A Phase 3, Randomized, Active-Controlled, Double-Blind Clinical Study to Evaluate a Switch to Doravirine/Islatravir (DOR/ISL 100 mg/0.25 mg) Once-Daily in Participants With HIV-1 Who Are Virologically Suppressed on Bictegravir/Emtricitabine/Tenofovir Alafenamide (BIC/FTC/TAF)
Phase: PHASE3
Conditions: HIV-1 Infection
Sponsor: Merck Sharp & Dohme LLC

Official Protocol Title:
NCT number:                NCT05630755
Document Date:           08-Aug-2024
A Phase 3, Randomized, Active-Controlled, Double-
Blind Clinical Study to Evaluate a Switch to Doravirine/
Islatravir (DOR/ISL 100 mg/0.25 mg) Once-Daily in 
Participants With HIV-1 Who Are Virologically 
Suppressed on Bictegravir/Emtricitabine/Tenofovir 
Alafenamide (BIC/FTC/TAF)

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TITLE PAGE
THIS PROTOCOL AND ALL OF THE INFORMATION RELATING TO IT ARE 
CONFIDENTIAL AND PROPRIETARY PROPERTY OF MERCK SHARP & 
DOHME LLC, RAHWAY, NJ, USA (MSD).
Protocol Title: A Phase 3, Randomized, Active-Controlled, Double-Blind Clinical Study to 
Evaluate a Switch to Doravirine/Islatravir (DOR/ISL 100 mg/0.25 mg) Once-Daily in 
Participants With HIV-1 Who Are Virologically Suppressed on 
Bictegravir/Emtricitabine/Tenofovir Alafenamide (BIC/FTC/TAF)
Protocol Number: 052-02
Compound Number: MK-8591A
Sponsor Name: Merck Sharp & Dohme LLC (hereafter called the Sponsor or MSD)
Legal Registered Address:
126 East Lincoln Avenue
P.O. Box 2000
Rahway, NJ 07065 USA
Regulatory Agency Identifying Number(s):
NCT
NCT05630755
EU CT
2022-502079-49-00
EudraCT
Not Applicable
JRCT
JRCT2051230003
WHO
Not Applicable
UTN
Not Applicable
IND
134,036
Approval Date:  08 August 2024
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Sponsor Signatory
Typed Name:
Title:
Date
Protocol-specific Sponsor contact information can be found in the Investigator Study 
File Binder (or equivalent).
Investigator Signatory
I agree to conduct this clinical study in accordance with the design outlined in this protocol 
and to abide by all provisions of this protocol.
Typed Name:
Title:
Date
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DOCUMENT HISTORY
Document
Date of Issue
Overall Rationale
Amendment 2
08-AUG-2024
To extend the blinded comparison period from 
Week 96 to Week 144 (Base Study) to provide 
additional safety and efficacy data, and to add an 
optional open-label extension (OLE) with access 
to DOR/ISL for up to Week 240 or until 
commercially available (whichever comes first).
Amendment 1
20-OCT-2023
To provide for increased HIV-1 RNA monitoring 
during pregnancy (if recommended in local 
guidelines), to clarify the management of 
participants with decreases in total lymphocyte 
and CD4+ T-cell counts and the management of 
participants with HIV-1 viremia.
Original Protocol
03-NOV-2022
Not applicable
PROTOCOL AMENDMENT SUMMARY OF CHANGES
Amendment: 02
Overall Rationale for the Amendment:
To extend the blinded comparison period from Week 96 to Week 144 (Base Study) to 
provide additional safety and efficacy data and to add an optional open-label extension 
(OLE) with access to DOR/ISL for up to Week 240 or until commercially available 
(whichever comes first).
Summary of Changes Table
Section Number 
and Name
Description of Change
Brief Rationale
Primary Reason for Amendment
Section 4.1 
Overall Design
Extended the blinded comparison period from 
Week 96 to Week 144 and added an optional 
OLE up to Week 240 or until DOR/ISL is 
commercially accessible (whichever comes 
first).
Study extension added to provide long-term 
comparative efficacy and safety data.
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Section Number and Name
Description of Change
Brief Rationale
Other Changes in Amendment
Section 1.1 Synopsis
Revised objectives, endpoints, study 
duration, duration of participation, and 
treatment period to reflect the extended 
base study and the added OLE.
Refer to rationale for Section 4.1.
Section 1.2 Schema
Updated the study schema to reflect the 
extended base study and the added OLE.
Refer to rationale for Section 4.1.
Section 1.3 Schedule of 
Activities
Added text above each SoA explaining the 
purpose of each SoA and relocated section 
references from notes
To clarify the applicability of each 
SoA.
1.3.1 Schedule of Activities –
Screening Through Week 144 –
(Base Study)
Added visits and study procedures for 
Weeks 108, 120, 132, 144, Early 
Discontinuation of Treatment, and End of 
Treatment Follow Up visits .
Refer to rationale for Section 4.1.
Added rows for Post-Base Study 
Disposition Planning at Weeks 120, 132 
and 144 and for Unblinding of Treatment 
Group Assignment at Week 144.
Refer to rationale for Section 4.1.
Added note to administer EQ-5D-5L and 
HIV-SI/SDM questionnaires only through 
Week 96.
Refer to rationale for Section 4.1.
Updated to collect HBV serology and 
HBV DNA for all participants annually.
To allow for annual hepatitis B 
surveillance to detect new exposures or 
change in immune status.
Added note for Chemistry to clarify that 
pregnant participants should not fast.
To avoid hypoglycemia and nonfasting 
results that could compromise analysis.
Added row for informed consent for the 
optional OLE (at Week 144).
Refer to rationale for Section 4.1.
Added note to specify that samples for 
inflammatory, renal, and energy and 
metabolism markers should not be 
collected from pregnant participants.
To reduce blood volume collection 
from pregnant participants.
Added note to specify that waist and hip 
measurements are not applicable for 
pregnant participants.
Results in pregnant participants would 
confound analysis.
Added footnote to clarify that the 
scheduled visit assessments should be 
performed if early discontinuation occurs 
at a scheduled visit.
Refer to rationale for Section 4.1.
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Section Number and Name
Description of Change
Brief Rationale
1.3.2 Schedule of Activities –
Viremia Confirmation and End 
of Treatment for Participants 
With Viremia (Except Those 
With Specified Decreases in 
Total Lymphocyte Count or 
CD4+ T-cell Count
Updated the End of Treatment activities 
for the base study and added End of 
Treatment activities for the OLE.
Refer to rationale for Section 4.1.
Replaced full with directed physical 
examination at the End of Treatment 
Follow-up (Base Study) visit.
To allow directed physical 
examinations to be performed if
clinically indicated.
Added DOR investigational PK 
assessment, as needed, using the same 
blood (plasma) sample collected for 
investigational ISL PK..
To characterize both DOR and ISL PK 
in the setting of viremia.
Removed blood sample collection for 
investigational PK at the End of Treatment 
Follow-Up (Base Study) visit.
ISL plasma concentrations are 
expected to be BLOQ by 42 days after 
the end of DOR/ISL study treatment.
Section 1.3.3 Schedule of 
Activities for Participants Who 
Meet the Discontinuation 
Criteria for Specified Decreases 
in Total Lymphocyte Count or 
CD4+ T-cell Count
Revised the End of Treatment activities 
for the base study and added End of 
Treatment activities for the OLE.
Refer to rationale for Section 4.1.
Added study intervention compliance 
review at the Total Lymphocyte Count 
and/or CD4+ T-Cell Count Confirmation 
visit. To assess compliance in the setting 
of confirmed specified decreases in total 
lymphocyte count and/or CD4+ T-cell 
count.
To assess compliance in the setting of 
confirmed specified decreases in total 
lymphocyte count and/or CD4+ T-cell 
count.
Removed DOR/ISL-only specification 
from Hematology and TBNK Panel/ CD4+ 
T-cell Count assessments at the End of 
Treatment Follow-Up (Base Study) visit.
To collect comparative data in both 
treatment groups at all visits.
Replaced full physical examination with 
directed physical examination to be 
performed if clinically indicated at the End 
of Treatment Follow-up (Base Study) 
visit.
Refer to rationale for Section 1.3.2 
regarding directed physical 
examination.
Removed investigational ISL PK blood 
sample collection at the End of Treatment 
Follow-Up (Base Study) visit.
See rationale for Section 1.3.2 
regarding investigational ISL PK.
Section 1.3.4 Schedule of 
Activities for Participants 
Whose Pregnancy or Postpartum 
Visit(s) Extends Beyond Week 
144
Removed week numbers for pregnancy 
visits.
To provide flexibility in timing of 
pregnancy visits in each trimester.
Extended the time period from Week 96 to 
Week 144 to consent to continue study 
intervention beyond Week 144.
Refer to rationale for Section 4.1.
Added dispensing of study intervention at 
the Pregnancy 4 visit for participants on 
DOR/ISL who opt to continue study 
intervention in the OLE, and noted that 
those on BIC/FTC/TAF should transition 
to commercially accessible ART.
Refer to rationale for Section 4.1.
Removed whole blood for FBR sample 
collection for participants whose 
pregnancy and/or postpartum visit(s) 
extends beyond Week 144.
Refer to rationale for section 1.3.1 
regarding reducing blood volume 
collected from pregnant participants.
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Section Number and Name
Description of Change
Brief Rationale
Section 1.3.5 Schedule of 
Activities – Week 148 Through 
Week 240 (Open-Label 
Extension)
Added SoA for the optional OLE.
Refer to rationale for Section 4.1.
Section 2.2.3 
Doravirine/Islatravir
Updated the number of participants with 
viral resistance across the program.
To update with new information.
Section 2.3 Benefit/Risk 
Assessment.
Updated the number of participants with 
viral resistance across the program.
Refer to rationale for Section 2.2.3.
Section 3 Hypotheses, 
Objectives, and Endpoints
Revised previously specified secondary 
and tertiary objectives to include Week 
144 and added hypothesis 4.
Refer to rationale for Section 4.1.
Added a tertiary objective and endpoint to 
evaluate total lymphocyte count.
To assess the effect of DOR/ISL vs 
BIC/FTC/TAF on total lymphocyte 
count through Week 144.
Added tertiary objectives and endpoints to 
evaluate the long-term efficacy and safety 
of DOR/ISL in the OLE.
Refer to rationale for Section 4.1.
Added a tertiary objective and endpoint to 
evaluate viral drug resistance in the OLE.
To assess long-term efficacy of 
DOR/ISL.
Section 4.2 Scientific Rationale 
for Study Design
Added rationale for the blinded treatment 
period (base study) through Week 144 and 
the added optional OLE from Week 144 
up to Week 240.
Refer to rationale for Section 4.1. 
Section 4.2.1.2 Safety Endpoints
Added TBNK to list of safety endpoints
and explanation of new safety endpoint for 
total lymphocyte count.
Refer to rationale for Section 3
regarding evaluation of total 
lymphocyte count.
Section 4.2.1.3 Weight, Body 
Composition, and Radiological 
and Laboratory Markers
Added Week 144 time point to rationale 
for assessment of weight, body 
composition, and radiological and 
laboratory markers.
Refer to rationale for Section 4.1.
Section 4.2.1.5 Patient-reported 
Outcomes
Added clarification that PROs should not 
be collected after Week 96.
Refer to rationale for Section 4.1.
Section 4.2.1.6 Planned 
Exploratory Biomarker 
Research
Removed sub-section 4.2.1.6.2 as not
applicable. 
Only genetic analysis and FBR are 
exploratory biomarker assessments.
Section 4.2.2 Rationale for the 
Use of Comparator/Placebo
Added reference supporting rationale for 
use of comparator (BIC/FTC/TAF) and 
matching placebo use in blinded therapy 
period through Week 144.
Refer to rationale for Section 4.1.
Section 4.3 Justification for 
Dose
Updated the number of participants with 
viral resistance across the program.
Refer to rationale for Section 2.2.3.
Section 6.1 Study Interventions 
Administered
Extended treatment period for all blinded 
study intervention in the base study from 
Week 96 to Week 144 and added open-
label DOR/ISL from Week 144 up to 
Week 240.
Refer to rationale for Section 4.1.
Section 6.3.3 Blinding
Extended blinding through Week 144.
Refer to rationale for Section 4.1.
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Section Number and Name
Description of Change
Brief Rationale
Section 6.5 Concomitant 
Therapy
Noted that recommendations for timing of 
medications or supplements containing 
polyvalent cations apply only to base 
study and that dofetilide is allowed during 
the OLE.
To clarify BIC/FTC/TAF dosing 
timing recommendations and 
contraindications.
Added metamizole, a strong CYP3A 
inducer, as a prohibited medication.
Metamizole is contraindicated to use 
with DOR.
Section 6.7 Intervention After 
the End of the Study
Revised end of study treatment and 
treatment transition procedures, as 
clinically appropriate and depending on 
whether or not DOR/ISL is commercially 
accessible, in the base study and OLE.
Refer to rationale for Section 4.1.
Section 7.1 Discontinuation of 
Study Intervention
Updated footnote a in Table 4 to add that 
total lymphocyte and/or CD4+ T-cell 
count discontinuation criteria will be 
established at Week 144 for participants in 
the OLE.
Refer to rationale for Section 4.1.
Section 8.1.1.3 Consent for 
Continuation of Study 
Intervention During Pregnancy
Added note that pregnant participants 
cannot switch study intervention.
Refer to rationale for Section 4.1.
Section 8.1.1.5 Consent for 
Open-Label Extension
Added section on consent for the optional 
OLE.
Refer to rationale for Section 4.1.
Section 8.1.8.1 Timing of Dose 
Administration
Clarified timing of dose administration 
during the base study and added timing of
dose administration during the OLE.
Refer to rationale for Section 4.1.
Section 8.1.9 Discontinuation 
and Withdrawal
Added discontinuation or withdrawal
procedure during the OLE.
Refer to rationale for Section 4.1.
Section 8.3.4 Confirmation of 
Contraception and Pregnancy 
Testing
Updated to include the OLE in the
Contraception requirement for 42 days 
after the last dose of study intervention.
Refer to rationale for Section 4.1.
Section 8.3.6 HBV Assessments
Revised to indicate that HBV serology and 
HBV DNA is to be checked annually for 
all participants.
Refer to rationale for Section 1.3.1 
regarding Hepatitis B surveillance.
Clarified that participants confirmed to be 
HBsAg-positive or to have quantifiable 
HBV DNA after randomization may be 
unblinded or allowed to continue study 
intervention, as deemed medically 
appropriate.
To avoid unnecessary unblinding if the 
principal investigator does not deem it 
necessary to guide care.
Section 8.3.9 Exploratory 
Clinical Marker Assessments
Added heading and relocated information 
from Section 8.8 about sample collection 
and assessments for inflammation, renal 
function, fasting lipid and metabolic 
profiles, (including waist/ and hip 
measurements, and DEXA.
Refer to rationale for Section 4.2.1.6.
Section 8.3.9.3 Fasting Lipid 
and Metabolic Profiles
Added to note that insulin-dependent
diabetic participants and pregnant 
participants should not fast and should not 
have insulin levels and lipids measured.
To avoid hypoglycemia, as nonfasting 
results could compromise analysis.
Section 8.3.10 Administration of 
Patient Questionnaires
Relocated section (moved from Section 
8.1.12).
To group PROs with safety 
assessments..
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Section Number and Name
Description of Change
Brief Rationale
Section 8.6.1 Blood Collection 
for Plasma ISL
Added DOR PK assessment (as needed).
Refer to rationale for Section 1.3.2
regarding DOR PK assessment in the 
setting of viremia.
Added sample collection for DOR and ISL 
PK assessment in pregnancy/postpartum in 
the OLE.
Refer to rationale for Section 4.1.
Section 8.9 Future Biomedical 
Research Sample Collection
Updated FBR-specific specimens 
collection description to include leftover 
specimens.
To update information regarding FBR 
consent and FBR-specific specimens 
collection.
Section 8.11.2.1 Fasting
Added additional fasting visit at Week 
144.
Refer to rationale for Section 4.1.
Noted that pregnant participants should 
not fast or have fasting laboratory 
assessments performed or insulin and 
lipids measured.
Refer to rationale for Section 1.31 
regarding hypoglycemia and nonfasting 
results.
Section 8.11.2.2. End of Base 
Study Week 144 Visit
Updated title and content to explain end of 
blinded base study procedures.
Refer to rationale for Section 4.1.
Section 8.11.2.3 Optional Open 
Label Extension Period (Week 
144 up to Week 240)
Added section to explain OLE activities.
Refer to rationale for Section 4.1.
Section 8.11.3.1 Discontinuation 
of Treatment
Updated title and content to explain 
Discontinuation of Treatment procedures 
for the base study (Early Discontinuation) 
and OLE (Discontinuation).
Refer to rationale for Section 4.1.
Section 8.11.3.2 End of 
Treatment Follow up
Updated title and content to explain end of 
treatment follow-up procedures for the 
base study and OLE.
Refer to rationale for Section 4.1.
Section 8.11.4 Viremia 
Confirmation
Noted that both DOR and ISL PK are to be 
collected at viremia confirmation.
To inform proper clinical management 
of participants with viremia.
Section 8.11.5 Management of 
Participants With Specified 
Decreases in Total Lymphocyte 
Count or CD4+ T-cell Count
Updated to specify that the same 
monitoring and discontinuation 
criteria/procedures apply in the base study 
and OLE.
Refer to rationale for Section 4.1.
Section 8.11.6 Clinical 
Management of Participants 
Who Become Pregnant
Clarified unblinding of participants who 
become pregnant prior to Week 144.
Refer to rationale for Section 4.1.
Section 8.11.6.1 Continuing 
Study Intervention in Pregnancy
Added management of participants who 
become pregnant and are eligible and 
consent to continue DOR/ISL during 
pregnancy in the OLE and beyond Week 
240, as applicable.
Refer to rationale for Section 4.1; the 
frequency of visits (every 3 months) 
will remain the same in the OLE as in 
the base study due to limited data on 
DOR/ISL use during pregnancy.
Specified that participants on 
BIC/FTC/TAF who are pregnant at Week 
144 will continue on BIC/FTC/TAF 
through the postpartum visit and complete 
the study.
Refer to rationale for Section 4.1.
Section 8.11.6.2 Discontinuing 
Study Intervention for 
Pregnancy
Clarified discontinuation procedures for 
participants who become pregnant and 
discontinue their assigned study 
intervention during the base study (Section 
1.3.1) or OLE (Section 1.3.5).
Refer to rationale for Section 4.1.
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Section Number and Name
Description of Change
Brief Rationale
Section 9 Key Statistical 
Considerations
Added clarification on how the data 
collected from the OLE will be 
summarized.
Refer to rationale for Section 4.1.
Section 9.1 Statistical Analysis 
Plan Summary
Updated to include extended study 
duration.
Refer to rationale for Section 4.1.
Multiplicity: Revised multiplicity strategy.
To enhance statistical rigor, a small 
alpha (0.00001) will be allocated for 
the Week 24 interim analysis.
Section 9.2 Responsibility for 
Analyses/In-house Blinding
Updated to reflect that study participants 
and site personnel will remain blinded 
until Week 144.
Refer to rationale for Section 4.1.
Section 9.4.1.1 Efficacy 
Endpoints
Added Week 144 to the secondary
efficacy objectives and endpoints and 
define the baseline for continuous 
parameters for OLE analyses.
Refer to rationale for Section 4.1.
Section 9.4.2 Safety Endpoints
Added Week 144 to the applicable safety 
objectives and endpoints and defined the 
baseline for OLE analyses.
Refer to rationale for Section 4.1.
Added base study objective and endpoints 
to assess total lymphocyte count for 
DOR/ISL vs BIC/FTC/TAF.
Refer to rationale for Section 3.
Section 9.5.1 Efficacy Analysis 
Populations
Removed the postbaseline data 
requirements for the FAS population and 
added PP analysis population.
To align with the FDA snapshot 
approach, participants who do not have 
on treatment postbaseline data will be 
categorized under "no data" in the 
window.
Added FAS and APaT for the OLE.
Refer to rationale for Section 4.1.
Section 9.5.2 Safety Analysis 
Populations
Added APaT-E population to analyze 
safety data from the OLE.
Refer to rationale for Section 4.1.
Section 9.6.1 Statistical 
Methods for Efficacy Analyses
Updated Table 8 (Definitions of Study 
Time Points) to include Week 108 through 
Week 240.
Refer to rationale for Section 4.1.
Specified Base Period or base study and 
added Week 144 for efficacy analyses in 
the base study and added efficacy analyses 
in the OLE.
Refer to rationale for Section 4.1.
Added text on how HBV acute infection/
reactivation will be handled in the OLE.
Refer to rationale for Section 4.1.
Updated Table 9 (Analysis Strategy for 
Key Efficacy Variables) to include Week 
144 for the secondary endpoints and H4.
Refer to rationale for Section 4.1.
Added efficacy analyses at Week 144 and 
in the OLE.
Refer to rationale for Section 4.1.
Section 9.6.2 Statistical 
Methods for Safety Analyses
Updated Table 10 (Definition of Study 
Time Points for DEXA Analyses) to 
include Week 144.
Refer to rationale for Section 4.1.
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Section Number and Name
Description of Change
Brief Rationale
Section 9.6.2.1 Overall Safety 
Assessment
Added safety analyses at Week 144 and in 
the OLE.
Refer to rationale for Section 4.1.
Excluded participants who become 
pregnant during the study from the 
analyses of continuous safety measures.
Refer to rationale for Section 3 
regarding evaluation of total 
lymphocyte count.
Added assessment of mean change from 
baseline in lymphocyte and lymphocyte 
subset counts in the base study.
Refer to rationale for Section 4.1.
Section 9.6.2.2 Assessment of 
Safety Topics of Special Interest
Specified time period (base study) and 
added Week 144 for assessments of 
opportunistic infections.
Refer to rationale for Section 4.1.
Section 9.6.2.3 Handling of 
Missing Data and Pregnancies 
in Safety Analyses
Added missing safety data handling in the 
OLE and extended base study period to 
Week 144 for data collection for pregnant 
participants.
Refer to rationale for Section 4.1.
Table 11: Added mean change from 
baseline safety parameters for 
lymphocytes.
Refer to rationale for Section 3 
regarding evaluation of total 
lymphocyte count.
Section 9.7 Interim Analyses
Updated to reflect that the study 
participants and site personnel will remain 
blinded until Week 144 and added H4.
Refer to rationale for Section 4.1.
Section 9.8 Multiplicity
Added a Type I error adjustment for the 
futility analysis, for statistical rigor.
To enhance statistical rigor, a small 
alpha (0.00001) will be allocated for 
the Week 24 IA.
Added the hypothesis 4 testing superiority 
of Group 1 to Group 2 as assessed by the 
percentage of participants with HIV-1 
RNA ≥50 copies/mL at Week 144.
Refer to rationale for Section 4.1.
Section 9.9.1.1 Sample Size and 
Power Calculations
Tables 12 and 13: Updated to 
accommodate the Type I error adjustment.
Refer to rationale for Section 9.8 
regarding Type I error adjustment.
Section 9.9.1.2 Evaluation of the 
Futility Criterion and Non-
Inferiority at Week 48
Table 15: Updated to accommodate the 
Type I error adjustment.
Refer to rationale for Section 9.8 
regarding Type I error adjustment.
Section 9.11 Compliance 
(Medication Adherence)
Updated the computation for blinded study 
intervention compliance in the base study
and added Week 144 time point.
Refer to rationale for Section 4.1.
Section 10.2 Appendix 2: 
Clinical Laboratory Tests
Table 18 Protocol-required Laboratory 
Assessments: Moved HbA1c to the 
Additional Chemistry at Fasting Visits 
row.
To clarify that HbA1c can be collected 
regardless of fasting or nonfasting 
status.
Updated footnote c to apply for all 
participants.
Refer to rationale for Section 1.3.1 
regarding HBV.
Updated blood volumes: Added table for 
OLE (Table 21), updated tables for base 
study (Tables 19 and 20), and removed 
table for FBR in pregnancy beyond Week 
144, that is no longer applicable.
Refer to rationale for Section 4.1
regarding removal of FBR sample 
collection in pregnancy/postpartum 
post-Week 144.
Throughout
Minor administrative, formatting, 
grammatical, and/or typographical 
changes were made throughout the 
document.
To ensure clarity and accurate 
interpretation of the intent of the 
protocol.
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TABLE OF CONTENTS
DOCUMENT HISTORY ........................................................................................................3
PROTOCOL AMENDMENT SUMMARY OF CHANGES...............................................3
1
PROTOCOL SUMMARY ............................................................................................20
1.1
Synopsis.................................................................................................................20
1.2
Schema ..................................................................................................................24
1.3
Schedule of Activities...........................................................................................25
1.3.1
Schedule of Activities – Screening Through Week 144 – (Base Study).....25
1.3.2
Schedule of Activities – Viremia Confirmation and End of Treatment 
for Participants With Viremia (Except Those With Specified Decreases 
in Total Lymphocyte Count or CD4+ T-cell Count) ...................................38
1.3.3
Schedule of Activities for Participants Who Meet the Discontinuation 
Criteria for Specified Decreases in Total Lymphocyte Count or CD4+ 
T-cell Count .................................................................................................42
1.3.4
Schedule of Activities for Participants Whose Pregnancy or Postpartum 
Visit(s) Extends Beyond Week 144.............................................................48
1.3.5
Schedule of Activities – Week 144 Through Week 240 (Open-label 
Extension) ....................................................................................................51
2
INTRODUCTION..........................................................................................................54
2.1
Study Rationale....................................................................................................54
2.2
Background ..........................................................................................................54
2.2.1
Islatravir.......................................................................................................54
2.2.2
Doravirine ....................................................................................................55
2.2.3
Doravirine/Islatravir.....................................................................................55
2.2.4
Information on Other Study-related Therapy ..............................................56
2.3
Benefit/Risk Assessment......................................................................................56
3
HYPOTHESES, OBJECTIVES, AND ENDPOINTS................................................60
4
STUDY DESIGN............................................................................................................63
4.1
Overall Design......................................................................................................63
4.2
Scientific Rationale for Study Design.................................................................64
4.2.1
Rationale for Endpoints ...............................................................................65
4.2.1.1
Efficacy Endpoints.............................................................................65
4.2.1.1.1
HIV-1 RNA Measurements .....................................................65
4.2.1.1.2
Definition of Clinically Significant Confirmed Viremia.........65
4.2.1.2
Safety Endpoints................................................................................66
4.2.1.3
Weight, Body Composition, and Radiological and Laboratory 
Markers ..............................................................................................66
4.2.1.4
Pharmacokinetic Endpoints ...............................................................67
4.2.1.5
Patient-reported Outcomes.................................................................67
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4.2.1.6
Planned Exploratory Biomarker Research.........................................68
4.2.1.6.1
Planned Genetic Analysis ........................................................68
4.2.1.7
Future Biomedical Research..............................................................68
4.2.2
Rationale for the Use of Comparator/Placebo .............................................69
4.2.3
Rationale for the Selected Participant Population .......................................69
4.2.4
Rationale for Collecting Race and Ethnicity Data.......................................70
4.2.5
Rationale for Collecting Gender Identity Data ............................................70
4.2.6
Rationale for Infant Safety Data Collection.................................................70
4.2.7
Rationale for Continuing Study Intervention During Pregnancy ................71
4.2.8
Rationale for Collecting Alcohol and Tobacco Use ....................................71
4.3
Justification for Dose...........................................................................................71
4.4
Beginning and End-of-Study Definition ............................................................72
4.4.1
Clinical Criteria for Early Study Termination .............................................73
5
STUDY POPULATION ................................................................................................74
5.1
Inclusion Criteria.................................................................................................74
5.2
Exclusion Criteria................................................................................................76
5.3
Lifestyle Considerations......................................................................................78
5.4
Screen Failures.....................................................................................................78
5.5
Participant Replacement Strategy......................................................................78
6
STUDY INTERVENTION............................................................................................79
6.1
Study Intervention(s) Administered...................................................................79
6.2
Preparation/Handling/Storage/Accountability .................................................81
6.2.1
Dose Preparation..........................................................................................81
6.2.2
Handling, Storage, and Accountability........................................................81
6.3
Measures to Minimize Bias: Randomization and Blinding..............................82
6.3.1
Intervention Assignment..............................................................................82
6.3.2
Stratification.................................................................................................82
6.3.3
Blinding........................................................................................................82
6.4
Study Intervention Compliance..........................................................................82
6.5
Concomitant Therapy..........................................................................................83
6.5.1
Rescue Medications and Supportive Care ...................................................85
6.6
Dose Modification (Escalation/Titration/Other)...............................................85
6.7
Intervention After the End of the Study............................................................85
6.8
Clinical Supplies Disclosure................................................................................86
6.9
Standard Policies..................................................................................................86
7
DISCONTINUATION OF STUDY INTERVENTION AND PARTICIPANT 
WITHDRAWAL............................................................................................................87
7.1
Discontinuation of Study Intervention...............................................................87
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7.2
Participant Withdrawal From the Study...........................................................88
7.3
Lost to Follow-up .................................................................................................89
8
STUDY ASSESSMENTS AND PROCEDURES........................................................90
8.1
Administrative and General Procedures ...........................................................90
8.1.1
Informed Consent.........................................................................................90
8.1.1.1
General Informed Consent.................................................................91
8.1.1.2
Consent and Collection of Specimens for Future Biomedical 
Research.............................................................................................91
8.1.1.3
Consent for Continuation of Study Intervention During 
Pregnancy...........................................................................................91
8.1.1.4
Consent for Postnatal Infant Safety Data Collection Through One 
Year of Age........................................................................................92
8.1.1.5
Consent for Open-Label Extension....................................................92
8.1.2
Inclusion/Exclusion Criteria ........................................................................92
8.1.3
Participant Identification Card.....................................................................92
8.1.4
Medical History ...........................................................................................92
8.1.5
Prior and Concomitant Medications Review...............................................93
8.1.5.1
Prior Medications...............................................................................93
8.1.5.2
Concomitant Medications..................................................................93
8.1.6
Assignment of Screening Number...............................................................93
8.1.7
Assignment of Randomization Number.......................................................93
8.1.8
Study Intervention Administration ..............................................................93
8.1.8.1
Timing of Dose Administration.........................................................94
8.1.9
Discontinuation and Withdrawal .................................................................94
8.1.9.1
Withdrawal From Future Biomedical Research ................................95
8.1.10
Participant Blinding/Unblinding..................................................................95
8.1.11
Calibration of Equipment.............................................................................96
8.2
Efficacy Assessments ...........................................................................................96
8.2.1
HIV-1 RNA..................................................................................................96
8.2.2
Management of Participants With Viremia .................................................96
8.2.2.1
Viremia Confirmation........................................................................97
8.2.2.1.1
Participants With Clinically Significant Confirmed Viremia 
(≥200 Copies/mL)....................................................................97
8.2.2.1.2
HIV-1 Viral Drug Resistance Testing......................................97
8.2.2.1.3
Participants With Low-level Viremia (≥50 and 
<200 Copies/mL) .....................................................................97
8.2.3
T and B Lymphocyte and Natural Killer Cell (TBNK) Profile ...................98
8.3
Safety Assessments...............................................................................................98
8.3.1
Physical Examinations.................................................................................98
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8.3.1.1
Weight................................................................................................99
8.3.2
Vital Signs....................................................................................................99
8.3.3
Electrocardiograms ......................................................................................99
8.3.4
Confirmation of Contraception and Pregnancy Testing ..............................99
8.3.5
Clinical Safety Laboratory Assessments ...................................................100
8.3.6
HBV Assessments......................................................................................100
8.3.7
HCV Assessment .......................................................................................101
8.3.8
Tobacco and Alcohol Assessments............................................................101
8.3.9
Exploratory Clinical Marker Assessments.................................................101
8.3.9.1
Inflammation....................................................................................102
8.3.9.2
Renal Function.................................................................................102
8.3.9.3
Fasting Lipid and Metabolic Profiles...............................................102
8.3.9.4
Waist, Hip and BMI Measurements.................................................103
8.3.9.5
DEXA Assessments.........................................................................103
8.3.10
Administration of Patient Questionnaires..................................................103
8.4
Adverse Events, Serious Adverse Events, and Other Reportable Safety 
Events..................................................................................................................104
8.4.1
Time Period and Frequency for Collecting AE, SAE, and Other 
Reportable Safety Event Information ........................................................104
8.4.2
Method of Detecting AEs, SAEs, and Other Reportable Safety Events....106
8.4.3
Follow-up of AE, SAE, and Other Reportable Safety Event Information.107
8.4.4
Regulatory Reporting Requirements for SAE ...........................................107
8.4.5
Pregnancy and Exposure During Breastfeeding ........................................107
8.4.6
Disease-related Events and/or Disease-related Outcomes Not Qualifying 
as AEs or SAEs..........................................................................................108
8.4.7
Events of Clinical Interest..........................................................................108
8.5
Treatment of Overdose......................................................................................108
8.6
Pharmacokinetics...............................................................................................108
8.6.1
Blood Collection for Plasma ISL...............................................................108
8.7
Pharmacodynamics............................................................................................109
8.8
Biomarkers .........................................................................................................109
8.8.1
Planned Genetic Analysis Sample Collection............................................109
8.9
Future Biomedical Research Sample Collection.............................................110
8.10
Health Economics Medical Resource Utilization and Health Economics.....110
8.11
Visit Requirements.............................................................................................110
8.11.1
Screening/Rescreening...............................................................................110
8.11.1.1
Screening..........................................................................................110
8.11.1.2
Rescreening......................................................................................110
8.11.2
Treatment Period........................................................................................111
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8.11.2.1
Fasting..............................................................................................111
8.11.2.2
End of Base Study Week 144 Visit..................................................112
8.11.2.3
Optional Open Label Extension (Week 144 to Week 240) .............112
8.11.3
Participants Who Discontinue Study Intervention.....................................113
8.11.3.1
Discontinuation of Treatment ..........................................................113
8.11.3.2
End of Treatment Follow-up............................................................114
8.11.4
Viremia Confirmation................................................................................114
8.11.5
Management of Participants With Specified Decreases in Total 
Lymphocyte Count or CD4+ T-cell Count................................................114
8.11.6
Clinical Management of Participants Who Become Pregnant...................115
8.11.6.1
Continuing Study Intervention in Pregnancy...................................116
8.11.6.1.1
Collection of Population PK Samples During Pregnancy 
and Postpartum (Participants Continuing DOR/ISL Only) ...117
8.11.6.2
Discontinuing Study Intervention for Pregnancy ............................118
8.11.6.3
Participants Who Choose to Breastfeed...........................................118
8.11.6.4
Infant Safety Data Collection...........................................................119
8.11.6.4.1
Schedule of Activities: Infant Safety Data Collection...........119
9
STATISTICAL ANALYSIS PLAN ...........................................................................120
9.1
Statistical Analysis Plan Summary...................................................................120
9.2
Responsibility for Analyses/In-house Blinding ...............................................122
9.3
Hypotheses/Estimation ......................................................................................122
9.4
Analysis Endpoints.............................................................................................122
9.4.1
Efficacy/Pharmacokinetics Endpoints .......................................................123
9.4.1.1
Efficacy Endpoints...........................................................................123
9.4.1.2
Pharmacokinetic Endpoints .............................................................124
9.4.2
Safety Endpoints........................................................................................124
9.4.3
Patient-reported Outcome Endpoints.........................................................125
9.5
Analysis Populations..........................................................................................126
9.5.1
Efficacy Analysis Populations...................................................................126
9.5.2
Safety Analysis Populations ......................................................................127
9.6
Statistical Methods.............................................................................................128
9.6.1
Statistical Methods for Efficacy Analyses.................................................128
9.6.2
Statistical Methods for Safety Analyses ....................................................135
9.6.2.1
Overall Safety Assessment ..............................................................136
9.6.2.2
Assessment of Safety Topics of Special Interest .............................137
9.6.2.3
Handling of Missing Data and Pregnancies in Safety Analyses......137
9.6.3
Summaries of Baseline Characteristics, Demographics, and Other 
Analyses.....................................................................................................139
9.6.3.1
Demographic and Baseline Characteristics .....................................139
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9.7
Interim Analyses ................................................................................................139
9.8
Multiplicity .........................................................................................................141
9.9
Sample Size and Power Calculations ...............................................................142
9.9.1
Sample Size and Power for Efficacy Analyses..........................................142
9.9.1.1
Evaluation of Non-inferiority and Superiority Hypotheses.............142
9.9.1.2
Evaluation of the Futility Criterion and Non-inferiority at 
Week 48 ...........................................................................................145
9.9.2
Sample Size and Power for Safety Analyses .............................................149
9.9.2.1
Evaluation of Adverse Events..........................................................149
9.10
Subgroup Analyses.............................................................................................150
9.11
Compliance (Medication Adherence)...............................................................151
9.12
Extent of Exposure.............................................................................................152
10
SUPPORTING DOCUMENTATION AND OPERATIONAL 
CONSIDERATIONS...................................................................................................153
10.1
Appendix 1: Regulatory, Ethical, and Study Oversight Considerations......153
10.1.1
Code of Conduct for Clinical Trials...........................................................153
10.1.2
Financial Disclosure...................................................................................156
10.1.3
Data Protection...........................................................................................157
10.1.3.1
Confidentiality of Data ....................................................................157
10.1.3.2
Confidentiality of Participant Records.............................................157
10.1.3.3
Confidentiality of IRB/IEC Information..........................................158
10.1.4
Committees Structure.................................................................................158
10.1.4.1
Executive Oversight Committee......................................................158
10.1.4.2
External Data Monitoring Committee .............................................158
10.1.4.3
Scientific Advisory Committee (SAC)............................................158
10.1.5
Publication Policy......................................................................................159
10.1.6
Compliance with Study Registration and Results Posting Requirements .159
10.1.7
Compliance with Law, Audit, and Debarment ..........................................159
10.1.8
Data Quality Assurance .............................................................................160
10.1.9
Source Documents .....................................................................................161
10.1.10
Study and Site Closure...............................................................................161
10.2
Appendix 2: Clinical Laboratory Tests............................................................162
10.3
Appendix 3: Adverse Events: Definitions and Procedures for Recording, 
Evaluating, Follow-up, and Reporting.............................................................173
10.3.1
Definitions of Medication Error, Misuse, and Abuse................................173
10.3.2
Definition of AE ........................................................................................173
10.3.3
Definition of SAE ......................................................................................174
10.3.4
Additional Events Reported.......................................................................176
10.3.5
Recording AE and SAE .............................................................................176
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10.3.6
Reporting of AEs, SAEs, and Other Reportable Safety Events to the 
Sponsor ......................................................................................................179
10.4
Appendix 4: Medical Device and Drug–Device Combination Products: 
Product Quality Complaints/Malfunctions: Definitions, Recording, and 
Follow-up ............................................................................................................181
10.5
Appendix 5: Contraceptive Guidance..............................................................182
10.5.1
Definitions..................................................................................................182
10.5.2
Contraceptive Requirements......................................................................184
10.6
Appendix 6: Collection and Management of Specimens for Future 
Biomedical Research..........................................................................................185
10.7
Appendix 7: Country-specific Requirements..................................................189
10.7.1
Country-specific Request for Germany .....................................................189
10.7.2
Country-specific Request for Canada ........................................................189
10.8
Appendix 8: Calculation of Creatinine Clearance and eGFR .......................190
10.8.1
Cockcroft-Gault Equations ........................................................................190
10.8.2
MDRD Equations.......................................................................................190
10.9
Appendix 9: AIDS-defining Opportunistic Infections that Require 
Discontinuation of Study Intervention.............................................................191
10.10 Appendix 10: Approved HIV-1 RNA Quantification Assays for Local 
Viral Load Monitoring ......................................................................................193
10.11 Appendix 11: Abbreviations .............................................................................194
11
REFERENCES.............................................................................................................198
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LIST OF TABLES
Table 1
Laboratory Exclusion Criteria......................................................................78
Table 2
Study Interventions......................................................................................80
Table 3
Prohibited Therapies ....................................................................................84
Table 4
Discontinuation Criteria for Specified Decreases in Total Lymphocyte 
Counts or CD4+ T-cell Counts ....................................................................................88
Table 5
Reporting Time Periods and Time Frames for Adverse Events and 
Other Reportable Safety Events.................................................................................105
Table 6
Collection of Population PK Samples........................................................109
Table 7
Collection of Population PK Samples During Pregnancy and 
Postpartum .................................................................................................................118
Table 8
Definitions of Study Time Points ..............................................................129
Table 9
Analysis Strategy for Key Efficacy Variables...........................................135
Table 10
Definition of Study Time Points for DEXA Analyses...............................136
Table 11
Analysis Strategy for Safety Parameters....................................................138
Table 12
Power (%) to Establish Non-inferiority at Week 48 Under Various 
Response Rate Assumptions......................................................................................143
Table 13
Power (%) to Establish Superiority at Week 48/96/144 Under Various 
Response Rate Assumptions......................................................................................144
Table 14
Probability of Not Meeting the Futility Criterion at the Week 24 Interim 
Analysis ....................................................................................................................145
Table 15
Probability of Not Meeting the Futility Criterion at the Week 24 Interim 
Analysis and the Conditional Power to Declare Non-inferiority at Week 48 for 
Various Underlying True Response Rates.................................................................147
Table 16
Estimate of Incidence of AEs and 95% Upper Confidence Bound Based 
on Hypothetical Numbers of Participants with AEs..................................................149
Table 17
Difference in Incidence (Percentage Points) of AEs (Group 1 Minus 
Group 2) That Can Be Ruled Out With 334 Participants in Group 1 and 
167 Participants in Group 2 .......................................................................................150
Table 18
Protocol-required Laboratory Assessments...............................................163
Table 19
Blood Volumes (Efficacy, Safety, and PK) in the Base Study..................166
Table 20
Blood Volumes (Genetic Analysis and FBR) in the Base Study...............169
Table 21
Blood Volumes (Efficacy, Safety, and PK) in the OLE ............................170
Table 22
Blood Volumes: Participants Whose Pregnancy or Postpartum Visit(s) 
Extends Beyond Week 144 (Efficacy, Safety, and PK).............................................172
Table 23
Approved HIV-1 RNA Quantification Assays for Local Viral Load 
Monitoring .................................................................................................................193
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LIST OF FIGURES
Figure 1
Study Schema and Treatment Plan ..............................................................24
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1
PROTOCOL SUMMARY
1.1
Synopsis
Protocol Title: A Phase 3, Randomized, Active-Controlled, Double-Blind Clinical Study to 
Evaluate a Switch to Doravirine/Islatravir (DOR/ISL 100 mg/0.25 mg) Once-Daily in 
Participants With HIV-1 Who Are Virologically Suppressed on 
Bictegravir/Emtricitabine/Tenofovir Alafenamide (BIC/FTC/TAF)
Short Title: DOR/ISL 100 mg/0.25 mg QD Blinded Switch
Acronym: Not applicable
Hypotheses, Objectives, and Endpoints:
Hypotheses are aligned with objectives in the Objectives and Endpoints table.
The following objectives will be evaluated in participants ≥18 years of age with HIV-1 who 
have been virologically suppressed (ie, HIV-1 RNA <50 copies/mL) for ≥3 consecutive 
months on BIC/FTC/TAF.
Primary Objective
Primary Endpoint
To evaluate the antiretroviral activity of a 
switch to DOR/ISL compared with 
continued BIC/FTC/TAF, as assessed by 
the percentage of participants with HIV-1 
RNA ≥50 copies/mL at Week 48
Hypothesis (H1): DOR/ISL is non-inferior 
to BIC/FTC/TAF, as assessed by the 
percentage of participants with HIV-1 RNA 
≥50 copies/mL at Week 48. A margin of 
4 percentage points is used to define 
non-inferiority.
Hypothesis (H2): DOR/ISL is superior to 
BIC/FTC/TAF, as assessed by the 
percentage of participants with HIV-1 RNA 
≥50 copies/mL at Week 48.
HIV-1 RNA
To evaluate the safety and tolerability of a 
switch from BIC/FTC/TAF to DOR/ISL 
compared with continued BIC/FTC/TAF, as 
assessed by review of the safety data 
accumulated through Week 48
Adverse events
Adverse events leading to discontinuation 
of study intervention
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Secondary Objectives
Secondary Endpoints
To evaluate the antiretroviral activity of a 
switch to DOR/ISL compared with
continued BIC/FTC/TAF, as assessed by 
the percentage of participants with HIV-1 
RNA ≥50 copies/mL at Week 96 and Week 
144
Hypothesis (H3): DOR/ISL is superior to 
BIC/FTC/TAF, as assessed by the 
percentage of participants with HIV-1 RNA 
≥50 copies/mL at Week 96.
Hypothesis (H4): DOR/ISL is superior to 
BIC/FTC/TAF, as assessed by the 
percentage of participants with HIV-1 RNA 
≥50 copies/mL at Week 144.
HIV-1 RNA
To evaluate the antiretroviral activity of a 
switch to DOR/ISL compared with
continued BIC/FTC/TAF, as assessed by 
the percentage of participants with the 
following at Week 48, Week 96, and 
Week 144:
- HIV-1 RNA <200 copies/mL
- HIV-1 RNA <50 copies/mL
HIV-1 RNA
To evaluate the immunologic effect of a 
switch to DOR/ISL compared with
continued BIC/FTC/TAF, as assessed by
the mean change from baseline in CD4+ T-
cell count at Week 48, Week 96, and 
Week 144
CD4+ T-cell count
To evaluate the development of viral drug
resistance to any study intervention at 
Week 48, Week 96, and Week 144
Viral resistance-associated substitutions
To evaluate the safety and tolerability of a 
switch from BIC/FTC/TAF to DOR/ISL 
compared with continued BIC/FTC/TAF, as 
assessed by review of the safety data 
accumulated through Week 144
Adverse events
Adverse events leading to discontinuation 
of study intervention
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Overall Design:
Study Phase
Phase 3
Primary Purpose
Treatment
Indication
HIV infection
Population
Participants ≥18 years of age with HIV-1 
who have been virologically suppressed for 
≥3 consecutive months on BIC/FTC/TAF
Study Type
Interventional
Intervention Model
Parallel
This is a multi site study.
Type of Control
Active Control
Study Blinding
Double-blind
Blinding Roles
Participants or Subjects
Sponsor
Investigator
Estimated Duration of Study
The Sponsor estimates that the study will 
require approximately 5 years from the time 
the first participant (or their legally 
acceptable representative) provides 
documented informed consent until the last 
participant’s last study-related contact.
Number of Participants:
Approximately 501 participants will be randomized.
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Intervention Groups and Duration:
Arm Name
Intervention 
Name
Unit Dose 
Strength(s)
Dosage 
Level(s)
Route of 
Administration
Treatment 
Period
Use
Group 1
doravirine/
islatravir
100 mg/
0.25 mg
100 mg/
0.25 mg QD
Oral
Day 1 to 
Week 144
Test Product
Group 1
placebo to 
bictegravir/
emtricitabine/
tenofovir 
alafenamide
0 mg
0 mg QD
Oral
Day 1 to 
Week 144
Placebo
Group 1
doravirine/
islatravir
100 mg/ 
0.25 mg
100 mg. 
0.25 mg QD
Oral
Week 144 up 
to Week 240
Test Product
Group 2
bictegravir/
emtricitabine/
tenofovir 
alafenamide
50 mg/
200 mg/
25 mg
50 mg/
200 mg/
25 mg QD
Oral
Day 1 to 
Week 144
Comparator
Group 2
placebo to 
doravirine/
islatravir
0 mg
0 mg QD
Oral
Day 1 to 
Week 144
Placebo
Group 2
doravirine/
islatravir
100 mg/ 
0.25 mg
100 mg/ 
0.25 mg QD
Oral
Week 144 up 
to Week 240
Test Product
QD=once-daily.
Study intervention will be extended open-label for participants who become pregnant on 
treatment and provide documented informed consent to continue their assigned study 
intervention (DOR/ISL or BIC/FTC/TAF), as specified in Sections 1.3.4 and 8.11.6.
Total Number of Intervention Groups/Arms
2
Duration of Participation
Each participant will participate in the 
blinded base study for approximately 
3 years from the time the participant 
provides documented informed consent 
through the final contact. After a screening 
phase of up to 45 days, each participant will 
receive the assigned blinded study 
intervention for approximately 144 weeks in 
the base study. After Week 144, participants 
will be given the option to continue in an
OLE and receive DOR/ISL for up to 96 
weeks or until DOR/ISL is commercially 
accessible (whichever comes first). 
Participants who discontinue study 
intervention or who become pregnant will 
be followed as described in the protocol.
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Study Governance Committees:
Executive Oversight Committee
Yes
Data Monitoring Committee
Yes
Clinical Adjudication Committee
No
Study governance considerations are outlined in Appendix 1.
Study Accepts Healthy Participants: No
A list of abbreviations is in Appendix 11.
1.2
Schema
The study design is depicted in Figure 1.
Figure 1
Study Schema and Treatment Plan
BIC=bictegravir; DOR=doravirine; FTC=emtricitabine; HIV-1= human immunodeficiency virus type 1; 
ISL=islatravir; N=total number of participants in the study; n=number of participants in the intervention group; 
OLE=open-label extension; TAF=tenofovir alafenamide.
a.
Participants are expected to enroll as soon as possible after eligibility is confirmed. In cases of unexpected 
delays in receiving repeat screening laboratory results, a screening period of up to 45 days is allowed.
b.
Only Group 2 participants in the OLE (ie, switch to DOR/ISL) have an extra visit at Week 148.
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1.3
Schedule of Activities
1.3.1
Schedule of Activities – Screening Through Week 144 – (Base Study)
This SoA applies to all participants in the blinded comparison period (Base Study). 
•
The Early Discontinuation of Treatment Visit applies to any participant who discontinues study intervention prior to Week 144
(Section 8.11.3). Manage participants with viremia per Sections 8.2.2 and 8.11.4 (SoA Section 1.3.2).
•
Manage participants with specified decreases in total lymphocyte and/or CD4+ T-cell counts per Section 8.11.5 (SoA 
Section1.3.3).
•
Manage pregnant participants per Section 8.11.6. 
•
For the OLE, see Sections 8.11.2.3 (SoA Section 1.3.5).
Study Period:
Screeninga
Blinded Intervention (Base Study)
End of Treatment
Notes
Visit Number:
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
Unscheduled
Scheduled 
Day/Week:
Screening
Day 1
(Fasting)
Week 4
Week 12
Week 24
(Fasting)
Week 36
Week 48
(Fasting)
Week 60
Week 72
Week 84
Week 96
(Fasting)
Week 108
Week 120
Week 132
Week 144
(Fasting)
Early 
Disconti
nuation 
of 
Treatmen
tb
End of 
Treatmen
t Follow-
Up (Base 
Study)
Visit Window
≤45 
day
NA
±7 days
(Calculate each visit from date of Day 1)
NA
42 (+7) 
days after 
end of 
treatment
Administrative Procedures
Informed Consent
X
Informed Consent 
for FBR
X
08WX9L

PRODUCT: MK-8591A
26
PROTOCOL/AMENDMENT NO.: 052-02
MK-8591A-052-02 FINAL PROTOCOL
08-AUG-2024
Study Period:
Screeninga
Blinded Intervention (Base Study)
End of Treatment
Notes
Visit Number:
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
Unscheduled
Scheduled 
Day/Week:
Screening
Day 1
(Fasting)
Week 4
Week 12
Week 24
(Fasting)
Week 36
Week 48
(Fasting)
Week 60
Week 72
Week 84
Week 96
(Fasting)
Week 108
Week 120
Week 132
Week 144
(Fasting)
Early 
Disconti
nuation 
of 
Treatmen
tb
End of 
Treatmen
t Follow-
Up (Base 
Study)
Visit Window
≤45 
day
NA
±7 days
(Calculate each visit from date of Day 1)
NA
42 (+7) 
days after 
end of 
treatment
Post Base Study 
Disposition 
Planning
X
X
X
Proactively discuss prior 
to the Week 144 visit (see 
Section 8.11.2.2).
Unblinding of 
Treatment Group 
Assignment
X
Complete after
documenting all AEs 
(including causality).
Informed Consent 
for OLE
X
Obtain prior to dispensing 
study intervention at 
Week 144.
Informed Consent 
for Study 
Intervention During 
Pregnancy
<-------------------------------------X----------------------------------->
Obtain upon confirmation 
of pregnancy. See 
Section 8.1.1.3.
Collect and Enter 
Data From Prenatal 
Care Provider
<------------------------------------X------------------------------------->
See Section 8.11.6 for 
prenatal safety 
monitoring.
Informed Consent 
for Infant Data 
Safety Collection
<-----------------------------------------X-------------------------------->
Obtain after confirmation 
of continuing pregnancy. 
See Sections 8.1.1.4 and 
8.11.6.4.
08WX9L

PRODUCT: MK-8591A
27
PROTOCOL/AMENDMENT NO.: 052-02
MK-8591A-052-02 FINAL PROTOCOL
08-AUG-2024
Study Period:
Screeninga
Blinded Intervention (Base Study)
End of Treatment
Notes
Visit Number:
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
Unscheduled
Scheduled 
Day/Week:
Screening
Day 1
(Fasting)
Week 4
Week 12
Week 24
(Fasting)
Week 36
Week 48
(Fasting)
Week 60
Week 72
Week 84
Week 96
(Fasting)
Week 108
Week 120
Week 132
Week 144
(Fasting)
Early 
Disconti
nuation 
of 
Treatmen
tb
End of 
Treatmen
t Follow-
Up (Base 
Study)
Visit Window
≤45 
day
NA
±7 days
(Calculate each visit from date of Day 1)
NA
42 (+7) 
days after 
end of 
treatment
Administration of 
EQ-5D-5L, 
HIVTSQ, and 
HIV-SI/SDM 
Patient 
Questionnaires
X
X
X
X
X
(X)
Administer in the order 
listed, before the 
participant is seen by the 
investigator and before 
discussing medical 
conditions or test results.
(Do not administer after 
the Week 96 visit).
Inclusion/Exclusion 
Criteria
X
X
Review prior to 
randomization on Day 1 
to confirm eligibility.
Participant 
Identification Card
X
X
Site personnel will add 
randomization number.
Medical History
X
Tobacco and 
Alcohol 
Assessments
X
X
X
X
08WX9L

PRODUCT: MK-8591A
28
PROTOCOL/AMENDMENT NO.: 052-02
MK-8591A-052-02 FINAL PROTOCOL
08-AUG-2024
Study Period:
Screeninga
Blinded Intervention (Base Study)
End of Treatment
Notes
Visit Number:
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
Unscheduled
Scheduled 
Day/Week:
Screening
Day 1
(Fasting)
Week 4
Week 12
Week 24
(Fasting)
Week 36
Week 48
(Fasting)
Week 60
Week 72
Week 84
Week 96
(Fasting)
Week 108
Week 120
Week 132
Week 144
(Fasting)
Early 
Disconti
nuation 
of 
Treatmen
tb
End of 
Treatmen
t Follow-
Up (Base 
Study)
Visit Window
≤45 
day
NA
±7 days
(Calculate each visit from date of Day 1)
NA
42 (+7) 
days after 
end of 
treatment
Prior and 
Concomitant 
Medications 
Review
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Register Study 
Visit in IRT
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Intervention 
Randomization
X
All pretreatment 
procedures should be 
completed prior to 
randomization on Day 1.
Dispense Study 
Intervention Using 
IRT
X
X
X
X
X
X
X
X
X
X
X
X
X
(X)
(Dispense at Week 144 
for participants entering 
the OLE and if needed for 
those whose pregnancy or 
Postpartum visit(s) 
extends past Week 144
see Section 1.3.4).
08WX9L

PRODUCT: MK-8591A
29
PROTOCOL/AMENDMENT NO.: 052-02
MK-8591A-052-02 FINAL PROTOCOL
08-AUG-2024
Study Period:
Screeninga
Blinded Intervention (Base Study)
End of Treatment
Notes
Visit Number:
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
Unscheduled
Scheduled 
Day/Week:
Screening
Day 1
(Fasting)
Week 4
Week 12
Week 24
(Fasting)
Week 36
Week 48
(Fasting)
Week 60
Week 72
Week 84
Week 96
(Fasting)
Week 108
Week 120
Week 132
Week 144
(Fasting)
Early 
Disconti
nuation 
of 
Treatmen
tb
End of 
Treatmen
t Follow-
Up (Base 
Study)
Visit Window
≤45 
day
NA
±7 days
(Calculate each visit from date of Day 1)
NA
42 (+7) 
days after 
end of 
treatment
Study Intervention 
Compliance 
Review
X
X
X
X
X
X
X
X
X
X
X
X
X
X
For participants whose 
pregnancy or Postpartum 
visit(s) extends past 
Week 144, see 
Section 1.3.4.
Efficacy Procedures
Plasma HIV-1 
RNA 
Quantification
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
See Section 8.2.1. See 
Section 8.11.6.1 for 
testing in participants who 
become pregnant.
Blood (Plasma) for 
HIV-1 Viral Drug 
Resistance Testing
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Analysis performed by 
Sponsor if indicated per 
Section 8.2.2.1.2.
Whole Blood for 
HIV-1 Viral Drug 
Resistance Testing
X
Analysis performed by 
Sponsor if indicated per 
Section 8.2.2.1.2.
TBNK Panel/CD4+ 
T-cell Count
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
08WX9L

PRODUCT: MK-8591A
30
PROTOCOL/AMENDMENT NO.: 052-02
MK-8591A-052-02 FINAL PROTOCOL
08-AUG-2024
Study Period:
Screeninga
Blinded Intervention (Base Study)
End of Treatment
Notes
Visit Number:
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
Unscheduled
Scheduled 
Day/Week:
Screening
Day 1
(Fasting)
Week 4
Week 12
Week 24
(Fasting)
Week 36
Week 48
(Fasting)
Week 60
Week 72
Week 84
Week 96
(Fasting)
Week 108
Week 120
Week 132
Week 144
(Fasting)
Early 
Disconti
nuation 
of 
Treatmen
tb
End of 
Treatmen
t Follow-
Up (Base 
Study)
Visit Window
≤45 
day
NA
±7 days
(Calculate each visit from date of Day 1)
NA
42 (+7) 
days after 
end of 
treatment
Safety Procedures
Full Physical 
Examination
X
X
Height
X
Weight
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Directed Physical 
Examination
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Vital Signs
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Local 12-lead ECG
X
Perform up to 7 days prior 
to Day 1 and after all 
other eligibility criteria 
are confirmed.
Contraceptive Use 
Confirmation
(POCBP Only)
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Contraception is required 
for 42 days after the last 
dose of study intervention 
(see Section 8.3.4).
Serum Pregnancy 
Test (hCG) 
(POCBP Only)
X
A highly sensitive urine 
pregnancy test may be 
performed instead of 
serum. See Section 5.1.
08WX9L

PRODUCT: MK-8591A
31
PROTOCOL/AMENDMENT NO.: 052-02
MK-8591A-052-02 FINAL PROTOCOL
08-AUG-2024
Study Period:
Screeninga
Blinded Intervention (Base Study)
End of Treatment
Notes
Visit Number:
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
Unscheduled
Scheduled 
Day/Week:
Screening
Day 1
(Fasting)
Week 4
Week 12
Week 24
(Fasting)
Week 36
Week 48
(Fasting)
Week 60
Week 72
Week 84
Week 96
(Fasting)
Week 108
Week 120
Week 132
Week 144
(Fasting)
Early 
Disconti
nuation 
of 
Treatmen
tb
End of 
Treatmen
t Follow-
Up (Base 
Study)
Visit Window
≤45 
day
NA
±7 days
(Calculate each visit from date of Day 1)
NA
42 (+7) 
days after 
end of 
treatment
Urine Pregnancy 
Test (hCG) 
(POCBP Only)
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Pregnancy must be
excluded on Day 1 before
randomization. Confirm 
positive or indeterminant 
urine test with serum.
HIV-1 and HIV-2 
Serology
X
Hepatitis B 
Serology and HBV 
DNA
X
X
X
X
Encourage HBV 
vaccination to participants 
who are not immune to 
HBV. Repeat serology 
and HBV DNA testing at 
Weeks 48, 96 and 144
(annual surveillance).
HBsAg and HBV 
DNA
(X)
(X)
(X)
(X)
(X)
(X)
(X)
(X)
(X)
(X)
(X)
(X)
(Only anti-HBc-positive 
participants at each visit. 
See Section 8.3.6.)
08WX9L

PRODUCT: MK-8591A
32
PROTOCOL/AMENDMENT NO.: 052-02
MK-8591A-052-02 FINAL PROTOCOL
08-AUG-2024
Study Period:
Screeninga
Blinded Intervention (Base Study)
End of Treatment
Notes
Visit Number:
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
Unscheduled
Scheduled 
Day/Week:
Screening
Day 1
(Fasting)
Week 4
Week 12
Week 24
(Fasting)
Week 36
Week 48
(Fasting)
Week 60
Week 72
Week 84
Week 96
(Fasting)
Week 108
Week 120
Week 132
Week 144
(Fasting)
Early 
Disconti
nuation 
of 
Treatmen
tb
End of 
Treatmen
t Follow-
Up (Base 
Study)
Visit Window
≤45 
day
NA
±7 days
(Calculate each visit from date of Day 1)
NA
42 (+7) 
days after 
end of 
treatment
Hepatitis B 
Serology and HBV 
DNA in Pregnant 
Participants 
(DOR/ISL Only)
<---------------------------------------(X)--------------------------------------->
Collect once after 
pregnancy is confirmed or 
report local laboratory 
results. See 
Section 8.11.6.1.
Hepatitis C 
Serology
X
See Section 8.3.7. Repeat 
screening if indicated per 
local standard of care.
Chemistry
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Fasting required at Day 1 
and Weeks 24, 48, 96, 
and 144 (see Section 
8.3.9.3 and Appendix 2).
Pregnant participants
should not fast.
Hematology
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
PT/INR
X
Urinalysis
X
X
X
X
X
X
X
X
AE/SAE Review
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
08WX9L

PRODUCT: MK-8591A
33
PROTOCOL/AMENDMENT NO.: 052-02
MK-8591A-052-02 FINAL PROTOCOL
08-AUG-2024
Study Period:
Screeninga
Blinded Intervention (Base Study)
End of Treatment
Notes
Visit Number:
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
Unscheduled
Scheduled 
Day/Week:
Screening
Day 1
(Fasting)
Week 4
Week 12
Week 24
(Fasting)
Week 36
Week 48
(Fasting)
Week 60
Week 72
Week 84
Week 96
(Fasting)
Week 108
Week 120
Week 132
Week 144
(Fasting)
Early 
Disconti
nuation 
of 
Treatmen
tb
End of 
Treatmen
t Follow-
Up (Base 
Study)
Visit Window
≤45 
day
NA
±7 days
(Calculate each visit from date of Day 1)
NA
42 (+7) 
days after 
end of 
treatment
Blood (Plasma) for 
ISL PK
X
X
X
X
X
At Week 4, if daytime 
dosing, obtain pre- and 
postdose or, if evening 
dosing, collect only 1 
sample irrespective of 
time of last dose. See 
Section 8.6.1 (Table 6). 
Do not collect if 
participant unblinded and 
assigned to 
BIC/FTC/TAF.
Blood (Plasma) for 
Investigational ISL 
PK
X
X
X
X
X
Do not collect during 
pregnancy or if participant 
unblinded and assigned to 
BIC/FTC/TAF. Analysis 
performed by Sponsor as 
needed. See Section 8.6.1.
08WX9L

PRODUCT: MK-8591A
34
PROTOCOL/AMENDMENT NO.: 052-02
MK-8591A-052-02 FINAL PROTOCOL
08-AUG-2024
Study Period:
Screeninga
Blinded Intervention (Base Study)
End of Treatment
Notes
Visit Number:
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
Unscheduled
Scheduled 
Day/Week:
Screening
Day 1
(Fasting)
Week 4
Week 12
Week 24
(Fasting)
Week 36
Week 48
(Fasting)
Week 60
Week 72
Week 84
Week 96
(Fasting)
Week 108
Week 120
Week 132
Week 144
(Fasting)
Early 
Disconti
nuation 
of 
Treatmen
tb
End of 
Treatmen
t Follow-
Up (Base 
Study)
Visit Window
≤45 
day
NA
±7 days
(Calculate each visit from date of Day 1)
NA
42 (+7) 
days after 
end of 
treatment
Blood (Plasma) for 
DOR and ISL PK 
in Pregnant 
Participants
(DOR/ISL Only)
<--------------------------------------X---------------------------------------------->
X
Collect during the 1st, 
2nd, and 3rd trimesters 
and postpartum. See
Section 8.11.6.1
(Table 7).
Waist and Hip 
Measurements
X
X
X
X
Not applicable to
pregnant participants
08WX9L

PRODUCT: MK-8591A
35
PROTOCOL/AMENDMENT NO.: 052-02
MK-8591A-052-02 FINAL PROTOCOL
08-AUG-2024
Study Period:
Screeninga
Blinded Intervention (Base Study)
End of Treatment
Notes
Visit Number:
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
Unscheduled
Scheduled 
Day/Week:
Screening
Day 1
(Fasting)
Week 4
Week 12
Week 24
(Fasting)
Week 36
Week 48
(Fasting)
Week 60
Week 72
Week 84
Week 96
(Fasting)
Week 108
Week 120
Week 132
Week 144
(Fasting)
Early 
Disconti
nuation 
of 
Treatmen
tb
End of 
Treatmen
t Follow-
Up (Base 
Study)
Visit Window
≤45 
day
NA
±7 days
(Calculate each visit from date of Day 1)
NA
42 (+7) 
days after 
end of 
treatment
DEXA Scan
(Only Where 
Permitted by Local 
Law)
X
X
X
X
Perform after all
eligibility criteria are 
confirmed. Must be
performed prior to 
45 days after Day 1 and 
±45 days of the 
Weeks 48, 96, and 144
visits. Perform only for 
participants with valid 
baseline images. Do not 
perform on pregnant 
participants. See 
Appendix 7 for country-
specific requirements.
Blood and Urine 
for Renal Markers
X
X
X
X
X
Do not collect during 
pregnancy.
Blood for 
Inflammatory 
Markers
X
X
X
X
X
Do not collect during 
pregnancy.
08WX9L

PRODUCT: MK-8591A
36
PROTOCOL/AMENDMENT NO.: 052-02
MK-8591A-052-02 FINAL PROTOCOL
08-AUG-2024
Study Period:
Screeninga
Blinded Intervention (Base Study)
End of Treatment
Notes
Visit Number:
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
Unscheduled
Scheduled 
Day/Week:
Screening
Day 1
(Fasting)
Week 4
Week 12
Week 24
(Fasting)
Week 36
Week 48
(Fasting)
Week 60
Week 72
Week 84
Week 96
(Fasting)
Week 108
Week 120
Week 132
Week 144
(Fasting)
Early 
Disconti
nuation 
of 
Treatmen
tb
End of 
Treatmen
t Follow-
Up (Base 
Study)
Visit Window
≤45 
day
NA
±7 days
(Calculate each visit from date of Day 1)
NA
42 (+7) 
days after 
end of 
treatment
Blood for Energy 
and Metabolism 
Markers
X
X
X
X
X
Do not collect during 
pregnancy.
Biomarkers
Blood for Genetic 
Analysisc
X
Collect predose. See 
Section 8.8.1.
Whole Blood for 
FBR
X
X
X
X
X
X
Optional participation;
requires FBR consent. 
Collect Day 1 sample 
predose; remaining 
samples may be collected 
at any time irrespective of 
last dose.
08WX9L

PRODUCT: MK-8591A
37
PROTOCOL/AMENDMENT NO.: 052-02
MK-8591A-052-02 FINAL PROTOCOL
08-AUG-2024
AE=adverse event; anti-HBc=hepatitis B core antibody; BIC=bictegravir; BP=blood pressure; DEXA=dual x-ray absorptiometry; DNA=deoxyribonucleic acid; 
DOR=doravirine; ECG=electrocardiogram; EQ-5D-5L=EuroQol 5-dimensional descriptive system, 5-level version; FBR=future biomedical research; FTC=emtricitabine; 
HBsAg=hepatitis B surface antigen; HBV=hepatitis B virus; hCG=human chorionic gonadotropin; HIV-1=human immunodeficiency virus type 1; HIV-2=human 
immunodeficiency virus type 2; HIV-SI/SDM=Human Immunodeficiency Virus Symptom Index/Symptom Distress Module; HIVTSQ=Human Immunodeficiency Virus 
Treatment Satisfaction Questionnaire; IEC=Independent Ethics Committee; INR=international normalized ratio; IRB=Institutional Review Board; IRT=Interactive 
Response Technology; ISL=islatravir; NA=not applicable; PK=pharmacokinetic(s); POCBP=participant(s) of childbearing potential; PT=prothrombin time; 
RNA=ribonucleic acid; RR=respiratory rate; SAE=serious adverse event; TAF=tenofovir alafenamide; TBNK=T and B Lymphocyte and Natural Killer Cell; temp=body 
temperature.
a Participants are expected to enroll as soon as possible after eligibility is confirmed. In cases of unexpected delays in receiving repeat screening laboratory results, a screening 
period of up to 45 days is allowed.
b Participants who discontinue at a Scheduled Visit, should complete the assessments for the Scheduled Visit as well as for the Early Discontinuation of Treatment Visit. 
Collection of laboratory samples should not be duplicated.
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 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 FBR if the participant (or their legally acceptable representative) provides documented informed consent for FBR. If the planned genetic 
analyses are not approved, but FBR is approved and consent is given, this sample will be collected for the purpose of FBR.
08WX9L

PRODUCT: MK-8591A
38
PROTOCOL/AMENDMENT NO.: 052-02
MK-8591A-052-02 FINAL PROTOCOL
08-AUG-2024
1.3.2
Schedule of Activities – Viremia Confirmation and End of Treatment for Participants With Viremia (Except Those 
With Specified Decreases in Total Lymphocyte Count or CD4+ T-cell Count)
This SoA only applies to participants requiring viremia confirmation in the base study and/or OLE.
•
Clinically significant confirmed viremia requires discontinuation (per Sections 8.2.2.1.1 and 8.11.4).
•
Manage participants with specified decreases in total lymphocyte and/or CD4+ T-cell counts per Section 8.11.5 (SoA Section 
1.3.3).
Study Period
Viremia 
Confirmation
End of Treatment
(Base Study)
End of Treatment
(OLE)
Notes
Visit Number
Unscheduled
Unscheduled
Unscheduled
Scheduled Day/Week
Viremia 
Confirmation
Early 
Discontinuation 
of Treatment
(Base Study)a
End of 
Treatment 
Follow-Up
(Base Study)
Discontinuation 
of Treatment 
(OLE)
End of 
Treatment 
Follow-Up 
(OLE)
Visit Window
Within 4 weeks 
(±1 week) of 
HIV-1 Viremia 
(≥50 copies/mL)
NA
42 (+7) days 
after end of 
treatment
NA
42 (+7) days 
after end of 
treatment
Administrative Procedures
Prior and 
Concomitant 
Medications Review
X
X
X
X
X
Register Study Visit 
in IRT
X
X
X
Study Intervention 
Compliance Review
X
X
Administration of 
EQ-5D-5L, HIVTSQ, 
and HIV-SI/SDM 
Patient Questionnaires
(X)
Administer in the order listed, before 
the participant is seen by the 
investigator and before discussing 
medical conditions or test results.
(Do not administer after Week 96 
visit).
08WX9L

PRODUCT: MK-8591A
39
PROTOCOL/AMENDMENT NO.: 052-02
MK-8591A-052-02 FINAL PROTOCOL
08-AUG-2024
Study Period
Viremia 
Confirmation
End of Treatment
(Base Study)
End of Treatment
(OLE)
Notes
Visit Number
Unscheduled
Unscheduled
Unscheduled
Scheduled Day/Week
Viremia 
Confirmation
Early 
Discontinuation 
of Treatment
(Base Study)a
End of 
Treatment 
Follow-Up
(Base Study)
Discontinuation 
of Treatment 
(OLE)
End of 
Treatment 
Follow-Up 
(OLE)
Visit Window
Within 4 weeks 
(±1 week) of 
HIV-1 Viremia 
(≥50 copies/mL)
NA
42 (+7) days 
after end of 
treatment
NA
42 (+7) days 
after end of 
treatment
Efficacy Procedures
Plasma HIV-1 RNA 
Quantification
X
X
X
X
X
See Section 8.2.1.
Plasma for HIV-1 
Drug Resistance
X
(X)
(X)
(Do not collect at Discontinuation of 
Treatment Visit if collected at the 
Viremia Confirmation Visit.)
Analysis performed by Sponsor if 
indicated per Section 8.2.2.1.2.
TBNK 
Panel/CD4+ T-cell 
Count
X
X
Safety Procedures
Full Physical 
Examination 
X
Directed Physical 
Examination
X
X
X
Weight
X
X
Vital Signs
X
X
Contraceptive Use 
Confirmation 
(POCBP Only)
X
X
X
X
X
Contraception required for 42 days 
after the last dose of study 
intervention (Section 8.3.4).
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Study Period
Viremia 
Confirmation
End of Treatment
(Base Study)
End of Treatment
(OLE)
Notes
Visit Number
Unscheduled
Unscheduled
Unscheduled
Scheduled Day/Week
Viremia 
Confirmation
Early 
Discontinuation 
of Treatment
(Base Study)a
End of 
Treatment 
Follow-Up
(Base Study)
Discontinuation 
of Treatment 
(OLE)
End of 
Treatment 
Follow-Up 
(OLE)
Visit Window
Within 4 weeks 
(±1 week) of 
HIV-1 Viremia 
(≥50 copies/mL)
NA
42 (+7) days 
after end of 
treatment
NA
42 (+7) days 
after end of 
treatment
Urine Pregnancy Test 
(hCG) (POCBP Only)
X
X
X
X
X
Confirm positive or indeterminant 
urine test with serum. If positive, 
manage participant per 
Section 8.11.6. For participants 
known to be pregnant, defer until 6 
weeks postpartum.
Chemistry
X
Hematology
X
X
Urinalysis
X
AE/SAE Review
X
X
X
X
X
Pharmacokinetics
Blood (Plasma) for 
Investigational ISL 
PK (and DOR, if 
applicable) 
X
X
Do not collect during pregnancy or if 
participant unblinded and assigned to 
BIC/FTC/TAF. Analysis performed 
by Sponsor as needed. see 
Section 8.6.1.
Blood (Plasma) for 
DOR and ISL PK
X
X
X
Only for pregnant participants on 
DOR/ISL. Collect irrespective of 
time of last dose and record time of 
last dose of study intervention in 
appropriate source documentation.
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08-AUG-2024
Study Period
Viremia 
Confirmation
End of Treatment
(Base Study)
End of Treatment
(OLE)
Notes
Visit Number
Unscheduled
Unscheduled
Unscheduled
Scheduled Day/Week
Viremia 
Confirmation
Early 
Discontinuation 
of Treatment
(Base Study)a
End of 
Treatment 
Follow-Up
(Base Study)
Discontinuation 
of Treatment 
(OLE)
End of 
Treatment 
Follow-Up 
(OLE)
Visit Window
Within 4 weeks 
(±1 week) of 
HIV-1 Viremia 
(≥50 copies/mL)
NA
42 (+7) days 
after end of 
treatment
NA
42 (+7) days 
after end of 
treatment
Biomarkers
Whole Blood for FBR
X
(X)
Optional participation; requires FBR 
consent. Collect irrespective of time 
of last dose. (If collected at 
preceding Viremia Confirmation 
Visit, do not collect at Early 
Discontinuation of Treatment visit).
AE=adverse event; BIC=bictegravir; BP=blood pressure; EQ-5D-5L=EuroQol 5-dimensional descriptive system, 5-level version; FBR=future biomedical research; 
FTC=emtricitabine; hCG=human chorionic gonadotropin; HIV-1=human immunodeficiency virus type 1; HIV-SI/SDM=Human Immunodeficiency Virus Symptom 
Index/Symptom Distress Module; HIVTSQ=Human Immunodeficiency Virus Treatment Satisfaction Questionnaire; IRT=Interactive Response Technology; 
ISL=islatravir; NA=not applicable; PK=pharmacokinetic(s); POCBP=participant/participants of childbearing potential; RNA=ribonucleic acid; RR=respiratory rate; 
SAE=serious adverse event; TAF=tenofovir alafenamide; TBNK=T and B Lymphocyte and Natural Killer Cell; temp=body temperature.
a Participants who discontinue at a Scheduled Visit, should complete the assessments for the scheduled visit as well as for the Early Discontinuation of Treatment Visit. 
Collection of laboratory samples should not be duplicated.
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1.3.3
Schedule of Activities for Participants Who Meet the Discontinuation Criteria for Specified Decreases in Total 
Lymphocyte Count or CD4+ T-cell Count
This SoA only applies to participants with specified decreases in total lymphocyte and/or CD4+ T-cell counts in the base study and/or 
OLE per Section 8.11.5.
•
Manage participants with Viremia per Sections 8.2.2 and 8.11.4 (SoA Section1.3.2).
Study Period
Total 
Lymphocyte 
Count or 
CD4+ T-cell 
Count 
Confirmation
End of Treatment
(Base Study)
End of Treatment
(OLE)
Total Lymphocyte 
Count or 
CD4+ T-cell 
Count Monitoring 
(DOR/ISL Only)
Notes
Visit Number
Unscheduled
Unscheduled
Unscheduled
Unscheduled
Visit Name
Total 
Lymphocyte 
Count or 
CD4+ T-cell 
Count 
Confirmation
Early 
Discontinuation 
of Treatment
(Base Study)a
End of 
Treatment 
Follow-up
(Base Study)
Discontinuation 
of Treatment 
(OLE)
End of Treatment 
Follow-up (OLE)
Total Lymphocyte 
Count or 
CD4+ T-cell Count 
Monitoring
See Sections 7.1, 8.1.9, 
and 8.11.5 for details 
regarding discontinuation 
and monitoring.
Visit Window
Within 10 to
14 weeks after 
initial 
decrease
NA
42 (+7) days 
after 
discontinuing 
study 
intervention
NA
42 (+7) days 
after 
discontinuing 
study 
intervention
Every 10 to 
14 weeks after 
discontinuing study 
intervention
Administrative Procedures
Prior and 
Concomitant 
Medications
Review
X
X
X
X
X
X
Register Study 
Visit in IRT
X
X
X
X
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Study Period
Total 
Lymphocyte 
Count or 
CD4+ T-cell 
Count 
Confirmation
End of Treatment
(Base Study)
End of Treatment
(OLE)
Total Lymphocyte 
Count or 
CD4+ T-cell 
Count Monitoring 
(DOR/ISL Only)
Notes
Visit Number
Unscheduled
Unscheduled
Unscheduled
Unscheduled
Visit Name
Total 
Lymphocyte 
Count or 
CD4+ T-cell 
Count 
Confirmation
Early 
Discontinuation 
of Treatment
(Base Study)a
End of 
Treatment 
Follow-up
(Base Study)
Discontinuation 
of Treatment 
(OLE)
End of Treatment 
Follow-up (OLE)
Total Lymphocyte 
Count or 
CD4+ T-cell Count 
Monitoring
See Sections 7.1, 8.1.9, 
and 8.11.5 for details 
regarding discontinuation 
and monitoring.
Visit Window
Within 10 to
14 weeks after 
initial 
decrease
NA
42 (+7) days 
after 
discontinuing 
study 
intervention
NA
42 (+7) days 
after 
discontinuing 
study 
intervention
Every 10 to 
14 weeks after 
discontinuing study 
intervention
Study 
Intervention 
Compliance 
Review
X
X
Administration 
of EQ-5D-5L, 
HIVTSQ, and 
HIV-SI/SDM 
Patient 
Questionnaires
(X)
Administer in the order 
listed, before the 
participant is seen by the 
investigator and before 
discussing medical 
conditions or test results.
(Do not administer after 
the Week 96 visit).
Efficacy Procedures
Plasma HIV-1 
RNA 
Quantification
X
X
X
X
See Section 8.2.1.
Plasma for 
HIV-1 Drug 
Resistance 
X
X
Analysis performed by 
Sponsor if indicated per 
Section 8.2.2.1.2.
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Study Period
Total 
Lymphocyte 
Count or 
CD4+ T-cell 
Count 
Confirmation
End of Treatment
(Base Study)
End of Treatment
(OLE)
Total Lymphocyte 
Count or 
CD4+ T-cell 
Count Monitoring 
(DOR/ISL Only)
Notes
Visit Number
Unscheduled
Unscheduled
Unscheduled
Unscheduled
Visit Name
Total 
Lymphocyte 
Count or 
CD4+ T-cell 
Count 
Confirmation
Early 
Discontinuation 
of Treatment
(Base Study)a
End of 
Treatment 
Follow-up
(Base Study)
Discontinuation 
of Treatment 
(OLE)
End of Treatment 
Follow-up (OLE)
Total Lymphocyte 
Count or 
CD4+ T-cell Count 
Monitoring
See Sections 7.1, 8.1.9, 
and 8.11.5 for details 
regarding discontinuation 
and monitoring.
Visit Window
Within 10 to
14 weeks after 
initial 
decrease
NA
42 (+7) days 
after 
discontinuing 
study 
intervention
NA
42 (+7) days 
after 
discontinuing 
study 
intervention
Every 10 to 
14 weeks after 
discontinuing study 
intervention
TBNK 
Panel/CD4+ 
T-cell Count
X
X
X
X
X
X
Safety Procedures
Full Physical 
Examination
X
Directed 
Physical 
Examination
X
X
X
Weight
X
X
Vital Signs
X
X
Contraceptive 
Use 
Confirmation 
(POCBP Only)
X
X
X
X
Contraception is required 
for 42 days after the last 
dose of study 
intervention.
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Study Period
Total 
Lymphocyte 
Count or 
CD4+ T-cell 
Count 
Confirmation
End of Treatment
(Base Study)
End of Treatment
(OLE)
Total Lymphocyte 
Count or 
CD4+ T-cell 
Count Monitoring 
(DOR/ISL Only)
Notes
Visit Number
Unscheduled
Unscheduled
Unscheduled
Unscheduled
Visit Name
Total 
Lymphocyte 
Count or 
CD4+ T-cell 
Count 
Confirmation
Early 
Discontinuation 
of Treatment
(Base Study)a
End of 
Treatment 
Follow-up
(Base Study)
Discontinuation 
of Treatment 
(OLE)
End of Treatment 
Follow-up (OLE)
Total Lymphocyte 
Count or 
CD4+ T-cell Count 
Monitoring
See Sections 7.1, 8.1.9, 
and 8.11.5 for details 
regarding discontinuation 
and monitoring.
Visit Window
Within 10 to
14 weeks after 
initial 
decrease
NA
42 (+7) days 
after 
discontinuing 
study 
intervention
NA
42 (+7) days 
after 
discontinuing 
study 
intervention
Every 10 to 
14 weeks after 
discontinuing study 
intervention
Urine 
Pregnancy 
Test (hCG) 
(POCBP Only)
X
X
X
X
Confirm positive or 
indeterminant urine test 
with serum. If positive, 
manage participant per 
Section 8.11.6. For 
participants known to be 
pregnant, defer until 6 
weeks postpartum.
Chemistry 
X
Hematology
X
X
X
X
X
X
Urinalysis
X
AE/SAE 
Review
X
X
X
X
X
X
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08-AUG-2024
Study Period
Total 
Lymphocyte 
Count or 
CD4+ T-cell 
Count 
Confirmation
End of Treatment
(Base Study)
End of Treatment
(OLE)
Total Lymphocyte 
Count or 
CD4+ T-cell 
Count Monitoring 
(DOR/ISL Only)
Notes
Visit Number
Unscheduled
Unscheduled
Unscheduled
Unscheduled
Visit Name
Total 
Lymphocyte 
Count or 
CD4+ T-cell 
Count 
Confirmation
Early 
Discontinuation 
of Treatment
(Base Study)a
End of 
Treatment 
Follow-up
(Base Study)
Discontinuation 
of Treatment 
(OLE)
End of Treatment 
Follow-up (OLE)
Total Lymphocyte 
Count or 
CD4+ T-cell Count 
Monitoring
See Sections 7.1, 8.1.9, 
and 8.11.5 for details 
regarding discontinuation 
and monitoring.
Visit Window
Within 10 to
14 weeks after 
initial 
decrease
NA
42 (+7) days 
after 
discontinuing 
study 
intervention
NA
42 (+7) days 
after 
discontinuing 
study 
intervention
Every 10 to 
14 weeks after 
discontinuing study 
intervention
Pharmacokinetics
Blood 
(Plasma) for 
Investigational 
ISL PK
X
X
Do not collect during 
pregnancy or if 
participant unblinded and 
assigned to 
BIC/FTC/TAF. Analysis 
performed by Sponsor as 
needed. See 
Section 8.6.1.
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Study Period
Total 
Lymphocyte 
Count or 
CD4+ T-cell 
Count 
Confirmation
End of Treatment
(Base Study)
End of Treatment
(OLE)
Total Lymphocyte 
Count or 
CD4+ T-cell 
Count Monitoring 
(DOR/ISL Only)
Notes
Visit Number
Unscheduled
Unscheduled
Unscheduled
Unscheduled
Visit Name
Total 
Lymphocyte 
Count or 
CD4+ T-cell 
Count 
Confirmation
Early 
Discontinuation 
of Treatment
(Base Study)a
End of 
Treatment 
Follow-up
(Base Study)
Discontinuation 
of Treatment 
(OLE)
End of Treatment 
Follow-up (OLE)
Total Lymphocyte 
Count or 
CD4+ T-cell Count 
Monitoring
See Sections 7.1, 8.1.9, 
and 8.11.5 for details 
regarding discontinuation 
and monitoring.
Visit Window
Within 10 to
14 weeks after 
initial 
decrease
NA
42 (+7) days 
after 
discontinuing 
study 
intervention
NA
42 (+7) days 
after 
discontinuing 
study 
intervention
Every 10 to 
14 weeks after 
discontinuing study 
intervention
Biomarkers
Whole Blood 
for FBR
(X)
Optional participation; 
requires FBR consent. 
Collect irrespective of 
time of last dose. (If 
collected at preceding 
CD4/Lymph
Confirmation visit, do 
not collect at Early 
Discontinuation of 
Treatment visit).
AE=adverse event; BIC=bictegravir; BP=blood pressure; DOR=doravirine; EQ-5D-5L=EuroQol 5-dimensional descriptive system, 5-level version; FBR=future biomedical 
research; FTC=emtricitabine; hCG=human chorionic gonadotropin; HIV-1=human immunodeficiency virus type 1; HIV-SI/SDM=Human Immunodeficiency Virus 
Symptom Index/Symptom Distress Module; HIVTSQ=Human Immunodeficiency Virus Treatment Satisfaction Questionnaire; IRT=Interactive Response Technology; 
ISL=islatravir; NA=not applicable; PK=pharmacokinetic(s); POCBP=participants/participants of childbearing potential; RNA=ribonucleic acid; RR=respiratory rate; 
SAE=serious adverse event; TAF=tenofovir alafenamide; TBNK=T and B Lymphocyte and Natural Killer Cell; temp=body temperature.
a
Participants who discontinue at a Scheduled Visit, should complete the assessments for the scheduled visit as well as for the Early Discontinuation of Treatment Visit. 
Collection of laboratory samples should not be duplicated.
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1.3.4
Schedule of Activities for Participants Whose Pregnancy or Postpartum Visit(s) Extends Beyond Week 144
This SoA only applies to eligible participants who are pregnant at Week 144 or who become pregnant in the OLE and consent to 
continue study intervention during pregnancy. Participants will have visits every 12 weeks during the pregnancy and once postpartum. 
If delivery is premature or the 1st trimester visit is missed, the participant may have ≤3 visits before delivery plus the postpartum visit. 
See Section 8.11.6.
•
Manage participants with viremia per Sections 8.2.2 and 8.11.4 (SoA 1.3.2).
•
Participants with specified decreases in total lymphocyte and/or CD4+ T-cell counts per Section 8.11.5 (SoA 1.3.3).
Study Period
Pregnancy
Postpartum
End of Treatmenta
Notes
Visit Number
Unscheduled
Unscheduled
Unscheduled
Unscheduled
Unscheduled
Scheduled Week
Pregnancy 1
Pregnancy 2
(12 weeks 
from 
Pregnancy 1)
Pregnancy 3
(12 weeks 
from 
Pregnancy 2)
Pregnancy 4
(Postpartum 
≤8 weeks after 
delivery)
End of Treatment Follow-up
Visit Window
±7 days
42 (+7) days after the end of 
treatment
Administrative Procedures
Collect and Enter 
Data From Prenatal 
Care Provider
<--------------------------------------X----------------------------------->
Obtain relevant prenatal clinical 
and laboratory data to monitor the 
safety of the mother and fetus per 
Section 8.11.6.
Register Study Visit 
in IRT
X
X
X
X
Dispense Study 
Intervention Using 
IRT
X
X
X
(X)
(DOR/ISL 
Only)
(Postpartum participants on 
DOR/ISL may continue treatment 
through the OLE [Section 1.3.5] if 
not yet commercially accessible; 
those on BIC/FTC/TAF should 
transition to commercially 
accessible ART at their postpartum 
visit per Section 8.6.11.1).
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Study Period
Pregnancy
Postpartum
End of Treatmenta
Notes
Visit Number
Unscheduled
Unscheduled
Unscheduled
Unscheduled
Unscheduled
Scheduled Week
Pregnancy 1
Pregnancy 2
(12 weeks 
from 
Pregnancy 1)
Pregnancy 3
(12 weeks 
from 
Pregnancy 2)
Pregnancy 4
(Postpartum 
≤8 weeks after 
delivery)
End of Treatment Follow-up
Visit Window
±7 days
42 (+7) days after the end of 
treatment
Study Intervention 
Compliance Review
X
X
X
X
Prior and 
Concomitant 
Medications 
Review
X
X
X
X
X
Efficacy Procedures
Plasma HIV-1 RNA 
Quantification
X
X
X
X
X
See Section 8.2.1. Manage 
participants with viremia per 
Section 1.3.2 and 8.2.2.
Plasma for HIV-1 
Drug Resistance
X
X
X
X
X
Analysis performed by Sponsor if 
indicated per Section 8.2.2.1.2.
TBNK Panel/CD4+ 
T-cell Count
X
X
X
X
X
Safety Procedures
Weight
X
X
X
X
X
Directed Physical 
Examination
X
X
X
X
X
Vital Signs
X
X
X
X
X
Hepatitis B 
Serology and HBV 
DNA (DOR/ISL 
only)
<--------------------X-------------------->
Collect once after pregnancy is 
confirmed or report local laboratory 
results. See Section 8.11.6.1.
Chemistry
X
X
X
X
X
Hematology
X
X
X
X
X
Urinalysis
X
X
X
X
X
AE/SAE Review
X
X
X
X
X
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Study Period
Pregnancy
Postpartum
End of Treatmenta
Notes
Visit Number
Unscheduled
Unscheduled
Unscheduled
Unscheduled
Unscheduled
Scheduled Week
Pregnancy 1
Pregnancy 2
(12 weeks 
from 
Pregnancy 1)
Pregnancy 3
(12 weeks 
from 
Pregnancy 2)
Pregnancy 4
(Postpartum 
≤8 weeks after 
delivery)
End of Treatment Follow-up
Visit Window
±7 days
42 (+7) days after the end of 
treatment
Pharmacokinetics
Blood (Plasma) for 
DOR and ISL PK
X
X
X
X
X
Collect only for participants on 
DOR/ISL during the 1st, 2nd, and 
3rd trimesters and postpartum per 
Section 8.11.6.1.1 (Table 7).
AE=adverse event; BIC=bictegravir; BP=blood pressure; DNA=deoxyribonucleic acid; DOR=doravirine; FBR=future biomedical research; FTC=emtricitabine; HBV=hepatitis 
B virus; HIV-1=human immunodeficiency virus type 1; IRT=Interactive Response Technology; ISL=islatravir; PK=pharmacokinetic(s); OLE=open-label extension; 
RNA=ribonucleic acid; RR=respiratory rate; SAE=serious adverse event; TAF=tenofovir alafenamide; TBNK=T and B Lymphocyte and Natural Killer Cell; 
temp=temperature.
a
The procedures in this End of Treatment Follow-up Visit should be followed for those participants not continuing in the OLE.
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1.3.5
Schedule of Activities – Week 144 Through Week 240 (Open-label Extension)
This SoA only applies to participants who enter the optional OLE at Week 144.
•
Duration of participation in the OLE is dependent on when DOR/ISL becomes commercially accessible, with a maximum 
treatment duration of 96 weeks (ie, total study intervention duration of up to 240 weeks).
•
Manage participants with viremia per Sections 8.2.2 and 8.11.4 (SoA Section 1.3.2).
•
Manage participants with specified decreases in total lymphocyte and/or CD4+ T-cell counts per Section 8.11.5 (SoA Section 
1.3.3).
•
Manage pregnant participants per Section 8.11.6 (SoA Section 1.3.4).
Study Period
Optional OLE
End of Treatment
Notes
Visit Number
16
17
18
19
20
Unscheduled
Unscheduled
Scheduled Day/Week
Week 148 
(Group 2 
Only)
Week 168
Week 192
Week 216
Week 240
Discontinuation 
of Treatment
(OLE)a
End of Treatment 
Follow-up 
(OLE)
Visit Window
±14 days 
(Calculate each visit from date of Day 1)
NA
42 (+7) days after 
end of treatment
Evaluate Local 
Accessibility of 
DOR/ISL
X
X
X
X
X
Once DOR/ISL is commercially accessible, 
participants should return to the study-site for 
the Discontinue of Treatment visit and 
transition to the local supply.
Prior and Concomitant 
Medication Review
X
X
X
X
X
X
X
Register Study Visit in 
IRT
X
X
X
X
X
X
Dispense Study 
Intervention Using IRT
X
X
X
X
(X)
(Dispense at Week 240 if needed for pregnant
participants see Section 1.3.4).
Study Intervention 
Compliance Review
X
X
X
X
X
X
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Study Period
Optional OLE
End of Treatment
Notes
Visit Number
16
17
18
19
20
Unscheduled
Unscheduled
Scheduled Day/Week
Week 148 
(Group 2 
Only)
Week 168
Week 192
Week 216
Week 240
Discontinuation 
of Treatment
(OLE)a
End of Treatment 
Follow-up 
(OLE)
Visit Window
±14 days 
(Calculate each visit from date of Day 1)
NA
42 (+7) days after 
end of treatment
Plasma HIV-1 RNA 
Quantification
X
X
X
X
X
X
See Section 8.2.1.
TBNK Panel/CD4+ T-
cell Count
X
X
X
X
X
X
Blood (Plasma) for 
HIV-1 Drug Resistance
X
X
X
X
X
X
Analysis will be performed by Sponsor if 
indicated per Section 8.2.2.1.2.
Hepatitis B Serology 
and HBV DNA
X
X
Encourage HBV vaccination to participants
who are not immune to HBV. Repeat serology 
and HBV DNA testing at Weeks 192 and 240
(annual surveillance).
HBsAg and HBV DNA
(X)
(X)
(X)
(X)
(X)
(Only anti-HBc-positive participants, at each 
visit.) See Section 8.3.6.
Hematology
X
X
X
X
X
X
Directed Physical 
Examination
X
X
X
X
X
X
X
AE/SAE Review
X
X
X
X
X
X
X
Contraceptive Use 
Confirmation
(POCBP Only)
X
X
X
X
X
X
X
Contraception is required 42 days after the last 
dose of study intervention.
Urine Pregnancy Test 
(hCG) (POCBP Only)
X
X
X
X
X
X
X
Manage participants who have a positive or 
indeterminant urine test per Sections 1.3.4 and 
8.11.6. For participants known to be pregnant, 
defer until 6 weeks postpartum.
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Study Period
Optional OLE
End of Treatment
Notes
Visit Number
16
17
18
19
20
Unscheduled
Unscheduled
Scheduled Day/Week
Week 148 
(Group 2 
Only)
Week 168
Week 192
Week 216
Week 240
Discontinuation 
of Treatment
(OLE)a
End of Treatment 
Follow-up 
(OLE)
Visit Window
±14 days 
(Calculate each visit from date of Day 1)
NA
42 (+7) days after 
end of treatment
Informed Consent for 
Study Intervention 
During Pregnancy
< ---------------X--------------- >
Obtain upon confirmation of pregnancy. See 
Sections 1.3.4 and 8.1.1.3.
AE=adverse event; anti-HBc=hepatitis B core antibody; BIC=bictegravir; BP=blood pressure; DEXA=dual-energy X-ray absorptiometry; DNA=deoxyribonucleic acid; 
DOR=doravirine; ECG=electrocardiogram; EQ-5D-5L=EuroQol 5-dimensional descriptive system, 5-level version; FBR=future biomedical research; FTC=emtricitabine; 
HBV=hepatitis B virus; hCG=human chorionic gonadotropin; HIV-1=human immunodeficiency virus type 1; HIV-2= human immunodeficiency virus type 2; 
HIV-SI/SDM=Human Immunodeficiency Virus Symptom Index/symptom distress module; INR=international normalized ratio; IRT=interactive response technology; 
ISL=islatravir; NA=not applicable; OLE=open-label extension PK=pharmacokinetic(s); POCBP=participant/participants of childbearing potential; PT=prothrombin time; 
RNA=ribonucleic acid; RR=respiratory rate; SAE=serious adverse event; TAF=tenofovir alafenamide; TBNK=T and B lymphocyte and natural killer cells; temp=body 
temperature.
a
If discontinuation occurs at a scheduled visit, perform Discontinuation of Treatment (OLE) visit assessments.
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2
INTRODUCTION
DOR/ISL (also known as MK-8591A) is a novel 2-drug FDC of DOR (100 mg) (an approved 
NNRTI) and ISL (0.25 mg) (an investigational NRTTI). DOR/ISL is being developed for QD 
treatment of HIV-1 infection.
2.1
Study Rationale
As treatment regimens have improved, HIV-1 infection has become a chronic, manageable
condition, and PLWH receiving effective ART regimens can expect to live near-normal 
lifespans [Trickey, A., et al 2017]. Anticipating that individuals can receive decades of 
treatment during their lifetime, long-term tolerability and safety of antiretrovirals have 
become increasingly important considerations.
The current standard of care for the treatment of HIV-1 is a combination of 2 NRTIs with a 
third agent (eg, InSTI, NNRTI, or PI) [Panel on Antiretroviral Guidelines for Adults and 
Adolescents 2022] [European AIDS Clinical Society 2021] [World Health Organization 
2021]. Although these 3-drug regimens are well tolerated and highly efficacious, the current 
paradigm of lifelong daily treatment is associated with a need for simpler and safer regimens 
that reduce overall drug exposure [Llibre, J. M., et al 2018] [Cahn, P., et al 2019] [Panel on 
Antiretroviral Guidelines for Adults and Adolescents 2022]. As this population ages, there is 
increasing concern about polypharmacy, long-term toxicity, and DDIs related to comorbidity 
and multimorbidity and risks associated with the emergence of HIV-1 variants resistant to 
InSTI, NRTI, and NNRTI treatments.
There is evidence that 2-drug regimens can achieve efficacy comparable to that of 3-drug 
regimens, offer better tolerability, and improve quality of life; all of which can support 
adherence and help to sustain virologic suppression [Llibre, J. M., et al 2018] [Cahn, P., et al 
2019] [Panel on Antiretroviral Guidelines for Adults and Adolescents 2022]. The 
effectiveness 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 effective and well tolerated 2-drug regimen for the 
treatment of HIV-1 infection in the switch setting due to its potent antiretroviral activity 
(including activity against common NRTI- and NNRTI-resistant variants), multiple 
mechanisms of action, lack of food requirements, and favorable DDI profiles observed to 
date (see Section 2.2.3).
2.2
Background
Refer to the approved local labeling for DOR and to the IB for ISL for detailed background 
information.
2.2.1
Islatravir
ISL is a novel and potent NRTTI that blocks HIV-1 reverse transcriptase by novel 
mechanisms of action. It is a nucleoside analog that is converted to the pharmacologically 
active triphosphate (ISL-TP) form via endogenous intracellular kinases. It acts through 
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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, and 
favorable drug resistance profile. At the proposed dose of 0.25 mg QD, ISL achieves higher 
steady-state IQs (the ratio of drug exposure to viral susceptibility [Ctrough/IC50]) against 
wild-type HIV-1 than any NRTI currently approved for treatment. It also exhibits potent 
activity against the most prevalent NRTI resistance mutations, including M184V.
2.2.2
Doravirine
DOR, a potent NNRTI with demonstrated efficacy and good tolerability, was first approved 
for the treatment of HIV-1 infection by the FDA and EMA in 2018. It is differentiated from 
other NNRTIs by its distinct resistance profile, low likelihood of selection for viral resistance 
in vivo, and low potential for DDIs. It exhibits potent activity against both wild-type HIV-1 
virus and frequently transmitted NNRTI-resistant variants (eg, K103N, Y181C, G190A, and 
E138K) in vitro. The efficacy and safety profiles of DOR have been well characterized in 
Phase 3 studies conducted in treatment-naïve adult participants [Orkin, C., et al 2019]
[Molina, J. M., et al 2018] and in virologically suppressed adult participants switching from a 
stable antiretroviral regimen [Johnson, M., et al 2019].
2.2.3
Doravirine/Islatravir
DOR/ISL is an FDC containing DOR (100 mg) and ISL (0.25 mg), administered as a single-
tablet QD. DOR and ISL represent 2 distinct antiretroviral agents that inhibit reverse 
transcription by different mechanisms. Based on the profile of each and data available to 
date, the combination DOR/ISL is expected to be well tolerated and highly efficacious, with 
a high barrier to resistance. The combination has demonstrated additive antiretroviral 
activity, with complementary resistance profiles, and suppressed the emergence of resistance 
in vitro at clinically relevant concentrations.
DOR/ISL (100 mg/0.75 mg) has demonstrated antiretroviral activity in Phase 3 studies in 
virologically suppressed (MK-8591A-017 and MK-8591A-018) and TN adults 
(MK-8591A-020) with HIV-1. Additional details are available in the IB.
In MK-8591-011 (Phase 2, dose-ranging study), ISL doses of 0.25, 0.75, and 2.25 mg were 
administered to treatment-naïve adults initially in 3-drug regimens (ISL+DOR+3TC) until 
virologic suppression (HIV-1 RNA <50 copies/mL) was achieved, at which point the 
regimen was simplified to a 2-drug regimen (ISL+DOR) for maintenance of suppression. The 
DOR+ISL regimens achieved efficacy (HIV-1 RNA <50 copies/mL) comparable with the 
FDC comparator (DOR/3TC/TDF) used in MK-8591-011. No participant met criteria for 
clinically significant confirmed viremia (HIV-1 RNA ≥200 copies/mL) through Week 144. 
The overall AE profile for ISL+DOR (±3TC) was similar for each dose of ISL and generally 
comparable with DOR/3TC/TDF through Week 144. Differences in changes from baseline in 
total lymphocyte and CD4+ T-cell counts were observed for the different ISL dose groups 
(see Section 2.3).
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In MK-8591A-020, DOR/ISL (100 mg/0.75 mg) was non-inferior to BIC/FTC/TAF, as 
assessed by the percentage of participants achieving virologic suppression (HIV-1 RNA 
<50 copies/mL) at Week 48 (88.9% vs 88.3%, respectively). Treatment-emergent resistance 
was observed for 2 participants (DOR/ISL group), which was considered in both cases to be 
due to nonadherence to treatment, as the participant’s ISL levels were BLOQ at the time of 
viremia.
2.2.4
Information on Other Study-related Therapy
BIC/FTC/TAF was first approved in 2018 for the treatment of HIV-1 infection and will be 
administered at the approved marketed dose. Refer to the approved local labeling for detailed 
information for BIC/FTC/TAF.
2.3
Benefit/Risk Assessment
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 100 mg/0.25 mg FDC in Phase 3 studies.
There remains significant unmet need for novel ART as an alternative option for HIV-1 
treatment that is suitable across the population of PLWH, including the elderly and those 
with multiple comorbidities. High in vitro potency against wild-type HIV-1 virus and a high 
barrier to resistance make DOR and ISL suitable candidates for treatment of HIV-1 infection. 
Administration of ISL in doses of 0.25, 0.75, and 2.25 mg with DOR 100 mg and 3TC 
300 mg in MK-8591-011 achieved virological suppression in >90% of treatment-naïve 
participants by Week 24, which was maintained after switching from the 3-drug regimen 
(ISL+DOR+3TC) to the 2-drug regimen (ISL+DOR) through Week 144. The antiviral 
efficacy and overall AE profile through Week 72 (the dose-ranging part of MK-8591-011) 
were not distinguishable among the 3 ISL dose groups (0.25, 0.75, and 2.25 mg).
DOR/ISL (100 mg/0.75 mg QD) was highly efficacious in maintaining virologic suppression 
(>95% and >93% of participants had HIV-1 RNA <50 copies/mL at Week 48) in participants 
who switched from various baseline ARTs, including BIC/FTC/TAF, in the 2 Phase 3 studies 
(MK-8591A-017 and MK-8591A-018, respectively). To date, viral resistance was observed 
for 2 participants receiving DOR/ISL across the Phase 2 (MK-8591-011) and Phase 3 
(MK-8591A-017, MK-8591A-018, and MK-8591A-020) programs, in which 1693 TN and 
virologically-suppressed participants with HIV-1 infection received DOR/ISL. These
participants were enrolled in the MK-8591A-020 study. Across the ISL clinical development 
program involving approximately 2300 participants enrolled in Phase 2 and Phase 3 studies, 
there was a low incidence of drug-related AEs, SAEs, and deaths with ISL when 
administered alone or with DOR; decreases in lymphocyte counts were observed.
Comprehensive nonclinical safety evaluation of DOR and ISL as mono-entities has not 
revealed toxicities of concern. Nonclinical developmental and reproductive toxicity studies 
did not identify any clinically relevant concerns that would preclude continued dosing of 
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DOR/ISL in participants who become pregnant during the study. Both DOR and ISL may be 
administered without regard to food and have a low potential for DDIs, a favorable attribute 
for those who have multiple chronic comorbidities.
Decreases in total lymphocyte and lymphocyte subset (including CD4+ T-cell) counts have 
been observed in Phase 2 and Phase 3 studies with ISL given QM (60 and 120 mg), QW 
(20 mg in combination with MK-8507, an NNRTI), and QD (0.75 mg in combination with 
DOR 100 mg). As a result, dosing was stopped in December 2021 for ISL 60 mg QM for 
HIV-1 PrEP, ISL QW 20 mg (with MK-8507) for HIV-1 treatment, and DOR/ISL 
(100 mg/0.75 mg) QD for HIV-1 treatment in pediatric participants.
The Sponsor has conducted a comprehensive investigation into ISL-related decreases in 
lymphocyte counts to identify possible mechanism(s) of action and to assess the timing and 
extent of lymphocyte decreases while on treatment with ISL and the recovery of lymphocyte 
counts when off-treatment with ISL.
Investigations of possible mechanisms for the lymphocyte decreases support the conclusion 
that the preferential accumulation of ISL-TP in lymphocytes can lead to inhibition of cell 
growth and apoptosis at high ISL-TP concentrations. Toxicity due to high TP levels is a 
common mechanism among HIV nucleoside analog drugs. Mitochondrial toxicity is not a 
contributing mechanism to the decrease in lymphocytes.
An overall summary of the comprehensive investigation into ISL-related decreases in 
lymphocyte counts is as follows:
•
No changes in general hematology parameters (including hemoglobin, basophils, 
eosinophils, monocytes, leukocytes, neutrophils, platelets) were observed for participants 
receiving ISL alone or in combination with other ART in any study.
•
ISL dose-dependent decreases from baseline were observed in mean total lymphocyte 
counts and lymphocyte subset (CD4+ T-cell, CD8+ T-cell, B-cell) counts, with greater 
decreases observed at the higher ISL doses administered QW (20 mg) and QM (60 mg) 
compared with QD (0.75 mg) administration.
-
In VS participants in MK-8591A-017 and MK-8591A-018 receiving DOR/ISL 
100 mg/0.75 mg QD, mean percent changes from baseline were observed in total 
lymphocyte (-10.6% and -8.4%, respectively), CD4+ T-cell (-0.68% and +0.87%, 
respectively), CD8+ T-cell (-8.2% and -7.4%, respectively), and B-cell (-4.4% 
and -8.6%, respectively) counts at Week 48.
-
In VS participants in MK-8591-013 receiving ISL 20 mg + MK-8507 100 to 400 mg 
QW, mean percent changes from baseline were observed in total lymphocyte (-15.1% 
to -30.9%), CD4+ T-cell (-7.6% to -28.1%), CD8+ T-cell (-18.1% to -32.8%), and 
B-cell (-36.8% to -46.3%) counts were observed at Week 24.
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-
In participants with low risk of HIV-1 infection receiving ISL 60 or 120 mg QM for 
PrEP, the on-treatment mean decreases from baseline in total lymphocyte count 
were -21.3% and -35.6% at Week 24, respectively.
•
Stabilization of the decreases from baseline in mean total lymphocyte count and 
lymphocyte subset counts observed for the DOR/ISL 100 mg/0.75 mg QD program 
occurred between Weeks 48 and 72, depending on the lymphocyte subset.
•
Decreases from baseline in mean total lymphocyte count and lymphocyte subset counts 
were not associated with increased incidence of infection.
•
A return toward baseline in lymphocyte and lymphocyte subset counts has been observed 
across the ISL clinical development program. However, a full recovery was not observed 
by 24 weeks after stopping ISL. The most robust data on recovery of the lymphocyte 
counts available at this point was from the studies involving administration of ISL QW 
(20 mg) and QM (60-120 mg), as detailed below. Data on recovery to baseline following 
discontinuation of DOR/ISL 100 mg/ 0.75 mg QD in VS adults (MK-8591A-017 and 
MK-8591A-018) is not yet available.
•
Approximately 6 months after discontinuation of ISL 20 mg QW in adult VS participants 
(MK-8591-013), among those with ≥30% decrease in total lymphocyte or CD4+ T-cell 
counts at their last on-treatment measurement and at least 1 follow-up result, 10/40 (25%) 
and 15/32 (47%) participants demonstrated an increase in total lymphocyte and CD4+ 
T-cell counts, respectively, to within 10% of baseline.
•
Approximately 5 months after discontinuation of ISL 60 mg QM in adults at risk of 
HIV-1 infection, 43 (29.9%) of the 144 participants in MK-8591-022 and MK-8591-024 
with a ≥30% decrease in total lymphocyte count at the last on-treatment visit 
demonstrated an increase in total lymphocyte counts to within 10% of baseline.
Overall, the evaluation of data from across the ISL clinical programs to date suggests that the 
decrease in mean total lymphocyte and lymphocyte subset counts is ISL dose-dependent, 
with lower doses less likely to cause decreases. A new FDC of DOR/ISL containing a 
0.25-mg dose of ISL will be evaluated in the current study. In the dose-ranging phase of 
MK-8591-011 (Part 1 and Part 2 through Week 72), participants who received ISL 0.25 mg 
QD had changes in total lymphocyte and CD4+ T-cell counts comparable to those observed 
for participants in the DOR/3TC/TDF comparator group. The results of modeling analyses of 
ISL exposure-effect predict no meaningful decreases in total lymphocyte or CD4+ T-cell 
counts with the 0.25 mg daily dose (see Section 4.3). To mitigate any risk, close monitoring 
and discontinuation criteria (Sections 1.3.3, 7.1, and 8.11.5) for individuals who experience 
significant decreases in lymphocytes are included in this protocol.
BIC/FTC/TAF is currently an approved InSTI based single-tablet regimen for the treatment 
of HIV-1 infection in patients naïve to ART or to replace the current ART regimen in those 
who are virologically suppressed. Refer to the approved local labeling for detailed 
benefit-risk information on BIC/FTC/TAF.
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Additional details regarding DOR can be found in the local product label. Details regarding 
ISL and DOR/ISL can be found in the accompanying IB.
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3
HYPOTHESES, OBJECTIVES, AND ENDPOINTS
Hypotheses are aligned with objectives in the Objectives and Endpoints table.
The following objectives will be evaluated in participants ≥18 years of age with HIV-1 who 
have been virologically suppressed (ie, HIV-1 RNA <50 copies/mL) for ≥3 consecutive 
months on BIC/FTC/TAF.
Primary Objective
Primary Endpoint
To evaluate the antiretroviral activity of a 
switch to DOR/ISL compared with continued 
BIC/FTC/TAF, as assessed by the 
percentage of participants with HIV-1 RNA 
≥50 copies/mL at Week 48
Hypothesis (H1): DOR/ISL is non-inferior 
to BIC/FTC/TAF, as assessed by the 
percentage of participants with HIV-1 RNA 
≥50 copies/mL at Week 48. A margin of 
4 percentage points is used to define 
non-inferiority.
Hypothesis (H2): DOR/ISL is superior to 
BIC/FTC/TAF, as assessed by the 
percentage of participants with HIV-1 RNA 
≥50 copies/mL at Week 48.
HIV-1 RNA
To evaluate the safety and tolerability of a 
switch from BIC/FTC/TAF to DOR/ISL 
compared with continued BIC/FTC/TAF, as 
assessed by review of the safety data 
accumulated through Week 48
Adverse events
Adverse events leading to discontinuation 
of study intervention
Secondary Objectives
Secondary Endpoints
To evaluate the antiretroviral activity of a 
switch to DOR/ISL compared with continued 
BIC/FTC/TAF, as assessed by the 
percentage of participants with HIV-1 RNA 
≥50 copies/mL at Week 96 and Week 144
Hypothesis (H3): DOR/ISL is superior to 
BIC/FTC/TAF, as assessed by the 
percentage of participants with HIV-1 RNA 
≥50 copies/mL at Week 96.
Hypothesis (H4): DOR/ISL is superior to 
BIC/FTC/TAF, as assessed by the 
percentage of participants with HIV-1 RNA 
≥50 copies/mL at Week 144.
HIV-1 RNA
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To evaluate the antiretroviral activity of a 
switch to DOR/ISL compared with continued 
BIC/FTC/TAF, as assessed by the 
percentage of participants with the following 
at Week 48, Week 96, and Week 144:
- HIV-1 RNA <200 copies/mL
- HIV-1 RNA <50 copies/mL
HIV-1 RNA
To evaluate the immunologic effect of a 
switch to DOR/ISL compared with continued 
BIC/FTC/TAF, as assessed by the mean 
change from baseline in CD4+ T-cell count 
at Week 48, Week 96, and Week 144
CD4+ T-cell count
To evaluate the development of viral drug 
resistance to any study intervention at 
Week 48, Week 96, and Week 144
Viral resistance-associated substitutions
To evaluate the safety and tolerability of a 
switch from BIC/FTC/TAF to DOR/ISL 
compared with continued BIC/FTC/TAF, as 
assessed by review of the safety data 
accumulated through Week 144
Adverse events
Adverse events leading to discontinuation 
of study intervention
Tertiary/Exploratory Objectives
Tertiary/Exploratory Endpoints
To evaluate the effects on weight, body 
composition, fasting lipid and metabolic 
profiles, bone density, renal function, and 
inflammation of a switch to DOR/ISL 
compared with continued BIC/FTC/TAF, as 
assessed by the mean change in these 
parameters from baseline at Week 48,
Week 96, and Week 144
Weight, body composition, BMD, and 
laboratory markers
To evaluate the effect of DOR/ISL compared 
with BIC/FTC/TAF on total lymphocyte 
count at Weeks 48, 96, and 144
Total lymphocyte count
To describe PROs (HRQoL, HIV treatment 
satisfaction, and HIV symptoms) after a 
switch to DOR/ISL compared with continued 
BIC/FTC/TAF at Week 48 and Week 96
EQ 5D 5L, HIVTSQ, and HIV SI/SDM
To evaluate the pharmacokinetics of ISL 
when administered as a component of 
DOR/ISL
Pharmacokinetic values, e.g. AUC, Cmax, 
and C24
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To evaluate the long-term antiretroviral 
activity of DOR/ISL in participants initially 
randomized to Group 1 and the antiretroviral 
activity of a switch to DOR/ISL in 
participants initially randomized to Group 2, 
as assessed by the percentage of participants 
with
- HIV-1 RNA ≥50 copies/mL,
- HIV-1 RNA <50 copies/mL,
- HIV-1 RNA <200 copies/mL
in those enrolled in the open-label extension
HIV-1 RNA
To evaluate the long-term immunologic 
effect of DOR/ISL, as assessed by mean 
changes in CD4+ T-cell count over time in 
participants enrolled in the open-label 
extension
CD4+ T-cell count
To evaluate the long-term effect of DOR/ISL 
on total lymphocyte count in participants 
enrolled in the open-label extension
Total lymphocyte count
To evaluate the development of viral drug 
resistance to DOR/ISL in the open-label 
extension
Viral resistance associated substitutions
To evaluate the long-term safety and 
tolerability of DOR/ISL, as assessed by 
review of the safety data accumulated in 
participants enrolled in the open-label 
extension
Adverse events
Adverse events leading to discontinuation 
of study intervention
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 and association 
to clinical data collected in this study
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4
STUDY DESIGN
4.1
Overall Design
This is a Phase 3, randomized, active-controlled, multi-site, double-blind study to evaluate a 
switch from BIC/FTC/TAF QD to DOR/ISL (100 mg/0.25 mg QD) in participants with 
HIV-1 who have been virologically suppressed on BIC/FTC/TAF for ≥3 consecutive months 
with no history of virologic treatment failure.
The study consists of a screening period of up to 45 days and a blinded treatment period 
(base study) of 144 weeks with participants receiving either DOR/ISL or BIC/FTC/TAF, 
followed by an optional OLE of up to 96 weeks with participants continuing on or switching 
to DOR/ISL (Figure 1).
Base Study
A total of approximately 501 participants will be randomized in a 2:1 ratio into 1 of 
2 treatment groups (Figure 1):
•
Group 1 (n=approximately 334): Switch from BIC/FTC/TAF QD to DOR/ISL 
(100 mg/0.25 mg QD) on Day 1 and continue DOR/ISL QD through Week 144 (taken 
with matching placebo to BIC/FTC/TAF through Week 144).
•
Group 2 (n=approximately 167): Continue BIC/FTC/TAF QD through Week 144 (taken 
with matching placebo to DOR/ISL (100 mg/0.25 mg QD) through Week 144).
All participants will receive 144 weeks of assigned blinded therapy in the base study. 
Participants who complete the last visit in the base study (Week 144) will be given an option 
to receive open-label DOR/ISL until it is commercially accessible (Section 6.7). Study 
intervention will be extended open-label for participants who become pregnant on treatment 
and provide documented informed consent to continue their assigned study intervention 
(DOR/ISL or BIC/FTC/TAF in the base study or open-label DOR/ISL in the OLE), as 
specified in Sections 1.3.4 and 8.11.6.Clinical site personnel and participants will remain 
blinded through Week 144 while Sponsor personnel will remain blinded through Week 48. 
Efficacy and safety laboratory results, including HIV-1 RNA, will remain unmasked 
throughout the study. At Week 144, all participants and site personnel will be unblinded.
Participants and all field and study-site personnel will remain blinded through the end of the 
base study (Week 144). Any participants with clinically significant confirmed viremia 
(Section 4.2.1.1.2) will be assessed for development of viral drug resistance and 
discontinuation from study intervention per the SoA (Section 1.3.2) and Section 7.1.
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Participant safety will be monitored by an independent eDMC through periodic review of 
efficacy and safety data throughout the study per the timing specified in the eDMC charter 
(Appendix 1). Additionally, the following IA is planned (see Section 9.7):
•
Week 24 IA: An IA to assess futility will be performed by the external unblinded 
statistician when approximately 30% of the total target enrollment has completed the 
Week 24 visit assessments. The nonbinding futility criterion is described in Section 9.7.
Open-Label Extension (OLE)
At Week 144, participants from both groups who meet criteria in Section 8.11.2.3 and 
consent to enter the OLE will continue (Group 1) or switch to (Group 2) open label DOR/ISL 
up to Week 240 or until it is commercially accessible (whichever comes first). Procedures to 
be followed upon exiting the OLE are outlined in Section 6.7.
Consistent with global HIV-1 treatment guidelines [Food and Drug Administration (CDER) 
2015] [European AIDS Clinical Society 2021] the OLE consists of in-clinic visits every 6 
months to assess maintenance of virologic suppression, CD4+ T-cell count and tolerability. 
Group 2 (BIC/FTC/TAF) participants who switch to DOR/ISL at Week 144 will have a 
follow-up visit at Week 148 to assess, for continued viral suppression and tolerability 4 
weeks after the switch, in accordance with HIV-1 treatment guidelines. Where local 
treatment guidelines require visits more frequently than every 6 months, these are permitted 
and should be conducted by the primary investigator and/or the treating physician.
Specific procedures to be performed during the study, including prescribed times and 
associated visit windows, are outlined in Section 1.3 of the SoA. Details of each procedure 
are provided in Section 8.
4.2
Scientific Rationale for Study Design
Base Study
The randomized, active-controlled, non-inferiority study design is consistent with the FDA 
CDER 2015 Guidance for Industry: Human Immunodeficiency Virus-1 Infection: 
Developing Antiretroviral Drugs for Treatment [Food and Drug Administration (CDER) 
2015] and is considered appropriate for a treatment-experienced study population that is 
switching from another stable ART regimen with HIV RNA <50 copies/mL. Small 
differences in virologic efficacy, emergence of resistance, and loss of tolerability or safety 
may be detected prior to 48 weeks of treatment, particularly for therapies with largely 
comparable characteristics. Thus, an efficacy and safety outcome through 48 weeks is 
aligned with current regulatory guidance [Food and Drug Administration (CDER) 2015], and 
the primary efficacy and safety analyses will occur after 48 weeks of treatment with 
DOR/ISL or BIC/FTC/TAF. A 2:1 randomization ratio optimizes collection of efficacy and 
safety data on the DOR/ISL investigational product relative to the approved BIC/FTC/TAF 
comparator product taken by the Group 2 participants in this study. The blinded treatment 
(base study) duration is 144 weeks to allow for collection of long-term comparative efficacy 
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and safety data for DOR/ISL vs. BIC/FTC/TAF. Participants and investigators remain 
blinded for the duration of comparative data collection to minimize potential bias.
Open-Label Extension (OLE)
The primary rationale for the OLE is to provide access to DOR/ISL until it is commercially 
accessible. Participation in the OLE is optional and allows eligible participants who are 
deriving benefit from treatment in the DOR/ISL group to continue DOR/ISL and avoid 
interruption of treatment. The OLE also allows participants assigned to the comparator to 
have the option to switch to DOR/ISL at the completion of the base study in accordance with 
standard practice in HIV trials. The OLE will also allow for long-term efficacy and safety 
data collection for DOR/ISL.
4.2.1
Rationale for Endpoints
4.2.1.1
Efficacy Endpoints
4.2.1.1.1
HIV-1 RNA Measurements
The primary efficacy endpoint in this study is plasma HIV-1 RNA ≥50 copies/mL. Eligible 
participants in the switch population being studied are virologically suppressed, with HIV-1 
RNA <50 copies/mL at screening. The assessment of interest is the percentage of participants 
who are unable to maintain virologic suppression after switching to a new antiretroviral 
regimen.
Clinical studies of antiretroviral agents in multiple drug classes have demonstrated that 
virologic suppression of HIV-1 RNA to <50 copies/mL reflects a clinically relevant standard 
used across development programs for antiretroviral therapies and in clinical practice 
[Vandenhende, M. A., et al 2015]. Suppressing HIV-1 RNA to <50 copies/mL preserves the 
immune system and minimizes the risk of opportunistic infections and disease progression.
The secondary efficacy endpoint of plasma HIV-1 RNA <200 copies/mL corresponds to the 
clinically relevant threshold. With values ≥200 copies/mL, there is an increased risk of 
development of resistance.
4.2.1.1.2
Definition of Clinically Significant Confirmed Viremia
For the purpose of managing participants in this study, clinically significant confirmed 
viremia is defined as:
•
Two consecutive occurrences 4 weeks (±1 week) apart of HIV-1 RNA ≥200 copies/mL at 
any time during the study.
There is currently no global standard for the definition of low-level viremia 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 
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results in treatment modification or more frequent virologic monitoring [Panel on 
Antiretroviral Guidelines for Adults and Adolescents 2022]. PLWH with HIV-1 RNA ≥50 
and <200 copies/mL have a lower risk of developing resistance compared with those with 
HIV-1 RNA ≥200 copies/mL. Therefore, study participants with HIV-1 RNA ≥50 and 
<200 copies/mL should continue their current regimen, with HIV-1 RNA levels monitored as 
outlined in Section 8.2.2.
If a participant has an HIV-1 RNA value ≥50 copies/mL, a reflex HIV-1 RNA test will be 
conducted by the central laboratory on the same plasma sample obtained at that visit, if 
available. For management of participants see Section 8.2.2.
4.2.1.2
Safety Endpoints
Safety evaluations will include physical examinations (including vital signs) and laboratory 
tests (eg, hematology, TBNK, 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.
Due to decreases in total lymphocyte counts observed in clinical studies with DOR/ISL 
100mg/0.75mg, these parameters will be evaluated at Weeks 48, 96, 144 and the OLE.
4.2.1.3
Weight, Body Composition, and Radiological and Laboratory Markers
The study will evaluate changes from baseline at Week 48, Week 96, and Week 144 in 
weight, body composition, BMD, and laboratory markers in the treatment groups to evaluate 
the impact of DOR/ISL on the following outcomes per the SoA (Section 1.3):
Inflammation
Causes of persistent inflammation and thrombotic activity in patients with HIV-1 remain 
topics of debate and ongoing research [Baker, J. V., et al 2011] [Knudsen, T. B., et al 2016]
[Wang, H., et al 2016]; thus, key indicators of inflammation will be measured 
(Section 8.3.9.1).
Weight
Increases in body weight have been reported in PLWH on long-term ART and have long 
been considered a return-to-health phenomenon. However, evidence suggests that excess 
weight gain may be associated with certain ARV agents, which may have long-term health 
effects [Bailin, S. S., et al 2020] [Shah, S., et al 2021] [Buzon-Martin, L. 2020] [Wood, B. R. 
2021]. In contrast, other ARV drugs, such as TDF and EFV, may have an anti-obesogenic 
effect [Hill, A., et al 2019]. Compared with other antiretroviral classes, use of integrase 
inhibitors in patients with HIV-1 has been associated with greater increases in body weight 
[Hill, A., et al 2019]. The mean change in weight will be compared between participants who 
switch to DOR/ISL and participants who continue taking BIC/FTC/TAF (Sections 8.3.1 
and 8.3.9.4).
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Body Composition
Decreases in BMD and lipodystrophy (peripheral and central fat redistribution) have been 
reported in patients with HIV-1 receiving ART [Panel on Antiretroviral Guidelines for 
Adults and Adolescents 2022] [McComsey, G. A., et al 2018], particularly with the use of 
certain NRTIs. Key indicators of body composition (including waist-to-hip ratio and DEXA 
assessments) will be measured (Sections 8..3.9.4 and 8.3.9.5, respectively).
Fasting Lipid and Metabolic Profiles
Some antiretrovirals have been associated with lipid abnormalities [U.S. Prescribing 
Information 2017]; thus, key indicators of fasting lipid profiles will be measured 
(Section 8.3.9.3).
Insulin resistance has been reported with certain antiretroviral therapies [Carr, A., et al 1998]. 
It is associated with metabolic complications including diabetes, cardiovascular disease, fatty 
liver, and weight gain [Vazquez-Carrera, M. 2016]. Fasting insulin and glucose will be 
measured to calculate HOMA-IR, and HbA1c (fasting or nonfasting) will be measured to 
evaluate glycemic control over time.
The adipokines, leptin and adiponectin, will be measured as exploratory assessments of 
metabolic function and predictors of weight gain [Taylor, E. B. 2021]. These are established 
markers for lipid metabolism and energy utilization to be explored against BIC/FTC/TAF, 
particularly as more data emerge about the metabolic effects of InSTIs.
Renal Function
Decreases in renal function have been noted with the use of certain NRTIs [U.S. Prescribing 
Information 2019]; thus, key indicators of renal function will be measured (Section 8.3.9.2).
4.2.1.4
Pharmacokinetic Endpoints
PK samples collected from all participants as described in the SoAs (Section 1.3) and 
Section 8.6 will be used to evaluate PK concentrations of ISL, and, as appropriate, 
PK-efficacy, PK-pharmacodynamic, and PK-AE relationships of ISL. PK values including 
AUC, Cmax, and C24 will be explored.
4.2.1.5
Patient-reported Outcomes
PROs can provide unique information on the impact of HIV infection and its treatment from 
the patient’s perspective as some domains are difficult to observe or are subjective and best 
collected through patient report. HIV infection and its treatment can impair HRQoL. 
Symptom burden associated with HIV treatment has decreased with improvements in ART 
regimens, but persists despite viral suppression and immunologic recovery. In conjunction 
with efficacy and safety, PRO data may help clinicians and patients in making informed 
decisions on appropriate ART regimens. HTA authorities in many countries recommend 
patient perspectives data and HRQoL measurement as part of their drug benefit evaluations. 
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HRQoL data are used to estimate health utility scores, which inform cost-effectiveness model 
analysis.
This study will include 3 self-administered PRO questionnaires (Sections 1.3 SoA, 8.1.12, 
and 9.4.3). The EQ-5D-5L, a generic HRQoL questionnaire, will provide a simple 
descriptive profile and index value for health status used to compute health utilities for health 
economic analyses. The HIVTSQ is a 10-item instrument used to measure satisfaction with 
medications for people with HIV infection. The status version (HIVTSQs) will be used to 
evaluate treatment satisfaction over time. The HIV-SI (also known as the HIV-SDM) is a 
20-item HIV disease-specific questionnaire designed to assess the prevalence and burden of 
adverse effects associated with ART regimens. The PRO questionnaires will be completed up 
to Week 96 at the time points specified in the SoA (Sections 1.3.1, 1.3.2, and 1.3.3).
4.2.1.6
Planned Exploratory Biomarker Research
4.2.1.6.1
Planned Genetic Analysis
Genetic variation may impact a participant’s response to therapy, susceptibility to, severity, 
and progression of disease. Variable response to therapy may be due to genetic determinants 
that impact drug ADME; 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 multistudy assessment of genetic factors involved 
in the response to understand study disease or related conditions.
See Section 8.8.1.
4.2.1.7
Future Biomedical Research
The Sponsor will conduct FBR 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 FBR.
Such research is for biomarker testing to address emergent questions not described elsewhere 
in the protocol and will only be conducted on specimens from appropriately consented 
participants. The objective of collecting/retaining specimens for FBR 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 
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the correct drug/vaccine at the correct time. The details of FBR research are presented in 
Appendix 6.
4.2.2
Rationale for the Use of Comparator/Placebo
The 3-drug regimen of BIC/FTC/TAF will be the comparator in this study. BIC/FTC/TAF 
has been approved by the EMA and the FDA for both treatment-naïve and switch patients 
and is a recommended initial regimen for most people infected with HIV-1 [Panel on 
Antiretroviral Guidelines for Adults and Adolescents 2022]. Although some previous switch 
studies have been conducted within-class (eg, from one NNRTI to another), this study is 
designed to compare switching to DOR/ISL from an InSTI-containing regimen. The 
InSTI-containing regimen was chosen as the comparator because the InSTI class is 
recommended by both the US Department of Health and Human Services [Panel on
Antiretroviral Guidelines for Adults and Adolescents 2022] and the European AIDS Clinical 
Society [European AIDS Clinical Society 2021] as part of all first-line, standard-of-care 
treatment regimens. However, emerging data suggest that some InSTIs may have tolerability 
issues including possible weight gain and CNS side effects. Furthermore, long-term renal and 
bone defects have been associated with the use of TAF [U.S. Prescribing Information 2016]. 
Thus, some patients may want to switch from the combination of BIC/FTC/TAF [Norwood, 
J., et al 2017] [Hoffmann, C., et al 2017].
Matching placebo will be used to provide a robust evaluation of the safety and tolerability 
profile of DOR/ISL by maintaining double-blind, double-dummy therapy through Week 144.
4.2.3
Rationale for the Selected Participant Population
The rationale for the participant population selected for this study is as follows:
•
Participants Switching ART Regimens: Many ART regimens are associated with a 
high likelihood of achieving and maintaining undetectable HIV-1 RNA levels. Although 
70% of all PLWH globally know their HIV status, only 44% are virologically suppressed 
[Joint United Nations Programme on HIV/AIDS 2017]. Drug-associated adverse effects 
and toxicities, food requirements, high pill burdens, frequent dosing, and DDIs with 
concomitant medications are among the reasons that may contribute to lack of adherence 
to prescribed ART regimens. These are the same motivators for patients and prescribers 
to consider switching components of an ART regimen, even in the setting of viral
suppression before failure can occur.
Furthermore, as the population ages, it is anticipated that switches will become even 
more common in the setting of increasing concern about polypharmacy, long-term 
toxicity, and DDIs related to co- and multimorbidity and risks associated with the 
emergence of HIV-1 variants that are resistant to InSTI, NRTI, and NNRTI treatments.
Life expectancy for PLWH receiving suppressive ART is generally similar to people 
without HIV infection [Farahani, M., et al 2017] [Wandeler, G., et al 2016]. The leading 
cause of mortality in PLWH is no longer attributed to HIV-related complications, but 
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rather to comorbid conditions commonly associated with an aging population (eg, 
diabetes, cardiovascular disease, renal disease, cancer).
Participants With Virological Suppression for ≥3 Months: With increasing prevalence of 
early treatment initiation, increasing life expectancy for those who are infected with HIV-1, 
and decreasing incidence rates of new HIV-1 infections in many parts of the world, an 
important population in need of improved treatment regimens is those who are already 
virologically suppressed. Data from the Phase 2 study (MK-8591-011) demonstrate that after 
receiving at least 3 consecutive months of the 3-drug regimen, ISL+DOR+3TC, almost all 
participants with HIV-1 RNA <50 copies/mL maintained virologic suppression on a 2-drug 
regimen, ISL+DOR, through an additional 24 weeks. Based on the results of MK-8591-011, 
enrollment in this study will be open to those who have demonstrated stable suppression with 
HIV-1 RNA <50 copies/mL for ≥3 consecutive months.
4.2.4
Rationale for Collecting Race and Ethnicity Data
The differential effect on efficacy and safety based on any demographic parameter, including 
race or ethnicity, cannot be predicted when evaluating a new investigational drug. Therefore, 
it is important to collect race and ethnicity data to ensure that there is not a differential effect 
based on these parameters and to gain assurance the results observed in the clinical study will 
be representative of the drug’s use in a broader population. As an example, non-Caucasian 
patients 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 persons [Burger, D., et al 2005]. As another example, among PLWH in the 
US, those of African heritage have been found to be less likely to maintain virologic 
suppression compared with other groups, and the factors contributing to this remain to be 
elucidated [Weintrob, A. C., et al 2009] [Ribaudo, H. J., et al 2013]. Thus, subgroup analyses 
on race and ethnicity will be performed to better understand how these parameters may 
influence clinical outcome and toxicity.
4.2.5
Rationale for Collecting Gender Identity Data
Transgender people, defined as those whose gender identities and/or expressions differ from 
the sex assigned to them at birth, have a high prevalence and incidence of HIV infection 
globally [Poteat, T., et al 2016]. When considering HIV treatment, the WHO considers 
transgender people to be a separate key population because of their specific health needs and 
high vulnerability [Department of HIV/AIDS 2015]. Data will be collected in this study to 
assess clinical outcomes in the transgender population.
4.2.6
Rationale for Infant Safety Data Collection
Follow-up through 1 year of age for infants born to participants who become pregnant while 
receiving study intervention provides the ability to monitor growth and development as well 
as potential adverse effects that may be associated with prenatal drug exposure. Growth 
parameters (ie, length, weight, and head circumference) within normal range at 
approximately 1 year of age are key noninvasive indicators that a serious congenital 
malformation caused by in utero drug exposure is unlikely.
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4.2.7
Rationale for Continuing Study Intervention During Pregnancy
The US Department of Health and Human Services guidelines currently advise that persons 
who become pregnant while receiving ART for HIV infection should continue their regimen 
provided it is safe, well tolerated, and effective at virologic suppression, because altering the 
regimen could cause an increase in viral load [Panel on Treatment of Pregnant Women with 
HIV Infection and Prev 2018]. Nonclinical developmental and reproductive toxicology 
studies did not identify any teratogenicity or other clinically relevant concerns that would 
preclude continued dosing of DOR/ISL in participants who become pregnant and provide 
documented informed consent to continue study intervention (where allowed by local 
regulations, health authorities, and ethics committees and as appropriate based on available 
data/local standard-of-care guidelines) (Sections 8.1.1.3 and 8.11.6).
There are no clinical data currently available to support breastfeeding by participants who are 
receiving DOR/ISL or BIC/FTC/TAF.
4.2.8
Rationale for Collecting Alcohol and Tobacco Use
Both alcohol use and tobacco use are associated with poor health outcomes. A significant 
number of PLWH across the world die from cardiovascular disease, non-AIDS malignancies, 
and liver disease, which are associated with alcohol and tobacco use [Farahani, M., et al 
2017]. New or worsening existing clinical signs/symptoms, including abnormal laboratory 
results, can be influenced by alcohol and/or tobacco use. The prospective collection of these 
data, occurring once prior to randomization and annually thereafter, is intended to assist in 
the medical management of study participants to help better understand comorbid disease 
outcomes as well as the primary investigators’ determination of the likelihood that the study 
intervention may have caused a potential AE (ie, causality assessment). With smoking and 
alcohol use as known risk factors for cardiovascular disease and liver disease, collection of 
data to monitor these risks among participants is essential to comprehensive safety 
monitoring and better understanding of the safety profile of the IMP(s) against the 
background of comorbid conditions.
4.3
Justification for Dose
IQ (Ctrough/IC50) is the ratio of drug exposure to viral susceptibility. In a Phase 1b proof of 
concept study (MK-8591-003), single doses as low as 0.5 mg ISL showed robust 
antiretroviral activity at 7 days postdose; this low single dose provided an IQ threshold of 5 
for wild-type HIV-1 virus. Simulations suggest the ISL-TP trough concentrations achieved 
24 hours after a single dose of 0.25 mg ISL provide IQs of ~11 for wild-type virus and ~2 for 
M184V virus. After 3 daily doses of 0.25 mg ISL, IQs increase to ~29 for wild-type virus 
and ~6 for M184V/I virus. Steady-state concentrations at later time points will produce even 
higher IQs, as ISL-TP reaches steady state at ~28 days. These simulations support the 
selection of 0.25 mg ISL in combination with 100 mg DOR to maintain virologic suppression 
in participants who switch from a stable ART regimen, BIC/FTC/TAF, at baseline.
In the Phase 2 clinical study (MK-8591-011), 3 daily doses of ISL (0.25, 0.75, and 2.25 mg) 
were evaluated in combination with DOR (100 mg) + 3TC for 24 weeks and subsequently 
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with DOR alone through Week 48. All 3 doses of ISL with DOR ± 3TC demonstrated potent 
antiretroviral activity comparable with the comparator (DOR/3TC/TDF) at Week 24 (as a 
3-drug regimen, ISL+DOR+3TC) and at Week 48 (as a 2-drug regimen, ISL+DOR). Overall, 
no ISL dose response for efficacy was observed. Graphical analysis of steady-state ISL-TP 
trough concentrations and response at Week 48 from MK-8591-011 showed no trends in 
exposure-response. The totality of these efficacy data supports the conclusion that the dose 
range studied (0.25 to 2.25 mg daily) is on the plateau of the dose-response curve. 
MK-8591-011 also demonstrated that all doses of ISL studied, when administered with DOR 
+ 3TC or DOR alone, had a favorable AE and tolerability profile through Week 144, 
comparable with that of DOR/3TC/TDF. In the dose-ranging phase of MK-8591-011 (Part 1 
and Part 2 through Week 72), participants who received ISL 0.25 mg QD had similar 
changes in total lymphocyte count and comparable increases in CD4+ T-cell count to those in 
the DOR/3TC/TDF group. See Section 2.2.3 for additional DOR/ISL background 
information.
DOR will be administered at the approved dose of 100 mg. This dose has been studied in 
Phase 1 to Phase 3 studies in treatment-naïve and virologically suppressed participants with 
HIV-1 and was selected based upon favorable efficacy, safety, tolerability, and metabolic 
profiles, as confirmed in Phase 3 studies [Orkin, C., et al 2019] [Molina, J. M., et al 2018]
[Johnson, M., et al 2019]. Of note, in MK-1439A-024 and MK-1439A-030 [Johnson, M., et 
al 2019] [Wong, A., et al 2019], among 32 participants infected with HIV-1 harboring the 
NNRTI resistance mutations K103N, Y181C, and/or G190A at study entry, all achieved 
virologic suppression following 48 weeks of treatment with DOR/3TC/TDF (24 of 
32 participants had been virologically suppressed on PI or InSTI regimens and 8 had been 
treatment-naïve). Across the Phase 2 and Phase 3 DOR/ISL program, viral resistance was 
observed for 2 TN participants who had received DOR/ISL in study MK-8591A-020.
In summary, a 0.25 mg dose of ISL in combination with 100 mg DOR is predicted to have an 
acceptable safety profile and provide concentrations that will demonstrate potent 
antiretroviral activity against both wild-type virus and most common NRTI- and 
NNRTI-resistant variants.
4.4
Beginning and End-of-Study Definition
The overall study begins when the first participant (or their legally acceptable representative) 
provides documented informed consent. The overall study ends when the last participant 
completes the last study-related contact, withdraws consent, or is lost to follow-up (Section 
7.3). For purposes of analysis and reporting, the overall study ends when the Sponsor 
receives the last laboratory test result or at the time of final contact with the last participant, 
whichever comes last.
If the study includes countries in the European Economic Area (EEA), the local start of the 
study in the EEA is defined as First Site Ready (FSR) in any Member State.
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4.4.1
Clinical Criteria for Early Study Termination
The clinical study may be terminated early if the extent (incidence and/or severity) of 
emerging effects/clinical endpoints is such that the risk/benefit ratio to the study population 
as a whole is unacceptable. In addition, further recruitment in the study or at (a) particular 
study-site(s) may be stopped due to insufficient compliance with the protocol, GCP, and/or 
other applicable regulatory requirements, procedure-related problems or the number of 
discontinuations for administrative reasons is too high.
Early study termination may also be considered if the futility criterion is met at the Week 24 
IA (Section 9.7).
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5
STUDY POPULATION
Participants ≥18 years of age with HIV-1 who have been virologically suppressed for 
≥3 consecutive months on BIC/FTC/TAF will be enrolled in this study.
As stated in the Code of Conduct for Clinical Trials (Appendix 1.1), this study includes 
participants of varying age (as applicable), race, ethnicity, and sex (as applicable). The 
collection and use of these demographic data will follow all local laws and participant 
confidentiality guidelines while supporting the study of the disease, its related factors, and 
the IMP under investigation.
Prospective approval of protocol deviations to recruitment and enrollment criteria, also 
known as protocol waivers or exemptions, is not permitted.
5.1
Inclusion Criteria
An individual is eligible for inclusion in the study if the individual meets all of the following 
criteria:
Type of Participant and Disease Characteristics
1. Is HIV-1 positive with plasma HIV-1 RNA <50 copies/mL at screening.
Note: A single repeat of the plasma HIV-1 RNA screening test will be allowed, provided 
results are available within the 45-day screening window.
2. Has been receiving BIC/FTC/TAF therapy with documented viral suppression (HIV-1 
RNA <50 copies/mL) for ≥3 consecutive months prior to providing documented 
informed consent and has no history of prior virologic treatment failure on any past or 
current regimen.
Notes:
An HIV-1 RNA result above the lower level of detection (ie, transient detectable viremia) 
that is not clinically significant during the 3 months prior to providing documented 
informed consent is acceptable.
Previous regimen switches for tolerability, side effects, dosing convenience, or cost are 
permitted if they occurred >3 months prior to providing documented informed consent.
Demographics
3. Is an individual of any sex/gender, at least 18 years of age, at the time of providing the 
informed consent.
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Participants Assigned Female Sex at Birth
4. A participant assigned female sex at birth is eligible to participate if not pregnant or 
breastfeeding, and at least one of the following conditions applies:
•
Is not a POCBP
OR
•
Is a POCBP and:
-
Uses an acceptable contraceptive method or is abstinent from penile-vaginal 
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 42 days 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. Contraceptive use by 
POCBPs should be consistent with local regulations regarding the methods of 
contraception for those participating in clinical studies. If the contraception 
requirements in the local label for any of the study interventions are more stringent 
than the requirements above, the local label requirements are to be followed.
-
Has a negative highly sensitive pregnancy test (urine or serum as required by local 
regulations) within 24 hours (for urine test) or 72 hours (for serum test) before the 
first dose of study intervention. If a urine test cannot be confirmed as negative (eg, an 
ambiguous result), a serum pregnancy test is required. In such cases, the participant 
must be excluded from participation if the serum pregnancy result is positive. 
Additional requirements for pregnancy testing during and after study intervention are 
in Section 8.3.4 and Appendix 2.
-
Medical history, menstrual history, and recent sexual activity has been reviewed by 
the investigator to decrease the risk for inclusion of a POCBP with an early 
undetected pregnancy.
Informed Consent
5. The participant (or legally acceptable representative) has provided documented informed 
consent for the study. The participant may also provide consent for FBR. However, the 
participant may participate in the study without participating in FBR.
Note: See Appendix 7 for country-specific requirements.
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5.2
Exclusion Criteria
An individual must be excluded from the study if the individual meets any of the following 
criteria:
Medical Conditions
1. Has HIV-2 infection.
2. Has hypersensitivity or other contraindication to any of the components of the study 
interventions as determined by the investigator.
3. Has a diagnosis of an active AIDS-defining opportunistic infection within 30 days prior 
to screening.
4. Has active HBV infection (defined as HBsAg-positive or HBV DNA-positive).
Note: Past HBV infection or previous HBV vaccination (defined as HBsAg-negative and 
anti-HBs-positive is not an exclusion criterion).
5. Has chronic HCV infection (detectable HCV RNA) with laboratory values consistent 
with cirrhosis (serum albumin <2.8 g/dL or INR >1.7 or platelets <100 × 109 cells/L in 
the absence of another explanation for the abnormal laboratory values).
Note: Treatment with direct-acting antiviral therapies is not exclusionary.
6. Has a history of malignancy ≤5 years prior to providing documented informed consent 
except for adequately treated basal cell or squamous cell skin cancer, in situ cervical 
cancer, or cutaneous Kaposi’s sarcoma.
7. Has a history or current evidence of any condition (including active tuberculosis), 
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
8. Is taking or is anticipated to require systemic immunosuppressive therapy, immune 
modulators, or strong and moderate CYP3A inducers (or any other prohibited therapies 
outlined in Section 6.5) from 45 days prior to Day 1 through the study treatment period.
Note: Time-limited courses of corticosteroids (eg, for asthma exacerbation) are allowed.
9. Has taken long-acting HIV therapy at any time (eg, cabotegravir, lenacapavir).
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Prior/Concurrent Clinical Study Experience
10. Is currently participating in or has participated in a clinical study and received (or is 
receiving) an investigational compound or device from 45 days prior to Day 1 through 
the study treatment period.
Notes:
Participants who have had prior exposure to ISL (any duration any time prior to Day 1) 
are excluded.
BIC/FTC/TAF is not considered investigational in countries where it has received health 
authority approvals, regardless of commercial availability.
Participants completing other clinical studies who are receiving placebo or approved 
therapy may be eligible to enroll without waiting 45 days with approval from the 
Sponsor.
Concurrent participation in observational or noninterventional studies may be permitted 
and must be discussed with the Sponsor prior to enrollment and through study duration.
Diagnostic Assessments
11. Has a documented or known virologic resistance to DOR, as demonstrated by any of the 
following DOR resistance substitutions in reverse transcriptase: 
V106A/M, V108I, Y188L, H221Y, P225H, F227C/L/V, M230I/L, L234I, P236L, or 
Y318F.
Notes:
Participants who do not have documentation of resistance testing may enroll.
This exclusionary list is for the purpose of this study and includes major (or primary) 
DOR resistance substitutions, but not substitutions that are minor and found as naturally 
occurring polymorphisms.
12. Has exclusionary laboratory values (completed by the central laboratory) within 45 days 
prior to Day 1 as listed in Table 1.
Note: A single repeat of a laboratory screening test will be allowed for test results that 
are unexpected based on documented prior laboratory results, but the repeat test results 
must be available within the 45-day screening window.
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Table 1
Laboratory Exclusion Criteria
Laboratory Assessment
Exclusionary Values
ALP
>3 × ULN
AST
>5 × ULN
ALT
>5 × ULN
Calculated CrCl
≤30 mL/min based on the Cockcroft-Gault equation 
(Appendix 8)
CD4+ T-cell Count
<50 cells/mm3
Hemoglobin
<9.0 g/dL (female) or <10.0 g/dL (male)
Total Lymphocyte Count
<0.650 × 109 cells/L (Grade 1 DAIDS criteria)
ALP=alkaline phosphatase; ALT=alanine aminotransferase; AST=aspartate 
aminotransferase; CrCl=creatinine clearance; DAIDS=Division of AIDS; ULN=upper 
limit of normal.
Other Exclusions
None
5.3
Lifestyle Considerations
There are no lifestyle restrictions.
5.4
Screen Failures
Screen failures are defined as participants who consent to participate in the clinical study, but 
are not subsequently randomized in the study. A minimal set of screen-failure information is 
required to ensure transparent reporting of screen-failure participants to meet the CONSORT 
publishing requirements and to respond to queries from regulatory authorities. Minimal 
information includes demography, screen-failure details, eligibility criteria, and any AEs or 
SAEs meeting reporting requirements as outlined in the data entry guidelines.
5.5
Participant Replacement Strategy
A participant who discontinues from study intervention OR withdraws from the study will 
not be replaced.
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6
STUDY INTERVENTION
Study intervention is defined as any investigational intervention(s), marketed product(s), 
placebo, or medical device(s) intended to be administered to a study participant according to 
the study protocol.
Clinical supplies (study intervention[s] provided by the Sponsor) will be packaged to support 
enrollment. Clinical supplies will be affixed with a clinical label in accordance with 
regulatory requirements.
6.1
Study Intervention(s) Administered
The study intervention(s) to be used in this study are outlined in Table 2.
Country-specific requirements are noted in Appendix 7.
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Table 2
Study Interventions
Arm 
Name
Arm Type
Intervention 
Name
Intervention 
Type
Dose 
Formulation
Unit Dose 
Strength(s)
Dosage 
Level(s)
Route of 
Administration
Treatment 
Period
Use
IMP or 
NIMP/
AxMP
Sourcing
Group 1 Experimental doravirine/
islatravir
Drug
Tablet
100 mg/
0.25 mg
100 mg/
0.25 mg 
QD
Oral
Day 1 to 
Week 144
Test 
Product
IMP
Provided 
centrally 
by the 
Sponsor
Group 1 Experimental placebo to 
bictegravir/
emtricitabine/
tenofovir 
alafenamide
Drug
Tablet
0 mg
0 mg 
QD
Oral
Day 1 to 
Week 144
Placebo
IMP
Provided 
centrally 
by the 
Sponsor
Group 1 Experimental doravirine/
islatravir
Drug
Tablet
100 mg/ 
0.25 mg
100 mg. 
0.25 mg 
QD
Oral
Week 144 up 
to Week 240
Test 
Product
IMP
Provided 
centrally 
by 
Sponsor
Group 2 Active 
Comparator
bictegravir/
emtricitabine/
tenofovir 
alafenamide
Drug
Tablet
50 mg/
200 mg/
25 mg
50 mg/
200 mg/
25 mg 
QD
Oral
Day 1 to 
Week 144
Comparator IMP
Provided 
centrally 
by the 
Sponsor
Group 2 Active 
Comparator
placebo to 
doravirine/
islatravir
Drug
Tablet
0 mg
0 mg 
QD
Oral
Day 1 to 
Week 144
Placebo
IMP
Provided 
centrally 
by the 
Sponsor
Group 2 Experimental doravirine/
islatravir
Drug
Tablet
100 mg/ 
0.25 mg
100 mg/ 
0.25 mg 
QD
Oral
Week 144 up 
to Week 240
Test 
Product
IMP
Provided 
centrally 
by 
Sponsor
EEA=European Economic Area; IMP=investigational medicinal product; NIMP/AxMP=noninvestigational/auxiliary medicinal product; QD=once-daily.
The classification of IMP and NIMP/AxMP in this table is based on guidance issued by the European Commission and applies to countries in the EEA. Country differences with 
respect to the definition/classification of IMP and NIMP/AxMP may exist. In these circumstances, local legislation is followed.
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Study intervention will be extended open-label for participants who become pregnant on 
treatment and provide documented informed consent to continue their assigned unblinded 
study intervention (DOR/ISL or BIC/FTC/TAF), as specified in Sections 1.3.4 and 8.11.6.
All supplies indicated in Table 2 will be provided per the “Sourcing” column depending on 
local country operational requirements. If local sourcing, every attempt should be made to 
source these supplies from a single lot/batch number where possible (eg, not applicable in the 
case where multiple lots or batches may be required due to the length of the study, etc).
Refer to Section 8.1.8 for details regarding administration of the study intervention.
All placebos were created by the Sponsor to match the active product.
6.2
Preparation/Handling/Storage/Accountability
6.2.1
Dose Preparation
There are no specific calculations or evaluations required to be performed to administer the 
proper dose to each participant. The rationale for selection of doses to be used in this study is 
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.
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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.
6.3
Measures to Minimize Bias: Randomization and Blinding
6.3.1
Intervention Assignment
Intervention randomization will occur centrally using an IRT system. There are 2 study 
intervention arms. Participants will be assigned randomly in a 2:1 ratio to Group 1 
(DOR/ISL) or Group 2 (BIC/FTC/TAF), respectively.
6.3.2
Stratification
No stratification based on age, sex, or other characteristics will be used in this study.
6.3.3
Blinding
A double-blinding technique with in-house blinding will be used. DOR/ISL and 
BIC/FTC/TAF will be packaged identically relative to their matching placebos so that the 
blind is maintained.
As described in Section 4.1, clinical site personnel and participants will remain blinded 
through Week 144, while Sponsor personnel will remain blinded through Week 48. Sponsor 
personnel involved in performing and reviewing results of the Week 48 analysis will be 
unblinded at the time of the Week 48 database lock.
The Sponsor may have a limited unblinded team not involved with day-to-day conduct of the 
study that will review unblinded data for internal programmatic decision-making. 
Participants and all field and study-site personnel will remain blinded through Week 144.
Restricted Sponsor personnel involved in performing and reviewing PK data may be 
unblinded before the Week 48 database lock to allow timely completion of population PK 
modeling. No personnel directly associated with study conduct will be unblinded before the 
database lock at Week 48. Before granting select personnel access to unblinded PK data, an 
official memo detailing unblinding procedures will be generated per Sponsor SOP. This 
memo will list the names of the personnel who will have access to unblinded PK data before 
the Week 48 database lock.
6.4
Study Intervention Compliance
Participants should be instructed to bring the study intervention bottles to their visits. At each 
visit, the number of tablets remaining in the study packaging will be counted, reviewed, and 
recorded. The results will be used to assess participant compliance. If a discrepancy is noted, 
the investigator/study coordinator must discuss the discrepancy with the participant and the 
explanation must be documented. All participants should be reminded of the importance of 
taking their study intervention as instructed for the entire duration of the study.
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Decisions to temporarily withhold study intervention because of an AE or other reason(s) 
will be reviewed on a case-by-case basis by the investigator.
Interruptions from the protocol-specified treatment plan that are expected to be 
≥7 consecutive days require consultation between the investigator and the Sponsor and 
written documentation of the collaborative decision on participant management.
•
When participants self-administer study intervention(s) at home, compliance with study 
intervention will be assessed at each visit. Compliance will be assessed by direct 
questioning, counting returned tablets/capsules, etc, during the site visits and documented 
in the source documents and CRF. Deviation(s) from the prescribed dosage regimen 
should be recorded in the CRF.
•
A record of the number of DOR/ISL/placebo and BIC/FTC/TAF/placebo tablets 
dispensed to and taken by each participant must be maintained and reconciled with study 
intervention and compliance records. Intervention start and stop dates, including dates for 
intervention delays will also be recorded in the CRF.
6.5
Concomitant Therapy
Medications or vaccinations specifically prohibited in the exclusion criteria are not allowed 
during time periods specified by this protocol for that medication or vaccination. If there is a 
clinical indication for any medications or vaccinations specifically prohibited, 
discontinuation from study intervention may be required. The investigator should discuss any 
questions regarding this with the Sponsor Clinical Director. The final decision on any 
supportive therapy or vaccination rests with the investigator and/or the participant’s primary 
physician. However, the decision to continue the participant on study intervention requires 
the mutual agreement of the investigator, the Sponsor, and the participant.
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
•
Dosage information including dose and frequency
The Sponsor Clinical Director should be contacted if there are any questions regarding prior 
or concomitant therapy.
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 their medical judgment when assessing a participant’s prior and concomitant 
therapy(ies). The Sponsor Clinical Director or designee should be contacted if there are any 
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questions about a therapy not on the list below or regarding potential DDIs with a specific 
treatment that the participant may plan to receive.
In instances where the local product circular for DOR or BIC/FTC/TAF is more restrictive 
with regard to prohibited (ie, contraindicated or not recommended) therapy(ies), the local 
product circular supersedes this section. In addition, the below recommendations for 
coadministration with BIC/FTC/TAF should be followed for all participants receiving 
blinded study intervention:
•
For participants taking metformin, close monitoring is recommended (BIC/FTC/TAF 
may increase metformin levels). Sucralfate and inhibitors of P-gp and/or BCRP should be 
used with caution. Refer to the local product circular for BIC/FTC/TAF for additional 
information.
•
For participants taking medications or oral supplements containing polyvalent cations 
(eg, Mg, Al, Ca, Fe) during the base study, study intervention should be taken either 2 
hours before or 6 hours after taking any polyvalent cation-containing medicine.
Concomitant medications (i.e. dofetilide), prohibited during the base study due to interaction 
with BIC/FTC/TAF will be allowed during the OLE.
Table 3
Prohibited Therapies
Therapy Type
Prohibited Therapy(ies)
Strong and moderate 
CYP3A inducers
Including, but not limited to:
Carbamazepine
Oxcarbazepine
Phenobarbital
Phenytoin
Enzalutamide
Rifabutin
Rifampin
Rifapentine
Mitotane
St. John’s Wort
Herbal remedies (only those that are strong or moderate CYP3A inducers)
Modafinil
Bosentan
Nafcillin
Lumacaftor
Metamizole
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Therapy Type
Prohibited Therapy(ies)
Nonstudy ART
All nonstudy antiretrovirals (with the exception of BIC/FTC/TAF during the 
screening period and intrapartum treatment [eg, IV AZT] in the case of 
pregnancy) including treatments for a viral infection other than HIV-1, such as 
hepatitis B, with an agent that is active against HIV-1.
Long-acting HIV therapy (eg, cabotegravir, lenacapavir) is not permitted at 
any time.
Time-limited course of ritonavir as a pharmacokinetic enhancer is permissible
(eg, nirmatrelvir/ritonavir for the treatment of COVID-19).
Immunosuppressive 
therapies
Immune therapy agents, immune modulators, or other systemic 
immunosuppressive therapy, including interferon-based treatment for hepatitis
Time-limited courses of corticosteroids (eg, for asthma exacerbation) are 
permitted.
Investigational agents
All nonstudy investigational agents including devices
Any agents (eg, vaccine or therapy for COVID-19) approved locally for 
Emergency Authorized Use, or equivalent, that do not have a known or 
anticipated DDI with study intervention, are permitted.
Antiarrhythmics
Dofetilide
Additional prohibited 
therapies based on ISL
Pentostatin
ART=antiretroviral therapy; AZT=zidovudine; BIC=bictegravir; COVID-19=coronavirus disease caused by severe acute 
respiratory syndrome coronavirus 2; CYP3A=cytochrome P450 3A; DDI=drug-drug interaction; FTC=emtricitabine; 
HIV=human immunodeficiency virus; HIV-1=human immunodeficiency virus type 1; ISL=islatravir; IV=intravenous; 
TAF=tenofovir alafenamide.
6.5.1
Rescue Medications and Supportive Care
No rescue or supportive medications are specified for use in this study.
6.6
Dose Modification (Escalation/Titration/Other)
No dose modification of DOR/ISL or BIC/FTC/TAF is allowed during the study (see 
Section 4.3 for dose justification).
6.7
Intervention After the End of the Study
If DOR/ISL is commercially accessible, participants in both groups who complete the Week 
144 visit should follow end of treatment procedures in Section 1.3.1 and transition to 
commercially accessible DOR/ISL or local standard of care, as clinically appropriate.
If DOR/ISL is not commercially accessible, participants in both groups who complete the 
Week 144 visit will be provided the option to receive DOR/ISL in an OLE until Week 240 or 
until DOR/ISL becomes commercially accessible (whichever comes first). Participants who
do not enter the OLE should follow Section 1.3.1 and transition to local standard of care as 
clinically appropriate.
The OLE ends at Week 240. Provided DOR/ISL development continues, there will be a 
future mechanism (eg, prelicense patient access program) beyond the end of the study for 
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participants to continue receiving DOR/ISL until it becomes commercially accessible. The 
details of this mechanism will vary per local regulations.
6.8
Clinical Supplies Disclosure
The emergency unblinding call center will use the intervention/randomization schedule for 
the study to unblind participants and to unmask study intervention identity. The emergency 
unblinding call center should only be used in cases of emergency (see Section 8.1.10). If the 
emergency unblinding call center is not available for a given site in this study, the central 
electronic intervention randomization system (IRT) should be used to unblind participants 
and to unmask study intervention identity. The Sponsor will not provide random 
code/disclosure envelopes or lists with the clinical supplies.
Clinical site personnel and participants will remain blinded through Week 144 while Sponsor 
personnel will remain blinded through Week 48.
6.9
Standard Policies
At the close of the study after unblinding, a letter is to be sent by the investigator to those 
participants who received placebos in the image of the comparator product to provide the 
following advice:
“You have participated in a study conducted by the Sponsor. This letter is to advise you that 
you were among those who received a look-alike tablet created by the Sponsor to resemble 
the drug/vaccine BIKTARVY 50/200/25 mg (BICTEGRAVIR/EMTRICITABINE/ 
TENOFOVIR ALAFENAMIDE) as much as possible. You did not receive the active 
drug/vaccine BIKTARVY 50/200/25 mg (BICTEGRAVIR/EMTRICITABINE/ 
TENOFOVIR ALAFENAMIDE) as manufactured by Gilead Sciences, Inc.”
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7
DISCONTINUATION OF STUDY INTERVENTION AND PARTICIPANT 
WITHDRAWAL
7.1
Discontinuation of Study Intervention
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.
Discontinuation of study intervention does not represent withdrawal from the study.
Participants who discontinue study intervention before completion of the protocol-specified 
treatment period may continue to be monitored in the study as specified in Section 8.11.3,
unless the participant has withdrawn from the study (see Section 7.2).
A participant must be discontinued from study intervention for any of the following reasons:
•
The participant or participant’s legally acceptable representative requests to discontinue 
study intervention.
•
After prolonged study intervention interruption that prohibits restarting study intervention 
(per Section 6.4).
•
The participant has a medical condition or personal circumstance (for pregnancy, see 
Section 8.11.6), which in the opinion of the investigator and/or Sponsor, places the 
participant at unnecessary risk from continued administration of study intervention.
•
The participant chooses to breastfeed.
Note: Study intervention can continue until breastfeeding is initiated.
•
The participant has clinically significant confirmed viremia as defined in 
Section 4.2.1.1.2. Do not discontinue prior to consultation with the Sponsor when 
feasible.
•
The participant has a new AIDS-defining opportunistic infection as listed in Appendix 9, 
ie, a Category C condition according to the CDC 1993 Revised Classification System for 
HIV Infection and Expanded Surveillance Case Definition for AIDS Among Adolescents 
and Adults [Centers for Disease Control (CDC) 1992].Table 4
•
The participant has an SAE or Grade 4 laboratory AE assessed by the investigator to be 
related to study intervention AND that is life-threatening or results in prolonged 
hospitalization.
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•
A participant must be discontinued from study intervention and managed per 
Section 8.11.5 if any of the criteria in Table 4 are confirmed. If the investigator believes 
there is an alternative explanation for the result (eg, COVID-19), consultation between 
the investigator and Sponsor is required when evaluating the participant for 
discontinuation.
Table 4
Discontinuation Criteria for Specified Decreases in Total Lymphocyte Counts 
or CD4+ T-cell Counts
Laboratory 
Test
Criteriona
Confirmationb,c
Total 
lymphocyte 
count
A new on-treatment value <1.0 × 109 cells/L with a 
≥30% decline from baselinea
Repeat measurement 10 to 
14 weeks later (or at the next 
scheduled study visit)
CD4+ T-cell 
count
If at baselinea:
And on treatment:
Repeat measurement 10 to 
14 weeks later (or at the next 
scheduled study visit)
≥500 cells/mm3
<350 cells/mm3
≥350 to ≤499 cells/mm3
≥30% decline from 
baseline and 
<350 cells/mm3
≥200 to ≤349 cells/mm3
≥30% decline from 
baseline and 
<200 cells/mm3
≤199 cells/mm3
≥30% decline from 
baseline
CD4+=cluster of differentiation 4-positive; DOR=doravirine; ISL=islatravir; N/A=not applicable; OLE=open-label 
extension; SoA=Schedule of Activities.
a Baseline is at Day 1 for all participants during the Base Study and for Group 1 participants during the OLE.
Baseline is at Week 144 for Group 2 participants during the OLE (ie, last value before initiation of 
DOR/ISL).
b If the on-treatment measurement meets the specified discontinuation criteria, a consecutive, confirmatory 
measurement within 10 to 14 weeks is required. Confirmatory laboratory measurements can be conducted at 
the next clinic visit if the next scheduled visit occurs within the interval required for repeat testing. Note: If 
repeat testing at the next scheduled visit occurs sooner than 10 weeks and shows resolution, the results may 
be used to confirm the resolution, and testing should be resumed per the routine SoA. If repeat testing at the 
next scheduled visit occurs sooner than 10 weeks and does not show resolution, discontinuation is not
required. Testing is still required in the timeframe of 10 to 14 weeks to confirm discontinuation.
c The time frame for confirmation of decreases in total lymphocyte count or CD4+ T-cell count may be 
extended in the setting of intercurrent illness, immunization, or treatment nonadherence or other treatment 
interruption. Allow approximately 4 weeks following resolution of illness, immunization, or treatment 
nonadherence or other treatment interruption before collecting the confirmation sample.
In addition to this list of discontinuation criteria, country-specific discontinuation criteria are 
in Appendix 7.
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.
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If a participant withdraws from the study, they will no longer receive study intervention or be 
followed at scheduled protocol visits.
Specific details regarding procedures to be performed at the time of withdrawal from the 
study, as well as specific details regarding withdrawal from FBR, are outlined in 
Section 8.1.9. The procedures to be performed should a participant repeatedly fail to return 
for scheduled visits and/or if the study site is unable to contact the participant are outlined in
Section 7.3.
7.3
Lost to Follow-up
If a participant fails to return to the clinic for a required study visit and/or if the site is unable 
to contact the participant, the following procedures are to be performed:
•
The site must attempt to contact the participant and reschedule the missed visit. If the 
participant is contacted, the participant should be counseled on the importance of 
maintaining the protocol-specified visit schedule.
•
The investigator or designee must make every effort to regain contact with the participant 
at each missed visit (eg, telephone calls and/or a certified letter to the participant’s last 
known mailing address or locally equivalent methods). These contact attempts should be 
documented in the participant’s medical record.
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8
STUDY ASSESSMENTS AND PROCEDURES
•
Study procedures and their timing are summarized in the SoA.
•
Adherence to the study design requirements, including those specified in the SoA, is 
essential and required for study conduct.
•
The investigator is responsible for ensuring that procedures are conducted by 
appropriately qualified (by education, training, and experience) staff. Delegation of 
study-site personnel responsibilities will be documented in the Investigator Trial File 
Binder (or equivalent).
•
All study-related medical decisions must be made by an investigator who is a qualified 
physician.
•
All screening evaluations must be completed and reviewed to confirm that potential 
participants meet all eligibility criteria. The investigator will maintain a screening log to 
record details of all participants screened and to confirm eligibility or record reasons for 
screening failure, as applicable.
•
Procedures conducted as part of the participant’s routine clinical management (eg, blood 
count) and obtained before providing documented informed consent or assent, when 
applicable, may be used for screening or baseline purposes provided the procedures meet 
the protocol-specified criteria and were performed within the time frame defined in the 
SoA.
•
Additional evaluations/testing may be deemed necessary by the investigator and or the 
Sponsor for reasons related to participant safety. In some cases, such evaluation/testing 
may be potentially sensitive in nature (eg, HIV, hepatitis C), and thus local regulations 
may require that additional informed consent or assent, when applicable, be obtained 
from the participant. In these cases, such evaluations/testing will be performed in 
accordance with those regulations.
The amount of blood collected from each participant over the duration of the study is 
provided in Appendix 2.
Repeat or unscheduled samples may be taken for safety reasons or for technical issues with 
the samples.
8.1
Administrative and General Procedures
8.1.1
Informed Consent
The investigator or medically qualified designee (consistent with local requirements) must 
obtain documented informed consent from each potential participant (or their legally 
acceptable representative) prior to participating in this clinical study or FBR. If there are 
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changes to the participant’s status during the study (eg, health or age of majority 
requirements), the investigator or medically qualified designee must ensure the appropriate 
documented informed consent is in place.
8.1.1.1
General Informed Consent
Informed consent given by the participant or their legally acceptable representative must be 
documented on a consent form. The form must include the study protocol number, study 
protocol title, dated signature, and agreement of the participant (or his/her legally acceptable 
representative) and of the person conducting the consent discussion.
A copy of the signed and dated informed consent form should be given to the participant (or 
their legally acceptable representative) before participation in the study.
The initial ICF, any subsequent revised ICF, and any written information provided to the 
participant must receive the IRB/IEC’s approval/favorable opinion in advance of use. The 
participant 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.
Informed consent will adhere to IRB/IEC requirements, applicable laws and regulations, and 
Sponsor requirements.
8.1.1.2
Consent and Collection of Specimens for Future Biomedical Research
The investigator or medically qualified designee will explain the FBR consent to the 
participant, or the participant’s legally acceptable representative, answer all of his/her 
questions, and obtain documented informed consent before performing any procedure-related 
to FBR. A copy of the informed consent will be given to the participant before performing 
any procedure-related to FBR.
8.1.1.3
Consent for Continuation of Study Intervention During Pregnancy
Upon confirming that a participant is pregnant (Section 8.3.4), the investigator or medically 
qualified designee and the participant will discuss the potential benefits and risks of 
continuing (or discontinuing) study intervention (Section 8.11.6). A separate consent is 
required to continue study intervention (regardless of treatment group or whether participant 
has been unblinded to treatment assignment) in participants who become pregnant 
(Section 8.11.6.1). Open-label study intervention (DOR/ISL or BIC/FTC/TAF, depending on 
study intervention assignment at the time of the confirmatory pregnancy test) will be 
provided for participants in either treatment group who consent to continue study 
intervention during pregnancy. Note, participants who become pregnant are not allowed to 
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switch study intervention at any time during the pregnancy. The investigator or medically 
qualified designee will explain the consent to the participant, or the participant’s legally 
acceptable representative, answer all of their questions, and obtain documented informed 
consent before continuing study intervention. A copy of the informed consent will be given 
to the participant.
8.1.1.4
Consent for Postnatal Infant Safety Data Collection Through One Year of 
Age
Once a pregnancy is confirmed to be continuing, the investigator or medically qualified 
designee will explain the consent for infant safety data collection to the participant, or the 
participant’s legally acceptable representative, answer all questions, and obtain documented 
informed consent to collect any data related to infant safety. A copy of the informed consent 
will be given to the participant.
8.1.1.5
Consent for Open-Label Extension
The investigator or medically qualified designee will explain the consent for the OLE to the 
participant, or the participant’s legally acceptable representative, answer all of his/her 
questions, and obtain documented informed consent before performing any procedure-related 
to OLE. A copy of the informed consent will be given to the participant. The participant must 
be informed that once DOR/ISL becomes commercially accessible they will discontinue 
from the study.
8.1.2
Inclusion/Exclusion Criteria
All inclusion and exclusion criteria will be reviewed by the investigator, who is a qualified 
physician, to ensure that the participant qualifies for the study.
8.1.3
Participant Identification Card
All participants will be given a participant identification card identifying them as participants 
in a research study. The card will contain study-site contact information (including direct 
telephone numbers) to be used in the event of an emergency. The investigator or qualified 
designee will provide the participant with a participant identification card immediately after 
the participant provides documented informed consent. At the time of intervention
randomization, site personnel will add the treatment/randomization number to the participant 
identification card.
The participant ID card also contains contact information for the emergency unblinding call 
center so that a health care provider can obtain information about study intervention in 
emergency situations where the investigator is not available.
8.1.4
Medical History
A medical history will be obtained by the investigator or qualified designee. The medical 
history should include information pertaining to the diagnosis of HIV-1 and AIDS (if 
applicable) and year diagnosed. If the participant has been previously diagnosed with any 
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AIDS-defining conditions or CD4+ T-cell count <200 cells/mm3, the condition as well as a 
corresponding medical history of AIDS must be recorded. In addition, participants’ history of 
smoking and alcohol consumption should be obtained and recorded on the appropriate eCRF. 
For participants assigned female sex at birth, childbearing potential should be assessed. 
Menstrual history, contraceptive use, and recent sexual activity should be reviewed for 
POCBP to exclude potential or early, undiagnosed pregnancy prior to and on Day 1.
8.1.5
Prior and Concomitant Medications Review
8.1.5.1
Prior Medications
The investigator or qualified designee will review prior medication use and record prior 
medication(s) taken by the participant within 45 days before the first dose of study 
intervention.
All prior ARTs taken by the participant from the initiation of their therapy (if available) will 
be recorded before the first dose of study intervention.
8.1.5.2
Concomitant Medications
The investigator or qualified designee will record medication(s), if any, taken by the 
participant during the study.
8.1.6
Assignment of Screening Number
All consented participants will be given a unique screening number that will be used to 
identify the participant for all procedures that occur before randomization. Each participant 
will be assigned only 1 screening number. Screening numbers must not be reused for 
different participants.
Any participant who is screened multiple times will retain the original screening number 
assigned at the Screening Visit. Specific details on the screening/rescreening visit 
requirements are in Section 8.11.1.
8.1.7
Assignment of Randomization Number
All eligible participants will be randomly allocated and will receive a randomization number. 
The randomization number identifies the participant for all procedures occurring after 
treatment randomization. Once a randomization number is assigned to a participant, it can 
never be reassigned to another participant.
A single participant cannot be assigned more than 1 randomization number.
8.1.8
Study Intervention Administration
Study intervention will be provided per Table 2 and dispensed through the IRT system at 
visits indicated in the SoA (Sections 1.3.1, 1.3.4, and 1.3.5).
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Study intervention should begin within 24 hours of randomization (ie, on the day of 
randomization after all pretreatment assessments, as specified in the SoA, are performed or 
as soon as possible after randomization).
8.1.8.1
Timing of Dose Administration
From Day 1 to Week 144, participants will take 2 tablets of blinded study intervention QD at
approximately the same time each day (1 tablet from each of 2 containers taken together):
(1) Bottle A: DOR/ISL or matching placebo; and
(2) Bottle B: BIC/FTC/TAF or matching placebo.
From Week 144 to 240 participants will take 1 tablet of open-label DOR/ISL QD at 
approximately the same time each day.
Study intervention will be taken without regard to food. If more than 1 Bottle A is dispensed, 
the participant is instructed to use all of the medication in 1 Bottle A before opening another 
Bottle A (and similarly for Bottle B).
If a participant misses a dose of any of the study interventions, the following guidance should 
be followed:
•
If ≤12 hours from the missed dose, the missed dose should be taken, and the normal 
dosing schedule resumed.
•
If >12 hours from the missed dose, the missed dose should be skipped, and the normal 
dosing schedule resumed. The participant should not double the next dose to compensate 
for what has been missed.
For participants who become pregnant and consent to continue their assigned study 
intervention, see Section 8.11.6.1.
8.1.9
Discontinuation and Withdrawal
Participants who discontinue study intervention before completion of the base study should 
have an Early Discontinuation visit performed per the SoA (Section 1.3.1) and should be 
encouraged to continue to be followed as outlined in the SoA and Section 8.11.3.1.
Participants who end study intervention while in the OLE (after Week 144 and prior to Week 
240) should have a Discontinuation of Study Treatment (OLE) visit performed per the SoA 
(Section 1.3.5) and should be followed as outlined in the SoA and Section 8.11.3.2.
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.
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Participants who discontinue study intervention due to specified decreases in total 
lymphocyte count or CD4+ T-cell count (Table 4) should be managed per Section 8.11.5 
until their counts recover. Participants who become pregnant and discontinue study 
intervention should be managed per Section 8.11.6.2.
8.1.9.1
Withdrawal From Future Biomedical Research
Participants may withdraw their consent for FBR. Participants may withdraw consent at any 
time by contacting the study investigator. If medical records for the study are still available, 
the investigator will contact the Sponsor using the designated mailbox 
(clinical.specimen.management@MSD.com). Subsequently, the participant’s consent for 
FBR will be withdrawn. A letter will be sent from the Sponsor to the investigator confirming 
the withdrawal. It is the responsibility of the investigator to inform the participant of 
completion of withdrawal. Any analyses in progress at the time of request for withdrawal or 
already performed before 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.
If the medical records for the study are no longer available (eg, if the investigator is no longer 
required by regulatory authorities to retain the study records) or the specimens have been 
completely anonymized, there will no longer be a link between the participant’s personal 
information and their specimens. In this situation, the request for specimen withdrawal 
cannot be processed.
8.1.10
Participant Blinding/Unblinding
STUDY INTERVENTION IDENTIFICATION INFORMATION IS TO BE UNMASKED 
ONLY IF NECESSARY FOR THE WELFARE OF THE PARTICIPANT. EVERY 
EFFORT SHOULD BE MADE NOT TO UNBLIND.
For emergency situations where the investigator or medically qualified designee (consistent 
with local requirements) needs to identify the intervention used by a participant and/or the 
dosage administered, he/she will contact the emergency unblinding call center by telephone 
and make a request for emergency unblinding. As requested by the investigator or medically 
qualified designee, the emergency unblinding call center will provide the information to 
him/her promptly and report unblinding to the Sponsor. Before contacting the emergency 
unblinding call center to request unblinding of a participant’s intervention assignment, the 
investigator who is a qualified physician should make reasonable attempts to enter the 
intensity of the AEs observed, the relation to study intervention, the reason thereof, etc, in the 
medical record. If it is not possible to record this assessment in the medical record before the 
unblinding, the unblinding should not be delayed.
If unblinding has occurred, the circumstances around the unblinding (eg, date, reason, and 
person performing the unblinding) must be documented promptly, and the Sponsor Clinical 
Director notified as soon as possible.
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Once an emergency unblinding has taken place, the investigator, site personnel, and Sponsor 
personnel may be unblinded so that the appropriate follow-up medical care can be provided 
to the participant.
Participants whose treatment assignment has been unblinded by the investigator or medically 
qualified designee and/or nonstudy treating physician should continue to be monitored in the 
study.
Additionally, the investigator or medically qualified designee must go into the IRT system 
and perform the unblind in the IRT system to update drug disposition. If the emergency 
unblinding call center is not available for a given site in this study, the IRT system should be 
used for emergency unblinding if this is required for participant safety.
8.1.11
Calibration of Equipment
The investigator or qualified designee has the responsibility to ensure that any device or 
instrument used for a clinical evaluation/test during a clinical study that provides information 
about inclusion/exclusion criteria and/or safety or efficacy parameters shall be suitably 
calibrated and/or maintained to ensure that the data obtained are reliable and/or reproducible. 
Documentation of equipment calibration must be retained as source documentation at the 
study site.
8.2
Efficacy Assessments
8.2.1
HIV-1 RNA
Plasma HIV-1 RNA quantification will be performed at the central laboratory using a PCR 
assay with a lower limit of detection of <50 copies/mL.
8.2.2
Management of Participants With Viremia
When viremia (HIV-1 RNA ≥50 copies/mL) is detected (Section 4.2.1.1.2), the investigator 
should query the participant regarding adherence to study intervention, intercurrent illness, or 
recent immunization. All cases of viremia must be confirmed, and the participant should 
continue to take the full assigned dosage of study intervention while awaiting confirmation.
If a participant has an on-treatment HIV-1 RNA value ≥50 copies/mL, a reflex HIV-1 RNA 
test will be conducted by the central laboratory on the same plasma sample obtained at that 
visit, if available. Management of participants should be based on reflex HIV-1 RNA results 
if available.
•
If the reflex HIV-1 RNA result is <50 copies/mL, no further action is required.
•
If the reflex HIV-1 RNA result is ≥50 copies/mL or there is insufficient sample available 
for reflex testing, the participant will be asked to return to the clinic in 4 weeks (±1 week) 
for viremia confirmation (see Section 8.2.2.1 and the SoA in Section 1.3.2).
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8.2.2.1
Viremia Confirmation
At the Viremia Confirmation Visit:
•
If the HIV-1 RNA value is ≥50 copies/mL, a reflex HIV-1 RNA test will be conducted by 
the central laboratory on the same plasma sample obtained at that visit, if available.
•
If the reflex HIV-1 RNA result is <50 copies/mL, no further action is required.
•
If the HIV-1 RNA result is ≥200 copies/mL (on both primary and reflex tests, if 
available) on consecutive visits 4 weeks (±1 week) apart, then clinically significant 
viremia is confirmed, and the participants will be assessed for potential discontinuation 
from study intervention (Sections 7.1 and 8.2.2.1.1).
Allow approximately 4 weeks after resolution of illness, immunization, or treatment 
nonadherence or other treatment interruption before drawing these confirmation samples.
8.2.2.1.1
Participants With Clinically Significant Confirmed Viremia
(≥200 Copies/mL)
Participants with confirmed HIV-1 RNA of ≥200 copies/mL (per Section 4.2.1.1.2) will be 
assessed for development of viral drug resistance (Section 8.2.2.1.2) and discontinuation 
from study intervention (Section 7.1).
If it is determined that study intervention discontinuation is appropriate, Early 
Discontinuation of Treatment and End of Treatment Follow-up visit procedures should be 
completed (Sections 1.3.2 and 8.11.3) and the participant managed by the investigator per 
local standard of care.
8.2.2.1.2
HIV-1 Viral Drug Resistance Testing
Participants with confirmed HIV-1 RNA ≥200 copies/mL at any time during the study will 
be assessed for development of viral drug resistance.
Samples will be collected for genotypic and phenotypic HIV-1 viral drug resistance testing 
per the SoA (Section 1.3) and used to assess resistance-associated substitutions and viral 
susceptibility as applicable during the study. If clinically significant viremia is confirmed, the 
plasma sample from the Viremia Confirmation Visit will be the primary sample used for 
HIV-1 genotypic and phenotypic testing.
8.2.2.1.3
Participants With Low-level Viremia (≥50 and <200 Copies/mL)
Participants with confirmed HIV-1 RNA ≥50 and <200 copies/mL should continue study 
intervention and all regularly scheduled study visits during which HIV-1 RNA levels will be 
monitored per the SoA (approximately every 3 months). Additional visits may be conducted 
to monitor HIV-1 RNA levels more frequently than every 3 months, if appropriate, after 
discussion with the Sponsor.
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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.
8.2.3
T and B Lymphocyte and Natural Killer Cell (TBNK) Profile
A TBNK panel, including CD4+ T-cell count (Table 18), will be performed as specified in 
Appendix 2. Refer to Section 8.11.5 for guidance on management of participants with 
decreased total lymphocyte count or decreased CD4+ T-cell count. TBNK panel assessments 
that are considered exploratory do not need to be evaluated by the investigator.
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 (from prestudy 
to poststudy visits), including approximate blood volumes drawn by visit and by sample type 
per participant, can be found in Table 19, Table 20, Table 21, and Table 22 in Appendix 2.
Planned time points for all safety assessments are provided in the SoA.
8.3.1
Physical Examinations
A complete physical examination will be conducted by an investigator or medically qualified 
designee (consistent with local requirements) 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 and weight will also be measured and recorded at the visits specified in the SoA 
(Section 1.3). Height measurements should be taken using a stadiometer (recommended but 
not required). Participants should remove their shoes and stand as tall and straight as 
possible. Weight measurements should be taken per Section 8.3.1.1.
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.
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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 rest and will include pulse, 
systolic and diastolic BP, body temperature, and RR.
Note: Oral temperatures are preferred but not required.
8.3.3
Electrocardiograms
A local 12-lead ECG will be obtained and reviewed by an investigator or medically qualified 
designee (consistent with local requirements) as outlined in the SoA. Results must be 
available prior to randomization. Sites are to use an ECG machine that automatically 
calculates the HR and measures PR, QRS, QT, and QTc intervals. Clinically significant 
findings must be documented in the source documents and captured in the appropriate eCRF.
If an ECG is performed for any medical reason while the participant is on study intervention 
or during the follow-up period, any clinically significant changes compared with the baseline 
ECG must be appropriately reported as per requirements of safety reporting.
8.3.4
Confirmation of Contraception and Pregnancy Testing
POCBP are required to confirm heterosexual abstinence or use of contraception to prevent 
pregnancy during the base study, optional OLE, and for 42 days after the last dose of study 
intervention (base study or OLE). POCBP will be tested for pregnancy at each visit as 
outlined in Sections 1.3 and 5.1, Appendix 2, and Appendix 5.
Participants who are POCBP should be asked at study visits per the SoA to verbally confirm 
heterosexual abstinence or use of contraception since the prior visit, according to the 
Contraceptive Guidance in Appendix 5. Confirmation should be noted in the source 
documents for each visit.
Urine pregnancy test kits will be provided by the central laboratory to perform locally at each 
visit. In the event of a positive or indeterminant urine pregnancy test result, serum pregnancy 
testing for confirmation of the pregnancy must be performed by the central laboratory. A 
duplicate serum pregnancy test may be sent to a local laboratory to expedite results per 
investigator discretion. Positive urine pregnancy tests (except those from the screening visit), 
which have been confirmed by serum testing must be reported to the Sponsor using the 
appropriate eCRF within 24 hours of learning of the event. If a participant becomes pregnant, 
refer to Section 8.11.6.
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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 participation in the study.
8.3.5
Clinical Safety Laboratory Assessments
Refer to Appendix 2 for the list of clinical laboratory tests to be performed and to the SoA for 
the timing and frequency.
•
The investigator or medically qualified designee (consistent with local requirements) 
must review the laboratory report, document this review, and record any clinically 
relevant changes occurring during the study in the AE section of the CRF. The laboratory 
reports must be filed with the source documents. Clinically significant abnormal 
laboratory findings are those which are not associated with the underlying disease, unless 
judged by the investigator to be more severe than expected for the participant’s condition.
•
All protocol-required laboratory assessments, as defined in Table 18 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 until a new baseline is established as determined by the investigator.
•
If laboratory values indicate specified decreases in total lymphocyte count or 
CD4+ T-cell count (Table 4), participants must be managed per Section 8.11.5. TBNK 
panel assessments that are considered exploratory do not need to be evaluated by the 
investigator (Section 8.2.3 and Table 18).
8.3.6
HBV Assessments
Participants coinfected with HIV-1 and HBV who discontinue an antiretroviral medication 
that also has activity against HBV (3TC, FTC, TAF, or TDF) may experience an acute 
exacerbation of HBV. Therefore, participants who have evidence of past HBV exposure 
(anti-HBc-positive) and who meet enrollment criteria will be closely monitored during the 
study.
All eligible participants must be HBsAg-negative and HBV DNA-negative at screening. 
Individuals who are anti-HBc-positive and HBV DNA-positive at screening are excluded. 
Individuals who are anti-HBc-positive, but HBV DNA-negative at screening are eligible to 
enroll. All participants will have repeat hepatitis B serology and HBV DNA testing at 
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Weeks 48, Week 96 and Week 144 during the base study (per the SoA Section 1.3.1) and at 
Week 192 during the OLE (per the SoA Section 1.3.5).
For the duration of the study (base study and OLE), participants who are anti-HBc-positive
should be monitored for possible HBV reactivation. Samples will be taken to monitor for 
HBsAg and HBV DNA per the SoA (Section 1.3). Investigators should also pay close 
attention to changes from baseline in ALT, AST, bilirubin, and alkaline phosphatase.
Participants who are confirmed to be HBsAg-positive or have confirmed quantifiable HBV 
DNA after randomization may be unblinded and managed by the investigator per local 
standard of care and/or referred for management of their HBV infection (See Appendix 7 for 
Country-specific requirements). Participants may be allowed to continue study intervention if 
deemed medically appropriate upon consultation with the Sponsor. After Week 144 while in 
the OLE, participants who are confirmed to be HBsAg positive or have confirmed 
quantifiable HBV DNA will be managed by the investigator per local standard of care and/or 
referred for management of their HBV infection.
8.3.7
HCV Assessment
HCV serology will be performed at screening and if the individual is HCV antibody-positive, 
reflex testing will be performed for HCV RNA to assess study eligibility. Repeat if indicated 
per local standard of care.
8.3.8
Tobacco and Alcohol Assessments
Participants’ use of tobacco/vaping and alcohol will be obtained and recorded as specified in 
the SoA (Section 1.3.1).
8.3.9
Exploratory Clinical Marker Assessments
The following samples will be collected and assessments performed as specified in the SoA 
(Section 1.3.1) and Appendix 2 (Table 18) for exploratory evaluation of markers of 
inflammation, renal function, body composition, and energy and metabolism:
•
Blood for inflammatory markers (Section 8.3.9.1)
•
Blood for renal function markers (Section 8.3.9.2)
•
Urine for renal function markers (Section 8.3.9.2)
•
Blood for fasting lipid and metabolic profiles (sample collected as part of Chemistry 
panel [Section 8.3.5]) (Section 8.3.9.3)
•
Blood for energy and metabolism markers (Section 8.3.9.3)
•
Waist and hip measurements (Section 8.3.9.4)
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•
DEXA (Section 8.3.9.5)
8.3.9.1
Inflammation
Blood samples will be collected to evaluate the inflammatory and thrombotic response as 
measured by the following laboratory markers, as indicated in the SoA (Section 1.3.1):
•
IL-6
•
D-dimer
•
sCD-163
•
hs-CRP
8.3.9.2
Renal Function
Urine and blood samples will be collected to evaluate renal function as measured by key 
indicators, such as the following potential analytes and calculations, as indicated in the SoA 
(Section 1.3.1) and Appendix 2 (Table 18):
•
Urine: albumin/Cr, eGFR, protein, B-2M/Cr, and RBP/Cr
•
Serum: cystatin-C and Cr
Equations for CrCl and eGFR calculation (Cockcroft-Gault and MDRD equations, 
respectively) are in Appendix 8.
8.3.9.3
Fasting Lipid and Metabolic Profiles
Participants will be asked to fast for at least 8 hours prior to visits where blood will be taken 
to measure insulin, glucose, HDL-C, LDL-C, TG, TC, and non-HDL-C as specified in the 
SoA (Section 1.3.1). HOMA-IR will be calculated.
Note: Participants with type 1 diabetes mellitus and participants who are pregnant should not 
fast and should not have insulin levels tested. Participants with type 2 diabetes mellitus 
taking medications that may result in hypoglycemia should delay their morning dose of 
diabetic medication while fasting and take it after the blood draw for testing.
HbA1c should be collected for all nonpregnant participants irrespective of fasting or 
nonfasting status; HgbA1c should not be collected in pregnant participants.
Blood to evaluate energy and metabolism, as measured by the adipokines, leptin and 
adiponectin, will be collected as indicated in the SoA (Section 1.3.1).
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8.3.9.4
Waist, Hip and BMI Measurements
Participants should be asked to stand erect, relaxed and should not hold in their stomach 
during measurements. Waist circumference will be measured midway between the iliac crest 
and the lower rib margin. Hip circumference will be measured at the intertrochanteric level. 
Measurements should be taken with a stretch-resistant measuring tape. Waist-to-hip ratios 
will be calculated as waist (cm)/hip (cm) circumferences.
BMI will be calculated by the Sponsor using weight and height measurements taken as 
specified in the SoA (Section 1.3) and Section 8.3.1.
8.3.9.5
DEXA Assessments
DEXA images to monitor fat distribution and BMD should be collected from all 
participants/sites willing and able to have the test performed and according to country law 
(Section 1.3.1). These participants will undergo total body DEXA scans for BMD of the 
spine and hip as well as peripheral and trunk fat. Participants will not be excluded from 
participation in the study if unwilling/unable to have DEXA images performed.
Only those participants who are confirmed eligible to be randomized will undergo DEXA 
images for BMD of the spine and hip as well as peripheral and trunk fat. For Day 1 
(baseline), DEXA images should be performed after eligibility is confirmed and may be 
performed up to 45 days after randomization. The DEXA images at subsequent visits should 
be performed ±45 days of the scheduled visit. Only participants with valid baseline DEXA 
images should have DEXA images performed at subsequent visits as indicated in the SoA 
(Section 1.3). If DEXA scans cannot be performed within the protocol-specified time 
window or at a site approved by the central imaging reader, consultation is required between 
the investigator and the Sponsor to confirm the clinical appropriateness of performing further 
testing.
DEXA images will be evaluated by a central imaging reader. For clinical management of the 
participant, the DEXA images should be concurrently reviewed and interpreted locally by a 
qualified individual. Clinically significant findings noted in the local interpretation of the 
baseline DEXA images should be recorded in the participant’s medical history. Refer to the 
Site Imaging Manual for additional details regarding DEXA procedures including participant 
preparation instructions to be considered before DEXA imaging.
DEXA should not be performed on pregnant participants.
8.3.10
Administration of Patient Questionnaires
Participants will complete 3 PRO questionnaires to be administered in the following order: 
EQ 5D 5L, HIVTSQ, and HIV SI/SDM, as specified in the SoA (Sections 1.3.1, 1.3.2, and 
1.3.3). Participants are to complete the questionnaires on their own at the site on paper during 
the appropriate study visit (see SoA) prior to being seen by the investigator, discussing any 
medical conditions with the study personnel, or receiving any medical results. The 
questionnaires should not be administered to participants who are unable to complete 
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questionnaires unassisted or for whom native language translations of the questionnaires are 
unavailable.
The participant responses to questionnaires will be entered into the appropriate eCRF by site 
staff according to data entry guidelines.
PROs are not administered after Week 96.
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 need to document if an SAE was associated with a medication error, misuse, or 
abuse.
Investigators remain responsible for following up AEs, SAEs, and other reportable safety 
events for outcome according to Section 8.4.3. The investigator, who is a qualified physician, 
will assess events that meet the definition of an AE or SAE as well as other reportable safety 
events with respect to seriousness, intensity/toxicity, and causality.
8.4.1
Time Period and Frequency for Collecting AE, SAE, and Other Reportable 
Safety Event Information
All AEs, SAEs, and other reportable safety events that occur after the participant provides 
documented informed consent, but before intervention randomization, must be reported by 
the investigator if the participant is receiving placebo run-in or other run-in treatment; if the 
event causes the participant to be excluded from the study, or is the result of a protocol-
specified intervention, including, but not limited to washout or discontinuation of usual 
therapy, diet, or a procedure.
From the time of intervention randomization through study duration, all AEs, SAEs, and 
other reportable safety events must be reported by the investigator.
Additionally, any SAE brought to the attention of an investigator at any time outside the 
period specified in the previous paragraph must be reported immediately to the Sponsor if the 
event is considered related to study intervention.
For infants born to participants who become pregnant and consent to infant safety data 
collection, SAEs (including perinatal HIV-1 infection) occurring through 1 year of age must 
be reported by the investigator to the Sponsor within 24 hours of learning of the event.
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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 the investigator 
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.
Exception: A positive pregnancy test at the time of initial screening is not a reportable event 
unless the participant has received study intervention.
Table 5
Reporting Time Periods and Time Frames for Adverse Events and Other 
Reportable Safety Events
Type of Event
Reporting Period:
Consent to 
Randomization/
Allocation
Reporting Period:
Randomization/
Allocation 
Through 
Protocol-specified 
Follow-up Period
Reporting 
Period:
After the 
Protocol-
specified 
Follow-up 
Period
Time Frame 
to Report 
Event and 
Follow-up 
Information to 
Sponsor
NSAE
Report if:
– due to protocol-
specified 
intervention
– causes exclusion
– participant is 
receiving placebo 
run-in or other run-
in treatment
Report all
Not required
Per data entry 
guidelines
SAE
Report if:
– due to protocol-
specified 
intervention
– causes exclusion
– participant is 
receiving placebo 
run-in or other run-
in treatment
Report all
Report if:
– drug/vaccine 
related.
(Follow 
ongoing to 
outcome)
Within 
24 hours of 
learning of 
event
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Type of Event
Reporting Period:
Consent to 
Randomization/
Allocation
Reporting Period:
Randomization/
Allocation 
Through 
Protocol-specified 
Follow-up Period
Reporting 
Period:
After the 
Protocol-
specified 
Follow-up 
Period
Time Frame 
to Report 
Event and 
Follow-up 
Information to 
Sponsor
Pregnancy/Lactation 
Exposure
Report if:
– participant has been 
exposed to any 
protocol-specified 
intervention (eg, 
procedure, washout,
or run-in treatment 
including placebo 
run-in)
Exception: A positive 
pregnancy test at the 
time of initial 
screening is not a 
reportable event.
Report all
Previously 
reported –
Follow to 
completion/
termination; 
report outcome
Within 
24 hours of 
learning of 
event
ECI (requiring
regulatory reporting)
Report if:
– due to intervention
– causes exclusion
Report
– potential DILI
– requiring
regulatory 
reporting
Not required
Within 
24 hours of 
learning of 
event
ECI (does not require 
regulatory reporting)
Report if:
– due to intervention
– causes exclusion
Report
– non-DILI ECIs 
and those not 
requiring 
regulatory 
reporting
Not required
Within 
5 calendar days 
of learning of 
event
Cancer
Report if:
– due to intervention
– causes exclusion
Report all
Not required
Within 
5 calendar days 
of learning of 
event (unless 
serious)
Overdose
Report if:
– receiving placebo 
run-in or other run-
in medication 
Report all
Not required
Within 
5 calendar days 
of learning of 
event
DILI=drug-induced liver injury; ECI=event of clinical interest; NSAE=nonserious adverse event; SAE=serious 
adverse event.
8.4.2
Method of Detecting AEs, SAEs, and Other Reportable Safety Events
Care will be taken not to introduce bias when detecting AEs and/or SAEs and other 
reportable safety events. Open-ended and nonleading verbal questioning of the participant is 
the preferred method to inquire about AE occurrence.
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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. 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). The investigator will also make every attempt to 
follow nonserious AEs that occur in randomized participants for outcome. Further 
information on follow-up procedures is given in Appendix 3.
8.4.4
Regulatory Reporting Requirements for SAE
Prompt notification (within 24 hours) by the investigator to the Sponsor of SAE is essential 
so that legal obligations and ethical responsibilities toward 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 SAEs) 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 (spontaneously reported to the 
investigator or their designee), that occurs in a participant during the study are reportable to 
the Sponsor.
All reported pregnancies must be followed to the completion/termination of the pregnancy.
Any pregnancy complication will be reported as an AE or SAE.
The medical reason (example: maternal health or fetal disease) for an elective termination of 
a pregnancy will be reported as an AE or SAE. Prenatal testing showing that the fetus will be 
born with severe abnormalities/congenital anomalies that leads to an elective termination of a 
pregnancy will be reported as an SAE for the fetus.
Pregnancy outcomes of ectopic pregnancy, spontaneous abortion, missed abortion, benign 
hydatidiform mole, blighted ovum, fetal death, intrauterine death, miscarriage, and stillbirth 
must be reported as serious events (Important Medical Events). If the pregnancy continues to 
term, the outcome (health of infant) must also be reported.
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8.4.6
Disease-related Events and/or Disease-related Outcomes Not Qualifying as 
AEs or SAEs
This section is not applicable to the study.
8.4.7
Events of Clinical Interest
Selected serious and nonserious AEs are also known as ECIs and must be reported to the 
Sponsor.
Events of clinical interest for this study include:
1. Potential DILI events defined as an elevated AST or ALT laboratory value that is greater 
than or equal to 3× the ULN and an elevated total bilirubin laboratory value that is greater 
than or equal to 2× the ULN and, at the same time, an alkaline phosphatase laboratory 
value that is less than 2× the ULN, as determined by way of protocol-specified laboratory 
testing or unscheduled laboratory testing.*
*Note: These criteria are based on 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
In this study, an overdose is any dose higher than twice the prescribed dose of study 
intervention (3 or more tablets of a single study intervention) in a day.
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
Venous blood samples will be collected for measurement of ISL. The Sponsor may assess 
these samples for DOR as needed. Sample collection, storage, and shipment instructions for 
plasma samples will be provided in the Operations/Laboratory manual.
Investigational PK samples will be collected (except during pregnancy or when the 
participant has been unblinded and is known to be taking BIC/FTC/TAF) as outlined in the 
SoA (Section 1.3). Investigational ISL PK samples will be collected irrespective of time of 
last dose. The time of last dose of study intervention taken prior to the sample collection will 
be verbally reported to study staff by the participant and recorded in the appropriate source 
documentation. Analysis of these samples will be performed by the Sponsor as needed.
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Population PK samples will be collected from all participants as outlined in Table 6. The 
time of dose of study intervention taken prior to the sample collection will be verbally 
reported to study staff by the participant and recorded in the appropriate source 
documentation.
At the Week 4 visit, participants who routinely take their study intervention during the day 
will have a predose and postdose sample collected per Table 6. Participants who routinely 
take their study intervention in the evening should continue to do so, and will have only 
1 sample collected at the Week 4 visit, irrespective of the time of the last dose.
For participants receiving DOR/ISL (base study or OLE) who become pregnant and consent 
to continue DOR/ISL, PK samples will be collected to evaluate DOR and ISL concentration 
levels per Table 7 in Section 8.11.6.1.
Table 6
Collection of Population PK Samples
Study Visit
Sample Time Relative to Dose of Study Interventiona
Day 1
Predose
Week 4
Daytime dosing: Predose AND within 0.5 to 2 hours postdose
OR
Evening dosing: Only 1 sample irrespective of time of last dose
Week 12
Irrespective of time of last dose
Week 24
Irrespective of time of last dose
Week 48
Irrespective of time of last dose
PK=pharmacokinetic(s).
a Time of last dose and time of PK sample collection must be documented for all samples.
8.7
Pharmacodynamics
Pharmacodynamic parameters will not be evaluated in this study.
8.8
Biomarkers
Collection of samples for other biomarker research is also part of this study. The following 
samples for biomarker research are required and will be collected from all participants as 
specified in the SoA:
•
Blood for genetic analysis
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 FBR if the participant provides 
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documented informed consent for FBR. If the planned genetic analysis is not approved, but 
FBR is approved and consent is given, this sample will be collected for the purpose of FBR.
Sample collection, storage, and shipment instructions for planned genetic analysis samples 
will be in the Operations/Laboratory Manual.
8.9
Future Biomedical Research Sample Collection
If the participant has provided documented informed consent for FBR, FBR-specific 
specimen collections, including leftover specimens, will be obtained. The following 
specimens will be included for FBR:
•
Whole blood for future biomedical research
•
Leftover extracted DNA for future research
•
Leftover main study plasma from HIV-1 RNA quantification
•
Leftover main study plasma from HIV-1 viral 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.
8.11.1
Screening/Rescreening
8.11.1.1
Screening
Prior to randomization, potential participants will be evaluated to determine that they fulfill 
the entry requirements as set forth in Section 5. Participants are expected to enroll as soon as 
possible after eligibility is confirmed. In cases of unexpected delays in receiving repeat 
screening laboratory results, a screening period of up to 45 days is allowed.
8.11.1.2
Rescreening
If the screening window has been exceeded, participants are allowed to rescreen one time 
after approval from the Sponsor. Once a participant has started the rescreening process, a 
new screening period (ie, an additional ≤45-day window) will begin, during which time 
screening procedures will be repeated.
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The following assessments must be repeated for participants who are rescreened:
•
Vital signs, weight, and directed physical examination
•
Review medical history and prior/concomitant medications for new information
•
All laboratory assessments (includes serum and/or urine hCG pregnancy testing for 
POCBP)
•
Review of AEs
If the informed consent form has been updated, participants should be reconsented before 
rescreening. If no updates have been made, documented informed consent during the original 
screening period should be reviewed with the participant and a verbal reconsent to continue 
in the study should be documented.
If a participant had a Day 1 ECG during the original screening period, it should be repeated 
(at the Day 1 visit or within 7 days prior).
If a participant had a baseline Day 1 DEXA scan during the original screening period and 
>45 days have elapsed, the Day 1 DEXA should be repeated. If ≤45 days have elapsed since 
the DEXA, it is not necessary to repeat the Day 1 DEXA scan during rescreening.
Participants who were previously considered screen failures because the duration of 
BIC/FTC/TAF was <3 consecutive months are allowed to rescreen if they have continued to 
receive BIC/FTC/TAF therapy with documented viral suppression (HIV-1 RNA 
<50 copies/mL) for ≥3 consecutive months before the rescreening visit and have no history 
of prior virologic treatment failure on any past or current regimen.
8.11.2
Treatment Period
All procedures and their timing should be completed per the SoA (Section 1.3).
8.11.2.1
Fasting
Visits at Day 1, Weeks 24, 48, 96, and 144 require that participants fast (ie, do not consume 
any food or beverages except water) for at least 8 hours prior to the visit. The 
investigator/study coordinator must remind participants to fast prior to these visits and must 
confirm with participants their fasting status and record in the appropriate source 
documentation and laboratory requisition(s).
Note: Participants with type 1 diabetes mellitus and participants who are pregnant should not 
fast and should not have insulin levels or lipids tested. Participants with type 2 diabetes 
mellitus taking medications that may result in hypoglycemia should delay their morning dose 
of diabetic medication while fasting and take it after the blood draw for testing.
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8.11.2.2
End of Base Study Week 144 Visit
Procedures for the blinded treatment period (base study) are to be conducted per the SoA 
(Section 1.3.1). Week 144 represents the end of the base study and the end of blinded 
treatment administration. Prior to the end of the base study/Week 144 visit, site staff should 
proactively discuss the potential plan for treatment to facilitate either a transition to locally 
available ART or DOR/ISL in the optional OLE. For participants who are entering the OLE, 
the Week 144 visit serves as the start of the OLE, and open-label DOR/ISL will be dispensed 
and participants will follow procedures outlined in SoA (Section 1.3.5).
Participants who complete Week 144 should follow End of Treatment Follow-up Visit 
assessments per the Week 144 SoA (Section 1.3.1).
Participants who are pregnant at Week 144 will be managed per Section 8.11.6 (SoA 1.3.4).
Participants who have laboratory values at the Week 144 visit that meet any of the 
discontinuation criteria for specified decreases in total lymphocyte counts or CD4+ T-cell 
counts (Section 7.1 and Table 4) must be managed per Section 8.11.5.
8.11.2.3
Optional Open Label Extension (Week 144 to Week 240)
If DOR/ISL is not commercially accessible by Week 144, participants in both treatment 
groups will be provided the option to enroll in an OLE to receive open-label DOR/ISL up to 
Week 240 or until DOR/ISL becomes commercially accessible (whichever comes first) per 
the SoA (Section 1.3.5).
A participant entering the OLE must meet all of the following criteria:
•
Is considered, in the opinion of the investigator, to benefit from continued study 
participation.
•
Understands the procedures in study extension and provides documented informed 
consent to enter the study extension.
•
Does not meet any of the discontinuation criteria (See Section 7.1).
Once DOR/ISL becomes commercially accessible, participants should be contacted and 
informed that they will complete the Discontinuation of Treatment (OLE) visit and transition 
to DOR/ISL or other commercially accessible ART at their next study visit (or sooner at the 
PIs discretion). In rare circumstances and with permission of the Sponsor, study participation 
may be extended for a limited amount of time to ensure all participants are able to secure 
continued treatment access in the commercial market before exiting the study.
The Week 240 Visit represents the end of treatment in the study.
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Manage participants with viremia per Section 8.11.4 (SoA 1.3.2). Manage participants with 
specified decreases in total lymphocyte and/or CD4+ T-cell counts per Section 8.11.5 (SoA 
1.3.3). Manage participants who are pregnant per Section 8.11.6 (SoA 1.3.4).
8.11.3
Participants Who Discontinue Study Intervention
A participant must be discontinued from study intervention for any of the reasons listed in 
Section 7.1.
When it is determined that discontinuation from study intervention is appropriate, the 
participant should have both an Early Discontinuation of Treatment visit (Section 8.11.3.1) 
and an End of Treatment Follow-up visit (Section 8.11.3.2) conducted. After the visit 
procedures are completed, the participant will be withdrawn from the study and managed for 
treatment of their HIV-1 infection per local standard of care.
Participants who discontinue study intervention due to confirmed specified decreases in total 
lymphocyte count or CD4+ T-cell count (Table 4) must be managed per Section 8.11.5.
Participants who discontinue study intervention due to other reasons, but have laboratory 
values at the Early Discontinuation of Treatment visit that meet any of the discontinuation 
criteria for specified decreases in total lymphocyte count or CD4+T-cell count (Table 4) must 
be managed per Section 8.11.5.
8.11.3.1
Discontinuation of Treatment
Participants who discontinue study intervention due to specified decreases in total 
lymphocyte counts or CD4+ T-cell counts (per Section 7.1) will be managed per Section 
8.11.5.
Early Discontinuation (Base Study)
Participants who discontinue study intervention prior to Week 144 for any reason(s) should 
have an Early Discontinuation of Treatment visit as outlined in the SoA (Section 1.3.1, 1.3.2, 
or 1.3.3). If discontinuation occurs during the time frame of a scheduled study visit, the 
assessments for the scheduled visit as well as the Early Discontinuation of Treatment visit 
should be conducted, however, collection of laboratory samples should not be duplicated.
Discontinuation (OLE)
Participants in the OLE who discontinue DOR/ISL prior to Week 240 for any reason(s) 
should have a Discontinuation of Treatment (OLE) visit as outlined in the SoA (Sections 
1.3.2, 1.3.3 or 1.3.5). Participants who complete Week 240 should follow assessments per the 
Week 240 SoA (Section 1.3.5).
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8.11.3.2
End of Treatment Follow-up
Participants who discontinue study intervention for any reason(s) will have an End of 
Treatment Follow-up Visit 42 days (+7 days) after the last dose of study intervention. 
Assessments for this visit are outlined in Sections 1.3.1, 1.3.2, 1.3.3, and 1.3.5, as applicable.
8.11.4
Viremia Confirmation
If a participant has a viral load of ≥50 copies/mL (confirmed as described in 
Sections 4.2.1.1.2 and 8.2.2.1) at any time during the study, a Viremia Confirmation Visit 
must be conducted within 4 weeks (±1 week) after the initial HIV-1 viremia, as specified in 
the SoA (Section 1.3.2). If a scheduled visit is to occur within the time frame that a 
participant would return for a Viremia Confirmation Visit, the assessments for the scheduled 
visit should be conducted, and the HIV-1 viral drug resistance sample must be collected. PK 
will be assessed for both DOR and ISL (from same sample) at the time of viremia 
confirmation.
8.11.5
Management of Participants With Specified Decreases in Total Lymphocyte 
Count or CD4+ T-cell Count
To meet the protocol-defined discontinuation criteria in the base study or the OLE, 
participants must have a confirmed total lymphocyte count or CD4+ T-cell count that 
indicates a specified decrease on 2 consecutive measurements 10 to 14 weeks apart. A 
minimum interval of 10 weeks between consecutive tests is required to meet discontinuation 
criteria. The confirmation visit must occur within 10 to14 weeks after the initial decrease (or 
at the next scheduled visit), as specified in the SoA (Section 1.3.3) and Table 4.
Management of Participants Who Discontinue Study Intervention Due to Specified 
Decreases in Total Lymphocyte Count or CD4+ T-cell Count
Participants discontinued from study intervention due to specified decreases in total 
lymphocyte count or CD4+ T-cell count (Section 7.1 and Table 4) should undergo 
assessments for the Discontinuation of Treatment Visit and the End of Treatment Follow-up 
visit (regardless of treatment assignment) as specified in the SoA (Section 1.3.3, 1.3.5). After 
discontinuation from study intervention, participants will be managed for treatment of their 
HIV-1 infection per local standard of care. Consult with Sponsor prior to discontinuation or 
unblinding if the investigator believes there is an alternative explanation for the result (eg, 
COVID-19). No subsequent monitoring is required for participants in the BIC/FTC/TAF 
group who meet discontinuation criteria in Table 4.
Monitoring for Participants Receiving DOR/ISL
After completion of the Discontinuation of Treatment Visit (base study or OLE) and the End 
of Treatment Follow-up visit, participants who discontinued for confirmed decreases in 
CD4+ T-cell count or lymphocyte counts (per Table 4), should have monitoring visits every 
10 to 14 weeks (Section 1.3.3). Participants should be monitored until the total lymphocyte 
count or CD4+T-cell count no longer meet the criteria in Table 4 at 2 consecutive visits. If 
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conditions that impact lymphocytes arise during the follow-up monitoring period, and are 
expected to persist, monitoring may be stopped.
Management of Participants Receiving DOR/ISL Who Discontinue Study Intervention
Due to Reasons Other Than Decreases in Total Lymphocyte Count or CD4+ T-cell Count
Participants noted to have their first decreases in total lymphocyte count or CD4+ T-cell 
count that meets the criteria for Table 4 at the Discontinuation of Treatment Visit (base study 
or OLE) or at the Week 144 visit only require monitoring as described above if the count 
declines are confirmed by the End of Treatment Follow-up Visit.
8.11.6
Clinical Management of Participants Who Become Pregnant
If a participant becomes pregnant (confirmed by a positive serum pregnancy test), the 
investigator should refer the participant to a local provider for obstetric (prenatal) care per 
local standard of care. The provider should be informed of the participant’s study 
participation by site personnel.
All pregnancies must be followed to completion or termination of the pregnancy by the 
investigator per Section 8.4.5. Severity assessment of AEs that are pregnancy-related 
complications should follow guidance provided as part of the DAIDS Table for Grading the 
Severity of Adult and Pediatric Adverse Events, July 2017, version 2.1 (Appendix 3) 
“Addendum 1: Female Genital Grading Table for Use in Microbicide Studies,” particularly 
the section “Complications of Pregnancy” [National Institute of Allergy and Infectious 
Diseases 2017].
Participants with a confirmed pregnancy prior to Week 144 should be unblinded by the 
investigator (Section 8.1.10). Upon Sponsor consultation and approval, unblinding is not 
required in participants who will not have a continuing pregnancy (ie, pregnancy termination 
or nonviable pregnancy).
Upon confirmation of pregnancy by serum testing, the investigator or appropriate designee 
should discuss the following with the participant:
•
The appropriateness of continuing study intervention based on available data and local 
standard-of-care guidelines (where allowed by local regulations, health authorities, and 
ethics committees). For participants receiving BIC/FTC/TAF, the investigator should 
refer to the local product circular and local guidelines to determine if treatment may be 
continued. Documented informed consent must be obtained to continue study 
intervention regardless of treatment assignment (Section 8.1.1.3)
•
Joining a pregnancy registry (the Antiretroviral Pregnancy Registry), which collects 
information about the outcome of the pregnancy, if applicable
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Upon confirming that the pregnancy is continuing, the site will discuss with the participant 
(per timing at the discretion of the Principal Investigator):
•
Intentions for breastfeeding (Section 8.11.6.3)
•
Consenting to infant safety data collection per Sections 8.1.1.4 and 8.11.6.4
8.11.6.1
Continuing Study Intervention in Pregnancy
Participants who become pregnant and consent to continue their assigned study intervention 
(Section 8.1.1.3) will be transitioned to open-label study intervention (DOR/ISL or 
BIC/FTC/TAF) and should complete all remaining protocol-specified visits and procedures 
per the regular schedule in the applicable SoA (Section 1.3), with the following exceptions:
•
Only participants receiving DOR/ISL will have PK samples collected (per the timing in 
Table 7). Participants in the BIC/FTC/TAF group will not have PK collection.
•
DEXA scans will not be performed for either group.
•
Participants on DOR/ISL who are pregnant at Week 144 will have the opportunity to 
continue into the OLE.
•
Participants on BIC/FTC/TAF who are pregnant at Week 144 will continue on 
BIC/FTC/TAF through the postpartum visit and will then complete the study.
Pregnancy visits are to occur at least every 12 weeks (~1 during each trimester and a 
postpartum visit ≤8 weeks after delivery) in both the base study and the OLE (Sections 1.3.1 
and 1.3.4, as applicable). This applies to participants whose pregnancy extends beyond Week 
240 (Section 1.3.4). More frequent HIV-1 RNA testing should be performed per local 
guidelines or as determined by the investigator or Sponsor. If HIV-1 RNA testing is 
performed in a local laboratory with an approved assay (Appendix 10), the results must be 
promptly recorded in the appropriate CRF.
For participants receiving study intervention and continuing their pregnancy, prenatal care 
should be coordinated between the investigator and the local obstetric care provider. The 
investigator (or designee) is responsible for reviewing records from prenatal care at each 
study visit and obtaining relevant clinical and laboratory data from the obstetric care provider 
to monitor the safety and well-being of the mother and fetus. Relevant data obtained by the 
site should be entered into the appropriate CRF and source documentation.
The participant’s medical records will be collected and reviewed by the study-site for:
•
Clinical safety laboratory assessments
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•
Pregnancy screening laboratory assessments (for participants on DOR/ISL only) for 
hepatitis B serology and HBV DNA; if local laboratory test results are unavailable, 
collect central laboratory sample
•
Plasma HIV-1 RNA level
•
Results of 2nd trimester ultrasound(s) providing gestational age and anatomic survey
•
Any complications associated with the pregnancy
•
Outcome of pregnancy
•
Information that could indicate congenital abnormalities
For participants who are pregnant at the last regularly scheduled study visit (Week 144 [base 
study] or Week 240 [OLE]), their visit schedule will be extended through the duration of the 
pregnancy to allow assessments through each trimester and postpartum and, as applicable, a 
42-day follow-up period with an End of Treatment Follow-up visit (Section 1.3.4). After 
completion of the pregnancy, the participant will have completed the study after completing 
either the postpartum visit (if the participant chooses to breastfeed) or the End of Treatment 
Follow-up visit (if the participant does not choose to breastfeed and completed the 42-day 
follow-up period) (Section 1.3.4). Participants on DOR/ISL at the completion of the 
pregnancy will have continued access to DOR/ISL through the OLE, until DOR/ISL
becomes commercially accessible per Section 6.7. Participants on BIC/FTC/TAF at the 
completion of their pregnancy will have their last dispensing of study intervention at their 3rd 
trimester (Pregnancy 3) visit per the SoA (Section 1.3.4).
8.11.6.1.1
Collection of Population PK Samples During Pregnancy and Postpartum 
(Participants Continuing DOR/ISL Only)
For participants who continue DOR/ISL, PK samples will be collected at their scheduled 
visit/pregnancy visit during the 1st, 2nd, and 3rd trimesters and postpartum to evaluate DOR 
and ISL concentration levels per Table 7. These samples will be used to characterize the PK 
profile of DOR/ISL during pregnancy. Participants who do not learn of their pregnancy until 
the 2nd trimester may not have had a PK sample collection during the 1st trimester.
Participants who routinely take their DOR/ISL during the day will have a predose and 
2 postdose samples collected per Table 7. Participants who routinely take their DOR/ISL in 
the evening should continue to do so and will have only 1 sample collected at the 
2nd Trimester, 3rd Trimester, and Postpartum visits, irrespective of the time of the last dose. 
Time of last dose and time of PK sample collection must be documented for all samples. The 
time of last dose of study intervention taken prior to the sample collection will be verbally 
reported to study staff by the participant and recorded in the appropriate source 
documentation.
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Table 7
Collection of Population PK Samples During Pregnancy and Postpartum
Study Visit
Sample Time Relative to Dose of DOR/ISLa
1st Trimesterb
Daytime dosing: Predose
OR
Evening dosing: Irrespective of time of last dose
2nd Trimester
Daytime dosing: Predose AND within 0.5 to 2 hours AND within 4 to 
6 hours postdose
OR
Evening dosing: Only 1 sample irrespective of time of last dose
3rd Trimester
Daytime dosing: Predose AND within 0.5 to 2 hours AND within 4 to 
6 hours postdose
OR
Evening dosing: Only 1 sample irrespective of time of last dose
Postpartumc
Daytime dosing: Predose AND within 0.5 to 2 hours AND within 4 to 
6 hours postdose
OR
Evening dosing: Only 1 sample irrespective of time of last dose
DOR=doravirine; ISL=islatravir; PK=pharmacokinetic(s).
a Time of last dose and time of PK sample collection must be documented for all samples.
b Collect at the scheduled 1st Trimester visit after a participant reports gravid status. (May not be collected if 
participant does not learn of their pregnancy until after the first trimester.)
c Postpartum visit ≤8 weeks after delivery.
8.11.6.2
Discontinuing Study Intervention for Pregnancy
Participants who become pregnant and discontinue their assigned study intervention should 
have a Discontinuation of Treatment Visit (Base Study or OLE) per the SoA (Section 1.3.1
or 1.3.5, as applicable). If the decision to discontinue study intervention occurs during the 
time frame of a scheduled study visit, the assessments for the Scheduled Visit as well as for 
the Discontinuation of Treatment Visit should be completed. Collection of laboratory 
samples should not be duplicated. In addition, these participants will have an End of 
Treatment Follow-up Visit 42 days (+7 days) after the last dose of study intervention.
The investigator (or local HIV care provider, if not the study-site) should develop a new 
treatment plan per local standard of care before discontinuing study intervention to minimize 
the risk of a gap in ART.
8.11.6.3
Participants Who Choose to Breastfeed
A participant who chooses to breastfeed must discontinue study intervention before initiating 
breastfeeding (Section 7.1) and be followed in the study per Section 8.11.6.2. The 
investigator (or local HIV care provider, if not the study-site) should make every effort to 
develop a new treatment plan (per local standard of care) within sufficient time prior to 
delivery to minimize the likelihood of a gap in ART.
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8.11.6.4
Infant Safety Data Collection
For participants who become pregnant while receiving study intervention, or within 42 days 
after the last dose of study intervention, the data in Section 8.11.6.4.1 should be obtained by 
the site and entered into the appropriate CRF and source documentation.
Infant SAEs, including perinatal HIV-1 infection, will be collected as per Section 8.4.1 and 
should be reviewed at the participant’s scheduled study visits that occur during this time. 
Infant safety data collection will be captured if exposure to study intervention occurs during 
pregnancy.
8.11.6.4.1
Schedule of Activities: Infant Safety Data Collection
Time Point
At Birtha
1-Year After Birtha,b
Visit Name
NA
Infant Follow-up-1
Administrative and Safety Procedures
Infant Informed Consent
Xc
Gestational Age at Birth
X
Apgar Score
X
Length
X
X
Weight
X
X
Head Circumference
X
X
Directed Pediatric Examination
X
Concomitant Medications Reviewd
X
X
Review Infant SAEse
---------------------------X----------------------------
HIV=human immunodeficiency virus; NA=Not applicable; SAE=serious adverse event.
a Data to be collected and entered at the site within 12 weeks of each time point.
b If a participant withdraws from the study, data for this time point 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 the participant’s regularly scheduled study visits.
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9
STATISTICAL ANALYSIS PLAN
This section outlines the statistical analysis strategy and procedures for the study. If, after the 
study has begun, but prior to final database lock, changes are made to primary and/or key 
secondary hypotheses, or the statistical methods related to those hypotheses, then the 
protocol will be amended (consistent with ICH Guideline E9). Changes to exploratory or 
other nonconfirmatory analyses made after the protocol has been finalized, but prior to final 
database lock, will be documented in an sSAP and referenced in the CSR for the study. 
Posthoc exploratory analyses will be clearly identified in the CSR. Other planned analyses 
(eg, those specific to the analyses of PK data, PROs, and FBR) will be documented in 
separate analysis plans. Data collected from the OLE for those participants who consent to 
enter the OLE, will be summarized separately using only descriptive statistics.
9.1
Statistical Analysis Plan Summary
Key elements of the SAP are summarized below; the comprehensive plan is provided in 
Sections 9.2 through 9.12.
Study Design Overview
A Phase 3, Randomized, Active-Controlled, Double-Blind Clinical Study 
to Evaluate a Switch to Doravirine/Islatravir (DOR/ISL 100 mg/0.25 mg) 
Once-Daily in Participants With HIV-1 Virologically Suppressed on 
Bictegravir/Emtricitabine/Tenofovir Alafenamide (BIC/FTC/TAF)
Treatment Assignment
Approximately 501 participants will be randomly assigned in a 2:1 ratio 
to receive either DOR/ISL (Group 1) or BIC/FTC/TAF (Group 2). 
Clinical site personnel and participants will remain blinded to study 
intervention assignments through Week 144, while Sponsor personnel 
will remain blinded through Week 48.
Analysis Populations
Efficacy: FAS, PP, and Resistance Analysis Subset
Safety: APaT
Primary Endpoints
1.
Percentage of participants with HIV-1 RNA ≥50 copies/mL at 
Week 48
2.
Percentage of participants who experience AEs and percentage of 
participants who discontinue study intervention due to AEs through 
Week 48
Secondary Endpoints
1.
Percentage of participants with HIV-1 RNA ≥50 copies/mL at 
Week 96 and Week 144
2.
Percentage of participants with HIV-1 RNA <200 and 
<50 copies/mL at Week 48, Week 96 and Week 144
3.
Mean change from baseline in CD4+ T-cell count at Week 48,
Week 96 and Week 144
5.
Viral resistance-associated substitutions
6.
General safety and tolerability through Week 144
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Statistical Methods for Key 
Efficacy Analyses
For the primary hypothesis (H1), DOR/ISL will be considered non-inferior 
to BIC/FTC/TAF if the upper bound of the 2-sided multiplicity-adjusted 
95% CI for the between-treatment difference in the percentage of 
participants with HIV-1 RNA ≥50 copies/mL at Week 48 (DOR/ISL 
minus BIC/FTC/TAF) is less than 4 percentage points (non-inferiority 
margin). The CI will be based on the unstratified Miettinen and Nurminen 
method [Miettinen, O. and Nurminen, M. 1985]. The FDA snapshot 
algorithm [Food and Drug Administration (CDER) 2015] will be used to
handle missing data for the analysis of the primary efficacy hypothesis.
Statistical Methods for Key 
Safety Analyses
For overall safety endpoints, specific AEs, and safety topics of special 
interest that meet predefined threshold rules, point estimates and 2-sided 
nominal 95% CIs for the differences between treatment groups (DOR/ISL 
minus BIC/FTC/TAF) in the percentages of participants with events will 
be provided using the unstratified Miettinen and Nurminen method 
[Miettinen, O. and Nurminen, M. 1985].
IAs
An IA will be performed when approximately 30% of participants have 
completed the Week 24 visit assessments. Results will be reviewed by an 
eDMC. All available efficacy and safety data for participants enrolled at 
the time of the Week 24 IA will be reviewed, and the data from the first 
30% of participants who reach Week 24 will be included in the futility 
assessment. The nonbinding futility criterion is if the upper bound of the 
2-sided 95% CI for the treatment difference (DOR/ISL minus 
BIC/FTC/TAF) in the percentage of participants with Week 24 HIV-1 
RNA ≥200 copies/mL is greater than 8 percentage points, consideration 
may be given to stop the study. Additional details are provided in 
Section 9.7.
In addition, the eDMC will periodically review efficacy and safety data 
(per the timelines specified in the eDMC charter).
Multiplicity
The Type 1 error rate over the multiple efficacy hypothesis tests will be 
controlled by a sequential testing procedure. A formal futility analysis at 
Week 24 is planned as described in Section 9.7, a small amount of alpha 
(α=0.00001) will be allocated for this IA, purely for statistical rigor. The 
following efficacy hypotheses will be tested sequentially at a 1-sided 
2.499% Type 1 error rate in the following order:
Primary efficacy hypothesis (H1) testing non-inferiority of DOR/ISL to 
BIC/FTC/TAF at Week 48
Primary efficacy hypothesis (H2) testing superiority DOR/ISL to 
BIC/FTC/TAF at Week 48
Secondary efficacy hypothesis (H3) testing superiority of DOR/ISL to 
BIC/FTC/TAF at Week 96
Secondary efficacy hypothesis (H4) testing superiority of DOR/ISL to 
BIC/FTC/TAF at Week 144
These hypotheses will be assessed by the percentage of participants with 
HIV-1 RNA ≥50 copies/mL at the indicated time points. Testing will stop 
with the first of these tests failing to reach statistical significance and all 
subsequent tests would not be considered for statistical significance. In this 
way, the overall 1-sided 2.5% Type 1 error rate in testing these hypotheses 
is strongly controlled.
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Sample Size and Power 
The planned sample size is 501 participants (334 in the DOR/ISL group 
and 167 in the BIC/FTC/TAF group). For the primary efficacy endpoint of 
the percentage of participants with HIV-1 RNA ≥50 copies/mL at 
Week 48, the study has 93.3% power to demonstrate that DOR/ISL is 
non-inferior to BIC/FTC/TAF at a 1-sided 2.5% alpha-level if the true rate 
of participants with HIV-1 RNA ≥50 copies/mL at Week 48 is 1.5% in 
both treatment groups. This power calculation does not account for the 
futility assessment at Week 24.
9.2
Responsibility for Analyses/In-house Blinding
The statistical analysis of the data obtained from this study will be the responsibility of the 
Clinical Biostatistics department of the Sponsor.
Day 1 through Week 48 will be conducted as a double-blind study under in-house blinding 
procedures. The official, final database for Day 1 through Week 48 will not be unblinded 
until medical/scientific review has been performed, protocol deviations have been identified, 
and data have been declared final and complete. The clinical database and Sponsor personnel 
directly involved in the Week 48 analysis and reporting will become unblinded at the time of 
the Week 48 database lock, although study participants and site personnel will remain 
blinded until Week 144.
PK data may be unblinded early for the purpose of preparing a population PK model. A 
separate team from the protocol team will be unblinded for the purpose of preparing the PK 
model. Efficacy and safety data will not be unblinded for the purpose of preparing the PK 
model. Interim data or results will not be shared with the protocol team before unblinding of 
the Sponsor at the Week 48 database lock.
The Clinical Biostatistics department will generate the randomized allocation schedule(s) for 
study intervention assignment. Randomization will be implemented via an IRT.
Blinding issues related to the planned IAs are described in Section 9.7.
9.3
Hypotheses/Estimation
Objectives and hypotheses of the study are stated in Section 3.
Success of this study is predicated only on establishing non-inferiority of DOR/ISL to 
BIC/FTC/TAF, as assessed by the percentage of participants with HIV-1 RNA 
≥50 copies/mL at Week 48 (ie, establishing statistical significance of H1).
9.4
Analysis Endpoints
Efficacy and safety endpoints that will be evaluated for within- and/or between-treatment 
differences are listed below.
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9.4.1
Efficacy/Pharmacokinetics Endpoints
9.4.1.1
Efficacy Endpoints
An initial description of efficacy measures is provided in Section 4.
Percentage of Participants With HIV-1 RNA ≥50 Copies/mL
A PCR assay with a lower level of detection of <50 copies/mL will be used to measure the 
HIV-1 RNA level in blood samples obtained at each visit. The primary objective will be 
assessed based on the percentage of participants with HIV-1 RNA ≥50 copies/mL at 
Week 48. A secondary objective will assess the percentage of participants with HIV-1 RNA 
≥50 copies/mL at Weeks 96 and 144.
The percentage of participants with HIV-1 RNA ≥50 copies/mL will be summarized over 
time for participants who consent to the OLE.
Percentage of Participants With HIV-1 RNA <200 Copies/mL and Percentage of 
Participants With HIV-1 RNA <50 Copies/mL
Secondary objectives addressing the antiretroviral activity following a switch to DOR/ISL 
will be assessed based upon the percentage of participants with HIV-1 RNA <200 copies/mL 
at Weeks 48, 96 and 144, as well as the percentage of participants with HIV-1 RNA 
<50 copies/mL at Weeks 48, 96 and 144.
The percentage of participants with <50 copies/mL and <200 copies/mL will be summarized 
over time for participants who consent to the OLE.
Change From Baseline in CD4+ T-cell Count
The mean change from baseline in CD4+ T-cell count will be calculated at each time point at 
which CD4+ T-cell count is collected. A secondary objective will compare the mean change 
from baseline in CD4+ T-cell count between treatment groups at Weeks 48, 96, and 144.
For analyses of the mean change from baseline in CD4+ T-cell count, baseline measurements 
are defined as the Day 1 value for each participant. In the rare event when data for this visit 
are missing, the value obtained at the most recent screening visit will be used as baseline, 
when available.
The change from baseline in CD4+ T-cell count during the OLE will be analyzed over time 
for participants who consent to the OLE. The baseline for Group 2 will be the Week 144 
measurement (or, if the Week 144 measurement is not available, the last measurement before
the switch to DOR/ISL).
Clinically Significant Confirmed Viremia
Participants with clinically significant confirmed viremia as defined in Section 4.2.1.1.2 will 
be identified.
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Viral Resistance-associated Substitutions
Participants who meet the definition of clinically significant confirmed viremia 
(Section 4.2.1.1.2), or who discontinue study intervention for another reason and have HIV-1 
RNA ≥200 copies/mL at the time of discontinuation, will be assessed for development of 
viral drug resistance. Among such participants, those with HIV-1 RNA ≥400 copies/mL will 
be included in the resistance analyses. In addition, anyone for whom available genotypic or 
phenotypic data show evidence of resistance, irrespective of viral load, will also be included 
in the resistance analyses. The resistance analyses will count the number of participants in 
each treatment group who have evidence of resistance-associated substitutions. The data will 
be summarized with primary interest at Weeks 48, 96, 144, and during the OLE.
9.4.1.2
Pharmacokinetic Endpoints
PK samples collected from all participants as described in the SoA (Section 1.3) and 
Section 8.6 will be used to evaluate PK concentrations of ISL, and as appropriate, 
PK-efficacy, PK-pharmacodynamic, and PK-AE relationships of ISL.
9.4.2
Safety Endpoints
An initial description of safety measures is provided in Section 4.
Safety and tolerability will be assessed by clinical review of all relevant parameters including 
AEs, laboratory values, and vital signs.
Adverse Events
The following clinical and laboratory AEs will be summarized: 1) participants with at least 
1 AE; 2) participants with at least 1 drug-related AE; 3) participants with at least 1 SAE; 
4) participants with at least 1 Grade 3 or 4 AE; 5) participants with at least 1 serious and 
drug-related AE; 6) participants with at least 1 AE, which is both Grade 3 or 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; and 9) 
participants with an AE leading to death.
Predefined Limits of Change in Laboratory Parameters
For the summaries of laboratory test results, participants must have both a baseline and a 
post-randomization on-treatment measurement to be included. Participants’ laboratory values 
(based on their most abnormal laboratory test values in the direction of interest while on 
study intervention) will be classified as to whether they fall outside of the PDLC and are 
worse in grade (ie, more abnormal in the direction of interest) than at baseline. The criteria 
are adapted from the DAIDS Table for Grading the Severity of Adult and Pediatric Adverse 
Events, July 2017, version 2.1 (Appendix 3) [National Institute of Allergy and Infectious 
Diseases 2017].
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Weight, Laboratory Markers, and Bone Mineral Density
The mean change from baseline to Weeks 48, 96, and 144 in select weight, laboratory 
markers, and BMD of fasting lipid and metabolic profiles, renal function, inflammation, and 
body composition will be summarized.
Total Lymphocyte Count
The mean change from baseline in total lymphocyte count will be calculated at each time 
point at which lymphocyte counts are assessed. The mean change from baseline in total 
lymphocyte count between treatment groups will be conducted at Weeks 48, 96, and 144.
For analyses of the mean change from baseline in lymphocyte, baseline measurements are 
defined as the Day 1 value for each participant. In the rare event when data for this visit are 
missing, the value obtained at the most recent screening visit will be used as baseline, when 
available.
The change from baseline in lymphocytes during the OLE will be analyzed over time for 
participants who consent to the OLE. The baseline for Group 2 will be the Week 144 
measurement (or, if the Week 144 measurement is not available, the last measurement before
the switch to DOR/ISL).
Definition of Baseline Measurements for Safety Analyses
For analyses of changes from baseline in safety parameters (eg, weight, vital signs, 
laboratory, and BMD), 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.
For analyses of DEXA parameters (ie, bone density and body composition), if no Day 1 or 
screening values are available, the earliest measurement within 45 days after the start of 
study intervention will be used as baseline, when available.
The change from baseline in safety parameters during the OLE will be analyzed over time for 
participants who consent to the OLE. The baseline for Group 2 will be the Week 144 
measurement (or, if the Week 144 measurement is not available, the last measurement before
the switch to DOR/ISL).
9.4.3
Patient-reported Outcome Endpoints
An initial description of patient-reported outcome measures is provided in Section 4.2.1.5.
PROs from each questionnaire at Day 1 and Weeks 4, 12, 48, and 96 will be summarized for 
each treatment group.
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9.5
Analysis Populations
9.5.1
Efficacy Analysis Populations
FAS
The FAS population will serve as the primary population for the analysis of efficacy data in 
the base study. The FAS population consists of all randomized participants who meet the 
following criteria:
•
Receive at least 1 dose of study intervention
•
Have baseline data for those analyses that require baseline data
Note that the number of participants included in the FAS population may vary across 
endpoints due to the applicability of exclusion criteria to each endpoint (eg, the need for 
baseline data only applies to those endpoints that are derived relative to baseline).
Participants will be included in the treatment group to which they are randomized for the 
analysis of efficacy data using FAS population.
PP Analysis Population
The secondary analysis set for the efficacy analyses in the base study is defined as the PP 
analysis population, which will exclude participants in the FAS population who had at least 
one major deviation that may substantially affect the results of the efficacy endpoints. 
Potential deviations that may result in the exclusion of a participant from the Per-Protocol 
population include:
•
Receipt of any ongoing prohibited therapies listed in Table 3
•
Nonadherence to study intervention: <95% drug compliance rate (see Section 9.11)
•
Pregnancy
•
Unblinding for any reason (eg, due to HBV reactivation, accidental unblinding, etc)
The PP analysis will be performed for the percentage of participants with HIV-1 RNA 
≥50 copies/mL at Weeks 48, 96 and 144, the percentage of participants with HIV-1 RNA 
<50 copies/mL at Weeks 48, 96 and 144, and the percentage of participants with HIV-1 RNA 
<200 copies/mL at Weeks 48, 96 and 144 (see Table 9).
The final determination of major protocol deviations, and thereby the composition of the 
Per-Protocol population, will be made prior to unblinding of the Sponsor at the Week 48 
database lock and will be documented. A participant who deviates from the protocol at 
randomization (eg, violation of certain inclusion or exclusion criteria, such as the use of a 
prohibited prior treatment) will be excluded from the Per-Protocol population. For 
participants who have major deviations from the protocol during the study (eg, taking a 
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prohibited concomitant medication), data obtained after the deviation will be excluded from 
analysis. As such, the composition of the Per-Protocol population may vary by the analysis 
time point, based on the number of participants who satisfy the Per-Protocol criteria at that 
time point. Participants will be included in the treatment group to which they are randomized 
for the analysis of efficacy data using the Per-Protocol population.
FAS for the OLE (FAS-E)
The FAS-E population will be used to analyze efficacy data in the OLE. It consists of all 
FAS participants in the base study who entered the OLE and received at least 1 dose of study 
intervention during the extension.
Resistance Analysis Subset
The resistance analysis subset will include all participants in the FAS with HIV-1 RNA 
≥400 copies/mL and any participants for whom available genotypic or phenotypic data show 
evidence of resistance, irrespective of viral load.
9.5.2
Safety Analysis Populations
APaT
The APaT population will be used for the analysis of safety data in the base study. The APaT 
population consists of all randomized participants who receive at least 1 dose of study 
intervention. Participants will be included in the treatment group corresponding to the study 
intervention they actually received for the analysis of safety data using the APaT population. 
For most participants, this will be the treatment group to which they are randomized. 
Participants who take incorrect study intervention for the entire treatment period will be 
included in the treatment group corresponding to the study intervention actually received.
At least 1 laboratory or vital sign measurement obtained subsequent to at least 1 dose of 
study intervention is required for inclusion in the analysis of each specific parameter. To 
assess change from baseline, a baseline measurement is also required. The composition of the 
APaT population may vary based on the availability of baseline measurements for the 
relevant safety parameters of interest.
APaT-E
The APaT-E population will be used to analyze safety data from the OLE. It consists of all 
APaT participants in the base study who entered the OLE and received at least 1 dose of 
study intervention during the extension.
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9.6
Statistical Methods
The statistical methods used to evaluate the primary and secondary objectives are described 
below. Methods related to evaluation of exploratory objectives will be described in the sSAP.
Definition of On-treatment Measurements for Efficacy Analyses
For participants who have either discontinued or completed study intervention, all 
measurements within 1 day following the last dose of study intervention will be considered to 
be on-treatment measurements. For participants who are on study intervention (ie, have not 
discontinued or completed study intervention), all measurements will be considered to be 
on-treatment measurements.
Definition of On-treatment Measurements for Safety Analyses
For participants who have either discontinued or completed study intervention, all 
measurements within 42 days following the last dose of study intervention will be considered 
to be on-treatment measurements; the 42-day window was selected to account for the 
half-life of ISL. For participants who are on study intervention (ie, have not discontinued or 
completed study intervention), all measurements will be considered to be on-treatment 
measurements.
9.6.1
Statistical Methods for Efficacy Analyses
Time Windows
Definitions of time windows (day-ranges) and target days for the scheduled study visits, 
which will be used for all statistical analyses by time point, are shown in Table 8. 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
Treatment Phase
Treatment Period
Visit
Day-Rangea
Target Daya
Pretreatment
Baseline
Day 1
≤1
1
Treatment
Blinded Intervention: 
DOR/ISL or 
BIC/FTC/TAF
Week 4
≥2 and ≤56
29
Week 12
≥57 and ≤126
85
Week 24
≥127 and ≤210
169
Week 36
≥211 and ≤294
253
Week 48
≥295 and ≤378
337
Week 60
≥379 and ≤462
421
Week 72
≥463 and ≤546
505
Week 84
≥547 and ≤630
589
Week 96
≥631 and ≤714
673
Week 108
≥715 and ≤798
757
Week 120
≥799 and ≤882
841
Week 132
≥883 and ≤966
925
Week 144
Participants who 
do not consent to 
enroll in the OLE:
≥967 and ≤1051
Participants who 
consent to enroll in 
the OLE:
≥967 and ≤the last 
day of blinded 
intervention
1009
Treatment 
Extensionb
Open-label Intervention: 
DOR/ISL
Week 148c
Group 1: NA
Group 2: ≥first day 
of open-label 
intervention and 
≤1106
Group 1: 
NA
Group 2: 
1037
Week 168
Group 1: ≥first day 
of open-label 
intervention and 
≤1260
Group 2: ≥1107
and ≤1260
Group 1 and 
Group 2: 
1177
Week 192
1261≥ and ≤1428
1345
Week 216
1429≥ and ≤1596
1513
Week 240
1597≥ and ≤1764
1681
BIC=bictegravir; DOR=doravirine; FTC=emtricitabine; ISL=islatravir; OLE=Open-label extension; TAF=tenofovir 
alafenamide.
a Day-ranges and target days are computed relative to the first day of study intervention.
b The treatment extension phase visits apply only to participants who consent to the OLE.
C The Week 148 visit applies only to participants in Group 2.
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Missing Data Approaches
Three approaches will be used to handle missing HIV-1 RNA values. The primary approach 
for analysis of the percentage of participants with HIV-1 RNA ≥50 copies/mL is the FDA 
“snapshot” algorithm [Food and Drug Administration (CDER) 2015]. Using this approach, 
for data collected in a given analysis window (see Table 8), the last available measurement 
while the participant is on treatment is used to define the virologic outcome. Virologic 
outcome is defined according to the following categories:
•
HIV-1 RNA <50 copies/mL: participants who have the last available on-treatment 
HIV-1 RNA measurement <50 copies/mL within the time point of interest analysis 
window specified in Table 8.
•
HIV-1 RNA ≥50 copies/mL: this includes participants:
-
Who have the last available on-treatment HIV-1 RNA measurement ≥50 copies/mL 
within the time point of interest analysis window specified in Table 8.
-
Who do not have on-treatment HIV-1 RNA data in the time point of interest analysis 
window and:
◦
Who discontinue study intervention prior to or in the time point of interest 
analysis window due to lack of efficacy, or
◦
Who discontinue study intervention prior to or in the time point of interest 
analysis window due to reasons other than lack of efficacy and have the last 
available on-treatment HIV-1 RNA measurement ≥50 copies/mL.
•
No Virologic Data in Specified Analysis Time Window: this includes participants who 
do not have on-treatment HIV-1 RNA data in the time point of interest analysis window 
specified in Table 8 because of the following:
-
Discontinued study intervention due to AE or death: this includes participants who 
discontinued study intervention because of an AE or death at any time point from 
Day 1 through the analysis window if this resulted in no on-treatment HIV-1 RNA 
measurements during the specified window and have the last available on-treatment 
HIV-1 RNA measurement <50 copies/mL. In addition, this category will include 
participants who discontinued study intervention because of an AE or death and had 
no on-treatment HIV-1 RNA measurements during the entirety of the study.
-
Discontinued study intervention for other reasons: this includes participants who 
discontinued study intervention prior to or in the time point of interest analysis 
window due to reasons other than lack of efficacy and AE/death (ie, lost to follow-up, 
noncompliance with study intervention, physician decision, protocol deviation, 
withdrawal by participant, etc) and have the last available on-treatment HIV-1 RNA 
measurement <50 copies/mL. In addition, this category will include participants who 
discontinued study intervention due to reasons other than lack of efficacy and 
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AE/death and had no on-treatment HIV-1 RNA measurements during the entirety of 
the study.
-
On study intervention but missing data in window: only data in the predefined 
analysis window can be used for the statistical analysis at a given time point for 
participants remaining on study intervention. Participants with HIV-1 RNA results 
outside this window will be classified as “on study intervention, but missing data in 
window” regardless of the out of window HIV-1 RNA results.
For the primary evaluation of non-inferiority as assessed by the percentage of participants 
with HIV-1 RNA ≥50 copies/mL, the parameter for evaluation is the number of participants 
classified as “HIV-1 RNA ≥50 copies/mL” according to the FDA snapshot algorithm defined 
above, divided by the number of participants in the FAS. For the secondary endpoint 
involving those with HIV-1 RNA <50 copies/mL, the parameter for evaluation is the number 
of participants classified as “HIV-1 RNA <50 copies/mL” according to the FDA snapshot 
algorithm, divided by the number of participants in the FAS. The percentages of participants 
with HIV-1 RNA <50 copies/mL will be summarized by treatment groups at all scheduled 
study visit timepoints. Similar logic will also be used to define the percentage of participants 
with HIV-1 RNA <200 copies/mL in accordance with the relevant secondary endpoint.
A second approach, the M=F approach, will be performed as a sensitivity analysis for the 
percentage of participants with HIV-1 RNA <50 copies/mL. Under this approach, 
participants who 1) have the last available on-treatment measurement within the time point of 
interest analysis window specified in Table 8 <50 copies/mL, OR 2) are on study 
intervention and have no HIV-1 RNA measurements within the time point of interest analysis 
window specified in Table 8 and have both the immediately preceding and immediately 
subsequent on-treatment HIV-1 RNA values <50 copies/mL, will be classified as a virologic 
success (ie, HIV-1 RNA <50 copies/mL) at the time point of interest. Participants with other 
reasons for missing data will be classified as a virologic failure (ie, HIV-1 RNA 
≥50 copies/mL) at the time point of interest.
A third approach, the OF approach, will also be performed as a sensitivity analysis for the 
percentage of participants with HIV-1 RNA ≥50 copies/mL and for the percentage of 
participants with HIV-1 RNA <50 copies/mL. Under this approach, participants with 
nonintermittent missing data who discontinue study intervention early due to lack of efficacy 
or who discontinue study intervention for other reasons and are failures (HIV-1 RNA 
≥50 copies/mL) at the time of study intervention discontinuation are considered to be failures 
at time points thereafter. Participants who discontinue study intervention for reasons other 
than lack of efficacy and who are not failures at the time of study intervention 
discontinuation will be excluded from the analyses at subsequent time points. Participants 
with intermittent missing data will be considered to be successes (HIV-1 RNA 
<50 copies/mL) if both the immediately preceding and immediately subsequent on-treatment 
HIV-1 RNA values are <50 copies/mL; all other intermittent missing results will be imputed 
as failures.
The same supportive approaches as described above will similarly be used for the analysis of 
the percentage of participants with HIV-1 RNA <200 copies/mL.
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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 in the base study.
Non-inferiority of DOR/ISL (Group 1) to BIC/FTC/TAF (Group 2) with respect to the 
percentage of participants with HIV-1 RNA ≥50 copies/mL at Week 48 will be evaluated 
using the unstratified method of Miettinen and Nurminen [Miettinen, O. and Nurminen, M. 
1985]. For the evaluation of the primary hypothesis at Week 48, a margin of 4 percentage 
points is used to define the non-inferiority of a switch to DOR/ISL at Day 1 to the 
continuation of baseline BIC/FTC/TAF for 48 weeks; non-inferiority will be concluded if the 
upper bound of the 2-sided 95% CI for the between-group difference in the percentage of 
participants with HIV-1 RNA ≥50 copies/mL (Group 1 minus Group 2) is less than 
4 percentage points. The choice of non-inferiority margin is based on the amount of virologic
failure that is clinically acceptable; with an anticipated virologic failure rate of approximately 
2%, a stringent margin of 4 percentage points is clinically acceptable.
Superiority of Group 1 to Group 2 with respect to the percentage of participants with HIV-1 
RNA ≥50 copies/mL at Week 48 and 96 will also be evaluated using the unstratified method 
of Miettinen and Nurminen [Miettinen, O. and Nurminen, M. 1985]. For the evaluation of the 
efficacy superiority hypotheses, superiority will be concluded if the upper bound of the 
2-sided 95% CI for the between-group difference in the percentage of participants with 
HIV-1 RNA ≥50 copies/mL (Group 1 minus Group 2) is less than 0 percentage points.
To summarize virologic response over time, the difference in percentages between treatment 
groups at each time point through Week 144 will be estimated and the associated 2-sided 
95% CI will be derived in a similar fashion to that described for the primary efficacy 
analysis.
In addition, for participants who become pregnant and consent to continue study intervention, 
a listing of HIV-1 RNA values over time at the scheduled visits will be provided.
In the OLE, the percentage of participants with HIV-1 RNA ≥50 copies/mL will be 
summarized at the scheduled visits using the DAO approach. This analysis will be 
summarize based on number of participants who have reached the timepoint of interest.
Percentage of Participants With HIV-1 RNA <200 Copies/mL and 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 <200 copies/mL and the percentage of 
participants with HIV-1 RNA <50 copies/mL in the base study. These endpoints will be 
summarized by treatment group at each time point, with primary interest at Weeks 48, 96 and 
144 by comparing Group 1 and Group 2. For these time points of interest, the difference in 
percentages between treatment groups (Group 1 minus Group 2) and the associated 2-sided 
95% CI will be calculated using the unstratified Miettinen and Nieminen method [Miettinen, 
O. and Nurminen, M. 1985]. Supportive analyses using the M=F and OF approaches (as 
defined above) will also be presented.
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In the OLE the percentage of participants with HIV-1 RNA <50 and <200 copies/mL will be 
summarized in a similar manner as for those with HIV-1 RNA ≥50 copies/mL.
The percentages of participants with HIV-1 RNA <20 copies/mL (the LLOQ of the assay), 
20 to <50, 50 to <100, 100 to <200, 200 to <400 and ≥400 copies/mL will be summarized by 
treatment groups at all scheduled study visit timepoints.
Change From Baseline in CD4+ T-cell Count
The mean change from baseline in CD4+ T-cell count will be summarized by treatment 
group at each time point at which CD4+ T-cell count is scheduled to be collected in the base 
study. To estimate the treatment difference (Group 1 minus Group 2), and corresponding 
2-sided 95% CI, in mean changes from baseline in CD4+ T-cell count at each time point, 
with primary interest at Weeks 48, 96 and 144, a cLDA method proposed by Liang and Zeger 
[Liang, K-Y and Zeger, S. L. 2000] will be used. This model assumes a common mean 
across treatment groups at baseline and a different mean for each treatment at each of the 
post-baseline time points. In this model, the response vector consists of the baseline value 
and the values observed at each post-baseline time point. The analysis model will adjust for 
treatment group, time, and the interaction of time-by-treatment group. Time is treated as a 
categorical variable so that no restriction is imposed on the trajectory of the means over time. 
An unstructured covariance matrix will be used to model the correlation among repeated 
measurements. The Kenward-Roger adjustment [Kenward, M. G. and Roger, J. H. 1997] will 
be used with restricted (or residual) maximum likelihood to make proper statistical inference.
Although the baseline measurement is included in the response vector, it is independent of 
treatment, and hence, the baseline means are constrained to be the same for different 
treatment groups. Of note, if there are no missing data, the estimated treatment difference 
from the above cLDA model will be identical to that from a traditional longitudinal 
ANCOVA model, which uses the baseline value as a covariate. However, unlike longitudinal 
ANCOVA, the cLDA model accounts for variability in the baseline values, thus providing 
more accurate standard errors and CIs for individual treatment effects. Moreover, this model 
allows the inclusion of participants who are missing either the baseline or post-baseline 
measurements, thereby increasing efficiency. Details of the model specification, 
assumptions, and SAS implementation codes will be provided in the sSAP.
The cLDA method assumes that data are MAR. In this study, it is expected that 
MAR/MCAR mechanisms will underlie most of the missingness, and the proportion of data 
MNAR, driven solely by unobserved values of the study endpoints, will be small. Reasons 
for discontinuation from the study may include lack of efficacy, death, withdrawal of 
consent, protocol deviations, lost to follow-up (eg, relocation), etc. Missing data caused by a 
participant’s relocation are likely to be MCAR. Missing data caused by discontinuations due 
to lack of efficacy may belong to MAR because this type of discontinuation may depend on 
the observed efficacy outcomes. The MAR or MNAR mechanisms might each underlie the 
other reasons to some extent. If the assigned study intervention in large part determines the 
loss of data for these other reasons, the mechanism may be close to MAR, because the 
intervention assignment is an observed variable and included in the analysis model.
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The estimates of the between-group differences in the mean change from baseline in 
CD4+ T-cell count will not be subject to an absolute criterion for similarity as the clinical 
interpretation of treatment difference is dependent upon the absolute values at baseline and 
the magnitude and direction of the CD4+ T-cell count changes observed in each treatment 
arm.
In addition to CD4+ T-cell count, the observed mean CD4+ T-cell percentage will also be 
summarized by study intervention groups at each timepoint at which the TBNK panel/CD4+ 
T-cell count is scheduled to be collected.
During the OLE, the change from baseline in CD4+ T-cell count will be summarized 
separately using descriptive statistics based on the DAO approach. For assessments of 
change from baseline in Group 2 during the OLE, the baseline measurement will be taken as 
the Week 144 measurement (or, if the Week 144 measurement is not available, the last 
measurement before the switch to DOR/ISL).
Clinically Significant Confirmed Viremia
The number of participants with clinically significant confirmed viremia, as defined in 
Section 4.2.1.1.2, will be summarized for each treatment group.
Viral Resistance-associated Substitutions
The number of participants in the resistance analysis subset with genotypic and/or phenotypic 
resistance to each study intervention will be summarized for each treatment group with 
primary interest at Weeks 48, 96, 144, and timepoints of interest during the OLE.
Unblinding of Participants During the Base Study
Given the objective nature of the HIV-1 RNA efficacy endpoint, if a participant becomes 
unblinded during the base study for any reason (eg, due to a safety event, acute 
infection/reactivation of HBV or pregnancy that requires unblinding, or accidental 
unblinding), such participants will not be treated as treatment failures in the primary efficacy 
analyses on the FAS population due to the unblinding alone.
HBV Acute Infection/Reactivation
If the clinical management of HBV acute infection/reactivation requires the addition of a 
concomitant therapy that is also active against HIV-1, efficacy assessments in these 
participants from that point forward will be handled in a similar manner as the FDA snapshot 
algorithm classification rules for participants with missing data due to discontinuation of 
study intervention in base study. During the OLE, efficacy assessments from that point 
forward in these participants will be reported separately.
Participants Who Discontinue Due to Pregnancy or Breastfeeding
For participants who become pregnant and choose to discontinue study intervention or 
participants who choose to breastfeed and must discontinue study intervention in the base 
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study, efficacy assessments from that point forward will be handled in a similar manner as 
the FDA snapshot algorithm classification rules for participants with missing data due to 
discontinuation of study intervention. Results for participants who become pregnant during 
the study will be reported separately.
Table 9 summarizes the key efficacy analyses of the base study.
Table 9
Analysis Strategy for Key Efficacy Variables
Endpoint/Variable (Description, Time 
Point)
Primary vs 
Supportive 
Approacha
Statistical 
Method
Analysis 
Population
Missing 
Data 
Approach
Primary Hypotheses H1 and H2
Percentage of participants with HIV-1 
RNA ≥50 copies/mL at Week 48
P
M&N
FAS
Snapshot
S
M&N
PP
OF
Secondary Hypotheses H3 and H4
Percentage of participants with HIV-1 
RNA ≥50 copies/mL at Weeks 96 and 
144
P
M&N
FAS
Snapshot
S
M&N
PP
OF
Secondary Endpoints
Percentage of participants with HIV-1 
RNA <200 and <50 copies/mL at 
Weeks 48, 96 and 144
P
M&N
FAS
Snapshot
S
M&N
FAS
M=F
S
M&N
PP
OF
Mean change from baseline in CD4+ 
T-cell count at Weeks 48, 96 and 144
P
cLDAb
FAS
Model-based
cLDA=constrained longitudinal data analysis; FAS=Full Analysis Set; HIV-1=human immunodeficiency 
virus type 1; M=F=missing equal to failure; M&N=Miettinen and Nurminen; OF=Observed Failure; 
PP=Per-Protocol; RNA=ribonucleic acid.
a P=primary approach; S=supportive approach.
b The cLDA model will include terms for treatment group, time, and the interaction of time-by-treatment 
group.
The strategy to address multiplicity issues with regard to multiple treatment comparisons, 
multiple endpoints, multiple time points, and/or IAs is described in Sections 9.7 and 9.8.
9.6.2
Statistical Methods for Safety Analyses
Safety and tolerability will be assessed by clinical review of AEs and other relevant 
parameters, including laboratory test results and vital signs. For analyses of safety by time 
point, the same analysis windows as specified in Table 8 will be used, unless otherwise 
specified. Analysis windows for DEXA measurements are provided in Table 10.
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Table 10
Definition of Study Time Points for DEXA Analyses
Treatment Phase
Treatment Period
Visit
Day-Rangea
Target Daya
Pretreatment
Baseline
Day 1
≤45
1
Treatment
Blinded Intervention: 
DOR/ISL or 
BIC/FTC/TAF
Week 48
≥253 and ≤420
337
Week 96
≥589 and ≤756
673
Week 144
≥925 and ≤1092
1099
BIC=bictegravir; DEXA=dual x-ray absorptiometry; DOR=doravirine; FTC=emtricitabine; ISL=islatravir; 
TAF=tenofovir alafenamide.
a Day-ranges and target days are computed relative to the first day of study intervention.
9.6.2.1
Overall Safety Assessment
The overall safety evaluation in the base study will include a summary by treatment group of 
the number and percentage of participants with any AE, with a drug-related AE, with an 
SAE, with a Grade 3 or 4 AE, with an AE that is both serious and drug-related, with an AE 
that is both Grade 3 or 4 and drug-related, who discontinued study intervention due to an AE, 
who discontinued study intervention due to a drug-related AE, and with an AE resulting in 
death. Point estimates and 2-sided 95% CIs for the differences between treatment groups 
(Group 1 minus Group 2) in the percentages of participants with the event will be provided. 
The CIs for the between-group differences will be provided using the unstratified Miettinen 
and Nurminen method [Miettinen, O. and Nurminen, M. 1985].
The number and percentage of participants with specific AEs will also be provided. Point 
estimates and 2-sided 95% CIs for the differences between treatment groups (Group 1 minus 
Group 2) in the percentages of participants with specific AEs will be provided for AEs that 
occur in at least 8 participants in the DOR/ISL treatment group or at least 2 participants in 
the BIC/FTC/TAF group. These thresholds for the numbers of events were chosen because 
the 95% CI for the between-group difference in percent incidence will always include 0 when 
fewer participants per group have events and thus would add little to the interpretation of 
potentially meaningful differences. The CIs for the between-group differences will be 
provided using the unstratified Miettinen and Nurminen method [Miettinen, O. and 
Nurminen, M. 1985].
CIs that are not adjusted for multiplicity should only be regarded as helpful descriptive 
measures for the review of the safety profile and not as a formal method for assessing 
statistical significance of between-group differences. Point estimates and 2-sided 95% CIs for 
the differences between treatment groups (Group 1 minus Group 2) in the percentages of 
participants with safety parameters that meet predefined limits of change will be provided 
based on the same criteria used above for specific AEs.
For continuous safety measures, such as change from baseline in laboratory and vital signs 
parameters, summary statistics for baseline, on-treatment, and change from baseline values 
will be provided by treatment group. For participants who become pregnant during the study, 
measurements collected after the estimated date of conception will be excluded from the 
analyses. Missing data will not be imputed.
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For the mean change from baseline to Weeks 48, 96 and 144 in weight, the treatment 
difference (Group 1 minus Group 2) and corresponding 2-sided 95% CI will be estimated 
using ANCOVA models adjusted by baseline weight, sex at birth, race, and treatment group.
For the mean change from baseline to Weeks 48, 96, and 144 in total lymphocyte count, the 
treatment difference (Group 1 minus Group 2) and corresponding 2-sided 95% CI will be 
estimated using ANCOVA models adjusted by baseline value and treatment group.
For lipid profile analyses, participants who receive lipid-lowering therapy at baseline will be 
excluded from all analyses. For participants who initiate lipid-lowering therapy during the 
study, the last lipid measurement before initiating the lipid-lowering therapy will be carried 
forward. For participants who become pregnant, lipid data collected after the estimated date 
of conception will be excluded. Missing lipid data will not be imputed; as such, any 
participant with a missing value will be excluded from the analyses. The percentages of 
participants who initiate or modify lipid-lowering therapy prior to Weeks 48, 96 and 144 will 
be summarized by treatment group. Additional details will be provided in the sSAP.
Safety data for participants who consent to continue the treatment in the OLE (from Week 
144 to Week 240) will be summarized separately. Additional details are provided in the 
sSAP.
9.6.2.2
Assessment of Safety Topics of Special Interest
Opportunistic infections are considered safety topics of special interest in the base study.
The number and percentage of participants with any opportunistic infection will be 
summarized by treatment group. The point estimate and 2-sided 95% CI for the difference 
between treatment groups (Group 1 minus Group 2) in the percentage of participants with 
any opportunistic infection will be provided. The number and percentage of participants with 
specific opportunistic infections will also be summarized by treatment group. Point estimates 
and 2-sided 95% CIs for the differences between treatment groups (Group 1 minus Group 2) 
in the percentages of participants with these events will be provided based on the criteria 
described above for specific AEs. CIs for between-treatment group differences will be 
provided using the unstratified Miettinen and Nurminen method [Miettinen, O. and 
Nurminen, M. 1985]. Opportunistic infections will be identified through SMQs using the 
MedDRA dictionary. SMQs on both broad and narrow PTs will be performed and will be 
summarized separately.
9.6.2.3
Handling of Missing Data and Pregnancies in Safety Analyses
Missing safety parameters, unless otherwise specified, will not be imputed; as such, any 
participant with a missing value will be excluded from the analysis. Change from baseline 
summaries require a baseline value. Baseline measurements are defined as 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. If no baseline 
result is available for a given analysis, that participant will not be included in the analysis. 
Safety data for participants who consent to enter the OLE at Week 144 will be summarized 
from Week 144 to Week 240. For the assessment of change from baseline in Group 2 at 
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Week 240, baseline will be the Week 144 measurement (or, if the Week 144 measurement is 
not available, the last measurement before the switch to DOR/ISL).
For participants who become pregnant during the study, all safety data collected on or after 
the estimated date of conception will be summarized separately from the primary and 
secondary safety analyses. Data collected for participants whose pregnancy or postpartum 
visit(s) extends beyond Week 144 will be reported separately. Infant safety data will also be 
reported separately.
Table 11 summarizes the analysis strategy for safety endpoints in the base study.
Table 11
Analysis Strategy for Safety Parameters
Analysis Part
Safety Endpoint
Descriptive 
Statistics
95% Between-group 
CI
Overall Safety 
Assessment
Any AE
X
X
Any drug-related AE
X
X
Any SAE
X
X
Any Grade 3 or 4 AE
X
X
Any serious drug-related AE
X
X
Any Grade 3 or 4 drug-related AE
X
X
Discontinued study intervention due to an AE X
X
Discontinued study intervention due to a 
drug-related AE
X
X
AE resulting in death
X
X
Specific AEs
X
Xa
SOCs, PDLCs
X
Xa
Mean Change from Baseline (Laboratory, 
Vital Signs, Body Composition, and 
Lymphocyte Parameters)
X
X
Assessment of 
Safety Topics of 
Special Interest
Any Opportunistic Infection
X
X
Specific Opportunistic Infections and 
Corresponding SOCs
X
Xa
AE=adverse event; CI=confidence interval; PDLC=predefined limit of change; SAE=serious adverse event; 
SOC=system organ class.
a The between-group 95% CI will only be provided for events that occur in at least 8 participants in Group 1 
or at least 2 participants in Group 2.
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9.6.3
Summaries of Baseline Characteristics, Demographics, and Other Analyses
9.6.3.1
Demographic and Baseline Characteristics
The comparability of the treatment groups for each relevant demographic and baseline 
characteristic will be assessed by the use of tables and/or graphs. No statistical hypothesis 
tests will be performed on these characteristics. The number and percentage of participants 
screened and randomized and the primary reasons for screening failure and discontinuation 
will be displayed. Demographic variables (eg, age, race, region, etc), baseline characteristics, 
primary and secondary diagnoses, and prior and concomitant therapies will be summarized 
by treatment either by descriptive statistics or categorical tables.
9.7
Interim Analyses
Study enrollment is likely to be ongoing at the time of the IA. Blinding to treatment 
assignment will be maintained at all investigational sites until Week 144. The information 
regarding participants’ treatment groups from IA results will not be shared with the 
investigators prior to week 144.
An eDMC will serve as the primary reviewer of the interim efficacy and safety review results 
and may make recommendations for discontinuation of the study or for protocol 
modifications to an executive committee of the Sponsor. If the eDMC recommends 
modifications to the design of the protocol or discontinuation of the study, this executive 
committee (and potentially other limited Sponsor personnel) may be unblinded to results at 
the treatment level to act on these recommendations. The extent to which individuals are 
unblinded with respect to results of interim efficacy and safety reviews will be documented. 
Additional logistical details will be provided in the DMC charter.
Once approximately 30% of target enrollment (n=150 participants) have completed the 
Week 24 visit assessments, the Week 24 IA will be conducted by the external unblinded 
statistician to assess futility. This analysis will be reviewed by the eDMC. All available 
efficacy and safety data for all participants enrolled at the time of the Week 24 IA will be 
reviewed. The futility analysis will include the first approximately 30% of study participants 
who complete the Week 24 visit assessments. The nonbinding futility criterion is as follows:
Nonbinding Futility Criterion: If the upper bound of the 2-sided 95% CI for the 
between-group difference (Group 1 minus Group 2) in the percentage of participants with 
HIV-1 RNA ≥200 copies/mL at Week 24 is greater than 8 percentage points, consideration 
may be given to stop the study. The CI will be based on the unstratified Miettinen and 
Nurminen method [Miettinen, O. and Nurminen, M. 1985].
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For the purpose of the futility assessment, those classified as HIV-1 RNA ≥200 copies/mL 
will include participants:
•
Who have the last available on-treatment HIV-1 RNA measurement within the Week 24 
analysis visit window specified in Table 8 ≥200 copies/mL.
Note: For such participants, if the HIV-1 RNA value of ≥200 copies/mL is not confirmed 
at the subsequent assessment (ie, the participant does not meet the criteria for clinically 
significant confirmed viremia [Section 4.2.1.1.2]), their virologic outcome will be 
reassessed for the primary efficacy analysis (Section 9.6.1).
•
Who do not have on-treatment HIV-1 RNA data in the Week 24 analysis visit window 
specified in Table 8 and
-
Discontinued study intervention prior to or in the Week 24 analysis visit window due 
to lack of efficacy or clinically significant confirmed viremia (Section 4.2.1.1.2), or
-
Discontinued study intervention prior to or in the Week 24 analysis visit window due 
to reasons other than lack of efficacy/clinically significant confirmed viremia and 
have their last on-treatment HIV-1 RNA measurement ≥50 copies/mL.
Note: Such participants will be classified as virologic failures (ie, HIV-1 RNA 
≥50 copies/mL) in the primary efficacy analysis (Section 9.6.1) in accordance with 
the FDA snapshot approach.
The endpoint of HIV-1 RNA ≥200 copies/mL for the futility assessment is clinically 
meaningful as it is a threshold associated with increased likelihood of development of viral 
drug resistance and subsequently a potential need to switch to a new regimen, while values 
<200 copies/mL do not necessarily indicate the need for a change in therapy. Furthermore, 
use of this endpoint protects against over-interpretation of transient viremia (ie, an HIV-1 
RNA measurement ≥50 copies/mL in a previously suppressed person that quickly resolves to 
<50 copies/mL); a single value of HIV-1 RNA ≥200 copies/mL is more likely to indicate a 
true treatment failure than a single value ≥50 copies/mL and is thus a useful measure for 
assessing futility at the Week 24 IA.
Given the anticipated small number of participants with HIV-1 RNA ≥200 copies/mL at 
Week 24 and the expected sample sizes of 100 participants in Group 1 and 50 participants in 
Group 2 included in the futility assessment, the specified futility criterion is sensitive to 
imbalances in the number of failures (ie, HIV-1 RNA ≥200 copies/mL) between the 
treatment groups. For example, if there are 2 failures out of 100 participants in Group 1 and 0 
failures out of 50 participants in Group 2, the estimated treatment difference is 2% and the 
upper bound of the between-group 95% CI is 7.03, which would not meet the futility 
criterion. However, if there are 3 failures in Group 1 and 0 failures in Group 2, then the 
treatment difference is 3% and the upper bound of the between-group 95% CI is 8.48, thus 
meeting the futility criterion and leading to consideration to stop the study. If there are 3 
failures in Group 1 and 1 failure in Group 2, then the treatment difference is 1% and the 
upper bound of the between-group 95% CI is 6.84, which would not meet the futility 
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criterion. However, with 4 failures in Group 1 and 1 failure in Group 2, the treatment 
difference is 2% and the upper bound of the between-group 95% CI is 8.25, which meets the 
futility criterion. Additional details on the operational characteristics of the futility criterion 
are provided in Section 9.9.1.
The eDMC will review accumulating efficacy and safety data at regular intervals throughout 
the study duration, or at modified intervals based on the recommendation of the eDMC. The 
eDMC will recommend steps to ensure the safety of study participants and the integrity of 
the study as needed.
An analysis will be conducted to test the primary non-inferiority efficacy hypothesis once all 
participants have completed the Week 48 visit assessments. This will be the formal 
evaluation of the primary non-inferiority efficacy hypothesis, and the Sponsor will become 
unblinded at that time. The analysis of the data will be performed by the unblinded team of 
the Sponsor. All available efficacy and safety data will be reviewed at this interim time point. 
Treatment-level results from this analysis will be provided to the eDMC.
Since the hypotheses listed in Section 3 will be tested only at Week 48 or Week 96 (and not 
at the Week 24 IA nor any periodic review of data by the eDMC) and as there is no plan to 
stop the trial early for a positive efficacy finding, testing of H1, H2, H3, and H4 will not be 
adjusted for multiplicity on account of any eDMC reviews. The multiplicity strategy for 
hypothesis testing is described in Section 9.8.
While the study remains blinded to the Sponsor (ie, until the Week 48 database lock), 
treatment-level results from all IAs will be provided to the eDMC by the external unblinded 
statistician. Prior to final study unblinding, the external unblinded statistician will not be 
involved in any discussions regarding modifications to the protocol, statistical methods, 
identification of protocol deviations, or data validation efforts after the IAs.
The Sponsor may have a limited unblinded team not involved with day-to-day conduct of the 
study that will review unblinded data for internal programmatic decision-making. 
Participants and all field and study-site personnel will remain blinded throughout the study.
If the study is stopped early, the CSR will include all available data up to and including the 
close-out visits. This approach to include all available information is in line with the ICH-E9 
guideline.
9.8
Multiplicity
As noted in Section 9.7, an eDMC will convene at routine intervals to monitor efficacy and 
safety. A formal futility analysis at Week 24 is planned as described in Section 9.7; a small 
among of alpha (α=0.00001) will be allocated for this IA, purely for statistical rigor.
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Though the eDMC will convene at routine intervals to monitor efficacy and safety, there are 
no other planned for futility. The following efficacy hypotheses will be tested sequentially at 
a 1-sided 2.499% Type 1 error rate sequentially:
1. Primary efficacy hypothesis (H1) testing non-inferiority of Group 1 to Group 2 as 
assessed by the percentage of participants with HIV-1 RNA ≥50 copies/mL at Week 48.
2. Primary efficacy hypothesis (H2) testing superiority of Group 1 to Group 2 as assessed 
by the percentage of participants with HIV-1 RNA ≥50 copies/mL at Week 48.
3. Secondary efficacy hypothesis (H3) testing superiority of Group 1 to Group 2 as assessed 
by the percentage of participants with HIV-1 RNA ≥50 copies/mL at Week 96.
4. Secondary efficacy hypothesis (H4) testing superiority of Group 1 to Group 2 as assessed 
by the percentage of participants with HIV-1 RNA ≥50 copies/mL at Week 144.
Testing will stop with the first of these tests failing to reach statistical significance, and all 
subsequent tests would not be considered for statistical significance. In this way, the overall 
1-sided 2.499% Type 1 error rate in testing these hypotheses is strongly controlled.
9.9
Sample Size and Power Calculations
9.9.1
Sample Size and Power for Efficacy Analyses
9.9.1.1
Evaluation of Non-inferiority and Superiority Hypotheses
This section presents power calculations for the efficacy hypotheses of demonstrating 
non-inferiority of DOR/ISL to BIC/FTC/TAF and demonstrating superiority of DOR/ISL to 
BIC/FTC/TAF. The power calculations provided in this section do not account for the futility 
assessment at the Week 24 IA or the sequential testing strategy described in Section 9.8.
For efficacy analyses using the FDA snapshot algorithm, missing data (eg, due to study 
intervention discontinuation) are classified as either HIV-1 RNA ≥50 copies/mL (which will 
contribute to both the numerator and denominator in the calculation of the percentage of 
participants with HIV-1 RNA ≥50 copies/mL) or as No Virologic Data in Specified Analysis 
Time Window (which will contribute only to the denominator in the calculation of the 
percentage of participants with HIV-1 RNA ≥50 copies/mL). Therefore, the impact of 
missing data on study power is subsumed within the rates of HIV-1 RNA ≥50 copies/mL 
assumed in the power calculations throughout Section 9.9.1.
Non-inferiority will be concluded if the upper bound of the 2-sided 95% CI for the 
between-group difference in the percentage of participants with HIV-1 RNA ≥50 copies/mL 
at Week 48/96 (Group 1 minus Group 2) is less than 4 percentage points. The choice of 
non-inferiority margin is based on the amount of virologic failure that is clinically 
acceptable; with an anticipated virologic failure rate of approximately 1.5% to 2%, a 
stringent margin of 4 percentage points is clinically acceptable. The observed percentages of 
participants with HIV-1 RNA ≥50 copies/mL at Week 48 are based on experience with 
MK-8591A-017 and MK-8591A-018. They are 0.0% in DOR/ISL group and 1.5% in 
Baseline ART group in MK-8591A-017 and 0.6% in DOR/ISL group and 0.3% in 
BIC/FTC/TAF group in MK-8591A-018.
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Table 12 summarizes the power to declare DOR/ISL non-inferior to BIC/FTC/TAF under 
various assumptions for the response rate (ie, the percentage of participants with HIV-1 RNA 
≥50 copies/mL) in Group 2 and the underlying between-group difference in response rates. 
For example, if the true rate of participants with HIV-1 RNA ≥50 copies/mL at Week 48/96 
is 1.5% in both groups, this study has approximately 93.3% power to demonstrate 
non-inferiority. If the true rates are 2.0% in both groups, this study has approximately 87.0% 
power to demonstrate non-inferiority.
Table 12
Power (%) to Establish Non-inferiority at Week 48 Under Various Response 
Rate Assumptions
True Response 
Rate in Group 2
True Difference in Response Rates (Group 1 Minus Group 2)
-1.0 
Percentage 
Points
-0.5 
Percentage 
Points
0.0 
Percentage 
Points
0.5 Percentage 
Points
1.0 
Percentage 
Points
0.5%
NA
100
99.9
96.9
83.8
0.75%
NA
100
99.4
93.5
77.7
1.0%
100
100
98.2
89.4
72.1
1.25%
100
99.7
96.1
84.9
67.2
1.5%
100
99.0
93.3
80.6
63.1
1.75%
99.8
97.7
90.2
76.6
59.5
2.0%
99.4
95.9
87.0
72.9
56.3
2.25%
98.7
93.8
83.8
69.5
53.3
2.5%
97.5
91.5
80.7
66.3
50.5
2.75%
96.2
89.1
77.6
63.2
48.0
3.0%
94.6
86.6
74.6
60.3
45.6
ART=antiretroviral therapy; BIC=bictegravir; CI=confidence interval; DOR=doravirine; FTC=emtricitabine; 
HIV-1=human immunodeficiency virus type 1; ISL=islatravir; NA=not applicable; PASS=power analysis 
and sample size; RNA=ribonucleic acid; TAF=tenofovir alafenamide.
334 participants in Group 1 and 167 participants in Group 2
The response rate is the percentage of participants with HIV-1 RNA ≥50 copies/mL at Week 48/96.
The non-inferiority margin is 4 percentage points. To establish non-inferiority, the upper bound of the 
2-sided 95% CI for the difference between groups (Group 1 minus Group 2) in the percentage of participants 
with HIV-1 RNA ≥50 copies/mL must be <4 percentage points. The 95% CI is based on the unstratified 
Miettinen and Nurminen method [Miettinen, O. and Nurminen, M. 1985]. The 1-sided Type 1 error is 
0.0249. Calculations were performed using PASS 16.
The observed percentages of participants with HIV-1 RNA ≥50 copies/mL at Week 48 are based on 
experience with MK-8591A-017 and MK-8591A-018. They are 0.0% in DOR/ISL group and 1.5% in 
Baseline ART group in MK-8591A-017 and 0.6% in DOR/ISL group and 0.3% in BIC/FTC/TAF group in 
MK-8591A-018.
Table 13 summarizes the power to declare DOR/ISL superior to BIC/FTC/TAF with regard 
to the percentage of participants with HIV-1 RNA ≥50 copies/mL under various assumptions 
for the response rate in each treatment group. For example, if the percentage of participants 
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with Week 48/96 HIV-1 RNA ≥50 copies/mL is assumed to be 0.5% in Group 1 and 3% in 
Group 2, then this study will have approximately 64.7% power to demonstrate superiority.
Table 13
Power (%) to Establish Superiority at Week 48/96/144 Under Various 
Response Rate Assumptions
Group 1:
True Rate of Participants with 
HIV-1 RNA ≥50 Copies/mL at 
Week 48/96/144
Group 2:
True Rate of Participants With 
HIV-1 RNA ≥50 Copies/mL at 
Week 48/96/144
Probability of 
Demonstrating 
Superiority at 
Week 48/96/144
0.5%
0.75%
8.1%
0.5%
1%
13.0%
0.5%
1.5%
24.1%
0.5%
2%
37.8%
0.5%
3%
64.7%
0.75%
1%
6.7%
0.75%
1.5%
14.4%
0.75%
2%
25.1%
0.75%
3%
51.5%
1%
1.25%
5.8%
1%
1.5%
8.7%
1%
2%
16.7%
1%
3%
38.6%
1.5%
1.75%
4.8%
1.5%
2%
7.1%
1.5%
2.5%
13.3%
1.5%
3%
21.6%
2%
2.5%
6.3%
2%
2.75%
8.7%
2%
3%
11.2%
BIC=bictegravir; CI=confidence interval; DOR=doravirine; FTC=emtricitabine; HIV-1=human 
immunodeficiency virus type 1; ISL=islatravir; RNA=ribonucleic acid; TAF=tenofovir alafenamide.
334 participants in Group 1 and 167 participants in Group 2
To establish superiority of DOR/ISL to BIC/FTC/TAF, the upper bound of the 2-sided 95% CI for the 
difference between groups (Group1 minus Group 2) in the percentage of participants with HIV-1 RNA 
≥50 copies/mL must be <0 percentage points. The CI is based on the Miettinen and Nurminen method 
[Miettinen, O. and Nurminen, M. 1985]. The 1-sided Type 1 error is 0.0249. Power was estimated via 10,000 
simulations for each scenario. Calculations were performed in R 3.5.0.
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9.9.1.2
Evaluation of the Futility Criterion and Non-inferiority at Week 48
The futility assessment will be conducted on the first approximately 30% of the total planned 
study enrollment (approximately 100 participants in Group 1 and 50 participants in Group 2) 
who complete the Week 24 visit assessments. The study may be stopped if the upper bound 
of the 2-sided 95% CI for the difference in the percentage of participants with HIV-1 RNA 
≥200 copies/mL at Week 24 (Group 1 minus Group 2) is greater than 8 percentage points.
Table 14 summarizes the probability of not meeting the futility criterion at Week 24 under 
various assumptions for the response rate (ie, the percentage of participants with HIV-1 RNA 
≥200 copies/mL) in Group 2 and the underlying between-group difference in response rates. 
For example, if the true rate of participants with HIV-1 RNA ≥200 copies/mL at Week 24 
among 100 participants in Group 1 and 50 participants in Group 2 is 0.75% in both groups, 
then the probability of not meeting the futility criterion is 0.971. If the true rates are 1.0% in 
both groups, then the probability of not meeting the futility criterion is 0.946. If the true rate 
in Group 1 is 2.0% and the true rate in Group 2 is 1.0%, then the probability of not meeting 
the futility criterion is 0.757.
Table 14
Probability of Not Meeting the Futility Criterion at the Week 24 Interim 
Analysis
True Response Rate 
in 
Group 2
True Difference in Response Rates (Group 1 Minus Group 2)
-1.0 
Percentage
Points
-0.5 
Percentage 
Points
0.0 
Percentage 
Points
0.5 Percentage 
Points
1.0 Percentage 
Points
0.50%
NA
1.000
0.989
0.935
0.839
0.75%
NA
0.999
0.971
0.900
0.797
1.0%
1
0.991
0.946
0.864
0.757
1.25%
0.999
0.976
0.917
0.827
0.720
1.5%
0.993
0.956
0.885
0.791
0.684
1.75%
0.981
0.931
0.853
0.756
0.652
2.0%
0.964
0.904
0.820
0.723
0.622
2.25%
0.943
0.875
0.789
0.692
0.595
2.5%
0.919
0.846
0.758
0.664
0.570
2.75%
0.894
0.817
0.730
0.638
0.549
3.0%
0.868
0.790
0.704
0.615
0.529
CI=confidence interval; HIV-1=human immunodeficiency virus type 1; NA=not applicable; PASS=power 
analysis and sample size; RNA=ribonucleic acid.
100 participants in Group 1 and 50 participants in Group 2
The response rate is the percentage of participants with HIV-1 RNA ≥200 copies/mL at Week 24.
Futility Criterion: Upper bound of the 2-sided 95% CI for the between-group difference in the percentage of 
participants with HIV-1 RNA ≥200 copies/mL at Week 24 (Group 1 minus Group 2) is >8 percentage points.
The 95% CI is based on the unstratified Miettinen and Nurminen method [Miettinen, O. and Nurminen, M. 
1985]. The 1-sided Type 1 error is 0.025. Calculations were performed using PASS 16.
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The probability of not meeting the futility criterion at the Week 24 IA and the power to 
demonstrate non-inferiority at Week 48 under a variety of assumptions is presented in 
Table 15.
The power calculations shown in Table 15 incorporate the futility assessment stopping rules. 
Of interest is the likelihood that the study would not meet the futility criterion at Week 24 for 
a variety of assumed Week 24 response rates and also whether the non-inferiority criterion at 
Week 48 would be subsequently met (ie, the conditional power of declaring DOR/ISL 
non-inferior to BIC/FTC/TAF at Week 48).
For example, if the true rate of participants with HIV-1 RNA ≥200 copies/mL at Week 24 is 
0.5% in both groups, the rate of HIV-1 RNA ≥50 copies/mL at Week 48 among participants 
who had HIV-1 RNA ≥200 copies/mL at Week 24 is 95% in both groups, and the rate of 
HIV-1 RNA ≥50 copies/mL at Week 48 among participants who had HIV-1 RNA 
<200 copies/mL at Week 24 is 1% in both groups, then the probability of not meeting the 
futility criterion at the Week 24 IA is 98.9% and the subsequent power to declare non-
inferiority of DOR/ISL to BIC/FTC/TAF at Week 48 is 93.8%.
Additional power calculations are provided in the sSAP.
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Table 15
Probability of Not Meeting the Futility Criterion at the Week 24 Interim Analysis and the Conditional Power to Declare 
Non-inferiority at Week 48 for Various Underlying True Response Rates
Parameter
Base Case
More 
Conservative 
Base Case
Most 
Conservative 
Base Case
Low Efficacy for 
DOR/ISL; Low 
Efficacy for 
BIC/FTC/TAF
Low Efficacy for 
DOR/ISL; High 
Efficacy for 
BIC/FTC/TAF
High Efficacy 
for DOR/ISL; 
Low Efficacy for 
BIC/FTC/TAF
High Efficacy 
for DOR/ISL; 
High Efficacy 
for 
BIC/FTC/TAF
Lowest Efficacy 
for DOR/ISL; 
High Efficacy 
for 
BIC/FTC/TAF
Group 
1
Group 
2
Group 
1
Group 
2
Group 
1
Group 
2
Group 
1
Group 
2
Group 
1
Group 
2
Group 
1
Group 
2
Group 
1
Group 
2
Group 
1
Group 
2
Assumptionsa
% with Week 24 
HIV-1 RNA 
≥200 copies/mL
0.5%
0.5%
0.75%
0.75%
1.0%
1.0%
1.5%
1.0%
1.5%
0%
0%
1.0%
0%
0%
3%
0%
% with Week 48 
HIV-1 RNA 
≥50 copies/mL if 
Week 24 HIV-1 RNA 
≥200 copies/mL
95%
95%
100%
100%
100%
100%
100%
100%
100%
92%
92%
100%
92%
92%
100%
92%
% with Week 48 
HIV-1 RNA 
≥50 copies/mL if 
Week 24 HIV-1 RNA 
<200 copies/mL
1%
1%
1.25%
1.25%
1.5%
1.5%
3%
2%
3%
0.5%
0.5%
2%
0.5%
0.5%
3%
0.5%
% with Week 48 
HIV-1 RNA 
≥50 copies/mL
1.5%
1.5%
2.0%
2.0%
2.5%
2.5%
4.5%
3.0%
4.5%
0.5%
0.5%
3.0%
0.5%
0.5%
5.9%
0.5%
Study Power
Probability of Not 
Meeting the Futility 
Criterionb
98.9%
97.0%
94.7%
86.5%
81.1%
~100%
~100%
42.4%
Conditional Power to 
Establish 
Non-inferiority at 
Week 48c
93.8%
87.8%
82.4%
35.9%
2.4%
~100%
99.9%
0.2%
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Parameter
Base Case
More 
Conservative 
Base Case
Most 
Conservative 
Base Case
Low Efficacy for 
DOR/ISL; Low 
Efficacy for 
BIC/FTC/TAF
Low Efficacy for 
DOR/ISL; High 
Efficacy for 
BIC/FTC/TAF
High Efficacy 
for DOR/ISL; 
Low Efficacy for 
BIC/FTC/TAF
High Efficacy 
for DOR/ISL; 
High Efficacy 
for 
BIC/FTC/TAF
Lowest Efficacy 
for DOR/ISL; 
High Efficacy 
for 
BIC/FTC/TAF
Group 
1
Group 
2
Group 
1
Group 
2
Group 
1
Group 
2
Group 
1
Group 
2
Group 
1
Group 
2
Group 
1
Group 
2
Group 
1
Group 
2
Group 
1
Group 
2
ART=antiretroviral therapy; BIC=bictegravir; CI=confidence interval; COVID-19=coronavirus disease 2019; DOR=doravirine; FTC=emtricitabine; HIV-1=human 
immunodeficiency virus type 1; ISL=islatravir; RNA=ribonucleic acid; TAF=tenofovir alafenamide.
The calculations assume 100 participants in Group 1 and 50 participants in Group 2 for the assessment of futility at Week 24 and 334 participants in Group 1 and 167 participants 
in Group 2 for the assessment of non-inferiority at Week 48.
a The assumptions for calculating power are based on observed rates in the MK-8591A-017 and MK-8591A-018 switch studies and the BIC/FTC/TAF switch studies, Trials 1844 
and 1878. Specifically, MK-8591A-017 showed a rate ≥50 copies/mL at Week 48 of 0.0% in the DOR/ISL arm and 1.5% in the continued baseline ART arm; MK-8591A-018 
showed a rate ≥50 copies/mL at Week 48 of 0.6% in the DOR/ISL arm and 0.3% in the BIC/FTC/TAF arm. In the BIC/FTC/TAF Trials 1844 and 1878, the rates of HIV-1 RNA 
≥50 copies/mL at Week 48 were 1% and 2%, respectively, in the BIC/FTC/TAF arms. For the 3 base cases, the assumed percentages of participants with HIV-1 RNA 
≥50 copies/mL at Week 48 are generally higher than the rates observed across the MK-8591A-017 and MK-8591A-018 study arms and, therefore, are considered to be 
conservative. The conservative rates were selected in recognition that MK-8591A-017 and MK-8591A-018 were conducted during the global COVID-19 pandemic, during 
which time participants may have been restricted to home stay or limited travel, potentially leading to higher adherence to study intervention and subsequently lower rates of 
virologic failure than would be otherwise expected.
b Futility Criterion: Upper bound of the 2-sided 95% CI for the between-group difference in the percentage of participants with HIV-1 RNA ≥200 copies/mL at Week 24 
(Group 1 minus Group 2) is greater than 8 percentage points. Values for the probability of not meeting the futility criterion were calculated via simulation.
c Each value was calculated via 10,000 simulations to evaluate first whether the futility criterion was met and if not, evaluate non-inferiority between groups using the 
unstratified Miettinen and Nurminen method [Miettinen, O. and Nurminen, M. 1985]. The non-inferiority margin is 4 percentage points and the Type 1 error is 0.0249 (1-sided). 
Calculations were performed in R 3.5.0.
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9.9.2
Sample Size and Power for Safety Analyses
9.9.2.1
Evaluation of Adverse Events
The probability of observing at least 1 of a particular type of AE in this study depends on the 
number of participants treated and the underlying percentage of participants with that AE in 
the study population.
If the underlying incidence of a particular AE is 1%, there is a 96.5% chance of observing at 
least 1 AE among 334 participants in a treatment group and an 81.3% chance of observing at 
least 1 AE among 167 participants in a treatment group. If no AE of that type is observed 
among 334 participants in a treatment group, this study will provide 97.5% confidence that 
the underlying percentage of participants with that particular AE is <1.10% (1 in every 
91 participants) in the treatment group; if no AE of that type is observed among 
167 participants in a treatment group, this study will provide 97.5% confidence that the 
underlying percentage of participants with that particular AE is <2.18% (1 in every 
45 participants) in the treatment group.
The point estimate and the upper bound of the corresponding 2-sided 95% CI for the 
underlying percentage of participants with an AE given various hypothetical observed 
numbers of participants with the AE within each treatment group are provided in Table 16. 
These calculations are based on the exact binomial method proposed by Clopper and Pearson
[Clopper, C. J. and Pearson, E. S. 1934].
Table 16
Estimate of Incidence of AEs and 95% Upper Confidence Bound Based on 
Hypothetical Numbers of Participants with AEs
Number of Participants in 
the Treatment Group
Number of Participants 
With Adverse Event
Estimate of 
Incidence
95% Upper 
Confidence Bounda
334
0
0%
0.9%
167
0
0%
1.8%
334
1
0.3%
0.3%
167
1
0.6%
3.3%
334
2
0.6%
2.1%
167
2
1.2%
4.3%
334
5
1.5%
3.5%
167
5
3.0%
6.8%
334
10
3.0%
5.4%
167
10
6.0%
10.7%
334
15
4.5%
7.3%
167
15
9.0%
14.4%
334
20
6.0%
9.1%
167
20
12.0%
17.9%
334
25
7.5%
10.9%
167
25
15.0%
21.3%
334
30
9.0%
12.6%
167
30
18.0%
24.6%
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Number of Participants in 
the Treatment Group
Number of Participants 
With Adverse Event
Estimate of 
Incidence
95% Upper 
Confidence Bounda
AE=adverse event; CI=confidence interval.
a Based on the 2-sided exact 95% CI for a binomial proportion (Clopper and Pearson method [Clopper, C. J. and Pearson, 
E. S. 1934]). In the 0-event case, the CI is 1-sided (α=0.05 all in the upper tail).
Table 17 gives the difference in the incidence of an AE (Group 1 minus Group 2) that can be 
ruled out with different power levels and 95% confidence when there are 334 participants in 
Group 1 and 167 participants in Group 2. The underlying incidence of the AE is assumed to 
be the same for the 2 treatment groups. For example, for a reasonably common AE, which
occurs in 20% of participants in both groups, the study has 80% power to declare with 95% 
confidence that the true difference between the treatment groups is no more than 
11.7 percentage points. The calculations are based on an asymptotic method proposed by 
Miettinen and Nurminen [Miettinen, O. and Nurminen, M. 1985].
Table 17
Difference in Incidence (Percentage Points) of AEs (Group 1 Minus Group 2) 
That Can Be Ruled Out With 334 Participants in Group 1 and 167 Participants in Group 2
Target Power
Underlying AE Incidence Rate
1%
5%
10%
20%
30%
40%
50%
80%
5.1
7.7
9.6
11.7
12.8
13.2
13.1
85%
5.5
8.3
10.3
12.5
13.7
14.1
14.0
90%
6.1
9.1
11.2
13.6
14.8
15.3
15.1
95%
7.1
10.3
12.6
15.2
16.5
17.0
16.7
AE=adverse event; CI=confidence interval.
Values represent the upper bound of the 2-sided 95% CI (unstratified Miettinen and Nurminen [Miettinen, O. 
and Nurminen, M. 1985]) for the difference in AE incidences (Group 1 minus Group 2) assuming the 
incidences are the same.
9.10
Subgroup Analyses
To assess whether the treatment effect with respect to the primary efficacy endpoint of the 
percentage of participants with HIV-1 RNA ≥50 copies/mL at Week 48 and the secondary
efficacy endpoint of the percentage of participants with HIV-1 RNA <50 copies/mL at 
Week 48 is consistent across various subgroups of the study population, the 
between-treatment group effect (with a nominal 95% CI based on the unstratified Miettinen 
and Nurminen method [Miettinen, O. and Nurminen, M. 1985]) will be estimated within each 
subgroup of the following classification variables:
•
Age category (<50 years of age, ≥50 years of age)
•
Sex at birth (female, male)
•
Gender identity (boy/man, girl/woman, transgender boy/man, transgender girl/woman, 
genderqueer/non-binary/gender non-conforming, other)
•
Region (North America, South America, Europe, Asia, Africa, etc)
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•
Race (White, Black, Asian, Other)
•
Ethnicity (Hispanic/Latino, not Hispanic/Latino)
•
Chronic hepatitis C status (HCV-infected, HCV-uninfected)
•
Duration of BIC/FTC/TAF therapy prior to enrollment (≥1 year, <1 year)
The snapshot approach will be used to handle missing values in these subgroup analyses.
9.11
Compliance (Medication Adherence)
In this study, as part of the routine recording of the amount of study intervention taken by 
each participant, the number of tablets remaining in study packaging will be counted, 
reviewed, and recorded at regular intervals. These results will be used to calculate participant 
compliance.
For the main analysis of compliance in this study, a day within the study will be considered 
an “On Therapy” day if the participant takes at least 1 tablet from any bottle provided for this 
study.
In the base 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 blinded 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 time point of interest (ie, Weeks 48, 96 or 144) for those participants who are on the 
blinded study intervention for the entire blinded study period of interest. For participants who 
discontinue the blinded study intervention prior to or within the blinded study period of 
interest, the “Number of Days Should be On Therapy” will be the number of days from 
Day 1 to the date of discontinuation of the blinded study intervention.
For each participant and each blinded study period of interest, percent compliance will be 
calculated using the following formula:
For the secondary analysis of base study compliance, a day within the study will be 
considered an “On Therapy” day if the participants take at least 1 tablet from the bottle
containing the active blinded study intervention. The definition of the “Number of Days 
Should be On Therapy” and the formula for calculating percent compliance are the same as 
defined above for the main analysis of compliance. This secondary compliance measure will 
be used to identify exclusions from the PP population (see Section 9.5.1).
Summary statistics will be provided for percent compliance by treatment group for the FAS 
population.
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9.12
Extent of Exposure
The extent of exposure to study intervention for all randomized and treated participants will 
be summarized in the base study. The number of participants exposed to various doses 
(actual total daily dose) for defined periods of time will be tabulated, along with a summary 
of the mean (range) duration participants were exposed to various doses.
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10
SUPPORTING DOCUMENTATION AND OPERATIONAL CONSIDERATIONS
10.1
Appendix 1: Regulatory, Ethical, and Study Oversight Considerations
10.1.1
Code of Conduct for Clinical Trials
Merck Sharp & Dohme LLC, Rahway, NJ, USA (MSD)
I.
Introduction
A. Purpose
Merck Sharp & Dohme LLC, Rahway, NJ, USA (MSD), through its subsidiaries, 
conducts clinical trials worldwide to evaluate the safety and effectiveness of our 
products. As such, we are committed to designing, planning, 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 MSD’s global standards, local and/or national 
regulations (including all applicable data protection laws and regulations), and 
International Council for Harmonisation Good Clinical Practice (ICH GCP) E6 and 
ICH General Considerations for Clinical Studies E8, and in accordance with the 
ethical principles that have their origin in the Declaration of Helsinki.
B. Scope
Highest ethical and scientific standards shall be endorsed for all clinical 
interventional investigations sponsored by MSD irrespective of the party (parties) 
employed for their execution (e.g., contract research organizations, collaborative 
research efforts). This Code is not intended to apply to trials that are observational in 
nature, or which are retrospective. Further, this Code does not apply to investigator-
initiated trials, which are not under the full control of MSD.
II. Scientific Issues
A. Trial Conduct
1. Trial Design
Except for pilot or estimation trials, clinical trial protocols will be hypothesis-
driven to assess safety, efficacy, and/or pharmacokinetic or pharmacodynamic 
indices of MSD or comparator products. Alternatively, MSD may conduct 
outcomes research trials, trials to assess or validate various endpoint measures, or 
trials to determine patient preferences, etc.
The design (i.e., participant population, duration, statistical power) must be 
adequate to address the specific purpose of the trial and shall respect the data 
protection rights of all participants, trial site staff and, where applicable, third 
parties. Input may be considered from a broad range of stakeholders, including 
patient advocacy groups/patients representing the trial population, caregivers, and 
healthcare providers to ensure operational feasibility. Trial design also includes 
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proactive identification of critical to quality factors utilizing a risk-based 
approach. Plans are then developed to assess and mitigate risks to those factors as 
appropriate during the trial. All trial protocols are and will be assessed for the 
need and capability to enroll underrepresented groups. Participants must meet 
protocol entry criteria to be enrolled in the trial.
2. Site Selection
MSD’s clinical trials are conducted globally in many different countries and in 
diverse populations, including people of varying age, race, ethnicity, gender, and 
accounting for other potential disease related factors. MSD selects investigative 
sites based on medical expertise, access to appropriate participants, adequacy of 
facilities and staff, previous performance in clinical trials, as well as budgetary 
considerations. Prior to trial initiation, sites are evaluated by MSD personnel (or 
individuals acting on behalf of MSD) to assess the ability to successfully conduct 
the trial. Individuals involved in trial conduct receive training commensurate with 
their role prior to their becoming involved in the trial.
Where appropriate, and in accordance with regulatory authority guidance, MSD 
will make concerted efforts to raise awareness of clinical trial opportunities in 
various communities. MSD will seek to engage underrepresented groups and 
those disproportionately impacted by the disease under study. MSD will support 
clinical trial investigators to enroll underrepresented groups and expand access to 
those who will ultimately use the products under investigation.
3. Site Monitoring/Scientific Integrity
Investigative trial sites are monitored to assess compliance with the trial protocol 
and Good Clinical Practice (GCP). MSD reviews clinical data for accuracy, 
completeness, and consistency. Data are verified versus source documentation 
according to standard operating procedures. Per MSD policies and procedures, if 
potential fraud, scientific/research misconduct, privacy incidents/breaches or 
Clinical Trial-related Significant Quality Issues are reported, such matters are 
investigated. When necessary, appropriate corrective and/or preventative actions 
are defined and regulatory authorities and/or ethics review committees are 
notified.
B. Publication and Authorship
Regardless of trial outcome, MSD commits to publish the primary and secondary 
results of its registered trials of marketed products in which treatment is assigned, 
according to the pre-specified plans for data analysis. To the extent scientifically 
appropriate, MSD seeks to publish the results of other analyses it conducts that are 
important to patients, physicians, and payers. Some early phase or pilot trials are 
intended to be hypothesis generating rather than hypothesis testing; in such cases, 
publication of results may not be appropriate since the trial may be underpowered and 
the analyses complicated by statistical issues such as multiplicity.
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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 and ICH Guidelines. 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. Trial designs include procedures and systems for 
the identification, monitoring, and reporting of safety concerns. 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.
During trial planning, the need for an independent Data Monitoring Committee 
(DMC) is assessed. DMC review of data accumulated during the conduct of the trial 
is integral to the well-being of trial participants.
C. Confidentiality
MSD is committed to safeguarding participant confidentiality, to the greatest extent 
possible, as well as all applicable data protection rights. Unless required by law, only 
the investigator, Sponsor (or individuals acting on behalf of MSD), ethics committee, 
and/or regulatory authorities will have access to confidential medical records that 
might identify the participant by name.
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D. Genomic Research
Genomic research will only be conducted in accordance with a protocol and informed 
consent authorized by an ethics committee.
E. Trial Results
At the time of providing informed consent and in accordance with local laws and 
regulations, participants should be informed about the plans for availability of trial 
results.
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 medical record 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 
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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, frequently 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.
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 before transmission to the Sponsor.
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By signing this protocol, the investigator agrees to treat all participant data used and 
disclosed in connection with this study in accordance with all applicable privacy laws, rules,
and regulations.
10.1.3.3
Confidentiality of IRB/IEC Information
The Sponsor is required to record the name and address of each IRB/IEC that reviews and 
approves this study. The Sponsor is also required to document that each IRB/IEC meets 
regulatory and ICH GCP requirements by requesting and maintaining records of the names 
and qualifications of the IRB/IEC members and to make these records available for 
regulatory agency review upon request by those agencies.
10.1.4
Committees Structure
10.1.4.1
Executive Oversight Committee
The EOC is comprised of members of Sponsor Senior Management. The EOC will receive 
and decide on 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 
Analyses) and recommend to the EOC whether the study should continue in accordance with 
the protocol.
Specific details regarding composition, responsibilities, and governance, including the roles 
and responsibilities of the various members and the Sponsor protocol team; meeting 
facilitation; the study governance structure; and requirements for and proper documentation 
of DMC reports, minutes, and recommendations will be described in the DMC charter that is 
reviewed and approved by all the DMC members.
10.1.4.3
Scientific Advisory Committee (SAC)
This study was developed in collaboration with a SAC. The SAC is comprised of both 
Sponsor and non-Sponsor scientific experts who provide scientific and strategic guidance on 
various aspects of the clinical trial and/or development, which may include study design, 
interpretation of study results, and subsequent peer-reviewed scientific publications.
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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 ICMJE 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 trials Regulation 536/2014, 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, https://euclinicaltrials.eu, or other local registries. MSD, as 
Sponsor of this study, will review this protocol and submit the information necessary to 
fulfill these requirements. MSD entries are not limited to FDAAA or the EMA clinical trials 
Regulation 536/2014 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 Regulation 536/2014, 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, ICH 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.
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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.
For investigators located in countries with serious breach reporting requirements, investigator 
will promptly report to the Sponsor any serious breach or suspected serious breach that 
occurs in compliance with those requirements. Unless more specifically defined in the 
applicable requirements, a serious breach is any breach of the applicable clinical trial 
regulation or of the clinical trial protocol which is likely to affect to a significant degree: (i) 
the safety or rights of a trial participant, or (ii) the reliability and robustness of the data 
generated in the clinical trial.
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.
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Study monitors will perform ongoing source data review and verification to confirm that data 
entered into the CRF by authorized site personnel are accurate, complete, and verifiable from 
source documents; that the safety and rights of participants are being protected; and that the 
study is being conducted in accordance with the currently approved protocol and any other 
study agreements, ICH GCP, and all applicable regulatory requirements.
Records and documents, including participants’ documented informed consent, pertaining to 
the conduct of this study must be retained by the investigator for 15 years after study 
completion unless local regulations or institutional policies require a longer retention period
(eg, EU CTR: 25 years after the end of the study). No records may be destroyed during the 
retention period without the written approval of the Sponsor. No records may be transferred 
to another location or party without written notification to the Sponsor.
10.1.9
Source Documents
Source documents provide evidence for the existence of the participant and substantiate the 
integrity of the data collected. The investigator/institution should maintain adequate and 
accurate source documents and study records that include all pertinent observations on each 
of the site’s participants. Source documents and data should be attributable, legible, 
contemporaneous, original, accurate, and complete. Changes to source data should be 
traceable, should not obscure the original entry, and should be explained if necessary (eg, via 
an audit trail). Source documents are filed at the investigator’s site.
Data reported on the CRF or entered in the eCRF that are transcribed from source documents 
must be consistent with the source documents or the discrepancies must be explained. The 
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 18 will be performed by a central laboratory.
Note: In rare instances, if central laboratory use is not feasible, local laboratory tests 
may be used at scheduled study visits after consultation with the Sponsor. Plasma 
HIV-1 RNA quantification requires use of a validated PCR assay with a lower limit of 
detection of <50 copies/mL (see Appendix 10).
•
Unscheduled local laboratory results are only required in the event that the central 
laboratory results are not available in time for either study intervention administration 
and/or response evaluation. If a local sample is required, it is important that the sample 
for central analysis is obtained at the same time, if feasible. Additionally, if the local 
laboratory results are used to make either a study intervention decision or response 
evaluation, the results must be entered into the CRF.
•
Protocol-specific requirements for inclusion or exclusion of participants are detailed in 
Section 5 of the protocol.
•
Additional tests may be performed at any time during the study as determined necessary 
by the investigator or required by local regulations.
•
The amount of blood collected from each participant over the duration of the study is 
provided in Table 19, Table 20, Table 21, and Table 22. Repeat or unscheduled samples 
may be taken for safety reasons or for technical issues with the samples.
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Table 18
Protocol-required Laboratory Assessments
Laboratory Assessments
Parameters
Hematology
Platelet 
Count
RBC Indices:
MCV
MCH
MCH concentration
RDW
WBC count with Differentiala:
Neutrophils
Lymphocytes
Monocytes
Eosinophils
Basophils
RBC Count
Hemoglobin
Hematocrit
TBNK Panel/
CD4+ T-cell Count
T and B Lymphocyte and Natural Killer Cell profile includes the following 
assessments:
CD3+CD4+ Percent
CD3+CD4+ Value/Absolute Count
CD3+CD8+ Percent
CD3+CD8+ Value/Absolute Count
CD4/CD8 Ratio
and the following exploratory assessments (which do not need to be evaluated 
by the investigator):
CD3+ Percent
CD3+ Value/Absolute Count
CD3-CD19+ Percent
CD3-CD19+ Value/Absolute Count
CD16+CD56+ Percent
CD16+CD56+ Value/Absolute Count
CD3+CD4+CD8+ Percent
CD3+CD4+CD8+ Value/Absolute Count
Coagulation
PT/INR
Chemistry
(nonfasting)
BUN
Potassium
AST/SGOT
Total bilirubin
Direct bilirubin
Indirect bilirubin
Albumin
Bicarbonate
Chloride
Phosphorous
Creatinine
Sodium
ALT/SGPT
Total Protein
Glucose 
(nonfasting)
Calcium
ALP
CrCl
eGFR by MDRD equation 
(Appendix 8)
CK
Lipase
Amylase
Mg
Additional Chemistry at 
Fasting Visits
(fasting for at least 8 h)
Glucose
HbA1c (collected regardless of participant’s fasting status)
HDL-C
LDL-C
TGs
TC
Non-HDL-C
Insulin b
HOMA-IR (calculation)
Routine Urinalysis (with 
microscopic exam as 
needed)
Specific gravity
pH, glucose, protein, blood, ketones, bilirubin, urobilinogen, nitrite, leukocyte 
esterase by dipstick
Pregnancy Testing
Serum and highly sensitive urine hCG (as needed for POCBP)
Hepatitis B Serologyc
HBsAg
Anti-HBs
Anti-HBc
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Laboratory Assessments
Parameters
HBV DNAc
HBV DNA
Hepatitis C Serology
Hepatitis C antibody (if positive, perform plasma HCV quantitative test) (at 
screening only)
HIV-1 and HIV-2 Serology
HIV-1 and HIV-2 antibody test
Virology
HIV-1 viral RNA quantification
HIV-1 viral drug resistance
PK
Plasma ISL PK
Plasma Investigational ISL PK (Samples will be collected from all 
participants. Analysis of these samples will be performed by the Sponsor as 
needed.)
Plasma ISL and DOR PK (Only participants on DOR/ISL who become 
pregnant during the study)
Renal Markers
Urine analysis:
Albumin/Cr
Protein
B-2M/Cr
RBP/Cr
Serum analysis:
Cystatin-C
Cr
Creatinine Clearance by Cockcroft-Gault equation (Appendix 8)
eGFR by MDRD equation (Appendix 8)
Inflammatory Markers
IL-6
D-dimer
sCD-163
hs-CRP
Energy and Metabolism 
Markers
Adipokines:
Leptin
Adiponectin
ALP=alkaline phosphatase; ALT=alanine aminotransferase; anti-HBc=hepatitis B core antibody; 
anti-HBs=hepatitis B surface antibody; AST=aspartate aminotransferase; 
B-2M/Cr=beta-2-microglobulin/creatinine ratio; BUN=blood urea nitrogen; CK=creatine kinase; 
Cr=creatinine; CrCl=creatinine clearance; DNA=deoxyribonucleic acid; DOR=doravirine; 
eGFR=estimated glomerular filtration rate; HbA1c=hemoglobin A1c; HBsAg=hepatitis B surface antigen; 
HBV=hepatitis B virus; hCG=human chorionic gonadotropin; HCV=hepatitis C virus; HDL-C=high-density 
lipoprotein cholesterol; HIV-1=human immune deficiency virus type 1; HIV-2=human immune deficiency 
virus type 2; HOMA-IR=Homeostatic Model Assessment of Insulin Resistance; hs-CRP=high-sensitivity C-
reactive protein; IL-6=interleukin-6; INR=international normalized ratio; ISL=islatravir; LDL-C=low-
density lipoprotein cholesterol; MCH=mean corpuscular hemoglobin; MCV=mean corpuscular volume; 
MDRD=Modification of Diet in Renal Disease; Mg=magnesium; non-HDL-C=non-high-density lipoprotein 
cholesterol; PK=pharmacokinetic(s); POCBP=participant(s) of childbearing potential; PT=prothrombin time; 
RBC=red blood cell; RBP/Cr=retinol-binding protein/creatinine ratio; RDW=red cell distribution width; 
RNA=ribonucleic acid; sCD-163=soluble CD-163; SGOT=serum glutamic-oxaloacetic transaminase; 
SGPT=serum glutamic-pyruvic transaminase; TBNK=T and B Lymphocyte and Natural Killer Cell; 
TC=total cholesterol; TG=triglyceride; WBC=white blood cell.
Notes:
a The central Laboratory may reflex to manual differential to further identify atypical or immature forms of 
leukocytes.
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Laboratory Assessments
Parameters
b Participants with type 1 diabetes mellitus should not fast and should not have insulin levels tested. 
Participants with type 2 diabetes mellitus taking medications that may result in hypoglycemia should delay 
their morning dose of diabetic medication while fasting and take it after the blood draw for testing.
c All participants will be screened for HBsAg, anti-HBs, anti-HBc, and HBV DNA. Repeat serology and 
HBV DNA testing at Weeks 48, 96, 144, 192 and 240 is to be performed for all participants. Participants 
who are anti-HBc-positive but HBV DNA-negative will have HBsAg and HBV DNA monitored for the 
duration of the study. Pregnant participants (on DOR/ISL only) will have a sample collected once after 
pregnancy is confirmed or local laboratory results reported for hepatitis B serology and HBV DNA.
The investigator (or medically qualified designee) must document their review of each 
laboratory safety report.
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Table 19
Blood Volumes (Efficacy, Safety, and PK) in the Base Study
Study Period
Screen
Blinded Intervention (Base Study)
Viremia Confirm
Total Lymphocyte/ 
CD4+ T-cell Confirm
Early Discon of 
Treatment
Total lymphocyte
/CD4+ T-cell Monitor
EoT Follow-upi
Scheduled Day/Week
Screening
Day 1
(fasting)
Week 4
Week 12
Week 24
(fasting)
Week 36
Week 48
(fasting)
Week 60
Week 72
Week 84
Week 96
(fasting)
Week 108
Week 120
Week 132
Week 144 
(fasting)
Unscheduled
Unscheduled
Unscheduled
Unscheduled
Unscheduled
Blood Parameter
Approximate Blood Volume (mL)
Plasma HIV-1 RNA Quantificationa
6
6
6
6
6
6
6
6
6
6
6
6
6
6
6
6
6
6
Blood (Plasma) for HIV-1 Drug 
Resistanceb
12
12
12
12
12
12
12
12
12
12
12
12
12
12
12
(12)
Whole Blood for HIV-1 Drug 
Resistance
4
HIV-1 and HIV-2 Serology
1
TBNK Panel/CD4+ T-cell Count
6
6
6
6
6
6
6
6
6
6
6
6
6
6
6
6
6
6
(6)
Hepatitis B Serology and Hepatitis C 
(Screening only) Serologyc
4
(4)
(4)
(4)
(4)
(4)
4
(4)
(4)
(4)
4
(4)
(4)
(4)
4
HBV DNAc
6
(6)
(6)
(6)
(6)
(6)
6
(6)
(6)
(6)
6
(6)
(6)
(6)
6
Hepatitis B Serology for Pregnant
Participants (DOR/ISL only)d
<---------------------------------(4)----------------------------->
HBV DNA for Pregnant Participants 
(DOR/ISL only)c
<---------------------------------(6)------------------------------>
Plasma HCV Quantitative Testc
(6)
Chemistry (includes Serum 
Pregnancy Test at Screening)
6
6
6
6
6
6
6
6
6
6
6
6
6
6
6
6
Hematology
4
4
4
4
4
4
4
4
4
4
4
4
4
4
4
4
4
4
(4)
HbA1c
2
2
2
2
2
Fasting Lipids
2
2
2
2
2
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Study Period
Screen
Blinded Intervention (Base Study)
Viremia Confirm
Total Lymphocyte/ 
CD4+ T-cell Confirm
Early Discon of 
Treatment
Total lymphocyte
/CD4+ T-cell Monitor
EoT Follow-upi
Scheduled Day/Week
Screening
Day 1
(fasting)
Week 4
Week 12
Week 24
(fasting)
Week 36
Week 48
(fasting)
Week 60
Week 72
Week 84
Week 96
(fasting)
Week 108
Week 120
Week 132
Week 144 
(fasting)
Unscheduled
Unscheduled
Unscheduled
Unscheduled
Unscheduled
Fasting Insuline
1
1
1
1
1
PT/INR
3
Blood for Inflammatory Biomarkers
11
11
11
11
11
Cystatin-C
2
2
2
2
2
Blood for Energy and Metabolism 
Markers
6
6
6
6
6
Blood (Plasma) for ISL PK (All 
Participants)
4
8
4
4
4
4
4
Blood (Plasma) for Investigational 
ISL(and DOR, if applicable) PKf
4
4
4
4
4
4
4
4
Blood (Plasma) for DOR and ISL PK 
During Pregnancyg
<-----------------(4 or 12, as indicated)----------->
Approximate Total Blood Volume 
per Visit (mL)
42
76
52
48
72
48
72
48
48
48
72
44
44
44
68
22
14
38
10
16
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Study Period
Screen
Blinded Intervention (Base Study)
Viremia Confirm
Total Lymphocyte/ 
CD4+ T-cell Confirm
Early Discon of 
Treatment
Total lymphocyte
/CD4+ T-cell Monitor
EoT Follow-upi
Scheduled Day/Week
Screening
Day 1
(fasting)
Week 4
Week 12
Week 24
(fasting)
Week 36
Week 48
(fasting)
Week 60
Week 72
Week 84
Week 96
(fasting)
Week 108
Week 120
Week 132
Week 144 
(fasting)
Unscheduled
Unscheduled
Unscheduled
Unscheduled
Unscheduled
anti-hBc=hepatitis B core antibody; Confirm=Confirmation; Discon=Discontinuation; DNA=deoxyribonucleic acid; DOR=doravirine; EoT=End of Treatment; 
HbA1c=hemoglobin A1c; HBsAg=hepatitis B surface antigen; HBV=hepatitis B virus; HCV=hepatitis C virus; HIV-1=human immunodeficiency virus type 1; HIV-2=human 
immunodeficiency virus type 2; INR=international normalized ratio; ISL=islatravir; Monitor=Monitoring; PK=pharmacokinetic(s); PT=prothrombin time; RNA=ribonucleic acid; 
TBNK=T and B Lymphocyte and Natural Killer Cell.
a Not included in total blood volume per visit: Pregnant participants who require more frequent HIV-1 RNA testing performed per local guidelines or as determined by the 
investigator.
b Do not collect at Early Discon if collected at previous Viremia Confirm.
c All participants will be screened for HBsAg, anti-HBs, anti-HBc, and HBV DNA as well as hepatitis C antibody (with reflex plasma HCV quantitative test if indicated) at 
screening. Participants with negative hepatitis B serologic testing at screening will have repeat testing at Weeks 48, 96, 144 and 192. Only participants who are anti-HBc-positive 
but HBV DNA-negative will have HBsAg and HBV DNA monitored for the duration of the study.
d Not included in total blood volume at each visit: Pregnant participants (DOR/ISL only) will have 1 sample collected once after pregnancy is confirmed or local laboratory results 
reported for HBsAg, anti-HBs, anti-HBc, and HBV DNA during pregnancy.
e Participants with type 1 diabetes mellitus and those who are pregnant should not fast and should not have insulin levels or lipids tested. Participants with type 2 diabetes mellitus 
taking medications that may result in hypoglycemia should delay their morning dose of diabetic medication while fasting and take it after the blood draw for testing.
f Investigational ISL PK samples will be collected from all participants. Analysis of these samples will be performed by the Sponsor as needed.
g Not included in total blood volume at each visit: During pregnancy, blood samples will be collected for PK sampling per Section 8.11.6.1 during the 1st trimester (4 mL), 
2nd trimester (12 mL), 3rd trimester (12 mL), and Postpartum (4 mL) study visits. For participants whose pregnancy or Postpartum visit(s) extends beyond Week 96, see Table 21
and Table 22.
h Blood volumes collected at the Total Lymphocyte Count/CD4+ T-cell Count Monitoring visit (DOR/ISL participants only) represent single monitoring visits every 10 to 
14 weeks after discontinuing study intervention.
i For the EoT Follow-up visit, the approximate total volume to be collected is for the assessments in Section 1.3.1 or 1.3.2 or 1.3.3 or 1.3.4 SoA, as indicated.
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Table 20
Blood Volumes (Genetic Analysis and FBR) in the Base Study
Study Period
Screen
Blinded Intervention (Base Study)
Viremia 
Confirm
Total 
Lymphocyte/ 
CD4+ T-cell 
Confirm
Early 
Discon of 
Treatment
Total 
Lymphocyte/ 
CD4+ T-cell 
Monitor 
(DOR/ISL o
nly)
EoT 
Follow-
up
Scheduled Day/Week
Screening
Day 1
(fasting)
Week 4
Week 12
Week 24
(fasting)
Week 36
Week 48
(fasting)
Week 60
Week 72
Week 84
Week 96
(fasting)
Week 108
Week 120
Week 132
Week 144 
(fasting)
Unscheduled
Unscheduled
Unscheduled
Unscheduled
Unscheduled
Blood Parameter
Approximate Blood Volume (mL)
Blood for Genetic Analysis
9
Whole Blood for FBR
8
8
8
8
8
8
8
Approximate Total Blood 
Volume per Visit (mL)
17
8
8
8
8
8
8
Confirm=Confirmation; Discon=Discontinuation; DOR=doravirine; EoT=End of Treatment; FBR=future biomedical research; ISL=islatravir; Monitor=Monitoring.
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Table 21
Blood Volumes (Efficacy, Safety, and PK) in the OLE
Study Period
Optional OLE
Viremia 
Confirmation
Total 
Lymphocyte/ 
CD4+ T-cell 
Confirmation
Total 
Lymphocyte/ 
CD4+ T-cell 
Monitoring 
(DOR/ISL only)
Discontinuation of 
Treatment (OLE)
End of Treatment Follow-up 
(OLE)a
Scheduled Day/Week
Week 148 (Group 2)
Week 168
Week 192
Week 216
Week 240
Unscheduled
Unscheduled
Unscheduled
Unscheduled
Unscheduled
Blood Parameter
Approximate Blood Volume (mL) a
Plasma HIV-1 RNA 
Quantification (PCR)
6
6
6
6
6
6
6
(6)
TBNK Panel/CD4+ T-cell 
Count
6
6
6
6
6
6
6
6
(6)
Blood (Plasma) for HIV-1 
Viral Drug Resistance 
Testing
12
12
12
12
12
12
12
(12)
Hematology
2
2
2
2
2
2
2
2
(2)
Chemistry
(6)
Hepatitis B Serology HBV 
DNA
10
10
HBsAg and HBV DNA 
(Group 2 participants with 
positive anti-HBc)
(10)
(10)
(10)
(10)
(10)
Blood (Plasma) for 
Investigational ISL PK
4
4
4
(4)
Blood (Plasma) for DOR and 
ISL PK
4
Blood (Plasma) for DOR and 
ISL PK (pregnant 
participants on DOR/ISL)
(4)
(4)
(4)
Total Blood Volume per 
Visit (mL)
26
26
36
26
36
22
12
12
26
40
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Study Period
Optional OLE
Viremia 
Confirmation
Total 
Lymphocyte/ 
CD4+ T-cell 
Confirmation
Total 
Lymphocyte/ 
CD4+ T-cell 
Monitoring 
(DOR/ISL only)
Discontinuation of 
Treatment (OLE)
End of Treatment Follow-up 
(OLE)a
Scheduled Day/Week
Week 148 (Group 2)
Week 168
Week 192
Week 216
Week 240
Unscheduled
Unscheduled
Unscheduled
Unscheduled
Unscheduled
Blood Parameter
Approximate Blood Volume (mL) a
a.
For the EoT Follow up visit, the approximate total volume to be collected is for the assessments in Section 1.3.5 SoA. Alternatively, see Section or 1.3.2 SoA or 1.3.3 
or 1.3.4 SoA, if as indicated.
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The assessments in Table 22 are for any participant who is pregnant on or after Week 144 
and whose visit schedule will be extended through the duration of the pregnancy to allow 
assessments through each trimester and postpartum.
Table 22
Blood Volumes: Participants Whose Pregnancy or Postpartum Visit(s) 
Extends Beyond Week 144 (Efficacy, Safety, and PK)
Visit Number
Unscheduled
Scheduled Week
Pregnancy 1a
Pregnancy 2a
Pregnancy 3a
Pregnancy 4
(Postpartum
≤8 weeks after 
delivery)
EoT 
Follow-up
Blood Parameter
Approximate Blood Volume (mL)
Plasma HIV-1 RNA 
Quantification
6
6
6
6
6
Plasma for HIV-1 Viral Drug 
Resistance Testing
15
15
15
15
15
TBNK Panel/CD4+ T-cell 
Count
6
6
6
6
6
Hepatitis B Serology and 
HBV DNA (DOR/ISL only)b
<-------------------(10)------------------->
Chemistry
6
6
6
6
6
Hematology
4
4
4
4
4
Blood (Plasma) for DOR and 
ISL PKc
4
12
12
4
4
Approximate Total Blood 
Volume per Visit (mL)
41
49
49
41
41
DNA=deoxyribonucleic acid; DOR=doravirine; EoT=End of Treatment; HBsAg=hepatitis B surface antigen; 
HBV=hepatitis B virus; HIV-1=human immunodeficiency virus type 1; ISL=islatravir; PK=pharmacokinetic(s); 
RNA=ribonucleic acid; TBNK=T and B Lymphocyte and Natural Killer Cell.
a If pregnancy visit occurs at the timeframe of a scheduled OLE study visit, collection of lab samples should occur per 
this table. Collection of laboratory samples should not be duplicated.
b.Not included in total blood volume at each visit: Pregnant participants (DOR/ISL only) will have 1 sample collected 
once after pregnancy is confirmed or local laboratory results reported for HBsAg, anti-HBs, anti-HBc, and HBV DNA 
during pregnancy.
c Collect PK samples during pregnancy per Section 8.11.6.1.1.
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10.3
Appendix 3: Adverse Events: Definitions and Procedures for Recording, 
Evaluating, Follow-up, and Reporting
10.3.1
Definitions of Medication Error, Misuse, and Abuse
Medication error
This is an unintended failure in the drug treatment process that leads to or has the potential to 
lead to harm to the patient.
Misuse
This refers to situations where the medicinal product is intentionally and inappropriately used 
not in accordance with the terms of the product information.
Abuse
This corresponds to the persistent or sporadic intentional, excessive use of a medicinal 
product for a perceived psychological or physiological reward or desired nontherapeutic 
effect.
10.3.2
Definition of AE
AE definition
•
An AE is any untoward medical occurrence in a clinical study participant, temporally 
associated with the use of study intervention, whether or not considered related to the 
study intervention.
•
Note: An AE can therefore be any unfavorable and unintended sign (including an 
abnormal laboratory finding), symptom, or disease (new or exacerbated) temporally 
associated with the use of a study intervention.
•
Note: For purposes of AE definition, study intervention includes any pharmaceutical 
product, biological product, vaccine, diagnostic agent, medical device, combination 
product, or protocol-specified procedure whether investigational or marketed (including 
placebo, active comparator product, or run-in intervention), manufactured by, licensed 
by, provided by, or distributed by the Sponsor for human use in this study.
Events meeting the AE definition
•
Any abnormal laboratory test results (hematology, clinical chemistry, or urinalysis) or 
other safety assessments (eg, ECG, radiological scans, vital signs measurements), 
including those that worsen from baseline, considered clinically significant in the medical 
and scientific judgment of the investigator.
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•
Exacerbation of a chronic or intermittent preexisting condition including either an 
increase in frequency and/or intensity of the condition.
•
New conditions detected or diagnosed after study intervention administration even 
though it may have been present before the start of the study.
•
Signs, symptoms, or the clinical sequelae of a suspected drug-drug interaction.
•
Signs, symptoms, or the clinical sequelae of a suspected overdose of either study 
intervention or a concomitant medication.
•
For all reports of overdose (whether accidental or intentional) with an associated AE, the 
AE term should reflect the clinical symptoms or abnormal test result. An overdose 
without any associated clinical symptoms or abnormal laboratory results is reported using 
the terminology “accidental or intentional overdose without adverse effect.”
•
Any new cancer or progression of existing cancer.
Events NOT meeting the AE definition
•
Medical or surgical procedure (eg, endoscopy, appendectomy): the condition that leads to 
the procedure is the AE.
•
Situations in which an untoward medical occurrence did not occur (social and/or 
convenience admission to a hospital).
•
Anticipated day-to-day fluctuations of preexisting disease(s) or condition(s) present or 
detected at the start of the study that do not worsen.
•
Surgical procedure(s) planned prior to informed consent to treat a preexisting condition 
that has not worsened.
•
Refer to Section 8.4.6 for protocol-specific exceptions.
10.3.3
Definition of SAE
If an event is not an AE per definition above, then it cannot be an SAE even if serious 
conditions are met.
An SAE is defined as any untoward medical occurrence that, at any dose:
a.
Results in death
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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 preexisting condition that has not 
worsened is not an SAE.) A preexisting condition is a clinical condition that is 
diagnosed prior to the use of an MSD product and is documented in the participant’s 
medical history.
d. Results in persistent or significant disability/incapacity
-
The term disability means a substantial disruption of a person’s ability to conduct 
normal life functions.
-
This definition is not intended to include experiences of relatively minor medical 
significance such as uncomplicated headache, nausea, vomiting, diarrhea, influenza, 
and accidental trauma (eg, sprained ankle) that may interfere with or prevent 
everyday life functions but do not constitute a substantial disruption.
e.
Is a congenital anomaly/birth defect
-
In offspring of participant taking the product regardless of time to diagnosis.
f.
Other important medical events
-
Medical or scientific judgment should be exercised in deciding whether SAE 
reporting is appropriate in other situations such as important medical events that may 
not be immediately life-threatening or result in death or hospitalization but may 
jeopardize the participant or may require medical or surgical intervention to prevent 1 
of the other outcomes listed in the above definition. These events should usually be 
considered serious.
-
Examples of such events include invasive or malignant cancers, intensive treatment in 
an emergency room or at home for allergic bronchospasm, blood dyscrasias, or 
convulsions that do not result in hospitalization, or development of drug dependency 
or drug abuse.
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10.3.4
Additional Events Reported
Additional events that require reporting
In addition to the above criteria, AEs meeting either of the below criteria, although not 
serious per ICH definition, are reportable to the Sponsor.
•
Is a cancer.
•
Is associated with an overdose.
10.3.5
Recording AE and SAE
AE and SAE recording
•
When an AE/SAE occurs, it is the responsibility of the investigator to review all 
documentation (eg, hospital progress notes, laboratory, and diagnostics reports) related to 
the event.
•
The investigator will record all relevant AE/SAE information on the AE 
CRFs/worksheets at each examination.
•
It is not acceptable for the investigator to send photocopies of the participant’s medical 
records to the Sponsor in lieu of completion of the AE CRF page.
•
There may be instances when copies of medical records for certain cases are requested by 
the Sponsor. In this case, all participant identifiers, with the exception of the participant 
number, will be blinded on the copies of the medical records before submission to the 
Sponsor.
•
The investigator will attempt to establish a diagnosis of the event based on signs, 
symptoms, and/or other clinical information. In such cases, the diagnosis (not the 
individual signs/symptoms) will be documented as the AE/SAE.
Assessment of intensity/toxicity
•
An event is defined as “serious” when it meets at least 1 of the predefined outcomes as 
described in the definition of an SAE, not when it is rated as severe.
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•
The investigator will make an assessment of intensity for each AE and SAE (and other 
reportable safety event) by recording the grade according to the NIH DAIDS Table for 
Grading the Severity of Adult and Pediatric Adverse Events, version 2.1. Any AE which 
changes DAIDS grade over the course of a given episode will have each change of grade 
recorded on the AE CRFs/worksheets.
-
Grade 1 Mild event: Mild symptoms causing no or minimal interference with usual 
social and functional activities with intervention not indicated.
-
Grade 2 Moderate event: Moderate symptoms causing greater than minimal 
interference with usual social and functional activities with intervention indicated.
-
Grade 3 Severe event: Severe symptoms causing inability to perform usual social and 
functional activities with intervention or hospitalization indicated.
-
Grade 4 Potentially life-threatening event: Potentially life-threatening symptoms 
causing inability to perform basic self-care functions with intervention indicated to 
prevent permanent impairment, persistent disability, or death.
-
Grade 5 Death: Deaths related to an AE.
Assessment of causality
•
Did the Sponsor’s product cause the AE?
•
The determination of the likelihood that the Sponsor’s product caused the AE will be 
provided by an investigator who is a qualified physician. The investigator’s signed/dated 
initials on the source document or worksheet that supports the causality noted on the AE 
form, ensures that a medically qualified assessment of causality was done. This initialed 
document must be retained for the required regulatory time frame. The criteria below are 
intended as reference guidelines to assist the investigator in assessing the likelihood of a 
relationship between the test product and the AE based upon the available information.
•
The following components are to be used to assess the relationship between the 
Sponsor’s product and the AE; the greater the correlation with the components and 
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)?
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-
Likely Cause: Is the AE not reasonably explained by another etiology such as 
underlying disease, other drug(s)/vaccine(s), or other host or environmental factors.
-
Dechallenge: Was the 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.
•
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 CRFs/worksheets by an 
investigator who is a qualified physician according to their 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.
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-
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.)
•
The investigator must review and provide an assessment of causality for each AE/SAE 
and document this in the medical notes.
•
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 their opinion of causality in light of follow-up information 
and send an SAE follow-up report with the updated causality assessment.
•
The causality assessment is 1 of the criteria used when determining regulatory reporting 
requirements.
Follow-up of AE and SAE
•
The investigator is obligated to perform or arrange for the conduct of supplemental 
measurements and/or evaluations as medically indicated or as requested by Sponsor to 
elucidate the nature and/or causality of the AE or SAE as fully as possible. This may 
include additional laboratory tests or investigations, histopathological examinations, or 
consultation with other health care professionals.
•
New or updated information will be recorded in the CRF.
•
The investigator will submit any updated SAE data to the Sponsor within 24 hours of 
receipt of the information.
10.3.6
Reporting of AEs, SAEs, and Other Reportable Safety Events to the Sponsor
AE, SAE, and other reportable safety event reporting to Sponsor via electronic data 
collection tool
•
The primary mechanism for reporting to the Sponsor will be the 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.
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-
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 email 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: Medical Device and Drug–Device Combination Products: Product 
Quality Complaints/Malfunctions: Definitions, Recording, and Follow-up
Not applicable to this study.
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10.5
Appendix 5: Contraceptive Guidance
10.5.1
Definitions
Participants of Childbearing Potential (POCBP)
A participant assigned female sex at birth is considered fertile and capable of becoming 
pregnant 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.
Participants assigned female sex at birth who are in the following categories are not capable 
of becoming pregnant and, therefore, not considered POCBP:
•
Premenarchal
•
Premenopausal with 1 of the following:
-
Documented hysterectomy
-
Documented bilateral salpingectomy
-
Documented bilateral oophorectomy
For individuals with permanent infertility due to an alternate medical cause other than the 
above (eg, Mullerian agenesis, androgen insensitivity), investigator discretion should be 
applied to determining study entry.
Note: Documentation can come from the site personnel’s review of the participant’s medical 
records, medical examination, or medical history interview.
•
Postmenopausal
-
A postmenopausal state is defined as no menses for 12 months without an alternative 
medical cause.
◦
A high FSH level in the postmenopausal range may be used to confirm a 
postmenopausal state in participants assigned female sex at birth who are not 
using hormonal contraception or HRT. However, in the absence of 12 months of 
amenorrhea, confirmation with two FSH measurements in the postmenopausal 
range is required.
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-
Participants assigned female sex at birth who are on HRT and whose menopausal 
status is in doubt will be required to use one of the nonhormonal highly effective 
contraception methods if they wish to continue their HRT during the study. 
Otherwise, they must discontinue HRT to allow confirmation of postmenopausal 
status before study enrollment.
Participants of Nonchildbearing Potential (PONCBP)
Participants assigned female sex at birth who are in the following categories are not capable 
of becoming pregnant and, therefore, in the following categories are considered PONCBP:
•
Premenopausal with 1 of the following:
-
Documented hysterectomy
-
Documented bilateral salpingectomy
-
Documented bilateral oophorectomy
For individuals with permanent infertility due to an alternate medical cause other than 
the above (eg, Mullerian agenesis, androgen insensitivity), investigator discretion 
should be applied to determining study entry.
Note: Documentation can come from the site personnel’s review of the participant’s 
medical records, medical examination, or medical history interview.
•
Postmenopausal
-
A postmenopausal state is defined as no menses for 12 months without an alternative 
medical cause.
◦
A high FSH level in the postmenopausal range may be used to confirm a 
postmenopausal state in participants assigned female sex at birth not using 
hormonal contraception or HRT. However, in the absence of 12 months of 
amenorrhea, confirmation with two FSH measurements in the postmenopausal 
range is required.
-
Participants assigned female sex at birth on HRT and whose menopausal status is in 
doubt must discontinue HRT to allow confirmation of postmenopausal status before 
study enrollment.
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10.5.2
Contraceptive Requirements
Contraceptives allowed during the study include:
Highly Effective Contraceptive Methods That Have Low User Dependency a
Failure rate of <1% per year when used consistently and correctly.
Progestogen-only contraceptive implant b,c
IUS b,c
Nonhormonal IUD
Bilateral tubal occlusion (Tubal occlusion includes tubal ligation)
Azoospermic partner (vasectomized or secondary to medical cause, confirmed by medical history) -
All sexual partner(s) of the POCBP must be azoospermic. The participant must provide verbal confirmation 
of partner azoospermia during Medical History. If not, an additional highly effective method of 
contraception should be used. A spermatogenesis cycle is approximately 90 days.
Highly Effective Contraceptive Methods That Are User Dependent a
Failure rate of <1% per year when used consistently and correctly.
Combined (estrogen- and progestogen-containing) hormonal contraception b,c

Oral

Intravaginal

Transdermal

Injectable
Progestogen-only hormonal contraception b,c

Oral

Injectable
Sexual Abstinence
Sexual abstinence is considered a highly effective method only if defined as refraining from penile-vaginal 
intercourse with a partner capable of producing sperm, 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. 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.
Methods That Are Not Considered Highly Effective
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
Penile/external or vaginal/internal condom with or without spermicide
Cervical cap, diaphragm, or sponge with spermicide
A combination of penile/external condom with either cervical cap, diaphragm, or sponge with spermicide 
(double barrier methods)
Note: The following are not acceptable methods of contraception:
Periodic abstinence (calendar, symptothermal, postovulation methods), withdrawal (coitus interruptus), spermicides 
only, and LAM
Penile/external and vaginal/internal condoms should not be used together (due to risk of failure with friction)d
a
Typical use failure rates are higher than perfect-use failure rates (ie, when used consistently and correctly)
b
If locally required, in accordance with CTFG guidelines, acceptable contraceptives are limited to those which inhibit 
ovulation.
c
IUS is a progestin releasing IUD
d
Vaginal/internal condom used for contraceptive purposes
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10.6
Appendix 6: Collection and Management of Specimens for Future Biomedical 
Research
1. Definitions
a.
Biomarker: A biological molecule found in blood, other body fluids, or tissues that is 
a sign of a normal or abnormal process or of a condition or disease. A biomarker may 
be used to see how well the body responds to a treatment for a disease or condition.1
b. Pharmacogenomics: The investigation of variations of DNA and RNA characteristics 
as related to drug/vaccine response.2
c.
Pharmacogenetics: A subset of pharmacogenomics, pharmacogenetics is the influence 
of variations in DNA sequence on drug/vaccine response.2
d. DNA: Deoxyribonucleic acid.
e.
RNA: Ribonucleic acid.
2. Scope of Future Biomedical Research3, 4
The specimens consented and/or collected in this study as outlined in Section 8.9 will be 
used in various experiments to understand:
-
The biology of how drugs/vaccines work
-
Biomarkers responsible for how a drug/vaccine enters and is removed by the body
-
Other pathways with which drugs/vaccines may interact
-
The biology of disease
The specimen(s) may be used for future assay development and/or drug/vaccine 
development.
It is now well recognized that information obtained from studying and testing clinical 
specimens offers unique opportunities to enhance our understanding of how individuals 
respond to drugs/vaccines, enhance our understanding of human disease, and ultimately 
improve public health through development of novel treatments targeted to populations 
with the greatest need. All specimens will be used by the Sponsor or those working for or 
with the Sponsor.
3. Summary of Procedures for Future Biomedical Research3, 4
a.
Participants for Enrollment
All participants enrolled in the clinical study will be considered for enrollment in 
future biomedical research.
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 
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signed by the participant will be kept at the clinical study site under secure storage for 
regulatory reasons.
A template of each study site’s approved informed consent will be stored in the 
Sponsor’s clinical document repository.
c.
eCRF Documentation for Future Biomedical Research Specimens
Documentation of participant consent for future biomedical research will be captured 
in the eCRFs. Any specimens for which such an informed consent cannot be verified 
will be destroyed.
d. Future Biomedical Research Specimen(s)
Collection of specimens for future biomedical research will be performed as outlined 
in the SoA. In general, if additional blood specimens are being collected for future 
biomedical research, these will usually be obtained at a time when the participant is 
having blood drawn for other study purposes.
4. Confidential Participant Information for Future Biomedical Research3, 4
In order to optimize the research that can be conducted with future biomedical research 
specimens, it is critical to link participants’ clinical information with future test results. In 
fact, little or no research can be conducted without connecting the clinical study data to 
the specimen. The clinical data allow specific analyses to be conducted. Knowing 
participant characteristics like sex, age, medical history, and intervention outcomes is
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 that 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.
5. Biorepository Specimen Usage3, 4
Specimens obtained for the Sponsor will be used for analyses using good scientific 
practices. Analyses using 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.
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6. Withdrawal From Future Biomedical Research3, 4
Participants may withdraw their consent for FBR and ask that their biospecimens not be 
used for FBR. Participants may withdraw consent at any time by contacting the study 
investigator. If medical records for the study are still available, the investigator will 
contact the Sponsor using the designated mailbox 
(clinical.specimen.management@MSD.com). Subsequently, the participant's specimens 
will be flagged in the biorepository and restricted to study use only. If specimens were 
collected from study participants specifically for FBR, 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 before 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.
If the medical records for the study are no longer available (eg, if the investigator is no 
longer required by regulatory authorities to retain the study records) or the specimens 
have been completely anonymized, there will no longer be a link between the 
participant’s personal information and their specimens. In this situation, the request for 
withdrawal of consent and/or destruction cannot be processed.
7. Retention of Specimens3, 4
Future biomedical research specimens will be stored in the biorepository for potential 
analysis for up to 20 years from the end of the 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 used in a particular 
study, the study site will ship directly to the Sponsor-designated biorepository. The 
specimens will be stored under strict supervision in a limited access facility, which 
operates to assure the integrity of the specimens. Specimens will be destroyed according 
to Sponsor policies and procedures and this destruction will be documented in the 
biorepository database.
8. Data Security3, 4
Databases containing specimen information and test results are accessible only to the 
authorized Sponsor representatives and the designated study administrator research 
personnel and/or collaborators. Database user authentication is highly secure, and is 
accomplished using network security policies and practices based on international 
standards to protect against unauthorized access.
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9. Reporting of Future Biomedical Research Data to Participants3, 4
No information obtained from exploratory laboratory studies will be reported to the 
participant, family, or physicians. Principle reasons not to inform or return results to the 
participant include lack of relevance to participant health, limitations of predictive 
capability, and concerns regarding misinterpretation.
If important research findings are discovered, the Sponsor may publish results, present 
results in national meetings, and make results accessible on a public website in order to 
rapidly report this information to doctors and participants. Participants will not be 
identified by name in any published reports about this study or in any other scientific 
publication or presentation.
10. Future Biomedical Research Study Population3, 4
Every effort will be made to recruit all participants diagnosed and treated on Sponsor 
clinical studies for future biomedical research.
11. Risks Versus Benefits of Future Biomedical Research3, 4
For future biomedical research, risks to the participant have been minimized and are 
described in the future biomedical research informed consent.
The Sponsor has developed strict security, policies, and procedures to address participant 
data privacy concerns. Data privacy risks are largely limited to rare situations involving 
possible breach of confidentiality. In this highly unlikely situation, there is risk that the 
information, like all medical information, may be misused.
12. Questions
Any questions related to the future biomedical research should be emailed directly to 
clinical.specimen.management@MSD.com.
13. References
1. National Cancer Institute [Internet]: Available from 
https://www.cancer.gov/publications/dictionaries/cancer-terms?cdrid=45618
2. International Council on Harmonisation [Internet]: E15: Definitions for Genomic 
Biomarkers, Pharmacogenomics, Pharmacogenetics, Genomic Data and Sample 
Coding Categories. Available from 
http://www.ich.org/products/guidelines/efficacy/efficacy-single/article/definitions-
for-genomic-biomarkers-pharmacogenomics-pharmacogenetics-genomic-data-and-
sample-cod.html
3. Industry Pharmacogenomics Working Group [Internet]: Understanding the Intent, 
Scope and Public Health Benefits of Exploratory Biomarker Research: A Guide for 
IRBs/IECs and Investigational Site Staff. Available at http://i-pwg.org/
4. Industry Pharmacogenomics Working Group [Internet]: Pharmacogenomics 
Informational Brochure for IRBs/IECs and Investigational Site Staff. Available at 
http://i-pwg.org/
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10.7
Appendix 7: Country-specific Requirements
10.7.1
Country-specific Request for Germany
Legally Acceptable Representative
Persons of legal age who are incapable of comprehending the nature, significance and 
implications of the clinical trial and of determining their will are excluded from the trial at 
German sites; therefore, all references to a participant’s “legally acceptable representative” in 
the protocol are not applicable for participants in Germany.
Exclusion of Persons who per Order of Court or Authorities Have Been Accommodated 
in an Institution, as per German Drug Law (AMG) §40(1) Sentence 3 No. 4
Persons who have been committed to an institution by virtue of an order issued either by the 
judicial or the administrative authorities are excluded from participation in this clinical trial 
in Germany.
DEXA Scans
Participants who enroll in Germany will not have DEXA scans as indicated in the SoA. This 
procedure will be omitted, and participants in Germany will not be included in the applicable 
analyses.
10.7.2
Country-specific Request for Canada
In Canada, in addition to the criteria in Section 7.1, a participant must be discontinued from 
study intervention per Section 8.11.3 for the following reason:
•
The participant becomes HBsAg-positive or have confirmed quantifiable HBV DNA 
after randomization, per Section 8.3.6.
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10.8
Appendix 8: Calculation of Creatinine Clearance and eGFR
10.8.1
Cockcroft-Gault Equations
•
If male:
•
If female:
10.8.2
MDRD Equations
eGFR estimated by MDRD-NKDEP:
eGFR (mL/min/1.73 m2) = 175 × (serum creatinine [mg/dL])-1.154 × (Age [years])-0.203 × 
0.742 (if female) × 1.212 (if Black)
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10.9
Appendix 9: AIDS-defining Opportunistic Infections that Require 
Discontinuation of Study Intervention
Per Section 7.1, a participant must be discontinued from study intervention if they have a 
new AIDS-defining opportunistic infection as listed below, ie, a Category C condition 
according to the CDC 1993 Revised Classification System for HIV Infection and Expanded 
Surveillance Case Definition for AIDS Among Adolescents and Adults [Centers for Disease 
Control (CDC) 1992].
•
Candidiasis of bronchi, trachea, or lungs
•
Candidiasis, esophageal
•
Cervical cancer, invasive
•
Coccidioidomycosis, disseminated or extrapulmonary
•
Cryptococcosis, extrapulmonary
•
Cryptosporidiosis, chronic intestinal (greater than 1 month's duration)
•
Cytomegalovirus disease (other than liver, spleen, or nodes)
•
Cytomegalovirus retinitis (with loss of vision)
•
Encephalopathy, HIV-related
•
Herpes simplex: chronic ulcer(s) (greater than 1 month's duration); or bronchitis, 
pneumonitis, or esophagitis
•
Histoplasmosis, disseminated or extrapulmonary
•
Isosporiasis, chronic intestinal (greater than 1 month's duration)
•
Kaposi's sarcoma
•
Lymphoma, Burkitt's (or equivalent term)
•
Lymphoma, immunoblastic (or equivalent term)
•
Lymphoma, primary, of brain
•
Mycobacterium avium complex or M. kansasii, disseminated or extrapulmonary
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•
Mycobacterium tuberculosis, any site (pulmonary or extrapulmonary)
•
Mycobacterium, other species or unidentified species, disseminated or extrapulmonary
•
Pneumocystis carinii pneumonia
•
Pneumonia, recurrent
•
Progressive multifocal leukoencephalopathy
•
Salmonella septicemia, recurrent
•
Toxoplasmosis of brain
•
Wasting syndrome due to HIV
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10.10 Appendix 10: Approved HIV-1 RNA Quantification Assays for Local Viral Load 
Monitoring
For this study, allowed US FDA-approved HIV-1 RNA quantification assays for local viral 
load monitoring are listed in Table 23.
This list represents the US FDA-approved nucleic acid testing assays for HIV-1 RNA 
detection and quantification that have a lower limit of detection of <50 copies/mL. 
Additional details can be found at: www.fda.gov/vaccines-blood-biologics/blood-blood-
products/approved-blood-products and www.fda.gov/vaccines-blood-biologics/hiv-1.
Table 23
Approved HIV-1 RNA Quantification Assays for Local Viral Load 
Monitoring
Tradename
Infectious 
Agent
Format
Specimen
Use
Manufacturer
APTIMA 
HIV-1 
Quant 
Assay
APTIMA 
HIV-1 
Quant Dx 
Assay
HIV-1
TMA
Plasma/ 
Serum
Patient Monitoring: 
Quantitation of HIV-1 RNA 
in plasma of HIV-1 infected 
individuals.
Addition of claim for 
Qualitative detection HIV-1 
RNA on Panther platform
Hologic Inc., 
San Diego, CA
US License 1592
COBAS 
HIV-1
Quantitative 
PCR
Plasma
Patient Monitoring: 
Quantitation of HIV-1 RNA 
in plasma of HIV-1 infected 
individuals
Roche Molecular 
Systems, Inc., 
Pleasanton, CA
US License 1636
Abbott 
RealTime 
HIV-1
ABBOTT 
Molecular, Inc., 
Des Plaines, IL
(US License NA)
Amplicor 
HIV-1 
Monitor 
Test
Roche Molecular 
Systems, Inc., 
Pleasanton, CA
US License 1636
COBAS 
AmpliPrep/
COBAS 
TaqMan 
HIV-1 Test
Roche Molecular 
Systems, Inc., 
Pleasanton, CA
US License 1636
FDA=United States Food and Drug Administration; HIV-1=human immunodeficiency virus type 1; NA=not 
available; PCR=polymerase chain reaction; RNA=ribonucleic acid; TMA=transcription-mediated 
amplification; US=United States.
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10.11 Appendix 11: Abbreviations
Abbreviation
Expanded Term
3TC
lamivudine
ADME
absorption, distribution, metabolism, and excretion
AE
adverse event
AIDS
acquired immunodeficiency syndrome
albumin/Cr
albumin/creatinine ratio
ALP
alkaline phosphatase
ALT
alanine aminotransferase
ANCOVA
analysis of covariance
anti-HBc
hepatitis B core antibody
anti-HBs
hepatitis B surface antibody
APaT
All-Participants-as-Treated
APaT-E
All-Participants-as-Treated in the Extension
ART
antiretroviral therapy
ARV
antiretroviral
AST
aspartate aminotransferase
AUC
area under the curve
B-2M/Cr
beta-2-microglobulin/creatinine ratio
BCRP
breast cancer resistance protein
BIC
bictegravir
BLOQ
below the limit of quantification
BMD
bone mineral density
BMI
body mass index
BP
blood pressure
C24
concentration after 24 hours
CDER
Center for Drug Evaluation and Research
CFR
Code of Federal Regulations
CI
confidence interval
cLDA
constrained longitudinal data analysis
Cmax
maximum plasma concentration
CNS
central nervous system
CONSORT
Consolidated Standards of Reporting Trials
COVID-19
coronavirus disease caused by severe acute respiratory syndrome 
coronavirus 2
Cr
creatinine
CrCl
creatinine clearance
CRF
Case Report Form 
CSR
Clinical Study Report
CTFG
Clinical Trial Facilitation Group
Ctrough
lowest concentration reached before the next dose is administered
CYP
cytochrome P450
DAIDS
Division of AIDS
DAO
data as observed
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Abbreviation
Expanded Term
DDI
drug-drug interaction
DEXA
dual x-ray absorptiometry
DILI
drug-induced liver injury
DMC
Data Monitoring Committee
DNA
deoxyribonucleic acid
DOR
doravirine
ECG
electrocardiogram
ECI
event of clinical interest
eCRF
electronic Case Report Form
EDC
electronic data collection 
eDMC
external Data Monitoring Committee
EEA
European Economic Area
EFV
efavirenz
eGFR
estimated glomerular filtration rate
EMA
European Medicines Agency
EOC
Executive Oversight Committee 
EQ-5D-5L
EuroQol 5-dimensional descriptive system, 5-level version
EU
European Union
FAS
Full Analysis Set
FAS-E
Full Analysis Set-Extension
FBR
future biomedical research
FDA
Food and Drug Administration
FDAAA
Food and Drug Administration Amendments Act
FDC
fixed-dose combination
FSH
follicle-stimulating hormone
FSR
first site ready
FTC
emtricitabine
GCP
Good Clinical Practice 
HbA1c
hemoglobin A1c
HBsAg
hepatitis B surface antigen
HBV
hepatitis B virus
hCG
human chorionic gonadotropin
HCV
hepatitis C virus
HDL-C
high-density lipoprotein cholesterol
HIV
human immunodeficiency virus
HIV-1
human immunodeficiency virus type 1
HIV-2
human immunodeficiency virus type 2
HIV SI/SDM
Human Immunodeficiency Virus Symptom Index (also known as 
the Human Immunodeficiency Virus Symptom Distress Module)
HIVTSQ
Human Immunodeficiency Virus Treatment Satisfaction 
Questionnaire
HIVTSQs
Human Immunodeficiency Virus Treatment Satisfaction 
Questionnaire status version
HOMA-IR
Homeostatic Model Assessment of Insulin Resistance
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Abbreviation
Expanded Term
HR
heart rate
HRQoL
health-related quality of life
HRT
hormone replacement therapy
hs-CRP
high-sensitivity C-reactive protein
HTA
Health Technology Assessment
IA(s)
interim analysis(ses)
IB
Investigator’s Brochure
IC50
inhibitory concentration required for 50% inhibition
ICF
Informed Consent Form
ICH
International Council for Harmonisation of Technical 
Requirements for Pharmaceuticals for Human Use
ICMJE
International Committee of Medical Journal Editors
IEC
Independent Ethics Committee
IL-6
interleukin-6
IMP
investigational medicinal product
IND
Investigational New Drug 
INR
international normalized ratio
InSTI
integrase strand transfer inhibitor
IQ
inhibitory quotient
IRB
Institutional Review Board
IRT
interactive response technology
ISL
islatravir
ISL-TP
islatravir-triphosphate
IUD
intrauterine device
IUS
intrauterine hormone-releasing system
LAM
lactational amenorrhea method
LDL-C
low-density lipoprotein cholesterol
M=F
missing data treated as treatment failure
MAR
missing at random
MCAR
missing completely at random
MDRD
Modification of Diet in Renal Disease
MedDRA
Medical Dictionary for Regulatory Activities
MNAR
missing not at random
NIMP
noninvestigational medicinal product
NKDEP
National Kidney Disease Education Program
NNRTI
non-nucleoside reverse transcriptase inhibitor
non-HDL-C
non-high-density lipoprotein cholesterol
NRTI
nucleoside/nucleotide analog reverse transcriptase inhibitor
NRTTI
nucleoside reverse transcriptase translocation inhibitor
OF
observed failure
OLE
open-label extension
PCR
polymerase chain reaction
PDLC
predefined limit of change
PI
protease inhibitor
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Abbreviation
Expanded Term
PK
pharmacokinetic(s)
PLWH
people living with HIV
POCBP
participant(s) of childbearing potential
PONCBP
participant(s) of nonchildbearing potential
PP
Per-Protocol
PrEP
pre-exposure prophylaxis
PRO
patient-reported outcome
PT
prothrombin time
PTs
preferred terms
QD
once-daily
QM
once-monthly
QW
once-weekly
RBC
red blood cell
RBP/Cr
retinol-binding protein/creatinine ratio
RNA
ribonucleic acid
RR
respiratory rate
SAC
Scientific Advisory Committee
SAE
serious adverse event 
SAP
Statistical Analysis Plan
SAS
Statistical Analysis System
sCD-163
soluble CD-163
SGOT
serum glutamic-oxaloacetic transaminase
SGPT
serum glutamic-pyruvic transaminase
SMQs
Standardized MedDRA Queries
SoA
schedule of activities
sSAP
supplemental Statistical Analysis Plan
SUSARs
suspected unexpected serious adverse reactions
TAF
tenofovir alafenamide
TBNK
T and B Lymphocyte and Natural Killer Cell
TC
total cholesterol
TDF
tenofovir disoproxil fumarate
TG
triglyceride
TN
treatment-naïve
ULN
upper limit of normal
US
United States
vs
versus
VS
virologically suppressed
WBC
white blood cell
WHO
World Health Organization
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11
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