72
Week 84
Week 96 
(Fasting)
Visit Window
≤45 
daysa
NA
±4 
days
+14 
days
±7 days
Confirmation of menarche
X
X
X
X
X
X
X
X
X
X
X
X
Day 1 collection must be prior to 
first dose of DOR/ISL. Females 
only; not required once menarche has 
been confirmed
Contraceptive Use Confirmation 
(WOCBP only)
X
X
X
X
X
X
X
X
X
X
X
X
Day 1 collection must be prior to 
first dose of DOR/ISL.
Urine Pregnancy Test (WOCBP 
only)
X
X
X
X
X
X
X
X
X
X
X
X
Confirm with serum test if urine test 
is positive. Day 1 testing must be 
prior to first dose of DOR/ISL
HIV-1 & -2 Serology
X
Hepatitis Serology (B and C) 
X
HCV RNA
X
Only hepatitis C antibody positive 
participants will undergo testing at 
Day 1.
HbsAg 
X
X
X
X
X
X
X
X
X
X
X
X
All participants will be tested at 
screening. Only anti-HBc-positive 
participants will undergo testing at 
subsequent visits
HBV DNA
X
X
X
X
X
X
X
X
X
X
X
X
Chemistry & Hematology
X
X
X
X
X
X
X
X
X
X
X
X
Day 1 collection must be prior to 
first dose of DOR/ISL. Fasting is 
required at Day 1, Week 48 & 96 
visits to evaluate fasting lipid profile, 
and blood glucose. Participants with 
abnormal results will be required to 
fast for periodic testing at other visits 
(Section 8.11.2.3).
PT/INR
X
Urinalysis
X
X
X
X
X
X
Review of Adverse Events
X
X
X
X
X
X
X
X
X
X
X
X
X
082RKV


PRODUCT: MK-8591A  
27
PROTOCOL/AMENDMENT NO.: 028-03 
MK-8591A-028-03 FINAL PROTOCOL
08-FEB-2022
Study Period
Screen
Treatment Period:
Open-Label DOR/ISL
Notes
Visit Number
1
2
3
4
5
6
7
8
9
10
11
12
13
Each visit should be calculated from 
date of Day 1
Scheduled Day/Week 
Screen
Day 1 
(Fasting)
Day 14 
Phone Call
Day 28
Week 8
Week 16
Week 24
Week 36
Week 48 
(Fasting)
Week 60
Week 72
Week 84
Week 96 
(Fasting)
Visit Window
≤45 
daysa
NA
±4 
days
+14 
days
±7 days
Pharmacokinetics
Blood (Plasma) for Intensive ISL 
PK
X
Collected from participants in the 
Intensive PK Cohort only:
Plasma: Predose & 0.5, 1, 2, 4, 8, 
12, 24 hours postdose on Day 28
PBMC: Predose & 4, 24 hours 
postdose on Day 28
Blood (PBMC) for ISL-TP PKb
X
Blood (Plasma) for Sparse ISL PK
X
X
X
X
X
X
X
X
X
X
X
See Section 8.6.1
Collected from all participants:
Day 1: predose
Day 28: predose
Week 8 and 16: random
Week 24: predose & 0.5 to 2 
hours postdose
Week 36: random
Week 48: predose & 0.5 to 2 
hours postdose
Weeks 60-96: random.
Biomarkers
Buccal swab (DNA) for Genetic 
Analysisc
X
082RKV


PRODUCT: MK-8591A  
28
PROTOCOL/AMENDMENT NO.: 028-03 
MK-8591A-028-03 FINAL PROTOCOL
08-FEB-2022
Study Period
Screen
Treatment Period:
Open-Label DOR/ISL
Notes
Visit Number
1
2
3
4
5
6
7
8
9
10
11
12
13
Each visit should be calculated from 
date of Day 1
Scheduled Day/Week 
Screen
Day 1 
(Fasting)
Day 14 
Phone Call
Day 28
Week 8
Week 16
Week 24
Week 36
Week 48 
(Fasting)
Week 60
Week 72
Week 84
Week 96 
(Fasting)
Visit Window
≤45 
daysa
NA
±4 
days
+14 
days
±7 days
antiHBc=hepatitis B core antibody; ART=antiretroviral therapy; DNA=deoxyribonucleic acid; DOR=doravirine; FBR=future biomedical research; HbsAg=hepatitis B surface 
antigen; HBV=hepatitis B virus; HCV=hepatitis C virus; HIV=human immunodeficiency virus; INR=international normalized ratio; IRT=Interactive Response Technology; 
ISL=islatravir; ISL-TP=islatravir-triphosphate; NA=not applicable; PBMC = peripheral blood mononuclear cell; PCR=polymerase chain reaction; PK=pharmacokinetic; 
PT=prothrombin time; RNA=ribonucleic acid; WOCBP=a woman/women of childbearing potential.
A A screening period of up to 45 days is allowed, but participants are expected to enroll as soon as possible after eligibility is confirmed.
B PBMC samples will also be analyzed for islatravir-diphosphate (ISL-DP) to ensure proper sample stabilization. No ISL-DP PK parameters will be reported.
C 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 provides consent for future biomedical research. If the planned genetic analyses are not approved, but 
future biomedical research is approved and consent is given, this sample will be collected for the purpose of future biomedical research.
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1.3.2
SoA – Viremia Confirmation and End of Treatment
Note:  As of Amendment 028-03, the Viremia Confirmation Visit is no longer applicable.
Study Period
Viremia 
Confirmation
End of Treatment
Notes
Visit Number
Unscheduled
Unscheduled
Scheduled Day/Week
Viremia 
Confirmation
Early 
Discontinuation of 
Treatment
End of Treatment
Follow-up
Visit Window
Within 2 to 4 
weeks of Viremia
(≥50 copies/Ml)
NA
42 (+7) days after the end of 
treatment
Administrative Procedures
Prior and Concomitant 
Medications Review
X
X
X
Register Study Visit in IRT
X
X
DOR/ISL Compliance Review 
X
X
Reconcile doses and assess DOR/ISL compliance
Efficacy Procedures
Plasma HIV-1 RNA 
Quantification 
(RealTime PCR)
X
X
X
CD4+ T-cell Count/TBNK
panel
X
X
Decreases in CD4+ T-cell count at the Early 
Discontinuation of Treatment visit and End of 
Treatment Follow-up visits should be managed per 
Section 1.3.3 and Section 8.11.5.
Plasma for Viral Drug 
Resistance Testing
X
X
X
Whole Blood for Proviral DNA 
Archive Resistance Testing
X
Testing performed via central laboratory once per 
confirmed low-level viremic episode.
Pharmacokinetic Procedures
Blood (Plasma) for 
Investigational PK
X
X
X
A random sample will be collected.
Safety Procedures
Full Physical Examination
X
X
Weight 
X
X
X
Height
X
X
X
Vital Signs 
X
X
Includes pulse, blood pressure, body temperature, and 
respiratory rate
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Study Period
Viremia 
Confirmation
End of Treatment
Notes
Visit Number
Unscheduled
Unscheduled
Scheduled Day/Week
Viremia 
Confirmation
Early 
Discontinuation of 
Treatment
End of Treatment
Follow-up
Visit Window
Within 2 to 4 
weeks of Viremia
(≥50 copies/Ml)
NA
42 (+7) days after the end of 
treatment
Confirmation of Menarche
X
X
X
Females only; not required once menarche has been 
confirmed
Contraception Use Confirmation 
(WOCBP only)
X
X
X
Urine Pregnancy Test (WOCBP 
only)
X
X
Confirm with serum test if urine test is positive
Chemistry/Hematology
X
X
Decreases in total lymphocyte counts at the Early 
Discontinuation of Treatment visit and End of 
Treatment Follow-up visit should be managed per 
Section 1.3.3 and Section 8.11.5.
Urinalysis
X
Review of Adverse Events
X
X
X
DOR=doravirine; HIV-1=human immunodeficiency virus type 1; IRT=interactive response technology; ISL=islatravir; NA=not applicable; PCR=polymerase chain reaction; 
PK=pharmacokinetics; RNA=ribonucleic acid; TBNK=T and B lymphocyte and natural killer cells; WOCBP=woman/women of childbearing potential.
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1.3.3
SoA – Monitoring of Participants with Confirmed Specified Decreases in CD4+ T-cell Counts and/or Total 
Lymphocyte Counts
Study Period
Extended Monitoring of CD4+ T-cell Count and/or Total 
Lymphocyte Count 
Notes
Visit Number
Unscheduled
Scheduled Day/Week
Monitoring for CD4+ T-cell and/or Total Lymphocytes
Visit Window
Every 4 to 6 weeks after End of Treatment Follow-up Visit
See Section 8.11.5 for details.
Prior and Concomitant Medications Review
X
Register Study Visit in IRT
X
CD4+ T-cell Count/TBNK Panel
X
Hematology
X
Review of Adverse Events
X
Blood (Plasma) for Investigational PK
X
A PK sample (random) will be 
collected at the first monitoring 
visit only.
IRT=interactive response technology; TBNK=T and B lymphocyte and natural killer cells
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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 once daily treatment of HIV-1 infection in adults and pediatric patients.
2.1
Study Rationale
Rationale for Amendment 028-03:
Downward trends of total lymphocytes and CD4+ T-cell counts were observed in some 
participants, which triggered ad hoc pediatric eDMC recommendations to discontinue study 
intervention administration for all participants and to initiate safety monitoring of 
participants.  The Sponsor accepted these recommendations.
Original Study Rationale:
As treatment regimens have improved, infection with HIV-1 has become a chronic, 
manageable condition, and those receiving effective ART regimens can now expect to live a 
near-normal lifespan [Trickey, A., et al 2017]. With anticipation of lifelong treatment and 
near-normal lifespans, the long-term tolerability and safety of antiretrovirals are increasingly 
important considerations for pediatric patients living with HIV-1.
The current standard of care for the treatment of HIV-1 infection is the use of a combination 
of 2 NRTIs with a third agent (eg, InSTI, NNRTI, or PI) [AIDS info 2017] [European AIDS 
Clinical Society 2016] [World Health Organization 2016]. Although such regimens have 
become increasingly well tolerated and highly efficacious, the current paradigm of lifelong
daily treatment is associated with a need for simpler and safer regimens, with reduced drug 
exposure.
There is accumulating evidence that simplified 2-drug regimens can achieve efficacy 
comparable to that of 3-drug regimens; improve tolerability and quality of life; and increase 
medication adherence; all of which can help to sustain virologic suppression [Llibre, J. M., et 
al 2018] [Cahn, P., et al 2019] [Panel on Antiretroviral Guidelines for Adults and 
Adolescents 2018]. The durability of 2-drug regimens depends on both components having 
distinct mechanisms of action with at least 1 of the components having a relatively high 
barrier to resistance.
DOR/ISL has the potential to be an ideal agent for the treatment of HIV-1 infection due to its
potent in vitro antiretroviral activity of each component (including activity against common 
NRTI- and NNRTI resistance-associated substitutions), inhibition of reverse transcriptase by 
multiple mechanisms of action, lack of food requirements, and favorable safety and DDI 
profile observed to date.
2.2
Background
Refer to the IBs/approved labeling for detailed background information on DOR and ISL.
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2.2.1
Islatravir
ISL is the first member of a new class of antiretroviral agents, known as NRTTIs, which 
block HIV-1 reverse transcriptase by novel mechanisms of action. ISL is an inactive 
nucleoside analog that is converted to the pharmacologically active triphosphate (ISL-TP) 
form via endogenous intracellular kinases. It acts through multiple mechanisms, including 
immediate chain termination by blocking translocation and delayed chain termination by 
preventing nucleotide excision [Michailidis E 2014].
ISL is differentiated from other HIV-1 antiretrovirals by its high potency, long half-life, 
favorable drug resistance profile, and broad pharmacologic distribution. ISL (at the proposed 
dose of 0.75 mg QD) achieves higher steady-state IQs (the ratio of drug exposure to viral 
susceptibility [Ctrough/IC50]) against wild-type HIV-1 than any NRTI currently approved 
for treatment. It also exhibits potent in vitro activity against the most prevalent NRTI
resistance-associated mutations, including M184V/I and TAMs.
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 the EMA in 2018. DOR is differentiated 
from other NNRTIs by its distinct resistance profile, low likelihood of selection for viral 
resistance in vivo, and low potential for DDIs. As compared with Efavirenz, DOR had fewer 
CNS-related AEs in Phase 3 studies. DOR exhibits potent activity against both wild-type 
HIV-1 virus and frequently transmitted NNRTI-resistance-associated substitutions (eg, 
K103N, Y181C, G190A, and E138K). The safety and efficacy profiles of DOR have been 
well characterized in Phase 3 clinical studies conducted in treatment-naïve adult participants 
[Orkin, C., et al 2018] [Molina, J. M., et al 2018] and in virologically suppressed adult 
participants switching from a stable antiretroviral regimen (MK-1439A Protocol 024)
[Johnson, M., et al 2019].
An ongoing Phase 1/2 clinical study (MK-1439 Protocol 027; IMPAACT 2014) is evaluating 
the PK, safety, and tolerability of DOR (100 mg) in children and adolescents. Modeling and 
simulation predicted that adolescents (≥12 to <18 years of age who weigh ≥35 kg) would 
have similar exposures as adults with the DOR 100 mg dose including adolescents who 
weigh between 35 and 45 kg. Initial results from MK-1439 Protocol 027 confirm that 
projected steady-state PK after a single-dose of DOR (100 mg) is similar to that observed in 
adults (9 adolescents living with HIV-1 (≥12 to <18 years of age who weigh ≥45 kg). The 
safety assessment in these 9 participants demonstrated 1 AE of Grade 1 diarrhea, which was 
considered unrelated to study intervention by the investigator.
2.2.3
Doravirine/Islatravir
DOR/ISL is an FDC tablet 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 
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additive antiretroviral activity in vitro and has suppressed emergence of resistance at 
clinically relevant concentrations.
DOR and ISL have been studied in a Phase 1 fixed-sequence, 2-period, multiple-dose, drug-
drug interaction clinical study (MK-8591 Protocol 10). This study indicated no clinically 
meaningful interactions between DOR and ISL.
The combination of DOR and ISL (administered as single-entities, ISL+DOR) 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 ISL+DOR and 3TC or an FDC of DOR, 3TC, and TDF 
(DOR/3TC/TDF). Participants receiving ISL+DOR+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 Week 48 and 96, the 
percentage of participants with HIV-1 RNA <50 copies/mL among those who received the 2-
drug regimen of ISL+DOR 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 >200 copies/mL cutoff. As such, no participant met the criteria for 
resistance testing. ISL+DOR, 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).
The clinical development program of DOR/ISL includes ongoing studies in virologically 
suppressed adults (P017 and P018), treatment-naïve adults (P020), heavily treatment 
experienced participants (P019), and participants <18 years of age and weighing at least 35 
kg (P028).
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 
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without regard to food, have a low potential for DDIs, and have favorable PK, and 
tolerability profiles.
In preclinical rat studies, chronic dosing of ISL at very high exposure levels (~204 fold 
greater than the estimated exposure in humans dosed at 0.75 mg) caused incisor breakage and 
molar discoloration. Incisor breakage or molar discoloration were not observed in studies 
conducted with other species including mice or monkeys. In the study with monkeys, no 
effects of ISL on dentition (unerupted dental buds) were observed based on results of micro-
CT scans. These findings are not considered to present a risk to the human pediatric 
population based on the high safety multiples, the lack of changes in developing teeth in 
juvenile rats, and the lack of dental changes in monkeys (monkey dentistry being 
evolutionarily and anatomically more similar to humans than rodents) and mice.
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 P017 and MK-8591A P018), approximately 95% of 658 
participants enrolled in the DOR/ISL arm completed the 48-week treatment period in both 
studies. In P017 and P018, the percentage of participants with HIV-1 RNA ≥50 copies/mL 
was <1% for the DOR/ISL group and a high percentage of participants (>93% to 95%) in the 
DOR/ISL group maintained virologic suppression (HIV-1 RNA <50 copies/mL) comparable 
to baseline ART and BIC/FTC/TAF, respectively, at Week 48. To date, no viral resistance to 
either component of DOR/ISL has been shown in the Phase 2 (MK-8591A Protocol 011) and 
Phase 3 studies (MK-8591A Protocols 017 and 018). 
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 
arms at Week 12 and Week 24. Decreases from baseline in total lymphocyte count were 
observed in all dosing arms of ISL + MK-8507 starting at Week 8 with further decreases 
continuing through Week 24. Twenty of 58 participants on ISL + MK-8507 had a decrease in 
total lymphocyte count of >30% (of which 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 
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participants, the decreased values remained 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 of MK-8591A Protocols 017 and 018, (DOR/ISL 100 mg/0.75 mg QD 
for HIV-1 treatment), mean decreases from baseline in total lymphocyte counts were 
observed 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 baseline ART group and 12.8% in BIC/FTC/TAF 
group. 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 longer-term is unknown, and the Sponsor is assessing the reversibility of 
the reductions in CD4+ T-cell counts 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 supports continuation of 
the Phase 3 clinical studies for the DOR/ISL 100 mg/0.75 mg HIV-1 once-daily treatment 
program.
With regard to this Phase 2 study in the pediatric population, the Sponsor decided to 
discontinue DOR/ISL dosing following review of the available data and benefit/risk 
assessment.
Additional details regarding specific benefits and risks for participants in this clinical study 
may be found in the accompanying IBs and informed consent documents.
3
HYPOTHESES, OBJECTIVES, AND ENDPOINTS
Note: As of amendment 028-03, the safety, tolerability, and antiviral activity of 
DOR/ISL will not be evaluated at Weeks 48 and 96 as dosing has been discontinued in 
all participants. Updated analyses are described in Section 9.
There are no hypotheses in this study. The following objectives will be evaluated in pediatric 
participants with HIV-1, who are <18 years of age, weigh ≥35 kg, are treatment-naïve or 
have been virologically suppressed on stable combination ART for ≥3 months.
Objectives
Endpoints
Primary
To evaluate the steady-state plasma 
pharmacokinetic profile of ISL as 
assessed by intensive pharmacokinetic 
sampling on Day 28 in the Intensive PK 
Cohort
ISL AUC0-24, Cmax, Tmax, t1/2, CL/F, 
Vz/F
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Objectives
Endpoints
To evaluate the steady-state intracellular 
pharmacokinetic profile of ISL-
triphosphate in peripheral blood 
mononuclear cells on Day 28 in the 
Intensive PK Cohort
ISL-triphosphate AUC0-24, Cmax, and 
C24
To evaluate the safety and tolerability of 
DOR/ISL as assessed by review of the 
accumulated safety data through Week 
24
Adverse events
Adverse events 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 study 
duration
Adverse events
Adverse events leading to 
discontinuation of study intervention
To evaluate the antiretroviral activity of 
DOR/ISL in virologically suppressed and 
treatment-naïve participants, separately,
as assessed by the percentage of 
participants with the following at Weeks 
24, 48, and 96:
Virologically Suppressed Cohort:
-
HIV-1 RNA ≥50 copies/mL
-
HIV-1 RNA ˂50 copies/mL
Treatment-Naïve Cohort:
-
HIV-1 RNA ˂50 copies/mL
HIV-1 RNA
To evaluate the immunologic effect of 
DOR/ISL in the Treatment-Naïve and 
Virologically Suppressed Cohorts
separately as measured by change from 
baseline in CD4+ T-cell count at Weeks 
24, 48, and 96
CD4+ T-cell count
To evaluate the development of viral 
drug resistance to DOR or ISL in 
participants who receive DOR/ISL
Viral resistance-associated substitutions
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Objectives
Endpoints
To evaluate the acceptability and 
palatability of the DOR/ISL tablet (whole 
and split)
Score on a palatability acceptability 
assessment scale
Tertiary/Exploratory
To evaluate the pharmacokinetics of ISL 
as assessed by sparse PK sampling 
through Week 96
Plasma concentration of ISL
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
4
STUDY DESIGN
4.1
Overall Design
Amendment 028-03
As of Amendment 028-03, all participants will have been brought to the clinic for an Early 
Discontinuation of Treatment visit so that non-study ART could be initiated. Participants 
who have CD4+ T-cell and/or total lymphocyte counts that are not decreased by >10% of the 
average baseline value at this visit will discontinue participation from the study at the End of 
Treatment Visit. Participants who have CD4+ T-cell and/or total lymphocyte values that are 
decreased by >10% of the average baseline value will have confirmation testing at the End of 
Treatment Follow-up Visit.  If that decrease in CD4+ T-cell and/or total lymphocyte count is 
not confirmed at the End of Treatment Visit, the participant will not require further 
monitoring.  If that decrease in CD4+ T-cell and/or total lymphocyte count is confirmed at 
the End of Treatment Visit, the participants will continue on the study with extended
monitoring every 4 to 6 weeks until two samples 12 weeks apart show a recovery of the 
counts to ≤10% of the average baseline value. After 6 months, if decreased counts persist, the 
Sponsor should be consulted. Participants who no longer want to undergo extended
monitoring should be advised to follow up with their HIV care provider.
Original Design
This is a Phase 2 nonrandomized, noncomparative, multisite, open-label study to evaluate 
ISL and ISL-TP PK and the safety, tolerability, and efficacy of DOR/ISL in pediatric 
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participants with HIV-1 who are treatment-naïve or virologically suppressed for ≥3 months 
with no history of treatment failure.
Approximately 45 participants (30 virologically suppressed, 15 treatment-naïve) will be 
enrolled to receive DOR/ISL at the adult dose [DOR (100 mg)/ISL (0.75 mg) FDC tablet 
administered QD] through Week 96.
Virologically Suppressed Cohort participants will be required to discontinue use of their 
current suppressive ART regimen and receive only DOR/ISL as ART during the study. 
Approximately 10 of the 30 participants from the Virologically Suppressed Cohort who 
provide consent for intensive PK sampling (plasma and PBMC) on Day 28 will comprise the 
Intensive PK Cohort. Results from evaluation of the Intensive PK Cohort will be used for 
dose confirmation of ISL (Section 9.6.1.1). Both Intensive PK Cohort and non-Intensive PK 
Cohort will enroll concurrently. If all 20 non-Intensive PK participants are enrolled prior to 
completing enrollment of the Intensive PK Cohort, then the non-Intensive PK Cohort will 
close to enrollment, and only the Intensive PK Cohort will remain open to enrollment. All 
participants, including those in the Intensive PK Cohort, will undergo sparse plasma PK 
sampling at prespecified visits during the study (Section 8.6).
Enrollment of the Treatment-Naïve Cohort will only begin when the adult Phase 3 ISL/DOR 
treatment-naïve study (P020) is open to full enrollment (see Section 4.2 below for additional 
details).
All participants will be evaluated for efficacy of DOR/ISL to maintain virologic suppression 
based on predefined, clinically significant, and confirmed viremia. Any participants with 
confirmed viremia, as described in Section 4.2.1.3.1, will be assessed for development of 
viral drug resistance and potential discontinuation from study intervention.
Participant safety will be monitored by an eDMC who will perform periodic reviews of 
safety data throughout the study (Section 9.7; Appendix 1). Details regarding eDMC will be 
provided in a charter.
At the end of Week 96, there will be a mechanism for all eligible participants to continue 
receiving study intervention without interruption until it becomes commercially accessible 
(Section 6.7).
Specific procedures to be performed during the study, as well as their prescribed times and 
associated visit windows, are outlined in the SoA in Section 1.3. Details of each procedure 
are provided in Section 8.
4.2
Scientific Rationale for Study Design
Amendment 028-03
Based on the Sponsor acceptance of the pediatric eDMC recommendation to stop study 
intervention administration in this study, Amendment 028-03 is designed to allow for 
discontinuation of study intervention for all participants, the follow-up of all participants
with specified decreases in CD4+ T-cell and/or total lymphocyte count, and the 
discontinuation from the study of participants who did not have these specified decreases.
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Original rationale:
The open-label, nonrandomized, PK-confirmatory study design is consistent with recent
published regulatory guidance for conducting clinical studies in the pediatric population 
[Food and Drug Administration 2019]. Aligned with this guidance, the known clinical and 
pharmacological profile of DOR/ISL provides sufficient support to safely evaluate DOR/ISL 
in pediatric patients living with HIV-1 in parallel with the pivotal Phase 3 clinical studies in 
adults. Conducting adult and pediatric studies in parallel accelerates the development of 
antiretrovirals in the pediatric population, providing clinically meaningful information about 
the use of DOR/ISL for the treatment of HIV-1 in pediatric patients earlier and more 
efficiently.
The design is considered appropriate for a treatment experienced study population that is 
switching from another stable ART regimen with HIV RNA <50 copies/mL and for a study 
population with HIV-1 who are naïve to antiretroviral therapy. The Phase 3 study in 
treatment-naïve adults (MK-8591A Protocol 020) is ongoing, and the P028 Treatment-Naïve 
Cohort will not begin enrollment until supportive data from the Sentinel Cohort in P020 is 
available.
As HIV-1 is a chronic viral infection for which antiretroviral treatment is administered 
indefinitely, participants will be treated for 96-weeks in this study to assess the durability of 
efficacy, emergence of resistance, and long-term safety.
4.2.1
Rationale for Endpoints
4.2.1.1
Pharmacokinetic Endpoints
Plasma PK
PK samples collected for analysis of ISL plasma concentrations will be used to calculate the 
steady-state plasma AUC0-24 and Cmax. These results will confirm that adequate exposures 
of ISL are achieved in pediatric participants <18 years of age weighing ≥35 kg and will 
support dosing recommendations in the pediatric population. As DOR/ISL is anticipated to 
be chronically dosed, steady-state PK endpoints are the most appropriate endpoints.
Intensive plasma PK samples will be collected from the Intensive PK Cohort participants
(Section 8.6). In addition to these results, data from sparse plasma PK sampling collected 
from all participants will be used in population PK models for ISL levels.
PBMC PK
PBMC PK samples collected from the Intensive PK Cohort participants (Section 8.6) will be 
used to evaluate intracellular ISL-TP levels, the active anabolite resulting from ISL dosing.
Intracellular PBMC trough levels (C24) are a better predictor of efficacy than the exposure 
(AUC) and can be used along with in vitro potency values to predict efficacy against both 
wild-type virus and drug resistant variants.
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4.2.1.2
Safety Endpoints
Note:  As of Amendment 028-03, study intervention administration has been 
discontinued, but the study will continue so that participants can be monitored for 
decreases in CD4+ T-cell and/or total lymphocyte counts.  If the specified decreases are 
present, those participants will be managed per Section 8.11.5.  
Safety evaluations will include physical examinations (including vital signs) and laboratory 
tests (hematology, chemistry, 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.
4.2.1.3
Efficacy Endpoints
Note: As of Amendment 028-03, HIV-1 RNA measurements will not be collected beyond 
the Early Discontinuation of Treatment Visit. Management of viremia after that visit 
will be at the discretion of the Investigator outside of the study.
Clinical studies of antiretroviral agents in multiple drug classes have demonstrated that 
virologic suppression of HIV-1 RNA to <50 copies/mL reflects a clinically relevant standard 
used across development programs for antiretroviral therapies and in clinical practice 
[Vandenhende, M. A., et al 2015]. Suppressing HIV-1 RNA to <50 copies/mL preserves the 
immune system and minimizes the risk of opportunistic infections and disease progression.
Plasma HIV-1 RNA <50 copies/mL is a well-established clinically meaningful endpoint for 
treatment-naïve patients. Plasma HIV-1 RNA ≥50 copies/mL is a clinically meaningful 
endpoint in virologically suppressed populations, as it reflects inability to maintain virologic 
suppression after switching to a new antiretroviral regimen.
4.2.1.3.1
Definition of Clinically Significant Confirmed Viremia
For the purpose of managing participants in this study, clinically significant confirmed 
viremia is defined as:

Virologic Rebound: A participant who is virologically suppressed and has 2
consecutive (2 to 4 weeks apart) occurrences of HIV-1 RNA ≥200 copies/mL at any 
time during the study.
Note: This definition is applicable to participants who are virologically suppressed at 
baseline and participants who are treatment-naïve at baseline and have achieved 
viral suppression (HIV-1 RNA <50 copies/mL).
or

Incomplete Virologic Response: A participant who is treatment-naïve at baseline 
and has 2 consecutive (2 to 4 weeks apart) occurrences of HIV-1 RNA ≥200 
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copies/mL at or after Week 24 in the absence of previous suppression of HIV-1 RNA 
to <50 copies/mL.
There is currently no global standard for definition of patients with low-level viremia (viral 
load ≥50 and <200 copies/mL), and the predictive implication of such low-level viremia is 
uncertain [Vandenhende, M. A., et al 2015] [Charpentier, C., et al 2014]. The US Department 
of Health and Human Services guidelines currently define virologic failure as confirmed HIV 
RNA ≥200 copies/mL and do not recommend that low-level viremia (detectable HIV RNA 
<200 copies/mL) automatically result in treatment modification or more frequent virologic 
monitoring [Panel on Antiretroviral Guidelines for Adults and Adolescents 2018]. 
Participants with HIV-1 RNA between 50 and 200 copies/mL have a lower risk of 
developing resistance compared to those with HIV-1 RNA >200 copies/mL and should 
continue on their current regimen, with HIV-1 RNA levels monitored as outlined in Section 
8.2.2.
4.2.1.4
Palatability and Acceptability Assessment Endpoints
Note: As of Amendment 028-03, study intervention administration has been 
discontinued, so palatability and acceptability assessments will no longer be performed.
Acceptability may play an important role in adherence to treatment in the pediatric 
population as it does in the adult population. Acceptability and swallowability of the whole 
and split tablet will be evaluated in all participants using the most frequently reported 
assessment to measure acceptability in pediatric participants, consisting of a visual analog 
scale that was modified by including a 5-point facial hedonic scale (FHS), an expression 
scale depicting various degrees of pleasure [Thompson, C., et al 2015].
4.2.1.5
Planned Exploratory Biomarker Research
4.2.1.5.1
Planned Genetic Analysis
Genetic variation may impact a participant’s response to therapy, susceptibility to, severity, 
and progression of disease. Variable response to therapy may be due to genetic determinants 
that impact drug absorption, distribution, metabolism, and excretion; mechanism of action of 
the drug; disease etiology; and/or molecular subtype of the disease being treated. Therefore, 
where local regulations and IRB/IEC allow, a sample will be collected for DNA analysis 
from consenting participants.
DNA samples may be used for research related to the study intervention(s), the disease under 
study, or related diseases. They may also be used to develop tests/assays including diagnostic 
tests related to the disease under study, related diseases, and study intervention(s). Genetic 
research may consist of the analysis of 1 or more candidate genes, the analysis of genetic 
markers throughout the genome, or analysis of the entire genome. Analysis may be 
conducted if it is hypothesized that this may help further understand the clinical data.
The samples may be analyzed as part of a multi-study assessment of genetic factors involved 
in the response to understand study disease or related conditions.
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4.2.1.6
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 Collecting Race and Ethnicity Data
The differential effect on the safety and efficacy based on any demographic parameter, 
including race or ethnicity, cannot be predicted when evaluating a new investigational drug. 
Therefore, it is important to collect race and ethnicity data to ensure there is not a differential 
effect based on these parameters and to gain assurance the results observed in the clinical 
study will be representative of the drug’s use in a broader patient population. As an example, 
non-Caucasian females and males were found to have higher plasma concentrations of EFV 
(an NNRTI) than their Caucasian counterparts, indicating an increased risk of EFV-induced 
toxicity in non-Caucasian patients [Burger, D., et al 2005]. As another example, among the 
population with HIV in the 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, race and ethnicity data will be collected in this study to characterize baseline 
demographics, and analyses on race and ethnicity may be performed to better understand 
how these parameters influence clinical outcome and toxicity.
4.2.3
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 
World Health Organization considers transgender people to be a separate key population 
because of their specific health needs and high vulnerability [Department of HIV/AIDS 
2015]. Thus, gender identity data will be collected in this study to characterize baseline 
demographics and assess clinical outcomes in the transgender population.
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4.2.4
Rationale for Collecting Infant Safety Follow-up Data
While women who become pregnant during the study will be required to discontinue therapy, 
it is important to collect information on infants born to participants who become pregnant 
while receiving DOR/ISL. Follow-up through 1-year of age for infants born to participants 
who become pregnant while receiving study intervention provides the ability to monitor 
growth and development as well as potential adverse effects that may be associated with 
prenatal drug exposure. Growth parameters (ie, length, weight, and head circumference) 
within normal range at approximately 1-year of age are key noninvasive indicators that a 
serious congenital malformation caused by in utero drug exposure is unlikely.
4.3
Justification for Dose
Note: As of Amendment 028-03, study intervention administration has been
discontinued.
Pediatric patients treated for HIV have response rates similar to adults when given a dose 
regimen that achieves exposures similar to those observed in adult patients. Pediatric 
participants who are <18 years of age and weigh ≥35 kg, are predicted to have similar plasma 
ISL and intracellular ISL-TP concentrations to adults and no dose adjustment is expected to 
be necessary in this population.
In the MK-8591 Protocol 011 of treatment-naïve adults, at Week 48, DOR+ISL maintained 
virologic suppression in participants who achieved <50 copies/mL on DOR+ISL+3TC by 
Week 24 and were maintained on DOR+ISL. All 3 dose levels of ISL (0.25, 0.75, and 
2.25 mg) administered with DOR±3TC in adults demonstrated potent antiretroviral activity 
comparable to DOR/3TC/TDF, as demonstrated by the proportion of participants with HIV-1 
RNA <50 copies/mL at Weeks 24 and 48. Overall, no ISL dose-response for efficacy was 
observed. Graphical analysis of steady-state ISL-TP trough concentrations and response at 
Week 48 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. ISL 0.75 mg was selected for study in adults who are naïve to treatment
(Protocol 020), virologically suppressed (Protocols 017 and 018), and heavily treatment 
experienced (Protocol 019) in the Phase 3 clinical program. Protocol 011 also demonstrated 
that all doses of ISL studied, when administered with DOR±3TC, had a favorable safety and 
tolerability profile through Week 48, comparable with that of DOR/3TC/TDF. Thus, based 
on projected exposure in this population, similar safety and tolerability is expected in 
pediatric participants enrolled in Protocol 028 as adults enrolled in Protocol 011.
A population PK model for ISL and ISL-TP was simulated at the 0.25, 0.75, and 2.25-mg 
doses for an adult population using demographic data from the NHANES database. The 
allometrically scaled model was also simulated with a 0.75-mg dose for a population of 
pediatric participants (who are <18 years of age and weigh ≥35 kg), also using data selected 
from the NHANES database. ISL plasma AUC0-24, the PK parameter most closely 
associated with ISL safety, was estimated for pediatric participants after ISL 0.75 mg QD 
dosing and compared with that from adults after ISL 2.25 mg QD dosing (a dose found to 
have a favorable safety and tolerability profile in adults in MK-8591A Protocol 011). Plasma 
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ISL AUC0-24 (geometric mean estimated to be 0.12 µM·hr) for pediatric participants (who 
are <18 years of age and weigh ≥35 kg) is expected to be approximately 2.3-fold lower than 
that at the 2.25-mg dose in adults (N=1000 simulated geometric mean of 0.28 µM·hr).
ISL-TP PBMC C24, the PK parameter most closely associated with ISL efficacy, was 
estimated for pediatric participants (who are <18 years of age and weigh ≥35 kg) after ISL 
0.75 mg QD dosing and compared to that from adults after ISL 0.25 mg dosing (a dose found 
to be on the plateau of efficacy in adults in MK-8591A Protocol 011). The ISL-TP PBMC 
C24 expected in pediatric participants (who are <18 years of age and weigh ≥35 kg) after 
daily dosing of ISL 0.75 mg (11.2 µM or 2.2 pmol/106 cells) is approximately 4.1-fold higher 
than that at the 0.25-mg dose in adults (N=1000 simulated geometric mean of 2.7 µM or 0.54 
pmol/106 cells).
Therefore, it is expected that ISL 0.75 mg QD is safe to study in pediatric participants
weighing ≥35 kg and sufficient levels of ISL-TP will be generated to provide efficacy 
comparable to the adult population.
The approved dose of DOR 100 mg has been studied in Phase 1 to 3 clinical studies in 
treatment-naïve and virologically suppressed participants with HIV-1. It was selected based 
on favorable efficacy, safety, tolerability, and metabolic profiles as confirmed in the Phase 3 
clinical studies conducted in adults [Orkin, C., et al 2018] [Molina, J. M., et al 2018] (MK-
1439A Protocol 024). Initial results from MK-1439 Protocol 027 indicate that projected 
steady-state PK after a single-dose of DOR (100 mg) in 9 adolescents living with HIV-1 (<18 
years of age, weighing ≥45 kg) is similar to that observed in adults. DOR plasma C24 is the 
PK parameter most closely associated with efficacy. It is expected that pediatric participants
dosed with DOR 100 mg QD will have C24 values ≥560 nM, corresponding to 0.6-fold the 
steady-state mean C24 for the 100-mg dose in adults.
In summary, a 0.75-mg dose of ISL in combination with 100 mg DOR is predicted to be 
tolerable and provide ISL-TP concentrations in participants <18 years of age, weighing 
≥35 kg that will demonstrate potent antiretroviral activity against both wild-type HIV-1 virus 
and most common NRTI- and NNRTI-resistance substitutions. Specific criteria for dose 
confirmation after PK evaluation in the Intensive PK Cohort are provided in Section 9.6.1.1.
4.4
Beginning and End of Study Definition
The overall study begins when the first participant (or 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).
4.4.1
Clinical Criteria for Early Study Termination
The clinical study may be terminated early if the extent (incidence and/or severity) of 
emerging effects/clinical endpoints is such that the risk/benefit ratio to the study population 
as a whole is unacceptable. In addition, further recruitment in the study or at (a) particular 
study site(s) may be stopped due to insufficient compliance with the protocol, GCP, and/or 
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other applicable regulatory requirements, procedure-related problems or the number of 
discontinuations for administrative reasons is too high.
5
STUDY POPULATION
Note: As of Amendment 028-03, the study has closed to enrollment.
Pediatric participants with HIV-1 who are <18 years of age, weigh ≥35 kg, and are treatment-
naïve or have been virologically suppressed for ≥3 months on any stable oral 2-drug or 3-
drug combination ART (± PK booster) and have not failed prior ART therapy 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. Meets one of the following:
a) Virologically Suppressed: Is HIV-1 positive at screening with plasma HIV-1 
RNA <50 copies/mL at screening
AND
Has been receiving continuous, stable oral 2-drug or 3-drug combination ART (±
PK booster) with documented viral suppression (HIV-1 RNA <50 copies/mL) for 
≥3 months prior to providing documented informed consent/assent and has no 
history of prior virologic treatment failure on any past or current regimen.
Note: A single episode of nonclinically significant HIV-1 RNA result (defined as 1 
or more measurement(s) of HIV-1 RNA above the limit of quantification, but
<200 copies/mL returning to levels below the lower limit of quantification; ie, 
transient detectable viremia) during the 3 months prior to screening is 
acceptable.
Note: A single repeat of the plasma HIV-1 RNA screening test will be allowed, 
provided results are available within the 45-day screening window.
Note: Any prior change of a single drug or multiple drugs simultaneously must 
have occurred due to tolerability or safety, access to medications, or 
simplification, and must not have been done for treatment failure.
OR
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b) Treatment-Naïve: Is HIV-1 positive with plasma HIV-1 RNA ≥500 copies/mL at 
screening
AND
Is naïve to ART defined as having received ≤10 days of prior therapy with any 
antiretroviral agent following a diagnosis of HIV-1 infection, except for use of
PrEP or PEP.
Note: The use of any PrEP or PEP prior to diagnosis of HIV-1 infection is 
permissible up to 1 month prior to screening.
Note: Treatment-naïve participants will only be allowed to enroll when the Phase 
3 ISL/DOR treatment-naïve study in adults (MK-8591A Protocol 020) is open to 
full enrollment after the Sentinel Cohort Week 24 interim analysis. Sites will be 
informed when treatment-naïve enrollment can begin.
Note: A single repeat of the plasma HIV-1 RNA screening test will be allowed, 
provided results are available within the 45-day screening window.
2. Able and willing to swallow available tablet formulation.
Demographics
3. Is male or female, <18 years of age, and weighing ≥35 kg at the time of signing the 
informed consent/assent.
Contraception/Pregnancy
4. A female participant is eligible to participate if she is not pregnant or breastfeeding, and 
at least one of the following conditions applies:
Is not a WOCBP
OR
Is a WOCBP and using an acceptable contraceptive method, or be abstinent from 
heterosexual intercourse as their preferred and usual lifestyle (abstinent on a long term 
and persistent basis), as described in Appendix 5 during the intervention period and for at 
least 6 weeks, corresponding to the time needed to eliminate any study intervention(s) 
(eg, 5 terminal half-lives)] after the last dose of study intervention. The investigator 
should evaluate the potential for contraceptive method failure (ie, noncompliance, 
recently initiated) in relationship to the first dose of study intervention.
A WOCBP must have a negative highly sensitive pregnancy test ([urine or serum] as 
required by local regulations) within 24 hours before the first dose of study intervention.
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If a urine test cannot be confirmed as negative (eg, an ambiguous result), a serum 
pregnancy test is required. In such cases, the participant must be excluded from 
participation if the serum pregnancy result is positive.
Additional requirements for pregnancy testing during and after study intervention are 
located in Appendix 2.
The investigator is responsible for review of medical history, menstrual history, and 
recent sexual activity to decrease the risk for inclusion of a woman with an early 
undetected pregnancy.
Informed Consent/Assent
5. The participant and legally acceptable representative have 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 
drugs as determined by the investigator.
3. Has an active diagnosis of hepatitis due to any cause, including active HBV infection 
(defined as HBsAg-positive or HBV DNA positive).
Note: Past HBV infection or previous HBV vaccination (defined as HBsAg-negative and 
positive for antibody against HBsAg) is not an exclusion criterion.
Note: Participants who do not demonstrate immunity to HBV are encouraged to be 
vaccinated against HBV.
Note: Chronic HCV infection (detectable HCV RNA) and treatment with direct-acting 
antiviral therapies are not exclusionary, provided the participant has stable liver function 
tests and no significant hepatic synthetic dysfunction. Significant hepatic synthetic 
dysfunction is defined as a serum albumin <2.8 g/dL or an INR >1.7 in the absence of 
another explanation for the abnormal laboratory value.
4. Has a history of malignancy ≤5 years prior to signing informed consent except for 
adequately treated basal cell or squamous cell skin cancer, in situ cervical cancer, or 
cutaneous Kaposi’s sarcoma.
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5. Has a history or current evidence of any condition (including active tuberculosis
infection), therapy, laboratory abnormality or other circumstance (including drug or 
alcohol use or dependence) that might, in the opinion of the investigator, confound the 
results of the study or interfere with the participant’s participation for the full duration of 
the study, such that it is not in the best interest of the participant to participate.
Prior/Concomitant Therapy
6. Is taking or is anticipated to require systemic immunosuppressive therapy, immune 
modulators, or any prohibited therapies outlined in Section 6.5 from 45 days prior to 
Day 1 through the study treatment period.
Note: Time-limited courses (≤7 consecutive days) of systemic corticosteroids (eg, for 
asthma exacerbation), topical steroids for the treatment of skin conditions, and systemic
steroids <0.5 mg/kg/day or <30 mg maximum daily prednisone equivalent dose
(whichever is less) are permitted.
7. Is currently taking long-acting cabotegravir-rilpivirine.
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 45 days prior to Day 1 through the study 
treatment period.
Note: Concurrent participation in observational studies are to be discussed with the 
Sponsor prior to enrollment and through the study treatment period.
Diagnostic Assessments
9. Has a documented or known virologic resistance to components of DOR/ISL, as 
demonstrated by any of the following:

DOR resistance substitutions in reverse transcriptase: V106A/M, V108I, 
Y188L, H221Y, P225H, F227C/L, M230I/L, L234I, P236L, or Y318F

ISL resistance substitution in reverse transcriptase: M184V/I
Note: Virologically Suppressed Cohort participants who do not have documentation of 
resistance testing may enroll.
Note: Treatment-Naïve Cohort participants will have resistance testing performed by the 
central laboratory as part of the screening assessments. However, if resistance testing 
results obtained from a local laboratory <90 days prior to the Screening Visit date 
through Day 1 are available prior to the availability of the central laboratory screening 
resistance results, the local results can be used to determine participant eligibility.
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10. Has exclusionary laboratory values within 45 days prior to Day 1 as listed in Table 1.
Note: A single repeat of a laboratory screening test will be allowed for test results that 
are unexpected based on documented prior laboratory results, but the repeat test results 
must be available within the 45-day screening window.
Table 1
Laboratory Exclusion Criteria
Laboratory Assessment
Exclusionary Values
AST SGOT
>5 × ULN
ALT SGPT
>5 × ULN
Lipase
≥ 3× ULN
eGFR
≤59 mL/min/1.73 m2
based on the Schwartz equation (Appendix 8)
Hemoglobin
<8.5 g/dL (female) or <9.00 g/dL (male)
ALT SGPT=alanine aminotransferase; AST SGOT=aspartate aminotransferase; eGFR= estimated 
glomerular filtration rate; ULN=upper limit of normal.
Other Exclusions
11. Is female and expecting to conceive or donate eggs at any time during the study.
Note: Investigators should provide appropriate guidance to female participants 
regarding egg donation after completion of the study treatment. Consistent with the 
recommendations for contraceptive use, it is recommended that all female participants 
refrain from egg donation for 6 weeks following their last dose of study treatment.
Note: Donation of sperm should follow local guidelines for individuals who are HIV-
positive
5.3
Lifestyle Considerations
There are no lifestyle restrictions.
5.4
Screen Failures
Screen failures are defined as participants who consent/assent to participate in the clinical 
study, but are not subsequently entered in the study. A minimal set of screen failure 
information is required to ensure transparent reporting of screen failure participants to meet 
the CONSORT publishing requirements and to respond to queries from regulatory 
authorities. Minimal information includes demography, screen failure details, eligibility 
criteria, and any AEs or SAEs meeting reporting requirements as outlined in the data entry 
guidelines.
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5.5
Participant Replacement Strategy
If a participant in the Intensive PK Cohort discontinues from study intervention OR 
withdraws from the study OR has nonevaluable intensive PK data, a replacement participant 
may be enrolled if deemed appropriate by the Sponsor. The replacement participant will be 
assigned a unique treatment number by the IRT. Participants will not be replaced in any other 
circumstances.
6
STUDY INTERVENTION
Note: As of Amendment 028-03, study intervention administration has been 
discontinued and all participants will have switched to non-study ART.
Study intervention is defined as any investigational intervention(s), marketed product(s), 
placebo, or medical device(s) intended to be administered to a study participant according to 
the study protocol.
Clinical supplies (DOR/ISL provided by the Sponsor) will be packaged to support enrollment 
and replacement participants as required. Clinical supplies will be affixed with a clinical 
label in accordance with regulatory requirements.
6.1
Study Intervention(s) Administered
Note: As of Amendment 028-03, study intervention administration has been 
discontinued and all participants will have switched to non-study ART.
The study intervention to be used in this study is outlined in Table 2.
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Table 2
Study Interventions
Arm 
Name
Arm 
Type
Intervention 
Name
Intervention 
Type
Dose 
Formu-
lation
Unit Dose 
Strength(s)
Dosage 
Level(s)
Route of 
Adminis-
tration
Treatment 
Period
Use
IMP/
NIMP
Sourcing
DOR/
ISL
Experi
mental
DOR/ISL
Drug
Tablet
100 mg/ 
0.75 mg
100 mg/ 
0.75 mg 
QD
Oral
Day 1 to 
Week 96
Experi
mental
IMP
Provided 
centrally by 
Sponsor
DOR=doravirine; ISL=Islatravir; QD=once daily
The classification of Investigational Medicinal Product (IMP) and Non-Investigational Medicinal Product (NIMP) in this table is based on guidance issued by 
the European Commission and applies to countries in the European Economic Area (EEA). Country differences with respect to the definition/classification of 
IMP/NIMP may exist. In these circumstances, local legislation is followed.
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All supplies indicated in Table 2 will be provided per the "Sourcing" column depending upon 
local country operational requirements. If local sourcing, every attempt should be made to 
source these supplies from a single lot/batch number where possible (eg, not applicable in the 
case where multiple lots or batches may be required due to the length of the study, etc.).
Refer to Section 8.1.8 for details regarding administration of the study intervention.
6.2
Preparation/Handling/Storage/Accountability
Note: As of Amendment 028-03, study intervention administration has been 
discontinued and all participants will have switched to non-study ART.
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
Note: As of Amendment 028-03, study intervention administration has been 
discontinued and all participants will have switched to non-study ART.
6.3.1
Intervention Assignment
Intervention allocation will occur centrally using an IRT system. All participants will be 
allocated by nonrandom assignment to receive DOR/ISL FDC.
6.3.2
Stratification
No stratification based on age, sex, or other characteristics will be used in this study.
6.3.3
Blinding
This is an open-label study; therefore, the Sponsor, investigator, and participant will know 
the intervention administered.
6.4
Study Intervention Compliance
Note: As of Amendment 028-03, study intervention administration has been 
discontinued and all participants will have switched to non-study ART.
Participants/guardians should bring the study intervention bottle(s) to their visits. At each 
visit, the number of doses remaining in the study packaging will be counted, reviewed, and 
recorded. The results will be used to assess participant compliance. If a discrepancy is noted, 
the investigator/study coordinator must discuss the discrepancy with the participant/guardian, 
and the explanation must be documented. When participants are dosed at the site, they will 
receive study intervention directly from the investigator or designee, under medical 
supervision. The date and time of each dose administered in the clinic will be recorded in the 
source documents and recorded in the CRF.
Participants/guardians should be reminded of the importance of taking the study intervention 
as instructed for the entire duration of the study.
Decisions to temporarily withhold study intervention because of an AE or other reasons 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
Note: As of Amendment 028-03, there are no study defined prohibited medications. The 
local label for the non-study ART should be consulted for potential drug interactions.
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Medications specifically prohibited in the exclusion criteria are not allowed during time 
periods specified by this protocol for that medication. If there is a clinical indication for any 
medications specifically prohibited, discontinuation from study intervention may be required. 
The investigator should discuss any questions regarding this with the Sponsor Clinical 
Director. The final decision on any therapy rests with the investigator and/or the participant’s 
primary physician. However, the decision to continue the participant on study intervention 
requires the mutual agreement of the investigator, the Sponsor, and the participant/guardian.
Any medication or vaccine (including over-the-counter or prescription medicines, vitamins, 
and/or herbal supplements or other specific categories of interest) that the participant is 
receiving at the time of enrollment or receives during the study must be recorded along with:
reason for use, dates of administration (including start and end dates), and dosage 
(information including dose and frequency).
Prior and concomitant therapies listed in Table 3 are not permitted from 45 days prior to Day 
1 through the study treatment period. Table 3 is not comprehensive, and the investigator 
should use his/her medical judgment when assessing whether a participant’s prior and 
concomitant therapy(ies) are prohibited. The Sponsor Clinical Director or designee should be 
contacted if there are any questions about a therapy not listed or regarding potential DDIs
with a specific treatment that the participant may plan to receive.
In instances where the local product circular for DOR is more restrictive with regard to 
prohibited (ie, contraindicated or not recommended) therapy(ies), the local product circular 
supersedes this section.
Table 3
Prohibited Therapies
Strong and moderate 
CYP3A inducers based on 
potential to reduce DOR 
concentrations
Including, but not limited to:
Carbamazepine
Oxcarbazepine
Phenobarbital
Phenytoin
Enzalutamide
Rifabutin
Rifampin 
Rifapentine
Mitotane
St. John’s Wort
Herbal remedies
Modafinil
Bosentan 
Nafcillin
Additional prohibited 
therapies based on ISL
Pentostatin
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Nonstudy ART 
All nonstudy antiretrovirals (with the exception of study 
drugs and baseline ART during the screening period) 
including treatments for a viral infection other than HIV-1, 
such as hepatitis B, with an agent that is active against 
HIV-1 (eg, adefovir, TDF, TAF, FTC, or 3TC).
Entecavir therapy for acquired HBV infection during the 
study is permitted.
Immunosuppressive 
therapies
Immune therapy agents, immune modulators or other 
systemic immunosuppressive therapy, including interferon-
based treatment for hepatitis and maintenance glucocorticoid 
therapy (≥0.5 mg/kg/day prednisone equivalent dose or 
≥30 mg daily dose for >7 consecutive days).
Note: Time-limited courses (≤7 consecutive days) of 
systemic corticosteroids (eg, for asthma exacerbation), 
topical steroids for the treatment of skin conditions, and 
systemic steroids <0.5 mg/kg/day or <30 mg maximum daily 
prednisone equivalent dose (whichever is less) are
permitted. 
Investigational agents 
All nonstudy investigational agents including devices
3TC=lamivudine; ART=antiretroviral therapy; CYP3A=cytochrome P450 3A; DOR=doravirine; FTC=
emtricitabine, HIV-1=human immunodeficiency virus-1; ISL=islatravir; TAF= tenofovir alafenamide; TDF=
tenofovir disoproxil fumarate
6.5.1
Rescue Medications and Supportive Care
No rescue or supportive medications are specified for use in this study.
6.6
Dose Modification
No dose modification is allowed during the study.
6.7
Intervention After the End of the Study
Note:  As of Amendment 028-03, this section is no longer applicable.
At the end of Week 96, provided development of DOR/ISL continues, there will be a 
mechanism for all eligible participants to continue receiving study intervention without 
interruption until it becomes commercially accessible. 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.
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6.8
Clinical Supplies Disclosure
Note:  As of Amendment 028-03, this section is no longer applicable.
This study is open-label; therefore, the participant, the study site personnel, the Sponsor, 
and/or designee are not blinded. Study intervention (name, strength, or potency) is included 
in the label text; random code/disclosure envelopes or lists are not provided.
7
DISCONTINUATION OF STUDY INTERVENTION AND PARTICIPANT 
WITHDRAWAL
7.1
Discontinuation of Study Intervention
Note:  As of Amendment 028-03, as study intervention administration will have
discontinued for all participants, this section is no longer applicable.
Discontinuation of study intervention does not represent immediate withdrawal from the 
study.
As certain data on clinical events beyond study intervention discontinuation may be 
important to the study, they must be collected through the participant’s last scheduled follow-
up, even if the participant has discontinued study intervention. Therefore, all participants 
who discontinue study intervention prior to completion of the protocol-specified treatment 
period will still continue to participate in the study as specified in Section 8.11.3.
Participants may discontinue study intervention at any time for any reason or be discontinued 
from the study intervention at the discretion of the investigator should any untoward effect 
occur. In addition, a participant may be discontinued from study intervention by the 
investigator or the Sponsor if study intervention is inappropriate, the study plan is violated, or 
for administrative and/or other safety reasons. Specific details regarding procedures to be 
performed at study intervention discontinuation are provided in Section 8.11.3.
A participant must be discontinued from study intervention but continue to be monitored per 
Section 8.11.3 for any of the following reasons:

The participant or participant’s legally acceptable representative requests to discontinue 
study intervention.

The participant has confirmed HIV-1 virologic rebound as defined in Section 4.2.1.3.1.

The participant has a medical condition or personal circumstance, which, in the opinion 
of the investigator and/or Sponsor, placed the participant at unnecessary risk from 
continued administration of study intervention.

The participant has a positive confirmatory serum pregnancy test.
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
The participant has an SAE or Grade 4 laboratory AE that is assessed by the investigator 
to be related to study intervention AND that is life-threatening or results in prolonged 
hospitalization.

The participant requires treatment for active tuberculosis infection.

The participant has an estimated eGFR of ≤59 mL/min/1.73m2 based on the Schwartz 
equation.
-
Note: eGFR should be confirmed by repeat analysis prior to discontinuing
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 8.1.10. 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, 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 maximum amount of blood collected from each participant over the duration of the study 
will not exceed approximately 521 mL for all participants in the Intensive PK Cohort or 
approximately 483 mL for all other participants (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 consent, and assent if applicable, from each potential participant and each 
participant’s legally acceptable representative prior to participating in a clinical study or 
future biomedical research. If there are changes to the participant’s status during the study 
(eg, health or age of majority requirements), the investigator or medically qualified designee 
must ensure the appropriate consent/assent is in place.
8.1.1.1
General Informed Consent/Assent
Informed consent given by the participant or their legally acceptable representative must be 
documented on a consent form. The form must include the trial protocol number, trial 
protocol title, dated signature, and agreement of the participant (or his/her legally acceptable 
representative) and of the person conducting the consent discussion. 
A copy of the signed and dated informed consent form should be given to the participant (or 
legally acceptable representative) before participation in the study. 
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The initial ICF, any subsequent revised ICF, and any written information provided to the 
participant must receive the IRB/IEC’s approval/favorable opinion in advance of use. The 
participant or his/her legally acceptable representative should be informed in a timely manner 
if new information becomes available that may be relevant to the participant’s willingness to 
continue participation in the study. The communication of this information will be provided 
and documented via a revised consent form or addendum to the original consent form that 
captures the participant’s or the participant’s legally acceptable representative’s dated 
signature.
Specifics about the study and the study population are to be included in the study informed 
consent form.
The informed consent will adhere to IRB/IEC requirements, applicable laws and regulations, 
and Sponsor requirements.
8.1.1.2
Consent/Assent for Intensive PK Cohort Blood Sample Collection for 
Plasma and PBMCs
The investigator or medically qualified designee will explain the Intensive PK Cohort blood 
sample collection for plasma and PBMCs to the participant and participant’s legally 
acceptable representative, answer all of his/her questions, and obtain documented informed 
consent and assent before performing any procedure related to the Intensive PK Cohort blood 
sample collection. After applicable consent and assent are obtained, these participants will 
have additional PK blood sample collection as specified in the SoA (Section 1.3) and Section 
8.6. A copy of the signed informed consent and assent will be given to the participant and 
participant’s legally acceptable representative.
8.1.1.3
Consent for Postnatal Infant Safety Data Collection Through One Year of 
Age
The investigator or medically qualified designee will explain the infant safety data collection
consent to the participant, answer all questions, and obtain documented informed consent 
before collecting any data related to infant safety (Section 8.3.6). A copy of the informed 
consent will be given to the participant.
8.1.1.4
Consent/Assent and Collection of Specimens for Future Biomedical 
Research
Note:  As of Amendment 028-03, specimens for FBR will not be collected, so this section 
is no longer applicable.
The investigator or medically qualified designee will explain the future biomedical research 
consent/assent to the participant/legal guardian, 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/legal guardian.
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8.1.2
Inclusion/Exclusion Criteria
Note: As of Amendment 028-03, this section is no longer applicable.
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
Note: As of Amendment 028-03, this section is no longer applicable.
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
allocation, 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
Note: As of Amendment 028-03, this section is no longer applicable.
A medical history will be obtained by the investigator or qualified designee. The medical 
history should include information pertaining to the diagnosis of HIV-1 and AIDS (if 
applicable) and year diagnosed. If the participant has been previously diagnosed with any 
AIDS-defining conditions or CD4+ T-cell count <200 cells/mm3, the condition as well as a 
corresponding medical history of AIDS must be reported.
8.1.5
Prior and Concomitant Medications Review
8.1.5.1
Prior Medications
Note: As of Amendment 028-03, this section is no longer applicable.
The investigator or qualified designee will review prior medication use and record prior 
medication taken by the participant within 45 days before first dose of study intervention.
All prior HIV medication use, regardless of timing, including PrEP or PEP, must be 
recorded.
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8.1.5.2
Concomitant Medications
The investigator or qualified designee will record medication, if any, taken by the participant 
during the study.
8.1.6
Assignment of Screening Number
Note: As of Amendment 028-03, this section is no longer applicable.
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 intervention allocation. Each 
participant will be assigned only 1 screening number. Screening numbers must not be re-used 
for different participants.
Any participant who is screened more than once 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/Allocation Number
Note: As of Amendment 028-03, this section is no longer applicable.
All eligible participants will be allocated, by nonrandom assignment, and will receive a 
treatment/allocation number. The treatment/allocation number identifies the participant for 
all procedures occurring after treatment allocation. Once a treatment/allocation number is 
assigned to a participant, it can never be reassigned to another participant.
A single participant cannot be assigned more than 1 treatment/allocation number.
8.1.8
Study Intervention Administration
Note:  As of Amendment 028-03, study intervention administration will have 
discontinued, so this section is no longer applicable.
Study intervention will be provided as per Table 2 and dispensed through the IRT system at 
visits indicated in the SoA (Section 1.3).
The first dose of study intervention will be administered at the study site at Visit 2 (Day 1). 
Subsequent dosing will be performed once daily by the participant at his/her home at 
approximately the same time each day unless otherwise specified in Section 8.1.8.1.
8.1.8.1
Timing of Dose Administration
Note: As of Amendment 028-03, this section is no longer applicable.
Participants will take (at their home) 1 tablet of study intervention (DOR/ISL) QD at the 
same time each day (with the exception of days where study intervention is to be observed at 
the site). Study intervention will be taken without regard to food. If more than 1 bottle of 
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study intervention is dispensed, the participant is instructed to use all study intervention in 
the bottle before opening another bottle.
Participants in the Intensive PK Cohort will be required to take their daily dose of DOR/ISL 
in the morning. All other participants may follow an alternative dosing schedule for 
DOR/ISL (eg, afternoon or evening).
The timing of dosing will be aligned with the timing of blood collection for PK analyses (see 
Sections 8.6.1 and 8.6.2 for timing of blood collection for PK).

Intensive PK Cohort Participants:
o
Participants in the Intensive PK Cohort are required to take DOR/ISL in the 
morning Day 1 through Day 29 to facilitate the scheduling of blood collection 
during the day on Day 28 and Day 29
o
Dose administration of DOR/ISL on Day 28 will be observed at the study site and 
must be planned to allow a predose PK blood draw (plasma), and a 4-hour 
postdose blood draw (PBMC) according to Sponsor instructions
o
Dose administration of DOR/ISL on Day 29 must be planned such that the Day 28 
24-hour postdose PK blood draw (plasma) can be obtained prior to taking the 
DOR/ISL dose on Day 29.
Note: Participants will be allowed to transition to an alternate dosing schedule for 
DOR/ISL (eg, afternoon or evening) beyond Day 29. Participants should take the 
dose of DOR/ISL at approximately the same time, each day.

All Participants:
o
DOR/ISL dosing for Day 1, Day 28, Week 24 and Week 48 visits will be 
observed at the study site and must be planned such that a predose PK blood draw
(plasma) can be obtained prior to the daily dose of DOR/ISL.
Note: If participants (excluding those in the Intensive PK Cohort) take their dose
of DOR/ISL without observation at the study site, and prior to the predose PK 
blood draw, then the timing of dose will be verbally reported to study staff by the 
participant or guardian and recorded in the appropriate source documentation.
o
For Week 8, 16, 36, 60, 72, 84, and 96 visits, the timing of DOR/ISL dose 
administration should be verbally reported to study staff by the participant or 
guardian and recorded in the appropriate source documentation
If a participant misses a dose of the study medication, 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
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
If >12 hours from the missed dose, the missed dose should be skipped, and the normal 
dosing schedule resumed. The participant should not double the next dose to compensate 
for what has been missed
8.1.9
Palatability and Acceptability Assessment
Note:  As of Amendment 028-03, this section is no longer applicable.
The questionnaire to assess palatability and acceptability is to be completed for all 
participants at the time of DOR/ISL administration on Days 1 and 28 (whole tablet), and
Week 24 (split tablet). The following recommendations should be considered when 
completing the questionnaire:
•
Age of less than 12 years: Combined completion where the participant completes the 
faces question, and the observer completes the remaining questions.
•
Ages 12 to less than 18 years: Completion directly by the participant, preferred when 
possible.
Observer assessments should be based on what the legally acceptable 
representative/caregiver/healthcare provider directly observed during and after intervention 
administration, including the participant’s facial expressions, behavior, and what the 
participant says. Only individuals who have actually observed the participant taking the 
intervention should complete the assessment.
Week 24 Assessment: The palatability of a split tablet is being evaluated at Week 24. The 
study staff will split the tablet using a pill splitter immediately prior to administration at the 
Week 24 visit. Both halves should be taken immediately after splitting. The splitting tool 
should be wiped immediately following each use. The tablet should only be split at Week 24 
for the palatability assessment, and not at any other time.
8.1.10
Discontinuation and Withdrawal
Participants who discontinue study intervention prior to completion of the treatment period 
should be encouraged to continue to be followed for all remaining study visits as outlined in 
the SoA and Section 8.11.3.
Participants who withdraw from the study should be encouraged to complete all applicable 
activities scheduled for the Early Discontinuation visit at the time of withdrawal. Any AEs 
that are present at the time of withdrawal should be followed in accordance with the safety 
requirements outlined in Section 8.4.
8.1.10.1
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) and have their 
specimens and all derivatives destroyed. 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 
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are still available, the investigator will contact the Sponsor using the designated mailbox 
(clinical.specimen.management@merck.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 or their legal guardian of completion of withdrawal. Any analyses in progress 
at the time of request for withdrawal or already performed prior to the request being received 
by the Sponsor will continue to be used as part of the overall research study data and results. 
No new analyses would be generated after the request is received.
In the event that the medical records for the main study are no longer available (eg, if the 
investigator is no longer required by regulatory authorities to retain the main study records) 
or the specimens have been completely anonymized, there will no longer be a link between 
the participant’s personal information and their specimens. In this situation, the request for 
specimen withdrawal cannot be processed.
8.1.11
Participant Blinding/Unblinding
This is an open-label study; there is no blinding for this study.
8.1.12
Calibration of Equipment
The investigator or qualified designee has the responsibility to ensure that any device or 
instrument used for a clinical evaluation/test during a clinical study that provides information 
about inclusion/exclusion criteria and/or safety or efficacy parameters shall be suitably 
calibrated and/or maintained to ensure that the data obtained are reliable and/or reproducible. 
Documentation of equipment calibration must be retained as source documentation at the 
study site.
8.1.13
Domiciling
Note: As of Amendment 028-03, this section is no longer applicable.
For Intensive PK Cohort participants who will undergo intensive PK sampling, the 
investigator may make arrangements (including local accommodations outside the context of 
hospitalization, if needed/warranted) such that all PK sampling at specified timepoints can be 
performed as scheduled.
8.2
Efficacy Assessments
8.2.1
HIV-1 RNA Quantification
Plasma HIV-1 RNA quantification will be performed at the central laboratory using a 
RealTime PCR assay with a lower limit of detection of 40 copies/mL.
8.2.2
Management of Study Participants with Viremia
Note:  As of Amendment 028-03, this section is no longer applicable.
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All cases of viremia must be confirmed, and the participant should continue to take the 
full assigned dosage of study intervention while awaiting confirmation.
For Virologically Suppressed Cohort participants, when viremia (HIV-1 RNA ≥50 
copies/mL) is detected (Section 4.2.1.3.1), the investigator should query the participant 
regarding adherence to study intervention, intercurrent illness, or recent immunization
For Treatment-Naïve Cohort participants, when viremia (HIV-1 RNA ≥50 copies/mL) is 
detected (Section 4.2.1.3.1) following suppression of HIV-1 RNA to <50 copies/mL at any 
time during the study or at or after Week 24 in the absence of previous suppression to 
<50 copies/mL, the investigator should query the participant regarding adherence to study 
intervention, intercurrent illness, or recent immunization.
8.2.2.1
Viremia Confirmation
Note: As of Amendment 028-03, this section is no longer applicable.
Confirmation of viremia requires 2 consecutive plasma HIV-1 RNA results of ≥50 copies/mL 
(Section 4.2.1.3.1) with the second sample collected at a “Viremia Confirmation” visit at 
least 2 weeks, but not more than 4 weeks from the date of the initial sample. This timeframe 
may be extended if study intervention is interrupted for 1 of the following circumstances:

Intercurrent illness: redraw 2 to 4 weeks following resolution of the illness, during 
which time the participant should continue to receive the assigned dosage of study 
intervention(s) without interruption;

Immunization: redraw at least 4 weeks following any immunization, during which 
time the participant should continue to receive the assigned dosage of study 
intervention(s) without interruption;

Toxicity management, noncompliance, or other reason: redraw 2 to 4 weeks 
following resuming the assigned dosage of study intervention(s).
8.2.2.2
Participants With Clinically Significant Viremia (≥200 Copies/mL)
Note: As of Amendment 028-03, this section is no longer applicable.
Study participants with confirmed HIV-1 RNA of ≥200 copies/mL (following prior 
suppression to HIV-1 RNA to <50 copies/mL OR at or after Week 24 in the absence of 
previous suppression to HIV-1 RNA <50 copies/mL) will be assessed for development of 
viral drug resistance (Section 8.2.2.4) and discontinuation from study intervention (Section 
7.1). Once it is determined that study intervention discontinuation is appropriate, Early 
Discontinuation and End of Treatment visit procedures should be completed (Sections 1.3.2 
and 8.11.3) and the participant managed by the investigator per local standard of care.
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8.2.2.3
Participants With Low-Level Viremia (≥50 and <200 Copies/mL)
Note: As of Amendment 028-03, this section is no longer applicable.
Study participants with confirmed HIV-1 RNA of ≥50 and <200 copies/mL should continue 
study intervention and all regularly scheduled study visits during which HIV-1 RNA levels 
will be monitored per SoA (approximately every 3 months). Additional visits may be 
conducted to monitor HIV-1 RNA levels more frequently than every 3 months, if 
appropriate, after discussion with the Sponsor. Participants with confirmed low-level viremia 
will not be automatically discontinued from study intervention, but will be included in the 
virologic failure rate calculated for the purposes of the efficacy analyses (Section 9.6.1).
Investigators should use their clinical judgment regarding the most appropriate clinical 
management of participants, if more stringent local guidelines apply, and may contact the 
Sponsor’s Clinical Director to discuss questions on clinical management of individual 
participants.
8.2.2.4
Viral Drug Resistance Testing
Participants with confirmed virologic rebound or incomplete virologic response (Section 
4.2.1.3.1), or who discontinue study intervention for another reason and have HIV-1 RNA 
≥200 copies/mL at the time of discontinuation, will be assessed for development of viral drug 
resistance. Samples with HIV-1 RNA ≥200 copies/mL that were collected either to confirm 
viremia or at discontinuation will be sent for genotypic and phenotypic resistance testing. 
Samples will be collected for genotypic and phenotypic HIV-1 drug resistance testing per 
SoA (Section 1.3) and used to assess resistance-associated substitutions as applicable during 
the study.
Whole blood samples will be collected per the SoA (Section 1.3) for proviral DNA archive 
resistance testing. The proviral DNA archive resistance testing sample will be collected at the 
viremia confirmation visit and only sent for analysis if the HIV-1 RNA is confirmed to be 
≥50 and <200 copies/mL at the viremia confirmation visit. The proviral DNA archive 
resistance testing sample should only be sent once per confirmed low-level viremic episode. 
8.2.3
T- and B-Lymphocyte and Natural Killer Cell (TBNK) Profile
A TBNK panel, including CD4+ T cell count, will be performed at the central laboratory 
(Appendix 2).
Refer to Section 8.11.5 for guidance on management of participants with decreased CD4+ T 
cell counts and/or decreased total lymphocyte counts.
8.3
Safety Assessments
Details regarding specific safety procedures/assessments to be performed in this study are 
provided. The total amount of blood to be drawn over the course of the study, including 
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approximate blood volumes drawn by visit and by sample type per participant, can be found 
in Table 14 in Appendix 2.
Planned time points for all safety assessments are provided in the SoA.
8.3.1
Physical Examinations
A full physical examination will be conducted by an investigator or medically qualified 
designee (consistent with local requirements) as per institutional standard at the visits 
specified in the SoA (Section 1.3). The full physical examination will include examination of 
body systems including, but not limited to, general appearance, skin, neck, eyes, ears, nose, 
throat, breast, lungs, heart, abdomen, back, lymph nodes, extremities, and nervous system.
Height will be measured and recorded at the visits specified in the SoA (Section 1.3). Height 
measurements should be taken using a stadiometer (recommended, but not required).
Participants should remove their shoes and stand as tall and straight as possible.
A brief directed physical examination will be conducted by an investigator or medically 
qualified designee (consistent with local requirements) per institutional standard at the visits 
specified in the SoA (Section 1.3). This examination will be sign- and symptom-directed and 
based on the participant’s condition and circumstances. The investigator should note any 
changes in the participant’s condition (body systems) since the last examination, not 
precluding examination of any body system(s) as clinically indicated.
Investigators should pay special attention to clinical signs related to previous serious 
illnesses.
8.3.1.1
Weight
Weight will be measured and recorded at the visits specified in the SoA (Section 1.3). 
Participants should remove their shoes and wear a single layer of clothing at each 
measurement.
8.3.2
Vital Signs
Vital signs will be measured after approximately 5 to 10 minutes of rest and will include 
temperature, pulse, respiratory rate, and systolic and diastolic blood pressure.
8.3.3
Confirmation of Menarche, Contraception, and Pregnancy Testing
Participants should be asked at study visits per SoA to verbally confirm menarche.
WOCBP are required to use contraception to prevent pregnancy during the study and will be 
tested for pregnancy at each visit as outlined in Section 1.3, Section 5.1, and Appendix 5.
WOCBP should be asked at study visits per SoA to verbally confirm their use of 
contraception since the prior visit, according to the Contraceptive Guidance in Appendix 5. 
Confirmation should be noted in the source documents for each visit.
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Urine pregnancy test kits will be provided by the central laboratory, and routine testing will 
be performed by the local laboratory. In the event of a positive urine pregnancy test result, 
serum pregnancy testing must be performed by the central laboratory. If a participant 
becomes pregnant, refer to Section 7.1 and Section 8.11.3.1.
8.3.4
Clinical Safety Laboratory Assessments
Refer to Appendix 2 for the list of clinical laboratory tests to be performed and to the SoA for 
the timing and frequency.

The investigator or medically qualified designee (consistent with local requirements) 
must review the laboratory report, document this review, and record any clinically 
relevant changes occurring during the study in the AE section of the CRF. The laboratory 
reports must be filed with the source documents. Clinically significant abnormal 
laboratory findings are those which are not associated with the underlying disease, unless 
judged by the investigator to be more severe than expected for the participant's condition.

All protocol-required laboratory assessments, as defined in Table 13 in Appendix 2, must 
be conducted in accordance with the laboratory manual and the SoA.

If laboratory values from nonprotocol-specified laboratory assessments performed at the 
institution’s local laboratory require a change in study participant management or are 
considered clinically significant by the investigator (eg, SAE or AE or dose 
modification), then the results must be recorded in the appropriate CRF (eg, SLAB).

For any laboratory tests with values considered clinically significantly abnormal during 
participation in the study or within 42 days after the last dose of study intervention, every 
attempt should be made to perform repeat assessments until the values return to normal or 
baseline or if a new baseline is established as determined by the investigator.
Note: Decreases in CD4+ T-cell and/or lymphocyte counts should be managed per 
Section 8.11.5.
8.3.5
HBV Assessments
Note: As of Amendment 028-03, HBV monitoring will not be performed after the Early 
Discontinuation of Treatment visit.
Participants coinfected with HIV-1 and HBV who discontinue an antiretroviral medication 
that also has activity against HBV (3TC, FTC, TAF, or TDF) may experience an acute 
exacerbation of HBV. Therefore, participants who have evidence of past HBV exposure 
(antiHBc positive) and who meet enrollment criteria will be closely monitored during the 
study.
All eligible participants must be HBsAg-negative at screening. Participants who are antiHBc 
positive and HBV DNA positive at screening are excluded. Participants who are antiHBc 
positive but HBV DNA negative at screening are eligible to enroll. For the duration of the 
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study, participants positive for antiHBc should be monitored for possible HBV reactivation. 
Samples will be taken to monitor HBsAg and HBV DNA each visit per SoA (Section 1.3). 
Investigators should also pay close attention to changes from baseline in ALT, AST, 
bilirubin, and alkaline phosphatase (included in chemistry laboratory assessments).
Participants who become HBsAg or HBV DNA positive during the study will be managed by 
the investigator per local standard of care and/or referred for management of their HBV 
infection. Participants may be allowed to continue study intervention if deemed medically 
appropriate upon consultation with the Sponsor.
Therapies indicated for HBV that also have potent activity against HIV (eg, adefovir, TDF, 
TAF, FTC, or 3TC) are prohibited (Section 6.5). Entecavir therapy for HBV infection is 
allowed.
8.3.6
Infant Safety Follow-up Assessments
Infants, born to participants who become pregnant while receiving study intervention or 
during the protocol-specified follow-up period and consent to infant follow-up, will have 
safety follow-up through approximately 1 year of age as outlined in Table 4. This infant 
safety follow-up data may be collected by phone call. Gestational age, Apgar score, length, 
weight, head circumference measurements, directed pediatric examination, concomitant 
medications and infant SAEs will be collected at birth. Infant informed consent, length, 
weight, head circumference measurements, concomitant medications and infant SAEs will be 
collected at 1 year of age. Infant SAEs, including congenital anomalies identifiable on 
physical examination at birth or shortly after birth, will be collected as per Section 8.4.1.
Table 4
Infant Safety Data Collection Through 1 Year of Age
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 ----------------------------
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Timepoint
At Birtha
1-Year After Birtha,b
Visit Name
N/A
Infant Follow-Up 1
Administrative and Safety Procedures
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.
8.4
Adverse Events, Serious Adverse Events, and Other Reportable Safety Events
The definitions of an AE or SAE, as well as the method of recording, evaluating, and 
assessing causality of AE and SAE and the procedures for completing and transmitting AE, 
SAE, and other reportable safety event reports can be found in Appendix 3.
Adverse events, SAEs, and other reportable safety events will be reported by the participant 
(or, when appropriate, by a caregiver, surrogate, or the participant's legally authorized 
representative).
The investigator and any designees are responsible for detecting, documenting, and reporting 
events that meet the definition of an AE or SAE as well as other reportable safety events. 
Investigators remain responsible for following up AEs, SAEs, and other reportable safety 
events for outcome according to Section 8.4.3.
The investigator, who is a qualified physician, will assess events that meet the definition of 
an AE or SAE as well as other reportable safety events with respect to seriousness, 
intensity/toxicity and causality.
8.4.1
Time Period and Frequency for Collecting AE, SAE, and Other Reportable 
Safety Event Information
All AEs, SAEs, and other reportable safety events that occur after the participant provides 
documented informed consent but before intervention allocation 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 allocation through the study duration, all AEs, SAEs, and other 
reportable safety events must be reported by the investigator.
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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 follow-up, 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 5.
For participants that continue to receive study intervention in a rollover study, the collection 
requirements of AEs, SAEs and other reportable safety events are amended as follows:
-
AEs, SAEs and other reportable safety events will be collected and recorded through 
the last treatment visit in this protocol. 
-
All new SAEs (including those considered related to study intervention) and new 
other reportable safety events (including pregnancy exposure) that occur after the last 
treatment visit will be collected in the rollover study. 
-
Pregnancy outcome and infant SAEs will be captured in this protocol, if pregnancy 
exposure is reported in this protocol.
-
The last collection of non-serious SAEs will be at the last treatment visit in this 
protocol.
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Table 5
Reporting Time Periods and Time Frames for Adverse Events and Other 
Reportable Safety Events
Type of Event
Reporting Time 
Period:
Consent to 
Randomization/ 
Allocation
Reporting Time 
Period:
Randomization/ 
Allocation through 
Protocol-specified 
Follow-up Period
Reporting Time 
Period:
After the 
Protocol-
specified Follow-
up Period
Time Frame 
to Report 
Event and 
Follow-up 
Information 
to Sponsor:
Nonserious 
Adverse Event 
(NSAE)
Report if:
- due to protocol-
specified intervention
- causes exclusion
- participant is receiving 
placebo run-in or other 
run-in treatment
Report all
Not required
Per data entry 
guidelines
Serious Adverse 
Event (SAE)
Report if:
- due to protocol-
specified intervention
- causes exclusion
- participant is receiving 
placebo run-in or other 
run-in treatment
Report all
Report if:
- drug/vaccine 
related.
(Follow ongoing 
to outcome)
Within 24 
hours of 
learning of 
event
Pregnancy/
Lactation 
Exposure
Report if:
- due to intervention
- causes exclusion
Report all
Previously 
reported – Follow 
to completion/
termination; 
report outcome
Within 24 
hours of 
learning of 
event
Event of Clinical 
Interest (require 
regulatory 
reporting)
Report if:
- due to intervention
- causes exclusion
Report
- Potential drug-
induced liver injury 
(DILI)
- Require regulatory 
reporting
Not required
Within 24 
hours of 
learning of 
event
Event of Clinical 
Interest (do not 
require 
regulatory 
reporting)
Report if:
- due to intervention
- causes exclusion
Report
- non-DILI ECIs and 
those not requiring 
regulatory reporting
Not required
Within 5 
calendar days 
of learning of 
event
Cancer
Report if:
- due to intervention
- causes exclusion
Report all
Not required
Within 5 
calendar days 
of learning of 
event
Overdose
Report if:
- receiving placebo run-
in or other run-in 
medication 
Report all
Not required
Within 5 
calendar days 
of learning of 
event
8.4.2
Method of Detecting AEs, SAEs, and Other Reportable Safety Events
Care will be taken not to introduce bias when detecting AEs and/or SAEs and other 
reportable safety events. Open-ended and nonleading verbal questioning of the participant is 
the preferred method to inquire about AE occurrence.
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8.4.3
Follow-up of AE, SAE, and Other Reportable Safety Event Information
After the initial AE/SAE report, the investigator is required to proactively follow each 
participant at subsequent visits/contacts. All AEs, SAEs, and other reportable safety events,
including pregnancy and exposure during breastfeeding, 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 allocated participants for 
outcome. Further information on follow-up procedures is given in Appendix 3.
8.4.4
Regulatory Reporting Requirements for SAE
Prompt notification (within 24 hours) by the investigator to the Sponsor of SAE is essential 
so that legal obligations and ethical responsibilities towards the safety of participants and the 
safety of a study intervention under clinical investigation are met.
The Sponsor has a legal responsibility to notify both the local regulatory authority and other 
regulatory agencies about the safety of a study intervention under clinical investigation. The 
Sponsor will comply with country-specific regulatory requirements and global laws and 
regulations relating to safety reporting to regulatory authorities, IRB/IECs, and investigators.
Investigator safety reports must be prepared for SUSARs according to local regulatory 
requirements and Sponsor policy and forwarded to investigators as necessary.
An investigator who receives an investigator safety report describing an SAE or other 
specific safety information (eg, summary or listing of SAE) from the Sponsor will file it 
along with the IB and will notify the IRB/IEC, if appropriate according to local requirements.
8.4.5
Pregnancy and Exposure During Breastfeeding
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 follow-up, SAEs 
(including perinatal HIV-1 infection) occurring through 1 year of age must be reported by the 
investigator to the Sponsor within 24 hours of learning of the event.
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8.4.6
Disease-related Events and/or Disease-related Outcomes Not Qualifying as 
AEs or SAEs
This section is not applicable to this study.
8.4.7
Events of Clinical Interest
Note:  As of Amendment 028-03, ECIs will be reported through 42 days after the last 
dose of study intervention.
Selected nonserious and SAEs are also known as ECIs and must be reported to the Sponsor.
Events of clinical interest for this study include:
1. An elevated AST or ALT lab value that is greater than or equal to 3X the upper limit of 
normal and an elevated total bilirubin lab value that is greater than or equal to 2X the 
upper limit of normal and, at the same time, an alkaline phosphatase lab value that is less 
than 2X the upper limit of normal, as determined by way of protocol-specified laboratory
testing or unscheduled laboratory testing.*
*Note: These criteria are based upon available regulatory guidance documents. The 
purpose of the criteria is to specify a threshold of abnormal hepatic tests that may require 
an additional evaluation for an underlying etiology. The study site guidance for 
assessment and follow-up of these criteria can be found in the Investigator Study File 
Binder (or equivalent). 
8.5
Treatment of Overdose
Note:  As of Amendment 028-03, as administration of study intervention will have 
discontinued, this section is no longer applicable.
In this study, an overdose is any dose higher than the prescribed dose of DOR/ISL 
(100 mg/0.75 mg daily).
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 Measurements
Note:  As of Amendment 028-03, plasma PK sample collection has been revised and will 
be collected only at the Early Discontinuation of Treatment and End of Treatment 
Follow-Up visits.
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Venous blood samples will be collected from all participants for the measurement of ISL 
concentrations in plasma (Table 6).
The timing of blood collection will be aligned with the timing of dose administration as 
outlined in Section 8.1.8.1. Study staff will observe and record the timing of DOR/ISL doses
administered to all participants at the investigational site on Day 1, Day 28, Week 24, and 
Week 48, which are PK sample collection days.
For participants who take DOR/ISL at night, there will be an exception to the time points 
outlined in the SoA. For these participants, 1 blood sample (assigned as “random”) will be
collected at the Week 48 visit irrespective of time of the last dose. If participants
administered their dose of DOR/ISL without observation at the study site at Week 48, then 
the dose timing will be verbally reported (Section 8.1.8) and the PK sample will be assigned 
as “random”.
For Week 8, 16, 36, 60, 72, 84, and 96 visits, the timing of DOR/ISL dose administration 
prior to the PK sample collection will be verbally reported to study staff by the participant or 
guardian and recorded in the appropriate source documentation.
Sample collection, storage, and shipment instructions for plasma samples will be provided in 
a separate manual.
Intensive blood sampling on Day 28 will be conducted only for participants in the Intensive 
PK Cohort. Participants in the Intensive PK Cohort will be required to take their daily dose 
of DOR/ISL in the morning. Sparse PK samples (plasma) will be collected from all
participants. Of note, a single predose sample on Day 28 will be collected from all 
participants (regardless of their participation in the Intensive PK Cohort).
PK samples (investigational, time relative to dose not specified) will also be drawn at the 
Viremia Confirmation Visit, Early Discontinuation of Treatment Visit, and the End of 
Treatment Follow-up Visit, (Section 1.3.2). The timing of DOR/ISL dose administration 
prior to the PK sample collection at these visits will be verbally reported to study staff by the 
participant or guardian and recorded in the appropriate source documentation. Analysis of 
these samples will be triggered by the Sponsor as needed.
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Table 6
Plasma Sample Collection Schedule for ISL Concentrations
Intensive PK Cohort Participants
All Participants
Day 28:

1 sample predosea

1 sample postdose, each for the 
following timepoints:
o
0.5 hour (±10 min)
o
1 hour (±15 min)
o
2 hours (±15 min)
o
4 hours (±1 hour)
o
8 hours (±2 hours)
o
12 hours (±2 hours)
o
24 hours (±4 hours)

Day 1: 1 sample predose

Day 28a: 1 sample predose

Week 8 and Week 16c: 1 sample, “random”

Week 24:
o
1 sample predose
o
1 sample at 0.5 hour (±10 min)
to 2 (±15 min) hours postdose

Week 36c: 1 sample, “random”

Week 48b:
o
1 sample predose
o
1 sample 0.5 hour (±10 min)
to 2 (±15 min) hours postdose

Week 60-96: 1 sample, “random”
PK=Pharmacokinetic
Note: All predose samples will be collected up to 3 hours prior to dosing
a A single predose sample will be taken from every participant on Day 28. Intensive PK Cohort Participants 
do not require 2 samples predose
b Participants who routinely take their study intervention in the evening should continue to do so and only 1 
sample will be taken at Week 48 visit irrespective of time of last dose. If participants administered their dose 
of DOR/ISL without observation at the study site at Week 48, then the dose timing will be verbally reported 
and the PK sample will be assigned as “random”.
c The time of the dose of DOR/ISL taken prior to the random PK sample collection on the Week 8,16, 36, 60, 
72, 84, and 96 visits will be verbally reported to study staff by the participant or guardian and recorded in the 
appropriate source documentation.
8.6.2
Blood Collection for ISL-TP Measurements in PBMCs
Note:  As of Amendment 028-03, this section is no longer applicable.
On Day 28, venous blood samples will be collected from participants in the Intensive PK 
Cohort for the measurement of ISL-TP (and ISL-DP for proper stabilization confirmation) 
concentrations in PBMCs.
One blood sample for PBMCs will be collected at each of the following timepoints on Day 
28: Predose (up to 3 hours prior to dosing), 4 hours (±1 hour), and 24 hours (±4 hours) 
postdose. The timing of blood collection will be aligned with the timing of dose 
administration as outlined in Section 8.1.8.1.
Sample collection, storage, and shipment instructions for PBMC samples will be provided in 
a separate manual.
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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 collected for planned analysis of the 
association between genetic variants in DNA and drug response. This sample will not be 
collected at the site if there is either a local law or regulation prohibiting collection, or if the 
IRB/IEC does not approve the collection of the sample for these purposes. If the sample is 
collected, leftover extracted DNA will be stored for future biomedical research if the 
participant provides documented informed consent for future biomedical research. If the 
planned genetic analysis is not approved, but future biomedical research is approved and 
consent is given, this sample will be collected for the purpose of future biomedical research.
Sample collection, storage, and shipment instruction for planned genetic analysis samples 
will be provided in the operations/laboratory manual.
Collection of samples for other biomarker research is also part of this study. The following 
samples for biomarker research are required and will be collected from all participants as 
specified in the SoA:
•
Buccal swabs for genetic analysis
8.9
Future Biomedical Research Sample Collection
If the participant provides documented informed consent for future biomedical research, the 
following specimens will be obtained as part of future biomedical research:

Leftover extracted DNA for future research

Leftover main study plasma from HIV-1 RNA quantification

Leftover main study plasma from HIV drug resistance samples
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.
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8.11.1
Screening/Rescreening
Note: As of Amendment 028-03, this section is no longer applicable.
Screening
Prior to allocation of study medication, potential participants will be evaluated to determine 
that they fulfill the entry requirements as set forth in Section 5. Participants are expected to 
enroll as soon as possible after eligibility is confirmed. In cases of unexpected delays in 
receiving repeat screening laboratory results, a screening period of up to 45 days is allowed.
Rescreening
If the screening window has been exceeded, participants are allowed to rescreen one time 
following approval from the Sponsor. Once a participant has started the rescreening process, 
a new screening period (ie, an additional ≤45-day window) will begin, during which time 
screening procedures may be repeated.
The following assessments must be repeated for participants who are rescreened:
•
Vital signs, weight, height and directed physical examination
•
Review medical history and prior/concomitant medications for new information
•
All laboratory assessments (includes urine pregnancy testing for WOCBP), with the 
exception of HIV-1 drug resistance testing
•
Review of AEs
If the informed consent form has been updated, participants should be reconsented before 
rescreening. If no updates have been made, documented informed consent signed during the 
original screening period should be reviewed with the participant and a verbal reconsent to 
continue in the study should be documented.
8.11.2
Treatment Period
All procedures and their timing should be completed as per SoA (Section 1.3).
8.11.2.1
Optional Nurse Visits and Telephone Visits
A visiting nurse service may be used (if locally available and approved for use) under 
extenuating circumstances and with Sponsor approval. If a visiting nurse service is utilized 
for any visit, the investigator should contact the participant by phone on the same day as the 
nurse visit, or as soon as possible to perform an investigator AE assessment.
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8.11.2.2
Day 14 Telephone Call
Note: As of Amendment 028-03, this section is no longer applicable.
A qualified medical designee noted on the study delegation log will be responsible for the 
Day 14 telephone call. During the call, participants will be asked about the use of 
concomitant medications in Section 8.1.5.2 and AEs experienced as described in 
Section 8.4.2. The participant/guardian will be reminded of the scheduled Day 28 visit date 
and planned dosing schedule for Day 28 and scheduled domiciling (as applicable). 
Adherence assessment and counseling will also be performed. Open-ended and nonleading 
verbal questioning of the participant is the preferred method to inquire about adherence to 
study intervention.
8.11.2.3
Fasting
Note: As of Amendment 028-03, this section is no longer applicable.
On Day 1, Week 48, and Week 96 visits, participants are required to fast (ie, do not consume 
any food or beverages except water) for at least 8 hours prior to the visit. Fasting chemistry 
tests for lipid profile and glucose will be performed at these visits. If the measurements are 
normal at baseline, then these measurements will be repeated only at 48 and 96 weeks. If the 
baseline fasting lipid profile or fasting glucose is abnormal, then the participant will be tested 
again at Week 24.
The investigator/study coordinator are responsible to remind participants to fast prior to these 
visits and to confirm with participants their fasting status in the appropriate source 
documentation.
8.11.3
Participants Who Discontinue Study Intervention
Note: As of Amendment 028-03, all participants should be managed per Sections 
8.11.3.2, 8.11.3.3, and 8.11.5.
A participant must be discontinued from study intervention but continue to be monitored for 
any of the reasons listed in Section 7.1.
For all discontinuations which are not related to pregnancy, when it is determined that 
discontinuation from study intervention is appropriate, the participant should have both an 
Early Discontinuation of Treatment visit (Section 8.11.3.2) and an End of Treatment Follow-
up Visit (Section 8.11.3.3) conducted. After the visit procedures are completed, the 
participant will be withdrawn from the study and managed by the investigator per local 
standard of care.
8.11.3.1
Participants Who Become Pregnant
If a participant becomes pregnant during the study (has a positive serum pregnancy test), 
study intervention should be discontinued, and the participant should be managed by the 
investigator per local standard of care, as appropriate.
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The participant should not be withdrawn from the study but should have an Early 
Discontinuation of Treatment visit (Section 8.11.3.2). If the pregnancy is reported at a 
scheduled study visit, the assessments for the Early Discontinuation of Treatment visit and 
the End of Treatment Follow-up (42 days after End of Treatment) should be conducted at 
that time (Section 1.3.2). These visits will be registered in IRT, concomitant medications will 
be reviewed, and safety assessments will be completed.
All reported pregnancies occurring during the study must be followed to the 
completion/termination of the pregnancy (Section 8.4.5). When assessing the severity of AEs 
that are pregnancy-related complications, please refer to the additional 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” (found on pages 
11-12 of the Addendum).
The participant will be asked to join a pregnancy registry, which collects information about 
the outcome of the pregnancy. Infants born to participants who become pregnant while 
receiving study intervention and consent/assent to infant follow-up will have follow-up data 
collected up to approximately 1 year of age (Section 8.3.6).
8.11.3.2
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.
Decreases in CD4+ T-cell and/or total lymphocyte counts at the Early Discontinuation of 
Treatment visit should be managed per Section 8.11.5.
8.11.3.3
End of Treatment Follow-up Visit
Participants who discontinue study intervention at any time (including at the Week 96 visit) 
for any reason(s) not related to pregnancy will have a safety follow-up visit in-clinic 
approximately 42 days after the last dose of study intervention. Assessments for this visit are 
outlined in Section 1.3.2.
Participants with decreases in CD4+ T-cell and/or total lymphocyte counts at the Early 
Discontinuation of Treatment Visit and confirmed at the End of Treatment Follow-up Visit 
will be followed every 4 to 6 weeks (Section 8.11.5 and Section 1.3.3). The End of 
Treatment Follow-up Visit will be conducted approximately 42 days after the last dose of 
study intervention. All activities outlined in Section 1.3.2 for the End of Treatment Follow-
up Visit should be performed at this time.
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8.11.4
Viremia Confirmation
Note:  As of Amendment 028-03, this section is no longer applicable.
For the Virologically Suppressed Cohort, if a participant has a viral load of ≥50 copies/mL at 
any time during the study, a Viremia Confirmation visit must be conducted within 2 to 4 
weeks of the initial HIV-1 viremia (Section 1.3.2 and 4.2.1.3.1).
For the Treatment-Naïve Cohort, if a participant has a viral load of ≥50 copies/mL following 
suppression of HIV-1 RNA to <50 copies/mL at any time during the study or at or after 
Week 24 in the absence of previous suppression, a Viremia Confirmation visit must be 
conducted within 2 to 4 weeks of the initial HIV-1 viremia (see Section 1.3.2 and Section 
4.2.1.3.1).
For both cohorts, 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 and whole blood for proviral DNA 
archive resistance test sample must be collected.
8.11.5
Management of Participants with Regards to CD4+ T-Cell Counts and/or 
Total Lymphocyte Counts

Participants discontinued from DOR/ISL should undergo assessments for CD4+ T-cell 
and total lymphocyte counts at the Early Discontinuation of Treatment Visit. The average 
baseline value (defined as the average of the screening [within 45 days prior to the first 
dose of study intervention] and Day 1 values) for CD4+ T-cells and total lymphocytes 
will be compared to the values at the Early Discontinuation of Treatment Visit.
o
If the CD4+ T-cell and/or total lymphocyte counts at the Early Discontinuation of 
Treatment Visit are not decreased by >10% of the average baseline value, the 
participant will proceed to an End of Treatment Follow-Up visit approximately 
42 days later and will discontinue from the study at that visit. If the CD4+ T-cell 
and/or total lymphocyte counts at the Early Discontinuation of Treatment Visit 
are >10% below average baseline value, the participant will need to have the 
decrease in counts confirmed at the End of Treatment Follow-up Visit. If at the 
End of Treatment Follow-up visit the counts are not decreased by >10% of the 
average baseline value, then the participant will discontinue from the study at the 
End of Treatment visit.
o
If the CD4+ T-cell and/or total lymphocyte counts at the Early Discontinuation of 
Treatment Visit are >10% below average baseline value, the participant will need 
to have the decrease in counts confirmed at the End of Treatment Follow-up Visit.  
If at the End of Treatment Follow-up visit the counts are still decreased by >10% 
of the average baseline value, then the CD4+ T-cell and total lymphocyte counts 
should be monitored every 4 to 6 weeks (per Section 1.3.3) until both the CD4+ 
T-cell count and total lymphocyte count are not decreased by >10% of the 
average baseline value on 2 measurements 12 weeks apart.
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Note: If a participant has 2 values 12 weeks apart that are ≤10% below average baseline 
value, but has more than 1 value >10% below average baseline value during the 12-week 
interval, then the participant will require continued monitoring.
If the CD4+ T-cell and/or total lymphocyte counts remain decreased by >10% of the 
average baseline value at 6 months, the Investigator should consult with the Sponsor.
9
STATISTICAL ANALYSIS PLAN
This section outlines the statistical analysis strategy and procedures for the study. Changes to 
analyses made after the protocol has been finalized will be documented in an sSAP and 
referenced in the CSR. Post hoc exploratory analyses will be clearly identified in the CSR.
9.1
Statistical Analysis Plan Summary
Key elements of the statistical analysis plan are summarized below; the comprehensive plan 
is provided in Sections 9.2 to 9.12.
Study Design Overview
A Phase 2 nonrandomized, noncomparative, open-label clinical study to 
evaluate the PK, safety, and efficacy of DOR/ISL in participants with HIV-1 
who are <18 years of age, weighing ≥35 kg, and have been virologically 
suppressed for ≥3 months or are treatment-naïve.
Treatment Assignment
All participants will receive DOR (100 mg)/ISL (0.75 mg) FDC QD.
Analysis Populations
PK: PP; Safety: APaT; Efficacy: FAS, and Resistance Analysis Subset.
Primary Endpoint(s)
PK:
1.
ISL steady-state AUC0-24, Cmax, Tmax, CL/F, Vz/F, t1/2 after 
administration of DOR/ISL QD for 28 days in the Intensive PK Cohort.
2.
ISL-triphosphate steady-state AUC0-24, Cmax, and C24 after 
administration of DOR/ISL QD for 28 days in the Intensive PK Cohort.
Safety:
1.
Percentage of participants experiencing AEs or discontinuing study 
intervention due to an AE through Week 24.
Key Secondary 
Endpoints
Safety:
1.
Percentage of participants experiencing AEs or discontinuing study 
intervention due to an AE through study duration.
Efficacy:
1.
Percentage of participants with HIV-1 RNA ≥50 copies/mL at Weeks 24, 
48, and 96 (for Virologically Suppressed Cohort only).
2.
Percentage of participants with HIV-1 RNA <50 copies/mL at Weeks 24, 
48, and 96.
3.
Change from baseline in CD4+ T-cell count at Weeks 24, 48, and 96.
4.
Development of viral drug resistance to DOR or ISL in participants 
treated with DOR/ISL.
Palatability and Acceptability of the Tablet (whole and split)
1.
5-point facial hedonic scale
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Statistical Methods for 
Key Analyses
PK (Intensive PK Cohort):
PK data from the Intensive PK Cohort will be used to estimate the posterior 
probabilities that in pediatric participants the true steady-state plasma ISL 
AUC0-24 is <0.28 µM·hr (ie, GM of plasma ISL AUC0-24 in adults 
following ISL 2.25 mg QD); the true steady-state PBMC ISL-TP C24 is 
˃2.68 µM (or 0.54 pmol/106 cells) (ie, GM of PBMC ISL-TP C24 in adults 
following ISL 0.25 mg QD). The PK profile is considered acceptable if the 
posterior probabilities are greater than 90% and 90% respectively.
Safety: Safety and tolerability will be assessed by clinical review of all 
relevant parameters including AEs, laboratory tests, and vital signs. 
Descriptive statistics will be provided for these safety parameters.
Efficacy: The percentage of participants with HIV-1 RNA ≥50 and <50 
copies/mL will be estimated with a 95% CI (via the Clopper-Pearson method). 
The primary missing data approach will be the FDA snapshot approach. 
Change from baseline in CD4+T-cell counts will be estimated using the DAO 
approach with a 95% CI based on the t-distribution. 
Interim Analyses
An eDMC will review the safety and tolerability data at regular intervals 
throughout the study. After the target enrollment has been met and all the 
participants have completed the Week 24 Visit, the primary safety and the 
secondary efficacy analysis at Week 24 will be conducted by the Sponsor and 
results will be shared with the eDMC.
Multiplicity
No multiplicity adjustment is needed as there are no hypotheses to be tested in 
the study.
Sample Size 
The Intensive PK Cohort size is supported by clinical trial simulations using 
the ISL population PK model based on adult data (from MK-8591-001, 002, 
003, 009, and 011) that indicated N=10 is required to estimate clearance in 
pediatric participants with adequate precision (relative standard error <30%).
9.2
Responsibility for Analyses
The statistical analysis of the data obtained from this study will be the responsibility of the 
Clinical Biostatistics department of the Sponsor. The statistical analyses of the PK data will 
be conducted in collaboration with the departments of Quantitative Pharmacology and 
Pharmacometrics and Clinical Research of the Sponsor.
This study will be conducted as a nonrandomized, open-label study, ie, participants, 
investigators, and Sponsor personnel will know the intervention administered.
The Clinical Biostatistics department will generate the allocation schedule for study 
intervention assignment. Allocation number will be assigned via an IRT.
9.3
Hypotheses/Estimation
There are no hypotheses to be tested in this study.
9.4
Analysis Endpoints
Initial descriptions of PK, safety, and efficacy measures are provided in Section 4.
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9.4.1
Pharmacokinetic Endpoints
Plasma PK Profile
Endpoints for the intensive plasma PK sampling (Intensive PK Cohort) are ISL steady-state 
AUC0-24, Cmax, Tmax, apparent terminal t1/2, CL/F, and Vz/F after administration of 
DOR/ISL QD in pediatric participants for 28 days.
Intracellular PK Profile
Endpoints for the PBMC PK sampling (Intensive PK Cohort) are ISL-TP steady-state
AUC0-24, Cmax, and C24 after administration of DOR/ISL QD in pediatric participants for 
28 days.
Population PK Modeling
Endpoints for the sparse plasma PK sampling for all participants are ISL plasma 
concentrations through Week 48.
9.4.2
Safety Endpoints
An initial description of safety measures is provided in Section 4.
Adverse Events
The following AEs will be summarized: 1) participants with at least 1 AE; 2) participants 
with at least 1 drug-related AE; 3) participants with at least 1 SAE; 4) participants with at 
least 1 serious and drug-related AE; 5) participants with at least 1 Grade 3 to 4 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 an AE; 8) participants who discontinued study 
intervention due to a drug-related AE; 9) participants with AE(s) leading to death.
Predefined Limits of Change in Laboratory Parameters
For the summaries of laboratory tests, participants must have both a baseline and 
postallocation 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 the PDLC and are 
worse in grade (ie, more abnormal in the direction of interest) than at baseline. The criteria 
are adapted from the DAIDS table for Grading the Severity of Adult and Pediatric Adverse 
Events, July 2017, version 2.1 (Appendix 3). A listing of the participants who meet the 
criteria will also be provided.
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9.4.3
Efficacy Endpoints
Note: As of Amendment 028-03, the available efficacy data will be summarized.
Percentage of Participants With HIV-1 RNA <50 copies/mL
The Abbott RealTime PRC 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 percentage of participants with HIV-1 RNA <50 copies/mL will be estimated 
separately for Treatment-Naïve and Virologically Suppressed Cohorts at each visit time point 
in the SoA. A second objective will be assessed based on the percentage of participants with
HIV-1 RNA <50 copies/mL at Weeks 24, 48, and 96.
Percentage of Participants With HIV-1 RNA ≥50 Copies/mL
The percentage of participants with ≥50 copies/mL will be estimated at each visit time point 
in the SoA for Virologically Suppressed Cohort. A second objective will be assessed based 
upon the percentage of participants with HIV-1 RNA ≥50 copies/mL at Weeks 24, 48, and 
96.
Change From Baseline in CD4+ T-cell Count
Change from baseline in CD4+ T-cell count will be assessed at Weeks 24, 48, and 96 in the 
Virologically Suppressed Cohort and the Treatment-Naïve Cohort separately.
For analyses of change from baseline (eg, change in CD4+ T-cell count, change in laboratory 
tests, etc.), baseline measurements are defined as the Day 1 value for each participant. In the 
rare event when data for this visit are missing, the value obtained at the most recent screening 
visit will be used as baseline, when available.
Clinically Significant Confirmed Viremia
Participants with confirmed virologic rebound or incomplete virologic response as defined in 
Section 4.2.1.3.1 will be identified.
Viral Resistance-associated Substitutions
Participants who meet the definition of confirmed virologic rebound or incomplete virologic 
response (Section 4.2.1.3.1), or who discontinue study intervention for another reason and 
have HIV-1 RNA ≥200 copies/mL at the time of discontinuation, will be assessed for 
development of viral drug resistance. Among such participants, those with HIV-1 RNA ≥400 
copies/mL or anyone for whom available genotypic or phenotypic data show evidence of 
resistance, irrespective of viral load, will be included for resistance analyses. The resistance 
analysis will summarize the number and percentage of participants who have evidence of 
resistance-associated substitutions with primary interest at Weeks 24, 48, and 96.
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9.5
Analysis Populations
9.5.1
Pharmacokinetic Analysis Population
Pharmacokinetic analyses will be conducted in a PP population, which consists of a subset of 
participants who comply with the protocol sufficiently to ensure that generated data will be 
likely to exhibit the effects of the study intervention, according to the underlying scientific 
model. Compliance with the protocol includes considerations such as exposure to study 
intervention, availability of measurements, and absence of important protocol deviations that 
may impact PK analyses.
At the end of the study, all participants who are compliant with the study procedures as 
aforementioned and have available data from at least 2 PK time points will be included in the
PP dataset. Any participants or data values excluded from analysis will be identified, along 
with their reason for exclusion, in the CSR.
9.5.2
Safety Analysis Population
Safety analyses will be conducted in the APaT population, which consists of all allocated 
participants who received at least 1 dose of study intervention.
At least 1 laboratory, or vital sign measurement obtained after at least 1 dose of study 
intervention is required for inclusion in the analysis of those respective safety parameters. 
For safety analyses that assess change from baseline, a baseline measurement is also 
required.
9.5.3
Efficacy Analysis Population
Details on the approach to handling missing data for efficacy analyses are provided in 
Section 9.6.3.
9.5.3.1
Full Analysis Set
The FAS will serve as the primary population for the analysis of efficacy data in this study. 
The FAS consists of all allocated participants who:

Receive at least 1 dose of study intervention

Have baseline data for those analyses that require baseline data
9.5.3.2
Resistance Analysis Subset
The resistance analysis subset will include 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.
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9.6
Statistical Methods
9.6.1
Pharmacokinetic Analyses
Note: As of Amendment 028-03, only descriptive statistics based on available data is 
applicable for this section.  Both non-model based and model-based analysis will be 
performed on available data, as applicable.
Individual values will be listed for each PK parameter and the following (non-model-based) 
descriptive statistics will be provided: N (number of participants with nonmissing data), 
arithmetic mean, standard deviation, arithmetic percent CV (calculated as 100 x standard 
deviation/arithmetic mean), median, minimum, maximum, GM, and geometric percent CV 
(calculated as 100 x sqrt (exp(s2) - 1), where s2 is the observed variance on the natural log
scale).
ISL plasma concentrations from sparse PK sampling will be summarized by nominal 
timepoint with the following descriptive statistics: N (number of participants with 
nonmissing data), arithmetic mean, standard deviation, arithmetic percent CV (calculated as 
100 x standard deviation/arithmetic mean), median, minimum, maximum, GM, IQR 
(interquartile range), and geometric percent CV (calculated as: 100 x sqrt(exp(s2) - 1), where 
s2 is the observed variance on the natural log scale).
ISL PK data will also be added to the ISL population PK model along with data collected 
from other studies. The analysis plan for the population PK analysis will be described in a 
separate MAP.
9.6.1.1
Dose Confirmation
Note:  As of Amendment 028-03, this section is no longer applicable.
In the Intensive PK Cohort, posterior probabilities with a noninformative flat prior will be 
used to assess whether pediatric participants have acceptable PK. Acceptable PK is defined 
as follows:

A posterior probability that the true ISL steady-state plasma exposure (AUC0-24) in 
pediatric participants does not exceed 0.28 µM·hr (corresponding to the GM exposure 
simulated using the population PK model for adults at ISL 2.25 mg QD) at Day 28
greater than 90%

A posterior probability that the true ISL-TP steady-state PBMC trough concentration 
(C24) in pediatric participants exceeds 2.68 µM (or 0.54 pmol/106 cells)
(corresponding to the GM exposure simulated using the population PK model for 
adults at ISL 0.25 mg QD) at Day 28 greater than 90%
If the participants in the Intensive PK Cohort meet the acceptable PK definition and there are 
no safety concerns, then the ISL dose will be established.
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If any of the acceptable PK definitions are not met, then an intensive review of all PK, safety, 
and efficacy data will be conducted.
The simulation-based justification for the posterior probability thresholds is provided in 
Section 9.9.1.
9.6.2
Safety Analyses
Note: As of Amendment 028-03, only descriptive statistics based on available data is 
applicable for this section. Events that are described below as either Tier 1, 2, or 3 
events will now all be summarized descriptively.
Safety and tolerability will be assessed by clinical review of all relevant parameters including 
AEs, laboratory tests, and vital signs. The analysis of safety results will follow the strategy in 
Table 7 at Week 24, 48, and 96.
Adverse Events
Percentage of participants with AEs in the broad categories of: any AE, a drug-related AE, an
SAE, an AE, which is both drug-related and serious, a Grade 3 to 4 AE, an AE that is both 
Grade 3 to 4 and drug-related, discontinuation of study intervention due to an AE, 
discontinuation of study intervention due to a drug-related AE, an AE leading to deaths, and 
specific AEs occurring with an incidence ≥ 10% will be provided along with the 
corresponding 95% CIs (Table 7). The 95% CIs for the safety parameters will be estimated 
using the Clopper-Pearson method [Clopper, C. J. 1934].
Continuous Measures
For continuous measures such as changes from baseline in laboratory and vital signs, 
summary statistics for baseline, on-treatment, and change from baseline values will be 
provided (Table 7). Missing safety laboratory, or vital signs will be handled using the DAO 
approach, ie, any missing value will be excluded from the analysis, with the exception that a 
missing Day 1 result will be replaced with the value obtained at the most recent screening 
visit will be used as baseline, when available. If no baseline result is available, that 
participant will not be included in the summary.
For PDLC assessments, 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 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.
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Table 7
Analysis Strategy for Safety Parameters
Safety Endpoint
Within Group 95% CI
Descriptive Statistics
Any AE
X
X
Any Drug-Related AE 
X
X
Any SAE
X
X
Any Drug-Related SAE
X
X
Discontinuation due to an AE
X
X
Discontinuation due to a Drug-Related AE
X
X
Any Grade 3 to 4 AE
X
X
Any Grade 3 to 4 Drug-Related AE
X
X
Death
X
X
Specific AEs, SOCs or PDLCs occurring with an 
incidence ≥ 10%
X
X
Specific AEs, SOCs or PDLCs occurring with an 
incidence < 10%
X
Change from Baseline Results (Labs, Vital Signs)
X
AE=adverse event; CI=confidence interval; SAE=serious adverse event; SOC=System Organ Class; 
PDLC=Predefined Limit of Change; X = results will be provided.
95% CIs will be calculated using the Clopper-Pearson method [Clopper, C. J. 1934].
9.6.3
Efficacy Analyses
Note: As of Amendment 028-03, this section is no longer applicable. Only descriptive 
statistics for all available data is applicable for this section. 
Time Windows for Analyses
Table 8 lists the definition of time windows that will be used for the purposes of the 
statistical analyses and the target relative day for the scheduled visits. The last available on-
treatment measurement within a window will be used for analyses at a specific time point, 
unless otherwise specified. Results from additional time points beyond Week 96 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.
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Table 8
Definitions of Study Time Points for Analyses
Treatment Phase
Visit
Day-Range Rules
Target Daya
Baseline
Day 1
≤1
1
Treatment
Day 28
≥2 and ≤42
28
Week 8
≥43 and ≤84
57
Week 16
≥85 and ≤126
113
Week 24
≥127 and ≤210
169
Week 36
≥211 and ≤294
253
Week 48
≥295 and ≤378
337
Week 60
≥379 and ≤462
421
Week 72
≥463 and ≤546
505
Week 84
≥547 and ≤630
589
Week 96
≥631 and ≤714
673
a Relative days and target days are computed from the first day of study intervention.
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 discontinuations because of 
treatment-associated reasons including adverse events (regardless of relationship to 
study intervention) or lack of efficacy

Nonintermittent missing values due to premature discontinuations because of other 
reasons which are not related to treatment such as loss to follow-up, protocol 
violation, participant withdrew consent, etc.
Three approaches will be used to handle missing values (Table 9). The primary approach for 
the analysis of the percentage of participants with HIV-1 RNA ≥50 copies/mL and the 
percentage of participants with HIV-1 RNA<50 is the FDA snapshot approach [Food and 
Drug Administration (CBER) 2015]. Under this approach, virologic outcome will be defined 
according to the following categories:

HIV-1 RNA <50 copies/mL: Participants who have the last available on-treatment 
HIV-1 RNA measurement < 50 copies/mL within the analysis window specified in
Table 8 for the time point of interest.
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
HIV-1 RNA ≥50 copies/mL: This includes participants who:
1) Have the last available on-treatment HIV-1 RNA measurement 
≥50 copies/mL within analysis window specified in Table 8 for the timepoint 
of interest.
2) Do not have on-treatment HIV-1 RNA data in the window of interest and

Who discontinue study intervention due to lack of efficacy prior to or 
in the analysis window for the time point of interest, or

Who discontinue study intervention due to reasons other than lack of 
efficacy prior to or in the analysis window for the time point of interest 
and have the last available on-treatment HIV-1 RNA measurement 
≥50 copies/mL

No Virologic Data in Specified Analysis Time Window: This includes participants 
who do not have on-treatment HIV-1 RNA data in the window for the time point of 
interest because of the following:
1) Discontinued study intervention due to AE or death: This includes participants 
who discontinued because of an AE or death at any time point from Day 1 
through the time window if this resulted in no virologic data on-treatment 
during the specified window and have the last available on-treatment HIV-1 
RNA measurement <50 copies/mL
2) Discontinued study intervention for other reasons: This includes participants 
who discontinued study intervention 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.) prior to 
or in the analysis window for the time point of interest and have the last 
available on-treatment HIV-1 RNA measurement <50 copies/mL
3) On study intervention but missing data in window: Only data in the window 
can be used for participants remaining on study intervention. Participants 
should be classified as on study, but missing data in window regardless of the 
HIV-1 RNA results outside the analysis window for the time point of interest.
The number of participants classified as “HIV-1 RNA ≥50 copies/mL” according to the FDA 
snapshot algorithm defined above, divided by the number of participants in the FAS, is the 
percentage of participants with HIV-1 RNA ≥50 copies/mL at a timepoint. Similarly, the 
percentage of participants with HIV-1 RNA <50 copies/mL at a timepoint is calculated using 
the number of participants classified as “HIV-1 RNA <50 copies/mL” according to the FDA 
snapshot algorithm defined above, divided by the number of participants in the FAS.
A second approach, the missing data treated as treatment failure (M=F) approach, will be 
performed as a sensitivity analysis for the percentage of participants achieving HIV-1 RNA 
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<50 copies/mL. Under this approach, participants who 1) have at least 1 on-treatment HIV-1 
RNA measurement within the analysis window specified in Table 8 for the time point of 
interest and have the last available on-treatment measurement within the window HIV-1 
RNA measurement <50 copies/mL at the timepoint of interest, OR 2) are on study 
intervention and have no HIV-1 RNA measurements within the analysis window specified in 
Table 8 for the time point of interest and have both the immediately preceding and 
immediately subsequent on-treatment HIV-1 RNA measurements <50 copies/mL, will be 
classified as a virologic “success” at the timepoint of interest. Participants with other reasons 
for missing data will be classified as a virologic failure at the timepoint of interest.
A third approach, the OF approach will also be performed as a sensitivity analysis for the 
HIV-1 RNA measurement <50 copies/mL endpoint. Under this approach, participants with 
nonintermittent missing data who prematurely discontinue study intervention due to lack of 
efficacy or who discontinue treatment for other reasons and are failures (HIV-1 RNA 
≥50 copies/mL) at the time of study intervention discontinuation are considered as failures at 
timepoints thereafter. Participants who discontinue study intervention for reasons other than 
lack of efficacy and who are not failures at the time of study intervention discontinuation will 
be excluded from the analyses at subsequent timepoints. Participants with intermittent 
missing data will be considered as successes if both the immediately preceding and 
immediately subsequent on-treatment HIV-1 RNA measurements are <50 copies/mL; all 
other intermittent missing results will be imputed as failures.
Percentage of Participants With HIV-1 RNA ≥50 Copies/mL
The snapshot approach will be used as the primary approach to analysis with respect to the 
percentage of participants with HIV-1 RNA ≥50 copies/mL.
The percentage of participants with HIV-1 RNA ≥50 copies will be estimated at Weeks 24, 
48, and 96. For each time point of interest, the associated 95% CI will be calculated based on 
the exact binomial method proposed by Clopper and Pearson (1934) [Clopper, C. J. 1934]. 
Virologic response over all time points will also be summarized in a similar fashion.
Percentage of Participants with HIV-1 RNA <50 copies/mL
The snapshot approach will be used as the primary approach to analysis with respect to the 
percentage of participants with HIV-1 RNA <50 copies/mL. The percentage of participants 
with HIV-1 RNA <50 copies/mL will be estimated at Weeks 24, 48, and 96. For each time 
point of interest, the associated 95% CI will be calculated based on the exact binomial 
method proposed by Clopper and Pearson (1934) [Clopper, C. J. 1934]. Virologic response 
over all time points will also be summarized in a similar fashion. The supportive analysis 
using the OF approach (as defined above) will also be presented.
Change From Baseline in CD4+ T-cell Count
Change from baseline in CD4+ T-cell count will be summarized at Weeks 24, 48, and 96
with the associated 95% CI calculated based on the t-distribution (Table 9).
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The DAO approach will be used to handle missing data for these analyses. Under the DAO 
approach, participants must have both a baseline measurement and at least 1 postbaseline 
measurement within the analysis window specified in Table 8 for the time point of interest 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 LOCF and BOCF methods to account for 
missing data.
Clinically Significant Confirmed Viremia
The number of participants with confirmed virologic rebound or incomplete virologic 
response, as defined in Section 4.2.1.3.1, will be summarized.
Viral Drug Resistance
The number of participants in the resistance analysis subset with genotypic and/or phenotypic 
resistance to the study intervention will be summarized.
Table 9
Analysis Strategy for Key Efficacy Variables
Endpoint/Variable 
(Description, Time Point)
Primary vs 
Supportive 
Approach
Statistical Method
Analysis 
Population
Missing Data 
Approach
Percentage of participants with 
HIV-1 RNA ≥50 copies/mL at 
Weeks 24, 48, and 96
P (for the 
Virologically 
Suppressed 
Cohort)
95% CI 
(Clopper-Pearson)
FAS
Snapshota
Percentage of participants with 
HIV-1 RNA <50 copies/mL at 
Weeks 24, 48, and 96
P (for the 
Treatment-
Naïve Cohort)
S (for the 
Virologically 
Suppressed 
Cohort)
95% CI 
(Clopper-Pearson)
FAS
Snapshota
S
95% CI 
(Clopper-Pearson)
FAS
M=F 
S
95% CI 
(Clopper-Pearson)
FAS
OF 
Change from baseline in 
CD4+ T-cell counts at Weeks 
24, 48, and 96
P
95% CI 
(t-distribution)
FAS
DAO
S
95% CI 
(t-distribution)
FAS
LOCF
S
95% CI 
(t-distribution)
FAS
BOCF
BOCF=Baseline Observation Carried Forward; CI=confidence interval; DAO=Data As Observed; FAS=Full 
Analysis Set; FDA=Food and Drug Administration; HIV=human immunodeficiency virus; LOCF=Last 
Observation Carried Forward; OF= Observed Failure; P=Primary approach; RNA=ribonucleic acid; 
S=Supportive approach; vs=versus.
a Number of participants who meet the endpoint clinical response criteria over total number in the FAS.
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9.6.4
Palatability and Acceptability Assessment of the Tablet (Whole and Split)
Note:  As of Amendment 028-03, study intervention administration will have been 
discontinued, so descriptive statistics will be prepared on available data.
Each participant will rate the palatability and respond to questions on the acceptability of 
treatment with oral DOR/ISL FDC tablet as outlined in the SoA (Section 1.3). This 
assessment will be based on the 5-point facial hedonic scale (FHS), an expression scale 
depicting various degrees of pleasure as an assessment of palatability (Section 4.2.1.4 and 
Section 8.1.9).
Descriptive statistics will be used to summarize the palatability and acceptability responses 
by cohorts on Day 1 and Day 28 for full tablet, and on Week 24 for split tablet. Missing data 
will not be imputed, and the analyses will be based on observed data only. These analyses 
will be based on the APaT population.
9.7
Interim Analyses
An eDMC will review accumulating safety data throughout the study as detailed in the 
eDMC Charter and will make recommendations for discontinuation of the study or protocol 
modifications to an executive committee of the Sponsor (Appendix 1).
9.8
Multiplicity
There will be no multiplicity adjustments in the analysis of this study.
9.9
Sample Size Calculations
Note: As of Amendment 028-03, the study has closed to enrollment therefore the 
following sample size calculations are no longer applicable.
9.9.1
Sample Size for PK Analysis
The Intensive PK Cohort size is supported by clinical trial simulations using the ISL 
population PK model based on adult data (from MK-8591-001, 002, 003, 009, and 011) that 
indicated N=10 is required to estimate clearance in pediatric participants with adequate 
precision (relative standard error <30%).
In addition, the operating characteristics of posterior probability-based thresholds for 
acceptable PK (defined in 9.6.1.1) are provided below. With approximately 10 participants in 
Intensive PK Cohort:

Assuming the log scale SD of steady-state plasma ISL AUC0-24 in pediatric 
participants (<18 years of age, weighing ≥35 kg) is 0.285 after the administration of 
DOR/ISL (100 mg/0.75 mg) QD, if the true steady-state ISL AUC0-24 is 0.12 µM·hr, 
the probability that this PK endpoint will be deemed within the acceptable range is 
>99%. The true SS plasma ISL AUC0-24 can be as high as 0.23 µM·hr to still have a 
conclusion of acceptable PK with 80% probability.
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
Assuming the log scale SD of steady-state PBMC ISL-TP C24 in pediatric 
participants is 0.496 after the administration of DOR/ISL (100 mg/0.75 mg) QD, if 
the true SS PBMC ISL-TP C24 is 11.22 µM (2.24 pmol/106 cells), the probability that 
this PK endpoint will be deemed within the acceptable range is >99%. The true SS 
PBMC ISL-TP C24 can be as low as 3.76 µM (0.75 pmol/106 cells) to still have a 
conclusion of acceptable PK with 80% probability.
9.9.2
Sample Size for Safety Analysis
The probability of observing at least 1 of a particular type of AE in this study depends on the 
number of participants treated and the underlying percentage of participants with that AE in 
the study population.
If the underlying incidence of a particular AE is 1% (1 of every 100 participants receiving 
DOR/ISL), there is a 36.4% chance of observing at least 1 of that particular AE among the 45
participants in the study. If no AE of that particular type is observed among the 45
participants in the study, this study will provide 97.5% confidence that the underlying 
percentage of participants with that particular AE is <6.4% (1 in every 16 participants).
The estimate of and the upper bound of the 95% CI for the underlying percentage of 
participants with a particular AE given various hypothetical observed numbers of participants 
with the AE are provided in Table 10. These calculations are based on the exact binomial 
method proposed by Clopper and Pearson [Clopper, C. J. 1934].
Table 10
Estimate of Incidence of AEs and 95% Upper Confidence Bound Based on
Hypothetical Numbers of Participants with AEs
Hypothetical Number of Participants 
with an AE 
(Estimate of Incidence, %)
95% Upper Confidence Bounda
N=30
(Virologically 
Suppressed Cohort)
0 (0)
9.5
1 (3.3)
17.2
2 (6.7)
22.1
3 (10.0)
26.5
N=15
(Treatment-Naïve 
Cohort)
0 (0)
18.1
1 (6.7)
31.9
2 (13.3)
40.5
3 (20.0)
48.1
N=45
(Pooled)
0 (0)
6.4
1 (2.2)
11.8
3 (6.7)
18.3
5 (11.1)
24.1
AE=adverse event; CI=confidence interval.
a Based on the 2-tailed exact CI for a binomial proportion (Clopper and Pearson method [Clopper, C. J. 1934]). In the 0 
event case, the 95% CI is one sided (α=0.05 all in the upper tail).
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9.9.3
Sample Size for Efficacy Analysis
The key efficacy objective for the Virologically Suppressed Cohort will be assessed based on 
the percentage of participants with HIV-1 RNA ≥50 copies/mL at Week 24. The anticipated
virologic failure rate for the study population is approximately 2%. With 30 participants, the 
maximum half-width of the 95% exact CI will be no greater than 19%. The calculation is 
based on the exact binomial method proposed by Clopper and Pearson [Clopper, C. J. 1934]
and is performed using SAS v9.4. Table 11 shows the 95% CIs for percentage of participants 
with HIV-1 RNA ≥50 copies/mL given varying assumptions of numbers of responders in 30
participants. Note that the intervals are not symmetric around the point estimate.
Table 11
Two-Sided 95% CIs for the Percentage of Participants With HIV-1 RNA ≥50
copies/mL at Week 24 (FAS)
Number of Responsesa (%)
Two-Sided 95% CIb
N=30
(Virologically 
Suppressed Cohort)
0 (0)
(0, 9.5)
1 (3.3)
(0.1, 17.2)
2 (6.7)
(0.8, 22.1)
3 (10.0)
(2.1, 26.5)
4 (13.3)
(3.8, 30.7)
a.
CI=confidence interval; FAS=full analysis set; HIV=human immunodeficiency virus.
b.
a Based on FDA snapshot approach; response refers to participants with HIV-1 RNA≥50 copies/mL.
b Based on the 2-tailed exact CI for a binomial proportion (Clopper and Pearson method [Clopper, C. J. 
1934]). In the 0-event case, the 95% CI is one sided (α=0.05 all in the upper tail).
The key efficacy objective for the Treatment-Naïve Cohort will be assessed based on the 
percentage of participants with HIV-1 RNA <50 copies/mL at Week 24. The anticipated rate 
of participants with HIV-1 RNA <50 copies/mL for the study population is approximately 
80% to 90%, based on experience from MK-8591 Protocol 011 and assuming DOR/ISL will 
be similarly active in adults and pediatric participants. With 15 participants, the maximum 
half-width of the 95% exact CI will be no greater than 26%. The calculation is based on the 
exact binomial method proposed by Clopper and Pearson [Clopper, C. J. 1934] and is 
performed using SAS v9.4. Table 12 shows the 95% CIs for percentage of participants with 
HIV-1 RNA <50 copies/mL given varying assumptions of numbers of responders in 15
participants. Note that the intervals are not symmetric around the point estimate.
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Table 12
Two-Sided 95% CIs for the Percentage of Participants With HIV-1 RNA <50
copies/mL at Week 24 (FAS)
Number of Responsesa (%)
Two-Sided 95% CIb
N=15
(Treatment-Naïve 
Cohort)
10 (66.7)
(38.4, 88.2)
11 (73.3)
(44.9, 92.2)
12 (80.0)
(51.9, 95.7)
13 (86.7)
(59.5, 98.3)
14 (93.3)
(68.1, 99.8)
c.
CI=confidence interval; FAS=full analysis set; HIV=human immunodeficiency virus.
d.
a Response refers to participants with HIV-1 RNA<50 copies/mL.
b Based on the 2-tailed exact CI for a binomial proportion (Clopper and Pearson method [Clopper, C. J. 
1934]).
9.10
Subgroup Analyses
Note: As of Amendment 028-03, subgroup analyses will no longer be conducted.
To assess the consistency of the response across various subgroups, the percentage of 
participants with HIV-1 RNA ≥50 copies/mL (Virologically Suppressed Cohort only) and
HIV-1 RNA <50 copies/mL, and associated 95% CIs will be estimated within each category 
of the following classification variables:

Age category (≤ median, > median)

Sex at birth

Gender identity

Region (North America, South America, Europe, Asia, Africa, etc.)
The consistency of the response will be assessed descriptively via summary statistics by 
category for the classification variables listed above as applicable based on the number 
available in each potential subgroup. Other clinically relevant variables may be identified for
which additional subgroup analyses may be performed. Subgroup summaries will be 
presented separately for the Virologically Suppressed and Treatment-Naïve Cohorts.
9.11
Compliance (Medication Adherence)
In this study, as part of the routine recording of the amount of study intervention taken by 
each participant in the study intervention CRF page, the number of tablets remaining in study 
packaging will be counted and reviewed at regular intervals.
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For the main analysis of compliance in this study, a day within the study will be considered 
an “On Therapy” day if the participant takes at least 1 tablet from any bottle provided for this 
study.
The “Number of Days Should be on Therapy” is the total number of days from Day 1 to the 
date of the last dose of study intervention for each participant. As such, the “Number of Days 
Should be on Therapy” will be the number of days from Day 1 to the date of the scheduled 
Week 96 visit for those participants who are on study intervention for the entire study period. 
For participants who discontinue study intervention early (ie, prior to completion of the study 
at Week 96), 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 for the FAS and will be presented 
separately for the Virologically Suppressed and Treatment-Naïve Cohorts.
9.12
Extent of Exposure
The extent of exposure to study intervention will be evaluated by summary statistics (N, 
mean, and range) for the “Number of Days on Therapy”.
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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 and Dohme Corp., a subsidiary of Merck & Co., Inc. (MSD)
Code of Conduct for Interventional Clinical Trials
I. Introduction
A. Purpose
MSD, through its subsidiaries, conducts clinical trials worldwide to evaluate the safety and effectiveness of our 
products. As such, we are committed to designing, implementing, conducting, analyzing, and reporting these trials 
in compliance with the highest ethical and scientific standards. Protection of participants in clinical trials is the 
overriding concern in the design and conduct of clinical trials. In all cases, MSD clinical trials will be conducted 
in compliance with local and/or national regulations (including all applicable data protection 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
The Sponsor will conduct this study in compliance with all applicable data protection 
regulations.
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Participants will be assigned a unique identifier by the Sponsor. Any participant records or 
datasets that are transferred to the Sponsor will contain the identifier only; participant names 
or any information that would make the participant identifiable will not be transferred.
The participant must be informed that his/her personal study-related data will be used by the 
Sponsor in accordance with local data protection law. The level of disclosure must also be 
explained to the participant. 
The participant must be informed that his/her medical records may be examined by Clinical 
Quality Assurance auditors or other authorized personnel appointed by the Sponsor, by 
appropriate IRB/IEC members, and by inspectors from regulatory authorities.
10.1.3.1
Confidentiality of Data
By signing this protocol, the investigator affirms to the Sponsor that information furnished to 
the investigator by the Sponsor will be maintained in confidence, and such information will 
be divulged to the IRB, IEC, or similar or expert committee; affiliated institution and 
employees, only under an appropriate understanding of confidentiality with such board or 
committee, affiliated institution and employees. Data generated by this study will be 
considered confidential by the investigator, except to the extent that it is included in a 
publication as provided in the Publications section of this protocol.
10.1.3.2
Confidentiality of Participant Records
By signing this protocol, the investigator agrees that the Sponsor (or Sponsor representative), 
IRB/IEC, or regulatory authority representatives may consult and/or copy study documents to 
verify worksheet/CRF data. By signing the consent form, the participant agrees to this 
process. If study documents will be photocopied during the process of verifying 
worksheet/CRF information, the participant will be identified by unique code only; full 
names/initials will be masked prior to transmission to the Sponsor.
By signing this protocol, the investigator agrees to treat all participant data used and 
disclosed in connection with this study in accordance with all applicable privacy laws, rules 
and regulations.
10.1.3.3
Confidentiality of IRB/IEC Information
The Sponsor is required to record the name and address of each IRB/IEC that reviews and 
approves this study. The Sponsor is also required to document that each IRB/IEC meets 
regulatory and ICH GCP requirements by requesting and maintaining records of the names 
and qualifications of the IRB/IEC members and to make these records available for 
regulatory agency review upon request by those agencies.
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10.1.4
Committees Structure
10.1.4.1
Executive Oversight Committee
The EOC is comprised of members of Sponsor Senior Management. The EOC will receive 
and decide upon any recommendations made by the DMC regarding the study.
10.1.4.2
External Data Monitoring Committee
To supplement the routine study monitoring outlined in this protocol, an external DMC will 
monitor the interim data from this study. The voting members of the committee are external 
to the Sponsor. The members of the DMC must not be involved with the study in any other 
way (eg, they cannot be study investigators) and must have no competing interests that could 
affect their roles with respect to the study.
The DMC will make recommendations to the EOC regarding steps to ensure both participant 
safety and the continued ethical integrity of the study. Also, the DMC will review interim 
study results, consider the overall risk and benefit to study participants (Section 9.7 [Interim 
Analysis]) and recommend to the EOC whether the study should continue in accordance with 
the protocol.
Specific details regarding composition, responsibilities, and governance, including the roles 
and responsibilities of the various members and the Sponsor protocol team ; meeting 
facilitation; the study governance structure; and requirements for and proper documentation 
of DMC reports, minutes, and recommendations will be described in the DMC charter that is 
reviewed and approved by all the DMC members.
10.1.5
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 FDAAA of 2007 and the EMA clinical trial Directive 2001/20/EC, the 
Sponsor of the study is solely responsible for determining whether the study and its results 
are subject to the requirements for submission to http://www.clinicaltrials.gov, 
www.clinicaltrialsregister.eu or other local registries. MSD, as Sponsor of this study, will 
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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 Council on Harmonisation of Technical Requirements for Registration of 
Pharmaceuticals for Human Use GCP: Consolidated Guideline and other generally accepted 
standards of GCP); and all applicable federal, state and local laws, rules and regulations 
relating to the conduct of the clinical study.
The Code of Conduct, a collection of goals and considerations that govern the ethical and 
scientific conduct of clinical investigations sponsored by MSD, is provided in this appendix 
under the Code of Conduct for Clinical Trials.
The investigator agrees not to seek reimbursement from participants, their insurance 
providers, or from government programs for procedures included as part of the study 
reimbursed to the investigator by the Sponsor.
The investigator will promptly inform the Sponsor of any regulatory authority inspection 
conducted for this study.
The investigator agrees to provide the Sponsor with relevant information from inspection 
observations/findings to allow the Sponsor to assist in responding to any citations resulting 
from regulatory authority inspection and will provide the Sponsor with a copy of the 
proposed response for consultation before submission to the regulatory authority. 
Persons debarred from conducting or working on clinical studies by any court or regulatory 
authority will not be allowed to conduct or work on this Sponsor’s studies. The investigator 
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.
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10.1.8
Data Quality Assurance
All participant data relating to the study will be recorded on printed or electronic CRF unless 
transmitted to the Sponsor or designee electronically (eg, laboratory data). The investigator 
or qualified designee is responsible for verifying that data entries are accurate and correct by 
physically or electronically signing the CRF.
Detailed information regarding Data Management procedures for this protocol will be 
provided separately.
The investigator must maintain accurate documentation (source data) that supports the 
information entered in the CRF.
The investigator must permit study-related monitoring, audits, IRB/IEC review, and 
regulatory agency inspections and provide direct access to source data documents.
Study documentation will be promptly and fully disclosed to the Sponsor by the investigator 
upon request and also shall be made available at the study site upon request for inspection, 
copying, review, and audit at reasonable times by representatives of the Sponsor or any 
regulatory authorities. The investigator agrees to promptly take any reasonable steps that are 
requested by the Sponsor or any regulatory authorities as a result of an audit or inspection to 
cure deficiencies in the study documentation and worksheets/CRFs.
The Sponsor or designee is responsible for the data management of this study including 
quality checking of the data.
Study monitors will perform ongoing source data review and verification to confirm that data 
entered into the CRF by authorized site personnel are accurate, complete, and verifiable from 
source documents; that the safety and rights of participants are being protected; and that the 
study is being conducted in accordance with the currently approved protocol and any other 
study agreements, ICH GCP, and all applicable regulatory requirements.
Records and documents, including participant's 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 
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traceable, should not obscure the original entry, and should be explained if necessary (eg, via 
an audit trail). Source documents are filed at the investigator’s site.
Data reported on the CRF or entered in the eCRF that are transcribed from source documents 
must be consistent with the source documents or the discrepancies must be explained. The 
investigator/institution may need to request previous medical records or transfer records, 
depending on the study. Also, current medical records must be available.
10.1.10
Study and Site Closure
The Sponsor or its designee may stop the study or study site participation in the study for 
medical, safety, regulatory, administrative, or other reasons consistent with applicable laws, 
regulations, and GCP.
In the event the Sponsor prematurely terminates a particular study site, the Sponsor or 
designee will promptly notify that study site’s IRB/IEC as specified by applicable regulatory 
requirement(s).
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10.2
Appendix 2: Clinical Laboratory Tests
The tests detailed in Table 13 will be performed by the central laboratory.

Local laboratory results are only required if the central laboratory results are not available 
in time for either study intervention administration (including Day 1), 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.

Any laboratory test results related to study endpoints (eg, HIV-1 RNA and CD4+ T-cell 
counts) must be provided by the central laboratory.

Additional tests may be performed at any time during the study as determined necessary 
by the investigator or required by local regulations.
Pregnancy testing:
Pregnancy testing requirements for study inclusion are described in Section 5.1. 
Additional serum or urine pregnancy tests may be performed, as determined necessary by 
the investigator or required by local regulation, to establish the absence of pregnancy at 
any time during the subject's participation in the study.
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Table 13
Protocol-required Laboratory Assessments
Laboratory 
Assessments
Parameters
Hematology
Platelet Count 
RBC Indices:
Mean corpuscular volume (MCV)
Mean corpuscular hemoglobin (MCH)
MCH concentration
Red Cell Distribution Width (RDW)
White Blood Cell 
(WBC) count with 
Differential:
Neutrophils
Lymphocytes
Monocytes
Eosinophils
Basophils
RBC Count
Hemoglobin
Hematocrit
CD4+ T-cell/(T-
Cell and B-Cell 
and Natural Killer 
Cell) TBNK panel
CD3+CD4+ T cell Count
CD3+CD8+ T cell Count
CD4/CD8 ratio
CD3+ CD45+
CD3- CD19+
CD16+ CD56+
CD3+CD4+ CD8+
Coagulation
Prothrombin time (PT)/ international normalized ratio (INR)
Chemistry
(nonfasting)
Blood Urea 
Nitrogen (BUN)
Potassium
Aspartate 
Aminotransferase
(AST)
Total bilirubin

Direct bilirubin

Indirect bilirubin
Albumin
Bicarbonate
Chloride
Phosphorous
Creatinine
Sodium
Alanine 
Aminotransferase
(ALT)
Total Protein
Glucose 
(nonfasting)
Calcium
Alkaline 
phosphatase
estimated Glomerular 
Filtration Rate (eGFR)
Creatinine Kinase
Lipase
Amylase
Magnesium
Additional 
Chemistry at 
fasting visits 
(fasting for at least 
8h)
Glucose [fasting]
High-density lipoprotein (HDL-C)
Low-density lipoprotein (LDL-C)
Triglycerides (TGs)
Total Cholesterol (TC)
Non-HDL-C
Routine Urinalysis
Specific gravity
pH, glucose, protein, blood, ketones, bilirubin, urobilinogen, nitrite, leukocyte esterase
Pregnancy testing
Serum (conducted by central lab) and urine (conducted by local lab) β human chorionic 
gonadotropin (β hCG) pregnancy test (for a woman/women of childbearing potential 
[WOCBP])
Hepatitis 
screening and 
monitoringa
Hepatitis B virus surface antigen (HBsAg)
Hepatitis B virus (HBV) surface antibody
AntiHBc (hepatitis B core antibody)
HBV DNA
Hepatitis C antibody (if positive perform plasma hepatitis C virus quantitative test- not 
required for study inclusion) 
Human 
immunodeficiency 
virus-1 (HIV-1) 
serology
HIV 1/2 antibody test
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Laboratory 
Assessments
Parameters
Virology
HIV-1 viral ribonucleic acid (RNA) quantification (RealTime polymerase chain 
reaction [PCR])
HIV-1 viral resistance
Proviral DNA archive resistance testing
Pharmacokinetics 
(PK)
Islatravir (ISL) Sparse PK, Intensive PK, and Investigational PKb
ISL-triphosphate in PBMCs (Intensive PK Cohort only)
a All participants will be screened for HBsAg, HBV surface antibody, antiHBc and HBV DNA. Participants 
that are antiHBc positive, but HBV DNA negative will have HBsAg and HBV DNA monitored for the 
duration of the study.
b Investigational PK samples will be collected per the SoA (Section 1.3). Analysis of these samples will be 
triggered by the Sponsor as needed.
The investigator (or medically qualified designee) must document their review of each 
laboratory safety report.
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Table 14
Estimated Blood Volumes
Note: As of Amendment 028-03, Table 14 is no longer applicable. Table 15 outlines the blood volume collection for the 
remainder of the study per the SoA in Sections 1.3.2 and 1.3.3. 
Visit Number
1
2
3
4
5
6
7
8
9
10
11
12
13
Viremia 
Confirmation
Treatment 
Discontinuation
End of Treatment 
Follow-up 
Scheduled Day/Week 
Screening
Day 1 
(Fasting)
Day 14 
Phone Call
Day 28
Week 8
Week 16
Week 24
Week 36
Week 48 
(Fasting)
Week 60
Week 72
Week 84
Week 96 
(Fasting)
Visit Window
≤45 
days
NA
±4 
days
+14 
days
±7 days
w/in 2-4 
wks of 
Viremia
NA
42 
(+7) 
days 
after 
EOT
Blood Parameter
Approximate Blood Volume (mL)
Blood (Plasma) HIV-1 RNA 
Quantification (Real Time PCR) 
6
6
6
6
6
6
6
6
6
6
6
6
6
6
6
CD4+ T-cell Count
4
4
4
4
4
4
Blood (Plasma) for HIV Viral 
Drug Resistance Testinga
12
6
6
6
6
6
6
6
6
6
6
6
12
12
6
Serology: HIV-1 & 2; Hepatitis 
(B and C)
5
HIV-1 Confirmation
1
HCV RNA (perform only if 
hepatitis C antibody positive -
not required for study inclusion) 
6
PT/INR 2.7 mL 
2.7
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Visit Number
1
2
3
4
5
6
7
8
9
10
11
12
13
Viremia 
Confirmation
Treatment 
Discontinuation
End of Treatment 
Follow-up 
Scheduled Day/Week 
Screening
Day 1 
(Fasting)
Day 14 
Phone Call
Day 28
Week 8
Week 16
Week 24
Week 36
Week 48 
(Fasting)
Week 60
Week 72
Week 84
Week 96 
(Fasting)
Visit Window
≤45 
days
NA
±4 
days
+14 
days
±7 days
w/in 2-4 
wks of 
Viremia
NA
42 
(+7) 
days 
after 
EOT
HBsAg (as required, at baseline 
part of Serology 2 mL)b
2
2
2
2
2
2
2
2
2
2
2
HBV DNA (as required)
6
6
6
6
6
6
6
6
6
6
6
6
Chemistry (after baseline, 
additional 2 mL is required if 
serum pregnancy needed)
3
3
3
3
3
3
3
3
3
3
3
3
3
3
Hematology
1
1
1
1
1
1
1
1
1
1
1
1
1
1
Blood (Plasma) for Sparse ISL 
PK
2
2
2
2
4
2
4
2
2
2
2
Blood (Plasma) for 
Investigational PK
2
2
Whole Blood for Proviral DNA 
Archive Resistance Testing
4
Maximum Total Blood 
Volume per Visit in mL (not in 
Intensive PK Cohort)
40.7
36
0
26
26
26
32
26
32
26
26
26
30
24
28
16
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Visit Number
1
2
3
4
5
6
7
8
9
10
11
12
13
Viremia 
Confirmation
Treatment 
Discontinuation
End of Treatment 
Follow-up 
Scheduled Day/Week 
Screening
Day 1 
(Fasting)
Day 14 
Phone Call
Day 28
Week 8
Week 16
Week 24
Week 36
Week 48 
(Fasting)
Week 60
Week 72
Week 84
Week 96 
(Fasting)
Visit Window
≤45 
days
NA
±4 
days
+14 
days
±7 days
w/in 2-4 
wks of 
Viremia
NA
42 
(+7) 
days 
after 
EOT
Pharmacokinetic Samples Intensive PK Cohort
Blood (Plasma) for Intensive 
ISLc
16
Blood (PBMC) for ISL-TP PK
24
Total Blood Volume per Visit 
in mL (Intensive PK Cohort)
40.7
36
0
64
26
26
32
26
32
26
26
26
30
24
28
16
Maximum Blood Volume in 
mL (Intensive PK Cohort) for 
Study Duration
459
Maximum Blood Volume in 
mL 
(Participants not in Intensive 
PK Cohort) for Study 
Duration
421
a Screening collection is only required in Treatment-Naïve Cohort (n=15)
b indicates collection only in participants meeting certain criteria (HCV RNA, HBsAg and HBV DNA)
c Day 28 Plasma for Intensive ISL PK total is 16 mL (2 mL noted for Sparse PK is not duplicated for Intensive PK Cohort)
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Table 15
Estimated Blood Volumes for Early Discontinuation of Treatment, End of Treatment Follow-up, and Extended Monitoring
of CD4+ T-cell and/or Lymphocyte Counts
Visit Name
Treatment Discontinuation
End of Treatment Follow-up
Extended Monitoring of CD4+ T-cell and/or 
Lymphocyte Counts
Visit Window
NA
42 (+7) days after EOT
4 to 6 weeks
Blood Parameter
Approximate Blood Volume (mL)
CD4+ T-cell/TBNK Count
4
4
4
Blood (Plasma) for HIV Viral 
Drug Resistance Testinga
12
6
Chemistry
(Additional 2 mL is required if 
serum pregnancy needed)
3
Hematology
1
1
1
Blood (Plasma) for 
Investigational PK
2
2
2 a
Maximum Total Blood Volume 
per Visit in mL 
22
13
5b
Maximum Blood Volume in 
mL for those who end at End 
of Treatment Follow-up
35
Maximum Blood Volume in 
mL for those who require 
extended monitoringa
67
a Taken at the first monitoring visit only
b For 6 blood draws for those who qualify for extended monitoring for 6 months (5 mL per month).  Total of 7 mL at the first monitoring visit only.  
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10.3
Appendix 3: Adverse Events: Definitions and Procedures for Recording, 
Evaluating, Follow-up, and Reporting
10.3.1
Definition of AE
AE definition
An AE is any untoward medical occurrence in a clinical study participant, temporally 
associated with the use of study intervention, whether or not considered related to the 
study intervention.
NOTE: An AE can therefore be any unfavorable and unintended sign (including an 
abnormal laboratory finding), symptom, or disease (new or exacerbated) temporally 
associated with the use of a study intervention.
NOTE: For purposes of AE definition, study intervention (also referred to as Sponsor’s 
product) includes any pharmaceutical product, biological product, vaccine, diagnostic 
agent, medical device, combination product, or protocol specified procedure whether 
investigational or marketed (including placebo, active comparator product, or run-in 
intervention), manufactured by, licensed by, provided by, or distributed by the Sponsor 
for human use in this study.
Events meeting the AE definition
Any abnormal laboratory test results (hematology, clinical chemistry, or urinalysis) or 
other safety assessments (eg, ECG, radiological scans, vital signs measurements), 
including those that worsen from baseline, considered clinically significant in the medical 
and scientific judgment of the investigator.
Exacerbation of a chronic or intermittent pre-existing condition including either an 
increase in frequency and/or intensity of the condition.
New conditions detected or diagnosed after study intervention administration even 
though it may have been present before the start of the study.
Note: Congenital disorders (eg, present from birth) not detected or diagnosed prior to 
study intervention administration do not qualify for reporting as AE.
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.”
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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?
◦
If yes, did the AE resolve or improve?
◦
If yes, this is a positive dechallenge.
◦
If no, this is a negative dechallenge.
(Note: This criterion is not applicable if: (1) the AE resulted in death or permanent 
disability; (2) the AE resolved/improved despite continuation of the Sponsor’s 
product; (3) the study is a single-dose drug study; or (4) Sponsor’s product(s) is/are 
only used 1 time.)
- Rechallenge: Was the participant re-exposed to the Sponsor’s product in this study?
◦
If yes, did the AE recur or worsen?
◦
If yes, this is a positive rechallenge.
◦
If no, this is a negative rechallenge.
(Note: This criterion is not applicable if: (1) the initial AE resulted in death or 
permanent disability, or (2) the study is a single-dose drug study; or (3) Sponsor’s 
product(s) is/are used only 1 time.)
NOTE: IF A RECHALLENGE IS PLANNED FOR AN AE THAT WAS SERIOUS AND 
MAY HAVE BEEN CAUSED BY THE SPONSOR’S PRODUCT, OR IF RE-EXPOSURE 
TO THE SPONSOR’S PRODUCT POSES ADDITIONAL POTENTIAL SIGNIFICANT 
RISK TO THE PARTICIPANT THEN THE RECHALLENGE MUST BE APPROVED IN 
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:
◦
There is evidence of exposure to the Sponsor’s product. The temporal sequence 
of the AE onset relative to the administration of the Sponsor’s product is 
reasonable. The AE is more likely explained by the Sponsor’s product than by 
another cause.
- No, there is not a reasonable possibility of Sponsor’s product relationship:
◦
Participant did not receive the Sponsor’s product OR temporal sequence of the 
AE onset relative to administration of the Sponsor’s product is not reasonable 
OR the AE is more likely explained by another cause than the Sponsor’s 
product. (Also entered for a participant with overdose without an associated 
AE.)
For each AE/SAE, the investigator must document in the medical notes that he/she has 
reviewed the AE/SAE and has provided an assessment of causality.
There may be situations in which an SAE has occurred and the investigator has minimal 
information to include in the initial report to the Sponsor. However, it is very important 
that the investigator always make an assessment of causality for every event before the 
initial transmission of the SAE data to the Sponsor.
The investigator may change his/her opinion of causality in light of follow-up 
information and send an SAE follow-up report with the updated causality assessment.
The causality assessment is 1 of the criteria used when determining regulatory reporting 
requirements.
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.
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New or updated information will be recorded in the CRF.
The investigator will submit any updated SAE data to the Sponsor within 24 hours of 
receipt of the information.
10.3.5
Reporting of AEs, SAEs, and Other Reportable Safety Events to the Sponsor
AE, SAE, and other reportable safety event reporting to Sponsor via electronic data 
collection tool
The primary mechanism for reporting to the Sponsor will be the EDC tool.
-
Electronic reporting procedures can be found in the EDC data entry guidelines (or 
equivalent).
-
If the electronic system is unavailable for more than 24 hours, then the site will 
use the paper AE Reporting form.
◦
Reference Section 8.4.1 for reporting time requirements.
The site will enter the SAE data into the electronic system as soon as it becomes 
available.
After the study is completed at a given site, the EDC tool will be taken off-line to prevent 
the entry of new data or changes to existing data.
If a site receives a report of a new SAE from a study participant or receives updated data 
on a previously reported SAE after the EDC tool has been taken off-line, then the site can 
report this information on a paper SAE form or by telephone (see next section).
Contacts for SAE reporting can be found in the Investigator Study File Binder (or 
equivalent).
SAE reporting to the Sponsor via paper CRF
If the EDC tool is not operational, facsimile transmission or secure e-mail of the SAE 
paper CRF is the preferred method to transmit this information to the Sponsor.
In rare circumstances and in the absence of facsimile equipment, notification by 
telephone is acceptable with a copy of the SAE data collection tool sent by overnight 
mail or courier service.
Initial notification via telephone does not replace the need for the investigator to 
complete and sign the SAE CRF pages within the designated reporting time frames.
Contacts and instructions for SAE reporting and paper reporting procedures can be found 
in the Investigator Study File Binder (or equivalent).
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10.4
Appendix 4: Device Events, Adverse Device Events, and Medical Device 
Incidents: Definitions, Collection, and Documentation
This appendix is not applicable.
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10.5
Appendix 5: Contraceptive Guidance
10.5.1
Definitions
Women of Childbearing Potential (WOCBP)
A woman (including a transgender male who is assigned female sex at birth) is considered 
fertile following menarche and until becoming postmenopausal unless permanently sterile 
(see below):
If fertility is unclear (eg, amenorrhea in adolescents or athletes) and a menstrual cycle cannot 
be confirmed before first dose of study intervention, additional evaluation should be 
considered.
Women in the following categories are not considered WOCBP:
Transgender women (assigned male sex at birth)
Premenarchal
Premenopausal female with 1 of the following:
- Documented hysterectomy
- Documented bilateral salpingectomy
- Documented bilateral oophorectomy
For individuals with permanent infertility due to an alternate medical cause other than the 
above (eg, Mullerian agenesis, androgen insensitivity), investigator discretion should be 
applied to determining study entry.
Note: Documentation can come from the site personnel’s review of the participant’s 
medical records, medical examination, or medical history interview.
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10.5.2
Contraception Requirements
Contraceptives allowed during the study includea:
Highly Effective Contraceptive Methods That Have Low User Dependencyb
Failure rate of <1% per year when used consistently and correctly.
Progestogen- only contraceptive implantc,d
IUSc,d,e
Non-hormonal IUD
Bilateral tubal occlusion
Azoospermic partner (vasectomized or secondary to medical cause)
This is a highly effective contraception method provided that the partner is the sole male sexual partner of 
the WOCBP and the absence of sperm has been confirmed. If not, an additional highly effective method 
of contraception should be used. A spermatogenesis cycle is approximately 90 days.
Note: Documentation of azoospermia can come from the site personnel’s review of the participant’s 
medical records, medical examination, or medical history interview.
Highly Effective Contraceptive Methods That Are User Dependentb
Failure rate of <1% per year when used consistently and correctly.
Combined (estrogen- and progestogen- containing) hormonal contraceptionc,d
- Oral
- Intravaginal
- Transdermal
- Injectable
Progestogen-only hormonal contraceptionc,d
- 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 8.8 will be 
used in various experiments to understand:
◦
The biology of how drugs/vaccines work
◦
Biomarkers responsible for how a drug/vaccine enters and is removed by the body
◦
Other pathways with which drugs/vaccines may interact
◦
The biology of disease
The specimen(s) may be used for future assay development and/or drug/vaccine 
development.
It is now well recognized that information obtained from studying and testing clinical 
specimens offers unique opportunities to enhance our understanding of how individuals 
respond to drugs/vaccines, enhance our understanding of human disease and ultimately 
improve public health through development of novel treatments targeted to populations 
with the greatest need. All specimens will be used by the Sponsor or those working for or 
with the Sponsor.
3. Summary of Procedures for Future Biomedical Research.
a.
Participants for Enrollment
All participants enrolled in the clinical study will be considered for enrollment in future 
biomedical research.
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b. Informed Consent
Informed consent for specimens (ie, DNA, RNA, protein, etc.) will be obtained during 
screening for protocol enrollment from all participants or legal guardians, at a study visit 
by the investigator or his or her designate. Informed consent for future biomedical 
research should be presented to the participants on the visit designated in the SoA. If 
delayed, present consent at next possible Participant Visit. Consent forms signed by the 
participant will be kept at the clinical study site under secure storage for regulatory 
reasons.
A template of each study site’s approved informed consent will be stored in the Sponsor’s 
clinical document repository.
c.
eCRF Documentation for Future Biomedical Research Specimens
Documentation of participant consent for future biomedical research will be captured in 
the eCRFs. Any specimens for which such an informed consent cannot be verified will be 
destroyed.
d. Future Biomedical Research Specimen(s)
Collection of specimens for future biomedical research will be performed as outlined in 
the SoA. In general, if additional blood specimens are being collected for future 
biomedical research, these will usually be obtained at a time when the participant is 
having blood drawn for other study purposes.
4. Confidential Participant Information for Future Biomedical Research
In order to optimize the research that can be conducted with future biomedical research 
specimens, it is critical to link 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@merck.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@merck.com.
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13. References
1. National Cancer Institute [Internet]: Available from 
https://www.cancer.gov/publications/dictionaries/cancer-terms?cdrid=45618
2. International Conference on Harmonization [Internet]: E15: Definitions for Genomic 
Biomarkers, Pharmacogenomics, Pharmacogenetics, Genomic Data and Sample 
Coding Categories. Available from 
http://www.ich.org/products/guidelines/efficacy/efficacy-single/article/definitions-
for-genomic-biomarkers-pharmacogenomics-pharmacogenetics-genomic-data-and-
sample-cod.html 
3. Industry Pharmacogenomics Working Group [Internet]: Understanding the Intent, 
Scope and Public Health Benefits of Exploratory Biomarker Research: A Guide for 
IRBs/IECs and Investigational Site Staff. Available at http://i-pwg.org/ 
4. Industry Pharmacogenomics Working Group [Internet]: Pharmacogenomics 
Informational Brochure for IRBs/IECs and Investigational Site Staff. Available at 
http://i-pwg.org/
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10.7
Appendix 7: Country-specific Requirements
10.7.1
Country-specific Requirement for Russia
In Russia, only participants ≥12 to <18 years of age weighing ≥35 kg at the time of signing 
the informed consent/assent will be enrolled in this study.
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10.8
Appendix 8: Calculation of Estimated Glomerular Filtration Rate
Schwartz Bedside equation [Schwartz, G. J. 2009]:
eGFR = 0.413 X Height (cm)/Scr

eGFR (estimated glomerular filtration rate) in units of mL/min/1.73 m2

Scr (standardized serum creatinine) in units of mg/dL
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10.9
Appendix 9: Abbreviations
Abbreviation
Expanded Term
3TC
lamivudine
AE
adverse event 
AIDS
acquired immunodeficiency syndrome
ALT
alanine aminotransferase
ANCOVA
analysis of covariance
antiHBc
hepatitis B core antibody
APaT
All Participants as Treated
ART
antiretroviral therapy
AST
aspartate aminotransferase
AUC
area under the curve
AUC0-24
area under the curve from 0 to 24 hours postdose
BIC
bictegravir
BMI
body mass index
BOCF
baseline observation carried forward
C24
concentration after 24 hours
CD4+
CD4-positive
CI
confidence interval
CONSORT
Consolidated Standards of Reporting Trials
Cmax
maximum (peak) observed drug plasma concentration
CL/F
apparent total clearance of the drug from plasma after oral administration
CNS
central nervous system 
Crcl
creatinine clearance
CRF
case report form 
CSR
Clinical Study Report
CTFG
Clinical Trial Facilitation Group 
Ctrough
lowest concentration reached by a drug before the next dose is administered
CYP
cytochrome P450
DAIDS
The Division of AIDS
DAO
Data As Observed
DDI
drug-drug interaction
DEXA
Dual X-ray Absorptiometry
DILI
drug-induced liver injury
DMC
Data Monitoring Committee 
DNA
deoxyribonucleic acid 
DOR
doravirine
DTG
dolutegravir
ECG
electrocardiogram 
ECI
event of clinical interest
eCRF
electronic case report form
EDC
electronic data collection 
eDMC
external Data Monitoring Committee
EFV
efavirenz
eGFR
estimated glomerular filtration rate
EMA
European Medicines Agency
EOC
Executive Oversight Committee 
EU
European Union
FAS
Full Analysis Set
FBR
Future Biomedical Research Consent
FDA
Food and Drug Administration
FDAAA
Food and Drug Administration Amendments Act
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Abbreviation
Expanded Term
FDC
fixed dose combination
FSH
follicle stimulating hormone 
FTC
emtricitabine
GCP
Good Clinical Practice 
HBc
hepatitis B core
HBV
hepatitis B virus
HBsAg
hepatitis B surface antigen
HCV
hepatitis C virus
HDL-C
high-density lipoprotein cholesterol
HIV-1
human immunodeficiency virus type 1
HIV
human immunodeficiency virus
HIV-SI
Human Immunodeficiency Virus Symptom Index
HIVTSQ
Human Immunodeficiency Virus Treatment Satisfaction Questionnaire
HOMA-IR
Homeostatic Model Assessment of Insulin Resistance
HRQoL
health-related quality of life
HRT
hormone replacement therapy
IB
Investigator’s Brochure 
IC50
concentration of drug needed to inhibit 50% of viral growth 
IC90
concentration of drug needed to inhibit 90% of viral growth 
ICF
Informed Consent Form 
ICH
International Council on Harmonisation
IEC
Independent Ethics Committee
IL-6
interleukin-6
IND
Investigational New Drug 
INR
international normalized ratio
InSTI
integrase strand transfer inhibitor
ISL
Islatravir
ISL-DP
Islatravir-diphosphate
ISL-TP
Islatravir-triphosphate
IQ
inhibitory quotient
IRB
Institutional Review Board 
IRT
Interactive Response Technology
IUD
intrauterine device
IUS
intrauterine hormone-releasing system
LDL-C
low-density lipoprotein cholesterol
LNG/EE
levonorgestrel/ethinyl estradiol
LOCF
last observation carried forward
M=F
missing data treated as treatment failure
MSD
Merck Sharp & Dohme, Corp.
NHANES
National Health & Nutrition Examination Survey
NNRTI
non-nucleoside reverse transcriptase inhibitor
NRTI
nucleoside analog reverse transcriptase inhibitor
NRTTI
nucleoside reverse transcriptase translocation inhibitor
OF
Observed Failure 
PBMC
peripheral blood mononuclear cell
PCR
polymerase chain reaction
PDLC
predefined limit of change
PEP
potentially exposed person
PI
protease inhibitor
PK
pharmacokinetic
PrEP
pre-exposure prophylaxis
QD
once daily
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Abbreviation
Expanded Term
RNA
ribonucleic acid
SAC
Scientific Advisory Committee
SAE
serious adverse event 
SAP
statistical analysis plan
SD
standard deviation
SoA
schedule of activities
SOC
System Organ Class
SOP
standard operating procedure
sSAP
supplemental statistical analysis plan
SUSAR
suspected unexpected serious adverse reaction
t1/2
elimination half-life of the drug
TAF
tenofovir alafenamide
TAM
thymidine analog mutation
TBNK
T and B lymphocyte and natural killer cell
TC
total cholesterol
TDF
tenofovir disoproxil fumarate
TG
triglyceride
TLOVR
Time to Loss of Virologic Response
Tmax
time at which the maximum plasma concentration of the drug is achieved
US
United States
Vz/F
apparent volume of distribution during terminal phase after non-intravenous 
administration
WOCBP
woman/women of childbearing potential 
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11
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