Clinical trial NCT04003103
Conditions: HIV-1 Infection
Sponsor: Merck Sharp & Dohme LLC
Start date: 2019-09-19; Completion date: 2022-11-24
Enrollment: 242 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This study will evaluate the safety, tolerability and pharmacokinetics (PK) of 6 once-monthly doses of oral islatravir (60 mg and 120 mg) compared with placebo in adults at low risk of HIV-1 infection

Detailed description:
This study is ongoing for collection of safety follow-up of infants born to mothers participating in the study. The present results are based on the Week 68 interim analysis.

Arms: arm 1: 60 mg islatravir + placebo for islatravir administered once monthly, orally in capsule form for 24 weeks arm 2: 120 mg islatravir administered once monthly, orally in capsule form for 24 weeks arm 3: Placebo for islatravir administered once monthly, orally in capsule form for 24 weeks
Interventions: intervention 1: Islatravir intervention 2: Placebo
Intervention descriptions: intervention 1: Islatravir 30 mg capsules taken by mouth. intervention 2: Placebo capsules taken by mouth.

Protocol documents:
Prot_000.pdf: 
Official Protocol Title: 
NCT number: 
NCT04003103 
Document Date: 
08-Dec-2021
A Phase 2a, Double-Blind, Placebo-Controlled Study to Evaluate the 
Safety, Tolerability, and Pharmacokinetics of Oral MK-8591 Once-
Monthly in Participants at Low-Risk for HIV-1 Infection


PRODUCT: MK-8591  
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Title Page
THIS PROTOCOL AMENDMENT AND ALL OF THE INFORMATION RELATING 
TO IT ARE CONFIDENTIAL AND PROPRIETARY PROPERTY OF MERCK 
SHARP & DOHME CORP., A SUBSIDIARY OF MERCK & CO., INC., NJ, U.S.A. 
(MSD).
Protocol Title: A Phase 2a, Double-Blind, Placebo-Controlled Study to Evaluate the Safety, 
Tolerability, and Pharmacokinetics of Oral MK-8591 Once-Monthly in Participants at Low-
Risk for HIV-1 Infection
Protocol Number: 016-03
Compound Number: MK-8591
Sponsor Name:
Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc.
(hereafter referred to as the Sponsor or MSD)
Legal Registered Address:
One Merck Drive
P.O. Box 100
Whitehouse Station, New Jersey, 08889-0100, U.S.A.
Regulatory Agency Identifying Number(s):
IND
128,595
Approval Date: 08 December 2021
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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 03
08-DEC-2021
The protocol was amended to add monitoring of lymphocytes and CD4+ 
T-cells in response to findings of decreases in lymphocytes (in studies of 
participants with or without HIV) and CD4+ T-cell counts (in studies of 
participants with HIV) in ISL clinical studies.
Amendment 02
18-NOV-2020
To extend the screening window; to allow rescreening of participants; and to 
modify the primary safety objective to include data through the last follow-up 
visit
Amendment 01
14-OCT-2019
To add NET-EN as a contraceptive option for participants in the 
Implant/Depot DDI PK Subset. To provide operational clarifications and 
make editorial corrections. 
Original Protocol
19-JUN-2019
Not applicable
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PROTOCOL AMENDMENT SUMMARY OF CHANGES
Amendment: 03
Overall Rationale for the Amendments:
The protocol was amended to add monitoring of lymphocytes and CD4+ T-cells in response to findings of decreases in lymphocytes 
(in studies of participants with or without HIV) and CD4+ T-cell counts (in studies of participants with HIV) in ISL clinical studies.
Summary of Changes Table:
Section # and Name
Description of Change 
Brief Rationale 
1.3.2 Schedule of Activities 
for the Extended, Unblinded 
PK Follow-up for 
Participants on MK-8591 in 
the PBMC/PK Bridging 
Subset
Appendix 2: Table 7
Added hematology and CD4+ T-cell count 
sample collection at FW 36 and FW 44 for 
participants in the PBMC/PK bridging 
subset who remain in the study.
Added CD4 assessment to the list of 
clinical laboratory assessments.
To add safety monitoring in response to findings of 
decreases in lymphocyte and CD4+ T-cell counts in a 
study in participants with HIV receiving a combination of 
ISL and another investigational drug. As dosing of 
participants has been completed and only PK substudy 
participants remain in the study, collection of hematology
samples was not added to study visits that had already 
been completed by all participants at the time of this 
amendment.
2.3 Benefit/Risk Assessment
Updated the benefit/risk assessment to 
include a summary of data related to 
decreased lymphocyte and CD4+ T-cell 
counts.
Updated to reflect findings relevant to PrEP population.
8 Study Assessments and 
Procedures
Appendix 2: Table 9
Updated blood volume based on additional 
hematology and CD4+ T-cell sample 
collection.
To reflect blood volume changes resulting from protocol 
updates.
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Section # and Name
Description of Change 
Brief Rationale 
Throughout
Editorial revisions.
Minor editorial changes to the text.
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Table of Contents
DOCUMENT HISTORY ........................................................................................................3
PROTOCOL AMENDMENT SUMMARY OF CHANGES...............................................4
1
PROTOCOL SUMMARY ............................................................................................13
1.1
Synopsis.................................................................................................................13
1.2
Schema ..................................................................................................................16
1.3
Schedule of Activities (SoA)................................................................................17
1.3.1
Schedule of Activities (Base Study) ............................................................17
1.3.2
Schedule of Activities for the Extended, Unblinded PK Follow-up for 
Participants on MK-8591 in the PBMC/PK Bridging Subset......................24
1.3.3
Schedule of Activities (HIV Infection Confirmation and Early 
Discontinuation)...........................................................................................25
2
INTRODUCTION..........................................................................................................29
2.1
Study Rationale....................................................................................................29
2.2
Background ..........................................................................................................29
2.2.1
Pharmaceutical and Therapeutic Background .............................................29
2.3
Benefit/Risk Assessment......................................................................................30
3
HYPOTHESES, OBJECTIVES, AND ENDPOINTS................................................31
4
STUDY DESIGN............................................................................................................32
4.1
Overall Design......................................................................................................32
4.2
Scientific Rationale for Study Design.................................................................34
4.2.1
Rationale for Endpoints ...............................................................................34
4.2.1.1
Safety Endpoints................................................................................34
4.2.1.2
Pharmacokinetic Endpoints ...............................................................35
4.2.1.2.1
PBMC/PK Bridging Subset .....................................................35
4.2.1.2.2
Tissue Biopsy Subset...............................................................35
4.2.1.2.3
Implant/Depot DDI Subset ......................................................35
4.2.1.3
Planned Exploratory Biomarker Research.........................................36
4.2.1.3.1
Planned Genetic Analysis ........................................................36
4.2.1.4
Future Biomedical Research..............................................................36
4.2.2
Rationale for the Use of Placebo .................................................................37
4.2.3
Rationale for Collecting Race and Ethnicity ...............................................37
4.2.4
Rationale for Collecting Infant Safety Follow-up Data...............................37
4.3
Justification for Dose...........................................................................................37
4.4
Beginning and End of Study Definition .............................................................38
4.4.1
Clinical Criteria for Early Study Termination .............................................38
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5
STUDY POPULATION ................................................................................................38
5.1
Inclusion Criteria.................................................................................................39
5.2
Exclusion Criteria................................................................................................41
5.3
Lifestyle Considerations......................................................................................43
5.4
Screen Failures.....................................................................................................43
5.5
Participant Replacement Strategy......................................................................43
6
STUDY INTERVENTION............................................................................................44
6.1
Study Intervention(s) Administered...................................................................44
6.2
Preparation/Handling/Storage/Accountability .................................................46
6.2.1
Dose Preparation..........................................................................................46
6.2.2
Handling, Storage, and Accountability........................................................46
6.3
Measures to Minimize Bias: Randomization and Blinding..............................47
6.3.1
Intervention Assignment..............................................................................47
6.3.2
Stratification.................................................................................................47
6.3.3
Blinding........................................................................................................47
6.4
Study Intervention Compliance..........................................................................48
6.5
Concomitant Therapy..........................................................................................48
6.5.1
Rescue Medications and Supportive Care ...................................................48
6.6
Dose Modification ................................................................................................49
6.7
Intervention After the End of the Study............................................................49
6.8
Clinical Supplies Disclosure................................................................................49
7
DISCONTINUATION OF STUDY INTERVENTION AND PARTICIPANT 
WITHDRAWAL............................................................................................................49
7.1
Discontinuation of Study Intervention...............................................................49
7.2
Participant Withdrawal From the Study...........................................................51
7.3
Lost to Follow-up .................................................................................................51
8
STUDY ASSESSMENTS AND PROCEDURES........................................................52
8.1
Administrative and General Procedures ...........................................................53
8.1.1
Informed Consent.........................................................................................53
8.1.1.1
General Informed Consent.................................................................53
8.1.1.2
Consent and Collection of Specimens for Future Biomedical 
Research.............................................................................................53
8.1.1.3
Consent for PBMC/PK Bridging Subset ...........................................54
8.1.1.4
Consent for Tissue Biopsy Subset .....................................................54
8.1.1.5
Consent for Implant/Depot DDI Subset.............................................54
8.1.1.6
Consent for Infant Safety Follow-up .................................................54
8.1.2
Inclusion/Exclusion Criteria ........................................................................54
8.1.3
Participant Identification Card.....................................................................54
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8.1.4
Medical History ...........................................................................................55
8.1.5
Prior and Concomitant Medications Review...............................................55
8.1.5.1
Prior Medications...............................................................................55
8.1.5.2
Concomitant Medications..................................................................55
8.1.6
Assignment of Screening Number...............................................................56
8.1.7
Assignment of Treatment/Randomization Number.....................................56
8.1.8
Study Intervention Administration ..............................................................56
8.1.8.1
Timing of Dose Administration.........................................................57
8.1.9
Discontinuation and Withdrawal .................................................................58
8.1.9.1
Withdrawal From Future Biomedical Research ................................58
8.1.10
Participant Blinding/Unblinding..................................................................58
8.1.11
Calibration of Equipment.............................................................................59
8.2
Efficacy Assessments ...........................................................................................59
8.3
Safety Assessments...............................................................................................59
8.3.1
Physical Examinations.................................................................................60
8.3.2
Vital Signs....................................................................................................60
8.3.3
Electrocardiograms ......................................................................................60
8.3.4
DEXA Assessment.......................................................................................61
8.3.5
Sexually Transmitted Infections ..................................................................61
8.3.6
HIV Risk Evaluation....................................................................................62
8.3.7
Infant Safety Follow-up Assessments..........................................................62
8.3.7.1
Schedule of Activities: Infant Safety Follow-up Through 1-Year 
of Age.................................................................................................63
8.3.8
Clinical Safety Laboratory Assessments .....................................................63
8.4
Adverse Events (AEs), Serious Adverse Events (SAEs), and Other 
Reportable Safety Events ....................................................................................64
8.4.1
Time Period and Frequency for Collecting AE, SAE, and Other 
Reportable Safety Event Information ..........................................................64
8.4.2
Method of Detecting AEs, SAEs, and Other Reportable Safety Events......67
8.4.3
Follow-up of AE, SAE, and Other Reportable Safety Event Information...67
8.4.4
Regulatory Reporting Requirements for SAE .............................................67
8.4.5
Pregnancy and Exposure During Breastfeeding ..........................................67
8.4.6
Disease-related Events and/or Disease-related Outcomes Not Qualifying 
as AEs or SAEs............................................................................................68
8.4.7
Events of Clinical Interest (ECIs)................................................................68
8.5
Treatment of Overdose........................................................................................68
8.6
Pharmacokinetics.................................................................................................68
8.6.1
Blood Collection for Plasma MK-8591 .......................................................69
8.6.2
Blood Collection for PBMC/PK Bridging Subset .......................................69
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8.6.2.1
Intracellular (PBMC) Samples...........................................................69
8.6.2.2
Mitra/VAMS™ Blood Samples.........................................................69
8.6.3
Tissue Collection for Tissue Biopsy Subset ................................................70
8.6.3.1
Rectal Tissue Sample.........................................................................70
8.6.3.2
Vaginal Tissue Sample ......................................................................71
8.6.3.3
Cervical Tissue Sample......................................................................71
8.6.4
Blood Collection for Implant/Depot DDI Subset ........................................71
8.7
Pharmacodynamics..............................................................................................72
8.8
Biomarkers ...........................................................................................................72
8.8.1
Laboratory Markers Associated with Clinical Outcome .............................72
8.8.2
Planned Genetic Analysis Sample Collection..............................................72
8.9
Future Biomedical Research Sample Collection...............................................73
8.10
Health Economics Medical Resource Utilization and Health Economics.......73
8.11
Visit Requirements...............................................................................................73
8.11.1
Screening/Rescreening.................................................................................73
8.11.1.1
Screening............................................................................................73
8.11.1.2
Rescreening........................................................................................73
8.11.2
Intervention Period.......................................................................................75
8.11.3
Discontinued Participants Continuing to be Monitored in the Study ..........75
8.11.3.1
Participants Who Become Pregnant...................................................76
8.11.4
HIV Infection Confirmation ........................................................................77
8.11.5
Follow-up Period .........................................................................................78
9
STATISTICAL ANALYSIS PLAN .............................................................................78
9.1
Statistical Analysis Plan Summary.....................................................................78
9.2
Responsibility for Analyses/In-house Blinding .................................................79
9.3
Hypotheses/Estimation ........................................................................................79
9.4
Analysis Endpoints...............................................................................................79
9.4.1
Safety Endpoints..........................................................................................80
9.4.2
Pharmacokinetics Endpoints........................................................................80
9.5
Analysis Populations............................................................................................80
9.6
Statistical Methods...............................................................................................81
9.6.1
Statistical Methods for Safety Analyses ......................................................81
9.6.2
Statistical Methods for Pharmacokinetics Analyses....................................83
9.7
Interim Analyses ..................................................................................................83
9.8
Multiplicity ...........................................................................................................83
9.9
Sample Size and Power Calculations .................................................................83
9.9.1
Sample Size and Probability Calculations for Safety Analysis ...................83
9.9.2
Sample Size and Probability Calculations for PK Analysis ........................85
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9.10
Subgroup Analyses...............................................................................................85
9.11
Compliance (Medication Adherence).................................................................86
9.12
Extent of Exposure...............................................................................................86
10
SUPPORTING DOCUMENTATION AND OPERATIONAL 
CONSIDERATIONS.....................................................................................................87
10.1
Appendix 1: Regulatory, Ethical, and Study Oversight Considerations........87
10.1.1
Code of Conduct for Clinical Trials.............................................................87
10.1.2
Financial Disclosure.....................................................................................89
10.1.3
Data Protection.............................................................................................89
10.1.3.1
Confidentiality of Data ......................................................................90
10.1.3.2
Confidentiality of Participant Records...............................................90
10.1.3.3
Confidentiality of IRB/IEC Information............................................90
10.1.4
Publication Policy........................................................................................90
10.1.5
Compliance with Study Registration and Results Posting Requirements ...91
10.1.6
Compliance with Law, Audit, and Debarment ............................................91
10.1.7
Data Quality Assurance ...............................................................................92
10.1.8
Source Documents .......................................................................................93
10.1.9
Study and Site Closure.................................................................................93
10.2
Appendix 2: Clinical Laboratory Tests..............................................................94
10.3
Appendix 3: Adverse Events: Definitions and Procedures for Recording, 
Evaluating, Follow-up, and Reporting.............................................................105
10.3.1
Definition of AE ........................................................................................105
10.3.2
Definition of SAE ......................................................................................106
10.3.3
Additional Events Reported.......................................................................107
10.3.4
Recording AE and SAE .............................................................................107
10.3.5
Reporting of AEs, SAEs, and Other Reportable Safety Events to the 
Sponsor ......................................................................................................111
10.4
Appendix 4: Device Events, Adverse Device Events, and Medical Device 
Incidents: Definitions, Collection, and Documentation..................................113
10.5
Appendix 5: Contraceptive Guidance..............................................................114
10.5.1
Definitions..................................................................................................114
10.5.2
Contraception Requirements......................................................................116
10.6
Appendix 6: Collection and Management of Specimens for Future 
Biomedical Research..........................................................................................117
10.7
Appendix 7: Country-specific Requirements..................................................122
10.8
Appendix 8: Risk Evaluation............................................................................123
10.9
Appendix 9: Calculation of Creatinine Clearance..........................................124
10.10 Appendix 10: Abbreviations .............................................................................125
11
REFERENCES.............................................................................................................128
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LIST OF TABLES
Table 1
Study Interventions..........................................................................................45
Table 2
Study Intervention Administration Schedule...................................................57
Table 3
Reporting Time Periods and Time Frames for Adverse Events and Other 
Reportable Safety Events.................................................................................66
Table 4
Analysis Strategy for Safety Parameters..........................................................83
Table 5
Estimate of Incidence of AEs and 95% Upper Confidence Bound Based 
on Hypothetical Number of Participants With a Particular AE Among 100 
Participants in Either MK-8591 Intervention Group .......................................84
Table 6
Difference in Incidence of AEs (MK-8591 Intervention Group Minus 
Placebo)  That Can Be Ruled Out....................................................................85
Table 7
Protocol-Required Clinical Laboratory Assessments......................................95
Table 8
PK Sample Collection Timepoints...................................................................99
Table 9
Blood Volumes ..............................................................................................103
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LIST OF FIGURES
Figure 1
Study Schema...................................................................................................16
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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-8591 Once-Monthly in Participants at Low-
Risk for HIV-1 Infection
Short Title: Safety and PK Study of Oral MK-8591 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 trial. The following objectives will be evaluated 
in adults at low-risk of HIV-1 infection:
Primary Objectives
Primary Endpoints
- To evaluate the safety and tolerability of 6 
once-monthly doses of MK-8591 (60 mg and 
120 mg) through the last follow-up visit.
- Adverse events 
- Adverse events leading to discontinuation 
of study intervention
Secondary Objectives
Secondary Endpoints
- To evaluate the safety and tolerability of 6 
once-monthly doses of MK-8591 (60 mg and 
120 mg) with follow-up of 4 weeks after the 
last dose.
- Adverse events 
- Adverse events leading to discontinuation 
of study intervention
To characterize the plasma pharmacokinetic 
profile of MK-8591 
Pharmacokinetic parameters: MK-8591 
AUC0-672hr, Cmax, Ctrough, t1/2
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Overall Design:
Study Phase
Phase 2
Primary Purpose
Prevention
Indication
Pre-exposure prophylaxis of HIV-1 Infection
Population
Adults at low-risk for HIV-1 infection
Study Type
Interventional
Intervention Model
Parallel
This is a multi-site study.
Type of Control
Placebo
Study Blinding
Double-blind
Masking
Investigator
Participant
Sponsor
Estimated Duration of Study
The Sponsor estimates that the study will require 
approximately 33 months 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 250 participants will be randomized in a 2:2:1 ratio to 1 of 3 intervention
groups: Group 1: MK-8591 60 mg (N ~ 100); Group 2: MK-8591 120 mg (N ~ 100); Group 
3: placebo (N ~ 50).
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Intervention Groups and Duration:
Intervention 
Groups
Intervention 
Group 
Name
Drug
Dose 
Levels
Dose 
Frequency
Route of 
Administration
Intervention
Perioda
Group 1
MK-8591
60 mg
Once 
monthly
Oral
24 weeks
Group 2
MK-8591
120 mg
Once 
monthly
Oral
24 weeks
Group 3
Placebob
Placebo
Once 
monthly
Oral
24 weeks
a
Last dose is administered at the Week 20 visit; final dosing period ends at Week 24.
b
Placebo product is created by the Sponsor to match the active product (30 mg capsule 
of MK-8591).
Total 
Number
3 intervention groups (2 active, 1 placebo)
Duration of 
Participation
Participants will be in the study for approximately 42 weeks (or 74 weeks if
in the PBMC/PK Bridging Subset) 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, each participant will receive 6 
once-monthly doses of assigned intervention with the final dose 
administered at Week 20. After the intervention period is complete (at 
Week 24), each participant will be followed for 12 weeks. Participants in 
the PBMC/PK Bridging Subset who received MK-8591 will also complete
an extended, unblinded PK follow-up period for an additional 32 weeks, for 
a total duration of participation of 74 weeks. Participants who discontinue 
study intervention early will be followed for 12 or 44 weeks after ending 
study intervention.
Sponsor approval is required to allow participants to be in the study for a 
longer duration than originally estimated; these cases will be determined 
collaboratively between the Sponsor and the investigator. In such cases, the 
site IRB/EC will be notified.
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Study Governance Committees:
Steering Committee
No
Executive Oversight Committee
No
Data Monitoring Committee
No
Clinical Adjudication Committee
No
Study Accepts Healthy Volunteers: Yes
A list of abbreviations used in this document can be found in Appendix 10.
1.2
Schema
The study design is depicted in Figure 1.
Figure 1
Study Schema
N=total number of participants in the study; n=number of participants in each treatment group; 
PBMC=peripheral blood mononuclear cells; PK=pharmacokinetic; QM=once monthly; wk=week.
a
Randomization to study intervention will occur at Day 1 and will be stratified by sex 
(female, male) and region (Africa, non-Africa).
b
The Sponsor will be unblinded at Week 24. Participants and investigators/clinical site 
personnel will remain blinded up to Week 36.
c
After Week 36, only participants in the PBMC/PK Bridging Subset who are randomized to 
receive MK-8591 will have an additional 32-week extended, unblinded PK follow-up
through Week 68.
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1.3
Schedule of Activities (SoA)
1.3.1
Schedule of Activities (Base Study)
Study Period
Screen
ing
Intervention (Blinded)
Follow-up (Blinded)
Notes
Visit Number
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
Scheduled 
Day/Week 
Screening
Day 1
Day 2
Week 1
Week 2
Week 3
Week 4
Week 8
Week 12
Week 16
Week 20
Week 21
Week 22
Week 23
Week 24
FW 1-2*
FW 2-3*
FW 4
FW 8
FW 12a
Calculate each visit from Day 1. 
* Only for PBMC/PK Bridging 
Subset
Visit Window 
(Days)
≤45 
days
NA
+ 1 day
± 2 days
± 7 days
± 2 days
± 7 days
Administrative Procedures
Informed consent
X
Providing documented informed 
consent for the main study will 
be considered the start of the 
screening window.
Informed consent 
for Future 
Biomedical 
Research
X
Participant 
identification 
card
X
X
Add randomization number on 
Day 1.
Inclusion/
exclusion criteria
(confirm 
eligibility)
X
X
Review prior to dose on Day 1.
Register study 
visit in IRT
X
X
X
X
X
X
X
X
X
X
X
X
Randomization
X
Dispense study 
intervention
using IRT and 
administer
X
X
X
X
X
X
Directly observed dosing. Add 
randomization number and visit 
number to bottle at time of 
dispensing.
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Study Period
Screen
ing
Intervention (Blinded)
Follow-up (Blinded)
Notes
Visit Number
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
Scheduled 
Day/Week 
Screening
Day 1
Day 2
Week 1
Week 2
Week 3
Week 4
Week 8
Week 12
Week 16
Week 20
Week 21
Week 22
Week 23
Week 24
FW 1-2*
FW 2-3*
FW 4
FW 8
FW 12a
Calculate each visit from Day 1. 
* Only for PBMC/PK Bridging 
Subset
Visit Window 
(Days)
≤45 
days
NA
+ 1 day
± 2 days
± 7 days
± 2 days
± 7 days
Offer condoms 
and lubricant
X
X
X
X
X
X
X
X
X
For sexually active participants. 
Document offer in participant 
chart.
Safety Procedures
Medical history
X
X
HIV-infection 
risk evaluation
X
X
X
X
X
X
X
X
X
X
X
Document in participant chart. 
Screening and Day 1 (prior to 
dose) based on Inclusion 
Criterion #3. Assess any changes 
in risk status and PrEP eligibility
using Appendix 8 after 
randomization.
Prior/concomitan
t medication 
review
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Prior to dose on Day 1.
Contraceptive 
use confirmation
X
X
X
X
X
X
X
X
X
X
X
Prior to dose on Day 1.
Document in participant chart.
Complete
physical exam
X
Symptom-
directed physical 
exam
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Prior to dose on Day 1.
Vital signs
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Prior to dose on Day 1.
Includes body temperature, 
pulse, respiratory rate, and 
systolic and diastolic blood 
pressure.
Height
X
Weight
X
X
X
X
X
X
X
X
X
X
X
Prior to dose on Day 1.
AE assessment
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Prior to and after dose on Day 1.
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Study Period
Screen
ing
Intervention (Blinded)
Follow-up (Blinded)
Notes
Visit Number
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
Scheduled 
Day/Week 
Screening
Day 1
Day 2
Week 1
Week 2
Week 3
Week 4
Week 8
Week 12
Week 16
Week 20
Week 21
Week 22
Week 23
Week 24
FW 1-2*
FW 2-3*
FW 4
FW 8
FW 12a
Calculate each visit from Day 1. 
* Only for PBMC/PK Bridging 
Subset
Visit Window 
(Days)
≤45 
days
NA
+ 1 day
± 2 days
± 7 days
± 2 days
± 7 days
12-lead ECG
X
X
At Week 20, perform postdose.
DEXA scan for 
body 
composition and 
BMD (subset 
where allowed 
per country 
regulations)
X
X
Baseline scan can occur any time 
between confirmation of 
eligibility and before 
randomization (repeat baseline 
can be performed up to 14 days 
after randomization).
Perform Week 24 scan ± 14 days 
of visit.
Laboratory Evaluations/Procedures
HIV-1 and HIV-
2 Screen
X
X
X
X
X
X
X
X
X
X
X
Prior to dose on Day 1.
HBV and HCV 
testing
X
Syphilis 
serologic testing
X
Rectal swab 
GC/CT testing
X
Oropharyngeal 
swab GC/CT 
testing
X
Vaginal swab 
GC/CT & 
trichomoniasis
testing (females 
only)
X
Urine GC/CT &
trichomoniasis
testing (males 
only)
X
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Study Period
Screen
ing
Intervention (Blinded)
Follow-up (Blinded)
Notes
Visit Number
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
Scheduled 
Day/Week 
Screening
Day 1
Day 2
Week 1
Week 2
Week 3
Week 4
Week 8
Week 12
Week 16
Week 20
Week 21
Week 22
Week 23
Week 24
FW 1-2*
FW 2-3*
FW 4
FW 8
FW 12a
Calculate each visit from Day 1. 
* Only for PBMC/PK Bridging 
Subset
Visit Window 
(Days)
≤45 
days
NA
+ 1 day
± 2 days
± 7 days
± 2 days
± 7 days
Serum pregnancy 
test (β-hCG)
X
Performed by the central 
laboratory per local regulations.
Urine pregnancy 
test (WOCBP 
only)
X
X
X
X
X
X
X
X
X
X
Performed by the local 
laboratory (kits provided) per 
local regulations. Prior to dosing 
on Day 1. Positive results to be 
confirmed with serum pregnancy 
test.c
Hematology 
X
X
X
X
X
X
X
X
X
X
X
Collect Day 1 samples prior to 
dosing. 
Refer to Appendix 2 and 
laboratory manual for specific 
laboratory tests.
Chemistry
X
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
X
Cystatin-C
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Urinalysis
X
X
X
X
X
X
X
X
X
X
X
Urinary analytes
X
X
X
X
Pharmacokinetics (All participants)
PK blood sample 
collection
X
X
X
X
X
X
X
X
X
X
X
X
X
X
On Day 1 and Week 20, collect 
predose AND 30-min postdose.
On Day 2 collect ~ 24 hours 
after Day 1 dose. On Weeks 4, 8, 
12 and 16, collect predose.
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Study Period
Screen
ing
Intervention (Blinded)
Follow-up (Blinded)
Notes
Visit Number
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
Scheduled 
Day/Week 
Screening
Day 1
Day 2
Week 1
Week 2
Week 3
Week 4
Week 8
Week 12
Week 16
Week 20
Week 21
Week 22
Week 23
Week 24
FW 1-2*
FW 2-3*
FW 4
FW 8
FW 12a
Calculate each visit from Day 1. 
* Only for PBMC/PK Bridging 
Subset
Visit Window 
(Days)
≤45 
days
NA
+ 1 day
± 2 days
± 7 days
± 2 days
± 7 days
Pharmacokinetics (PBMC/PK Bridging Subset)
Participants are from pre-
selected sites. Refer to 
laboratory/study operation 
manual for special collection and 
processing requirements.
Informed consent 
for PBMC/PK 
Bridging Subset 
sample collection
X
PBMC collection
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
At dosing visits, collect samples 
predose. On Day 2, collect 
~ 24 hours after Day 1 dose.
Mitra/VAMS™ venous sample 
at Day 1 and Week 20 are 
prepared from predose MK-8591 
PK blood samples.
Mitra/VAMS™ 
collection-
venous sample
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Pharmacokinetics (Tissue Biopsy Subset)
Participants are from pre-
selected sites. Refer to the 
laboratory/study operation 
manual for special collection and 
processing requirements.
Pap smear test 
(only females 
providing 
cervical biopsy 
sample) 
X
Not required if documented 
normal pap smear within 36 
months of screening is available. 
Send to local laboratory before 
randomization. 
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Study Period
Screen
ing
Intervention (Blinded)
Follow-up (Blinded)
Notes
Visit Number
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
Scheduled 
Day/Week 
Screening
Day 1
Day 2
Week 1
Week 2
Week 3
Week 4
Week 8
Week 12
Week 16
Week 20
Week 21
Week 22
Week 23
Week 24
FW 1-2*
FW 2-3*
FW 4
FW 8
FW 12a
Calculate each visit from Day 1. 
* Only for PBMC/PK Bridging 
Subset
Visit Window 
(Days)
≤45 
days
NA
+ 1 day
± 2 days
± 7 days
± 2 days
± 7 days
Informed consent 
for Tissue 
Biopsy Subset 
sample collection
X
Pelvic and/or 
rectal 
examination
X
X
X
X
X
Perform rectal exam prior to 
rectal biopsy, and pelvic exam 
prior to cervical and/or vaginal 
biopsy. Document exam in 
participant chart.
Rectal, vaginal, 
cervical tissue 
sample collection
X
X
X
X
At Week 4, collect predose.
Post-biopsy 
contact 
(only participants 
providing biopsy 
sample)
X
X
X
X
Call within 48 hours of the 
biopsy and document in 
participant chart.
Pharmacokinetics (Implant/Depot DDI Subset)
Participation is based on 
hormonal contraceptive use at 
screening (Section 8.6.4).
Informed consent 
for 
Implant/Depot 
DDI Subset 
sample collection
X
Blood sample 
collection for 
ENG, MPA, or 
NET levels
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
On Day 1, Week 8 and Week 20, 
collect predose AND 30-min 
postdose. On Weeks 4, 12 and 
16, collect predose.
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Study Period
Screen
ing
Intervention (Blinded)
Follow-up (Blinded)
Notes
Visit Number
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
Scheduled 
Day/Week 
Screening
Day 1
Day 2
Week 1
Week 2
Week 3
Week 4
Week 8
Week 12
Week 16
Week 20
Week 21
Week 22
Week 23
Week 24
FW 1-2*
FW 2-3*
FW 4
FW 8
FW 12a
Calculate each visit from Day 1. 
* Only for PBMC/PK Bridging 
Subset
Visit Window 
(Days)
≤45 
days
NA
+ 1 day
± 2 days
± 7 days
± 2 days
± 7 days
Biomarkers/FBR
Blood for 
Genetic 
Analysisb
X
Collect at predose from enrolled 
participants only.
AB=antibody; AE=adverse event; AG=antigen; β-hCG=beta human chorionic gonadotropin; BMD=bone mineral density; CG=Cockcroft-Gault; DDI=drug-drug interaction; 
DEXA=Dual X-ray Absorptiometry; DNA=deoxyribonucleic Acid; ECG=electrocardiogram; ENG=etonogestrel; FBR=future biomedical research; FW=follow-up week; 
GC/CT=Neisseria gonorrhoeae/Chlamydia trachomatis; HBV=hepatitis B virus; HCV=hepatitis C virus; HIV=human immunodeficiency virus; IRT=Interactive Response 
Technology; MPA=medroxyprogesterone acetate; NA=not applicable; NET=norethisterone or norethindrone; PBMC=peripheral blood mononuclear cell; PK=pharmacokinetics; 
PrEP=pre-exposure prophylaxis; WOCBP=a woman/women of childbearing potential.
a Participants who consent to participate in the PBMC/PK Bridging Subset and who are randomized to receive MK-8591 will have an additional 32-week extended, unblinded PK 
follow-up through Week 68 (FW 44 visit) (Section 1.3.2).
b This sample should be drawn for planned analysis of the association between genetic variants in DNA and drug response. This sample will not be collected at that site if there is 
either a local law or regulation prohibiting collection, or if the IRB/IEC does not approve the collection of the sample for these purposes. If the sample is collected, leftover 
extracted DNA will be stored for future biomedical research if the participant (or their legally acceptable representative) provides documented informed consent for future 
biomedical research. If the planned genetic analyses are not approved, but future biomedical research is approved and consent is given, this sample will be collected for the 
purpose of future biomedical research.
c For participants who become pregnant while receiving study intervention and consent to infant follow-up, their infant will have safety follow-up through approximately 1-year 
of age as outlined in the Schedule of Activities – Infant Safety Follow-up (Section 8.3.7).
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1.3.2
Schedule of Activities for the Extended, Unblinded PK Follow-up for Participants on MK-8591 in the PBMC/PK 
Bridging Subset
Study Period
Follow-up (Unblinded)
Notes
Visit Number
21
22
23
24
Scheduled Day/Week 
FW 20
FW 28
FW 36
FW 44
Calculate each visit from Day 1. 
Visit Window (Days)
±14 days
HIV-infection risk evaluation
X
X
X
X
Document in participant chart.
Assess any changes in risk status and 
PrEP eligibility (Appendix 8).
Concomitant medication review
X
X
X
X
AE assessment a
X
X
X
X
PBMC collection
X
X
X
X
Hematology
X
X
CD4+ T-cell count
X
X
AE=adverse event; FW=follow-up week; HIV=human immunodeficiency virus; PBMC=peripheral blood mononuclear cell; PK=pharmacokinetic; PrEP=pre-exposure prophylaxis; SAE=serious 
adverse event.
a During the extended, unblinded PK follow-up period (after FW 12 visit through FW 44 visit), only SAEs and nonserious AEs related to study procedures will be collected.
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1.3.3
Schedule of Activities (HIV Infection Confirmation and Early Discontinuation)
Study Period
HIV Infection 
Confirmationa
Early Discontinuationb
Notes
Visit Number
Unscheduled
Scheduled Day/Week
HIV Infection Confirmation 
Early Discontinuation from 
Study Intervention
Early Withdrawal 
from Study
Visit Window
Within 14 days of HIV-
positive test
NA
NA
Administrative Procedures
Offer condoms and 
lubricant
X
X
X
For sexually active participants. Document offer 
in participant chart.
Register study visit in 
IRT
X
Only needed if discontinuation from study 
intervention occurs prior to the participant 
receiving the final dose at the Week 20 visit.
Safety Procedures
HIV-infection risk 
evaluation
X
X
X
Document in participant chart.
Assess any changes in risk status and PrEP
eligibility (Appendix 8).
Concomitant 
medication review
X
X
X
Contraceptive use 
confirmation
X
X
X
Document in participant chart. 
Full physical exam
X
X
Vital signs
X
X
Includes body temperature, pulse, respiratory 
rate, and systolic and diastolic blood pressure
Weight
X
X
AE assessment
X
X
X
12-lead ECG
X
Only needs to be performed once post
randomization; should be done at the Early 
Discontinuation from Study Intervention visit for 
participants discontinuing from study 
intervention before the final dose at Week 20.
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Study Period
HIV Infection 
Confirmationa
Early Discontinuationb
Notes
Visit Number
Unscheduled
Scheduled Day/Week
HIV Infection Confirmation 
Early Discontinuation from 
Study Intervention
Early Withdrawal 
from Study
Visit Window
Within 14 days of HIV-
positive test
NA
NA
DEXA scan for body 
composition and BMD
(subset where allowed 
per country regulations)
X
X
Only needs to be performed once post
randomization, at the Early Discontinuation from 
Study Intervention visit for participants 
discontinuing from study intervention before the 
final dose at Week 20, or at the Early Withdrawal 
from Study visit for participants who withdraw 
from the study before the Week 24 study visit. 
Scans should preferably be performed within ±14 
days of the  discontinuation visit.
Laboratory Evaluations/Procedures
HIV-1 and HIV-2 
Screen
X
X
HIV-1 RNA (real time 
PCR)
X
HIV-1 drug resistance 
testing
X
Hematology 
X
X
Refer to Appendix 2 for list of specific laboratory 
tests.
Chemistry
X
X
Creatinine clearance 
calculation (CG)
X
X
Urinalysis
X
X
Urinary analytes 
(if not done at Week 12 
or 24)
X
X
Urine pregnancy test
(WOCBP only)
X
X
Conduct per local regulations. Positive results to 
be confirmed with serum pregnancy test.c
Pharmacokinetics (All participants)
PK blood sample 
collection
X
X
X
Not required if participant is beyond Week 24.
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Study Period
HIV Infection 
Confirmationa
Early Discontinuationb
Notes
Visit Number
Unscheduled
Scheduled Day/Week
HIV Infection Confirmation 
Early Discontinuation from 
Study Intervention
Early Withdrawal 
from Study
Visit Window
Within 14 days of HIV-
positive test
NA
NA
Pharmacokinetics (PBMC/PK Bridging Subset)
Participants are from pre-selected sites. Refer to 
laboratory/study operation manual for special 
collection and processing requirements.
PBMC collection
X
X
X
Mitra/VAMS™ sample 
collection- venous
X
X
Not required if participant is beyond Week 24.
Pharmacokinetics (Tissue Biopsy Subset)
Participants are from pre-selected sites. Refer to 
the laboratory/study operation manual for special 
collection and processing requirements.
Pelvic and/or rectal 
examination
X
X
Perform rectal exam prior to rectal biopsy, and 
pelvic exam prior to cervical and/or vaginal 
biopsy. Document exam in participant chart.
Rectal, vaginal, cervical 
tissue sample collection
X
X
Post-biopsy contact
(only participants who 
provided a biopsy)
X
X
Call within 48 hours of the biopsy and 
document in participant’s chart.
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Study Period
HIV Infection 
Confirmationa
Early Discontinuationb
Notes
Visit Number
Unscheduled
Scheduled Day/Week
HIV Infection Confirmation 
Early Discontinuation from 
Study Intervention
Early Withdrawal 
from Study
Visit Window
Within 14 days of HIV-
positive test
NA
NA
Pharmacokinetics (Implant/Depot DDI Subset)
Participation is based on hormone contraceptive 
use at screening.
Blood sample collection
for ENG, MPA, or NET
levels
X
X
blAB=antibody; AE=adverse event; AG=antigen; BMD=bone mineral density; CG=Cockcroft-Gault; DEXA=Dual X-ray Absorptiometry; ECG=electrocardiogram;
ENG=etonogestrel; FW=follow-up; HIV=human immunodeficiency virus; IRT=Interactive Response Technology; MPA=medroxyprogesterone acetate; NA=not applicable; 
NET=norethisterone or norethindrone; PBMC=peripheral blood mononuclear cell; PCR=polymerase chain reaction; PK=pharmacokinetics; RNA=ribonucleic acid; WOCBP=a 
women/women of childbearing potential.
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
For any participant who discontinues the study or study intervention early, follow-up should be conducted per Section 8.11.3.
An “Early Discontinuation from Study Intervention” visit is required if a participant discontinues study intervention before the final dose at Week 20. If a participant 
concurrently discontinues study intervention and withdraws from the study before the final dose at Week 20, then only the “Early Discontinuation from Study Intervention”
visit needs to be performed.
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. 
c
For participants who become pregnant while receiving study intervention and consent to infant follow-up, their infant will have safety follow-up through approximately 1-year 
of age as outlined in the Schedule of Activities – Infant Safety Follow-up (Section 8.3.7).
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2
INTRODUCTION
MK-8591 (also referred to as islatravir) is a novel, potent NRTTI being developed for 
treatment of HIV-1 infection and for prevention of HIV-1 infection in individuals currently 
uninfected with HIV-1 but who are at high risk of becoming infected. 
2.1
Study Rationale
HIV-1 infection remains a worldwide epidemic with an estimated 36.9 million individuals
infected globally [World Health Organization 2018]. Novel strategies to prevent HIV 
acquisition could help reduce the global burden. One proven biomedical intervention for the 
prevention of HIV-1 infection is PrEP. Despite FTC/TDF being approved in some countries
for use as PrEP, in 2017 approximately 1.8 million new HIV-1 infections occurred 
worldwide [World Health Organization 2018]. The ongoing epidemic and new infection rate 
has resulted in a growing collective care burden, particularly as a chronic infection, with a 
risk for complications, that will require life-long treatment for each individual infected with 
HIV-1. Therefore, additional options for PrEP remain urgently needed.
Approval of FTC/TDF for PrEP was based on data from 2 Phase 3 studies, which
demonstrated that efficacy is strongly correlated with adherence to daily therapy [Grant, R. 
M., et al 2010] [Baeten, J. M., et al 2012]; however, adherence to daily FTC/TDF had been 
shown to be suboptimal in many people at risk of HIV-1 infection [Marrazzo, J. M., et al 
2015] [Hojilla, J. C., et al 2018].
MK-8591 is differentiated from other antiretrovirals based on its high potency, long half-life, 
favorable drug resistance profile, and broad pharmacologic distribution. Because of the long 
intracellular half-life of the active form of MK-8591-TP, a QM dosing regimen is being 
investigated. This dosing schedule is anticipated to facilitate adherence and be highly 
effective in preventing HIV-1 acquisition.
This Phase 2a study will evaluate the safety, tolerability, and PK of 2 doses of oral MK-8591 
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 monthly dose of oral 
MK-8591 to be evaluated as PrEP in later efficacy studies.
2.2
Background
Refer to the IB for detailed background information on MK-8591.
2.2.1
Pharmaceutical and Therapeutic Background
MK-8591 is an antiretroviral agent, known as an NRTTI, which block HIV-1 reverse 
transcriptase by novel mechanisms of action. MK-8591 is an inactive nucleoside that is 
converted to the pharmacologically-active triphosphate form via endogenous intracellular 
kinases. It acts through multiple mechanisms, including both immediate chain termination by 
inhibiting translocation and delayed chain termination by preventing nucleotide excision 
[Michailidis E 2014].
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MK-8591 is extremely potent at low doses and has a very long intracellular half-life. In a 
monotherapy, proof of concept study in treatment-naïve HIV-1-infected participants (MK-
8591 Protocol 003), MK-8591, given in single doses as low as 0.5 mg, showed VL 
reductions greater than 1.0 log10 on average with no recrudescence for at least 7 days and no 
evidence of selection for any resistance-associated mutations. In healthy adult volunteers, 
MK-8591 has a plasma half-life of approximately 47 to 87 hours, while the active 
triphosphate (MK-8591-TP) demonstrates a half-life of approximately 120 to 210 hours in 
PBMCs. A rhesus macaque model demonstrated that levels of MK-8591-TP in rectal tissues 
were similar to those measured in vaginal tissues and both were at levels that suggest MK-
8591 could be effective for prophylaxis against HIV-1 in both men and women [Grobler, J. 
A., et al 2017]. Similarly, at steady state with daily dosing, MK-8591-TP levels in rectal and 
vaginal tissues have been found to be generally similar to one another and to concurrent 
levels in PBMCs, at levels projected to be efficacious for treatment and prevention (MK-
8591-009). Its high potency, long half-life and tissue distribution make MK-8591 a good 
candidate for further investigation as an HIV-chemoprophylactic agent.
2.3
Benefit/Risk Assessment
High potency against wild-type and resistant variants of HIV-1 virus, and a long half-life 
make ISL a suitable candidate for further development as a novel, long-acting PrEP agent. 
The comprehensive nonclinical safety evaluations of ISL, including developmental toxicity 
studies, have not revealed toxicities of concern. In a rhesus macaque SHIV intrarectal 
challenge model [Markowitz, M., et al 2019], ISL provided protection against infection at 
drug levels that are projected to be achieved with the dose regimen used in this study.
In a Phase 2 study (MK-8591-013) for once weekly HIV-1 treatment, decreases in 
lymphocyte and CD4+ T-cell counts from baseline were observed in the ISL 20 mg + 
MK-8507 treatment arms at Week 12 and Week 24. Decreases in lymphocytes were observed 
in all dosing arms of ISL + MK-8507 starting at Week 8 with further decreases continuing 
through Week 24. By Week 24, 20 of 58 participants on ISL + MK-8507 had a decrease in 
lymphocyte count of >30% (of which 9 had a >50% reduction). These reductions were more 
pronounced in the 2 higher MK-8507 dose arms (200 and 400 mg), potentially indicating a 
dose-response relationship. Dosing of ISL + MK-8507 in MK-8591-013 has been 
discontinued.
All clinical studies of ISL were evaluated for similar trends in lymphocytes and CD4+ 
T-cells across all indications and dosing regimens.
In 2 Phase 3 studies (MK-8591A-017 and MK-8591A-018) evaluating a switch to daily 
DOR/ISL in virologically suppressed participants, at Week 48 there were 10.6% and 8.5% 
mean decreases in lymphocyte counts from baseline in the DOR/ISL groups, compared with 
2.27% and 3.46% increases from baseline in the comparator arms. In the same studies, 
DOR/ISL-treated participants experienced a mean change in CD4+ T-cell counts of -0.7%
and 0.9%, compared with an increase of 8.7% in the baseline ART group and 12.8% in the 
BIC/FTC/TAF group. At this time, the data review support continuation of the Phase 3 
clinical studies for the DOR/ISL daily HIV-1 treatment program.
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Among participants in this study (MK-8591-016) at study Week 24, there was a 21% mean 
decrease in total lymphocytes observed in the 60 mg arm (the dose being evaluated in Phase 
3 PrEP trials), a 36% decrease in total lymphocytes observed in the 120 mg arm, and a 4% 
increase in the placebo arm compared to baseline values. Less than 5% of the participants in 
the ISL 60 mg arm had a >50% reduction in total lymphocyte counts during the study with 
3 of 95 participants reporting Grade 2 lymphocyte reductions and 1of 95 participants 
reporting a transient Grade 3 lymphocyte reduction (transient). Two (2 of 97) participants in 
the 120 mg arm had Grade 3 lymphocyte reductions. In this population of HIV-1 uninfected 
participants, the mean decreases in lymphocytes were in the normal range and there was no 
increase in clinical AEs related to infection. At this time, the data review support 
continuation of clinical studies for the ISL HIV-1 PrEP program with a dose of 60 mg 
monthly.
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. In this case, MK-8591 is being developed for 
the prevention of HIV-1 infection, and participants will be neither HIV-1–infected nor at 
high risk of infection, further reducing the potential for direct individual benefit.
Additional details regarding specific benefits and risks for participants in this clinical study 
may be found in the accompanying IB and informed consent documents.
3
HYPOTHESES, OBJECTIVES, AND ENDPOINTS
There are no hypotheses to be tested in this trial. The following objectives will be evaluated 
in adults at low-risk of HIV-1 infection:
Objectives
Endpoints
Primary

To evaluate the safety and tolerability of 6 once-
monthly doses of MK-8591 (60 mg and 120 mg)
through the last follow-up visit.

Adverse events 

Adverse events leading to 
discontinuation of study 
intervention
Secondary

To evaluate the safety and tolerability of 6 once-
monthly doses of MK-8591 (60 mg and 120 mg) 
with follow-up of 4 weeks after the last dose.

Adverse events 

Adverse events leading to 
discontinuation of study 
intervention

To characterize the plasma pharmacokinetic 
profile of MK-8591.
•
Pharmacokinetic parameters: 
MK-8591 AUC0-672hr, Cmax, 
Ctrough,  t1/2
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Objectives
Endpoints
Exploratory

To characterize the intracellular pharmacokinetic 
profile of MK-8591-triphosphate in peripheral 
blood mononuclear cells up to 48 weeks after 
the last dose of 6 once-monthly doses of MK-
8591 (60 mg and 120 mg).

Pharmacokinetic parameters: 
MK-8591-triphosphate AUC0-
672hr, Cmax, Ctrough, t1/2

To evaluate the amount of MK-8591, MK-8591-
triphosphate, and MK-8591-diphosphate in rectal, 
vaginal, and cervical tissue.

MK-8591, MK-8591-
triphosphate, and MK-8591-
diphosphate tissue 
concentration

To measure the plasma concentrations of 
etonogestrel, medroxyprogesterone acetate, and 
norethindrone among females who use an 
etonogestrel-releasing implant or injectable depot 
medroxyprogesterone acetate or injectable 
norethindrone enanthate.

Plasma concentrations of 
etonogestrel, 
medroxyprogesterone acetate, 
and norethindrone 

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
4
STUDY DESIGN
4.1
Overall Design
This is a randomized, double-blind, placebo-controlled, parallel-group, multicenter study of 
oral MK-8591 (also referred to as islatravir) administered QM in adults who are at low-risk 
of HIV-1 infection.
Approximately 250 participants will be randomized in a 2:2:1 ratio to 1 of 3 intervention 
groups (Group 1: MK-8591 60 mg; Group 2: MK-8591 120 mg; Group 3: placebo). At least 
40% of the study population will be women, at least 80% will be 45 years or younger, and at 
least 30% will be enrolled in Africa. Randomization will be stratified by sex (female, male) 
and region (Africa, non-Africa).
This study consists of a screening period (45 days), intervention period (24 weeks), and a 
follow-up period (12 or 44 weeks). Sponsor approval is required to allow participants to be in 
the study for a longer duration than originally estimated; these cases will be determined 
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collaboratively between the Sponsor and the investigator. In such cases, the site IRB/EC will 
be notified.
During the intervention period, participants will receive a total of 6 oral doses of the assigned 
blinded study intervention (MK-8591 [60 mg or 120 mg] or placebo), 1 dose every 4 weeks, 
starting on Day 1. The final dose will be administered at the Week 20 visit with the final 
dosing period through the Week 24 visit. All participants will complete a follow-up period 
for 12 weeks after the last dosing period (ie, for 12 weeks beyond Week 24). Participants 
who consent to participate in the PBMC/PK Bridging Subset and are randomized to receive 
MK-8591 will have extended unblinded PK follow-up through Week 68 (ie, FW 44 visit) 
(Section 1.3.2) and participants who discontinue study intervention early will be followed for 
12 or 44 weeks after stopping study intervention, respectively.
The primary safety assessment will include all accumulated safety data during the 
intervention and follow-up period. AEs leading to discontinuation from study intervention 
are assessed until Week 20 (last dose received). During the extended, unblinded PK follow-
up period (after FW 12 visit through FW 44 visit), only SAEs and nonserious AEs related to 
study procedures will be collected. The Sponsor will perform ongoing comprehensive review 
of all relevant safety parameters including AEs and laboratory values to assess for overall 
trends and outliers in reported AEs and event toxicities per standard monitoring procedures.
All participants will also be evaluated for plasma PK drug levels. Participants may also agree 
to participate in the following optional PK subsets:

PBMC/PK Bridging Subset (approximately n = 80): Participants will have PBMCs 
collected to measure MK-8591 and analyte drug levels. In parallel, blood samples will be 
collected using the Mitra/VAMS™PK collection method to assess concordance between
these 2 different sampling methods.

Tissue Biopsy Subset (approximately n = 40): Participants will have rectal, cervical 
and/or vaginal tissues biopsies collected to analyze MK-8591 and analyte drug levels in 
tissue.

Implant/Depot DDI Subset (approximately n = 30): Female participants who are using an 
ENG-releasing implant (ie, Nexplanon® or Implanon NXT®) or injectable-MPA or 
injectable-NET-EN (eg, Noristerat, Syngestal) will have blood samples collected to 
measure plasma concentrations of these hormonal contraceptives.
At Week 24, the Sponsor will be unblinded but participants and investigators/clinical site 
personnel will remain blinded up to Week 36 (FW 12 visit). Participants in the PBMC/PK
Bridging Subset will be unblinded to MK-8591/placebo after Week 36 (FW 12) and prior to 
Week 44, but will remain blinded, along with their respective investigators/clinical site 
personnel, to MK-8591 dose (60 mg versus 120 mg). Only participants assigned to MK-8591
in the PBMC/PK Bridging Subset will continue in the 32-week extended, unblinded PK 
follow-up period through Week 68 (FW 44 visit). Refer to the study binder for more details 
on the unblinding procedure.
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Specific procedures to be performed during the study, as well as their prescribed times and 
associated visit windows, are outlined in the SoA in Section 1.3. Details of each procedure 
are provided in Section 8.
4.2
Scientific Rationale for Study Design
The main objective of this study is to characterize the safety, tolerability, and PK of MK-
8591 in a larger and more diverse population than studied to date. The study will enroll 
participants who are at low-risk of HIV-1 infection, and as such, this is not an efficacy study.
According to CDC and WHO guidelines [Centers for Disease Control and Prevention 2018] 
[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 
is an approved product (FTC/TDF).
Based on population PK predictions for QM administration from clinical experience to date, 
MK-8591 doses of 60 mg and 120 mg QM are predicted to achieve threshold levels for HIV-
1 prevention that would last more than 4 weeks. Further, simulations using a population PK 
model based on Phase 1 study data predict that after 1 dose of 60 mg or 120 mg, intracellular 
MK-8591-TP levels may persist above the threshold concentration for more than 8 weeks
(Section 4.3). Therefore, in this study, participants will be followed for 12 to 44 weeks after 
the last dosing period of MK-8591 is completed at Week 24 to allow full characterization of 
the MK-8591-TP PK profile.
The number of participants (N ~ 250) and the 24-week intervention period duration allows 
characterization of the safety profile of MK-8591 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, ≥80% of the participants enrolled in this study will be ≤45 years, 
≥40% will be women, and ≥30% will be enrolled in Africa.
4.2.1
Rationale for Endpoints
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 (hematology, 
chemistry, and urinalysis) performed per the SoA (Section 1.3). AEs will be evaluated at 
each visit and assessed according to the guidelines in Section 8.4. Participants may be asked 
to return for unscheduled visits in order to perform additional safety monitoring.
Lipodystrophy and decreases in BMD have been reported in HIV-1-infected individuals 
taking some antiretroviral agents [AIDS info 2017] [Brown, T. T. 2006]. Based on the 
preclinical and clinical data to date, MK-8591 has not been associated with lipodystrophy or 
BMD issues. This study provides a greater opportunity to assess whether MK-8591 has any 
effect on body fat distribution or BMD because, unlike in HIV-1 treatment studies,
participants are neither infected with HIV nor on any other antiretroviral agents. Assessments
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of spine and hip BMD, as well as distribution of peripheral and trunk fat, will be conducted 
with DEXA scans per the SoA (Section 1.3) to evaluate if changes are observed with the use 
of 60 mg and 120 mg MK-8591 compared to each other and to placebo.
Additionally, 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 [Tetteh, R. A., et al 2017]. This study provides the opportunity to evaluate 
the impact of MK-8591 on renal functions as measured by laboratory markers, such as 
urinary (eg, albumin, protein, creatinine, B-2M/Cr, RBP/Cr) and serum (eg, creatinine, 
cystatin-C, and creatinine clearance) analytes and calculations.
4.2.1.2
Pharmacokinetic Endpoints
Sparse plasma PK samples will be collected from all participants and the data will be used in 
a population PK model for MK-8591 and MK-8591-TP levels (Section 8.6).
4.2.1.2.1
PBMC/PK Bridging Subset
The PBMC data collected from the PBMC/PK Bridging Subset will be used as part of the 
population PK model for MK-8591 and MK-8591-TP levels (Section 8.6). The
Mitra/VAMS™venous PK samples will not be used to evaluate the MK-8591 doses but 
rather to establish a correlation between this sampling method to more standard in-clinic PK 
sample collection methods (venipuncture) for potential use in future studies.
4.2.1.2.2
Tissue Biopsy Subset
Tissue biopsies will be performed at 4 different timepoints to collect rectal, vaginal, and/or
cervical tissue samples to measure the tissue concentrations of MK-8591, MK-8591-TP, and 
MK-8591-DP as described in the SoA (Section 1.3) and Section 8.6. The reason for including 
the MK-8591-DP in tissue concentrations measurement is to confirm and cross validate the 
MK-8591-TP to MK-8591-DP ratio. Moreover, this will also confirm stabilization of the 
tissue samples. The extent of antiretroviral penetration into genital tract mucosa may have 
implications for the prevention of sexual transmission of HIV. Therefore, the extent of MK-
8591 penetration to genital tract tissue will be measured in rectal (males and females) and 
vaginal and cervical mucosal tissue (females only). In addition, there is evidence that HIV 
may reside within anatomical “sanctuary sites,” where local drug exposure and viral 
dynamics may differ from those in the systemic compartment [Else, L. J., et al 2011]. Poor 
penetration of antiretrovirals into the mucosa of the genital tract might lead to suboptimal 
antiretroviral concentrations in these areas, leading to compartmentalized viral replication 
and re-entry of wild-type or drug-resistant strains into the systemic circulation [Else, L. J., et 
al 2011].
4.2.1.2.3
Implant/Depot DDI Subset
Plasma samples to measure concentrations of ENG, MPA, or NET will be collected as 
described in the SoA (Section 1.3) and Section 8.6. Although a Phase 1 clinical
pharmacology DDI study (MK-8591 Protocol 006) of oral contraceptive pills (levorgestrel 
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0.15 mg/ethinyl estradiol 0.03 mg) did not find any interactions with MK-8591, ENG-
releasing implants, injectable-MPA, and injectable-NET-EN deliver and maintain relatively 
lower levels of systemic hormones compared to daily, oral contraceptives. Because ENG,
MPA, and NET are metabolized via cytochrome P-450 3A4, which is the same metabolic 
pathway of levorgestrel and ethinyl estradiol, no DDIs are expected between ENG, MPA, or 
NET, and MK-8591. It is important, however, to evaluate these potential DDIs, as females 
who are at risk for sexual acquisition of HIV-1 infection may also be at risk for unintended 
pregnancy and want to prevent pregnancy with the use of implanted and injected hormones 
for contraception.
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 absorption, distribution, metabolism, and excretion; mechanism of action of 
the drug; disease etiology; and/or molecular subtype of the disease being treated. Therefore, 
where local regulations and IRB/IEC allow, a sample will be collected for DNA analysis 
from consenting participants.
DNA samples may be used for research related to the study intervention(s), the disease under 
study, or related diseases. They may also be used to develop tests/assays including diagnostic 
tests related to the disease under study, related diseases, and study intervention(s). Genetic 
research may consist of the analysis of 1 or more candidate genes, the analysis of genetic 
markers throughout the genome, or analysis of the entire genome. Analysis may be 
conducted if it is hypothesized that this may help further understand the clinical data.
The samples may be analyzed as part of a multi-study assessment of genetic factors involved 
in the response to understand study disease or related conditions.
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 future biomedical research 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 (as part of the main study) and will only be conducted on specimens from 
appropriately consented participants. The objective of collecting/retaining specimens for 
future biomedical research is to explore and identify biomarkers that inform the scientific 
understanding of diseases and/or their therapeutic treatments. The overarching goal is to use 
such information to develop safer, more effective drugs/vaccines, and/or to ensure that 
participants receive the correct dose of the correct drug/vaccine at the correct time. The 
details of future biomedical research are presented in Appendix 6.
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4.2.2
Rationale for the Use of Placebo
The primary goal of the study is to evaluate the safety and tolerability of oral MK-8591 in a 
population with low-risk of HIV-1-infection. A placebo-controlled study will allow for a 
robust, unbiased evaluation of the safety and tolerability profile of MK-8591.
4.2.3
Rationale for Collecting Race and Ethnicity
Differential effects on safety and efficacy based on any demographic parameter, including 
race or ethnicity, cannot be predicted for a new investigational intervention. Therefore, it is 
important to collect race and ethnicity data to investigate such differential effects
prospectively. Furthermore, it is important to record these demographic parameters to ensure
the results observed in the clinical study will be applicable to and representative of the 
intervention’s use in a broader patient population. As 1 example, non-Caucasian females and 
males were found to have higher plasma concentrations of EFV (an NNRTI) than their 
Caucasian counterparts. These findings could indicate an increased risk of EFV-induced 
toxicity in non-Caucasian patients [Burger, D., et al 2005]. As another example, among the 
population with HIV in the United States, those of African heritage have been found to be 
less likely to maintain virologic suppression compared to other groups and the factors 
contributing to this remain to be elucidated [Weintrob, A. C., et al 2009] [Ribaudo, H. J., et 
al 2013]. Thus, sub group analyses on race and ethnicity will be performed to better 
understand how these parameters may influence clinical outcome and toxicity.
4.2.4
Rationale for Collecting Infant Safety Follow-up Data
Although women who become pregnant during the study will be required to discontinue 
study intervention, it is important to collect information on infants born to participants who 
become pregnant while receiving MK-8591. Follow-up through 1-year of age for infants 
born to participants who become pregnant while receiving study intervention provides the 
ability to monitor growth and development as well as potential adverse effects that may be 
associated with prenatal drug exposure. Growth parameters (ie, length, weight, and head 
circumference) within normal range at approximately 1-year of age are key noninvasive 
indicators that a serious congenital malformation caused by in utero drug exposure is 
unlikely.
4.3
Justification for Dose
MK-8591 has been evaluated in 8 completed Phase 1 clinical studies and is currently being 
evaluated in 8 ongoing studies (2 Phase 1 studies, 2 Phase 2 studies [including the current 
study], and 4 Phase 3 studies).
In HIV-1 -infected and -uninfected adult participants, MK-8591 has demonstrated good 
tolerability when administered: as a single oral dose of up to 400 mg; as 3 once-weekly doses 
of up to 100 mg; as a daily dose of 5 mg for 6 weeks; and as 0.25 mg, 0.75 mg and 2.25 mg 
daily for at least 48 weeks (the treatment study of these doses is currently ongoing).
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In a Phase 1 study (MK-8591 Protocol 003) among HIV-1-infected, treatment-naïve 
participants, MK-8591 0.5 mg × 1 resulted in plasma HIV-1 RNA reduction of more than 
1.0 log10 copies/mL. In a rhesus macaque study, weekly administration of MK-8591 resulted
in statistically significant protection against Simian/HIV infection with a MK-8591-TP EC90
of ≈ 24 fmol/106 PBMC (or 0.024 pmol/106 cells) [Markowitz, M., et al 2019]. Based on 
these and other data [Deeks, S. G., et al 1998] [Anderson, P. L., et al 2014] [Anderson, P. L., 
et al 2012], a conservative PK threshold of 0.05 pmol/106 cells was chosen, which is 
approximately 5- to 7-fold above the in vitro IC50 for MK-8591.
Based on preclinical data and Phase 1 population PK modeling, a 60-mg dose is anticipated 
to achieve the threshold concentration of 0.05 pmol/106 cells of MK-8591-TP required for 
HIV-1 prevention efficacy for at least 4 weeks following each dose. In addition, a 120-mg 
dose will exceed the threshold concentration for at least 4 weeks following each dose and 
will also provide additional safety data with longer-term dosing at this level. Furthermore,
MK-8591-TP levels in rectal and vaginal tissues have been found to be generally similar to 
one another and to concurrent levels in PBMCs, at levels projected to be efficacious for 
treatment and prevention, suggesting protective levels will be maintained in anatomical sites 
of potential exposure to HIV-1 (MK-8591-009). This study will fully evaluate the duration of 
efficacious levels/concentrations with follow-up and evaluation through an extended PK 
washout of 12 to 44 weeks following the final dosing period.
Refer to the current IB for other preclinical and clinical data supporting dose selection for 
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 (ie, the 
participant is unable to be contacted by the investigator).
4.4.1
Clinical Criteria for Early Study Termination
The clinical study may be terminated early if the extent (incidence and/or severity) of 
emerging effects/clinical endpoints is such that the risk/benefit ratio to the study population 
as a whole is unacceptable. In addition, further recruitment in the study or at (a) particular 
study site(s) may be stopped due to insufficient compliance with the protocol, Good Clinical 
Practice (GCP), and/or other applicable regulatory requirements, procedure-related problems 
or the number of discontinuations for administrative reasons is too high.
5
STUDY POPULATION
Male/Female participants between the ages of 18 and 65 years (inclusive) will be enrolled in 
this study.
Prospective approval of protocol deviations to recruitment and enrollment criteria, also 
known as protocol waivers or exemptions, is not permitted.
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5.1
Inclusion Criteria
A participant will be eligible for inclusion in the study if the participant:
Type of Participant and Disease Characteristics
1. Is in general good health with laboratory values at screening within the acceptable ranges 
in the protocol.
•
Hemoglobin ≥10.5 g/dL for females and ≥11 g/dL for males
•
Absolute neutrophil count >1000 cells/mm3
•
Platelet count >125,000/mm3
•
Calculated creatinine clearance >90 mL/minute using the Cockcroft-Gault equation
(Appendix 9)
•
ALT and AST <1.25 x 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)
Note: Chemistry and hematology parameters which do not meet the inclusion criteria 
above may be repeated once during the screening period.
2. 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.
3. 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;
•
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;
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•
No new diagnosis of a 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 antiretroviral therapy for HIV-1 infection PrEP or post-exposure 
prophylaxis.
Note: Individuals who have participated in studies of an antiretroviral, such as Phase 1 
studies (excluding MK-8591), may be eligible after consultation with the Sponsor.
Demographics
4. Is male or female, from 18 years to 65 years of age inclusive, at the time of signing the 
informed consent.
Contraception/Pregnancy
Male Participants
Contraceptive use by men should be consistent with local regulations regarding the methods 
of contraception for those participating in clinical studies.
Female Participants
Contraceptive use by women should be consistent with local regulations regarding the 
methods of contraception for those participating in clinical studies.
5. A female participant is eligible to participate if she is not pregnant or breastfeeding, and 
at least one of the following conditions applies:
Is not a WOCBP
OR
Is a WOCBP and using an acceptable contraceptive method, or be abstinent from 
heterosexual intercourse as their preferred and usual lifestyle (abstinent on a long term 
and persistent basis), as described in Appendix 5 during the intervention period and for at 
least 16 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.
A WOCBP must have a negative highly sensitive pregnancy test ([urine or serum] as 
required by local regulations) within 24 hours before the first dose of study intervention.
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If a urine test cannot be confirmed as negative (eg, an ambiguous result), a serum 
pregnancy test is required. In such cases, the participant must be excluded from 
participation if the serum pregnancy result is positive.
Additional requirements for pregnancy testing during and after study intervention are 
located in Appendix 2.
The investigator is responsible for review of medical history, menstrual history, and 
recent sexual activity to decrease the risk for inclusion of a woman with an early 
undetected pregnancy.
Informed Consent
6. The participant (or legally acceptable representative) provides documented informed
consent for the study. The participant may also provide consent/assent for future 
biomedical research. However, the participant may participate in the main study without 
participating in future biomedical research.
Additional Categories
For female participants, the following criteria must also be met to provide cervical 
biopsy samples in the Tissue Biopsy Subset:
7. Has an acceptable Pap result documented within 36 months prior to randomization.
Note: Acceptable results are described in Section 8.1.4.
For female participants, the following criteria must also be met to enroll in the 
Implant/Depot DDI Subset:
8. Is currently using an ENG-releasing implant (ie, Nexplanon or Implanon NXT) or 
injectable-MPA or injectable-NET-EN.
5.2
Exclusion Criteria
The participant must be excluded from the study if the participant:
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.
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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 30 days prior to Day 
1 through the duration of the study.
Note: Time-limited courses of corticosteroids (eg, for asthma exacerbation) will be 
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 through the duration of 
the study.
7. Has previously been randomized in a study and received MK-8591.
Diagnostic Assessments
8. Has QTc interval (using Fridericia correction) >450 msec (for males) or >460 msec (for 
females) or deemed clinically abnormal by the investigator.
Other Exclusions
9. Is female and expecting to conceive or donate eggs at any time during the study.
Note: Investigators should provide appropriate guidance to female participants 
regarding egg donation after completion of the study intervention. Consistent with the 
recommendations for contraceptive use, it is recommended that all female participants 
refrain from egg donation for 16 weeks after their last dose of study intervention.
Note: Donation of sperm should follow local guidelines for men who are participating in 
a clinical study of an investigational product.
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.
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Additionally, a participant will be excluded from the Tissue Biopsy Subset, if the 
participant:
11. Is unwilling to abstain from the following prohibited therapies:

aspirin or NSAIDS for 7 days before biopsy.
Note: Daily or as needed use of low-dose aspirin (no more than 81 mg) is permitted.

heparin, enoxaparin, warfarin, clopidogrel, factor Xa inhibitors, and any other drugs 
that are associated with increased risk of bleeding for 3 days before biopsy and for 7 
days post-biopsy.
A participant will be excluded from providing a rectal, cervical and/or vaginal biopsy 
samples, if he or she:
12. Has carcinoma in situ of the cervix or invasive cervical cancer, rectal cancer, or 
abnormalities of the mucosa, or significant localizing symptom(s), including but not 
limited to presence of any unresolved injury, and infectious or inflammatory condition of 
the local mucosa.
A female participant will be excluded from providing cervical biopsy samples, if she:
13. Had a hysterectomy procedure and the cervix was removed (total hysterectomy).
5.3
Lifestyle Considerations
Participants who are sexually active should be counseled on safer sex practices to prevent 
acquisition of HIV or other sexually-transmitted infections.
5.4
Screen Failures
Screen failures are defined as participants who consent to participate in the clinical study, but 
are not subsequently randomized in the study. A minimal set of screen failure information is 
required to ensure transparent reporting of screen failure participants to meet the 
Consolidated Standards of Reporting Trials (CONSORT) publishing requirements and to 
respond to queries from regulatory authorities. Minimal information includes demography, 
screen failure details, eligibility criteria, and any AEs or SAEs meeting reporting 
requirements as outlined in the data entry guidelines.
5.5
Participant Replacement Strategy
A participant who discontinues from study intervention OR withdraws from the study will 
not be replaced.
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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 interventions to be used in this study are outlined in Table 1.
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Table 1
Study Interventions
Arm 
Namea
Arm 
Type
Intervention 
Name
Type
Dose 
Formulationb
Unit Dose 
Strength(s)
Dosage 
Level(s)
Route of 
Administration
Intervention 
Period
Use
IMP/
NIMPc
Sourcing
Group 1
Experi-
mental
MK-8591
Drug
Capsule
30 mg
60 mg QM
Oral
Day 1 to 
Week 24
Experimental
IMP
Central
Group 1
Experi-
mental
Placebo
Drug
Capsule
0 mg
0 mg QM
Oral
Day 1 to 
Week 24
Placebo
IMP
Central
Group 2
Experi-
mental
MK-8591
Drug
Capsule
30 mg
120 mg QM
Oral
Day 1 to 
Week 24
Experimental
IMP
Central
Group 3
Placebo 
Compar-
ator
Placebo
Drug
Capsule
0 mg 
0 mg QM
Oral
Day 1 to 
Week 24
Placebo
IMP
Central
IMP=investigational medicinal product; NIMP=non-investigational medicinal product; QM=once monthly.
a Each participant will take 4 capsules for each dose. Participants in Group 1 (60 mg MK-8591) will receive 2 capsules of 30 mg MK-8591 and 2 capsules of matching placebo; 
thus, these 2 types of study intervention are listed for Group 1. 
b Capsules should be swallowed whole.
c Definition IMP and NIMP is based on guidance issued by the European Commission. Regional and/or Country differences of the definition of IMP/NIMP may exist. In these 
circumstances, local legislation is followed.
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All supplies indicated in Table 1 will be provided per the "Sourcing" column depending upon 
local country operational requirements. If local sourcing, every attempt should be made to 
source these supplies from a single lot/batch number.
Refer to Section 8.1.8 for details regarding administration of the study intervention.
All placebos were created by the Sponsor to match the active product.
6.2
Preparation/Handling/Storage/Accountability
6.2.1
Dose Preparation
There are no specific calculations or evaluations required to be performed in order to 
administer the proper dose to each participant. The rationale for selection of doses to be used 
in this study is provided in Section 4.3.
6.2.2
Handling, Storage, and Accountability
The investigator or designee must confirm appropriate temperature conditions have been 
maintained during transit for all study intervention received, and any discrepancies are 
reported and resolved before use of the study intervention.
Only participants enrolled in the study may receive study intervention, and only authorized 
site staff may supply or administer study intervention. All study interventions must be stored 
in a secure, environmentally controlled, and monitored (manual or automated) area in 
accordance with the labeled storage conditions with access limited to the investigator and 
authorized site staff.
The investigator, institution, or the head of the medical institution (where applicable) is 
responsible for study intervention accountability, reconciliation, and record maintenance (ie, 
receipt, reconciliation, and final disposition records).
For all study sites, the local country Sponsor personnel or designee will provide appropriate 
documentation that must be completed for drug accountability and return, or local discard 
and destruction if appropriate. Where local discard and destruction is appropriate, the 
investigator is responsible for ensuring that a local discard/destruction procedure is 
documented.
The study site is responsible for recording the lot number, manufacturer, and expiry date for 
any locally purchased product (if applicable) as per local guidelines unless otherwise 
instructed by the Sponsor.
The investigator shall take responsibility for and shall take all steps to maintain appropriate 
records and ensure appropriate supply, storage, handling, distribution, and usage of study 
interventions in accordance with the protocol and any applicable laws and regulations.
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6.3
Measures to Minimize Bias: Randomization and Blinding
6.3.1
Intervention Assignment
Intervention randomization will occur centrally using an interactive response technology 
(IRT) system. There are 3 study intervention arms. Participants will be assigned randomly in 
a 2:2:1 ratio to MK-8591 (60 mg), MK-8591 (120 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-8591 and matching placebo will be packaged identically so that blind is 
maintained.
The Sponsor will be unblinded at Week 24 to allow for an interim evaluation of safety.
Participants and investigators/clinical site personnel will remain blinded up to Week 36 (FW 
12 visit). Participants in the PBMC/PK Bridging Subset will be unblinded to MK-
8591/placebo after Week 36 (FW 12) and prior to Week 44, but will remain blinded, along 
with their respective investigator/clinical site personnel, to MK-8591 dose (60 mg versus 120 
mg). Refer to the study binder for more details on the unblinding procedure.
To allow timely completion of population PK modeling, Sponsor PK personnel will be 
unblinded for the duration of the study. No personnel directly associated with study conduct 
will be unblinded before Week 24. Before granting access to select personnel to unblinded 
drug concentration data and information relevant for population PK modeling (eg, including, 
but not limited to PK sampling schedules, dosing records, etc.), an official memo detailing 
the unblinding procedures and listing of the personnel who will have access (before database 
lock) to the unblinded PK and relevant data will be generated per Sponsor SOP.
See Section 8.1.10 for a description of the method of unblinding a participant during the 
study should such action be warranted.
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6.4
Study Intervention Compliance
Interruptions from the protocol-specified treatment of ≥1 monthly dose require consultation 
between the site and the Sponsor and written documentation of the collaborative decision on 
participant management.
6.5
Concomitant Therapy
Medications specifically prohibited in the exclusion criteria are not allowed during 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 from 
30 days before receiving study intervention through the study duration for all participants:
•
Investigational agents (including devices), except for study intervention(s)
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 16-weeks from the last dose of MK-
8591 Protocol 016 study intervention.
•
Immune therapy agents, immune modulators, or other immunosuppressive therapies
Note: Time-limited courses of corticosteroids (eg, for asthma exacerbation) is allowed.
In addition, for participants (at selected sites) enrolled in the Tissue Subset:
•
Use of aspirin or NSAIDS is not permitted for 7 days before biopsy.
Note: Daily or as needed use of low-dose aspirin (81 mg or less) is permitted.
•
Use of heparin, enoxaparin, warfarin, clopidogrel, factor Xa inhibitors, and any other 
drugs that are associated with increased risk of bleeding is not permitted for 3 days before 
biopsy and for 7 days post-biopsy.
There are no restrictions identified for MK-8591 at this time.
6.5.1
Rescue Medications and Supportive Care
No rescue or supportive medications are specified for use in this study.
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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
antiretroviral therapy 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). In the 
event that the emergency unblinding call center is not available for a given site in this study, 
the central electronic intervention randomization system (IRT) should be used to unblind 
participants and to unmask study intervention identity. The Sponsor will not provide random 
code/disclosure envelopes or lists with the clinical supplies.
See Section 8.1.10 for a description of the method of unblinding a participant during the 
study, should such action be warranted.
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 prior to completion of the protocol-specified intervention 
period will still continue to participate in the study as specified in the SoA (Section 1.3) and 
Section 8.11.3.
Participants may discontinue study intervention at any time for any reason or be discontinued 
from the study intervention at the discretion of the investigator should any untoward effect
occur. In addition, a participant may be discontinued from study intervention by the 
investigator or the Sponsor if study intervention is inappropriate, the study plan is violated, or 
for administrative and/or other safety reasons. Specific details regarding procedures to be 
performed at study intervention discontinuation are provided in Section 8.1.9 and 
Section 8.11.3.
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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 has been unblinded before Week 24 by the 
investigator or through the emergency unblinding call center. If the participant’s 
treatment assignment has been unblinded before Week 24 by the Sponsor, the need for 
the participant to be discontinued from study intervention should be discussed 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), 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 (eg, lymphoma) after randomization.

The participant has confirmed HIV-1 or HIV-2 infection.
Note: Participants who become infected with HIV-1 or HIV-2 prior to Week 36 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 antiretroviral therapy will be provided by the study.
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
The participant has 1 of the following events that are life-threatening AND assessed by 
the investigator to be study drug-related:
o
SAE
OR
o
Grade 4 laboratory AE
For participants who are discontinued from study intervention but continue to be monitored 
in the study, all visits and procedures, as outlined in the SoA, should be completed.
Discontinuation from study intervention is “permanent.” Once a participant is discontinued, 
he/she shall not be allowed to restart study intervention.
7.2
Participant Withdrawal From the Study
A participant must be withdrawn from the study if the participant or participant’s legally 
acceptable representative withdraws consent from the study.
If a participant withdraws from the study, they will no longer receive study intervention or be 
followed at scheduled protocol visits.
Specific details regarding procedures to be performed at the time of withdrawal from the 
study, as well as specific details regarding withdrawal from future biomedical research, are 
outlined in Section 8.1.9. The procedures to be performed should a participant repeatedly fail 
to return for scheduled visits and/or if the study site is unable to contact the participant are 
outlined in Section 7.3.
7.3
Lost to Follow-up
If a participant fails to return to the clinic for a required study visit and/or if the site is unable 
to contact the participant, the following procedures are to be performed:

The site must attempt to contact the participant and reschedule the missed visit. If the 
participant is contacted, the participant should be counseled on the importance of 
maintaining the protocol-specified visit schedule.

The investigator or designee must make every effort to regain contact with the participant 
at each missed visit (eg, telephone calls and/or a certified letter to the participant’s last 
known mailing address or locally equivalent methods). These contact attempts should be 
documented in the participant’s medical record.
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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 9.
See Appendix 2 for detailed list of blood volume collections per sample type and visit. As 
shown in Appendix 2, the amount of blood collected for a participant is dependent on which 
subset(s) the participant is included in. Participants who consent to participate in the 
PBMC/PK Bridging Subset and received MK-8591 will have extended, unblinded PK 
follow-up through Week 68 (FW 44 visit) including collection of an additional 80 mL of 
blood.
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 or restarted on study 
intervention after an extended off-drug period. Further, per this amendment, the 
OnDemand™ device and Mitra/VAMS™ fingerstick samples are no longer being collected 
in this study. Therefore, the total amount of blood collected for a participant may be changed 
beyond what is listed in Appendix 2.
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8.1
Administrative and General Procedures
8.1.1
Informed Consent
The investigator or medically qualified designee (consistent with local requirements) must 
obtain documented informed consent from each potential participant or their legally 
acceptable representative prior to participating this clinical study or future biomedical 
research. If there are changes to the participant’s status during the study (eg, health or age of 
majority requirements), the investigator or medically qualified designee must ensure the 
appropriate documented informed consent is in place.
8.1.1.1
General Informed Consent
Informed consent given by the participant or their legally acceptable representative must be 
documented on a consent form. The form must include the trial protocol number, trial 
protocol title, dated signature, and agreement of the participant (or his/her legally acceptable 
representative) and of the person conducting the consent discussion.
A copy of the signed and dated informed consent form should be given to the participant (or 
their legally acceptable representative) before participation in the study.
The initial ICF, any subsequent revised ICF, and any written information provided to the 
participant must receive the IRB/IEC’s approval/favorable opinion in advance of use. The 
participant or his/her legally acceptable representative should be informed in a timely manner 
if new information becomes available that may be relevant to the participant’s willingness to 
continue participation in the study. The communication of this information will be provided 
and documented via a revised consent form or addendum to the original consent form that 
captures the participant’s or the participant’s legally acceptable representative’s dated 
signature.
If the investigator recommends continuation of study intervention beyond disease 
progression, the participant or their legally acceptable representative will be asked to provide 
documented informed consent.
Specifics about the study and the study population are to be included in the study informed 
consent form.
Informed consent will adhere to IRB/IEC requirements, applicable laws and regulations, and 
Sponsor requirements.
8.1.1.2
Consent and Collection of Specimens for Future Biomedical Research
The investigator or medically qualified designee will explain the future biomedical research 
consent to the participant, or the participant’s legally acceptable representative, answer all of 
his/her questions, and obtain documented informed consent before performing any procedure 
related to future biomedical research. A copy of the informed consent will be given to the 
participant before performing any procedure related to future biomedical research.
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8.1.1.3
Consent for PBMC/PK Bridging Subset
The investigator or medically qualified designee will explain the PBMC/PK bridging consent 
to the participant, answer all of his/her questions, and obtain documented informed consent 
before performing any procedure related to the PBMC/PK Bridging Subset. Participants who 
consent to participate in the PBMC/PK Bridging Subset and who are randomized to MK-
8591 will have extended, unblinded PK follow-up through Week 68 (FW 44 visit) (Section 
1.3.2). A copy of the informed consent will be given to the participant.
8.1.1.4
Consent for Tissue Biopsy Subset
The investigator or medically qualified designee will explain the tissue biopsy consent to the 
participant, answer all of his/her questions, and obtain documented informed consent before 
performing any procedure related to the Tissue Biopsy Subset. A copy of the informed 
consent will be given to the participant.
8.1.1.5
Consent for Implant/Depot DDI Subset
The investigator or medically qualified designee will explain the implant/depot DDI consent 
to the participant, answer all of her questions, and obtain documented informed consent 
before performing any procedure related to the Implant/Depot DDI Subset. A copy of the 
informed consent will be given to the participant.
8.1.1.6
Consent for Infant Safety Follow-up
Depending on applicable laws and regulations, a separate informed consent may be required 
for participation in the infant safety follow-up period (Section 8.3.7). If a separate consent is 
required, the investigator or medically qualified designee will explain the infant safety 
follow-up consent to the participant (or their legally acceptable representative), answer all 
questions, and obtain documented informed consent before collecting any data related to the 
infant follow-up. A copy of the informed consent will be given to the participant.
8.1.2
Inclusion/Exclusion Criteria
All inclusion and exclusion criteria will be reviewed by the investigator, who is a qualified 
physician, to ensure that the participant qualifies for the study.
8.1.3
Participant Identification Card
All participants will be given a participant identification card identifying them as participants 
in a research study. The card will contain study site contact information (including direct 
telephone numbers) to be used in the event of an emergency. The investigator or qualified 
designee will provide the participant with a participant identification card immediately after 
the participant provides documented informed consent. At the time of intervention
randomization, site personnel will add the treatment/randomization number to the participant 
identification card.
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The participant identification card also contains contact information for the emergency 
unblinding call center so that a healthcare provider can obtain information about study 
intervention in emergency situations where the investigator is not available.
8.1.4
Medical History
A medical history will be obtained by the investigator or qualified designee.
For female participants (at selected sites) interested in providing a cervical biopsy sample as 
part of the Tissue Biopsy Subset, the following criteria need to be met prior to 
randomization: 

Documentation is available indicating acceptable Pap results in the 36 months before the 
screening date. An acceptable Pap result is defined as a biopsy consistent with Grade 0 
according to the Female Genital Grading Table for Use in Microbicide Studies 
Addendum 1 to the DAIDS Table for Grading Adult and Pediatric Adverse Events, 
Version 1.0, November 2007.
OR

A Pap test can be performed by the site (sent to local laboratory for processing) before
randomization. If Pap testing is indicated and the participant declines, she can still 
provide a rectal and vaginal biopsy sample (assuming all other criteria are met) but are 
not eligible to provide a cervical biopsy sample during the study. 
8.1.5
Prior and Concomitant Medications Review
8.1.5.1
Prior Medications
The investigator or qualified designee will review prior medication use and record prior 
medication taken by the participant within 30 days before first dose of study intervention. 
For female participants in the Implant/Depot DDI Subset, the most recent date of an ENG-
releasing implant insertion or MPA injection or NET-EN injection (before the first dose of 
study intervention) should be recorded in the appropriate eCRF. 
8.1.5.2
Concomitant Medications
The investigator or qualified designee will record medication, if any, taken by the participant 
during the study.
For female participants in the Implant/Depot DDI Subset, the dates of all ENG-releasing 
implant insertions or MPA injection or NET-EN injection received during the study, 
including the follow-up period, should be recorded in the appropriate eCRF.
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8.1.6
Assignment of Screening Number
All consented participants will be given a unique screening number that will be used to 
identify the participant for all procedures that occur prior to randomization. Each participant 
will be assigned only 1 screening number. Screening numbers must not be re-used for 
different participants.
Any participant who is screened multiple times will retain the original screening number 
assigned at the initial screening visit. Specific details on the screening/rescreening visit 
requirements are provided in Section 8.11.1.
8.1.7
Assignment of Treatment/Randomization Number
All eligible participants will be randomly allocated and will receive a 
treatment/randomization number. The treatment/randomization number identifies the 
participant for all procedures occurring after treatment randomization. Once a 
treatment/randomization number is assigned to a participant, it can never be re-assigned to 
another participant.
A single participant cannot be assigned more than 1 treatment/randomization number.
8.1.8
Study Intervention Administration
All study intervention will be administered at the clinic/investigative site once per month 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, 2 bottles of blinded study intervention will be dispensed per 
participant, each containing 2 capsules (MK-8591 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-8591 60 mg): participants will receive 2 capsules of MK-8591 30 mg and 
2 capsules of matching placebo.

Group 2 (MK-8591 120 mg): participants will receive 4 capsules of MK-8591 30 mg.

Group 3 (Placebo): participants will receive 4 capsules of matching placebo.
All 4 capsules should be taken together, and the actual dosing time for each bottle will be 
recorded separately on the eCRF.
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8.1.8.1
Timing of Dose Administration
Participants will receive 6 observed QM doses of oral MK-8591 or matching placebo, 
starting at Day 1 with a final dose at Week 20 per the following dosing guidelines:

Participants should take the monthly dose of MK-8591/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 monthly dose of MK-8591/placebo and it is outside the 
dosing window (Table 2) for that study visit, the monthly 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.
Table 2
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.
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8.1.9
Discontinuation and Withdrawal
Participants who discontinue study intervention prior to completion of the final dose at 
Week 20 should return to the clinic for an “Early Discontinuation of Study Intervention”
visit and should be encouraged to continue to be followed for all remaining study visits as 
outlined in the SoA (Section 1.3) and Section 8.11.3.
When a participant withdraws from participation in the study, all applicable activities 
scheduled for the “Early Withdraw from Study” visit should be performed (at the time of 
withdrawal). Any AEs that are present at the time of withdrawal should be followed in 
accordance with the safety requirements outlined in Section 8.4.
8.1.9.1
Withdrawal From Future Biomedical Research
Participants may withdraw their consent for future biomedical research. Participants may 
withdraw consent at any time by contacting the investigator for the main study. If medical 
records for the main study are still available, the investigator will contact the Sponsor using 
the designated mailbox (clinical.specimen.management@merck.com). Subsequently, the 
participant's consent for future biomedical research will be withdrawn. A letter will be sent 
from the Sponsor to the investigator confirming the withdrawal. It is the responsibility of the 
investigator to inform the participant of completion of withdrawal. Any analyses in progress 
at the time of request for withdrawal or already performed prior to the request being received 
by the Sponsor will continue to be used as part of the overall research study data and results. 
No new analyses would be generated after the request is received.
In the event that the medical records for the main study are no longer available (eg, if the 
investigator is no longer required by regulatory authorities to retain the main study records) 
or the specimens have been completely anonymized, there will no longer be a link between 
the participant’s personal information and their specimens. In this situation, the request for 
specimen withdrawal cannot be processed.
8.1.10
Participant Blinding/Unblinding
STUDY INTERVENTION IDENTIFICATION INFORMATION IS TO BE UNMASKED 
ONLY IF NECESSARY FOR THE WELFARE OF THE PARTICIPANT. EVERY 
EFFORT SHOULD BE MADE NOT TO UNBLIND.
For emergency situations where the investigator or medically qualified designee (consistent 
with local requirements) needs to identify the intervention used by a participant and/or the 
dosage administered, he/she will contact the emergency unblinding call center by telephone 
and make a request for emergency unblinding. As requested by the investigator or medically 
qualified designee, the emergency unblinding call center will provide the information to 
him/her promptly and report unblinding to the Sponsor. Prior to contacting the emergency 
unblinding call center to request unblinding of a participant’s intervention assignment, the 
investigator who is a qualified physician should make reasonable attempts to enter the 
toxicity grade of the AEs observed, the relation to study intervention, the reason thereof, etc., 
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in the medical chart. If it is not possible to record this assessment in the chart prior to the 
unblinding, the unblinding should not be delayed.
In the event that unblinding has occurred, the circumstances around the unblinding (eg, date, 
reason, and person performing the unblinding) must be documented promptly, and the 
Sponsor Clinical Director notified as soon as possible.
Participants whose treatment assignment has been unblinded by the investigator or medically 
qualified designee and/or nonstudy treating physician should continue to be monitored in the 
study.
Additionally, the investigator or medically qualified designee must go into the IRT system 
and perform the unblind in the IRT system to update drug disposition. In the event that the 
emergency unblinding call center is not available for a given site in this study, the IRT 
system should be used for emergency unblinding in the event that this is required for 
participant safety.
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. 
Documentation of equipment calibration must be retained as source documentation at the 
study site.
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/tissue to be drawn/collected over the course of the study 
(from screening through follow-up visits), including approximate blood/tissue volumes 
drawn/collected by visit and by sample type per participant, can be found in 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.
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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).
For participants interested in the Tissue Biopsy Subset, the complete physical examination at 
screening should include pelvic and/or rectal examination. 
At all subsequent visits (Day 1 through FW 12), a brief symptom-directed physical 
examination will be conducted by an investigator or medically qualified designee (consistent 
with local requirements) per institutional standard, sign- and symptom-directed, and based on 
the participant’s condition and circumstances. The investigator should note any changes in 
the participant’s condition (body systems) since the last examination. This does not preclude 
examination of any of the body systems as clinically indicated.
For participants in the Tissue Biopsy Subset, at Week 1, Week 4, Week 24, and FW 8, a
rectal exam should be performed prior to rectal biopsy, and a pelvic exam prior to cervical 
and/or vaginal biopsy. 
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.
8.3.3
Electrocardiograms
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.
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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 semi-recumbent position for at least 10 minutes prior to each ECG 
measurement.
8.3.4
DEXA Assessment
DEXA images should be collected from all participants/sites willing and able to have the test 
performed and according to country law. Participants will not be excluded from participation 
in the study if unwilling/unable to have DEXA images performed.
Only those participants who are confirmed eligible to be randomized will undergo DEXA 
images for BMD of the spine and hip, as well as peripheral and trunk fat. For baseline
assessment, DEXA images should be performed any time after eligibility is confirmed and 
prior to randomization. If a repeat baseline DEXA image is required, it may be performed up 
to 14 days after randomization. The DEXA images at the Week 24 visit (both the original 
scan and a repeat, if necessary) should be performed ±14 days of the scheduled visit. Only 
participants with valid baseline DEXA images should have Week 24 DEXA images 
performed. 
For a participant who discontinues study intervention early or withdraws from the study prior 
to Week 24, DEXA images should preferably be performed within ±14 days of the 
discontinuation visit if possible.
DEXA images will be evaluated by a BICR; these analyses are not performed in real time 
and will not be provided to the site. For clinical management of the participant, the baseline 
and Week 24 DEXA images should be reviewed and interpreted by a local radiologist.
Clinically significant findings noted in the local interpretation of the baseline DEXA images 
(including those DEXA images that need to be repeated up to 14 days after randomization) 
should be recorded in the participant’s medical history. Clinically significant findings noted 
in the local interpretation of the Week 24 DEXA images should be recorded appropriately.
Refer to the Site Imaging Manual for additional details regarding DEXA procedures, 
including participant preparation instructions to be considered prior to DEXA imaging.
8.3.5
Sexually Transmitted Infections
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), a plasma sample will be sent to the central 
laboratory for genotypic and phenotypic viral drug resistance testing.
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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 for safety and PK as outlined in the SoA (Section 1.3).
Other STIs
Testing for GC/CT, syphilis, and trichomoniasis will be performed at Screening as described 
in the SoA (Section 1.3). Testing will be performed by the central laboratory. 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.
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 for safety and PK as outlined in the SoA 
(Section 1.3).
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 #3 (Section 5.1). A participant that does not meet all 
elements of Inclusion Criterion #3 should not be randomized. After randomization (Day 1), 
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 based on the list of questions included in Appendix 8.
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).
8.3.7
Infant Safety Follow-up Assessments
For participants who become pregnant while receiving study intervention (including the 
protocol-specified follow-up period) and consent to infant follow-up, their infant will have 
safety follow-up through approximately 1-year of age as outlined in Section 8.3.7.1. This 
infant safety follow-up data may be collected by phone call or during a participant’s 
scheduled study visit if occurring within the specified data collection window. Length, 
weight, and head circumference measurements will be collected at birth and at 1-year of age. 
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Infant SAEs, including congenital anomalies identifiable on physical examination at birth or 
shortly after birth, will be collected per Section 8.4.1 and should be reviewed at the 
participant’s scheduled study visits that occur during this time. 
8.3.7.1
Schedule of Activities: Infant Safety Follow-up Through 1-Year of Age
Study Period
Infant Safety Follow-up
Visit Name
Infant-Follow Up-1
Scheduled Day
At Birth
1-Year After Birtha
Visit Window
+90 days
+90 days
Administrative and Safety Procedures
Informed Consent (if applicable)b
X
Review pregnancy outcomec
X
Length
X
X
Weight
X
X
Head Circumference
X
X
Review Infant Serious Adverse Eventsd
X------------------------X
a If a participant withdraws from the study, data from 1-Year After Birth should be collected at the time 
of withdrawal.
b Depending on applicable laws and regulations, a separate informed consent may be required (Section 
8.1.1.6).
c Collect and report pregnancy outcome (health of infant) per Section 8.4.5.
d Collect SAEs, including any congenital anomalies, per Section 8.4.1 and review at participant’s 
regularly scheduled study visits.
8.3.8
Clinical Safety Laboratory Assessments
•
Refer to Appendix 2 for the list of clinical laboratory tests to be performed and to the 
SoA for the timing and frequency.

The investigator or medically qualified designee (consistent with local requirements) 
must review the laboratory report, document this review, and record any clinically 
relevant changes occurring during the study in the AE section of the case report form 
(CRF). The laboratory reports must be filed with the source documents. Clinically 
significant abnormal laboratory findings are those which are not associated with the 
underlying disease, unless judged by the investigator to be more severe than expected for 
the participant's condition.

All protocol-required laboratory assessments, as defined in Appendix 2, must be 
conducted in accordance with the laboratory/study operation manual and the SoA.
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
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 16 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.
8.4
Adverse Events (AEs), Serious Adverse Events (SAEs), and Other Reportable 
Safety Events
The definitions of an AE or SAE, as well as the method of recording, evaluating, and 
assessing causality of AE and SAE and the procedures for completing and transmitting AE, 
SAE, and other reportable safety event reports can be found in Appendix 3.
Adverse events, SAEs, and other reportable safety events will be reported by the participant 
(or, when appropriate, by a caregiver, surrogate, or the participant's legally authorized 
representative).
The investigator and any designees are responsible for detecting, documenting, and reporting 
events that meet the definition of an AE or SAE as well as other reportable safety events. 
Investigators remain responsible for following up AEs, SAEs, and other reportable safety 
events for outcome according to Section 8.4.3.
The investigator, who is a qualified physician, will assess events that meet the definition of 
an AE or SAE as well as other reportable safety events with respect to seriousness, 
intensity/toxicity and causality.
8.4.1
Time Period and Frequency for Collecting AE, SAE, and Other Reportable 
Safety Event Information
All AEs, SAEs, and other reportable safety events that occur after the participant provides 
documented informed consent but before intervention randomization must be reported by the 
investigator if the participant is receiving placebo run-in or other run-in treatment, if the 
event causes the participant to be excluded from the study, or is the result of a protocol-
specified intervention, including but not limited to washout or discontinuation of usual 
therapy, diet, or a procedure.
From the time of intervention randomization through 16 weeks after the last dose (FW 12 
visit), all AEs, SAEs, and other reportable safety events must be reported by the investigator. 
For participants in the PBMC/PK Bridging Subset any nonserious AEs related to a study 
procedure and all SAEs must be reported by the investigator through Week 68 (FW 44 visit).
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Additionally, any SAE brought to the attention of an investigator at any time outside of the 
time period specified in the previous paragraph must be reported immediately to the Sponsor 
if the event is considered related to study intervention.
For infants born to participants who become pregnant while receiving study intervention and 
consent to infant follow-up, SAEs occurring (in these infants) from the time of birth through 
1-year of age must be reported by the investigator to the Sponsor within 24 hours of learning 
of the event.
Investigators are not obligated to actively seek AEs or SAEs or other reportable safety events 
in former study participants. However, if the investigator learns of any SAE, including a 
death, at any time after a participant has been discharged from the study, and he/she 
considers the event to be reasonably related to the study intervention or study participation, 
the investigator must promptly notify the Sponsor.
All initial and follow-up AEs, SAEs, and other reportable safety events will be recorded and 
reported to the Sponsor or designee within the time frames as indicated in Table 3.
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Table 3
Reporting Time Periods and Time Frames for Adverse Events and Other 
Reportable Safety Events
Type of Event
Reporting Time 
Period:
Consent to 
Randomization/ 
Allocation
Reporting Time 
Period:
Randomization/ 
Allocation through 
Protocol-specified 
Follow-up Period
Reporting Time 
Period:
After the Protocol-
specified Follow-up 
Period
Time Frame 
to Report 
Event and 
Follow-up 
Information 
to Sponsor:
Nonserious 
Adverse Event 
(NSAE)
Report if:
- due to protocol-
specified intervention
- causes exclusion
- participant is 
receiving placebo 
run-in or other run-in 
treatment
Report all
Not required
Per data 
entry 
guidelines
Serious Adverse 
Event (SAE)
Report if:
- due to protocol-
specified intervention
- causes exclusion
- participant is 
receiving placebo 
run-in or other run-in 
treatment
Report all
Report if:
- drug/vaccine related.
(Follow ongoing to 
outcome)
Within 24 
hours of 
learning of 
event
Pregnancy
/Lactation 
Exposure
Report if:
- due to intervention
- causes exclusion
Report all
Previously reported –
Follow to 
completion/termination; 
report outcome
Within 24 
hours of 
learning of 
event
Event of Clinical 
Interest (require 
regulatory 
reporting)
Report if:
- due to intervention
- causes exclusion
Report
- Potential drug-
induced liver injury 
(DILI)
- Require regulatory 
reporting
Not required
Within 24 
hours of 
learning of 
event
Event of Clinical 
Interest (do not 
require regulatory 
reporting)
Report if:
- due to intervention
- causes exclusion
Report
- non-DILI ECIs and 
those not requiring 
regulatory reporting
Not required
Within 5 
calendar 
days of 
learning of 
event
Cancer
Report if:
- due to intervention
- causes exclusion
Report all
Not required
Within 5 
calendar 
days of 
learning of 
event
Overdose
Report if:
- receiving placebo 
run-in or other run-in 
medication 
Report all
Not required
Within 5 
calendar 
days of 
learning of 
event
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8.4.2
Method of Detecting AEs, SAEs, and Other Reportable Safety Events
Care will be taken not to introduce bias when detecting AEs and/or SAEs and other 
reportable safety events. Open-ended and nonleading verbal questioning of the participant is 
the preferred method to inquire about AE occurrence.
8.4.3
Follow-up of AE, SAE, and Other Reportable Safety Event Information
After the initial AE/SAE report, the investigator is required to proactively follow each 
participant at subsequent visits/contacts. All AEs, SAEs, and other reportable safety events,
including pregnancy and exposure during breastfeeding, events of clinical interest (ECIs), 
cancer, and overdose will be followed until resolution, stabilization, until the event is 
otherwise explained, or the participant is lost to follow-up (as defined in Section 7.3). In 
addition, the investigator will make every attempt to follow all nonserious AEs that occur in
randomized participants for outcome. Further information on follow-up procedures is given 
in Appendix 3.
8.4.4
Regulatory Reporting Requirements for SAE
Prompt notification (within 24 hours) by the investigator to the Sponsor of SAE is essential 
so that legal obligations and ethical responsibilities towards the safety of participants and the 
safety of a study intervention under clinical investigation are met.
The Sponsor has a legal responsibility to notify both the local regulatory authority and other 
regulatory agencies about the safety of a study intervention under clinical investigation. The 
Sponsor will comply with country-specific regulatory requirements and global laws and 
regulations relating to safety reporting to regulatory authorities, IRB/IECs, and investigators.
Investigator safety reports must be prepared for suspected unexpected serious adverse 
reactions (SUSARs) according to local regulatory requirements and Sponsor policy and 
forwarded to investigators as necessary.
An investigator who receives an investigator safety report describing an SAE or other 
specific safety information (eg, summary or listing of SAE) from the Sponsor will file it 
along with the IB and will notify the IRB/IEC, if appropriate according to local requirements.
8.4.5
Pregnancy and Exposure During Breastfeeding
Although pregnancy and infant exposure during breastfeeding are not considered AEs, any 
pregnancy or infant exposure during breastfeeding in a participant (spontaneously reported to 
the investigator or their designee) that occurs during the study are reportable to the Sponsor.
All reported pregnancies must be followed to the completion/termination of the pregnancy. 
Pregnancy outcomes of spontaneous abortion, missed abortion, benign hydatidiform mole, 
blighted ovum, fetal death, intrauterine death, miscarriage, and stillbirth must be reported as 
serious events (Important Medical Events). If the pregnancy continues to term, the outcome 
(health of infant) must also be reported.
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For infants born to participants who become pregnant while receiving study intervention and 
consent to infant follow-up, SAEs occurring (in these infants) from the time of birth through 
1-year of age must be reported by the investigator to the Sponsor within 24 hours of learning 
of the event.
8.4.6
Disease-related Events and/or Disease-related Outcomes Not Qualifying as 
AEs or SAEs
This section is not applicable to this study.
8.4.7
Events of Clinical Interest (ECIs)
Selected nonserious and SAEs are also known as ECIs and must be reported to the Sponsor.
Events of clinical interest for this study include:
•
An elevated AST or ALT lab value that is greater than or equal to 3X the upper limit of 
normal and an elevated total bilirubin lab value that is greater than or equal to 2X the 
upper limit of normal and, at the same time, an alkaline phosphatase lab value that is less 
than 2X the upper limit of normal, as determined by way of protocol-specified laboratory 
testing or unscheduled laboratory testing.*
*Note: These criteria are based upon available regulatory guidance documents. The 
purpose of the criteria is to specify a threshold of abnormal hepatic tests that may require 
an additional evaluation for an underlying etiology. The study site guidance for 
assessment and follow-up of these criteria can be found in the Investigator Study File 
Binder (or equivalent).
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 site in 
consultation with the Sponsor Clinical Director based on the clinical evaluation of the 
participant.
8.6
Pharmacokinetics
Refer to Appendix 2 and the SoA for the list of PK sample collection to be performed, 
including the timing and frequency. The decision as to which samples collected will be 
assayed for evaluation of PK will be collaboratively determined by the Sponsor (eg, samples 
at lower doses may not be assayed if samples at higher doses reveal undetectable drug 
concentrations). If indicated, these samples may also be assayed and/or pooled for assay in an 
exploratory manner for metabolites and/or additional pharmacodynamic markers.
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8.6.1
Blood Collection for Plasma MK-8591
Blood sample collection, storage, and shipment instructions for plasma samples will be 
provided in a laboratory/study operation manual. Plasma samples will be used for MK-8591 
PK analysis.
Plasma population PK samples will be collected from all participants as outlined in the SoA
(Section 1.3). On Day 1 and Week 20 visits, 2 samples will be collected (predose and 30-
minutes postdose). For all other dosing visits (Week 4, 8, 12 and 16), 1 predose sample is 
collected. On Day 2 (Visit 3) it is preferred that PK samples be collected approximately 
24 hours after the Day 1 dose; however, this is not a requirement. For all other non-dosing 
visits, the sample can be collected at any time during the study visit.
The exact time the dose of study intervention was taken prior to the sample collection and the 
time of PK sample collection will be recorded on the appropriate eCRF.
8.6.2
Blood Collection for PBMC/PK Bridging Subset
Participating sites will be trained on sample collection and processing procedures. The exact 
time when study intervention was taken before the sample collection and the time of sample 
collection will be recorded on the appropriate eCRF.
Participants in the PBMC/PK Bridging Subset (n ~ 80) are also permitted to participate in the 
Tissue Biopsy Subset and the Implant/Depot DDI Subset.
8.6.2.1
Intracellular (PBMC) Samples
Blood sample collection, storage, and shipment instructions for PBMC samples will be 
provided in the laboratory/study operation manual. PBMC samples will be used for MK-
8591 PK analysis.
PBMC samples will be collected in this subset of study participants at specific timepoints 
outlined in the SoA (Section 1.3). All PBMC samples should be collected predose on dosing 
visits (Day 1, Week 4, 8, 12, 16 and 20). On Day 2 (Visit 3) it is preferred that PBMC
samples be collected approximately 24 hours after the Day 1 dose; however, this is not a 
requirement. For all other non-dosing visits, the sample can be collected at any time during 
the study visit.
Participants in the PBMC/PK Bridging Subset who received MK-8591 will also have PBMC 
samples collected across 4 additional visits through 48 weeks after last dose (44 weeks after 
the intervention period) as outlined in the SoA (Section 1.3.2). 
8.6.2.2
Mitra/VAMS™Blood Samples
The Mitra® device, powered by VAMS™; Neoteryx, LLC), is a blood collection tool that 
will be used to obtain venous blood samples. The Mitra/VAMS™device will be used to 
absorb blood from a venous blood collection, which will then be analyzed for drug 
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concentrations. Further instructions on use of the Mitra/VAMS™device will be provided in 
the laboratory/study operation manual.
Timepoints for the collection of these samples can be found in the SoA (Section 1.3) and 
Appendix 2. Mitra/VAMS™venous samples at Day 1 and Week 20 are prepared from 
predose MK-8591 PK blood samples.
8.6.3
Tissue Collection for Tissue Biopsy Subset
Rectal, vaginal, and cervical tissue samples from mucosal biopsies will be collected for MK-
8591 PK analysis in a subset of approximately 40 participants enrolled into the Tissue 
Biopsy Subset at trained sites selected by the Sponsor. Biopsy samples will be obtained only 
from participants who agree to participate in the subset and procedures. Participants, at the 
selected sites, who do not consent to participate in this subset are still eligible to participate 
in the study if they meet all eligibility criteria. Participants who do consent to the subset may 
opt-out of providing a biopsy sample at any time.
Participants included in the Tissue Biopsy Subset are strongly encouraged also to participate 
in the PBMC/PK Bridging Subset to allow for the collection of paired PBMC and tissue 
samples which will allow characterization of the relationship between concentrations of MK-
8591-TP in PBMCs and concentration in tissues.
Participants in the Tissue Biopsy Subset may also participate in the Implant/Depot DDI 
Subset.
Male participants will provide rectal biopsy samples at timepoints specified in the SoA 
(Section 1.3). Female participants may choose to provide 1, 2 or all 3 tissue sample types 
(rectal, vaginal and cervical) at the timepoints specified in the SoA (Section 1.3). Tissue 
biopsy samples should be collected predose at Week 4. At the Week 1, Week 24 and Follow-
up Week 8 visit, the tissue biopsy samples can be collected at any timepoint during the clinic 
visit. The exact time when study intervention was taken before the sample collection and the 
time of sample collection will be recorded on the appropriate eCRF.
Rectal, vaginal, and cervical tissue sample collection, storage, and shipment instructions for 
samples will be provided in a laboratory/study operation manual. Biopsy samples will be 
obtained by medical specialists who have expertise in the procedures and according to the 
instructions provided separately and based on local standard of care. 
8.6.3.1
Rectal Tissue Sample
Participants undergoing the rectal biopsy will be administered a saline enema prior to the 
procedure. Immediately before the procedure, the medical specialist will examine the area 
around the anus and then carefully insert a gloved and lubricated finger into the anus to 
perform rectal examination for any abnormalities.
Biopsy samples of adequate size will be taken from participants. Details are provided in the 
laboratory/study operations manual. Use of any and all anesthesia or sedation should be 
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recorded in the concomitant medication section of the CRF. The site will follow-up with the 
participant within 48 hours after the rectal biopsy procedure to determine if any AEs have 
occurred since the procedure. 
8.6.3.2
Vaginal Tissue Sample
Immediately prior to the start of the biopsy procedure, the medical specialist will insert a 
speculum in the vagina and check for any abnormalities. If the medical specialist feels that a 
vaginal infection may be present upon initial examination, the participant may have 1 or 
2 vaginal swabs collected to assess the discharge. If the medical specialist feels there is any 
structural abnormality or lesion of the vagina that would preclude safe biopsy, the procedure 
should be deferred. 
Biopsy samples of adequate size will be taken from participants. Details are provided in the 
laboratory/study operations manual. Use of any and all anesthesia or sedation should be 
recorded in the concomitant medication section of the CRF. The site will follow-up with all 
female participants within 48 hours after the biopsy procedure to determine if any AEs have 
occurred since the procedure.
8.6.3.3
Cervical Tissue Sample
Immediately prior to the start of the biopsy procedure, the medical specialist will insert a 
speculum in the vagina and check for any abnormalities of the cervix. If the medical 
specialist feels that an infection or other abnormality may be present upon initial 
examination, the participant may have 1 or 2 vaginal swabs collected to assess the discharge.
If the medical specialist feels there is any structural abnormality or lesion of the cervix that 
would preclude safe biopsy, the procedure should be deferred.
Biopsy samples of adequate size will be taken from participants. Details are provided in the 
laboratory/study operations manual. Use of any and all anesthesia or sedation should be 
recorded in the concomitant medication section of the CRF. The site will follow-up with all 
female participants within 48 hours after the biopsy procedure to determine if any AEs have 
occurred since the procedure.
8.6.4
Blood Collection for Implant/Depot DDI Subset
Blood sample collection, storage, and shipment instructions for plasma concentrations of 
ENG, MPA, or NET will be provided in the laboratory/study operation manual. The exact 
time the dose of study intervention was taken prior to the sample collection and the time of 
plasma concentration sample collection will be recorded on the appropriate eCRF.
Plasma concentration samples will be collected from Implant/Depot DDI Subset participants 
(n ~ 30) as outlined in the SoA (Section 1.3). On Day 1, Week 8 and Week 20 visits, 
2 samples will be collected (predose and 30-minutes postdose). For all other dosing visits 
(Week 4, 12 and 16), 1 predose sample is collected. For all other non-dosing visits, the 
sample can be collected at any time during the study visit. 
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Participants included in the Implant/Depot DDI Subset are also permitted to participant in the 
PBMC/PK Bridging Subset and the Tissue Biopsy Subset.
Participants who are interested in participating in the Implant/Depot DDI substudy but who 
have not received the hormonal contraceptive prior to the screening visit (Visit 1) may be 
consented for the substudy and administered the contraceptive at the screening visit and 
return for collection of the screening sample for ENG, MPA, or NET levels within 
approximately 7 days after the screening visit. 
8.7
Pharmacodynamics
Pharmacodynamic parameters will not be evaluated in this study.
8.8
Biomarkers
Collection of samples for other biomarker research is also part of this study. The following 
samples for biomarker research will be collected from all participants as specified in the SoA 
(Section 1.3) and Appendix 2:
•
Urine and blood for renal function assessment
•
Blood for planned genetic analysis
8.8.1
Laboratory Markers Associated with Clinical Outcome
Urine and blood samples will be collected to evaluate renal function as measured by key 
indicators, such as the following potential analytes and calculations:
•
Urine: albumin, protein, creatinine, beta-2-microglobulin/creatinine ratio, and retinol 
binding protein/creatinine ratio
•
Serum: creatinine, cystatin-C, and creatinine clearance
8.8.2
Planned Genetic Analysis Sample Collection
The planned genetic analysis sample should be drawn for planned analysis of the association 
between genetic variants in DNA and drug response. This sample will not be collected at the 
site if there is either a local law or regulation prohibiting collection, or if the IRB/IEC does 
not approve the collection of the sample for these purposes. If the sample is collected, 
leftover extracted DNA will be stored for future biomedical research if the participant 
provides documented informed consent for future biomedical research. If the planned genetic
analysis is not approved, but future biomedical research is approved and consent is given, 
this sample will be collected for the purpose of future biomedical research.
Sample collection, storage, and shipment instruction for planned genetic analysis samples 
will be provided in the operations/laboratory manual.
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8.9
Future Biomedical Research Sample Collection
If the participant provides documented informed consent for future biomedical research, the 
following specimens will be obtained as part of future biomedical research:
•
Leftover DNA for future biomedical research
8.10
Health Economics Medical Resource Utilization and Health Economics
Health Economics OR Medical Resource Utilization and Health Economics are not evaluated 
in this study.
8.11
Visit Requirements
Visit requirements are outlined in Section 1.3. Specific procedure-related details are provided 
in Section 8.
8.11.1
Screening/Rescreening
8.11.1.1
Screening
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. Participants who were previously screened and confirmed to be a screen 
failure will not be permitted to be rescreened.
8.11.1.2
Rescreening
If the 45-day screening window has been exceeded, participants are allowed to rescreen 1 
time following approval from the Sponsor. Once a participant has started the rescreening 
process, a new screening period (ie, an additional ≤45-day window) will begin, during which 
time screening procedures may be repeated and are expected to be completed within this new 
45-day window.
Documented informed consent (for the main study and substudies) 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 trial 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.
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All Participants 
The following assessments must be repeated for all participants during rescreening:
•
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, urinalysis
A DEXA scan does not need to be repeated at rescreening if the participant had acceptable 
images from the original screening period and ≤60 days have passed since the date of the 
original acceptable DEXA images; however, DEXA scans must be done at rescreening if 
either of the above criteria are not met.
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 done at rescreening if any of the above criteria are not 
met:
•
Syphilis serologic testing
•
Rectal swab GC/CT testing
•
Oropharyngeal swab GC/CT testing
•
Vaginal swab GC/CT & trichomoniasis testing (females only)
•
Urine GC/CT & trichomoniasis testing (males only)
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Participants in the Tissue Biopsy PK Subset 
•
A Pap smear must be obtained at rescreening if >36 months has passed since the 
participant’s previous Pap smear.
•
A pelvic and/or rectal examination must be performed at rescreening if the participant did 
not have this examination at the original screening visit.
Participants in the Implant / DDI Subset 
•
Current contraceptive use must be evaluated at rescreening for female participants in the 
DDI subset.
•
A blood sample for ENG, MPA or NET levels should be collected at the rescreening
visit.
8.11.2
Intervention Period
During the 24-week intervention period, participants will receive a total of 6 oral QM doses 
of the assigned blinded study intervention (MK-8591 [60 mg or 120 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, and the final dosing period will be from the Week 20 dosing visit until the 
Week 24 visit.
8.11.3
Discontinued Participants Continuing to be Monitored in the Study
Participants who discontinue study intervention before the final dose at Week 20 should 
complete an “Early Discontinuation from Study Intervention” visit (Section 1.3.3), 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 if in the PBMC/PK Bridging Subset and randomized to 
MK-8591, the protocol-specified visits for the extended, unblinded PK follow-up period 
(Section 1.3.2).
When a participant should return for the follow-up visits (per Section 1.3.1) will be based on 
the date of last dose of study intervention.
•
A participant in the PBMC/PK Bridging Subset should return for the first follow-up visit 
(FW 1-2) approximately 1 or 2 weeks after the last dose of study intervention and return 
for the subsequent follow-up visits as outlined in the SoA. 
•
A participant who is not in the PBMC/PK Bridging Subset should return for the first 
follow-up visit (FW 4) approximately 4 weeks after the last dose of study intervention
and return for the subsequent follow-up visits as outlined in the SoA.
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If it is not feasible, due to an external circumstance (eg, unforeseen emergency, natural 
disaster), to use the date of a participant’s last dose of study intervention to calculate the 
follow-up visit schedule, the follow-up visit schedule for that participant will be determined 
collaboratively between the Sponsor and the investigator and documented in writing.
Participants who withdraw from the study during the “Intervention (Blinded)” period (prior
to the last dose of study intervention at Week 20) should have an “Early Discontinuation 
from Study Intervention” visit (Section 1.3.1); an “Early Withdrawal from Study” visit is not 
required. 
Participants who withdraw from the study between Week 20 (after the final dose of study 
intervention) and Week 24, or during the “Follow-up (Blinded)” phase (through FW 12 
[Week 36]), should have an “Early Withdrawal from Study” visit (Section 1.3.3) at the time 
of withdrawal. An “Early Withdrawal from Study” visit is not required for participants who 
withdraw from study during the extended, unblinded PK follow-up period (Section 1.3.2).
8.11.3.1
Participants Who Become Pregnant
•
If the participant becomes pregnant during the “Intervention (Blinded)” study period
(prior to the last dose of study intervention at Week 20), she should have an “Early 
Discontinuation from Study Intervention” visit (Section 1.3.3). If the pregnancy is 
reported at a scheduled study visit, the assessments for the “Early Discontinuation from 
Study Intervention” visit should be conducted at that time. The participant will then 
continue with the protocol-specified visits for the “Follow-up (Blinded)” study period 
listed in Section 1.3.1, using the guidance provided in Section 8.11.3 and, if in the 
PBMC/PK Bridging Subset, the protocol-specified visits for the extended, unblinded PK 
follow-up period (Section 1.3.2). 
•
If the participant becomes pregnant during the “Intervention (Blinded)” study period but 
after the last dose of study intervention at Week 20 or during the “Follow-up (Blinded)” 
study period (after Week 24 through Week 36 [FW 12 visit]), she should continue with 
the protocol-specified visits listed for this period in the SoA (Section 1.3.1), and if in the 
PBMC/PK Bridging Subset and randomized to MK-8591, the protocol-specified visits for 
the extended, unblinded PK follow-up period (Section 1.3.2).
•
If the participant becomes pregnant during the extended, unblinded PK follow-up period
(after Week 36 [FW 12 visit]), she should continue with the protocol-specified visits 
listed for this period in the SoA (Section 1.3.2).
All reported pregnancies will be followed to the completion/termination of the pregnancy 
(Section 8.4.5). Infants born to these participants will have safety follow-up data collected 
through approximately 1 year after birth (Section 8.3.7).
All reported pregnancies occurring after Week 36 (FW 12 visit) must be followed to the 
completion/termination of the pregnancy (Section 8.4.5). Infants born to these participants 
will not be followed.
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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 Section 1.3.3, including collection of an HIV-1 
RNA PCR sample. 
•
If the positive HIV- 1 /2 screen test is during the “Intervention (Blinded)” study period 
(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.
o
If the HIV-1 RNA PCR test is negative, the participant may be able to resume study 
intervention after consultation with the Sponsor. 
o
If the HIV-1 RNA PCR test is positive, the participant should complete an “Early 
Discontinuation from Study Intervention” visit, and then continue with the protocol-
specified visits for the “Follow-up (Blinded)” study period as listed in Section 1.3.1, 
and if in the PBMC/PK Bridging Subset and randomized to MK-8591, the protocol-
specified visits for the extended, unblinded PK follow-up period in Section 1.3.2. The 
participant should be referred to local medical providers for HIV care and treatment. 
No poststudy antiretroviral therapy will be provided by the study.
•
If the positive HIV- 1 /2 screen test is during the “Intervention (Blinded)” study period 
(prior to the last dose of study intervention at Week 20), and the HIV confirmation and 
differentiation test is positive, the participant should be immediately discontinued from
study intervention while waiting for the results of the HIV-1 RNA PCR test.
o
If the HIV-1 RNA PCR test is negative, the participant may be able to resume study 
intervention after consultation with the Sponsor. 
o
If the HIV-1 RNA PCR test is positive, the participant should complete an “Early 
Discontinuation from Study Intervention” visit, and then continue with the protocol-
specified visits for the “Follow-up (Blinded)” study period as listed in Section 1.3.1, 
and if in the PBMC/PK Bridging Subset and randomized to MK-8591, the protocol-
specified visits for the extended, unblinded PK follow-up period in Section 1.3.2. The 
participant should be referred to local medical providers for HIV care and treatment. 
No poststudy antiretroviral therapy will be provided by the study.
•
If the positive HIV- 1 / 2 screen test is during the “Intervention (Blinded)” study period 
but after the last dose of study intervention at Week 20 or during the “Follow-up 
(Blinded)” study period (after Week 24 through Week 36 [FW 12 visit]), the participant 
should continue with the protocol-specified visits listed for this period in the SoA 
(Section 1.3.1), and if in the PBMC/PK Bridging Subset and randomized to MK-8591, 
the protocol-specified visits for the extended, unblinded PK follow-up period (Section 
1.3.2).
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o
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.
8.11.5
Follow-up Period
During the 12-week blinded follow-up period, all participants will complete 3 monthly 
follow-up visits (ie, at FW 4, FW 8, and FW 12 visits) after the last dosing period (ie, at 
4, 8, and 12 weeks beyond Week 24).
All participants who are enrolled in the PBMC/PK Bridging Subset will have 2 additional 
visits during the 12-week blinded follow-up period: at 1-2 weeks and 2-3 weeks (ie, FW 1-2 
and FW 2-3 visits) after the last dosing period. Participants who are enrolled in the 
PBMC/PK Bridging Subset and who were randomized to receive MK-8591 60 mg or 120 mg 
will have another 4 visits, approximately every 2 months, during the extended, unblinded PK 
follow-up period (ie, FW 20, FW 28, FW 36, and FW 44 visits) after the last dosing period
(Section 1.3.2).
9
STATISTICAL ANALYSIS PLAN
This section outlines the statistical analysis strategy and procedures for the study. Changes to 
analyses made after the protocol has been finalized, but prior to final database lock, will be 
documented in a sSAP and referenced in the CSR for the study. Post hoc exploratory 
analyses will be clearly identified in the CSR.
9.1
Statistical Analysis Plan Summary
Key elements of the statistical analysis plan are summarized below; the comprehensive plan 
is provided in Sections 9.1 through 9.12.
Study Design Overview
A Phase 2a, double-blind, placebo-controlled study to evaluate the safety, 
tolerability, and PK of oral MK-8591 QM in participants at low-risk for 
HIV-1 infection
Treatment Assignment
A total of approximately 250 participants will be randomized to Group 1 
(60 mg MK-8591), Group 2 (120 mg MK-8591), or Group 3 (placebo) in a 
2:2:1 ratio.
Analysis Populations
Safety: APaT
Primary Endpoint(s)
AEs 
AEs leading to discontinuation of study intervention 
Key Secondary Endpoints
Plasma MK-8591 AUC0-672hr, Cmax, Ctrough and t1/2
Statistical Methods for Key 
Pharmacokinetic Analyses
Geometric means and 95% CIs will be provided for Plasma MK-8591 and 
PBMC MK-8591-TP AUC0-672hr, Cmax and Ctrough by dose level.
Statistical Methods for Key 
Safety Analyses
95% CIs (Tier 2 endpoints) will be provided for between-group differences 
in the percentage of participants with events; these analyses will be 
performed using the Miettinen and Nurminen method [Miettinen, O. and 
Nurminen, M. 1985].
Interim Analyses
There are no planned interim analyses for this study.
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Multiplicity
No multiplicity adjustment is necessary as there are no hypothesis tests for 
this protocol.
Sample Size and Power 
There are no hypotheses in this study. The primary objective will compare 
the 95% CI for between-group differences. Given the planned sample size 
of 250 participants (2:2:1), the study has 80% probability at an overall 2-
sided 5% α-level to rule out an 18.4% risk difference in AEs from the 
placebo group assuming an underlying incidence of 10% in the placebo 
group. The study has an 80% probability to rule out a 15% risk difference 
in AE between MK-8591 120 mg and 60 mg groups assuming an 
underlying incidence of 10% in the MK-8591 60 mg group.
Assuming plasma MK-8591 Cmax has a true between-participant standard 
deviation (log-scale) of 0.25, given 100 participants receiving MK-8591 at 
one of the dose levels, it is 80% likely that the half-width of the 95% CI for 
the true arithmetic mean Cmax on the log scale will be at most 0.0525.
9.2
Responsibility for Analyses/In-house Blinding
The statistical analysis of the data obtained from this study will be the responsibility of the 
Clinical Biostatistics department of the Sponsor.
For clinical site personnel, participants, and the Sponsor’s clinical team this study will be a 
double-blind study under in-house blinding procedures through Week 24. The Sponsor will 
be unblinded at Week 24.For the PBMC/PK Bridging Subset only, investigators/clinical site 
personnel and participants will be unblinded to MK-8591/placebo between Weeks 36 and 44 
while remaining blinded to MK-8591 dose. For those participants not in the PBMC/PK
Bridging Subset, participants and investigators/clinical site personnel will remain blinded for 
the duration of the study.
To allow timely completion of population PK modeling, Sponsor PK personnel will be 
unblinded for the duration of the study. No personnel directly associated with study conduct 
will be unblinded. Before granting select personnel access to unblinded drug concentration 
data and information relevant for population PK modeling (eg, including, but not limited to 
PK sampling schedules, dosing records, etc.), an official memo detailing unblinding 
procedures will be generated per Sponsor SOP. This memo will list the names of the 
personnel who will have access to unblinded PK and relevant data. 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.
9.3
Hypotheses/Estimation
There are no hypotheses to be tested in this study. Objectives of the study are stated in 
Section 3.
9.4
Analysis Endpoints
PK and safety endpoints that will be evaluated for between-group differences are listed 
below, followed by the descriptions of the derivations of selected endpoints.
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9.4.1
Safety Endpoints
Section 4 provides an initial description of safety measures.
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). In the extended, unblinded PK follow-up period (after FW 12 
visit through FW 44 visit), only SAEs and nonserious AEs related to study procedures will be 
collected. Safety and tolerability will be assessed by clinical review of all relevant parameters 
including AEs and laboratory values.
Adverse Events
The following AEs will be summarized: 1) participants with at least 1 AE; 2) participants 
with at least 1 drug-related AE; 3) participants with at least 1 SAE; 4) participants with at 
least 1 Grade 3 to 5 AE; 5) participants with at least 1 AE which is both serious and drug-
related; 6) participants with at least 1 AE which is both Grade 3 to 5 and drug-related; 7) 
participants who discontinued study therapy due to an AE; and 8) participants with an AE 
which results in death. The percentage of participants with specific AEs by system organ 
class will also be summarized.
Predefined Limits of Change in Laboratory Parameters 
Participants must have both a baseline and post-randomization on-treatment measurement to 
be included in the summaries of laboratory tests. Participants’ laboratory values (based on 
their most abnormal laboratory test values, in the direction of interest, while on study 
therapy) will be classified as to whether or not they fall outside of the PDLC and are worse in 
grade (ie, more abnormal in the direction of interest) than at baseline. The PDLC grading 
criteria are adapted from DAIDS Table for Grading the Severity of Adult and Pediatric 
Adverse Events, July 2017, Version 2.1. A listing of the participants who meet the PDLC 
grading criteria will be provided.
9.4.2
Pharmacokinetics Endpoints
There are no primary PK endpoints.
The secondary PK endpoints in the study are: Plasma MK-8591 PK parameters such as 
AUC0-672hr, Cmax, Ctrough, and t1/2.
Exploratory PK endpoints in the study are :PBMC MK-8591-TP PK parameters such as 
AUC0-672hr, Cmax, Ctrough, and t1/2; tissue concentrations of MK-8591, MK-8591-TP and MK-
8591-DP; as well as plasma concentrations of ENG, MPA, and NET (in a subset of 
participants).
9.5
Analysis Populations
Safety analyses will be conducted in the APaT population, which consists of all randomized 
participants who received at least 1 dose of study intervention. Participants will be included 
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in the group corresponding to the study intervention they actually received for the analysis of 
safety data using the APaT population. This will be the 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 group corresponding to the study intervention
actually received.
PK analyses will be conducted in 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. Compliance covers such considerations as exposure to treatment, 
availability of measurements, and absence of important protocol deviations. Important
protocol deviations will be identified to the extent possible prior to unblinding by individuals 
responsible for data collection/compliance, and its analysis and interpretation. Any 
participants or data values excluded from analysis will be identified, along with their reason 
for exclusion, in the CSR. At the end of the study, all participants who are compliant with the 
study procedure as aforementioned and have available data from at least one dose will be 
included in the PK analysis dataset. This population will be used for the PK analyses.
9.6
Statistical Methods
9.6.1
Statistical Methods for Safety Analyses
Safety and tolerability will be assessed by clinical review of all relevant parameters including 
AEs and laboratory tests.
Safety analyses will be performed for the following between-group comparisons: 
•
MK-8591 (60 mg) vs placebo 
•
MK-8591 (120 mg) vs placebo
•
MK-8591 (60 mg) vs MK-8591 (120 mg)
The analysis of safety results will follow a tiered approach (Table 4). The tiers differ with 
respect to the analyses that will be performed. AEs (specific terms as well as system organ 
class terms) and events that meet PDLCs in laboratory parameters are either pre-specified as 
“Tier 1” endpoints, or will be classified as belonging to "Tier 2" or "Tier 3" based on the 
number of events observed.
Safety parameters or AEs of special interest that are identified a priori constitute “Tier 1” 
safety endpoints that will be subject to inferential testing for statistical significance. There are 
no a priori clinical events of concern that have been identified; therefore, there are no Tier 1 
events for this protocol 
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Tier 2 Events
Tier 2 parameters will be assessed via point estimates with 95% CI provided for differences 
in the proportion of participants with events (also via the Miettinen and Nurminen method 
[Miettinen, O. and Nurminen, M. 1985]).
Membership in Tier 2 requires that at least 4 participants in any intervention group exhibit 
the event; all other AEs and predefined limits of change will belong to Tier 3.
The threshold of at least 4 events was chosen because the 95% CI for the between-group 
difference in percent incidence will always include zero when intervention groups of equal 
size each have less than 4 events and thus would add little to the interpretation of potentially 
meaningful differences. Because many 95% CIs for Tier 2 events may be provided without 
adjustment for multiplicity, the CIs should be regarded as a helpful descriptive measure to be 
used in review, not a formal method for assessing the statistical significance of the between-
group differences in AEs and safety parameters that meet predefined limits of change.
In addition to individual events that occur in 4 or more participants in any intervention group, 
the broad AE categories consisting of the proportion of participants with any AE, a drug-
related AE, a SAE, a Grade 3 to 5 AE, an AE which results in death, an AE which is both 
drug-related and serious, an AE which is both drug-related and Grade 3 to 5, and 
discontinuation due to an AE will be considered Tier 2 endpoints.
Tier 3 Events
Safety endpoints that are not Tier 1 or 2 events are considered Tier 3 events. Only point 
estimates by intervention group are provided for Tier 3 safety parameters.
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Table 4
Analysis Strategy for Safety Parameters
Safety Tier
Safety Endpoint
95% CI for 
Treatment 
Comparisona
Descriptive 
Statistics
Tier 2
Any AEb
X
X
Any Serious AE
X
X
Any Drug-Related AE
X
X
Any Grade 3 to 5 AE
X
X
Any Serious and Drug-Related AE
X
X
Any Grade 3 to 5 and Drug-Related AE
X
X
Discontinuation due to AE
X
X
AE which Results in Death
X
X
Specific AEs, SOCs, or PDLCs (incidence ≥4 participants in 
one of the intervention groups)
X
X
Tier 3
Specific AEs, SOCs or PDLCs (incidence <4 participants in 
all of the intervention groups)
X
AE=adverse event; CI =confidence interval; SOC=System Organ Class; PDLC=Predefined Limit of Change; X=results 
will be provided.
a 95% CIs will be based on the method of Miettinen and Nurminen [Miettinen, O. and Nurminen, M. 1985].
b Indicates broad AE category of the number of participants reporting any AE.
9.6.2
Statistical Methods for Pharmacokinetics Analyses
Plasma MK-8591 AUC0-672hr, Cmax, Ctrough, and t1/2 will be summarized separately by dose 
level as appropriate, with geometric means and 95% CIs based on natural log-transformed 
endpoints and t-distribution. 
PBMC MK-8591-TP AUC0-672hr, Cmax, Ctrough and t1/2 will be assessed with a similar method 
as above.
9.7
Interim Analyses
There are no planned interim analyses for this study.
9.8
Multiplicity
No multiplicity adjustment is planned for this study.
9.9
Sample Size and Power Calculations
9.9.1
Sample Size and Probability Calculations for Safety Analysis
The sample size of this study was chosen to allow for the accumulation of approximately 100 
person-years of safety data (200 participants × 0.5 years).
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While not the basis of the sample size for this study, information on the probability of 
observing a difference between intervention groups is provided. If the underlying incidence 
of a particular AE is 1%, there is a 63.4% chance of observing at least 1 AE among 
100 participants in either MK-8591 group. If no AE of that type is observed among the 
100 participants in the MK-8591 group, this study provides 97.5% confidence that the 
underlying percentage of participants with that particular AE is <3.62% (1 out of every 
27 participants).
The estimate of and the upper bound of the 95% CI for the underlying percentage of 
participants with a particular AE given various hypothetical observed number of participants 
with a particular AE within either MK-8591 group are provided in Table 5. These 
calculations are based on the exact binomial method proposed by Clopper and Pearson 
(1934) [Clopper, C. J. and Pearson, E. S. 1934].
Table 5
Estimate of Incidence of AEs and 95% Upper Confidence Bound Based on 
Hypothetical Number of Participants With a Particular AE Among 100 
Participants in Either MK-8591 Intervention Group
Hypothetical Number of
Participants with a Particular AE
Estimate of 
Incidence
95% Upper Confidence 
Bounda
0
0%
3.6
3
3%
6.3
5
5%
11.3
10
10%
17.6
15
15%
25.5
20
20%
29.2
AE=adverse event.
a Based on the two-tailed exact confidence interval of a binomial proportion [Clopper, C. J. and Pearson, E. S. 1934].
Table 6 summarizes differences in the incidence of AEs between the 2 MK-8591 groups and 
for either MK-8591 group compared with placebo that can be ruled out with different 
probabilities and 95% confidence for a variety of hypothetical underlying incidences of an 
AE. These calculations assume 100 participants in each MK-8591 group and 50 participants 
in the placebo group and that the underlying incidence of AEs is the same for both groups.
The calculations are based on an asymptotic method proposed by Farrington and Manning 
(1990) [Farrington, C. P. and Manning, G. 1990]; no multiplicity adjustments were made.
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Table 6
Difference in Incidence of AEs (MK-8591 Intervention Group Minus Placebo) 
That Can Be Ruled Out
Differencea in Percentage Points That Can Be Ruled Out with Target 
Probability Assuming the Underlying Incidence of the AE is:
Target Probability
10%
20%
30%
40%
50%
Compare MK-8591 to placebo
80
18.4
21.9
23.5
24.0
23.5
85
20.1
23.6
25.2
25.6
24.9
90
22.2
25.7
27.3
27.5
26.7
95
25.3
28.9
30.3
30.3
29.2
Compare MK-8591 intervention groups 
80
15.0
17.9
19.3
19.7
19.3
85
16.2
19.2
20.6
21.0
20.6
90
17.8
20.9
22.3
22.7
22.1
95
20.1
23.4
24.8
25.1
24.4
AE=adverse event.
a The upper bound of the two-sided 95% confidence interval [Farrington, C. P. and Manning, G. 1990] for the 
difference in AE incidences assuming the incidences are the same. Assuming 100 participants in the MK-8591 
intervention groups and 50 participants in the placebo group.
9.9.2
Sample Size and Probability Calculations for PK Analysis
No estimates of variability for AUC672hr or Ctrough following monthly oral dosing are 
available. The precision of the estimates of plasma MK-8591 Cmax can be assessed by 
calculating the half-width of the 95% CIs expected for the given sample size and assumed 
variability. The calculations for Cmax are based on assumed true between-participant standard 
deviations (log-scale) of 0.25 as observed in MK-8591 Protocol 001 and take into account 
the sampling distribution of the observed sample variance as described in [Wang, Y., et al 
2012]. For the given sample size (100 participants receiving MK-8591 at one of the dose 
levels) and assumed between-participant variability, it is 80% likely that the half-width of the 
95% CI for the true arithmetic mean Cmax on the log scale will be at most 0.0525 (the lower and 
upper 95% confidence limits for the true geometric mean Cmax will be OBS/1.05 and OBS ×
1.05, where OBS is the observed geometric mean).
9.10
Subgroup Analyses
To evaluate potential differential pharmacokinetics between groups, plasma MK-8591 will 
be assessed with a similar method as described in Section 9.6 within each category of the 
following classification variables:
•
Sex (female, male)
•
Race (white, non-white)
•
Region (Africa, non-Africa)
•
Age (≤45 years; >45 years)
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9.11
Compliance (Medication Adherence)
Study intervention data for MK-8591 and placebo will be collected during the study. A day 
within the study will be considered an “On-Therapy” day if the participant takes the required 
number of pills from all containers provided for this study. A participant will have to take all 
4 capsules per dose to be considered compliant.
For a participant who is followed for the entire study period, the “Number of Days Should be 
on Therapy” is the total number of days from randomization to the last scheduled day for 
treatment administration for that participant. For a participant who discontinued from the 
study permanently, the “Number of Days Should be on Therapy” is the total number of days 
from randomization to the last dose of study intervention.
For each participant, percent compliance will then be calculated using the following formula:
Summary statistics will be provided on percent compliance by intervention group for the 
APaT population.
9.12
Extent of Exposure
Each study participant is planned to be exposed to 6 doses of either 60 mg or 120 mg of 
MK-8591 or placebo over a 6-month period. The amount of intervention received by the 
participants during the study will be summarized.
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10
SUPPORTING DOCUMENTATION AND OPERATIONAL 
CONSIDERATIONS
10.1
Appendix 1: Regulatory, Ethical, and Study Oversight Considerations
10.1.1
Code of Conduct for Clinical Trials
Merck Sharp and Dohme Corp., a subsidiary of Merck & Co., Inc. (MSD)
Code of Conduct for Interventional Clinical Trials
I. Introduction
A. Purpose
MSD, through its subsidiaries, conducts clinical trials worldwide to evaluate the safety and effectiveness of our 
products. As such, we are committed to designing, implementing, conducting, analyzing, and reporting these trials 
in compliance with the highest ethical and scientific standards. Protection of participants in clinical trials is the 
overriding concern in the design and conduct of clinical trials. In all cases, MSD clinical trials will be conducted 
in compliance with local and/or national regulations, and International Council for Harmonisation Good Clinical 
Practice (ICH-GCP), and also in accordance with the ethical principles that have their origin in the Declaration of 
Helsinki.
B. Scope
Highest ethical and scientific standards shall be endorsed for all clinical interventional investigations sponsored by 
MSD irrespective of the party (parties) employed for their execution (e.g., contract research organizations, 
collaborative research efforts). This Code is not intended to apply to trials that are observational in nature, or 
which are retrospective. Further, this Code does not apply to investigator-initiated trials, which are not under the 
full control of MSD.
II. Scientific Issues
A. Trial Conduct
1. Trial Design
Except for pilot or estimation trials, clinical trial protocols will be hypothesis-driven to assess safety, efficacy 
and/or pharmacokinetic or pharmacodynamic indices of MSD or comparator products. Alternatively, MSD
may conduct outcomes research trials, trials to assess or validate various endpoint measures, or trials to 
determine patient preferences, etc.
The design (i.e., participant population, duration, statistical power) must be adequate to address the specific
purpose of the trial. Participants must meet protocol entry criteria to be enrolled in the trial. 
2. Site Selection
MSD selects investigative sites based on medical expertise, access to appropriate participants, adequacy of 
facilities and staff, previous performance in clinical trials, as well as budgetary considerations. Prior to trial 
initiation, sites are evaluated by MSD personnel (or individuals acting on behalf of MSD) to assess the ability 
to successfully conduct the trial.
3. Site Monitoring/Scientific Integrity
Investigative trial sites are monitored to assess compliance with the trial protocol and Good Clinical Practice
(GCP). MSD reviews clinical data for accuracy, completeness, and consistency. Data are verified versus 
source documentation according to standard operating procedures. Per MSD policies and procedures, if fraud, 
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scientific/research misconduct or serious GCP-non-compliance is suspected, the issues are investigated. 
When necessary, the clinical site will be closed, the responsible regulatory authorities and ethics review 
committees notified.
B. Publication and Authorship
Regardless of trial outcome, MSD commits to publish the primary and secondary results of its registered trials of 
marketed products in which treatment is assigned, according to the pre-specified plans for data analysis. To the 
extent scientifically appropriate, MSD seeks to publish the results of other analyses it conducts that are important 
to patients, physicians, and payers. Some early phase or pilot trials are intended to be hypothesis-generating rather 
than hypothesis testing; in such cases, publication of results may not be appropriate since the trial may be 
underpowered and the analyses complicated by statistical issues such as multiplicity.
MSD’s policy on authorship is consistent with the recommendations published by the International Committee of 
Medical Journal Editors (ICMJE). In summary, authorship should reflect significant contribution to the design and 
conduct of the trial, performance or interpretation of the analysis, and/or writing of the manuscript. All named 
authors must be able to defend the trial results and conclusions. MSD funding of a trial will be acknowledged in 
publications.
III. Participant Protection
A. Regulatory Authority and Ethics Committee Review (Institutional Review Board [IRB]/Independent Ethics 
Committee [IEC])
All protocols and protocol amendments will be submitted by MSD for regulatory authority 
acceptance/authorization prior to implementation of the trial or amendment, in compliance with local and/or 
national regulations.
The protocol, protocol amendment(s), informed consent form, investigator’s brochure, and other relevant trial 
documents must be reviewed and approved by an IRB/IEC before being implemented at each site, in compliance 
with local and/or national regulations. Changes to the protocol that are required urgently to eliminate an 
immediate hazard and to protect participant safety may be enacted in anticipation of ethics committee approval.  
MSD will inform regulatory authorities of such new measures to protect participant safety, in compliance with 
local and/or national regulations.
B. Safety
The guiding principle in decision-making in clinical trials is that participant welfare is of primary importance. 
Potential participants will be informed of the risks and benefits of, as well as alternatives to, trial participation. At 
a minimum, trial designs will take into account the local standard of care.
All participation in MSD clinical trials is voluntary. Participants enter the trial only after informed consent is 
obtained. Participants may withdraw from an MSD trial at any time, without any influence on their access to, or 
receipt of, medical care that may otherwise be available to them.
C. Confidentiality
MSD is committed to safeguarding participant confidentiality, to the greatest extent possible. Unless required by 
law, only the investigator, Sponsor (or individuals acting on behalf of MSD), ethics committee, and/or regulatory 
authorities will have access to confidential medical records that might identify the participant by name.
D. Genomic Research
Genomic research will only be conducted in accordance with a protocol and informed consent authorized by an 
ethics committee.
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IV. Financial Considerations
A. Payments to Investigators
Clinical trials are time- and labor-intensive. It is MSD’s policy to compensate investigators (or the sponsoring 
institution) in a fair manner for the work performed in support of MSD trials. MSD does not pay incentives to 
enroll participants in its trials. However, when enrollment is particularly challenging, additional payments may be 
made to compensate for the time spent in extra recruiting efforts.
MSD does not pay for participant referrals. However, MSD may compensate referring physicians for time spent 
on chart review and medical evaluation to identify potentially eligible participants.
B. Clinical Research Funding
Informed consent forms will disclose that the trial is sponsored by MSD, and that the investigator or sponsoring 
institution is being paid or provided a grant for performing the trial. However, the local ethics committee may 
wish to alter the wording of the disclosure statement to be consistent with financial practices at that institution. As 
noted above, all publications resulting from MSD trials will indicate MSD as a source of funding.
C. Funding for Travel and Other Requests
Funding of travel by investigators and support staff (e.g., to scientific meetings, investigator meetings, etc.) will be 
consistent with local guidelines and practices.
V. Investigator Commitment
Investigators will be expected to review MSD’s Code of Conduct as an appendix to the trial protocol, and in signing the 
protocol, agree to support these ethical and scientific standards.
10.1.2
Financial Disclosure
Financial Disclosure requirements are outlined in the US Food and Drug Administration 
Regulations, Financial Disclosure by Clinical Investigators (21 CFR Part 54). It is the 
Sponsor's responsibility to determine, based on these regulations, whether a request for 
Financial Disclosure information is required. It is the investigator's/subinvestigator's 
responsibility to comply with any such request.
The investigator/subinvestigator(s) agree, if requested by the Sponsor in accordance with 21 
CFR Part 54, to provide his/her financial interests in and/or arrangements with the Sponsor to 
allow for the submission of complete and accurate certification and disclosure statements. 
The investigator/subinvestigator(s) further agree to provide this information on a 
Certification/Disclosure Form, commonly known as a financial disclosure form, provided by 
the Sponsor. The investigator/subinvestigator(s) also consent to the transmission of this 
information to the Sponsor in the United States for these purposes. This may involve the 
transmission of information to countries that do not have laws protecting personal data.
10.1.3
Data Protection
Participants will be assigned a unique identifier by the Sponsor. Any participant records or 
datasets that are transferred to the Sponsor will contain the identifier only; participant names 
or any information that would make the participant identifiable will not be transferred.
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The participant must be informed that his/her personal study-related data will be used by the 
Sponsor in accordance with local data protection law. The level of disclosure must also be 
explained to the participant. 
The participant must be informed that his/her medical records may be examined by Clinical 
Quality Assurance auditors or other authorized personnel appointed by the Sponsor, by 
appropriate IRB/IEC members, and by inspectors from regulatory authorities.
10.1.3.1
Confidentiality of Data
By signing this protocol, the investigator affirms to the Sponsor that information furnished to 
the investigator by the Sponsor will be maintained in confidence, and such information will 
be divulged to the IRB, IEC, or similar or expert committee; affiliated institution and 
employees, only under an appropriate understanding of confidentiality with such board or 
committee, affiliated institution and employees. Data generated by this study will be 
considered confidential by the investigator, except to the extent that it is included in a 
publication as provided in the Publications section of this protocol.
10.1.3.2
Confidentiality of Participant Records
By signing this protocol, the investigator agrees that the Sponsor (or Sponsor representative), 
IRB/IEC, or regulatory authority representatives may consult and/or copy study documents to 
verify worksheet/CRF data. By signing the consent form, the participant agrees to this 
process. If study documents will be photocopied during the process of verifying 
worksheet/CRF information, the participant will be identified by unique code only; full 
names/initials will be masked prior to transmission to the Sponsor.
By signing this protocol, the investigator agrees to treat all participant data used and 
disclosed in connection with this study in accordance with all applicable privacy laws, rules 
and regulations.
10.1.3.3
Confidentiality of IRB/IEC Information
The Sponsor is required to record the name and address of each IRB/IEC that reviews and 
approves this study. The Sponsor is also required to document that each IRB/IEC meets 
regulatory and ICH GCP requirements by requesting and maintaining records of the names 
and qualifications of the IRB/IEC members and to make these records available for 
regulatory agency review upon request by those agencies.
10.1.4
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.
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If publication activity is not directed by the Sponsor, the investigator agrees to submit all 
manuscripts or abstracts to the Sponsor before submission. This allows the Sponsor to protect 
proprietary information and to provide comments.
Authorship will be determined by mutual agreement and in line with International Committee 
of Medical Journal Editors authorship requirements.
10.1.5
Compliance with Study Registration and Results Posting Requirements
Under the terms of the Food and Drug Administration Amendments Act (FDAAA) of 2007 
and the European Medicines Agency (EMA) clinical trial Directive 2001/20/EC, the Sponsor 
of the study is solely responsible for determining whether the study and its results are subject
to the requirements for submission to http://www.clinicaltrials.gov, 
www.clinicaltrialsregister.eu or other local registries. MSD, as Sponsor of this study, will 
review this protocol and submit the information necessary to fulfill these requirements. MSD 
entries are not limited to FDAAA or the EMA clinical trial directive mandated trials. 
Information posted will allow participants to identify potentially appropriate studies for their 
disease conditions and pursue participation by calling a central contact number for further 
information on appropriate study locations and study site contact information.
By signing this protocol, the investigator acknowledges that the statutory obligations under 
FDAAA, the EMA clinical trials directive, or other locally mandated registries are that of the 
Sponsor and agrees not to submit any information about this study or its results to those 
registries.
10.1.6
Compliance with Law, Audit, and Debarment
By signing this protocol, the investigator agrees to conduct the study in an efficient and 
diligent manner and in conformance with this protocol; generally accepted standards of GCP
(eg, International Conference on Harmonization of Technical Requirements for Registration 
of Pharmaceuticals for Human Use GCP: Consolidated Guideline and other generally 
accepted standards of GCP); and all applicable federal, state and local laws, rules and 
regulations relating to the conduct of the clinical study.
The Code of Conduct, a collection of goals and considerations that govern the ethical and 
scientific conduct of clinical investigations sponsored by MSD, is provided in this appendix 
under the Code of Conduct for Clinical Studies.
The investigator agrees not to seek reimbursement from participants, their insurance 
providers, or from government programs for procedures included as part of the study 
reimbursed to the investigator by the Sponsor.
The investigator will promptly inform the Sponsor of any regulatory authority inspection 
conducted for this study.
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The investigator agrees to provide the Sponsor with relevant information from inspection 
observations/findings to allow the Sponsor to assist in responding to any citations resulting 
from regulatory authority inspection and will provide the Sponsor with a copy of the 
proposed response for consultation before submission to the regulatory authority. 
Persons debarred from conducting or working on clinical studies by any court or regulatory 
authority will not be allowed to conduct or work on this Sponsor’s studies. The investigator 
will immediately disclose in writing to the Sponsor if any person who is involved in 
conducting the study is debarred or if any proceeding for debarment is pending or, to the best 
of the investigator’s knowledge, threatened.
10.1.7
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 
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Sponsor. No records may be transferred to another location or party without written 
notification to the Sponsor.
10.1.8
Source Documents
Source documents provide evidence for the existence of the participant and substantiate the 
integrity of the data collected. The investigator/institution should maintain adequate and 
accurate source documents and study records that include all pertinent observations on each 
of the site’s participants. Source documents and data should be attributable, legible, 
contemporaneous, original, accurate, and complete. Changes to source data should be 
traceable, should not obscure the original entry, and should be explained if necessary (eg, via 
an audit trail). Source documents are filed at the investigator’s site.
Data reported on the CRF or entered in the eCRF that are transcribed from source documents 
must be consistent with the source documents or the discrepancies must be explained. The 
investigator/institution may need to request previous medical records or transfer records, 
depending on the study. Also, current medical records must be available.
10.1.9
Study and Site Closure
The Sponsor or its designee may stop the study or study site participation in the study for 
medical, safety, regulatory, administrative, or other reasons consistent with applicable laws, 
regulations, and GCP.
In the event the Sponsor prematurely terminates a particular study site, the Sponsor or 
designee will promptly notify that study site’s IRB/IEC as specified by applicable regulatory 
requirement(s).
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10.2
Appendix 2: Clinical Laboratory Tests
The tests detailed in Table 7 will be performed by the central laboratory or by a referral 
laboratory as outlined in the PPD Central Laboratory Manual and the MK-8591 Protocol 016 
Study Operations Manual.
•
Local laboratory results are only required in the event that the central laboratory results 
are not available in time for either study intervention administration and/or response 
evaluation. If a local sample is required, it is important that the sample for central 
analysis is obtained at the same time. Additionally, if the local laboratory results are used 
to make either a study intervention decision or response evaluation, the results must be 
entered into the CRF.
Note: for female participants requiring a Pap test, it must be performed locally based on 
the requirements outlined in Section 8.1.4.
Note: External circumstances may require participants to have local lab 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 lab 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.
•
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.
•
Pregnancy testing:
o
Pregnancy testing requirements for study inclusion are described in Section 5.1.
o
Additional serum or urine pregnancy tests may be performed, as determined 
necessary by the investigator or required by local regulation, to establish the absence 
of pregnancy at any time during the participant’s participation in the study.
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Table 7
Protocol-Required Clinical Laboratory Assessments
Laboratory Assessments
Parameters
Pregnancy
Serum β-human chorionic gonadotropin (hCG) test
Urine β-human chorionic gonadotropin (hCG) test
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 Red Blood Cell (%, 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)
CD4% and absolute CD4/lymphocytes
CD8% and absolute CD8/lymphocytes
CD4/CD8 ratio
Chemistry (non-fasting)
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-Ca
Gamma Glutamyl Transferase (GGT)
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Laboratory Assessments
Parameters
Glucose (random)
Lactate Dehydrogenase (LDH)
Lipase
Magnesium (Mg)
Phosphorous
Potassium (K)
Protein, Total 
Sodium (Na)
Triglycerides
Urea Nitrogen, Blood (BUN)
Uric Acid
Urinalysis-
MACROSCOPIC 
Specific gravity
Appearance
Bilirubin
Blood
Color
Glucose
Ketones
Leukocyte Esterase (LE)
Nitrites
pH
Protein
Urobilinogen
Urinalysis- MICROSCOPIC
Amorphous Crystals
Bacteria
Calcium Carbonate Crystals
Calcium Oxalate Crystals
Calcium Phosphate Crystals
Cysteine Crystals
Granular Casts
Hyaline Casts
Leucine Crystals
Mucus
RBC
RBC Casts
Renal Epithelial Cells
Squamous Epithelial Cells
Transitional Epithelial Cells
Triple Phosphate Crystals
Tyrosine Crystals
Uric Acid Crystals
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Laboratory Assessments
Parameters
Waxy Casts
WBC
WBC Casts
Yeast
Urinary analytes
Albumin
Beta-2-microglobulin
Beta-2-microglobulin/creatinine ratio (B-2M/Cr) (calculated)
Creatinine
Protein
Retinol binding protein
Retinol binding protein/creatinine ratio (RBP/Cr) (calculated)
Hepatitis screen (Screening)
Hepatitis B virus surface antigen
Hepatitis B virus surface antibody
Hepatitis C virus antibody 
Plasma hepatitis C virus polymerase chain reaction (PCR)
quantitative test (performed if Hepatitis C virus antibody is 
positive)
Virology
Human immunodeficiency virus (HIV) 1&2 Antibody
HIV 1/2 Geenius Confirmation
HIV-1 viral RNA quantification (real time PCR)
HIV-1 drug resistance testing
Sexually transmitted 
infection (STI) Testing 
(Screening)
Rectal swab Neisseria gonorrhoeae (GC)/Chlamydia trachomatis 
(CT) testing
Oropharyngeal swab GC/CT testing
Urine GC/CT/trichomoniasis testing (males)
Vaginal swab GC/CT/trichomoniasis testing (females)
Syphilis serologic testing
(rapid plasma reagin [RPR], RPR with titer, treponema pallidum 
IgG, treponema pallidum IgG index value)
Pharmacokinetic (PK)
Sampling
Plasma PK (all participants)
Mitra/VAMS™(subset of participants)
Tissue Sampling 
(for PK analysis)
Rectal tissue biopsy (subset of participants)
Cervical tissue biopsy (subset of participants)
Vaginal tissue biopsy (subset of participants)
Peripheral blood 
mononuclear cells (PBMC)
(for PK analysis)
PBMC (subset of participants)
Plasma Hormone 
Measurement 
Etonogestrel (subset of participants)
Medroxyprogesterone acetate (subset of participants)
Norethindrone (subset of participants)
Biomarkers
Genetic Analysis
a Test requires a separate sample
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The PK sampling timepoints are detailed Table 8. Plasma will be collected for all participants 
and other sampling will be based on enrollment in a particular subset. The priority of PK 
sample collection is as follows:
1. Plasma
2. PBMC
3. Tissue biopsy
4. ENG/MPA/NET plasma concentration
5. Mitra/VAMS™venous
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Table 8
PK Sample Collection Timepoints
Study Day/Week
PK Sample Type
PK Sample Collection Time
(exact time must be documented)
Screening
(non-dosing visit)
ENG/MPA/NET plasma 
concentration
Sample can be collected at any time 
during the study visit. 
Day 1
(dosing visit)
Plasma 
Sample to be collected predose and 30-
minutes postdose.
 
PBMC
Sample to be collected predose.
Mitra/VAMS™
Venous
ENG/MPA/NET plasma 
concentration
Sample to be collected predose and 30-
minutes postdose.
Day 2
(non-dosing visit)
Plasma
Samples to be collected ~ 24 hours after 
Day 1 dose.
 
PBMC
Mitra/VAMS™
Venous
Week 1
(non-dosing visit)
Plasma
Samples can be collected at any time 
during the study visit.
 
PBMC
Mitra/VAMS™
Venous
Tissue Biopsy Sample(s)
ENG/MPA/NET plasma 
concentration
Week 2
(non-dosing visit)
Plasma
Samples can be collected at any time 
during the study visit.
PBMC
Mitra/VAMS™
venous
ENG/MPA/NET plasma 
concentration
Week 3
(non-dosing visit)
Plasma
Samples can be collected at any time 
during the study visit.
 
PBMC
Mitra/VAMS™
Venous
ENG/MPA/NET plasma 
concentration
Week 4
(dosing visit)
Plasma
Samples to be collected predose.
 
PBMC
Mitra/VAMS™
Venous
Tissue Biopsy Sample(s)
ENG/MPA/NET plasma 
concentration
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Study Day/Week
PK Sample Type
PK Sample Collection Time
(exact time must be documented)
Week 8
(dosing visit)
Plasma
Samples to be collected predose.
 
PBMC
Mitra/VAMS™
venous
ENG/MPA/NET plasma 
concentration
Sample to be collected predose and 30-
minutes postdose.
Week 12
(dosing visit)
Plasma
Samples to be collected predose.
 
PBMC
Mitra/VAMS™
Venous
ENG/MPA/NET plasma 
concentration
Week 16
(dosing visit)
Plasma
Samples to be collected predose.
 
PBMC
Mitra/VAMS™
Venous
ENG/MPA/NET plasma 
concentration
Week 20
(dosing visit)
Plasma
Sample to be collected predose and 30-
minutes postdose.
 
PBMC
Samples to be collected predose.
Mitra/VAMS™
Venous
ENG/MPA/NET plasma 
concentration
Sample to be collected predose and 30-
minutes postdose.
Week 21
(non-dosing visit)
Plasma
Samples can be collected at any time 
during the study visit.
 
PBMC
Mitra/VAMS™
Venous
ENG/MPA/NET plasma 
concentration
Week 22
(non-dosing visit)
Plasma
Samples can be collected at any time 
during the study visit.
 
PBMC
Mitra/VAMS™
venous
ENG/MPA/NET plasma 
concentration
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Study Day/Week
PK Sample Type
PK Sample Collection Time
(exact time must be documented)
Week 23
(non-dosing visit)
Plasma
Samples can be collected at any time 
during the study visit.
PBMC
Mitra/VAMS™
Venous
ENG/MPA/NET plasma 
concentration
Week 24
(non-dosing visit)
Plasma
Samples can be collected at any time 
during the study visit.
 
PBMC
Mitra/VAMS™
venous
Tissue Biopsy Sample(s)
ENG/MPA/NET plasma 
concentration
Follow-Up Week 1-2
(non-dosing visit)a
PBMC
Sample can be collected at any time 
during the study visit.
Follow-Up Week 2-3
(non-dosing visit)a
PBMC
Sample can be collected at any time 
during the study visit.
Follow-Up Week 4
(non-dosing visit)
PBMC
Samples can be collected at any time 
during the study visit.
ENG/MPA/NET plasma 
concentration
Follow-Up Week 8
(non-dosing visit)
PBMC
Samples can be collected at any time 
during the study visit.
Tissue Biopsy Sample(s)
ENG/MPA/NET plasma 
concentration
Follow-Up Week 12
(non-dosing visit)
PBMC
Samples can be collected at any time 
during the study visit.
ENG/MPA/NET plasma 
concentration
Follow-up Week 20b
(non-dosing visit)
PBMC
Sample can be collected at any time 
during the study visit.
Follow-up Week 28b
(non-dosing visit)
PBMC
Sample can be collected at any time 
during the study visit.
Follow-up Week 36b
(non-dosing visit)
PBMC
Sample can be collected at any time 
during the study visit.
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Study Day/Week
PK Sample Type
PK Sample Collection Time
(exact time must be documented)
Follow-up Week 44b
(non-dosing visit)
PBMC
Sample can be collected at any time 
during the study visit.
ENG=etonogestrel; MPA=medroxyprogesterone acetate; NET=norethisterone or norethindrone; 
PBMC=peripheral blood mononuclear cells; PK=pharmacokinetic; VAMS=volumetric absorptive 
microsampling.

PBMC and Mitra/VAMS™ venous samples only collected in participants included in the PBMC/PK 
Bridging Subset.

Tissue biopsy samples only collected in participants included in the Tissue Biopsy Subset.

ENG/MPA/NET plasma concentration samples only collected in participants included in the 
Implant/Depot DDI Subset.
a Visits only required for participants in the PBMC/PK Bridging Subset.
b Visits only required for participants in the PBMC/PK Bridging Subset who received MK-8591.
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Table 9
Blood Volumes
Study Period
Screening
Intervention (Blinded)
Follow-up (Blinded)
HIV-
Inf.
Crm
Erly 
Disc
Std 
Intvn
Erly 
Wth-
draw
Std
Scheduled 
Day/Week 
Screening
Day 1
Day 2
Week 1
Week 2
Week 3
Week 4
Week 8
Week 12
Week 16
Week 20
Week 21
Week 22
Week 23
Week 24
FW 1-2a
FW 2-3a
FW 4
FW 8
FW 12
Totals
Unscheduled
Unscheduled
Unscheduled
Blood 
Parameter
Approximate Blood Volume (mL)
HBV/HCV/HI
V (Serology)
3.5
HCV RNA 
(only tested if 
AB+)
6
Syphilis
4
Hematology 
2
2
2
2
2
2
2
2
2
2
2
2
2
Chemistry
6
6
6
6
6
6
6
6
6
6
6
6
6
6
6
6
Cystatin-C
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
Serum 
pregnancy test 
(β-hCG)
Off 
Chem
HIV 1&2 
Screen
Off 
HBV/ 
HCV/
HIV
2
2
2
2
2
2
2
2
2
2
2
2
HIV 
Confirmation 
(Geenius)
1
1
1
1
1
1
1
1
1
1
1
1
1
HIV RNA
6
HIV-1 drug 
resistance 
testing
12
PK blood 
sample 
collection (all 
participants)
8
4
4
4
4
4
4
4
4
8
4
4
4
4
4
4
4
Blood for 
Genetic 
Analysis
8.5
Total Blood 
Volume per 
Visit in mL 
(All Study 
Participants)
24.5
29.5
4
12
12
12
17
17
17
17
21
4
4
4
17
0
0
13
13
13
251
22
17
17
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Study Period
Screening
Intervention (Blinded)
Follow-up (Blinded)
HIV-
Inf.
Crm
Erly 
Disc
Std 
Intvn
Erly 
Wth-
draw
Std
Scheduled 
Day/Week 
Screening
Day 1
Day 2
Week 1
Week 2
Week 3
Week 4
Week 8
Week 12
Week 16
Week 20
Week 21
Week 22
Week 23
Week 24
FW 1-2a
FW 2-3a
FW 4
FW 8
FW 12
Totals
Unscheduled
Unscheduled
Unscheduled
Blood 
Parameter
Approximate Blood Volume (mL)
Pharmacokinetics (PBMC/PK Bridging Subset)b
PBMC sample
16
16
16
16
16
16
16
16
16
16
16
16
16
16
16
16
16
16
16
16
16
16
Additional 
Blood Volume 
Collected per 
Visit in mL 
(Participants 
in the 
PBMC/PK 
Bridging 
Subset)b
16
16
16
16
16
16
16
16
16
16
16
16
16
16
16
16
16
16
16
304
16
16
16
Pharmacokinetics (Implant/Depot DDI Subset) 
ENG or MPA 
sample
3
6
3
3
3
3
6
3
3
6
3
3
3
3
3
3
3
60
3
3
NET sample
6
12
6
6
6
6
12
6
6
12
6
6
6
6
6
6
6
120
6
6
AB=antibody; β-hCG=beta human chorionic gonadotropin; Crm=confirmation; Disc=discontinuation; ENG= etonogestrel; Erly=early; FW=follow-up week; HBV=hepatitis B virus; HCV=hepatitis C virus; HIV=human 
immunodeficiency virus; Inf=infection; Intvn=intervention; MPA=medroxyprogesterone acetate; NET=norethisterone or norethindrone; PBMC=peripheral blood mononuclear cells; PK=pharmacokinetic; RNA=ribonucleic acid; 
Std=study; WOCBP=a woman/women of childbearing potential; Wthdraw=withdrawal; VAMS=volumetric absorptive microsampling.
Note: All volumes are provided in mL.
a Visits are only required for participants in the PBMC/PK Bridging Subset.
b Participants in the PBMC/PK Bridging Subset and randomized to MK-8591 will have PBMC samples (16 mL) collected at FW 20, 28, 36 and 44 and hematology samples (2 mL) and CD4+ T-cell count samples (6 mL) collected 
at FW 36 and 44 (Total Additional Blood Volume = 80 mL).
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10.3
Appendix 3: Adverse Events: Definitions and Procedures for Recording, 
Evaluating, Follow-up, and Reporting
10.3.1
Definition of AE
AE definition

An AE is any untoward medical occurrence in a clinical study participant, temporally 
associated with the use of study intervention, whether or not considered related to the 
study intervention.

NOTE: An AE can therefore be any unfavorable and unintended sign (including an 
abnormal laboratory finding), symptom, or disease (new or exacerbated) temporally 
associated with the use of a study intervention.

NOTE: For purposes of AE definition, study intervention (also referred to as Sponsor’s 
product) includes any pharmaceutical product, biological product, vaccine, diagnostic 
agent, or protocol specified procedure whether investigational or marketed (including 
placebo, active comparator product, or run-in intervention), manufactured by, licensed 
by, provided by, or distributed by the Sponsor for human use in this study.
Events meeting the AE definition

Any abnormal laboratory test results (hematology, clinical chemistry, or urinalysis) or 
other safety assessments (eg, ECG, radiological scans, vital signs measurements), 
including those that worsen from baseline, considered clinically significant in the medical 
and scientific judgment of the investigator.

Exacerbation of a chronic or intermittent pre-existing condition including either an 
increase in frequency and/or intensity of the condition.

New conditions detected or diagnosed after study intervention administration even 
though it may have been present before the start of the study.

Signs, symptoms, or the clinical sequelae of a suspected drug-drug interaction.

Signs, symptoms, or the clinical sequelae of a suspected overdose of either study 
intervention or a concomitant medication.

For all reports of overdose (whether accidental or intentional) with an associated AE, the 
AE term should reflect the clinical symptoms or abnormal test result. An overdose 
without any associated clinical symptoms or abnormal laboratory results is reported using 
the terminology “accidental or intentional overdose without adverse effect.”
•
Any new cancer or progression of existing cancer.
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Events NOT meeting the AE definition
•
Medical or surgical procedure (eg, endoscopy, appendectomy): the condition that leads to 
the procedure is the AE.
•
Situations in which an untoward medical occurrence did not occur (social and/or 
convenience admission to a hospital).
•
Anticipated day-to-day fluctuations of pre-existing disease(s) or condition(s) present or 
detected at the start of the study that do not worsen.
•
Surgery planned prior to informed consent to treat a pre-existing condition that has not 
worsened.
•
Refer to Section 8.4.6 for protocol-specific exceptions.
10.3.2
Definition of SAE
If an event is not an AE per definition above, then it cannot be an SAE even if serious 
conditions are met.
An SAE is defined as any untoward medical occurrence that, at any dose:
a.   Results in death
b.   Is life-threatening
◦
The term “life-threatening” in the definition of “serious” refers to an event in which 
the participant was at risk of death at the time of the event. It does not refer to an 
event, which hypothetically might have caused death, if it were more severe.
c.   Requires inpatient hospitalization or prolongation of existing hospitalization
◦
Hospitalization is defined as an inpatient admission, regardless of length of stay, even 
if the hospitalization is a precautionary measure for continued observation. (Note: 
Hospitalization for an elective procedure to treat a pre-existing condition that has not 
worsened is not an SAE. A pre-existing condition is a clinical condition that is 
diagnosed prior to the use of an MSD product and is documented in the participant’s 
medical history.
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d.   Results in persistent or significant disability/incapacity
◦
The term disability means a substantial disruption of a person’s ability to conduct 
normal life functions.
◦
This definition is not intended to include experiences of relatively minor medical 
significance such as uncomplicated headache, nausea, vomiting, diarrhea, influenza, 
and accidental trauma (eg, sprained ankle) that may interfere with or prevent 
everyday life functions but do not constitute a substantial disruption.
e.   Is a congenital anomaly/birth defect
◦
In offspring of participant taking the product regardless of time to diagnosis.
f.   Other important medical events
◦
Medical or scientific judgment should be exercised in deciding whether SAE 
reporting is appropriate in other situations such as important medical events that may 
not be immediately life-threatening or result in death or hospitalization but may 
jeopardize the participant or may require medical or surgical intervention to prevent 1 
of the other outcomes listed in the above definition. These events should usually be 
considered serious.
◦
Examples of such events include invasive or malignant cancers, intensive treatment in 
an emergency room or at home for allergic bronchospasm, blood dyscrasias or 
convulsions that do not result in hospitalization, or development of drug dependency 
or drug abuse.
10.3.3
Additional Events Reported
Additional events that require reporting
In addition to the above criteria, AEs meeting either of the below criteria, although not 
serious per ICH definition, are reportable to the Sponsor.
•
Is a cancer
•
Is associated with an overdose
10.3.4
Recording AE and SAE
AE and SAE recording

When an AE/SAE occurs, it is the responsibility of the investigator to review all 
documentation (eg, hospital progress notes, laboratory, and diagnostics reports) related to 
the event.
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
The investigator will record all relevant AE/SAE information on the AE 
CRFs/worksheets at each examination.

It is not acceptable for the investigator to send photocopies of the participant’s medical 
records to the Sponsor in lieu of completion of the AE CRF page.

There may be instances when copies of medical records for certain cases are requested by 
the Sponsor. In this case, all participant identifiers, with the exception of the participant 
number, will be blinded on the copies of the medical records before submission to the 
Sponsor.

The investigator will attempt to establish a diagnosis of the event based on signs, 
symptoms, and/or other clinical information. In such cases, the diagnosis (not the 
individual signs/symptoms) will be documented as the AE/SAE.
Assessment of intensity

An event is defined as “serious” when it meets at least 1 of the predefined outcomes as 
described in the definition of an SAE, not when it is rated as severe.

The investigator will make an assessment of intensity for each AE and SAE (and other 
reportable safety event) by recording the grade according to the NIH DAIDS Table for 
Grading the Severity of Adult and Pediatric Adverse Events, version 2.1. Any AE which 
changes DAIDS grade over the course of a given episode will have each change of grade 
recorded on the AE CRFs/worksheets.
-
Grade 1 Mild event: Mild symptoms causing no or minimal interference with usual 
social and functional activities with intervention not indicated.
-
Grade 2 Moderate event: Moderate symptoms causing greater than minimal 
interference with usual social and functional activities with intervention indicated.
-
Grade 3 Severe event: Severe symptoms causing inability to perform usual social and 
functional activities with intervention or hospitalization indicated.
-
Grade 4 Potentially life-threatening event: Potentially life-threatening symptoms 
causing inability to perform basic self-care funtions with intervention indicated to 
prevent permanent impairment, persistent disability, or death.
-
Grade 5 Death: Deaths related to an AE.
Assessment of causality

Did the Sponsor’s product cause the AE?
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
The determination of the likelihood that the Sponsor’s product caused the AE will be 
provided by an investigator who is a qualified physician. The investigator’s signed/dated 
initials on the source document or worksheet that supports the causality noted on the AE 
form, ensures that a medically qualified assessment of causality was done. This initialed 
document must be retained for the required regulatory time frame. The criteria below are 
intended as reference guidelines to assist the investigator in assessing the likelihood of a 
relationship between the test product and the AE based upon the available information.

The following components are to be used to assess the relationship between the 
Sponsor’s product and the AE; the greater the correlation with the components and 
their respective elements (in number and/or intensity), the more likely the Sponsor’s 
product caused the AE:
-
Exposure: Is there evidence that the participant was actually exposed to the 
Sponsor’s product such as: reliable history, acceptable compliance assessment (pill 
count, diary, etc.), expected pharmacologic effect, or measurement of drug/metabolite 
in bodily specimen?
-
Time Course: Did the AE follow in a reasonable temporal sequence from 
administration of the Sponsor’s product? Is the time of onset of the AE compatible 
with a drug-induced effect (applies to studies with investigational medicinal product)?
-
Likely Cause: Is the AE not reasonably explained by another etiology such as 
underlying disease, other drug(s)/vaccine(s), or other host or environmental factors.
-
Dechallenge: Was the Sponsor’s product discontinued or dose/exposure/frequency 
reduced?
-
If yes, did the AE resolve or improve?
-
If yes, this is a positive dechallenge.
-
If no, this is a negative dechallenge.
(Note: This criterion is not applicable if: (1) the AE resulted in death or permanent 
disability; (2) the AE resolved/improved despite continuation of the Sponsor’s 
product; (3) the study is a single-dose drug study; or (4) Sponsor’s product(s) is/are 
only used 1 time.)
-
Rechallenge: Was the participant re-exposed to the Sponsor’s product in this study?
-
If yes, did the AE recur or worsen?
-
If yes, this is a positive rechallenge.
-
If no, this is a negative rechallenge.
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(Note: This criterion is not applicable if: (1) the initial AE resulted in death or 
permanent disability, or (2) the study is a single-dose drug study; or (3) Sponsor’s 
product(s) is/are used only 1 time.)
NOTE: IF A RECHALLENGE IS PLANNED FOR AN AE THAT WAS SERIOUS AND 
MAY HAVE BEEN CAUSED BY THE SPONSOR’S PRODUCT, OR IF RE-EXPOSURE 
TO THE SPONSOR’S PRODUCT POSES ADDITIONAL POTENTIAL SIGNIFICANT 
RISK TO THE PARTICIPANT THEN THE RECHALLENGE MUST BE APPROVED IN 
ADVANCE BY THE SPONSOR CLINICAL DIRECTOR, AND IF REQUIRED, THE 
IRB/IEC.

Consistency with study intervention profile: Is the clinical/pathological presentation 
of the AE consistent with previous knowledge regarding the Sponsor’s product or drug 
class pharmacology or toxicology?

The assessment of relationship will be reported on the case report forms/worksheets by 
an investigator who is a qualified physician according to his/her best clinical judgment, 
including consideration of the above elements.

Use the following scale of criteria as guidance (not all criteria must be present to be 
indicative of a Sponsor’s product relationship).
-
Yes, there is a reasonable possibility of Sponsor’s product relationship:
◦
There is evidence of exposure to the Sponsor’s product. The temporal sequence 
of the AE onset relative to the administration of the Sponsor’s product is 
reasonable. The AE is more likely explained by the Sponsor’s product than by 
another cause.
-
No, there is not a reasonable possibility of Sponsor’s product relationship:
◦
Participant did not receive the Sponsor’s product OR temporal sequence of the 
AE onset relative to administration of the Sponsor’s product is not reasonable 
OR the AE is more likely explained by another cause than the Sponsor’s 
product. (Also entered for a participant with overdose without an associated 
AE.)

For each AE/SAE, the investigator must document in the medical notes that he/she has 
reviewed the AE/SAE and has provided an assessment of causality.

There may be situations in which an SAE has occurred and the investigator has minimal 
information to include in the initial report to the Sponsor. However, it is very important 
that the investigator always make an assessment of causality for every event before the 
initial transmission of the SAE data to the Sponsor.

The investigator may change his/her opinion of causality in light of follow-up 
information and send an SAE follow-up report with the updated causality assessment.
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
The causality assessment is 1 of the criteria used when determining regulatory reporting 
requirements.
Follow-up of AE and SAE

The investigator is obligated to perform or arrange for the conduct of supplemental 
measurements and/or evaluations as medically indicated or as requested by Sponsor to 
elucidate the nature and/or causality of the AE or SAE as fully as possible. This may 
include additional laboratory tests or investigations, histopathological examinations, or 
consultation with other health care professionals.

New or updated information will be recorded in the CRF.

The investigator will submit any updated SAE data to the Sponsor within 24 hours of 
receipt of the information.
10.3.5
Reporting of AEs, SAEs, and Other Reportable Safety Events to the Sponsor
AE, SAE, and other reportable safety event reporting to Sponsor via electronic data 
collection tool

The primary mechanism for reporting to the Sponsor will be the electronic data collection 
(EDC) tool.
-
Electronic reporting procedures can be found in the EDC data entry guidelines (or 
equivalent).
-
If the electronic system is unavailable for more than 24 hours, then the site will use 
the paper AE Reporting form.
◦
Reference Section 8.4.1 for reporting time requirements.

The site will enter the SAE data into the electronic system as soon as it becomes 
available.

After the study is completed at a given site, the EDC tool will be taken off-line to prevent 
the entry of new data or changes to existing data.

If a site receives a report of a new SAE from a study participant or receives updated data 
on a previously reported SAE after the EDC tool has been taken off-line, then the site can 
report this information on a paper SAE form or by telephone (see next section).

Contacts for SAE reporting can be found in the Investigator Study File Binder (or 
equivalent).
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SAE reporting to the Sponsor via paper CRF

If the EDC tool is not operational, facsimile transmission or secure e-mail of the SAE 
paper CRF is the preferred method to transmit this information to the Sponsor.

In rare circumstances and in the absence of facsimile equipment, notification by 
telephone is acceptable with a copy of the SAE data collection tool sent by overnight 
mail or courier service.

Initial notification via telephone does not replace the need for the investigator to 
complete and sign the SAE CRF pages within the designated reporting time frames.

Contacts and instructions for SAE reporting and paper reporting procedures can be found 
in the Investigator Study File Binder (or equivalent).
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10.4
Appendix 4: Device Events, Adverse Device Events, and Medical Device 
Incidents: Definitions, Collection, and Documentation
Not applicable.
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10.5
Appendix 5: Contraceptive Guidance
10.5.1
Definitions
Women of Nonchildbearing Potential (WONCBP)
Women in the following categories are considered WONCBP:

Premenopausal female with 1 of the following:
-
Documented hysterectomy
-
Documented bilateral salpingectomy
-
Documented bilateral oophorectomy
For individuals with permanent infertility due to an alternate medical cause other than the 
above (eg, Mullerian agenesis, androgen insensitivity), investigator discretion should be 
applied to determining study entry.
Note: Documentation can come from the site personnel’s review of the participant’s 
medical records, medical examination, or medical history interview.

Postmenopausal female
-
A postmenopausal state is defined as no menses for 12 months without an alternative 
medical cause. 
◦
A high follicle stimulating hormone (FSH) level in the postmenopausal range may 
be used to confirm a postmenopausal state in women not using hormonal 
contraception or hormone replacement therapy (HRT). However, in the absence 
of 12 months of amenorrhea, confirmation with two FSH measurements in the 
postmenopausal range is required. 
-
Females on HRT and whose menopausal status is in doubt will be required to use one 
of the nonhormonal highly effective contraception methods if they wish to continue 
their HRT during the study. Otherwise, they must discontinue HRT to allow 
confirmation of postmenopausal status before study enrollment.
Women of Childbearing Potential (WOCBP)
A woman is considered fertile following menarche and until becoming postmenopausal 
unless permanently sterile (see below):
If fertility is unclear (eg, amenorrhea in adolescents or athletes) and a menstrual cycle cannot 
be confirmed before first dose of study intervention, additional evaluation should be 
considered.
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Women in the following categories are not considered WOCBP:

Premenarchal

Premenopausal female with 1 of the following:
-
Documented hysterectomy
-
Documented bilateral salpingectomy
-
Documented bilateral oophorectomy
For individuals with permanent infertility due to an alternate medical cause other than the 
above (eg, Mullerian agenesis, androgen insensitivity), investigator discretion should be 
applied to determining study entry.
Note: Documentation can come from the site personnel’s review of the participant’s 
medical records, medical examination, or medical history interview.

Postmenopausal female
-
A postmenopausal state is defined as no menses for 12 months without an 
alternative medical cause.
◦
A high follicle stimulating hormone (FSH) level in the postmenopausal range 
may be used to confirm a postmenopausal state in women not using hormonal 
contraception or hormone replacement therapy (HRT). However, in the 
absence of 12 months of amenorrhea, confirmation with two FSH 
measurements in the postmenopausal range is required.
-
Females on HRT and whose menopausal status is in doubt will be required to use 
one of the nonhormonal highly effective contraception methods if they wish to 
continue their HRT during the study. Otherwise, they must discontinue HRT to 
allow confirmation of postmenopausal status before study enrollment.
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10.5.2
Contraception Requirements
Contraceptives allowed during the study includea:
Highly Effective Contraceptive Methods That Have Low User Dependencyb
Failure rate of <1% per year when used consistently and correctly.

Progestogen-only contraceptive implantc

Intrauterine hormone-releasing system (IUS)d

Intrauterine device (IUD)

Bilateral tubal occlusion

Azoospermic partner (vasectomized or secondary to medical cause)
This is a highly effective contraception method provided that the partner is the sole male sexual partner of 
the WOCBP and the absence of sperm has been confirmed. If not, an additional highly effective method of 
contraception should be used. A spermatogenesis cycle is approximately 90 days.
Note: Documentation of azoospermia can come from the site personnel’s review of the participant’s 
medical records, medical examination, or medical history interview.
Highly Effective Contraceptive Methods That Are User Dependentb
Failure rate of <1% per year when used consistently and correctly.

Combined (estrogen- and progestogen- containing) hormonal contraceptionc
-
Oral
-
Intravaginal
-
Transdermal
-
Injectable

Progestogen-only hormonal contraceptionc
-
Oral
-
Injectable
Sexual Abstinence

Sexual abstinence is considered a highly effective method only if defined as refraining from heterosexual 
intercourse during the entire period of risk associated with the study intervention. The reliability of sexual 
abstinence needs to be evaluated in relation to the duration of the study and the preferred and usual lifestyle 
of the participant.
Acceptable Contraceptive Methods
Failure rate of >1% per year when used consistently and correctly.

Progesterone-only hormonal contraception where inhibition of ovulation is not the primary mode of action

Male or female condom with or without spermicide

Cervical cap, diaphragm, or sponge with spermicide

A combination of male condom with either cervical cap, diaphragm, or sponge with spermicide (double 
barrier methods)e
a.
Contraceptive use by men or women should be consistent with local regulations regarding the use of 
contraceptive methods for participants of clinical studies.
b.
Typical use failure rates are higher than perfect-use failure rates (ie, when used consistently and correctly).
c.
If locally required, in accordance with Clinical Trial Facilitation Group (CTFG) guidelines, acceptable 
contraceptive implants are limited to those which inhibit ovulation
d.
IUS is a progestin releasing IUD.
e.
A combination of male condom with either cap, diaphragm, or sponge with spermicide are considered 
acceptable, but not highly effective, birth control methods.
Note: The following are not acceptable methods of contraception:
-
Periodic abstinence (calendar, symptothermal, post-ovulation methods), withdrawal (coitus 
interruptus), spermicides only, and lactational amenorrhea method (LAM).
-
Male and female condom should not be used together (due to risk of failure with friction).
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10.6
Appendix 6: Collection and Management of Specimens for Future Biomedical 
Research
1.  Definitions
a.
Biomarker: A biological molecule found in blood, other body fluids, or tissues that is 
a sign of a normal or abnormal process or of a condition or disease. A biomarker may 
be used to see how well the body responds to a treatment for a disease or condition.1
b. Pharmacogenomics: The investigation of variations of DNA and RNA characteristics 
as related to drug/vaccine response.2
c.
Pharmacogenetics: A subset of pharmacogenomics, pharmacogenetics is the influence 
of variations in DNA sequence on drug/vaccine response.2
d. DNA: Deoxyribonucleic acid.
e.
RNA: Ribonucleic acid.
2.  Scope of Future Biomedical Research
The specimens consented and/or collected in this study as outlined in Section 8.9 will be 
used in various experiments to understand:
◦
The biology of how drugs/vaccines work
◦
Biomarkers responsible for how a drug/vaccine enters and is removed by the body
◦
Other pathways drugs/vaccines may interact with
◦
The biology of disease
The specimen(s) may be used for future assay development and/or drug/vaccine 
development.
It is now well recognized that information obtained from studying and testing clinical 
specimens offers unique opportunities to enhance our understanding of how individuals 
respond to drugs/vaccines, enhance our understanding of human disease and ultimately 
improve public health through development of novel treatments targeted to populations 
with the greatest need. All specimens will be used by the Sponsor or those working for or 
with the Sponsor.
3.  Summary of Procedures for Future Biomedical Research
a.
Participants for Enrollment
All participants enrolled in the clinical study will be considered for enrollment in 
future biomedical research 
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b. Informed Consent
Informed consent for specimens (ie, DNA, RNA, protein, etc.) will be obtained 
during screening for protocol enrollment from all participants or legal guardians, at a 
study visit by the investigator or his or her designate. Informed consent for future 
biomedical research should be presented to the participants on the visit designated in 
the SoA. If delayed, present consent at next possible Participant Visit. Consent forms 
signed by the participant will be kept at the clinical study site under secure storage for 
regulatory reasons.
A template of each study site’s approved informed consent will be stored in the 
Sponsor’s clinical document repository.
c.
eCRF Documentation for Future Biomedical Research Specimens
Documentation of participant consent for future biomedical research will be captured 
in the eCRFs. Any specimens for which such an informed consent cannot be verified 
will be destroyed.
d. Future Biomedical Research Specimen(s)
Collection of specimens for future biomedical research will be performed as outlined 
in the SoA. In general, if additional blood specimens are being collected for future 
biomedical research, these will usually be obtained at a time when the participant is 
having blood drawn for other study purposes.
4.  Confidential Participant Information for Future Biomedical Research
In order to optimize the research that can be conducted with future biomedical research 
specimens, it is critical to link participant' clinical information with future test results. In 
fact little or no research can be conducted without connecting the clinical study data to 
the specimen. The clinical data allow specific analyses to be conducted. Knowing 
participant characteristics like gender, age, medical history and intervention outcomes are 
critical to understanding clinical context of analytical results.
To maintain privacy of information collected from specimens obtained for future 
biomedical research, the Sponsor has developed secure policies and procedures. All 
specimens will be single-coded per ICH E15 guidelines as described below.
At the clinical study site, unique codes will be placed on the future biomedical research 
specimens. This code is a random number which does not contain any personally 
identifying information embedded within it. The link (or key) between participant 
identifiers and this unique code will be held at the study site. No personal identifiers will 
appear on the specimen tube.
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5.  Biorepository Specimen Usage
Specimens obtained for the Sponsor will be used for analyses using good scientific 
practices. Analyses utilizing the future biomedical research specimens may be performed 
by the Sponsor, or an additional third party (eg, a university investigator) designated by 
the Sponsor. The investigator conducting the analysis will follow the Sponsor’s privacy 
and confidentiality requirements. Any contracted third party analyses will conform to the 
specific scope of analysis outlined in future biomedical research protocol and consent.
Future biomedical research specimens remaining with the third party after specific 
analysis is performed will be reported to the Sponsor.
6.  Withdrawal From Future Biomedical Research
Participants may withdraw their consent for future biomedical research and ask that their 
biospecimens not be used for future biomedical research. Participants may withdraw 
consent at any time by contacting the investigator for the main study. If medical records 
for the main study are still available, the investigator will contact the Sponsor using the 
designated mailbox (clinical.specimen.management@merck.com). Subsequently, the 
participant's specimens will be flagged in the biorepository and restricted to main study 
use only. If specimens were collected from study participants specifically for future 
biomedical research, these specimens will be removed from the biorepository and 
destroyed. Documentation will be sent to the investigator confirming withdrawal and/or 
destruction, if applicable. It is the responsibility of the investigator to inform the 
participant of completion of the withdrawal and/or destruction, if applicable. Any 
analyses in progress at the time of request for withdrawal/destruction or already 
performed prior to the request being received by the Sponsor will continue to be used as 
part of the overall research study data and results. No new analyses would be generated 
after the request is received.
In the event that the medical records for the main study are no longer available (eg, if the 
investigator is no longer required by regulatory authorities to retain the main study 
records) or the specimens have been completely anonymized, there will no longer be a 
link between the participant’s personal information and their specimens. In this situation, 
the request for withdrawal of consent and/or destruction cannot be processed.
7.  Retention of Specimens
Future biomedical research specimens will be stored in the biorepository for potential 
analysis for up to 20 years from the end of the main study. Specimens may be stored for 
longer if a regulatory or governmental authority has active questions that are being 
answered. In this special circumstance, specimens will be stored until these questions 
have been adequately addressed.
Specimens from the study site will be shipped to a central laboratory and then shipped to 
the Sponsor-designated biorepository. If a central laboratory is not utilized in a particular 
study, the study site will ship directly to the Sponsor-designated biorepository. The 
specimens will be stored under strict supervision in a limited access facility which 
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operates to assure the integrity of the specimens. Specimens will be destroyed according 
to Sponsor policies and procedures and this destruction will be documented in the 
biorepository database.
8.  Data Security
Databases containing specimen information and test results are accessible only to the 
authorized Sponsor representatives and the designated study administrator research 
personnel and/or collaborators. Database user authentication is highly secure, and is 
accomplished using network security policies and practices based on international 
standards to protect against unauthorized access.
9.  Reporting of Future Biomedical Research Data to Participants
No information obtained from exploratory laboratory studies will be reported to the 
participant, family, or physicians. Principle reasons not to inform or return results to the 
participant include: Lack of relevance to participant health, limitations of predictive 
capability, and concerns regarding misinterpretation.
If important research findings are discovered, the Sponsor may publish results, present 
results in national meetings, and make results accessible on a public website in order to 
rapidly report this information to doctors and participants. Participants will not be 
identified by name in any published reports about this study or in any other scientific 
publication or presentation.
10. Future Biomedical Research Study Population
Every effort will be made to recruit all participants diagnosed and treated on Sponsor 
clinical studies for future biomedical research.
11. Risks Versus Benefits of Future Biomedical Research
For future biomedical research, risks to the participant have been minimized and are 
described in the future biomedical research informed consent.
The Sponsor has developed strict security, policies, and procedures to address participant 
data privacy concerns. Data privacy risks are largely limited to rare situations involving 
possible breach of confidentiality. In this highly unlikely situation, there is risk that the 
information, like all medical information, may be misused.
12. Questions
Any questions related to the future biomedical research should be emailed directly to 
clinical.specimen.management@merck.com.
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13. References
1. National Cancer Institute [Internet]: Available from 
https://www.cancer.gov/publications/dictionaries/cancer-terms?cdrid=45618
2. International Council on Harmonization [Internet]: E15: Definitions for Genomic 
Biomarkers, Pharmacogenomics, Pharmacogenetics, Genomic Data and Sample Coding 
Categories. Available from http://www.ich.org/products/guidelines/efficacy/efficacy-
single/article/definitions-for-genomic-biomarkers-pharmacogenomics-pharmacogenetics-
genomic-data-and-sample-cod.html
3. Industry Pharmacogenomics Working Group [Internet]: Understanding the Intent, Scope 
and Public Health Benefits of Exploratory Biomarker Research: A Guide for IRBs/IECs 
and Investigational Site Staff. Available at http://i-pwg.org/
4. Industry Pharmacogenomics Working Group [Internet]: Pharmacogenomics 
Informational Brochure for IRBs/IECs and Investigational Site Staff. Available at http://i-
pwg.org/
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10.7
Appendix 7: Country-specific Requirements
Not applicable.
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10.8
Appendix 8: Risk Evaluation
At each treatment and follow-up visit as specified in the SoA (1.3.1 and 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?
o
If no, no further questions.
o
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 1-4 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
AB
antibody
AE
adverse event 
AG
antigen
ALT 
alanine aminotransferase
APaT
All Participants as Treated
ART
antiretroviral therapy
AST 
aspartate aminotransferase
AUC
area under the curve
β-hCG
beta human chorionic gonadotropin
B-2M/Cr
Beta-2- microglobulin/creatinine ratio
BICR
blinded independent central review
BMD
bone mineral density
BMI
body mass index
CDC
Centers for Disease Control
CI
confidence interval
CrCL
creatinine clearance
Cmax
maximum (peak) observed drug plasma concentration
CONSORT
Consolidated Standards of Reporting Trials 
CRF
Case Report Form 
CSR
Clinical Study Report
CT
Chlamydia trachomatis 
CTFG
Clinical Trial Facilitation Group
Ctrough
Trough plasma concentration
DAIDS
Division of AIDS
DAO
Data-As-Observed
DDI
drug-drug interaction
DEXA
Dual-energy X-ray Absorptiometry
DILI
drug-induced liver injury
DMC
Data Monitoring Committee 
DNA
deoxyribonucleic acid 
DP
diphosphate
EC90
90% effective concentration
ECG
electrocardiogram 
ECI
event of clinical interest
eCRF
electronic Case Report Form
EDC
electronic data collection 
EFV
efavirenz
ENG
etonogestrel 
FBR
Future biomedical research
FDA
Food and Drug Administration
FDC
fixed dose combination
FSH
follicle stimulating hormone 
FTC
emtricitabine
FW
Follow up Week
GC
Neisseria gonorrhoeae
GCP
Good Clinical Practice 
HBsAg
Hepatitis B surface antigen
HBV
hepatitis B virus
HCV
hepatitis C virus
HDL
high-density lipoprotein
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Abbreviation
Expanded Term
HIV
human immunodeficiency virus
HRT
hormone replacement therapy
IB
Investigator’s Brochure 
IC50
half-maximal inhibitory concentration
ICF
Informed Consent Form 
ICH
International Conference for Harmonisation of Technical Requirements for 
Pharmaceutical for Human Use
I/E
Inclusion/Exclusion
IEC
Independent Ethics Committee
IND
Investigational New Drug 
IMP
investigational medicinal product
IRB
Institutional Review Board 
IRT
Interactive Response Technology
ISG
immediate switch group
IUD
intrauterine device
IUS
intrauterine hormone-releasing system
IV
intravenous
LAM
lactational amenorrhea method 
LDL
low-density lipoprotein
Mg
milligram
MPA
medroxyprogesterone acetate
MSD
Merck, Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc.
MTD
maximum tolerated dose 
NA
Not applicable
NC=F
Non-Completer=Failure
NDA
New Drug Application 
NET
norethisterone or norethindrone
NET-EN
norethindrone enanthate
NIMP
non-investigational medicinal product
NNRTI
non-nucleoside reverse transcriptase inhibitor
NOAEL
no observed adverse effect level 
NRTI
nucleoside analog reverse transcriptase inhibitor
NRTTI
nucleoside reverse transcriptase translocation inhibitor
NSAIDS
non-steroidal anti-inflammatory drugs 
OBS
observed
OF
Observed Failure 
PBMC
peripheral blood mononuclear cells
PCR
polymerase chain reaction
PDLC
predefined limit of change
PEP
post-exposure prophylaxis
PET
positron emission tomography 
PK
pharmacokinetic
PP
Per Protocol
PrEP
pre-exposure prophylaxis
PRO
patient-related outcome
QM
once monthly
QP2
department of quantitative pharmacology and pharmacometrics
RBP/Cr
retinol binding protein/creatinine ratio
RNA
ribonucleic acid
RPR
rapid plasma reagin
SAC
Scientific Advisory Committee
SAE
serious adverse event 
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08-DEC-2021
Abbreviation
Expanded Term
sCD-163
soluble CD-163
siDMC
standing internal Data Monitoring Committee
SGOT
serum glutamic-oxaloacetic transaminase 
SGPT
serum glutamic-pyruvic transaminase 
SoA
Schedule of Activities
SOC
System Organ Class
SOP
standard operating procedure
sSAP
supplemental statistical analysis plan
STI
sexually-transmitted infection
SUSAR
suspected unexpected serious adverse reaction
t1/2
apparent terminal half-life
TAF
tenofovir alafenamide
TDF
tenofovir disoproxil fumarate
TP
triphosphate
UDS
urine drug screen
ULN
upper limit of normal 
USDHHS
United States Department of Health and Human Services
VAMS
volumetric absorptive microsampling
VL
viral load
WHO
World Health Organization
WOCBP
woman/women of childbearing potential 
WONCBP
woman/women of nonchildbearing potential
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08-DEC-2021
11
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Grobler JA, McHale C, Freddo C, Dreyer D, 
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[Tetteh, R. A., et al 2017]
Tetteh RA, Yankey BA, Nartey ET, Lartey 
M, Leufkens HGM, Dodoo ANO. Pre-
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Wang Y, Jadhav PR, Lala M, Gobburu JV. 
Clarification on precision criteria to derive 
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[Weintrob, A. C., et al 2009]
Weintrob AC, Grandits GA, Agan BK, 
Ganesan A, Landrum ML, Crum-Cianflone 
NF, et al. Virologic response differences 
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[055GNM]
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SAP_001.pdf: 
Official Protocol Title: 
NCT number: 
NCT04003103 
Document Date: 
08-Dec-2021
A Phase 2a, Double-Blind, Placebo-Controlled Study to Evaluate the 
Safety, Tolerability, and Pharmacokinetics of Oral MK-8591 Once-
Monthly in Participants at Low-Risk for HIV-1 Infection


MK-8591
PAGE 1
PROTOCOL NO. 016
Supplemental SAP
       14 OCT 2019 – AMENDMENT 01
Supplemental Statistical Analysis Plan (sSAP)
1. INTRODUCTION
This supplemental SAP (sSAP) is a companion document to the protocol. In addition to the 
information presented in the protocol SAP which provides the principal features of confirmatory 
analyses for this trial, this supplemental SAP provides additional statistical analysis details/data 
derivations and documents modifications or additions to the analysis plan that are not “principal” 
in nature and result from information that was not available at the time of protocol finalization.     
2. SUMMARY OF CHANGES 
The following changes to the protocol SAP are detailed in this document: 
-
Section 3.10 Analysis of implant/depot DDI subgroup added
-
Section 3.11 Alternative compliance calculation added 
3. ANALYTICAL AND METHODOLOGICAL DETAILS
3.1
Statistical Analysis Plan Summary
Study Design Overview
A Phase 2a, double-blind, placebo-controlled study to evaluate the safety, tolerability, 
and PK of oral MK-8591 QM in participants at low-risk for HIV-1 infection
Treatment Assignment
A total of 250 participants will be randomized to Group 1 (60 mg MK-8591), Group 
2 (120 mg MK-8591), or Group 3 (placebo) in a 2:2:1 ratio.
Analysis Populations
Safety: APaT
Primary Endpoint(s)
AEs 
AEs leading to discontinuation of study intervention 
Key Secondary Endpoints Plasma MK-8591 AUC0-672hr, Cmax, Ctrough and t1/2
Intracellular MK-8591-TP AUC0-672hr, Cmax, Ctrough and t1/2
Statistical Methods for 
Key 
Pharmacokinetic 
Analyses
Geometric means and 95% CIs will be provided for Plasma MK-8591 and PBMC 
MK-8591-TP AUC0-672hr, Cmax and Ctrough by dose level.
Statistical Methods for 
Key Safety Analyses
95% CIs (Tier 2 endpoints) will be provided for between-group differences in the 
percentage of participants with events; these analyses will be performed using the 
Miettinen and Nurminen method [Miettinen, O. and Nurminen, M. 1985].
Interim Analyses
There are no planned interim analyses for this study.
Multiplicity
No multiplicity adjustment is necessary as there are no hypothesis tests for this 
protocol.
Sample Size and Power 
There are no hypotheses in this study. The primary objective will compare the 95% 
CI for between-group differences. Given the planned sample size of 250 participants 
(2:2:1), the study has 80% probability at an overall 2-sided 5% α-level to rule out an 
18.4% risk difference in AEs from the placebo group assuming an underlying 
incidence of 10% in the placebo group. The study has an 80% probability to rule out a 
15% risk difference in AE between MK-8591 120 mg and 60 mg groups assuming an 
underlying incidence of 10% in the MK-8591 60 mg group.
Assuming plasma MK-8591 Cmax has a true between-participant standard deviation 
(log-scale) of 0.25, given 100 participants receiving MK-8591 at one of the dose 
levels, it is 80% likely that the half-width of the 95% CI for the true arithmetic mean 
Cmax on the log scale will be at most 0.0525.
 
 
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PROTOCOL NO. 016
Supplemental SAP
       14 OCT 2019 – AMENDMENT 01
3.2
Responsibility for Analyses/In-House Blinding
The statistical analysis of the data obtained from this study will be the responsibility of the 
Clinical Biostatistics department of the Sponsor.
For clinical site personnel, participants, and the Sponsor’s clinical team this study will be a 
double-blind study under in-house blinding procedures through Week 24. The Sponsor will be 
unblinded at Week 24 for the primary safety assessment. For the PBMC/PK Bridging Subset 
only, investigators/clinical site personnel and participants will be unblinded to MK-8591/placebo 
between Weeks 36 and 44 while remaining blinded to MK-8591 dose. For those participants not 
in the PBMC/PK Bridging Subset, participants and investigators/clinical site personnel will 
remain blinded for the duration of the study.
To allow timely completion of population PK modeling, Sponsor PK personnel will be unblinded 
for the duration of the study. No personnel directly associated with study conduct will be 
unblinded. Before granting select personnel access to unblinded PK data, an official memo 
detailing unblinding procedures will be generated per Sponsor SOP. This memo will list the 
names of the personnel who will have access to unblinded PK data. 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.
3.3
Hypotheses/Estimation
There are no hypotheses to be tested in this study. Objectives of the study are stated in Section 3 
of the protocol.
3.4
Analysis Endpoints
3.4.1
Safety Endpoints
Section 4 of the protocol provides an initial description of safety measures.
The primary safety assessment will include all accumulated safety data during the intervention 
period with follow-up of 4 weeks after the last dose (Week 24 visit). AEs leading to 
discontinuation from study intervention are assessed until Week 20 (last dose received). In the 
extended, unblinded PK follow-up period (after FW 12 visit through FW 44 visit), only SAEs 
and nonserious AEs related to study procedures will be collected. Safety and tolerability will be 
assessed by clinical review of all relevant parameters including AEs and laboratory values. 
Adverse Events
The following AEs will be summarized: 1) participants with at least 1 AE; 2) participants with at 
least 1 drug-related AE; 3) participants with at least 1 SAE; 4) participants with at least 1 Grade 
3 to 5 AE; 5) participants with at least 1 AE which is both serious and drug-related; 6) 
participants with at least 1 AE which is both Grade 3 to 5 and drug-related; 7) participants who 
discontinued study therapy due to an AE; and 8) participants with an AE which results in death. 
The percentage of participants with specific AEs by system organ class will also be summarized.
 
 
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PROTOCOL NO. 016
Supplemental SAP
       14 OCT 2019 – AMENDMENT 01
Predefined Limits of Change in Laboratory Parameters 
Participants must have both a baseline and post-randomization on-treatment measurement to be 
included in the summaries of laboratory tests. Participants’ laboratory values (based on their 
most abnormal laboratory test values, in the direction of interest, while on study therapy) will be 
classified as to whether or not they fall outside of the PDLC and are worse in grade (ie, more 
abnormal in the direction of interest) than at baseline. The PDLC grading criteria are adapted 
from DAIDS Table for Grading the Severity of Adult and Pediatric Adverse Events, July 2017, 
Version 2.1. A listing of the participants who meet the PDLC grading criteria will be provided.
3.4.2
Pharmacokinetics Endpoints
There are no primary PK endpoints.
The secondary PK endpoints in the study are: plasma MK-8591 AUC0-672hr, Cmax, Ctrough, and t1/2
and PBMC MK-8591-TP AUC0-672hr, Cmax, Ctrough, and t1/2.
Exploratory endpoints include tissue concentrations of MK-8591, MK-8591-TP and MK-8591-
DP, as well as plasma concentrations of ENG, MPA, and NET (in a subset of participants).
3.5
Analysis Populations
Safety analyses will be conducted in the APaT population, which consists of all randomized 
participants who received at least 1 dose of study intervention. Participants will be included in 
the group corresponding to the study intervention they actually received for the analysis of safety 
data using the APaT population. This will be the 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 group corresponding to the study intervention actually 
received.
PK analyses will be conducted in 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. 
Compliance covers such considerations as exposure to treatment, availability of measurements, 
and absence of important protocol deviations. Important protocol deviations will be identified to 
the extent possible prior to unblinding by individuals responsible for data collection/compliance, 
and its analysis and interpretation. Any participants or data values excluded from analysis will be 
identified, along with their reason for exclusion, in the CSR. At the end of the study, all 
participants who are compliant with the study procedure as aforementioned and have available 
data from at least one dose will be included in the PK analysis dataset. This population will be 
used for the PK analyses.
 
 
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Supplemental SAP
       14 OCT 2019 – AMENDMENT 01
3.6
Statistical Methods
3.6.1
Statistical Methods for Safety Analyses
Safety and tolerability will be assessed by clinical review of all relevant parameters including 
AEs and laboratory tests.
Safety analyses will be performed for the following between-group comparisons: 

MK-8591 (60 mg) vs placebo

MK-8591 (120 mg) vs placebo

MK-8591 (60 mg) vs MK-8591 (120 mg)
The analysis of safety results will follow a tiered approach (Table 1). The tiers differ with respect 
to the analyses that will be performed. AEs (specific terms as well as system organ class terms) 
and events that meet PDLCs in laboratory parameters are either pre-specified as “Tier 1” 
endpoints, or will be classified as belonging to "Tier 2" or "Tier 3" based on the number of 
events observed.
Safety parameters or AEs of special interest that are identified a priori constitute “Tier 1” safety 
endpoints that will be subject to inferential testing for statistical significance. There are no a 
priori clinical events of concern that have been identified; therefore, there are no Tier 1 events 
for this protocol 
Tier 2 Events
Tier 2 parameters will be assessed via point estimates with 95% CI provided for differences in 
the proportion of participants with events (also via the Miettinen and Nurminen method 
[Miettinen, O. and Nurminen, M. 1985]).
Membership in Tier 2 requires that at least 4 participants in any intervention group exhibit the 
event; all other AEs and predefined limits of change will belong to Tier 3.
The threshold of at least 4 events was chosen because the 95% CI for the between-group 
difference in percent incidence will always include zero when intervention groups of equal size 
each have less than 4 events and thus would add little to the interpretation of potentially 
meaningful differences. Because many 95% CIs for Tier 2 events may be provided without 
adjustment for multiplicity, the CIs should be regarded as a helpful descriptive measure to be 
used in review, not a formal method for assessing the statistical significance of the between-
group differences in AEs and safety parameters that meet predefined limits of change.
In addition to individual events that occur in 4 or more participants in any intervention group, the 
broad AE categories consisting of the proportion of participants with any AE, a drug-related AE, 
a SAE, a Grade 3 to 5 AE, an AE which results in death, an AE which is both drug-related and 
serious, an AE which is both drug-related and Grade 3 to 5, and discontinuation due to an AE 
will be considered Tier 2 endpoints.
 
 
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Supplemental SAP
       14 OCT 2019 – AMENDMENT 01
Tier 3 Events
Safety endpoints that are not Tier 1 or 2 events are considered Tier 3 events. Only point 
estimates by intervention group are provided for Tier 3 safety parameters.
Table 1
Analysis Strategy for Safety Parameters
Safety Tier
Safety Endpoint
95% CI for 
Treatment 
Comparisona
Descriptive 
Statistics
Tier 2
Any AEb
X
X
Any Serious AE
X
X
Any Drug-Related AE
X
X
Any Grade 3 to 5 AE
X
X
Any Serious and Drug-Related AE
X
X
Any Grade 3 to 5 and Drug-Related AE
X
X
Discontinuation due to AE
X
X
AE which Results in Death
X
X
Specific AEs, SOCs, or PDLCs (incidence ≥4 participants in 
one of the intervention groups)
X
X
Tier 3
Specific AEs, SOCs or PDLCs (incidence <4 participants in 
all of the intervention groups)
X
AE=adverse event; CI =confidence interval; SOC=System Organ Class; PDLC=Predefined Limit of Change; X=results 
will be provided.
5% CIs will be based on the method of Miettinen and Nurminen [Miettinen, O. and Nurminen, M. 1985].
ndicates broad AE category of the number of participants reporting any AE.
3.6.2
Pharmacokinetics Analyses
Plasma MK-8591 AUC0-672hr, Cmax, Ctrough, and t1/2 will be summarized separately by dose 
level as appropriate, with geometric means and 95% CIs based on natural log-transformed 
endpoints and t-distribution. 
PBMC MK-8591-TP AUC0-672hr, Cmax, Ctrough and t1/2 will be assessed with a similar 
method as above.
3.7
Interim Analyses
There are no planned interim analyses for this study. 
3.8
Multiplicity
No multiplicity adjustment is planned for this study.  
 
 
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Supplemental SAP
       14 OCT 2019 – AMENDMENT 01
3.9
Sample Size and Power Calculations
3.9.1
Sample Size and Probability Calculations for Safety Analysis
The sample size of this study was chosen to allow for the accumulation of approximately 100 
person-years of safety data (200 participants × 0.5 years). 
While not the basis of the sample size for this study, information on the probability of observing 
a difference between intervention groups is provided. If the underlying incidence of a particular 
AE is 1%, there is a 63.4% chance of observing at least 1 AE among 100 participants in either 
MK-8591 group. If no AE of that type is observed among the 100 participants in the MK-8591
group, this study provides 97.5% confidence that the underlying percentage of participants with 
that particular AE is <3.62% (1 out of every 27 participants).
The estimate of and the upper bound of the 95% CI for the underlying percentage of participants 
with a particular AE given various hypothetical observed number of participants with a particular 
AE within either MK-8591 group are provided in Table 2. These calculations are based on the 
exact binomial method proposed by Clopper and Pearson (1934) [Clopper, C. J. and Pearson, E. 
S. 1934].
Table 3 summarizes differences in the incidence of AEs between the 2 MK-8591 groups and for 
either MK-8591 group compared with placebo that can be ruled out with different probabilities 
and 95% confidence for a variety of hypothetical underlying incidences of an AE. These 
calculations assume 100 participants in each MK-8591 group and 50 participants in the placebo 
group and that the underlying incidence of AEs is the same for both groups. The calculations are 
based on an asymptotic method proposed by Farrington and Manning (1990) [Farrington, C. P. 
and Manning, G. 1990]; no multiplicity adjustments were made. 
3.9.2
Sample size and Probability Calculations for PK Analysis
No estimates of variability for AUC672hr or Ctrough following monthly oral dosing are available. 
The precision of the estimates of plasma MK-8591 Cmax can be assessed by calculating the half-
width of the 95% CIs expected for the given sample size and assumed variability. The 
calculations for Cmax are based on assumed true between-participant standard deviations (log-
scale) of 0.25 as observed in MK-8591 Protocol 001 and take into account the sampling 
distribution of the observed sample variance as described in [Wang, Y., et al 2012]. For the given 
sample size (100 participants receiving MK-8591 at one of the dose levels) and assumed 
between-participant variability, it is 80% likely that the half-width of the 95% CI for the true 
arithmetic mean Cmax on the log scale will be at most 0.0525 (the lower and upper 95% confidence 
limits for the true geometric mean Cmax will be OBS/1.05 and OBS × 1.05, where OBS is the 
observed geometric mean).
 
 
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Table 2
Estimate of Incidence of AEs and 95% Upper Confidence Bound Based on 
Hypothetical Number of Participants With a Particular AE Among 100 Participants 
in Either MK-8591 Intervention Group
Hypothetical Number of 
Participants with a Particular 
AE
Estimate of 
Incidence
95% Upper Confidence 
Bounda
0
0%
3.6
3
3%
6.3
5
5%
11.3
10
10%
17.6
15
15%
25.5
20
20%
29.2
AE=adverse event.
a Based on the two-tailed exact confidence interval of a binomial proportion [Clopper, C. J. and Pearson, E. S. 1934].
 
 
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Table 3
Difference in Incidence of AEs (MK-8591 Intervention Group Minus Placebo) That 
Can Be Ruled Out
Differencea in Percentage Points That Can Be Ruled Out with Target 
Probability Assuming the Underlying Incidence of the AE is:
Target 
Probability
10%
20%
30%
40%
50%
Compare MK-8591 to placebo
80
18.4
21.9
23.5
24.0
23.5
85
20.1
23.6
25.2
25.6
24.9
90
22.2
25.7
27.3
27.5
26.7
95
25.3
28.9
30.3
30.3
29.2
Compare MK-8591 intervention groups 
80
15.0
17.9
19.3
19.7
19.3
85
16.2
19.2
20.6
21.0
20.6
90
17.8
20.9
22.3
22.7
22.1
95
20.1
23.4
24.8
25.1
24.4
AE=adverse event.
a The upper bound of the two-sided 95% confidence interval [Farrington, C. P. and Manning, G. 1990] for the difference in 
AE incidences assuming the incidences are the same. Assuming 100 participants in the MK-8591 intervention groups and 
50 participants in the placebo group.
3.10
Subgroup Analyses and Effect of Baseline Factors
To evaluate potential differential pharmacokinetics between groups, plasma MK-8591 will be 
assessed with a similar method as described in Section 9.6 within each category of the following 
classification variables:
•
Sex (female, male)
•
Race (white, non-white)
•
Region (Africa, non-Africa)
Ь
Age (İ45 years; >45 years)
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Safety will be assessed by treatment group within the implant/depot DDI subset.  This subset 
consists of those female participants who are using an ENG-releasing implant (ie, Nexplanon® 
or Implanon NXT®) or injectable-MPA or injectable-NET-EN (eg, Noristerat, Syngestal).
3.11
Compliance (Medication Adherence)
Study intervention data for MK-8591 and placebo will be collected during the study. A day 
within the study will be considered an “On-Therapy” day if the participant takes the required 
number of pills from all containers provided for this study. A participant will have to take all 
4 capsules per dose to be considered compliant.
For a participant who is followed for the entire study period, the “Number of Days Should be on 
Therapy” is the total number of days from randomization to the last scheduled day for treatment 
administration for that participant. For a participant who discontinued from the study 
permanently, the “Number of Days Should be on Therapy” is the total number of days from 
randomization to the last dose of study intervention.
For each participant, percent compliance will then be calculated using the following formula:
Summary statistics will be provided on percent compliance by intervention group for the APaT 
population.
If there are participants who only take partial doses at any visit, an alternative compliance 
measure will be calculated using the number of capsules taken using the following formula: 
Summary statistics will be provided for this alternative percent compliance by intervention group 
for the APaT population.
3.12
Extent of Exposure
Each study participant is planned to be exposed to 6 doses of either 60 mg or 120 mg of MK8591 
or placebo over a 6-month period. The amount of intervention received by the participants during 
the study will be summarized.
Alternative Percent Compliance ൌ
Number of Capsules Taken
Number of Capsules Should Have Taken ݔ100
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