A Phase 2a, Double-Blind, Placebo-Controlled Study to Evaluate the Safety, Tolerability, and Pharmacokinetics of Oral MK-8527 Once Monthly in Participants at Low-Risk for HIV-1 Infection
Phase: PHASE2
Conditions: HIV, HIV Pre-exposure Prophylaxis
Sponsor: Merck Sharp & Dohme LLC

Official Protocol Title:
NCT Number:                NCT06045507
Document Date:            03-Oct-2024
A Phase 2a, Double-Blind, Placebo-Controlled 
Study to Evaluate the Safety, Tolerability, and 
Pharmacokinetics of Oral MK-8527 Once 
Monthly in Participants at Low-Risk for HIV-1 
Infection

PRODUCT: MK-8527
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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 2a, Double-Blind, Placebo-Controlled Study to Evaluate the Safety, 
Tolerability, and Pharmacokinetics of Oral MK-8527 Once Monthly in Participants at Low-
Risk for HIV-1 Infection
Protocol Number: 007-02
Compound Number: MK-8527
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
NCT06045507
EU CT
Not applicable
EudraCT
Not applicable
JRCT
Not applicable
WHO
Not applicable
UTN
Not applicable
IND
165532
Approval Date: 03 October 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
03-OCT-2024 The protocol is being amended to unblind all 
Sponsor personnel except for a blinded medical 
monitoring team after the last expected Follow-up 
Week 4 visit, to enable earlier program strategic 
decision-making by the Sponsor.
Amendment 1
13-FEB-2024 The protocol is being amended to update 
contraception requirements for participants of 
childbearing potential and to remove contraception 
requirements for male participants with partners of 
childbearing potential.
Original Protocol
28-JUL-2023 Not applicable
PROTOCOL AMENDMENT SUMMARY OF CHANGES
Amendment: 02
Overall Rationale for the Amendment:
The protocol is being amended to unblind all Sponsor personnel except for a blinded medical 
monitoring team after the last expected Follow-up Week 4 visit, to enable earlier program 
strategic decision-making by the Sponsor.
Summary of Changes Table
Section Number and Name
Description of Change
Brief Rationale
Primary Reason for Amendment
Section 6.3.3 Blinding
Revised text to indicate that all 
Sponsor personnel except for a 
blinded medical monitoring team 
will be unblinded after the last 
expected Follow-up Week 4 
visit, to enable earlier program
strategic decision-making by the 
Sponsor.
The protocol currently permits select
Sponsor personnel to be unblinded 
during the study. This amendment is 
being made due to a change in strategy.
All Sponsor personnel except for a 
blinded medical monitoring team will 
be unblinded after the last expected 
Follow-up Week 4 visit, to enable 
earlier program strategic decision 
making by the Sponsor.
All participants and study-site personnel 
directly associated with study conduct 
will continue to remain blinded to study 
intervention assignment through 
Follow-up Week 8.
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Section Number and Name
Description of Change
Brief Rationale
Additional Changes
Section 1.2 Schema
Added text to footnote “b” to 
indicate the changes in blinding
strategy for the Sponsor.
See rationale for Section 6.3.3
Section 1.3.1 Schedule of 
Activities (Main)
Added footnote “f” to indicate 
the changes in blinding strategy
for the Sponsor.
See rationale for Section 6.3.3
Section 4.1 Overall Design
Updated to align with the 
changes in blinding strategy for 
the Sponsor.
See rationale for Section 6.3.3
Section 9.1 Responsibility for 
Analyses/In-house Blinding
Changed the word “unblinded”
to “locked” in the third sentence
of the second paragraph.
For alignment of timing with the 
changes in blinding strategy for the 
Sponsor.
Section 9.1 Responsibility for 
Analyses/In-house Blinding
Revised text to indicate that in 
addition to the unblinded 
Sponsor team that has been 
unblinded since the trial started, 
all other Sponsor personnel 
except for a blinded medical 
monitoring team will be 
unblinded after the last expected 
Follow-up Week 4 visit.
See rationale for Section 6.3.3
Throughout
Minor administrative, 
formatting, grammatical, and 
typographical changes were 
made throughout the document.
To ensure clarity and accurate 
interpretation of the intent of the 
protocol.
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TABLE OF CONTENTS
DOCUMENT HISTORY ........................................................................................................3
PROTOCOL AMENDMENT SUMMARY OF CHANGES...............................................3
1
PROTOCOL SUMMARY ............................................................................................12
1.1
Synopsis.................................................................................................................12
1.2
Schema ..................................................................................................................15
1.3
Schedule of Activities...........................................................................................16
1.3.1
Schedule of Activities (Main)......................................................................16
1.3.2
Schedule of Activities (HIV Infection Confirmation or Early 
Withdrawal From Study) .............................................................................22
2
INTRODUCTION..........................................................................................................24
2.1
Study Rationale....................................................................................................24
2.2
Background ..........................................................................................................24
2.2.1
Pharmaceutical and Therapeutic Background .............................................24
2.3
Benefit/Risk Assessment......................................................................................25
3
HYPOTHESES, OBJECTIVES, AND ENDPOINTS................................................27
4
STUDY DESIGN............................................................................................................28
4.1
Overall Design......................................................................................................28
4.2
Scientific Rationale for Study Design.................................................................28
4.2.1
Rationale for Endpoints ...............................................................................29
4.2.1.1
Safety Endpoints................................................................................29
4.2.1.2
Pharmacokinetic Endpoints ...............................................................30
4.2.1.2.1
PBMC Subset...........................................................................30
4.2.1.3
Planned Exploratory Biomarker Research.........................................30
4.2.1.3.1
Planned Genetic Analysis ........................................................30
4.2.1.4
Future Biomedical Research..............................................................31
4.2.2
Rationale for the Use of Placebo .................................................................31
4.2.3
Rationale for Collecting Race and Ethnicity ...............................................31
4.2.4
Rationale for Collecting Gender Identity Data ............................................31
4.3
Justification for Dose...........................................................................................32
4.4
Beginning and End-of-Study Definition ............................................................33
4.4.1
Clinical Criteria for Early Study Termination .............................................33
5
STUDY POPULATION ................................................................................................34
5.1
Inclusion Criteria.................................................................................................34
5.2
Exclusion Criteria................................................................................................36
5.3
Lifestyle Considerations......................................................................................37
5.4
Screen Failures.....................................................................................................37
5.5
Participant Replacement Strategy......................................................................38
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6
STUDY INTERVENTION............................................................................................39
6.1
Study Intervention(s) Administered...................................................................39
6.2
Preparation/Handling/Storage/Accountability .................................................41
6.2.1
Dose Preparation..........................................................................................41
6.2.2
Handling, Storage, and Accountability........................................................41
6.3
Measures to Minimize Bias: Randomization and Blinding..............................42
6.3.1
Intervention Assignment..............................................................................42
6.3.2
Stratification.................................................................................................42
6.3.3
Blinding........................................................................................................42
6.4
Study Intervention Compliance..........................................................................43
6.5
Concomitant Therapy..........................................................................................43
6.5.1
Rescue Medications and Supportive Care ...................................................44
6.6
Dose Modification ................................................................................................44
6.7
Intervention After the End of the Study............................................................44
6.8
Clinical Supplies Disclosure................................................................................44
6.9
Standard Policies..................................................................................................44
7
DISCONTINUATION OF STUDY INTERVENTION AND PARTICIPANT 
WITHDRAWAL............................................................................................................45
7.1
Discontinuation of Study Intervention...............................................................45
7.2
Participant Withdrawal From the Study...........................................................47
7.3
Lost to Follow-up .................................................................................................47
8
STUDY ASSESSMENTS AND PROCEDURES........................................................48
8.1
Administrative and General Procedures ...........................................................48
8.1.1
Informed Consent.........................................................................................48
8.1.1.1
General Informed Consent.................................................................49
8.1.1.2
Consent and Collection of Specimens for Future Biomedical 
Research.............................................................................................49
8.1.1.3
Consent for PBMC Subset.................................................................49
8.1.2
Inclusion/Exclusion Criteria ........................................................................49
8.1.3
Participant Identification Card.....................................................................50
8.1.4
Medical History ...........................................................................................50
8.1.5
Prior and Concomitant Medications Review...............................................50
8.1.5.1
Prior Medications...............................................................................50
8.1.5.2
Concomitant Medications..................................................................50
8.1.6
Assignment of Screening Number...............................................................50
8.1.7
Assignment of Treatment/Randomization Number.....................................50
8.1.8
Study Intervention Administration ..............................................................51
8.1.8.1
Timing of Dose Administration.........................................................51
8.1.9
Discontinuation and Withdrawal .................................................................52
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8.1.9.1
Withdrawal From Future Biomedical Research ................................52
8.1.10
Participant Blinding/Unblinding..................................................................53
8.1.11
Calibration of Equipment.............................................................................53
8.1.12
HIV Risk Reduction.....................................................................................54
8.2
Efficacy Assessments ...........................................................................................54
8.3
Safety Assessments...............................................................................................54
8.3.1
Physical Examinations.................................................................................54
8.3.2
Vital Signs....................................................................................................54
8.3.3
Electrocardiogram........................................................................................55
8.3.4
Sexually Transmitted Infections ..................................................................55
8.3.4.1
HIV Infection.....................................................................................55
8.3.4.2
Other STIs..........................................................................................55
8.3.5
Clinical Safety Laboratory Assessments .....................................................56
8.3.5.1
Renal Function Assessment...............................................................56
8.3.6
HIV Risk Evaluation....................................................................................56
8.3.7
Pregnancy Testing........................................................................................57
8.4
Adverse Events, Serious Adverse Events, and Other Reportable Safety 
Events....................................................................................................................57
8.4.1
Time Period and Frequency for Collecting AE, SAE, and Other 
Reportable Safety Event Information ..........................................................57
8.4.2
Method of Detecting AEs, SAEs, and Other Reportable Safety Events......59
8.4.3
Follow-up of AE, SAE, and Other Reportable Safety Event Information...60
8.4.4
Regulatory Reporting Requirements for SAE .............................................60
8.4.5
Pregnancy and Exposure During Breastfeeding ..........................................60
8.4.6
Disease-related Events and/or Disease-related Outcomes Not Qualifying 
as AEs or SAEs............................................................................................61
8.4.7
Events of Clinical Interest............................................................................61
8.5
Treatment of Overdose........................................................................................61
8.6
Pharmacokinetics.................................................................................................61
8.6.1
Blood Collection for Plasma MK-8527 (All Participants) ..........................62
8.6.2
Blood Collection of PBMC Samples (PBMC Subset Only)........................62
8.6.3
Blood Collection of Venous Microsampling (Mitra®/VAMS) (All 
Participants) .................................................................................................63
8.6.4
Collection of PK Samples in Participants Who Withdraw Consent or 
Require an HIV Infection Confirmation Visit .............................................65
8.7
Pharmacodynamics..............................................................................................65
8.8
Biomarkers ...........................................................................................................66
8.8.1
Planned Genetic Analysis Sample Collection..............................................66
8.9
Future Biomedical Research Sample Collection...............................................66
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8.10
Medical Resource Utilization and Health Economics.......................................66
8.11
Visit Requirements...............................................................................................66
8.11.1
Screening/Rescreening.................................................................................66
8.11.1.1
Screening............................................................................................67
8.11.1.2
Rescreening........................................................................................67
8.11.2
Intervention Period.......................................................................................68
8.11.2.1
AE Assessment Phone Call (Week 2)................................................68
8.11.3
Participants Discontinued From Study Intervention but Continuing to be 
Monitored in the Study ................................................................................68
8.11.3.1
Management of Participants with Specified Decreases in Total 
Lymphocyte Count or CD4+ T-cell Counts ......................................69
8.11.3.2
Participants Who Become Pregnant...................................................70
8.11.4
HIV Infection Confirmation ........................................................................70
8.11.5
Participants Who Withdraw Consent...........................................................71
8.11.6
Follow-up Period .........................................................................................71
9
KEY STATISTICAL CONSIDERATIONS ...............................................................73
9.1
Responsibility for Analyses/In-house Blinding .................................................73
9.2
Hypotheses/Estimation ........................................................................................73
9.3
Analysis Endpoints...............................................................................................73
9.3.1
Safety Endpoints..........................................................................................73
9.3.2
Pharmacokinetics Endpoints........................................................................74
9.4
Analysis Populations............................................................................................74
9.4.1
Safety Analysis Population..........................................................................74
9.4.2
PK Analysis Population...............................................................................74
9.5
Statistical Methods...............................................................................................74
9.5.1
Statistical Methods for Safety Analyses ......................................................74
9.5.2
Statistical Methods for Pharmacokinetics Analyses....................................75
9.6
Interim Analyses ..................................................................................................75
9.7
Multiplicity ...........................................................................................................75
9.8
Sample Size and Power Calculations .................................................................75
10
SUPPORTING DOCUMENTATION AND OPERATIONAL 
CONSIDERATIONS.....................................................................................................76
10.1
Appendix 1: Regulatory, Ethical, and Study Oversight Considerations........76
10.1.1
Code of Conduct for Interventional Clinical Trials .....................................76
10.1.2
Financial Disclosure.....................................................................................79
10.1.3
Data Protection.............................................................................................80
10.1.3.1
Confidentiality of Data ......................................................................80
10.1.3.2
Confidentiality of Participant Records...............................................80
10.1.3.3
Confidentiality of IRB/IEC Information............................................81
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10.1.4
Committees Structure...................................................................................81
10.1.4.1
Executive Oversight Committee........................................................81
10.1.4.2
Internal Data Monitoring Committee.................................................81
10.1.5
Publication Policy........................................................................................81
10.1.6
Compliance with Study Registration and Results Posting Requirements ...81
10.1.7
Compliance with Law, Audit, and Debarment ............................................82
10.1.8
Data Quality Assurance ...............................................................................83
10.1.9
Source Documents .......................................................................................83
10.1.10
Study and Site Closure.................................................................................84
10.2
Appendix 2: Clinical Laboratory Tests..............................................................85
10.3
Appendix 3: Adverse Events: Definitions and Procedures for Recording, 
Evaluating, Follow-up, and Reporting...............................................................93
10.3.1
Definitions of Medication Error, Misuse, and Abuse..................................93
10.3.2
Definition of AE ..........................................................................................93
10.3.3
Definition of SAE ........................................................................................94
10.3.4
Additional Events Reported.........................................................................95
10.3.5
Recording AE and SAE ...............................................................................95
10.3.6
Reporting of AEs, SAEs, and Other Reportable Safety Events to the 
Sponsor ........................................................................................................98
10.4
Appendix 4: Medical Device and Drug–Device Combination Products: 
Product Quality Complaints/Malfunctions: Definitions, Recording, and 
Follow-up ............................................................................................................100
10.5
Appendix 5: Contraceptive Guidance..............................................................101
10.5.1
Definitions..................................................................................................101
10.5.2
Contraceptive Requirements......................................................................103
10.6
Appendix 6: Collection and Management of Specimens for Future 
Biomedical Research..........................................................................................104
10.7
Appendix 7: Country-specific Requirements..................................................108
10.8
Appendix 8: Risk Evaluation............................................................................109
10.9
Appendix 9: Calculation of Creatinine Clearance..........................................110
10.10 Appendix 10: Abbreviations .............................................................................111
11
REFERENCES.............................................................................................................116
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LIST OF TABLES
Table 1
Laboratory Exclusion Criteria......................................................................37
Table 2
Study Interventions......................................................................................40
Table 3
Discontinuation Criteria for Specified Decreases in Total Lymphocyte 
Counts or CD4+ T-cell Counts ....................................................................46
Table 4
Study Intervention Administration Schedule...............................................52
Table 5
Reporting Periods and Time Frames for Adverse Events and Other 
Reportable Safety Events.............................................................................58
Table 6
Timepoints for Collection of Plasma MK-8527 Samples (All 
Participants) .................................................................................................62
Table 7
Timepoints for Collection of PBMC Samples (PBMC Subset Only) .........63
Table 8
Timepoints for Collection of Venous Microsampling (Mitra®/VAMS) 
PK Samples (PBMC Subset Only) ..............................................................64
Table 9
Timepoints for Collection of Venous Microsampling (Mitra®/VAMS) 
PK Samples (Participants Not in the PBMC Subset)...................................65
Table 10
Protocol-required Safety Laboratory Assessments......................................85
Table 11
Blood Volumes For Samples Collected From Participants in the United 
States and Israel ...........................................................................................89
Table 12
Blood Volumes for Samples Collected From Participants in South 
Africa ...........................................................................................................91
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LIST OF FIGURES
Figure 1
Study Schema...............................................................................................15
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1
PROTOCOL SUMMARY
1.1
Synopsis
Protocol Title: A Phase 2a, Double-Blind, Placebo-Controlled Study to Evaluate the Safety, 
Tolerability, and Pharmacokinetics of Oral MK-8527 Once Monthly in Participants at Low-
Risk for HIV-1 Infection
Short Title: Safety and Pharmacokinetic Study of Oral MK-8527 QM in Participants at 
Low-Risk for HIV-1 Infection 
Acronym: Not applicable
Hypotheses, Objectives, and Endpoints:
There are no hypotheses to be tested in this study.
The following objectives will be evaluated in adults at low-risk of human immunodeficiency 
virus type 1 (HIV-1) infection.
Primary Objective
Primary Endpoint
To evaluate the safety and tolerability of 
MK-8527 once monthly (3 mg, 6 mg, and 
12 mg) during treatment and through the 
last follow-up visit.
Adverse events
Adverse events leading to discontinuation 
of study intervention
Secondary Objectives
Secondary Endpoints
To characterize the plasma pharmacokinetic 
profile of MK-8527 once monthly (3 mg, 
6 mg, and 12 mg).
MK-8527 AUC0-last and Cmax
Overall Design:
Study Phase
Phase 2
Primary Purpose
Treatment
Indication
HIV infection
Population
Adults at low-risk for HIV-1 infection
Study Type
Interventional
Intervention Model
<<Intervention Model>>
This is a multi site study.
Type of Control
Placebo 
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Study Blinding
Double-blind 
Blinding Roles
Participants or Subjects 
Sponsor 
Investigator
Estimated Duration of Study
The Sponsor estimates that the study will 
require approximately 58 weeks 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 350 participants will be randomized in a 2:2:2:1 ratio to 1 of 4 intervention 
groups: Group 1: MK-8527 (3 mg), N=~100; Group 2: MK-8527 (6 mg), N=~100; Group 3: 
MK-8527 (12 mg), N=~100; Group 4: placebo, N=~50.
Intervention Groups and Duration:
Arm Name
Intervention 
Name
Unit Dose 
Strength(s)
Dosage 
Level(s)
Route of 
Administration
Regimen/
Treatment 
Period
Use
Group 1
MK-8527
3 mg
3 mg QM
Oral
Day 1 to 
Week 20
Test Product
Group 1
Placebo
0 mg
0 mg QM
Oral
Day 1 to 
Week 20
Placebo
Group 2
MK-8527
3 mg
6 mg QM
Oral
Day 1 to 
Week 20
Test Product
Group 2
Placebo
0 mg
0 mg QM
Oral
Day 1 to 
Week 20
Placebo
Group 3
MK-8527
3 mg
12 mg QM
Oral
Day 1 to 
Week 20
Test Product
Group 4
Placebo
0 mg
0 mg QM
Oral
Day 1 to 
Week 20
Placebo
QM=once monthly.
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Total Number of Intervention Groups/Arms
4 intervention groups (3 active, 1 placebo)
Duration of Participation
Participants will be in the study for 
approximately 34 weeks from the time the 
participant provides documented informed 
consent (for the main study) through the 
final contact. After a screening phase of up 
to 45 days (6 weeks), each participant will 
receive 6 once monthly doses of assigned 
intervention with the final dose 
administered at Week 20. All participants 
will complete an 8-week blinded follow-up 
period after the last dose.
Study Governance Committees:
Executive Oversight Committee
Yes 
Data Monitoring Committee
Yes (Internal)
Clinical Adjudication Committee
No 
Study governance considerations are outlined in Appendix 1.
Study Accepts Healthy Participants: Yes
A list of abbreviations is in Appendix 10.
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1.2
Schema
The study design is depicted in Figure 1.
Figure 1
Study Schema
FU W=follow-up week; N=total number of participants in the study; n=number of participants in each 
treatment group; PBMC=peripheral blood mononuclear cells; QM=once monthly.
a A subset of ~20 participants per study intervention group will be included in the PBMC Subset; 
these participants will have additional in-clinic visits as specified in the SoA (Section 1.3.1).
b Participants who discontinue study intervention early will be asked to complete the blinded 
follow-up visits. As per amendment 02, all Sponsor personnel except for a blinded medical 
monitoring team will be unblinded after the last expected Follow-up Week 4 visit.
c Randomization to study intervention will occur at Day 1 and will be stratified by sex (female, male) 
and region (Africa, non-Africa).
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1.3
Schedule of Activities
1.3.1
Schedule of Activities (Main)
Study Period
Screening
Study Intervention (Blinded)
Follow-up (Blinded)f
Notes
All Day 1 procedures are 
predose unless otherwise 
noted. 
Day 2 PK samples must be 
collected 24 hours (±6 hours) 
after the Day 1 dose.
Follow-up Day 1 PK samples 
must be collected 24 hours 
(±6 hours) after the Week 20 
dose.
Visit Number
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
Scheduled Day/Week
Screening
Day 1
Day 2
Week 1a
Week 2a
Week 3a
Week 4
Week 8
Week 12
Week 16
Week 20/
EOTb
Follow-up 
Day 1c
Follow-up 
Week 4c
(Week 24)
Follow-up 
Week 6a,c
(Week 26)
Follow-up 
Week 8c
(Week 28)
Window
≤45 
days
N/A
N/A
±2 days
±7 days
N/A
±7 days ±2 days ±7 days
Administrative Procedures
Informed consent
X
Informed consent marks the 
start of the screening window.
Informed consent for 
FBR
X
Inclusion/exclusion 
criteria
X
X
Participants may be rescreened 
1 time; see Section 8.11.1.2.
Participant 
identification card
X
X
Add randomization number on 
Day 1.
Register study visit in 
IRT
X
X
X
X
X
X
X
Randomization
X
Dispense study 
intervention using IRT 
and administer study 
intervention
X
X
X
X
X
X
Directly observed dosing. Add 
randomization number and 
visit number to the bottles at 
time of dispensing.
Offer condoms and 
lubricant
X
X
X
X
X
X
X
For sexually active 
participants. Document in 
participant chart.
Safety Procedures
Medical history
X
X
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Study Period
Screening
Study Intervention (Blinded)
Follow-up (Blinded)f
Notes
All Day 1 procedures are 
predose unless otherwise 
noted. 
Day 2 PK samples must be 
collected 24 hours (±6 hours) 
after the Day 1 dose.
Follow-up Day 1 PK samples 
must be collected 24 hours 
(±6 hours) after the Week 20 
dose.
Visit Number
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
Scheduled Day/Week
Screening
Day 1
Day 2
Week 1a
Week 2a
Week 3a
Week 4
Week 8
Week 12
Week 16
Week 20/
EOTb
Follow-up 
Day 1c
Follow-up 
Week 4c
(Week 24)
Follow-up 
Week 6a,c
(Week 26)
Follow-up 
Week 8c
(Week 28)
Window
≤45 
days
N/A
N/A
±2 days
±7 days
N/A
±7 days ±2 days ±7 days
HIV infection risk 
evaluation
X
X
X
X
X
X
X
X
X
Document in participant chart. 
Assess as per Inclusion 
Criterion #2 at Screening and 
Day 1 (prior to dose). After 
Day 1, assess changes in risk 
status and PrEP eligibility 
using Appendix 8.
Prior/concomitant 
medication review
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Contraceptive use 
confirmation 
(POCBP only)
X
X
X
X
X
X
X
X
X
Document in participant chart.
Complete physical 
exam
X
Symptom-directed 
physical exam
X
X
X
X
X
X
X
X
X
Vital signs
X
X
X
X
X
X
X
X
X
X
Includes body temperature, 
pulse, respiratory rate, and 
systolic and diastolic blood 
pressure.
Height
X
Weight
X
X
X
X
X
X
X
X
X
AE assessment
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Assess before and after dose on 
Day 1.
AE assessment phone 
call (participants not in 
PBMC Subset)
X
Participants not in the PBMC 
Subset will have this AE 
assessment phone call (no in-
clinic visit is required).
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Study Period
Screening
Study Intervention (Blinded)
Follow-up (Blinded)f
Notes
All Day 1 procedures are 
predose unless otherwise 
noted. 
Day 2 PK samples must be 
collected 24 hours (±6 hours) 
after the Day 1 dose.
Follow-up Day 1 PK samples 
must be collected 24 hours 
(±6 hours) after the Week 20 
dose.
Visit Number
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
Scheduled Day/Week
Screening
Day 1
Day 2
Week 1a
Week 2a
Week 3a
Week 4
Week 8
Week 12
Week 16
Week 20/
EOTb
Follow-up 
Day 1c
Follow-up 
Week 4c
(Week 24)
Follow-up 
Week 6a,c
(Week 26)
Follow-up 
Week 8c
(Week 28)
Window
≤45 
days
N/A
N/A
±2 days
±7 days
N/A
±7 days ±2 days ±7 days
12-lead ECG
X
X
Perform postdose at Week 20. 
Perform at EOT if participant 
discontinues study intervention 
early.
Laboratory Evaluations/Procedures
HIV-1 and HIV-2 
screen
X
X
X
X
X
X
X
X
X
Participants with a positive 
HIV-1/2 screen test will 
require additional testing. See 
Section 8.3.4.1.
HBV and HCV testing
X
Syphilis serologic 
testing
X
Urine GC/CT & 
trichomoniasis testing 
(females only)
X
Urine GC/CT testing 
(males only)
X
PT/INR
X
Serum pregnancy test 
(β-hCG) (POCBP only)
X
Performed by central 
laboratory per local 
regulations. If results are 
inconclusive, additional testing 
and/or verification of medical 
history will be required to 
confirm eligibility.
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Study Period
Screening
Study Intervention (Blinded)
Follow-up (Blinded)f
Notes
All Day 1 procedures are 
predose unless otherwise 
noted. 
Day 2 PK samples must be 
collected 24 hours (±6 hours) 
after the Day 1 dose.
Follow-up Day 1 PK samples 
must be collected 24 hours 
(±6 hours) after the Week 20 
dose.
Visit Number
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
Scheduled Day/Week
Screening
Day 1
Day 2
Week 1a
Week 2a
Week 3a
Week 4
Week 8
Week 12
Week 16
Week 20/
EOTb
Follow-up 
Day 1c
Follow-up 
Week 4c
(Week 24)
Follow-up 
Week 6a,c
(Week 26)
Follow-up 
Week 8c
(Week 28)
Window
≤45 
days
N/A
N/A
±2 days
±7 days
N/A
±7 days ±2 days ±7 days
Urine pregnancy test 
(POCBP only)
X
X
X
X
X
X
X
X
Mandatory and performed 
locally as per local regulations 
and prior to 
administering/dispensing study 
intervention. Do NOT dispense 
study intervention if urine 
pregnancy test is positive. 
Confirm with serum test if 
urine test is positive.
Hematologyd
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
TBNK Panel/CD4+ 
T-cell countd
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Chemistry
X
X
X
X
X
X
X
X
X
X
X
X
X
Creatinine clearance 
calculation (CG)
X
X
X
X
X
X
X
X
X
X
X
X
X
Cystatin-C
X
X
X
X
X
X
X
X
X
X
X
X
X
Pharmacokinetics (All Participants)
Plasma PK sample 
collection(s)
X
X
X
X
Some visits require more than 
1 sample collection. See 
Section 8.6 for additional 
details.
Pharmacokinetics (Participants NOT in the PBMC Subset)
Venous microsampling 
(eg, Mitra®/VAMS)
X
X
X
X
X
See Section 8.6 for additional 
details.
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Study Period
Screening
Study Intervention (Blinded)
Follow-up (Blinded)f
Notes
All Day 1 procedures are 
predose unless otherwise 
noted. 
Day 2 PK samples must be 
collected 24 hours (±6 hours) 
after the Day 1 dose.
Follow-up Day 1 PK samples 
must be collected 24 hours 
(±6 hours) after the Week 20 
dose.
Visit Number
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
Scheduled Day/Week
Screening
Day 1
Day 2
Week 1a
Week 2a
Week 3a
Week 4
Week 8
Week 12
Week 16
Week 20/
EOTb
Follow-up 
Day 1c
Follow-up 
Week 4c
(Week 24)
Follow-up 
Week 6a,c
(Week 26)
Follow-up 
Week 8c
(Week 28)
Window
≤45 
days
N/A
N/A
±2 days
±7 days
N/A
±7 days ±2 days ±7 days
Pharmacokinetics (PBMC Subset)
Participation in the PBMC 
Subset will be optional. 
Participants are from 
preselected sites. Refer to 
operation/laboratory manual 
for sample handling 
requirements.
Informed consent for 
PBMC Subset sample 
collection
X
PBMC collection
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Some visits require more than 
1 sample collection. See 
Section 8.6 for additional 
details.
Venous microsampling 
(eg, Mitra®/VAMS)
X
X
X
X
X
X
X
X
X
X
X
X
X
X
See Section 8.6 for additional 
details
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Study Period
Screening
Study Intervention (Blinded)
Follow-up (Blinded)f
Notes
All Day 1 procedures are 
predose unless otherwise 
noted. 
Day 2 PK samples must be 
collected 24 hours (±6 hours) 
after the Day 1 dose.
Follow-up Day 1 PK samples 
must be collected 24 hours 
(±6 hours) after the Week 20 
dose.
Visit Number
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
Scheduled Day/Week
Screening
Day 1
Day 2
Week 1a
Week 2a
Week 3a
Week 4
Week 8
Week 12
Week 16
Week 20/
EOTb
Follow-up 
Day 1c
Follow-up 
Week 4c
(Week 24)
Follow-up 
Week 6a,c
(Week 26)
Follow-up 
Week 8c
(Week 28)
Window
≤45 
days
N/A
N/A
±2 days
±7 days
N/A
±7 days ±2 days ±7 days
Biomarkers
Blood for genetic 
analysise
X
Collect predose from enrolled 
participants only
AE=adverse event; β-hCG=beta human chorionic gonadotropin; CG=Cockcroft-Gault; CT=chlamydia trachomatis; DNA=deoxyribonucleic acid; ECG=electrocardiogram; 
EOT=End of Treatment; FBR=future biomedical research; GC=Neisseria gonorrhoeae; HBV=hepatitis B virus; HCV=hepatitis C virus; HIV=human immunodeficiency virus; 
IEC=Independent Ethics Committee; INR=International Normalized Ratio; IRB=Institutional Review Board; IRT=Interactive Response Technology; N/A=not applicable; 
PBMC=peripheral blood mononuclear cells; PK=pharmacokinetic; POCBP=participants of childbearing potential; PrEP=pre-exposure prophylaxis; PT=prothrombin time; 
TBNK=T- and B-lymphocyte natural killer cell; VAMS=volumetric absorptive microsampling.
a.
Week 1, 2, and 3, and Follow-up Week 6 are in-clinic visits only for participants in the PBMC Subset. At Week 2, participants not in the PBMC Subset will have an AE 
assessment phone call only (no in-clinic visit is required).
b.
If Visit 11 is performed as an EOT visit prior to Week 20, all procedures listed should be performed but with the following procedure modifications: 1) no study intervention 
should be dispensed via the IRT or administered to the participant, 2) only 1 plasma PK sample should be collected at any time during the visit, and if in the PBMC Subset: 
only 1 PBMC sample and 1 VAMS venous sample should be collected at any time during the visit.
c.
All participants will attend visits at Follow-up Day 1, Follow-up Week 4 and Follow-up Week 8; the PBMC Subset will also have a visit at Follow-up Week 6. Follow-up 
visits represent different study weeks for a participant that completes the final Week 20 dose versus a participant that discontinues study intervention prior to Week 20. See 
Section 8.11.6 for additional details.
d.
Participants with confirmed decreases in total lymphocyte counts or CD4+ T-cell counts as outlined in Section 7.1, will be followed in the study until they no longer meet 
the criteria as outlined in Section 8.11.3.1.
e.
This sample should be drawn for planned analysis of the association between genetic variants in DNA and drug response. This sample will not be collected at that site if 
there is either a local law or regulation prohibiting collection, or if the IRB/IEC does not approve the collection of the sample for these purposes. If the sample is collected, 
leftover extracted DNA will be stored for 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.
f.
As per amendment 02, all Sponsor personnel except for a blinded medical monitoring team will be unblinded after the last expected Follow-up Week 4 visit.
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1.3.2
Schedule of Activities (HIV Infection Confirmation or Early Withdrawal From Study)
Study Period
HIV Infection Confirmationa
Early Withdrawal From Studyb
Notes
Visit Number
Unscheduled
Scheduled Day/Week
HIV Infection Confirmation
Early Withdrawal 
From Study
Visit Window
Within 14 days of 
HIV-positive test
NA
Administrative Procedures
Offer condoms and lubricant
X
For sexually active participants. Document in participant chart.
Register study visit in IRT
X
Safety Procedures
HIV infection risk evaluation
X
X
Document in participant chart. 
Assess any changes in risk status and PrEP eligibility 
(Appendix 8).
Concomitant medication review
X
X
Contraceptive use confirmation (POCBP 
only)
X
X
Document in participant chart. 
Symptom-directed physical exam
X
Vital signs
X
Includes body temperature, pulse, respiratory rate, and systolic 
and diastolic blood pressure
Weight
X
AE assessment
X
X
12-lead ECG
X
Only perform at the Early Withdrawal visit if the participant 
discontinues prior to the Week 20 ECG collection. 
Laboratory Evaluations/Procedures
HIV-1 and HIV-2 screen
X
HIV-1 RNA PCR
X
HIV-1 drug resistance testing
X
Urine pregnancy test (POCBP only)
X
Conduct per local regulations. Positive results to be confirmed 
with serum pregnancy test.
Hematology 
X
X
TBNK Panel/CD4+ T-cell count
X
X
Chemistry
X
Creatinine clearance calculation (CG)
X
Cystatin-C
X
Pharmacokinetics (All participants)
Plasma PK sample collection
X
X
Not required if participant is beyond Follow-up Day 1.
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Study Period
HIV Infection Confirmationa
Early Withdrawal From Studyb
Notes
Visit Number
Unscheduled
Scheduled Day/Week
HIV Infection Confirmation
Early Withdrawal 
From Study
Visit Window
Within 14 days of 
HIV-positive test
NA
Pharmacokinetics (PBMC Subset)
Participants are from preselected sites. Refer to laboratory/study 
operation manual for special collection and processing 
requirements.
PBMC collection
X
X
Venous microsampling 
(eg, Mitra®/VAMS)
X
X
AE=adverse event; CG=Cockcroft-Gault; ECG=electrocardiogram; HIV=human immunodeficiency virus; IRT=Interactive Response Technology; PBMC=peripheral blood 
mononuclear cells; PCR=polymerase chain reaction; PK=pharmacokinetic; POCBP=participants of childbearing potential; PrEP=pre-exposure prophylaxis; RNA=ribonucleic 
acid; TBNK=T- and B-lymphocyte natural killer cell; VAMS=volumetric absorptive microsampling.
a.
For any participant who has a positive HIV-1 or HIV-2 screen test, this visit should be conducted within 14 days of the positive result per Section 8.11.4.
b.
If a participant receives the final Week 20 dose of study intervention and then withdraws from the study, an “Early Withdrawal from Study” visit should be performed as the 
final study visit. See Section 8.11.5 for additional details.
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2
INTRODUCTION
MK-8527 is a novel deoxyadenosine analog with potent antiviral activity being developed for 
the prevention of HIV-1 infection.
2.1
Study Rationale
HIV-1 infection remains a worldwide epidemic with an estimated 38.4 million individuals 
infected globally at the end of 2021 [World Health Organization 2022]. Additional strategies 
to prevent HIV acquisition could help reduce the global burden. One proven biomedical 
intervention for the prevention of HIV-1 infection is PrEP. Although FTC/TDF and 
FTC/TAF have been approved in some countries for PrEP, approximately 1.5 million new 
HIV-1 infections occurred worldwide in 2021 [World Health Organization 2022]. 
Approximately 26 million individuals living with HIV at the end of 2021 were in the WHO 
African Region [World Health Organization 2022]. In this region, South Africa has a 
population of 32 million aged 15 to 49 years, of which ~18% were living with HIV in 2022 
[Joint United Nations Programme on HIV/AIDS 2023]. HIV is a chronic infection requiring 
life-long treatment and is associated with risks for multiple complications. The ongoing 
epidemic, fueled by more than 1 million new cases annually, results in a growing collective 
care burden. The efficacy of FTC/TDF for PrEP is strongly correlated with adherence to 
daily therapy [O Murchu, E., et al 2022]. However, adherence to daily therapy is suboptimal 
in many people at risk of HIV-1 infection [Hojilla, J. C., et al 2021].
MK-8527 is characterized by high potency and a long half-life. Because of the long 
intracellular half-life (~94 to 291 hours across doses in Phase 1 studies) of the active form of 
MK-8527 (MK-8527-TP), a QM dosing regimen is being investigated. A QM dosing 
schedule is anticipated to facilitate adherence, improve discretion, and be highly effective in 
preventing HIV-1 acquisition.
This Phase 2a study will evaluate the safety, tolerability, and PK of oral MK-8527 QM 
compared with placebo in adults at low-risk of HIV-1 infection. Results from this study, 
along with data from completed Phase 1 studies, will be used to select a QM dose of oral 
MK-8527 to be evaluated as PrEP in efficacy studies.
2.2
Background
Refer to the IB for detailed background information on MK-8527.
2.2.1
Pharmaceutical and Therapeutic Background
MK-8527 is a novel deoxyadenosine analog with antiretroviral activity that is being 
developed for the prevention of HIV-1 infection. The parent drug MK-8527 is converted 
intracellularly to its active triphosphate form, MK-8527-TP, which is a specific inhibitor of 
HIV-1 RT. In contrast to other approved NRTIs (AZT, TDF, FTC, and 3TC) with IC50 values 
>2.5 nM, MK-8527 is more potent with an in vitro IC50 of 0.21 nM. MK-8527 was 
comparable to TFV, ZDV, ABC, FTC, and 3TC in antiviral activity against isolates from 
11 commonly occurring HIV subtypes (based on the Phenosense® assay in HEK293 cells). 
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However, MK-8527 had an 11-fold decrease in potency against HIV subtypes with the 
M184V/I mutation.
 
 
 
 
The plasma half-life of MK-8527 was approximately 36 to 62 hours after single doses of 10, 
25, 50, 100, 150, and 200 mg (MK-8527 P001) and approximately 44 to 81 hours after 
multiple doses of 10, 20, and 40 mg (MK-8527 P003). The half-life of MK-8527-TP in 
PBMCs was approximately 94 to 266 hours in MK-8527 P001 and approximately 216 to 291 
hours in MK-8527 P003.
The antiretroviral activity of MK-8527 was evaluated in a Phase 1 open-label proof-of 
concept study in treatment-naïve participants with HIV-1 (MK-8527 P002). Antiretroviral 
activity following a single dose of MK-8527 (1 mg, 3 mg, or 10 mg) was assessed based on a 
mean HIV-1 viral load reduction of ≥1.0 log10 copies/mL at 7 days postdose. Participants 
receiving either a 3 mg or 10 mg dose of MK-8527 achieved a mean viral load reduction of 
1.63 log10 copies/mL and 1.36 log10 copies/mL, respectively, at 7 days postdose. 
Additionally, 11/12 participants receiving either 3 mg or 10 mg of MK-8527 achieved a viral 
load reduction of >1.0 log10 copies/mL at 7 days postdose. A single 1 mg dose of MK-8527 
led to a mean viral load reduction of 0.92 log10 copies/mL. Of the 5 participants who 
received the 1 mg dose, 2 did not achieve the >1.0 log10 copies/mL due to unknown reasons; 
the lack of response in these 2 participants was not due to appearance of mutant strains. 
Because of the inconsistent results at the 1 mg dose, a second proof-of-concept study (P004) 
was conducted. In MK-8527 P004 in treatment-naïve participants with HIV-1, single doses 
of MK-8527 (1 mg or 0.5 mg) achieved a mean HIV-1 viral load reduction of ≥1.0 log10 
copies/mL at 7 days postdose (see additional details in Section 4.3).
Overall, the PK properties of MK-8527, along with nonclinical and clinical data for 
MK-8527, support QM dosing.
 
 
 MK-8527 has a low 
potential to be a perpetrator of drug-drug interactions mediated by these transporters.
2.3
Benefit/Risk Assessment
It cannot be guaranteed that participants in clinical studies will directly benefit from 
participation, as clinical studies are designed to provide information about the safety and 
effectiveness of an investigational medicine. For this study, MK-8527 is being developed for 
CCI
CCI
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the prevention of HIV-1 infection; direct individual benefit to participants is minimal as 
participants in this study are neither HIV-1-infected nor at high risk of infection.
There remains significant unmet medical need for highly effective and well tolerated ART 
for PrEP that does not require daily dosing. High potency against wild-type HIV-1 and a long 
half-life make MK-8527 a suitable candidate for further development as a long-acting PrEP 
agent. Comprehensive nonclinical safety evaluation of MK-8527, including hematological 
and developmental toxicity studies, have not revealed toxicities of concern at the dose levels 
being evaluated in this study. MK-8527 demonstrated antiretroviral activity in the Phase 1 
study MK-8527 P002, with single 3 mg and 10 mg doses achieving the target reduction in 
viral load of 1.0 log10 copies/mL at 7 days postdose in treatment-naïve HIV-1 positive 
participants. MK-8527 has also demonstrated antiretroviral activity in an ongoing Phase 1 
study MK-8527 P004, with single 1 mg and 0.5 mg doses achieving the target reduction in 
viral load of 1.0 log10 copies/mL at 7 days postdose in treatment-naïve HIV-1 positive 
participants.
MK-8527 has been evaluated in 3 completed Phase 1 studies (P001, P002, P003) in 
56 healthy adult participants and 17 treatment-naïve adult participants with HIV-1. An 
additional 14 treatment-naïve adult participants have received MK-8527 in the ongoing 
Phase 1 study MK-8527 P004. Single doses of up to 200 mg and multiple doses up to 40 mg 
of MK-8527 have been generally well tolerated in the 3 completed studies. All drug-related 
AEs were mild to moderate in severity and resolved by the end of each study. No SAEs, 
deaths, or events of clinical interest were observed. Three participants discontinued study 
intervention due to an AE, none of which were considered related to MK-8527. No dose-
related changes in ECGs, vital signs, and laboratory test values were observed. The most 
frequently reported AEs were headache and nasopharyngitis.
MK-8527 is in the same antiretroviral class as ISL (MK-8591), an NRTI currently in 
development for the treatment of HIV-1 infection. Exposure/dose-dependent decreases in 
total lymphocyte and lymphocyte subset counts were observed in clinical studies with ISL. 
The risk of lymphocyte decreases for MK-8527 at the proposed doses is considered low 
based on available nonclinical and clinical data. In 3 completed Phase 1 studies, no AEs 
associated with lymphocyte reductions were observed, and mean lymphocyte counts were 
unchanged in both the single- and multiple-ascending dose studies. In the present study, 
hematology (including lymphocyte subsets) will be closely monitored; participants who meet 
predefined discontinuation criteria for total lymphocyte and CD4+ T-cell counts will be 
discontinued from study intervention.
Additional details regarding specific benefits and risks for participants participating in this 
clinical study may be found in the accompanying IB and informed consent documents.
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3
HYPOTHESES, OBJECTIVES, AND ENDPOINTS
There are no hypotheses to be tested in this study.
The following objectives will be evaluated in adults at low-risk of human immunodeficiency 
virus type 1 (HIV-1) infection.
Primary Objective
Primary Endpoint
To evaluate the safety and tolerability of 
MK-8527 once monthly (3 mg, 6 mg, and 
12 mg) during treatment and through the 
last follow-up visit.
Adverse events
Adverse events leading to discontinuation 
of study intervention
Secondary Objective
Secondary Endpoint
To characterize the plasma pharmacokinetic 
profile of MK-8527 once monthly (3 mg, 
6 mg, and 12 mg).
MK-8527 AUC0-last and Cmax
Tertiary/Exploratory Objectives
Tertiary/Exploratory Endpoints
To explore a relationship between 
intracellular MK-8527-MP, MK-8527-DP, 
and MK-8527-TP levels
PBMC MK-8527-MP, MK-8527-DP, and 
MK-8527-TP: AUC0-last, Cmax, Ctrough, 
concentrations at common time points
To characterize the intracellular 
pharmacokinetic profile of MK-8527-TP in 
peripheral blood mononuclear cells up to 8 
weeks after the last dose of MK-8527 once 
monthly (3 mg, 6 mg, and 12 mg).
MK-8527-TP AUC0-last, Ctrough, Cmax, and 
t1/2
To explore the relationship between genetic 
variation and response to study intervention, 
and mechanisms of disease. Variation 
across the human genome may be analyzed 
for association with the pharmacokinetic 
and safety 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 randomized, double-blind, placebo-controlled, parallel-group, multicenter study of 
oral MK-8527 administered QM in adults who are at low-risk of HIV-1 infection.
Approximately 350 participants will be randomized in a 2:2:2:1 ratio to 1 of 4 intervention 
groups: Group 1: MK-8527 (3 mg); Group 2: MK-8527 (6 mg); Group 3: MK-8527 (12 mg); 
and Group 4: Placebo. The screening window is 45 days and participants are allowed to 
rescreen 1 time (Section 8.11.1.2). The study population composition targets are: 30% 
women, 30% men, 80% aged 35 years, and 30% enrolled in Africa. Randomization will 
be stratified by sex (female, male) and region (Africa, non-Africa). 
Participants will receive a total of 6 oral doses of the assigned blinded study intervention, 
1 dose every 4 weeks, starting on Day 1. The final dose will be administered at the Week 20 
visit. After the last dose, all participants will complete an 8-week blinded follow-up period. 
The primary safety assessment will include all accumulated safety data during the 
intervention and follow-up period. AEs leading to discontinuation from study intervention 
will be assessed until Week 20 (last dose received). The Sponsor will perform an ongoing 
comprehensive review of safety parameters to assess for overall trends and outliers in 
reported AEs and event toxicities per standard monitoring procedures. 
All participants will be evaluated for plasma MK-8527 PK drug levels, and a subset 
(approximately N=20 participants per intervention group) will be evaluated for MK-8527-TP 
in PBMC (PBMC Subset).
All participants and the investigators/clinical site personnel directly associated with study 
conduct will remain blinded to study intervention assignment through the 8-week follow-up 
period. The siDMC (internal) will be responsible for an interim safety review once 50% of 
the planned enrollment has reached Week 12 or discontinued from study intervention. 
Additional meetings of the siDMC may be triggered based on criteria outlined in the 
SAP/siDMC charter. An unblinded Sponsor team will review PK and safety data on an 
ongoing basis for the duration of the study. As per amendment 02, all Sponsor personnel 
except for a blinded medical monitoring team will be unblinded after the last expected 
Follow-up Week 4 visit, to enable earlier program strategic decision-making by the Sponsor.   
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
The main objectives of this study are to characterize the safety, tolerability, and PK of 
MK-8527 in a larger and more diverse population than studied to date. The study will enroll 
participants who are not infected with HIV-1 and are at low-risk of HIV-1 infection. 
According to CDC and WHO guidelines [Centers for Disease Control and Prevention 2018] 
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[World Health Organization 2015], persons who are at substantial risk of HIV-1 infection 
should be referred for local HIV prevention services that may include PrEP, for which there 
are approved products (FTC/TDF, FTC/TAF, or cabotegravir IM). 
Population PK predictions based on clinical data to date indicate that MK-8527 6 mg to 8 mg 
QM will achieve threshold levels against wild-type virus for HIV-1 prevention that would 
last at least 4 weeks. Participants will be followed for 8 weeks after the last dose of MK-8527 
to allow for full characterization of the MK-8527-TP PK profile.
The number of participants (N=~350), the inclusion of a placebo group, and the 6 QM doses 
allow for characterization of the safety profile of MK-8527 before the initiation of Phase 3 
prevention efficacy studies. To ensure a study population that is representative of individuals 
most at risk for HIV-1 infection and corresponding to the demographics for the target 
population of the Phase 3 efficacy studies, the study population will comprise 30% women, 
30% men, 80% of participants aged 35 years, and 30% enrolled in Africa.
4.2.1
Rationale for Endpoints
Efficacy is not being evaluated in this study.
4.2.1.1
Safety Endpoints
The primary safety endpoints are the number of participants experiencing AEs and the 
number of participants discontinuing study intervention due to AEs. Safety evaluations will 
include physical examinations (including vital signs) and laboratory tests performed per the 
SoA (Section 1.3). AEs will be evaluated at each visit and assessed according to the 
guidelines in Section 8.4. Participants may be asked to return for unscheduled visits in order 
to perform additional safety monitoring.
Dose-dependent decreases in total lymphocyte and lymphocyte subset counts were observed 
in clinical studies with ISL, another investigational NRTI agent. The risk of lymphocyte 
decreases for MK-8527 at the proposed doses is considered low based on available 
nonclinical and clinical data. To further assess the risk, hematology with lymphocyte subset 
counts will be monitored, in conjunction with MK-8527 in plasma and MK-8527-TP in 
PBMC measurements to allow correlation with any dose-related effects. 
In this study, criteria for discontinuation of study intervention for confirmed on-treatment 
decreases of total lymphocyte count <1000 cells/mm3 or CD4+ T-cell count <500 cells/mm3
are based on literature that identifies an increased frequency of infections or increased risk of 
infections when cell counts drop below these levels, whether caused by disease (eg, HIV 
infection, systemic lupus erythematosus, rheumatoid arthritis) or by disease-modifying drugs 
[Giovannoni, G., et al 2018] [Spiezia, A. L., et al 2022] [Merayo-Chalico, J., et al 2013] 
[Subesinghe, S., et al 2020] [Warny, M., et al 2018], and DAIDS criteria (Version 2.1, July 
2017) [National Institute of Allergy and Infectious Diseases 2017]. In addition, 
discontinuation requires a confirmed ≥30% decrease from baseline in either total 
lymphocytes or CD4+ T-cell counts (Table 3) so that participants whose baseline total 
lymphocyte counts or CD4+ T-cell counts are just above the discontinuation thresholds are 
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not discontinued for laboratory findings that are within the natural variability of these tests. A 
30% decrease was chosen based on published literature demonstrating that lymphocyte 
counts vary as much as 25% in healthy adults when measured as frequently as day-to-day 
and over longer periods of time (every 6 months for many years) [Aziz, N., et al 2019] [Aziz, 
N., et al 2019a] [Statland, B. E., et al 1978].
Studies have shown that impaired kidney function (usually mild or moderate) may occur in a 
small proportion of people on FTC/TDF for PrEP, especially if they have other risk factors 
such as older age, diabetes mellitus, preexisting chronic kidney disease, and acute or chronic 
liver disease [Tetteh, R. A., et al 2017] [Wyatt, C. M., et al 2006] [Nadkarni, G. N., et al 
2015]. This study provides the opportunity to evaluate the impact of MK-8527 on renal 
function as measured by serum analytes and calculations (eg, creatinine, cystatin-C, CrCl).
4.2.1.2
Pharmacokinetic Endpoints
Plasma samples (sparse) will be collected from all participants during the study. PK data will 
be used for building a population PK model for MK-8527 and MK-8527-TP.
4.2.1.2.1
PBMC Subset
The PBMC data collected from participants in the PBMC Subset will be used to build a 
population PK model for MK-8527 and MK-8527-TP. Sparse PBMC data from this study 
will be pooled with sparse PBMC data from Phase 1 studies to build a population PK model. 
The Mitra®/VAMS venous PK samples will not be used to evaluate doses of MK-8527, but 
to establish a correlation between this sampling method with more standard in-clinic PK 
sample collection methods (venipuncture) for potential use in future studies.
4.2.1.3
Planned Exploratory Biomarker Research
4.2.1.3.1
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.
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In addition to studying variation across the human genome, variation across the human 
genome may be analyzed for association with the PK and safety data collected in this study.
4.2.1.4
Future Biomedical Research
The Sponsor will conduct FBR on DNA specimens for which consent was provided during 
this clinical study.
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 participants receive the correct dose of the 
correct drug/vaccine at the correct time. The details of FBR are presented in Appendix 6.
4.2.2
Rationale for the Use of Placebo
The primary objective of the study is to evaluate the safety and tolerability of oral MK-8527 
in a population with low-risk of HIV-1-infection. A placebo-control is being used to allow 
for a robust, unbiased evaluation of the safety and tolerability profile of MK-8527.
4.2.3
Rationale for Collecting Race and Ethnicity
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 people [Burger, D., et al 2005]. As another example, among people living with 
HIV in the United States, 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].
4.2.4
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 safety and toxicity in the transgender population.
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4.3
Justification for Dose
In MK-8527 P002, a Phase 1 proof-of-concept study in treatment-naïve participants with 
HIV-1, antiretroviral activity following a single dose of MK-8527 (1 mg, 3 mg, or 10 mg) 
was assessed based on a mean HIV-1 viral load reduction of ≥1.0 log10 copies/mL at 7 days 
postdose. Participants receiving either a 3 mg or 10 mg dose of MK-8527 achieved a mean 
viral load reduction of 1.63 log10 copies/mL and 1.36 log10 copies/mL, respectively, at 
7 days postdose. Additionally, 11/12 participants receiving either 3 mg or 10 mg of MK-8527 
achieved a viral load reduction of >1.0 log10 copies/mL at 7 days postdose. A single 1 mg 
dose of MK-8527 led to a mean viral load reduction of 0.92 log10 copies/mL. Of the 5 
participants who received the 1 mg dose, 2 did not achieve the >1.0 log10 copies/mL due to 
unknown reasons; the lack of response in these 2 participants was not due to appearance of 
mutant strains.
A single 1 mg dose of MK-8527 is being re-evaluated in a second Phase 1 proof-of-concept 
study (MK-8527 P004) in treatment-naïve participants with HIV-1 and preliminary results 
are available from this study for the single dose of 1 mg and 0.5 mg. Seven of 8 participants 
receiving a single 1 mg dose of MK-8527 achieved a viral load reduction of >1 log10 
copies/mL at 7 days postdose, with the eighth participant achieving a reduction of 0.98 log10 
copies/mL. The mean viral load decline at 7 days postdose for the 1 mg dose was 1.38 log10. 
Based on these results, the 0.5 mg dose was evaluated with all 6 participants who received 
the dose achieving a viral load reduction of ≥1.0 log10 copies/mL at 7 days postdose. The 
mean viral load decline at 7 days postdose was 1.39 log10. The results for both doses suggest 
similar efficacy was achieved for both the 1 mg and 0.5 mg doses.
The viral load data from P002 and P004, along with PK (MK-8527-TP C168) data for doses 
studied in P002 (1 mg, 3 mg, and 10 mg) and P004 (1 mg and 0.5 mg) were used to construct
an exposure-response model. From the analysis, the threshold of MK-8527-TP 0.03 pmol/106
cells is predicted to achieve efficacy against wild-type HIV-1 virus. At the threshold of 
MK-8527-TP 0.03 pmol/106 cells, a >1.0 log drop in viral load is projected in a treatment 
naive population. This threshold represents an IQ (inhibitory quotient), defined as the ratio of 
Ctrough and the in vitro IC50, of ~3.
Although the selected threshold of 0.03 pmol/106 cells is predicted to achieve efficacy 
against the wild-type HIV-1 virus, the threshold is not anticipated to maintain efficacy 
against the M184V/I variant. Transmission rates are low for NRTI mutants, likely because of 
reduced replicative fitness. Surveillance data of transmitted drug resistance have been 
collected for several years. While the prevalence of various mutations varies over time and 
by geography, these surveys consistently show that transmission of NRTI mutants is low
[Chimukangara, B., et al 2019] [Rhee, S. Y., et al 2020]. For M184V/I, globally these rates 
are <1% [McClung, R. P., et al 2022].
 
 
CCI
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A preliminary Phase 1 population PK model was developed to determine the doses that 
would achieve the efficacy threshold defined above. Based on this model, a ≥6 mg QM dose 
of MK-8527 should provide efficacy in >90% of the population based on the threshold of 
0.03 pmol/106 cells. The 3 mg dose, despite being projected to be a suboptimal dose based on 
current data, would help characterize PK at a lower dose, allowing for any future refinements 
of the current projected efficacious dose based on subsequent lower dose panels of MK-8527 
being studied in P004 and further refinement of the population PK model. The third dose 
evaluated in this study (12 mg QM) is 2-fold higher than the projected efficacious dose and 
will help provide safety and tolerability data in the Phase 2 study. In addition, the 12 mg dose 
will provide PK data at a dose >6 mg to help refine a potential Phase 3 dose and will 
potentially help to cover effects due to intrinsic and extrinsic factors. The dose of MK-8527 
for Phase 3 may be interpolated from the 3 doses evaluated in this study.
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.
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 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 as described in Appendix 1.10.
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5
STUDY POPULATION
Participants between the ages of 18 and 65 years (inclusive) 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 confirmed HIV-uninfected based on negative HIV-1/HIV-2 test result before 
randomization (completed by the central laboratory).
Note: Additional testing to confirm suspected HIV infection during screening will be 
performed in accordance with local guidelines. If HIV infection is confirmed, the 
participant is not eligible for the study and will be referred for appropriate care, as 
necessary.
2. Has low-risk of HIV infection, defined as all of the following within 12 months prior to 
the screening visit or the rescreening visit (if applicable) (based on self-report by 
participant or medical history [if available]):
•
No anal or vaginal intercourse with someone known to be HIV-infected or of 
unknown HIV infection status who is at increased risk of HIV infection (see 
Appendix 8);
•
No stimulant use (cocaine [including crack], methamphetamine, or non-physician 
prescribed pharmaceutical-grade stimulants) or inhaled nitrate;
•
No illicit injection drug use of any kind;
•
No new diagnosis of an STI such as GC, CT, incident syphilis, or trichomoniasis;
•
Not greater than 3 different sexual partners for receptive or insertive vaginal or anal 
sex; and,
•
No history of antiretrovirals for HIV-1 PrEP or PEP.
Note: Individuals who have participated in studies of an antiretroviral, such as Phase 1 
studies (excluding MK-8527 and MK-8591), may be eligible after consultation with the 
Sponsor.
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Demographics
3. Is an individual of any sex/gender, from 18 years to 65 years of age inclusive, at the time 
of providing the informed consent.
Male Participants
Note: Contraceptive use by male participants should be consistent with local regulations 
regarding the methods of contraception for those participating in clinical studies.
Female Participants
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 8 weeks 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 a urine test) or 72 hours (for a 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 8.3.5.
-
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.
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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 hypersensitivity or other contraindication to any of the components of the study 
interventions as determined by the investigator.
2. Has an active diagnosis of hepatitis due to any cause, including active HBV infection 
(defined as HbsAg-positive) or HCV infection (defined as detectable HCV RNA).
Note: Past HBV infection or previous HBV vaccination (defined as HbsAg-negative and 
positive for antibody against HbsAg), or prior/inactive HCV infection (defined as 
undetectable HCV RNA) are not exclusionary.
3. Has a history of malignancy ≤5 years prior to signing informed consent except for 
adequately treated basal cell or squamous cell skin cancer or in situ cervical cancer.
4. Has a history or current evidence of any condition, 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
5. Is taking or is anticipated to require systemic immunosuppressive therapy, immune 
modulators, or any prohibited therapies outlined in Section 6.5 from 60 days prior to 
Day 1 through the duration of the study.
Note: Time-limited courses of corticosteroids (eg, for asthma exacerbation) and topical 
agents are allowed.
Prior/Concurrent Clinical Study Experience
6. Is currently participating in or has participated in an interventional clinical study with an 
investigational compound or device within 30 days prior to Day 1 (60 days if the 
investigational compound falls into the category outlined above in criterion #5) through 
the duration of the study.
Note: Concurrent participation in observational or noninterventional studies may be 
permitted and should be discussed with the Sponsor before enrollment and through study 
duration.
7. Has previously received MK-8527 or MK-8591.
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Diagnostic Assessments
8. Has QTc intervals (using Fridericia correction) >450 msec (for males) or >460 msec (for 
females) or an ECG finding deemed clinically abnormal by the investigator.
9. Has exclusionary laboratory values within 45 days prior to Day 1 as listed in Table 1.
Note: Chemistry, hematology, and CD4+ T-cell count parameters that meet the exclusion 
criteria may be repeated once during the screening period.
Table 1
Laboratory Exclusion Criteria
Laboratory Assessment
Exclusionary Values
Hemoglobin 
<10.5 g/dL for females and <11 g/dL for males
Lymphocyte 
<1000 cells/mm3
CD4+ T-cell Count 
<500 cells/mm3 
Absolute neutrophil count 
<1000 cells/mm3
Platelet count 
<125,000/mm3
Calculated creatinine clearance 
<90 mL/minute using the Cockcroft-Gault equation (Appendix 9)
Albumin
≤3.5 g/dL
INR
≥1.7
ALT
≥1.25 × ULN
AST 
≥1.25 × ULN
Total bilirubin 
>ULN unless history of Gilbert’s disease (If Gilbert’s disease is 
the proposed etiology, this must be documented in the 
participant’s chart)
ALT=alanine aminotransferase; AST=aspartate aminotransferase; INR=International Normalized Ratio; ULN=upper 
limit of normal.
Other Exclusions
10. Is or has an immediate family member (eg, spouse, parent/legal guardian, sibling, or 
child) who is investigational site or Sponsor staff directly involved with this study.
5.3
Lifestyle Considerations
Participants who are sexually active should be counseled on safer sex practices to prevent 
acquisition of HIV or other STIs.
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.
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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 will be packaged to support enrollment. Clinical supplies will be affixed 
with a clinical label in accordance with regulatory requirements. Administration of study 
intervention will be witnessed by the investigator and/or study staff.
6.1
Study Intervention(s) Administered
The study intervention(s) to be used in this study are outlined in Table 2.
At each monthly dosing visit, 4 bottles of blinded study intervention will be dispensed per 
participant, each containing 1 capsule (MK-8527 or placebo). All participants will take a 
total of 4 capsules for the assigned dose as follows:
•
Group 1 (MK-8527 3 mg): Participants will receive 1 capsule of MK-8527 (3 mg) and 
3 capsules of matching placebo.
•
Group 2 (MK-8527 6 mg): Participants will receive 2 capsules of MK-8527 (3 mg) and 
2 capsules of matching placebo.
•
Group 3 (MK-8527 12 mg): Participants will receive 4 capsules of MK-8527 (3 mg).
•
Group 4 (Placebo): Participants will receive 4 capsules of matching placebo.
All 4 capsules should be swallowed within ~5 minutes. The exact time of dosing, for each 
bottle, must be documented and reported on the study medication eCRF.
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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
Regimen/
Treatment 
Period
Use
IMP or 
NIMP/
AxMP
Sourcing
Group 1
Experimental MK-8527
Drug
Capsule
3 mg
3 mg QM
Oral
Day 1 to 
Week 20
Test 
Product
IMP
Central
Group 1
Experimental Placebo
Drug
Capsule
0 mg
0 mg QM
Oral
Day 1 to 
Week 20
Placebo IMP
Central
Group 2
Experimental MK-8527
Drug
Capsule
3 mg
6 mg QM
Oral
Day 1 to 
Week 20
Test 
Product
IMP
Central
Group 2
Experimental Placebo
Drug
Capsule
0 mg
0 mg QM
Oral
Day 1 to 
Week 20
Placebo IMP
Central
Group 3
Experimental MK-8527
Drug
Capsule
3 mg
12 mg QM Oral
Day 1 to 
Week 20
Test 
Product
IMP
Central
Group 4
Placebo 
Comparator
Placebo
Drug
Capsule
0 mg
0 mg QM
Oral
Day 1 to 
Week 20
Placebo IMP
Central
EEA=European Economic Area; IMP=investigational medicinal product; NIMP/AxMP=noninvestigational/auxiliary medicinal product; QM=once monthly.
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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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.
Refer to Section 8.1.8 for details regarding administration of the study intervention.
All placebos were created by the Sponsor to match the active product.
6.2
Preparation/Handling/Storage/Accountability
6.2.1
Dose Preparation
There are no specific calculations or evaluations required to be performed in order to 
administer the proper dose to each participant. The rationale for selection of doses to be used 
in this study is provided in Section 4.3.
6.2.2
Handling, Storage, and Accountability
The investigator or designee must confirm appropriate temperature conditions have been 
maintained during transit for all study intervention received, and any discrepancies are 
reported and resolved before use of the study intervention.
Only participants enrolled in the study may receive study intervention, and only authorized 
site staff may supply or administer study intervention. All study interventions must be stored 
in a secure, environmentally controlled, and monitored (manual or automated) area in 
accordance with the labeled storage conditions with access limited to the investigator and 
authorized site staff.
The investigator, institution, or the head of the medical institution (where applicable) is 
responsible for study intervention accountability, reconciliation, and record maintenance (ie, 
receipt, reconciliation, and final disposition records).
For all study sites, the local country Sponsor personnel or designee will provide appropriate 
documentation that must be completed for drug accountability and return, or local discard 
and destruction if appropriate. Where local discard and destruction is appropriate, the 
investigator is responsible for ensuring that a local discard/destruction procedure is 
documented.
The study site is responsible for recording the lot number, manufacturer, and expiry date for 
any locally purchased product (if applicable) as per local guidelines unless otherwise 
instructed by the Sponsor.
The investigator shall take responsibility for and shall take all steps to maintain appropriate 
records and ensure appropriate supply, storage, handling, distribution, and usage of study 
interventions in accordance with the protocol and any applicable laws and regulations.
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6.3
Measures to Minimize Bias: Randomization and Blinding
6.3.1
Intervention Assignment
Intervention randomization will occur centrally using an IRT system. There are 4 study 
intervention arms. Participants will be assigned randomly in a 2:2:2:1 ratio to MK-8527 
(3 mg), MK-8527 (6 mg), MK-8527 (12 mg), or placebo, respectively.
6.3.2
Stratification
Intervention randomization will be stratified according to the following factors:
1. Sex (female, male) (as assigned at birth)
2. Region (Africa, non-Africa)
The effects of study interventions may differ between these subgroups of sex and region. 
Therefore, sex and region are selected as the stratification factors to ensure that intervention 
groups will be well-balanced, and the effects of study interventions will not be confounded 
by those demographic characteristics.
6.3.3
Blinding
A double-blinding technique with in-house blinding will be used. The participant, the 
investigator, and Sponsor personnel or delegate(s) who are involved in the study intervention 
administration or clinical evaluation of the participants are unaware of the intervention 
assignments. MK-8527 and matching placebo will be packaged identically so that blinding is 
maintained.
All participants and study-site personnel directly associated with study conduct will remain 
blinded to study intervention assignment through Follow-up Week 8. 
Two in-house teams of Sponsor personnel will be unblinded and will have access to 
treatment group assignments throughout the study duration:
•
The unblinded clinical review team consisting of roles including but not limited to a 
clinical director, clinical scientist, statistician, and statistical programmer. This team will 
be responsible for an ongoing review of safety data, such as reported AEs, and laboratory 
data.
•
The PK personnel responsible for population PK modeling.
The Sponsor’s internal processes and procedures will be followed for documentation and 
handling of unblinded data by the unblinded Sponsor personnel. As per amendment 02, all 
Sponsor personnel except for a blinded medical monitoring team will be unblinded after the 
last expected Follow-up Week 4 visit, to enable earlier program strategic decision-making by 
the Sponsor.
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See Section 8.1.10 for a description of the method of unblinding a participant during the 
study should such action be warranted. Refer to the study binder for more details on the 
unblinding procedure.
6.4
Study Intervention Compliance
Interruptions from the protocol-specified treatment ≥1 monthly dose require consultation 
between the investigator and the Sponsor and written documentation of the collaborative 
decision on participant management.
When participants are dosed at the site, they will receive study intervention directly from the 
investigator or designee, under medical supervision. The date and time of each dose 
administered in the clinic will be recorded in the source documents and recorded in the CRF. 
6.5
Concomitant Therapy
Medications specifically prohibited in the exclusion criteria are not allowed during the 
ongoing study or during time periods specified by this protocol for that medication. If there is 
a clinical indication for any medications specifically prohibited, discontinuation from study 
intervention may be required. The investigator should discuss any questions regarding this 
with the Sponsor Clinical Director. The final decision on any supportive therapy rests with 
the investigator and/or the participant’s primary physician. However, the decision to continue 
the participant on study intervention requires the mutual agreement of the investigator, the 
Sponsor, and the participant.
The following are specific restrictions for prior and concomitant therapies not permitted for 
all participants:
•
Investigational agents (including devices, but not including compounds covered below), 
except for study intervention(s), from 30 days before receiving study intervention through 
the study duration. 
Note: Participants are not permitted to enroll in a study of an investigational compound 
or investigational device during the entire study duration. Participants that discontinue 
study intervention early should refrain from enrolling in a study of an investigational 
compound or investigational device until at least 8 weeks from the last dose of study 
intervention in this study.
•
Immune therapy agents, immune modulators, or other immunosuppressive therapies 
(ie, compounds that may affect lymphocyte counts), from 60 days before receiving study 
intervention through the study duration.
Note: Time-limited courses of corticosteroids (eg, for asthma exacerbation) and topical 
agents are allowed.
Note: Compounds with long half-lives (ie, 14 days) should be discussed with the 
Sponsor prior to participant enrollment.
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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.
There are no restrictions identified for MK-8527 at this time.
6.5.1
Rescue Medications and Supportive Care
No rescue or supportive medications are specified for use in this study.
6.6
Dose Modification
A participant’s dose will not be modified during the study.
Decisions to temporarily withhold study intervention dosing because of an AE will be 
reviewed on a case by-case basis by the investigator. Interruptions from the protocol-
specified dosing plan require consultation between the site and the Sponsor, and written 
documentation of the collaborative decision on participant management.
6.7
Intervention After the End of the Study
There is no study-specified intervention following the end of the study; no poststudy ART 
will be provided.
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.
See Section 8.1.10 for a description of the method of unblinding a participant during the 
study, should such action be warranted.
6.9
Standard Policies
Not applicable.
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7
DISCONTINUATION OF STUDY INTERVENTION AND PARTICIPANT 
WITHDRAWAL
7.1
Discontinuation of Study Intervention
Discontinuation of study intervention does not represent withdrawal from the study.
As certain data on clinical events beyond study intervention discontinuation may be 
important to the study, they must be collected through the participant’s last scheduled follow-
up, even if the participant has discontinued study intervention. Therefore, all participants 
who discontinue study intervention before completion of the protocol-specified treatment 
period (last dose at Week 20) will still continue to be monitored in the study and participate 
in the study visits and procedures as specified in Section 1.3 and Section 8.11.3 unless the 
participant has withdrawn from the study Section 7.2.
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.
A participant must be discontinued from study intervention, but continue to be monitored in 
the study for any of the following reasons:
•
The participant or participant’s legally acceptable representative requests to discontinue 
study intervention.
•
The participant’s treatment assignment is unblinded before Week 20.  
Note: The need for the participant to be discontinued from study intervention due to 
unblinding will be determined collaboratively between the investigator and the Sponsor’s 
Clinical Director.
•
The participant has a medical condition or personal circumstance which, in the opinion of 
the investigator and/or Sponsor, placed the participant at unnecessary risk from continued 
administration of study intervention.
Note: If a participant has a change in HIV-1-associated risk behavior (Appendix 8), 
he/she may become eligible to receive a medication approved PrEP (eg, FTC/TDF, 
FTC/TAF, or cabotegravir IM), and discontinuation from study intervention may be 
indicated. The investigator should discuss any changes in HIV-1-associated risk behavior 
with the Sponsor’s Clinical Director. The decision to continue the participant on study 
intervention or discontinue the participant with referral to locally available HIV 
prevention services, including services for approved PrEP, will be determined by 
agreement between the investigator and the Sponsor.
Note: If a participant requires PEP for potential occupational or non-occupational HIV 
exposure, the decision to continue the participant on study intervention or discontinue the 
participant will be determined by agreement between the investigator and the Sponsor.
•
The participant has a confirmed positive serum pregnancy test.
•
The participant develops a malignancy after randomization.
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•
The participant has confirmed HIV-1 or HIV-2 infection.
Note: Participants who become infected with HIV-1 or HIV-2 prior to Follow-up Week 8 
may have their treatment unblinded. 
Note: Participants who become infected with HIV-1 or HIV-2 during the study will stop 
receiving study intervention and will be referred to local medical providers for HIV care 
and treatment. No poststudy ART will be provided by the study.
•
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.
•
A participant must be discontinued from study intervention and managed per 
Section 8.11.3.1 if any of the criteria in Table 3 are confirmed. Participants should 
interrupt QM blinded dosing pending confirmatory testing. 
Note: 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 from study intervention.
Table 3
Discontinuation Criteria for Specified Decreases in Total Lymphocyte Counts 
or CD4+ T-cell Counts
Laboratory Test
Criteriona
Confirmationb,c
Total lymphocyte 
count
A confirmed on-treatment value 
<1000 cells/mm3 with a ≥30% decline from 
baseline
Repeat measurement 1 to 4 weeks 
later or at the next scheduled study 
visit, whichever is sooner
CD4+ T-cell count
A confirmed on-treatment value 
<500 cells/mm3 with a ≥30% decline from 
baseline 
Repeat measurement 1 to 4 weeks 
later or at the next scheduled study 
visit, whichever is sooner
a Baseline is defined as the Day 1 value. If a Day 1 value is not available, then the most recent screening value prior to 
Day 1 should be considered a participant’s baseline value.
b If a measurement meets the specified discontinuation criteria, a consecutive, confirmatory measurement within the 
specified time frame 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.
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 study intervention dosing interruptions (due to missed study visits). 
Allow approximately 4 weeks following resolution of illness, immunization, or study intervention dosing interruptions 
before collecting the confirmation sample to allow for evaluation of a potential other causal effect.
Discontinuation from study intervention is “permanent.” Once a participant is discontinued, 
he/she shall not be allowed to restart study intervention.
Participants who are discontinued from study intervention prior to the final dose at Week 20, 
should continue to be monitored. All follow-up visits and procedures, as outlined in the SoA 
in Section 1.3.1, should be completed.
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7.2
Participant Withdrawal From the Study
A participant must be withdrawn from the study if the participant or participant’s legally 
acceptable representative withdraws consent from the study.
If a participant withdraws from the study, they will no longer receive study intervention or be 
followed at scheduled protocol visits.
Specific details regarding procedures to be performed at the time of withdrawal from the 
study, as outlined in the SoA in Section 1.3.2 (Early Withdrawal from Study visit), 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.
•
Additional evaluations/testing may be deemed necessary by the investigator and or the 
Sponsor for reasons related to participant safety. In some cases, such evaluation/testing 
may be potentially sensitive in nature (eg, HIV, hepatitis C), and thus local regulations 
may require that additional informed consent be obtained from the participant. In these 
cases, such evaluations/testing will be performed in accordance with those regulations.
•
The volume of blood collected from a participant over the duration of the study is 
provided in Table 11 (US and Israel) and Table 12 (South Africa). Participants who 
provide documented informed consent to participate in the PBMC Substudy will have 
additional blood collected over the duration of the study as noted in Table 11 and
Table 12.
•
Repeat or unscheduled samples may be taken for safety reasons, for technical issues with 
the samples, or may be required for participants who are rescreened. Therefore, the total 
amount of blood collected for a participant may be changed beyond what is listed in 
Table 11 and Table 12.
8.1
Administrative and General Procedures
8.1.1
Informed Consent
Informed consent will adhere to IRB/IEC requirements, applicable laws and regulations, and 
Sponsor requirements. The 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.
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 their legally acceptable 
representative) and of the person conducting the consent discussion.
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A copy of the signed and dated ICF should be given to the participant (or their legally 
acceptable representative) before participation in the study.
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 
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
Specifics about the study and the study population are to be included in the ICF.
The participant (or their 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.
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 PBMC Subset
Participation in the PBMC Subset will be optional. The investigator or medically qualified 
designee will explain the PBMC Subset consent to the participant, answer all of his/her 
questions, and obtain documented informed consent before performing any procedure related 
to the PBMC Subset. Participants who consent to participate in the PBMC Subset will have
additional weekly visits between Day 2 and Week 4 and 1 additional follow-up visit (Follow-
up Week 6) (Section 1.3.1). A copy of the ICF will be given to the participant.
If a participant withdraws consent for the PBMC Subset during the study, the participant 
does not need to be discontinued. In this situation, the site should revert the participant to the 
visits and procedures applicable for participants not in the PBMC Subset, for the remainder 
of 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.
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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.
8.1.5
Prior and Concomitant Medications Review
8.1.5.1
Prior Medications
The investigator or qualified designee will review before medication use, including any 
protocol-specified washout requirement, and record prior medication taken by the participant 
within 30 days before the first dose of study intervention.
8.1.5.2
Concomitant Medications
The investigator or qualified designee will record medication, if any, taken by the participant 
during the study.
8.1.6
Assignment of Screening Number
All consented participants will be given a unique screening number that will be used to 
identify the participant for all procedures that occur 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. Pre-trial screening logs may be collected for review by 
the Sponsor. If applicable, any information that would make the participant identifiable will 
be removed.
8.1.7
Assignment of Treatment/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 
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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
All study intervention will be administered at the clinic/investigative site QM per the SoA 
(Section 1.3). Administration of study intervention will be witnessed by the investigator 
and/or study staff. There are no meal restrictions for dosing; therefore, all dosing can occur 
without regard to food.
At each monthly dosing visit, 4 bottles of blinded study intervention will be dispensed per 
participant, each containing 1 capsule (MK-8527 or placebo; Section 6.1). All participants 
will take a total of 4 capsules, swallowed whole, for the assigned dose as follows:
•
Group 1 (MK-8527 3 mg): participants will receive 1 capsule of MK-8527 (3 mg) and 
3 capsules of matching placebo.
•
Group 2 (MK-8527 6 mg): participants will receive 2 capsules of MK-8527 (3 mg) and 
2 capsules of matching placebo.
•
Group 3 (MK-8527 12 mg): participants will receive 4 capsules of MK-8527 (3 mg).
•
Group 4 (Placebo): participants will receive 4 capsules of matching placebo.
All 4 capsules should be taken together, and the actual dosing time will be recorded on the 
eCRF.
8.1.8.1
Timing of Dose Administration
Participants will receive 6 observed QM doses of oral MK-8527 or matching placebo, 
starting at Day 1 with a final dose at Week 20 per the following dosing guidelines:
•
Participants should take the QM dose of MK-8527/placebo within ±2 days (Week 4) or 
±7 days (Weeks 8, 12, 16, 20) of the ideal dosing day (calculated based on Day 1).
•
If a participant is late for a QM dose of MK-8527/placebo and it is outside the dosing 
window (Table 4) for that study visit, the QM dose should be skipped/missed, and the 
normal dosing schedule resumed (based on the ideal dosing day) at the next dosing visit.
Note: This guidance may be modified after consultation with the study Sponsor. Participants 
should not double the next dose to compensate for what has been missed.
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Table 4
Study Intervention Administration Schedule
Study Dosing 
Visits
Ideal Dosing Day
Study Visit Window
per SoA
Dosing Window
Day 1
Day 1
N/A
N/A
Week 4
Day 29
±2 days
Day 27 to Day 31
±2 days
Day 27 to Day 31
Week 8
Day 57
±7 days
Day 50 to 64
±7 days
Day 50 to 64
Week 12
Day 85
±7 days
Day 78 to 92
±7 days
Day 78 to 92
Week 16
Day 113
±7 days
Day 106 to 120
±7 days
Day 106 to 120
Week 20
Day 141
±7 days
Day 134 to 148
±7 days
Day 134 to 148
N/A=not applicable; SoA=Schedule of Activities.
8.1.9
Discontinuation and Withdrawal
Participants who discontinue study intervention before completion of the final dose at 
Week 20 should return to the clinic for an EOT visit (Visit 11) and should be encouraged to 
continue to be followed as outlined in the SoA (Sections 1.3.1 and 1.3.2) and Section 8.11.3.
Participants who withdraw from the study should be encouraged to complete all applicable 
activities scheduled for the “Early Withdrawal from Study” visit (Section 1.3.2) at the time of 
withdrawal. Any AEs that are present at the time of withdrawal should be followed in 
accordance with the safety requirements outlined in Section 8.4.
8.1.9.1
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 
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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 
toxicity grade 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.
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 must be discontinued from study 
intervention, but 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.
At the end of the study, random code/disclosure envelopes or lists and unblinding logs are to 
be returned to the Sponsor or designee.
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. 
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Documentation of equipment calibration must be retained as source documentation at the 
study site.
8.1.12
HIV Risk Reduction
Participants will be offered condoms, lubricants, and HIV risk reduction counseling.
8.2
Efficacy Assessments
There are no efficacy assessments in this study.
8.3
Safety Assessments
Details regarding specific safety procedures/assessments to be performed in this study are 
provided. The total amount of blood to be drawn over the course of the study, including 
approximate blood volumes drawn by visit and by sample type per participant, can be found 
in the Appendix 2.
Note: External circumstances (eg, rescreening, hemolysis) may necessitate repeat testing, 
which may change the total amount of blood collected for a participant beyond what is listed 
in Appendix 2.
Planned time points for all safety assessments are provided in the SoA.
8.3.1
Physical Examinations
At the screening visit, a complete physical examination will be conducted by an investigator 
or medically qualified designee (consistent with local requirements) as per institutional 
standard. The complete physical examination will include examination of body systems 
(including, but not limited to, general appearance, skin, neck, eyes, ears, nose, throat, breast, 
lungs, heart, abdomen, back, lymph nodes, extremities, and nervous system). 
At subsequent visits as per the SoA, a brief directed physical examination will be conducted 
by an investigator or medically qualified designee (consistent with local requirements) per 
institutional standard. 
Height and weight will also be measured and recorded at the visits specified in the SoA
(Section 1.3).
8.3.2
Vital Signs
Vital signs will be measured after approximately 5 to 10 minutes of rest and will include 
temperature, pulse, respiratory rate, and systolic and diastolic blood pressure.
Note: Oral temperatures should be taken. If an oral temperature measurement is not possible, 
a temporal, tympanic, rectal, or axillary temperature measurement may be taken and should 
be recorded appropriately.
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8.3.3
Electrocardiogram
Procedures for printing, archiving, and review of ECGs will be specified by the central 
vendor.
Sites will receive an immediate, machine-read QTcF value when the ECG is performed using 
the central vendor supplied machine. This value may change on the final cardiologist-read 
ECG report; therefore, sites should use only the final ECG report QTcF value from the 
screening visit to determine participant eligibility. 
In some instances, the Sponsor may request that the site do a repeat ECG to further evaluate a 
potentially clinically significant ECG finding.
Special care must be taken for proper lead placement by qualified personnel. Skin should be 
clean and dry prior to lead placement. Participants may need to be shaved to ensure proper 
lead placement. Female participants may need to remove their bra. Participants should be 
resting in the semirecumbent position for at least 10 minutes prior to each ECG 
measurement.
8.3.4
Sexually Transmitted Infections
8.3.4.1
HIV Infection
Participants who have a positive HIV-1/2 screen test while on study intervention will return 
to the site for a confirmatory HIV-1 RNA PCR test and collection of a viral drug resistance 
sample, as soon as possible and no later than 14 days after receiving the positive HIV-1/2 
screen test result. If HIV-1 infection is confirmed and the HIV-1 RNA PCR results meet the 
criteria for testing (HIV-1 RNA ≥200 copies/mL) genotypic and phenotypic viral drug 
resistance testing will be performed on collected plasma samples (by the central laboratory). 
Participants with confirmed HIV-1 infection will be discontinued from study intervention 
and referred to local medical providers for HIV care and treatment; they should remain in the 
study and continue to be followed as outlined in the SoA (Section 1.3). No poststudy ART 
will be provided.
8.3.4.2
Other STIs
Testing for GC/CT, syphilis, and trichomoniasis (females only) will be performed at 
Screening as described in the SoA (Section 1.3.1). Participants with a confirmed STI at 
screening are not eligible for the study and should be referred for treatment as per local 
guidelines.
Participants with a positive syphilis test result and with documentation of adequate antibiotic 
treatment for the syphilis infection (>12 months prior to screening or rescreening [if 
applicable]) may be considered eligible for the study after consultation between the 
investigator and Sponsor Clinical Director.
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During the study, symptomatic testing for STIs will be at the study investigators discretion.
Participants with a confirmed STI while on study intervention may be required to discontinue 
study intervention but will be followed in the study as outlined in the SoA (Section 1.3). 
Sites should report STIs as per local reporting requirements.
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 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 8 weeks after the last dose of study intervention, every 
attempt should be made to perform repeat assessments until the values return to normal or 
baseline or if a new baseline is established as determined by the investigator.
8.3.5.1
Renal Function Assessment
Blood samples will be collected to evaluate renal function as measured by key indicators 
such as serum creatinine and serum cystatin-C (Appendix 2) and CrCl (Appendix 9).
8.3.6
HIV Risk Evaluation
At screening and again at Day 1 prior to randomization, a participant’s risk status should be 
evaluated based on Inclusion Criterion #2 (Section 5.1). A participant that does not meet all 
elements of Inclusion Criterion #2 should not be randomized. After randomization (Day 1), 
at each treatment and follow-up visit as specified in the SoA (Sections 1.3.1 and 1.3.2), 
participants will be screened by appropriate study-site personnel for changes in HIV risk
behaviors based on the list of questions included in Appendix 8.
Any participant who develops a risk for HIV infection at any time during the study should be 
brought to the attention of the Sponsor. No further study intervention should be administered 
from the time the site is made aware of the change in risk status until the Sponsor has 
provided guidance. 
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Upon assessment of the increase in risk status, the Sponsor will determine: a) the 
appropriateness of continuing study intervention and/or b) the necessity to refer the 
participant for applicable services (eg, substance use, mental health, PrEP).
8.3.7
Pregnancy Testing
POCBP are required to use contraception to prevent pregnancy during the study and will be 
tested for pregnancy at each visit as outlined in Section 1.3, Section 5.1, and Appendix 5.
Participants who are not on contraception at screening should be counseled about available 
options and directed to start their chosen method prior to randomization.
Participants should be asked at study visits per the SoA to verbally confirm their use of 
contraception since the prior visit, according to the Contraceptive Guidance in Appendix 5. 
Confirmation should be noted in the source documents for each visit.
Pregnancy testing using a highly sensitive urine β-hCG pregnancy test kit will be performed 
at the study site. In the event of a positive urine pregnancy test result, a confirmatory highly 
sensitive serum β-hCG pregnancy test will be performed. If a participant becomes pregnant, 
refer to Section 8.11.3. Once a continuing pregnancy has been confirmed, monthly urine 
pregnancy tests should be deferred until 1 month following the end of the pregnancy.
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 
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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.
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 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. All AEs, SAEs, and other reportable safety events, 
including pregnancy and exposure during breastfeeding, ECIs, cancer, and overdose will be 
followed until resolution, stabilization, until the event is otherwise explained, or the 
participant is lost to follow-up (as defined in Section 7.3). In addition, the investigator will 
make every attempt to follow all nonserious AEs that occur in 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 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 this 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).
2. A lymphocyte count that meets DAIDS criteria for Grade 3 (<500 cells/mm3) or higher 
grade, as determined by way of protocol-specified laboratory testing or unscheduled 
laboratory testing at any time during the study.
3. A CD4+ T-cell count that meets DAIDS criteria for Grade 3 (<200 cells/mm3) or higher 
grade, as determined by way of protocol-specified laboratory testing or unscheduled 
laboratory testing at any time during the study.
8.5
Treatment of Overdose
In this study, an overdose is defined as a participant taking more than 1 dose (>4 capsules) 
within 14 days.
Decisions regarding dose interruptions or modifications will be made by the investigator in 
consultation with the Sponsor Clinical Director based on the clinical evaluation of the 
participant.
8.6
Pharmacokinetics
Refer to the SoA in Section 1.3.1 and Table 6, Table 7, Table 8, and Table 9 for the list of PK 
sample collection timepoints. For participants who withdrawal consent or require an HIV 
Infection Confirmation visit, refer to PK sample collection details in Section 1.3.2 of the SoA 
and Section 8.6.4. 
The decision as to which samples collected will be measured for evaluation of PK will be 
collaboratively determined by the Sponsor (eg, samples at lower doses may not be measured 
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if samples at higher doses reveal undetectable drug concentrations). If indicated, these 
samples may also be measured and/or pooled for assay in an exploratory manner for 
metabolites and/or additional pharmacodynamic markers. Blood samples collected may be 
stored and further analysis may be performed, if required.
8.6.1
Blood Collection for Plasma MK-8527 (All Participants)
Sample collection, storage, and shipment instructions for plasma samples will be provided in 
an Operations/Laboratory Manual.
PK samples will be collected from all participants as outlined in Table 6. The exact time of 
dosing of study intervention prior to the sample collection and the time of PK sample 
collection will be recorded on the appropriate source documentation.
Table 6
Timepoints for Collection of Plasma MK-8527 Samples (All Participants)
Study Visit (Day/Week)
Time Relative to Dosea
Day 1
One sample to be collected predose
One sample to be collected 30 min (±15 min) postdose
One sample to be collected 4 hours (±30 min) postdose
Day 2
One sample to be collected 24 hours (±6 hours) after Day 1 dose 
Week 20/EOT
(Visit 11)
If Week 20: 
One sample to be collected 30 min (±15 min) postdose
One sample to be collected 4 hours (±30 min) postdose
If EOT: One sample to be collected at any time during the visit
Follow-up Day 1
One sample to be collected 24 hours (±6 hours) after the Week 20 dose.
If Visit 11 was performed as an early EOT visit (no study intervention 
dosing), then one sample can be collected at any time during the visit.
EOT=End of Treatment.
a
Indicates time relative to monthly oral capsule administration up to and including the Week 20 dose.
8.6.2
Blood Collection of PBMC Samples (PBMC Subset Only)
Sample collection, storage, and shipment instructions for PBMC samples will be provided in 
an Operations/Laboratory Manual.
Participating sites will be trained on sample collection and processing procedures. The exact 
time of dosing of study intervention prior to the sample collection and the time of PK sample 
collection will be recorded on the appropriate source documentation.
Timepoints for the collection of these samples are provided in Table 7.
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Table 7
Timepoints for Collection of PBMC Samples (PBMC Subset Only)
Study Visit (Day/Week)
Time Relative to Dosea
Day 1
One sample to be collected predose
One sample to be collected 4 hours (±30 min) postdose
Day 2
One sample to be collected 24 hours (±6 hours) after Day 1 dose 
Week 1
One sample to be collected at any time during the visit
Week 2
One sample to be collected at any time during the visit
Week 3
One sample to be collected at any time during the visit
Week 4 
One sample to be collected predose
Week 8
One sample to be collected predose
Week 12
One sample to be collected predose
Week 16
One sample to be collected predose
Week 20/EOT
(Visit 11)
If Week 20: 
One sample to be collected predose
One sample to be collected 4 hours (±30 min) postdose
If EOT: One sample to be collected at any time during the visit
Follow-up Day 1
One sample to be collected 24 hours (±6 hours) after the Week 20 dose.
If Visit 11 was performed as an early EOT visit (no study intervention 
dosing), then one sample can be collected at any time during the visit.
Follow-up Week 4
One sample to be collected at any time during the visit
Follow-up Week 6
One sample to be collected at any time during the visit
Follow-up Week 8
One sample to be collected at any time during the visit
EOT=End of Treatment; PBMC=peripheral blood mononuclear cell.
a
Indicates time relative to monthly oral capsule administration up to and including the Week 20 dose.
8.6.3
Blood Collection of Venous Microsampling (Mitra®/VAMS) (All Participants)
The VAMS blood collection technique will be used to obtain venous blood samples from all 
study participants; however, the timepoints for collection are different for participants in the 
PBMC Subset (Table 8) and those not in the PBMC Subset (Table 9). 
Sites will be trained on sample collection and processing procedures. The exact time of 
dosing of study intervention prior to the sample collection and the time of PK sample 
collection will be recorded on the appropriate source documentation.
Further instructions on use of the device, which follow VAMS blood collection technique 
will be provided in a Laboratory/Operations Manual.
Timepoints for the collection of VAMS samples in PBMC Subset participants are provided 
in Table 8.
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Table 8
Timepoints for Collection of Venous Microsampling (Mitra®/VAMS) PK 
Samples (PBMC Subset Only)
Study Visit (Day/Week)
Time Relative to Dosea
Day 1
One sample to be collected predoseb
Day 2
One sample to be collected 24 hours (±6 hours) after Day 1 dose 
Week 1
One sample to be collected at any time during the visit
Week 2
One sample to be collected at any time during the visit
Week 3
One sample to be collected at any time during the visit
Week 4
One sample to be collected predose
Week 8
One sample to be collected predose
Week 12
One sample to be collected predose
Week 16
One sample to be collected predose
Week 20/EOT
(Visit 11)
If Week 20: One sample to be collected predoseb
If EOT: one sample to be collected at any time during the visit
Follow-up Day 1
One sample to be collected 24 hours (±6 hours) after the Week 20 dose.
If Visit 11 was performed as an early EOT visit (no study intervention 
dosing), then one sample can be collected at any time during the visit.
Follow-up Week 4 
One sample to be collected at any time during the visit
Follow-up Week 6
One sample to be collected at any time during the visit.
Follow-up Week 8 
One sample to be collected at any time during the visit
EOT=End of Treatment; PBMC=peripheral blood mononuclear cell; PK=pharmacokinetic; VAMS=volumetric 
absorptive microsampling.
a
Indicates time relative to monthly oral capsule administration up to and including the Week 20 dose.
b
No VAMS sample is required to correspond with the 4-hour postdose PBMC sample collection.
Timepoints for the collection of VAMS samples in participants not in the PBMC Subset are 
provided in Table 9.
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Table 9
Timepoints for Collection of Venous Microsampling (Mitra®/VAMS) PK 
Samples (Participants Not in the PBMC Subset)
Study Visit (Day/Week)
Time Relative to Dosea
Week 4 
One sample to be collected predose
Week 8
One sample to be collected predose
Week 12
One sample to be collected predose
Week 16
One sample to be collected predose
Week 20/EOT
If Week 20: One sample to be collected predose
If EOT: One sample to be collected at any time during the visit
EOT=End of Treatment; PBMC=peripheral blood mononuclear cell; PK=pharmacokinetic; VAMS=volumetric 
absorptive microsampling.
a
Indicates time relative to monthly oral capsule administration up to and including the Week 20 dose.
8.6.4
Collection of PK Samples in Participants Who Withdraw Consent or Require 
an HIV Infection Confirmation Visit 
This section outlines the PK sample collection requirements for participants that withdraw 
consent or require an HIV Infection Confirmation visit. Refer to the SoA in Section 1.3.2 for 
additional details.
Participants that Withdraw Consent
Participant should have an “Early Withdrawal From Study” visit as per the SoA in 
Section 1.3.2. At this visit:
•
All participants will have 1 plasma PK sample collection (if the participant has not yet 
completed the Follow-up Day 1 visit) at any time during the visit. 
•
In addition, participants in the PBMC Subset will have 1 PBMC sample and 1 VAMS 
venous sample collected, at any time during the visit.
Participants that Require an HIV Infection Confirmation Visit
Participant should have an HIV Infection Confirmation visit as per the SoA in Section 1.3.2. 
At this visit:
•
All participants will have 1 plasma PK sample collection (if the participant has not yet 
completed the Follow-up Day 1 visit) at any time during the visit. 
•
In addition, participants in the PBMC Subset will have 1 PBMC sample and 1 VAMS 
venous sample collected, at any time during the visit.
Refer to Section 8.11.4 for details on the management of participants in the study based on 
the results of the HIV infection confirmation testing.
8.7
Pharmacodynamics
Pharmacodynamic parameters will not be evaluated in this study.
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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 planned genetic analysis.
8.8.1
Planned Genetic Analysis Sample Collection
The planned genetic analysis sample should be drawn for planned analysis of the association 
between genetic variants in DNA and drug response. This sample will not be collected at the 
site if there is either a local law or regulation prohibiting collection, or if the IRB/IEC does 
not approve the collection of the sample for these purposes. If the sample is collected, 
leftover extracted DNA will be stored for FBR if the participant provides 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.
The planned genetic analysis sample should be obtained pre-dose on Day 1 but may be 
collected at the next scheduled blood draw, if needed. 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 provides documented informed consent for FBR, the following specimens 
will be obtained as part of FBR:
•
Leftover specimens listed in Section 8.8.
8.10
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
Approximately 45 days before intervention randomization, potential participants will be 
evaluated to determine that they fulfill the entry requirements as set forth in Section 5. 
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8.11.1.1
Screening
The screening window, which is a ≤45-day window prior to randomization, will begin on the 
date of the documented main study consent for the participant. During the screening window, 
potential participants will be evaluated to determine that they fulfill the entry requirements as 
set forth in Section 5. Select screening procedures may be repeated after consultation with 
the Sponsor. If a participant has passed the 45-day screening window, the participant may be 
allowed to rescreen.
8.11.1.2
Rescreening
If the 45-day screening window has been exceeded, participants are allowed to rescreen 1 
time. Once a participant has started the rescreening process, a new screening period (ie, an 
additional ≤45-day window) will begin, during which time screening procedures may be 
repeated and are expected to be completed within this new 45-day window. 
Documented informed consent (for the main study, FBR [if applicable], PBMC Subset [if 
applicable] and all other locally applicable study consent forms [eg, Greenphire]) obtained 
during the original screening period should be reviewed with the participant, including any 
screening procedures that need to be repeated, and a verbal reconsent to continue in the study
should be documented. 
Evaluation of eligibility will be determined through repeating select screening procedures 
during the rescreening process to ensure that participants are still at low-risk for HIV-1 
infection and in generally good health, as outlined below. If a procedure is required to be 
repeated at rescreening, that result will be used to confirm eligibility.
All Participants
The following assessments must be repeated for all participants during rescreening:
•
Register the rescreening in the IRT system
•
Review medical history, HIV infection risk, prior/concomitant medications use, and 
contraceptive use
•
Review AEs
•
12-lead ECG
•
Complete physical examination
•
Complete set of vital signs, including height and weight
•
HIV-1 and HIV-2 testing
•
HBV and HCV testing
•
Serum pregnancy test
•
Hematology, chemistry, CrCl, cystatin-C, TBNK Panel, and PT/INR
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The following assessments do not need to be repeated at rescreening if the participant had a 
negative test result at the original screening visit, ≤60 days have passed since the date of the 
original sample collection, and the participant does not report an increase in risk for HIV 
infection; however, testing must be performed at rescreening if any of the above criteria are 
not met:
•
Syphilis serologic testing
•
Urine GC/CT & trichomoniasis testing (females only)
•
Urine GC/CT testing (males only)
8.11.2
Intervention Period
During the intervention period, participants will receive a total of 6 oral doses of the assigned 
blinded study intervention (MK-8527 [3 mg, 6 mg, or 12 mg] or placebo) per the SoA. 
Administration of study intervention will be witnessed by the investigator and/or study staff 
approximately every 4 weeks starting on Day 1. The final dose will be administered at the 
Week 20 visit.
After Day 2, participants in the PBMC Subset will return to the site at Weeks 1, 2, and 3 for 
additional required assessments, per the SoA (Section 1.3.1).
8.11.2.1
AE Assessment Phone Call (Week 2)
A phone call to collect safety information will be made at Week 2 for participants not in the 
PBMC Subset. The investigator is responsible for ensuring that all telephone contacts are 
performed by a staff member who is a health care professional qualified to elicit a discussion 
with the participant that will lead to a clinically meaningful disclosure on the participant’s 
well-being. Telephone contacts are to be documented in the source documents and in the 
EDC tool (if required) and the investigator must review the entry within 2 days. However, if 
the participant reports any clinically concerning events (eg, SAEs, ECIs) during a telephone 
call, then the investigator must be promptly notified. The investigator will contact the 
participant to determine if a clinic visit is warranted.
If the participant cannot be reached by telephone at the regularly scheduled time, the site 
should make at least 3 attempts (in addition to the initial phone call) to contact the participant 
within 48 hours of the missed scheduled time. The participant’s reliable contact person 
should be called if attempts to contact the participant are not successful. All phone contacts 
and attempts should be recorded in source documents.
8.11.3
Participants Discontinued From Study Intervention but Continuing to be 
Monitored in the Study
Participants who discontinue study intervention before the final dose at Week 20 should 
complete an EOT visit (Visit 11) (Section 1.3.1), and then continue with the protocol-
specified visits for the “Follow-up (Blinded)” study period as listed in the SoA 
(Section 1.3.1) and further described in Section 8.11.6.
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For the EOT visit, the site should perform all procedures, as listed in the SoA (Section 1.3.1) 
for Visit 11 (Week 20/EOT), except for the following procedure modifications: 
1. No study intervention should be dispensed via the IRT or administered to the 
participant. The site should call the IRT to register the EOT visit.
2. One sample for plasma MK-8527 PK collected, at any time during the visit.
3. If in the PBMC Subset: only 1 PBMC sample and 1 VAMS venous sample should be 
collected, at any time during the visit.
If a participant discontinues study intervention before the final dose at Week 20, the EOT 
visit (Visit 11) should be performed in place of the next study visit. If a participant 
discontinues study intervention and also withdraws from the study before the final dose at 
Week 20, then only the EOT visit (Visit 11) should be performed in place of the next study 
visit. If a participant receives the final Week 20 dose of study intervention and then 
withdraws from the study, an “Early Withdrawal From Study” visit should be performed as 
the final study visit as outlined in Section 1.3.2 of the SoA.
8.11.3.1
Management of Participants with Specified Decreases in Total Lymphocyte 
Count or CD4+ T-cell Counts
Participants discontinued from study intervention (prior to the final dose at Week 20) due to 
confirmed decreases in total lymphocyte count or CD4+ T-cell count (Section 7.1 and 
Table 3) should undergo assessments for the EOT visit (Visit 11) as specified in the SoA in 
Section 1.3.1. To meet the protocol-defined discontinuation criteria, participants must have a 
confirmed total lymphocyte count or CD4+ T-cell count that indicates a specified decrease 
on 2 consecutive measurements 1 to 4 weeks apart (Table 3). Note: 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 study intervention dosing interruptions 
(due to missed study visits). Allow approximately 4 weeks following resolution of illness, 
immunization, or study intervention dosing interruptions before collecting the confirmation 
sample to allow for evaluation of a potential other causal effect. Consult with the Sponsor
prior to discontinuation if the investigator believes there is an alternative explanation for the 
result (eg, COVID-19).
After discontinuation from study intervention, participants should continue to be followed in 
the study, by completing the follow-up visits as outlined in the SoA in Section 1.3.1. 
Total lymphocyte counts and CD4+ T-cell counts will also be monitored during follow-up 
(after last dose at Week 20). If a participant has a confirmed decrease in total lymphocyte 
count or CD4+ T-cell count as per Section 7.1, Table 3, after the last dose at Week 20, 
participants should continue to be followed in the study, by completing the follow-up visits 
as outlined in the SoA in Section 1.3.1.
If at the Follow-up Week 8 visit the participants total lymphocyte count and/or CD4+ T-cell 
count has not returned to ≥1000 cells/mm3 or ≥500 cells/mm3, respectively, on 2 consecutive 
measurements, the participants should continue to be followed in the study with 
approximately monthly unscheduled visits. At the unscheduled visit, the site should complete 
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an AE assessment and collect hematology and TBNK Panel/CD4+ T-cell samples for 
evaluation by the central laboratory. Participants should continue with the unscheduled visits 
until the total lymphocyte count and/or CD4+ T-cell count has returned to ≥1000 cells/mm3
or ≥500 cells/mm3, respectively, on 2 consecutive measurements.
8.11.3.2
Participants Who Become Pregnant
If a participant becomes pregnant prior to the last dose of study intervention at Week 20, an 
EOT visit (Visit 11) as per the SoA in Section 1.3.1 should be performed. If the pregnancy is 
reported at a scheduled study visit (eg, Week 8), the assessments/procedures for the EOT 
visit (Visit 11) should be conducted at that time. The participant will then continue with the 
protocol-specified visits for the “Follow-up (Blinded)” study period (Follow-up Day 1, 
Follow-up Week 4, etc) as listed in the SoA in Section 1.3.1. 
If the participant becomes pregnant after the last dose of study intervention at Week 20 or 
during the “Follow-up (Blinded)” study period they should continue with the protocol-
specified follow-up visits listed for this period in the SoA in Section 1.3.1. 
All reported pregnancies will be followed to the completion/termination of the pregnancy 
(Section 8.4.5).
8.11.4
HIV Infection Confirmation
Participants who have a positive HIV-1/2 screen test should return to the site for an “HIV 
Infection Confirmation” visit within 14 days of the site receiving the positive test result and 
have procedures performed as specified in the SoA in Section 1.3.2, including collection of 
an HIV-1 RNA PCR sample. 
•
If the positive HIV-1/2 screen test is prior to the last dose of study intervention at 
Week 20, and the HIV confirmation and differentiation test is negative, the participant 
may continue study intervention while waiting for the results of the HIV-1 RNA PCR 
test.
•
If the HIV-1 RNA PCR test is negative, the participant can continue to take study 
intervention.
•
If the HIV-1 RNA PCR test is positive, the participant should complete an EOT visit
(Visit 11), and then continue with the protocol-specified visits for the “Follow-up 
(Blinded)” study period as listed in the SoA in Section 1.3.1. The participant should 
be referred to local medical providers for HIV care and treatment. No poststudy ART
will be provided by the study.
•
If the positive HIV-1/2 screen test is prior to the last dose of study intervention at 
Week 20, and the HIV confirmation and differentiation test is positive, the participant 
should not receive additional doses of study intervention while waiting for the results of 
the HIV-1 RNA PCR test.
•
If the HIV-1 RNA PCR test is negative, the participant may be able to resume study 
intervention after consultation with the Sponsor. 
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•
If the HIV-1 RNA PCR test is positive, the participant should be permanently 
discontinued from study intervention and complete an EOT visit (Visit 11), and then 
continue with the protocol-specified visits for the “Follow-up (Blinded)” study period 
as listed in the SoA in Section 1.3.1. The participant should be referred to local 
medical providers for HIV care and treatment. No poststudy ART will be provided by 
the study.
•
If the positive HIV-1/2 screen test is after the last dose of study intervention at Week 20 
or during the “Follow-up (Blinded)” study period, the participant should continue with 
the protocol-specified visits listed for this period in the SoA in Section 1.3.1.
•
The study investigator should utilize the results of the HIV confirmation and 
differentiation test and HIV-1 RNA PCR to determine the appropriate follow-up care 
for the participant.
If a participant has repeated positive HIV-1/2 screening tests which the investigator considers 
to be false positive results (due to the biology of the participant), after consultation between 
the site and the Sponsor, and written documentation of the collaborative decision, HIV RNA 
testing can be performed at each scheduled visits to avoid the participant needing to return 
for an HIV confirmation visit with each false positive screening test result.  
8.11.5
Participants Who Withdraw Consent
Participants who withdraw from the study should be encouraged to complete all applicable 
activities scheduled for the “Early Withdrawal From Study” visit (Section 1.3.2) at the time 
of withdrawal.
8.11.6
Follow-up Period
During the 8-week blinded follow-up period, all participants will complete 3 monthly follow-
up visits: Follow-up Day 1, Follow-up Week 4, and Follow-up Week 8. PBMC Subset 
participants will have 1 additional follow-up visit at Follow-up Week 6.
The follow-up visits represent different study day/weeks for a participant that completes the 
final Week 20 dose and a participant that discontinues study intervention prior to Week 20, 
as outlined below. 
A participant that completes the final Week 20 study intervention dose will return to the site 
for follow-up visits based on the following: 

Visit 12/Follow-up Day 1 (all participants): this visit should be completed 
~24 hours after the Week 20 study intervention dose; PK samples must be collected 
24 hours (±6 hours) after the Week 20 dose.

Visit 13/Follow-up Week 4 (all participants): this visit should be completed 
24 weeks (±7 days) from the Day 1 (Visit 2).

Visit 14/Follow-up Week 6 (PBMC Subset only): this visit should be completed 
26 weeks (±2 days) from the Day 1 (Visit 2).
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
Visit 15/Follow-up Week 8 (all participants): this visit should be completed 
28 weeks (±7 days) from the Day 1 (Visit 2). 
A participant that discontinues study intervention prior to the Week 20 dose, will return to 
the site for follow-up visit based on the EOT (Visit 11) date:

Visit 12/Follow-up Day 1 (all participants): this visit should be completed 
~24 hours after the EOT visit (Visit 11).

Visit 13/Follow-up Week 4 (all participants): this visit should be completed 4 
weeks (±7 days) from the EOT visit (Visit 11).  

Visit 14/Follow-up Week 6 (PBMC Subset only): this visit should be completed 6 
weeks (±2 days) from the EOT visit (Visit 11).

Visit 15/Follow-up Week 8 (all participants): this visit should be completed 8 
weeks (±7 days) from the EOT visit (Visit 11).
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9
KEY STATISTICAL CONSIDERATIONS
This section outlines the principal statistical analysis strategy and procedures for the study. 
Changes to analyses made after the protocol has been finalized, but prior to unblinding, will 
be documented in an amendment of the SAP and referenced in the CSR for the study. Post 
hoc exploratory analyses will be clearly identified in the CSR.
9.1
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.
This study will be conducted as a double-blind study under in-house blinding procedures. To 
allow programmatic decisions, there will be an unblinded Sponsor team to review data on an 
ongoing basis for the duration of the study. The official, final database will not be locked 
until medical/scientific review has been performed, protocol deviations have been identified, 
and data have been declared final and complete. The detailed list of unblinded Sponsor team 
is presented in section 6.3.3 of the protocol. All Sponsor personnel except for a blinded 
medical monitoring team will be unblinded after the last expected Follow-up Week 4 visit.
The Clinical Biostatistics department of the Sponsor will generate the randomized allocation 
schedule for study treatment assignment. 
9.2
Hypotheses/Estimation
There are no hypotheses to be tested in this study. Objectives of the study are stated in 
Section 3 of the protocol.
9.3
Analysis Endpoints
Safety and PK endpoints that will be evaluated for within- and between-treatment differences 
are listed below.
9.3.1
Safety Endpoints
The primary safety assessment will include all accumulated safety data through the last 
follow-up visit. AEs leading to discontinuation from study intervention are assessed until 
Week 20 (last dose received). Safety and tolerability will be assessed by clinical review of all 
relevant parameters including AEs and laboratory test results.
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9.3.2
Pharmacokinetics Endpoints
The secondary PK endpoints for the study are MK-8527 AUC0-last and Cmax.
Exploratory PK endpoints are:

PBMC MK-8527-MP, MK-8527-DP, and MK-8527-TP: AUC0-last, Cmax, Ctrough, 
concentrations at common time points

MK-8527-TP AUC0-last, Ctrough, Cmax, and t1/2
9.4
Analysis Populations
9.4.1
Safety Analysis Population
Safety Analyses will be conducted in the APaT population, which consists of all 
randomized/allocated participants who received at least one 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. This will 
generally be the treatment group to which they are randomized except for participants who 
take incorrect study intervention for the entire treatment period; such participants will be 
included in the treatment group corresponding to the study intervention actually received. 
9.4.2
PK Analysis Population
The PK analysis population consists of the subset of participants who comply with the 
protocol sufficiently to ensure that generated data will be likely to exhibit the effects of 
treatment, according to the underlying scientific model. Any participants or data values 
excluded from analysis will be identified, along with their reason for exclusion, in the CSR.
9.5
Statistical Methods
9.5.1
Statistical Methods for Safety Analyses
Safety and tolerability will be assessed by clinical review of AEs and other relevant 
parameters, including laboratory test results. 
The overall safety endpoints include the number of participants with at least one AE, SAE, 
drug-related AE, drug-related SAE, Grade 3 to 4 AE, drug-related Grade 3 to 4 AE, 
discontinuation from study intervention due to an AE; and AE resulting in death. 
The safety evaluation will include a summary by treatment group of the number and 
percentage of participants with each type of AE. For overall safety endpoints, point estimates 
and 95% CIs for the differences between MK-8527 and placebo in the percentages of 
participants with events will be provided using the M&N method [Miettinen, O. and 
Nurminen, M. 1985].
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For continuous safety measures, such as change from baseline in laboratory values, summary 
statistics for baseline, on-treatment, and change from baseline values will be provided by 
treatment group. 
9.5.2
Statistical Methods for Pharmacokinetics Analyses
Plasma MK-8527 endpoints will be summarized separately by dose level as appropriate, with 
geometric means and %GCV.
9.6
Interim Analyses
The siDMC will be responsible for an interim safety review as specified in the SAP. An 
interim safety analysis will be performed once 50% of the planned enrollment has reached 
Week 12 or discontinued from study intervention. Additional details will be specified in the 
SAP/siDMC charter.    
Study enrollment may be ongoing at the time of the IA. Blinding to treatment assignment 
will be maintained at all investigational sites. The results of the IA will not be shared with the 
investigators prior to the completion of the study. Participant-level unblinding will be 
restricted to an internal unblinded statistician and scientific programmer performing the IA, 
who will have no other responsibilities associated with the study. Details will be provided in 
the SAP/siDMC charter.
9.7
Multiplicity
No multiplicity adjustment is planned for this study. 
9.8
Sample Size and Power Calculations
The sample size of this study will allow for the accumulation of approximately 150 person-
years of safety data on MK-8527.
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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 Interventional 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 siDMC regarding the study.
10.1.4.2
Internal Data Monitoring Committee
To supplement the routine monitoring outlined in this protocol, a separate internal DMC will 
monitor the interim data from this study. The internal DMC is comprised of members of 
Sponsor Senior Management, none of whom are directly associated with the conduct of this 
study. The internal DMC will monitor the study progress for evidence of any adverse effects 
of study intervention. The internal DMC will also make recommendations to the Sponsor 
study team regarding steps to ensure both participant safety and the continued ethical 
integrity of the study in the internal DMC charter.
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 
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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.
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 
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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.
Study monitors will perform ongoing source data review and verification to confirm that data 
entered into the CRF by authorized site personnel are accurate, complete, and verifiable from 
source documents; that the safety and rights of participants are being protected; and that the 
study is being conducted in accordance with the currently approved protocol and any other 
study agreements, ICH GCP, and all applicable regulatory requirements.
Records and documents, including participants’ documented informed consent, pertaining to 
the conduct of this study must be retained by the investigator for 15 years after study 
completion unless local regulations or institutional policies require a longer retention period. 
No records may be destroyed during the retention period without the written approval of the 
Sponsor. No records may be transferred to another location or party without written 
notification to the Sponsor.
10.1.9
Source Documents
Source documents provide evidence for the existence of the participant and substantiate the 
integrity of the data collected. The investigator/institution should maintain adequate and 
accurate source documents and study records that include all pertinent observations on each 
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of the site’s participants. Source documents and data should be attributable, legible, 
contemporaneous, original, accurate, and complete. Changes to source data should be 
traceable, should not obscure the original entry, and should be explained if necessary (eg, via 
an audit trail). Source documents are filed at the investigator’s site.
Data reported on the CRF or entered in the eCRF that are transcribed from source documents 
must be consistent with the source documents or the discrepancies must be explained. The 
investigator/institution may need to request previous medical records or transfer records, 
depending on the study. Also, current medical records must be available.
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 safety laboratory tests detailed in Table 10 will be tested by a regional central 
laboratory in South Africa or by a global central laboratory in all other countries 
participating in the study. The differences in blood volumes between Table 11 and 
Table 12 are due to use of 2 different testing laboratories. PK samples will be tested by 
contract laboratories or the Sponsor’s bioanalytical group.
•
Local laboratory results are only required if the central laboratory results are not available 
in time for either study intervention administration and/or response evaluation. If a local 
sample is required, it is important that the sample for central analysis is obtained at the 
same time. Additionally, if the local laboratory results are used to make either a study 
intervention decision or response evaluation, the results must be entered into the CRF.
Note: External circumstances may require participants to have local laboratory testing 
performed in place of samples being sent to the central laboratory for evaluation. 
Allowance for the use of local labs must be determined collaboratively between the 
Sponsor and the investigator and the site IRB/EC will be notified. The local laboratory 
results must be entered into the CRF.
•
Protocol-specific requirements for inclusion or exclusion of participants are detailed in 
Section 5.1 and Section 5.2 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 investigator (or medically qualified designee) must document their review of each 
laboratory safety report.
•
Laboratory/analyte results that could unblind the study will not be reported to 
investigative sites or other blinded personnel until the study has been unblinded.
•
If a participant is confirmed HIV-infected and is unblinded, results from HIV-1 drug 
resistance testing may be provided to site personnel.
•
If a participant is confirmed HIV-infected and is not unblinded, results from HIV-1 drug 
resistance testing will not be provided to site personnel who are directly involved in 
supporting the study, as there is the potential for the data to unblind the participants 
intervention group. HIV-1 drug resistance testing may be provided to site personnel not 
associated with the study. HIV-1 resistance results will be blinded to the study team and 
site personnel associated with the study.
Table 10
Protocol-required Safety Laboratory Assessments
Laboratory Assessments
Parameters
Pregnancy
Urine Pregnancy Test (POCBP only) (Highly sensitive urine) human 
chorionic gonadotropin (hCG) pregnancy test (performed locally)
Positive urine pregnancy to be confirmed with serum pregnancy test 
- Highly sensitive serum human chorionic gonadotropin (hCG) 
pregnancy test
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Laboratory Assessments
Parameters
  PT/INR
Activated partial thromboplastin time (APTT) 
Prothrombin time (PT)
International normalized ratio prothrombin time (INR)
Hematology
Hematocrit (Hct)
Hemoglobin (Hb)
Red blood cell (RBC) Count
White blood cell (WBC) Count
Platelet Count
Mean Corpuscular Hemoglobin (MCH)
Mean Corpuscular Hemoglobin Concentration (MCHC)
Mean Corpuscular Volume (MCV)
Mean Platelet Volume (MPV)
Red Cell Distribution Width (RDW)
CBC, Nucleated RBC (%, abs)
WBC Differential, Basophils (%, abs)
WBC Differential, Eosinophils (%, abs)
WBC Differential, Immature Granulocyte (%, abs)
WBC Differential, Lymphocytes (%, abs)
WBC Differential, Monocytes (%, abs)
WBC Differential, Neutrophils, Total (%, abs)
TBNK Panel/CD4+ T-Cell 
count  
T and B Lymphocytes 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+ CD45+ Percent
CD3+ CD45+ Value/Absolute Count
CD3-CD19+ Percent
CD3-CD19+ Value/Absolute Count
CD3-CD16+CD56+ Percent 
CD3-CD16+CD56+ Value/Absolute Count 
CD3+CD4+CD8+ Percent 
CD3+CD4+CD8+ Value/Absolute Count 
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Laboratory Assessments
Parameters
Chemistry 
Albumin
Alkaline Phosphatase (ALP)
Alanine Aminotransferase (ALT/SGPT)
Aspartate Aminotransferase (AST/SGOT)
Amylase
Bicarbonate
Bilirubin, Direct
Bilirubin, Indirect
Bilirubin, Total
Calcium (Ca)
Chloride (Cl)
Cholesterol, Total
Creatine Phosphokinase (CPK)
Creatinine
Creatinine Clearance (calculated)
Cystatin-C
Gamma Glutamyl Transferase (GGT)
Glucose (fasting)
Glucose (random)
Lactate Dehydrogenase (LDH)
Lipase
Magnesium (Mg)
Phosphorous
Potassium (K)
Protein, Total 
Sodium (Na)
Triglycerides
Urea Nitrogen, Blood (BUN)
Uric Acid
Hepatitis screen (Screening)
Hepatitis B virus surface antigen (HBsAg)
Hepatitis B Serology (HBsAb/HBcAb)
Hepatitis C virus (HCV) antibody 
Plasma Hepatitis C virus PCR quantitative test (performed if 
Hepatitis C virus antibody is positive)
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Laboratory Assessments
Parameters
Virology
HIV-1/2 antibody + antigen screening test
HIV-1/2 confirmation and differentiation test
HIV-1 RNA PCR – to be performed if participant has a positive 
HIV-1/2 screening test result (or upon request)
HIV-1 drug resistance testing - to be performed if HIV-1 RNA is 
≥200 copies/mL (or upon request)
STI Testing (Screening)
All participants: Syphilis testing will be performed based on an 
algorithm including the following tests: Syphilis antibody screen, 
rapid plasma reagin [RPR], RPR titer, Treponema pallidum IgG, 
Treponema pallidum IgG index
Female testing: Urine for Trichomonas, Gonorrhea (GC), Chlamydia 
(CT)
Male testing: Urine for GC/CT
PK Sampling
Plasma for MK-8527 PK
Peripheral blood mononuclear cells (PBMC) for PK – PBMC 
Subset only
Venous Microsampling (Mitra®/VAMS) for PK
Biomarkers 
Genetic analysis 
CBC=complete blood count; HIV=human immunodeficiency virus; IgG=immunoglobulin G; PCR=polymerase chain 
reaction; PK=pharmacokinetic; POCBP=participant of childbearing potential; RNA-ribonucleic acid; SGOT=serum 
glutamic oxaloacetic transaminase; SGPT=serum glutamic pyruvic transaminase; VAMS=volumetric absorptive 
microsampling.
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Table 11
Blood Volumes For Samples Collected From Participants in the United States and Israel
Study Period
Screenin
g
Intervention (Blinded)
Follow-up (Blinded)
HIV 
Infection 
Conf
Early 
Withdrawal 
From Study
Scheduled Day/Week 
Screening
Day 1
Day 2
Week 1a
Week 2 a
Week 3 a
Week 4
Week 8
Week 12
Week 16
Week 20
\EOTc
FD 1
FW 4
FW 6a
FW 8
Totals
Unscheduled
Unscheduled
All Participants
HIV-1/2 Screen
Off HBV/ HCV/HIV
3.5
3.5
3.5
3.5
3.5
3.5
3.5
3.5
28
3.5
HIV-1/2 Confirmation and 
Differentiation
HBV/HCV/HIV (Serology)
5
5
HCV RNA (only tested if 
AB+)
3.5
3.5
Syphilis
4
4
PT/INR
2.7
2.7
Serum pregnancy test (β-
hCG) (POCBP only)
Off Chem
0
Hematology
2
2
2
2
2
2
2
2
2
2
2
22
2
2
TBNK Panel/CD4+ T-cell 
Count
6
6
6
6
6
6
6
6
6
6
6
66
6
6
Chemistry
4
4
4
4
4
4
4
4
4
36
4
Cystatin-C
2
2
2
2
2
2
2
2
2
18
2
Plasma PK sample collection 
9
3
6
3
21
3b
3b
Venous Microsampling (eg, 
Mitra®/VAMS)
2.6
2.6
2.6
2.6
2.6
13
HIV-1 RNA PCR
0
6
HIV-1 drug resistance testing
0
12
Blood for Genetic Analysis
8.5
8.5
Total Blood Volume per 
Visit in mL (All 
Participants)
29.2
35
11
0
0
0
20.1
20.1
20.1
20.1
26.1
11
17.5
0
17.5
227.7
29
20.5
PBMC Substudy Only
PBMC sample
32
16
16
16
16
16
16
16
16
32
16
16
16
16
256
16
16
Venous Microsampling (eg, 
Mitra®/VAMS)
2.6
2.6
2.6
2.6
2.6
2.6
2.6
2.6
2.6
23.4
2.6
2.6
Hematology
2
2
2
2
8
TBNK Panel/CD4+ T-cell 
Count
6
6
6
6
24
Chemistry
4
4
4
4
16
Cystatin-C
2
2
2
2
8
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Study Period
Screenin
g
Intervention (Blinded)
Follow-up (Blinded)
HIV 
Infection 
Conf
Early 
Withdrawal 
From Study
Scheduled Day/Week 
Screening
Day 1
Day 2
Week 1a
Week 2 a
Week 3 a
Week 4
Week 8
Week 12
Week 16
Week 20
\EOTc
FD 1
FW 4
FW 6a
FW 8
Totals
Unscheduled
Unscheduled
Additional Blood Volume 
Collected per Visit in mL 
(Participants in the PBMC 
Subset)
34.6
18.6
32.6
32.6
32.6
16
16
16
16
32
18.6
18.6
32.6
18.6
335.4
18.6
18.6
β-hCG=beta human chorionic gonadotropin; EOT=End of Treatment; FD=follow-up day; FW=follow-up week; 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; PK=pharmacokinetic(s); PBMC=peripheral blood mononuclear cell; PCR=polymerase chain 
reaction; POCBP=participant of childbearing potential; PT=prothrombin time; RNA=ribonucleic acid; TBNK=T- and B-Lymphocyte and Natural Killer Cell.
a. Visits at Week 1, Week 2, Week 3, and Follow-up Week 6 are for participants who provide consent to participate in the PBMC Subset only.
b. Not collected if the participant is beyond Follow-up Day 1.
c. If performed as an EOT visit (as per Section 1.3.1), not all samples are required therefore the blood volume is reduced; refer to Section 8.11.3 for additional details. 
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Table 12
Blood Volumes for Samples Collected From Participants in South Africa
Study Period
Screening
Intervention (Blinded)
Follow-up (Blinded)
HIV 
Infection 
Conf
Early 
Withdrawal
From Study
Scheduled Day/Week 
Screening
Day 1
Day 2
Week 1a
Week 2 a
Week 3 a
Week 4
Week 8
Week 12
Week 16
Week 20
\EOTc
FD 1
FW 4
FW 6a
FW 8
Totals
Unscheduled
Unscheduled
All Participants
HIV Elisa 4th Generation
HIV Confirmatory Test (Bio Rad 
Geenius)
3.5
3.5
3.5
3.5
3.5
3.5
3.5
3.5
3.5
31.5
3.5
HBV/HCV/HIV (Serology)
3.5
3.5
HCV RNA (only tested if AB+)
3.5
3.5
Syphilis 
3.5
3.5
PT/INR
2.7
2.7
Serum pregnancy test (β-hCG) 
(POCBP only)
Off Chem
0
Hematology
4 
4
4
-
-
-
4
4
4
4
4
4
4
-
4
44
4
4
TBNK Panel/CD4+ T-cell Count
4
4
4
-
-
-
4
4
4
4
4
4
4
-
4
44
4
4
Chemistry
5
5
5
5
5
5
5
5
5
45
5
Cystatin-C
3.5
3.5
3.5
3.5
3.5
3.5
3.5
3.5
3.5
31.5
3.5
Plasma PK sample collection 
9
3
6
3
21
3b
3b
Venous Microsampling (eg, 
Mitra®/VAMS)
2.6
2.6
2.6
2.6
2.6
13
HIV-1 RNA PCR
0
6 
HIV-1 drug resistance testing
0
12
Blood for Genetic Analysis
8.5
8.5
Total Blood Volume per Visit in mL 
(All Participants)
33.2
37.5
11
0
0
0
22.6
22.6
22.6
22.6
28.6
11
20
0
20
251.7
29
23
PBMC Substudy Only
PBMC sample
32
16
16
16
16
16
16
16
16
32
16
16
16
16
256
16
16
Venous VAMS Microsampling
2.6
2.6
2.6
2.6
2.6
2.6
2.6
2.6
2.6
23.4
2.6
2.6
Hematology
4
4
4
4
16
TBNK Panel/CD4+ T-cell Count
4
4
4
4
16
Chemistry
5
5
5
5
20
Cystatin-C
3.5
3.5
3.5
3.5
14
Additional Blood Volume Collected 
per Visit in mL (Participants in the 
PBMC Subset)
34.6
18.6
35.1
35.1
35.1
16
16
16
16
32
18.6
18.6
35.1
18.6
345.4
18.6
18.6
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Study Period
Screening
Intervention (Blinded)
Follow-up (Blinded)
HIV 
Infection 
Conf
Early 
Withdrawal
From Study
Scheduled Day/Week 
Screening
Day 1
Day 2
Week 1a
Week 2 a
Week 3 a
Week 4
Week 8
Week 12
Week 16
Week 20
\EOTc
FD 1
FW 4
FW 6a
FW 8
Totals
Unscheduled
Unscheduled
β-hCG=beta human chorionic gonadotropin; EOT=End of Treatment; FD=follow-up day; FW=follow-up week; 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; PK=pharmacokinetic(s); PBMC=peripheral blood mononuclear cell; PCR=polymerase chain 
reaction; POCBP=participant of childbearing potential; PT=prothrombin time; RNA=ribonucleic acid; TBNK=T- and B-Lymphocyte and Natural Killer Cell.
a. Visits at Week 1, Week 2, Week 3, and Follow-up Week 6 are for participants who provide consent to participate in the PBMC Subset only.
b. Not collected if the participant is beyond Follow-up Day 1.
c. If performed as an EOT visit (as per Section 1.3.1), not all samples are required therefore the blood volume is reduced; refer to Section 8.11.3 for additional details. 
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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.
•
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.
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•
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
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.
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-
This definition is not intended to include experiences of relatively minor medical 
significance such as uncomplicated headache, nausea, vomiting, diarrhea, influenza, 
and accidental trauma (eg, sprained ankle) that may interfere with or prevent 
everyday life functions but do not constitute a substantial disruption.
e.
Is a congenital anomaly/birth defect
-
In offspring of participant taking the product regardless of time to diagnosis.
f.
Other important medical events
-
Medical or scientific judgment should be exercised in deciding whether SAE 
reporting is appropriate in other situations such as important medical events that may 
not be immediately life-threatening or result in death or hospitalization but may 
jeopardize the participant or may require medical or surgical intervention to prevent 1 
of the other outcomes listed in the above definition. These events should usually be 
considered serious.
-
Examples of such events include invasive or malignant cancers, intensive treatment in 
an emergency room or at home for allergic bronchospasm, blood dyscrasias, or 
convulsions that do not result in hospitalization, or development of drug dependency 
or drug abuse.
10.3.4
Additional Events Reported
Additional events that require reporting
In addition to the above criteria, AEs meeting either of the below criteria, although not 
serious per ICH definition, are reportable to the Sponsor.
•
Is a cancer.
•
Is associated with an overdose.
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.
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•
The investigator will attempt to establish a diagnosis of the event based on signs, 
symptoms, and/or other clinical information. In such cases, the diagnosis (not the 
individual signs/symptoms) will be documented as the AE/SAE.
Assessment of intensity/toxicity
•
An event is defined as “serious” when it meets at least 1 of the predefined outcomes as 
described in the definition of an SAE, not when it is rated as severe.
•
The investigator will make an assessment of intensity for each AE and SAE (and other 
reportable safety event) by recording the grade according to the NIH DAIDS Table for 
Grading the Severity of Adult and Pediatric Adverse Events, version 2.1. Any AE that 
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 study intervention cause the AE?
•
The determination of the likelihood that the study intervention caused the AE will be 
provided by an investigator who is a qualified physician. The investigator’s signed/dated 
initials on the source document or worksheet that supports the causality noted on the AE 
form ensures that a medically qualified assessment of causality was done. This initialed 
document must be retained for the required regulatory time frame. The criteria below are 
intended as reference guidelines to assist the investigator in assessing the likelihood of a 
relationship between the test product and the AE based upon the available information.
•
The following components are to be used to assess the relationship between the 
study intervention and the AE; the greater the correlation with the components and 
their respective elements (in number and/or intensity), the more likely the study 
intervention caused the AE:
-
Exposure: Is there evidence that the participant was actually exposed to the study 
intervention such as: reliable history, acceptable compliance assessment (pill count, 
diary, etc), expected pharmacologic effect, or measurement of drug/metabolite in 
bodily specimen?
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Time Course: Did the AE follow in a reasonable temporal sequence from 
administration of the study intervention? Is the time of onset of the AE compatible 
with a drug-induced effect (applies to studies with IMP)?
-
Likely Cause: Is the AE not reasonably explained by another etiology such as 
underlying disease, other drug(s)/vaccine(s), or other host or environmental factors.
-
Dechallenge: Was the study intervention discontinued or dose/exposure/frequency 
reduced?
◦
If yes, did the AE resolve or improve?
◦
If yes, this is a positive dechallenge.
◦
If no, this is a negative dechallenge.
(Note: This criterion is not applicable if: (1) the AE resulted in death or permanent 
disability; (2) the AE resolved/improved despite continuation of the study 
intervention; (3) the study is a single-dose drug study; or (4) study intervention (s) 
is/are only used 1 time.)
-
Rechallenge: Was the participant reexposed to the study intervention 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; (2) the study is a single-dose drug study; or (3) study 
intervention (s) is/are used only 1 time.)
NOTE: IF A RECHALLENGE IS PLANNED FOR AN AE THAT WAS SERIOUS AND 
MAY HAVE BEEN CAUSED BY THE STUDY INTERVENTION, OR IF REEXPOSURE 
TO THE STUDY INTERVENTION POSES ADDITIONAL POTENTIAL SIGNIFICANT 
RISK TO THE PARTICIPANT THEN THE RECHALLENGE MUST BE APPROVED IN 
ADVANCE BY THE SPONSOR CLINICAL DIRECTOR AS PER DOSE 
MODIFICATION GUIDELINES IN THE PROTOCOL, AND IF REQUIRED, THE 
IRB/IEC.
•
Consistency with study intervention profile: Is the clinical/pathological presentation of 
the AE consistent with previous knowledge regarding the study intervention or drug class 
pharmacology or toxicology?
•
The assessment of relationship will be reported on the case report forms/worksheets by 
an investigator who is a qualified physician according to 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 study intervention relationship).
-
Yes, there is a reasonable possibility of study intervention relationship:
◦
There is evidence of exposure to the study intervention. The temporal sequence of 
the AE onset relative to the administration of the study intervention is reasonable. 
The AE is more likely explained by the study intervention than by another cause.
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-
No, there is not a reasonable possibility of study intervention relationship:
◦
Participant did not receive the study intervention OR temporal sequence of the AE 
onset relative to administration of the study intervention is not reasonable OR the 
AE is more likely explained by another cause than the study intervention. (Also 
entered for a participant with overdose without an associated AE.)
•
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.
•
For studies in which multiple agents are administered as part of a combination regimen, 
the investigator may attribute each AE causality to the combination regimen or to a single 
agent of the combination. In general, causality attribution should be assigned to the 
combination regimen (ie, to all agents in the regimen). However, causality attribution 
may be assigned to a single agent if in the investigator’s opinion, there is sufficient data 
to support full attribution of the AE to the single agent.
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.
-
Reference Section 8.4.1 for reporting time requirements.
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•
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 following menarche and 
capable of becoming pregnant 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, Müllerian 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 2 FSH measurements in the postmenopausal range 
is required.
-
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.
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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, 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, Müllerian 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 2 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
Failure rate of <1% per year when used consistently and correctly.
Progestogen-only contraceptive implant
IUSa
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
Failure rate of <1% per year when used consistently and correctly.
Combined (estrogen- and progestogen-containing) hormonal contraceptionb
- Oral
- Intravaginal
- Transdermal
- Injectable
Progestogen-only hormonal contraceptionb
- 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 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 spermicidec
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)
a
IUS is a progestin releasing IUD 
b
If locally required, in accordance with CTFG guidelines, acceptable contraceptives are limited to those which inhibit 
ovulation
c
Vaginal/internal condom used for contraceptive purposes 
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 condom should not be used together (due to risk of failure with friction)c
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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 
signed by the participant will be kept at the clinical study site under secure storage for 
regulatory reasons.
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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.
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 
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(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.
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.
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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
Not applicable to this study.
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10.8
Appendix 8: Risk Evaluation
At each treatment and follow-up visit as specified in the SoA (Section 1.3.1 and 
Section 1.3.2), participants will be screened by appropriate study-site personnel for changes 
in HIV risk behaviors. The following questions should be used based on the CDC 
Recommended Indications for PrEP [Centers for Disease Control and Prevention 2018]:
•
Are you sexually active?
-
If no, no further questions.
-
If yes, are you in a mutually monogamous partnership with a recently tested/known to 
be HIV-negative partner?
◦
If yes, no further questions.
◦
If no, is one or more of the following true?
1. You are in an ongoing sexual relationship with an HIV-positive partner. 
2. You infrequently use condoms during sex with 1 or more partners of unknown 
HIV status who are known to be at substantial risk of HIV infection (defined as a 
person who injects drugs, a man who has sex with men, someone sexually active 
with other partners where the HIV incidence is >3% as per WHO guidelines for 
PrEP) [World Health Organization 2015].
3. You have had anal sex without condoms (receptive or insertive) since last visit.
4. You have had a bacterial STI (syphilis, gonorrhea in women or men) diagnosed or 
reported since last visit.
Any response of ‘YES’ to the above questions 1 through 4 should be considered 
a change in HIV risk status and consultation with the Sponsor is required prior 
to dispensing further study intervention.
Changes in HIV risk status may be discovered by the interviewer-administered questions 
above, participant’s self-reporting or as deemed by the study investigator or designee upon 
medical history and/or physical exam review.
Increases in a participant’s HIV risk status at any time during the study should be brought to 
the attention of the Sponsor. No further study intervention should be administered from the 
time the site is made aware of the change in risk status until the Sponsor has provided 
guidance.
Upon assessment of the increase in risk status, the Sponsor will determine: a) the 
appropriateness of continuing study intervention and/or b) the necessity to refer the 
participant for applicable services (eg, substance use, mental health, PrEP).
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10.9
Appendix 9: Calculation of Creatinine Clearance
Cockcroft-Gault equations for participants ≥18 years old:

If male:

If female:
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10.10 Appendix 10: Abbreviations
Abbreviation
Expanded Term
3TC
lamivudine
ABC
abacavir
ADME
absorption, distribution, metabolism, and excretion
AE
adverse event
ALT
alanine aminotransferase
APaT
All-Participants-as-Treated
ART
antiretroviral therapy
AST
aspartate aminotransferase
AUC0-last
area under the concentration-time curve from dosing to the time of the last 
measured concentration
AZT
azidothymidine
BSEP
bile salt export pump
C168
concentration at 168 hours
CDC
Centers for Disease Control and Prevention
CG
Cockcroft-Gault
CI
confidence interval
Cmax
maximum plasma concentration
CNS
central nervous system
CONSORT
Consolidated Standards of Reporting Trials
COVID-19
coronavirus disease caused by the SARS-CoV-2 virus
CrCl
creatinine clearance
CRF
Case Report Form
CSR
Clinical Study Report
CT
chlamydia trachomatis
CTFG
Clinical Trial Facilitation Group
Ctrough
concentration reached by a drug immediately before the next dose is 
administered
CYP
cytochrome P450
DAIDS
Division of AIDS
DDI
drug-drug interaction
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Abbreviation
Expanded Term
DILI
drug-induced liver injury
DMC
Data Monitoring Committee
DNA
deoxyribonucleic acid
DP
diphosphate
ECG
electrocardiogram
ECI
event of clinical interest
eCRF
electronic Case Report Form
EDC
electronic data collection
EEA
European Economic Area
EFV
efavirenz
EMA
European Medicines Agency
EOC
Executive Oversight Committee
EOT
End of Treatment
FBR
future biomedical research
FDA
Food and Drug Administration
FDAAA
Food and Drug Administration Amendments Act
FSH
follicle stimulating hormone
FTC
emtricitabine
GC
Neisseria gonorrhoeae
GCP
Good Clinical Practice
GCV
geometric coefficient of variation
GERD
gastroesophageal reflux disease
HBcAb
hepatitis B core antibody
HBsAg
hepatitis B surface antigen
HBV
hepatitis B virus
hCG
human chorionic gonadotropin
HCV
hepatitis C virus
HIV
human immunodeficiency virus
HIV-1
human immunodeficiency virus type 1
HIV-2
human immunodeficiency virus type 2
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Abbreviation
Expanded Term
HRT
hormone replacement therapy
IA(s)
interim analysis(ses)
IB
Investigator’s Brochure
IC50
concentration of a drug or inhibitor needed to inhibit a biological process 
or response by 50%
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
IM
intramuscular
IMP
Investigational Medicinal Product
IND
Investigational New Drug
IQ
inhibitory quotient
IRB
Institutional Review Board
IRT
interactive response technology
ISL
islatravir, MK-8591
IUD
intrauterine device
IUS
intrauterine hormone-releasing system
JRCT
Japan Registry of Clinical Trials
M&N
Miettinen & Nurminen method
MP
monophosphate
NCT
Clinicaltrials.gov identifier
NDA
New Drug Application
NNRTI
non- nucleoside reverse transcriptase inhibitor
NRTI
nucleoside reverse transcriptase inhibitor
OAT1
organic anion transporter 1
OAT3
organic anion transporter 3
OATP1B1
organic anion transporting polypeptide 1B1
OCT2
organic cation transporter 2
PBMC
peripheral blood mononuclear cell
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Abbreviation
Expanded Term
PCR
polymerase chain reaction
PEP
post-exposure prophylaxis
P-gp
p-glycoprotein
PK
pharmacokinetic(s)
POCBP
participant of childbearing potential
PONCBP
participant of nonchildbearing potential
PrEP
pre-exposure prophylaxis
QM
once monthly
QTc
QT interval corrected for heart rate
QTcF
QT interval corrected for heart rate by Fridericia's formula
RNA
ribonucleic acid
RT
reverse transcriptase
SAC
Scientific Advisory Committee
SAE
serious adverse event
SAP
Statistical Analysis Plan
SD
standard deviation
SGOT
serum glutamic oxaloacetic transaminase
SGPT
serum glutamic pyruvic transaminase
siDMC
Standing Internal Data Monitoring Committee
SLAB
supplemental laboratory test(s)
SoA
schedule of activities
SOC
standard of care
SOP
Standard Operating Procedures
sSAP
supplemental Statistical Analysis Plan
STI
sexually transmitted infection
SUSAR
suspected unexpected serious adverse reaction
t½
half-life
TAF
tenofovir alafenamide
TBNK
T- and B-lymphocyte and natural killer cell
TDF
tenofovir disoproxil
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Abbreviation
Expanded Term
TFV
tenofovir
TP
triphosphate
ULN
upper limit of normal
US
United States
UTN
Universal Trial Number
VAMS
volumetric absorptive microsampling
WBC
white blood cell
WHO
World Health Organization
ZDV
zidovudine
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