Clinical trial NCT04515641
Conditions: Human Immunodeficiency Virus (HIV) Infection
Sponsor: Merck Sharp & Dohme LLC
Start date: 2020-11-05; Completion date: 2021-09-13
Enrollment: 12 participants; Allocation: NON_RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This is an open-label, single-dose study of the plasma pharmacokinetics (PK), safety, and tolerability of islatravir (ISL, MK-8591), and the intracellular PK of ISL triphosphate (ISL-TP) in male and female adult participants with moderate hepatic impairment and in healthy matched control participants.

Detailed description:

Arms: arm 1: Participants receive a single dose of ISL 60 mg. arm 2: Participants receive a single dose of ISL 60 mg.
Interventions: intervention 1: Islatravir
Intervention descriptions: intervention 1: Two ISL 30 mg capsules taken by mouth.

Protocol documents:
Prot_SAP_000.pdf: 
Official Protocol Title: 
NCT number: 
NCT04515641 
Document Date: 
29-Apr-2021
An Open-Label, Single-Dose Study to Evaluate the 
Pharmacokinetics of Islatravir (MK-8591) in Participants with 
Moderate Hepatic Impairment


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: An Open-Label, Single-Dose Study to Evaluate the Pharmacokinetics of 
Islatravir (MK-8591) in Participants with Moderate Hepatic Impairment
Protocol Number: 030-01
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: 29 April 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
MK-8591-030-01
29-APR-2021
The original protocol is being amended to reduce the minimum number of 
required participants from 3 to 2 who have a score of 2 or higher on at least one 
of the laboratory parameters in inclusion criterion #2 in Section 5.1.2, in order 
to optimize recruitment of hepatically impaired participants. Additionally, the 
emergency unblinding call center and photograph of rash related text, as well as 
minor edits to the inform consent text in Section 8.4.1 are included in the 
amendment.
Original Protocol
(MK-8591-030-00)
21-JULY-2020
Not applicable
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PROTOCOL AMENDMENT SUMMARY OF CHANGES
Amendment: [01]
Overall Rationale for the Amendments:
The original protocol is being amended to reduce (from 3 to 2) the minimum number of required participants with a score of 2 or 
higher on at least one of the laboratory parameters in inclusion criterion #2 in Section 5.1.2, in order to optimize recruitment of 
hepatically impaired participants. Additionally, the emergency unblinding call center and photograph of rash related text, as well as 
minor edits to the inform consent text in Section 8.4.1 are included in the amendment.
Summary of Changes Table:
Section # and Name
Description of Change 
Brief Rationale 
5.1.2, Inclusion Criteria for 
Hepatically Impaired 
Participants
Reduced the minimum number of required 
participants with a score of 2 or higher on 
at least one of the laboratory parameters 
from 3 to 2 (inclusion criterion #2).
Potential participants with the lab abnormality criterion 
appear quite rare in the pool of recruitable subjects. In 
order to optimize recruitment of potential subjects with 
moderate hepatic insufficiency in general and facilitate 
the understanding of the effect of hepatic insufficiency, 
this requirement is being eased. 
8.1.10, Participant 
Blinding/Unblinding
Added emergency unblinding call center 
related text.
“The emergency unblinding call center 
will be available so that a health care 
provider can obtain information about 
study intervention in emergency situations 
where the investigator is not available.”
Text was added to clarify that an emergency unblinding 
call center is available for the study.
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Section # and Name
Description of Change 
Brief Rationale 
8.3.5, Photograph of Rash
Added the new section for photographing 
skin reactions.
“Photographs of any rash are highly 
recommended to be taken immediately, 
along with any additional information that 
may assist the investigator in the 
evaluation of the skin reaction, skin 
eruption or rash occurrence, in determining 
etiology and drug relationship.”
Photographs are necessary to assist the investigator to 
evaluate the skin reaction, skin eruption or rash 
occurrence. As such, text was added regarding the 
recommended evaluation.
10.8, Appendix 8: Blood 
Volume Table
Removed “1” in prestudy column and 
added 1 to the count in the treatment 
period column for the following sample 
collection listed in the table:

Blood for Genetic Analysis

Blood for Plasma ISL

Blood for plasma M4
To correct typographic errors. There is no sample 
collection in prestudy for the three sample types per 
Section 1.3 Schedule of Activities.
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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...........................................................................................17
2
INTRODUCTION..........................................................................................................20
2.1
Study Rationale....................................................................................................20
2.2
Background ..........................................................................................................20
2.2.1
Pharmaceutical and Therapeutic Background .............................................21
2.2.2
Preclinical and Clinical Studies ...................................................................21
2.2.3
Ongoing Clinical Studies.............................................................................22
2.3
Benefit/Risk Assessment......................................................................................23
3
HYPOTHESES, OBJECTIVES, AND ENDPOINTS................................................23
4
STUDY DESIGN............................................................................................................25
4.1
Overall Design......................................................................................................25
4.2
Scientific Rationale for Study Design.................................................................27
4.2.1
Rationale for Endpoints ...............................................................................27
4.2.1.1
Efficacy Endpoints.............................................................................27
4.2.1.2
Safety Endpoints................................................................................27
4.2.1.3
Pharmacokinetic Endpoints ...............................................................27
4.2.1.4
Pharmacodynamic Endpoints.............................................................28
4.2.1.5
Planned Exploratory Biomarker Research.........................................28
4.2.1.5.1
Planned Genetic Analysis ........................................................28
4.2.1.6
Future Biomedical Research..............................................................28
4.2.2
Rationale for the Use of Comparator/Placebo .............................................28
4.3
Justification for Dose...........................................................................................29
4.4
Beginning and End of Study Definition .............................................................29
4.4.1
Clinical Criteria for Early Study Termination .............................................29
5
STUDY POPULATION ................................................................................................29
5.1
Inclusion Criteria.................................................................................................30
5.1.1
Inclusion Criteria for Healthy Participants ..................................................30
5.1.2
Inclusion Criteria for Hepatically Impaired Participants.............................31
5.2
Exclusion Criteria................................................................................................33
5.2.1
Exclusion Criteria for Healthy Participants.................................................33
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5.2.2
Exclusion Criteria for Hepatically Impaired Participants............................35
5.3
Lifestyle Considerations......................................................................................37
5.3.1
Meals and Dietary Restrictions....................................................................37
5.3.2
Caffeine, Alcohol, and Tobacco Restrictions ..............................................38
5.3.2.1
Caffeine Restrictions..........................................................................38
5.3.2.2
Alcohol Restrictions...........................................................................38
5.3.2.3
Tobacco Restrictions..........................................................................38
5.3.3
Activity Restrictions ....................................................................................38
5.4
Screen Failures.....................................................................................................38
5.5
Participant Replacement Strategy......................................................................39
6
STUDY INTERVENTION............................................................................................39
6.1
Study Intervention(s) Administered...................................................................39
6.2
Preparation/Handling/Storage/Accountability .................................................41
6.2.1
Dose Preparation..........................................................................................41
6.2.2
Handling, Storage, and Accountability........................................................41
6.3
Measures to Minimize Bias: Randomization and Blinding..............................42
6.3.1
Intervention Assignment..............................................................................42
6.3.2
Stratification.................................................................................................42
6.3.3
Blinding........................................................................................................42
6.4
Study Intervention Compliance..........................................................................42
6.5
Concomitant Therapy..........................................................................................42
6.5.1
Rescue Medications and Supportive Care ...................................................44
6.6
Dose Modification (Escalation/Titration/Other)...............................................44
6.6.1
Stopping Rules.............................................................................................44
6.7
Intervention After the End of the Study............................................................44
6.8
Clinical Supplies Disclosure................................................................................44
7
DISCONTINUATION OF STUDY INTERVENTION AND PARTICIPANT 
WITHDRAWAL............................................................................................................44
7.1
Discontinuation of Study Intervention...............................................................44
7.2
Participant Withdrawal From the Study...........................................................45
7.3
Lost to Follow-up .................................................................................................45
8
STUDY ASSESSMENTS AND PROCEDURES........................................................45
8.1
Administrative and General Procedures ...........................................................46
8.1.1
Informed Consent.........................................................................................46
8.1.1.1
General Informed Consent.................................................................46
8.1.1.2
Consent and Collection of Specimens for Future Biomedical 
Research.............................................................................................47
8.1.2
Inclusion/Exclusion Criteria ........................................................................47
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8.1.3
Participant Identification Card.....................................................................47
8.1.4
Medical History ...........................................................................................47
8.1.5
Prior and Concomitant Medications Review...............................................47
8.1.5.1
Prior Medications...............................................................................47
8.1.5.2
Concomitant Medications..................................................................48
8.1.6
Assignment of Screening Number...............................................................48
8.1.7
Assignment of Treatment/Randomization Number.....................................48
8.1.8
Study Intervention Administration ..............................................................48
8.1.8.1
Timing of Dose Administration.........................................................48
8.1.9
Discontinuation and Withdrawal .................................................................48
8.1.9.1
Withdrawal From Future Biomedical Research ................................49
8.1.10
Participant Blinding/Unblinding..................................................................49
8.1.11
Domiciling ...................................................................................................49
8.1.12
Calibration of Equipment.............................................................................50
8.2
Efficacy/Immunogenicity Assessments ..............................................................50
8.3
Safety Assessments...............................................................................................50
8.3.1
Physical Examinations.................................................................................50
8.3.2
Vital Signs....................................................................................................50
8.3.2.1
Resting Vital Signs ............................................................................51
8.3.3
Electrocardiograms ......................................................................................51
8.3.4
Clinical Safety Laboratory Assessments .....................................................52
8.3.5
Photograph of Rash......................................................................................53
8.4
Adverse Events, Serious Adverse Events, and Other Reportable Safety 
Events....................................................................................................................53
8.4.1
Time Period and Frequency for Collecting AE, SAE, and Other 
Reportable Safety Event Information ..........................................................53
8.4.2
Method of Detecting AEs, SAEs, and Other Reportable Safety Events......55
8.4.3
Follow-up of AE, SAE, and Other Reportable Safety Event Information...55
8.4.4
Regulatory Reporting Requirements for SAE .............................................55
8.4.5
Pregnancy and Exposure During Breastfeeding ..........................................55
8.4.6
Disease-related Events and/or Disease-related Outcomes Not Qualifying 
as AEs or SAEs............................................................................................56
8.4.7
Events of Clinical Interest............................................................................56
8.5
Treatment of Overdose........................................................................................56
8.6
Pharmacokinetics.................................................................................................56
8.6.1
Blood Collection for Plasma ISL and PBMC ISL-TP.................................57
8.6.2
Urine Collection for Urinary MK-8591 and M4..........................................57
8.7
Pharmacodynamics..............................................................................................57
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8.8
Biomarkers ...........................................................................................................57
8.8.1
Planned Genetic Analysis Sample Collection..............................................57
8.9
Future Biomedical Research Sample Collection...............................................57
8.10
Visit Requirements...............................................................................................57
8.10.1
Screening......................................................................................................58
8.10.2
Treatment Period/Visit.................................................................................58
8.10.3
Discontinued Participants Continuing to be Monitored in the Study ..........58
8.10.4
Poststudy......................................................................................................58
8.10.5
Critical Procedures Based on Study Objectives: Timing of Procedure.......58
8.10.6
Study Design/Dosing/Procedures Modifications Permitted Within 
Protocol Parameters .....................................................................................59
9
STATISTICAL ANALYSIS PLAN .............................................................................60
9.1
Statistical Analysis Plan Summary.....................................................................60
9.2
Responsibility for Analyses.................................................................................61
9.3
Hypotheses/Estimation ........................................................................................61
9.4
Analysis Endpoints...............................................................................................61
9.5
Analysis Populations............................................................................................62
9.6
Statistical Methods...............................................................................................62
9.7
Interim Analyses ..................................................................................................64
9.8
Multiplicity ...........................................................................................................64
9.9
Sample Size and Power Calculations .................................................................64
10
SUPPORTING DOCUMENTATION AND OPERATIONAL 
CONSIDERATIONS.....................................................................................................65
10.1
Appendix 1: Regulatory, Ethical, and Study Oversight Considerations........65
10.1.1
Code of Conduct for Clinical Trials.............................................................65
10.1.2
Financial Disclosure.....................................................................................67
10.1.3
Data Protection.............................................................................................67
10.1.3.1
Confidentiality of Data ......................................................................68
10.1.3.2
Confidentiality of Participant Records...............................................68
10.1.3.3
Confidentiality of IRB/IEC Information............................................68
10.1.4
Publication Policy........................................................................................68
10.1.5
Compliance with Study Registration and Results Posting Requirements ...69
10.1.6
Compliance with Law, Audit, and Debarment ............................................69
10.1.7
Data Quality Assurance ...............................................................................70
10.1.8
Source Documents .......................................................................................71
10.1.9
Study and Site Closure.................................................................................71
10.2
Appendix 2: Clinical Laboratory Tests..............................................................72
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10.3
Appendix 3: Adverse Events: Definitions and Procedures for Recording, 
Evaluating, Follow-up, and Reporting...............................................................74
10.3.1
Definition of AE ..........................................................................................74
10.3.2
Definition of SAE ........................................................................................75
10.3.3
Additional Events Reported.........................................................................76
10.3.4
Recording AE and SAE ...............................................................................76
10.3.5
Reporting of AEs, SAEs, and Other Reportable Safety Events to the 
Sponsor ........................................................................................................80
10.4
Appendix 4: Medical Device and Drug-device Combination Products: 
Product Quality Complaints/Malfunctions: Definitions, Recording, and 
Follow-up ..............................................................................................................81
10.5
Appendix 5: Contraceptive Guidance................................................................82
10.5.1
Definitions....................................................................................................82
10.5.2
Contraception Requirements........................................................................83
10.6
Appendix 6: Collection and Management of Specimens for Future 
Biomedical Research............................................................................................84
10.7
Appendix 7: Country-specific Requirements....................................................89
10.8
Appendix 8: Blood Volume Table ......................................................................90
10.9
Appendix 9: 12-Lead Electrocardiogram Abnormality Criteria ....................91
10.10 Appendix 10: Algorithm for Assessing Out of Range Laboratory Values .....93
10.11 Appendix 11: Abbreviations ...............................................................................94
11
REFERENCES...............................................................................................................97
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LIST OF TABLES
Table 1
Severity of Liver Disease Classification..........................................................26
Table 2
Study Interventions..........................................................................................40
Table 3
Allocation of Participants to Treatment...........................................................42
Table 4
Reporting Time Periods and Time Frames for Adverse Events and Other 
Reportable Safety Events.................................................................................54
Table 5
Pharmacokinetic (Blood) Collection Windows ...............................................59
Table 6
Protocol-required Safety Laboratory Assessments..........................................72
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LIST OF FIGURES
Figure 1
Study Design....................................................................................................16
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1
PROTOCOL SUMMARY
1.1
Synopsis
Protocol Title: An Open-Label, Single-Dose Study to Evaluate the Pharmacokinetics of 
Islatravir (MK-8591) in Participants with Moderate Hepatic Impairment
Short Title: Islatravir (MK-8591, ISL) Hepatic Impairment Study
Acronym: Not applicable
Hypotheses, Objectives, and Endpoints:
The study population includes male and female participants with moderate hepatic 
impairment between the ages of 18 and 75 years (inclusive) and healthy matched controls.
Primary Objectives
Primary Endpoints
- To evaluate the plasma pharmacokinetics of 
ISL (e.g., AUC0-∞, AUC0-last, Cmax, Tmax, 
apparent terminal t½, CL/F, and Vz/F) after a 
single oral dose of 60 mg ISL in participants 
with moderate hepatic impairment compared to 
healthy control participants.
Estimation: In participants with moderate 
hepatic impairment, plasma pharmacokinetics 
(AUC0-∞, Cmax) of ISL following a single 
60 mg ISL dose will be estimated and 
compared to those observed in healthy mean 
matched control participants.
- AUC0-∞, AUC0-last, Cmax, Tmax, 
apparent terminal t½, CL/F, and Vz/F of 
plasma ISL
Secondary Objectives
Secondary Endpoints
- To evaluate the safety and tolerability of ISL 
in participants with moderate hepatic 
impairment.
- Adverse experiences, laboratory safety 
tests, ECGs, and VSs.
- To evaluate the intracellular 
pharmacokinetics (e.g., AUC0-∞, AUC0-last, 
Cmax, C24, C168, C672, Tmax, and apparent 
terminal t½) of ISL triphosphate (ISL-TP) in 
peripheral blood mononuclear cells (PBMCs) 
after a single oral dose of 60 mg ISL in 
participants with moderate hepatic impairment 
compared to healthy control participants.
- AUC0-∞, AUC0-last, Cmax, C24, 
C168, C672, Tmax, and apparent terminal 
t½ of ISL-TP in PBMC 
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Overall Design:
Study Phase
Phase 1
Primary Purpose
Treatment
Indication
Treatment and prevention of HIV Infection
Population
Participants with Moderate Hepatic Impairment and Healthy 
Participants 
Study Type
Interventional
Intervention Model
Single Group
This is a single-site study.
Type of Control
Healthy matched control participants
Study Blinding
Unblinded Open-label
Blinding Roles
No Blinding
Estimated Duration of Study
The Sponsor estimates that the study will require 
approximately 6 months from the time the first participant 
signs the informed consent until the last participant’s last 
study-related telephone call or visit.
Number of Participants:
Approximately 12 participants will be allocated.
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Intervention Groups and Duration:
Intervention 
Groups
Intervention Group 
Name
Drug
Dose 
Strength
Dose 
Frequency
Route of 
Administration
Use
Moderate Hepatic 
Impairment Group
MK-8591 (ISL)
60 mg
Single dose
Oral 
Experimental
Healthy Matched 
Control Group 
MK-8591 (ISL)
60 mg
Single dose
Oral 
Experimental 
Total 
Number of 
Intervention 
Groups/ 
Arms
2
Duration of 
Participation
Each participant will participate in the study for approximately 2 months from 
the time the participant signs the Informed Consent Form through the final 
contact. 
Study Governance Committees:
Steering Committee
No
Executive Oversight Committee
No
Data Monitoring Committee
No
Clinical Adjudication Committee
No
There are no governance committees in this study.
Study Accepts Healthy Volunteers: Yes
A list of abbreviations used in this document can be found in Appendix 11.
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1.2
Schema
The study design is depicted in Figure 1.
Figure 1
Study Design
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1.3
Schedule of Activities
All Participants
Intervention
Notes:
Scheduled Day
1
2
2
3
4
5
6
8
Scheduled Hour
Screening Check-
in
Pre-
dose
0
0.25 0.5
1
2
4
6
8
12
24
36
48
72
96 120 168
Administrative/Study Procedures
Informed Consent
X
Informed Consent for Future Biomedical 
Research
X
Participant Identification Card
X
Inclusion/Exclusion Criteria
X
X
Medical History
X
Includes substance use 
(drugs, alcohol, tobacco and 
caffeine)
Prior/Concomitant Medication Review
X
X
X-------------------------------------------------------------------------------X
Refer to Section 8.1.5.
Assignment of Screening Number 
X
Refer to Section 8.1.6.
Assignment of Treatment Number
X
Domiciling 
X-------------------------------------------------------------------------------------------------X
Refer to Section 8.1.11.
MK-8591 (ISL) Administration
X
Safety Procedures
Full physical examination
X
Xa
Symptom-driven PE may be 
performed at other times, at 
the Investigator’s discretion. 
Refer to Section 8.3.1.
Height
X
Refer to Section 8.3.1.
Weight
X
Refer to Section 8.3.1.
Assessment of Liver Function using 
Child-Pugh Classification
X
To be performed in 
participants with Hepatic 
impairment only.
Vital Signs (heart rate, blood pressure)
X
X
X
X Refer to Section 8.3.2
Respiratory Rate
X
X
Refer to Section 8.3.2
Body Temperature
X
X
Refer to Section 8.3.2
12-lead ECG
X
X
X
X Refer to Section 8.3.3
Hepatitis B and C screen (per site SOP)
X
For healthy participants only
HIV-1, HIV-2 Screen
X
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All Participants
Intervention
Notes:
Scheduled Day
1
2
2
3
4
5
6
8
Scheduled Hour
Screening Check-
in
Pre-
dose
0
0.25 0.5
1
2
4
6
8
12
24
36
48
72
96 120 168
Serum/urine β-Human Chorionic 
Gonadotropin (β-hCG)
X
Xa
Required for WOCBP.  
Serum or urine β-hCG at 
predose (per site SOP). 
Serum β-hCG required at 
Screening.  Refer to Section 
10.2
Serum Follicle Stimulating Hormone 
(FSH)
X
For WONCBP. Refer to 
Section 10.2 and 10.5
GC/CT (gonorrhea + chlamydia) screen 
X
Per site SOP
Syphilis serologic screening 
X
Per site SOP
Trichomonas testing 
X
If available, per site SOP
Urine or Blood Drug Screen (UDS/BDS) 
(per site SOP)/alcohol screen
X
Xa
Any additional UDS/BDS 
and alcohol screen are 
conducted per site SOP.  
Refer to Section 10.2
Hematology, urinalysis, and chemistry
X
Xa
``
X
X Refer to Section 8.3.4 and 
10.2.
AE/SAE review
X--------------------------------------------------------------------------------------------------------------X
Refer to Section 8.4.
Pharmacokinetics/Biomarkers
Blood Collection for Plasma ISL 
Xa
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X Refer to Section 8.6.1.
Blood collection for M4 metabolite 
Xa
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Blood for PBMC ISL-TP b
Xa
X
X
X
X
X
Urine collection for ISL and M4 
metabolite 
Xc
X------------------------------X X-------X X------X X------X x-x x-x x--x x--x
Urine intervals: Predose, 0-4, 
4-8, 8-24, 24-48,48-72,
72-96,96-120,120-144,
144-168 hr
Blood for Genetic Analysis 
X
Collect predose from enrolled
participants only.
See Section 8.8
a. Pre-dose PE, pregnancy test, urine drug screen, safety labs, and blood sample for plasma ISL/M4 metabolite/PBMC ISL-TP can be conducted/collected within 24 hours prior to 
study drug administration.  Results from predose safety labs and drug/alcohol screen must be reviewed prior to treatment allocation.
b. PBMC samples will also be analyzed for ISL diphosphate (ISL-DP) to check that sample stabilization is performed properly.  No ISL-DP concentrations or PK parameters will 
be reported.
c. A spot urine sample will be collected prior to study drug administration.
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All Participants
Intervention 
Notes 
Scheduled Day 
11
15
18
22
Post-trial visit/
Day 29 d
Scheduled Hour
240
336
408
504
672
Administrative/ Study Procedures
Concomitant Medication Review
X
X
X
X
X
Safety Procedures
Vital Signs (heart rate, blood pressure)
X
X
X
X
X
Refer to Section 8.3.2
AE/SAE review
X
X
X
X
X
Hematology, urinalysis, and chemistry
X
HIV-1, HIV-2
X
Pharmacokinetics 
Blood for PBMC ISL-TP PK
X
X
X
X
X
d. Post-trial study procedures will be conducted on Day 29 of the study
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2
INTRODUCTION
Islatravir (MK-8591, ISL) is a novel, potent NRTTI being developed both for treatment of 
HIV-1 infection and for prevention of HIV-1 infection in uninfected individuals at high risk.  
Currently, ISL is being evaluated in Phase 2 and Phase 3 trials at a dose of 0.75 mg QD (in 
combination with 100 mg doravirine, DOR; NCT03272347, NCT04223778, NCT04223791, 
NCT04233216, NCT04233879) and in a Phase 2 trial at doses of 60 mg and 120 mg QM 
(NCT04003103).  Additional programs, with other doses and administration frequencies 
within the range of 0.75-120 mg, are being considered as well.
2.1
Study Rationale
The liver is involved in drug clearance through multiple oxidative and conjugative metabolic 
pathways and through biliary excretion. Hepatic insufficiency from acute or chronic liver 
disease may affect excretion and metabolism, leading to accumulation of drug and 
metabolites. Hepatic disease can therefore alter the levels of drugs, potentially leading to an 
effect on efficacy and/or safety.
Islatravir will be administered to HIV patients with liver disease, including those co-infected 
with hepatitis C virus (HCV).  Based on the evidence to date, a major effect of hepatic 
insufficiency on islatravir PK seems unlikely, but possible.  In preclinical studies, hepatic 
metabolic pathways do not appear to play an important role in islatravir metabolism.  The 
major metabolite of islatravir, M4 (4’-ethynyl-2-fluoro-2’deoxyinosine), is formed by 
adenosine deaminase (ADA), which is a ubiquitously expressed enzyme with relatively high 
activity in liver.  Therefore, hepatic insufficiency could result in decreased ADA activity, 
potentially leading to modestly higher levels of islatravir in participants with hepatic 
insufficiency.  A greater understanding of the effects of hepatic insufficiency on islatravir PK 
is thus considered important.
This Phase 1 study will evaluate the general tolerability and pharmacokinetics (PK) of a 
single 60 mg dose of ISL in participants with moderate hepatic insufficiency, compared to 
participants in good health.
2.2
Background
Refer to the IB/approved labeling for detailed background information on MK-8591 
(islatravir, ISL).
HIV-1 infection remains a global health challenge, with close to 37 million people living 
with HIV/AIDS worldwide.  The use of ever-improving highly effective ARVs has greatly 
improved the natural history of HIV infection, such that HIV infection has become a chronic 
illness, provided patients remain adherent in taking ARV therapy. Globally, almost two 
million people yearly become newly infected with HIV, thus demonstrating a need for 
effective prevention strategies that could reduce this infection rate.  There are numerous 
barriers for many individuals in taking daily medication, including access to medication and 
stigma.  Several recent advances in the field, including simplification from 3- to 2-drug 
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discontinuations due to a drug-related AE. For all Phase 1 studies with oral administration, 
the most frequently reported drug-related AE (≥2% of participants in any protocol) was 
headache. 
Following oral administration, plasma PK data indicate that ISL was rapidly absorbed with a 
median Tmax of 0.5 hr, and an apparent terminal t½ of 47 to 64 hr after single doses. 
Intracellular ISL-TP levels reached Cmax between 6 to 24 hr and declined with an apparent 
terminal t½ of 79 to 214 hr. Over the entire Phase 1 clinical program, ISL plasma exposure 
and ISL-TP levels appeared to increase in an approximately dose-proportional manner 
between ISL doses of 0.25 and 400 mg. M4 levels, when assessed, correspond to ~30-40% 
of ISL plasma parent levels at all dose levels tested.  Following administration of 30 mg ISL 
with a high-fat meal, PK of ISL-TP in PBMCs were largely unaffected.  Examinations of 
DDIs between ISL and DTG/TDF, ISL and LNG/EE, ISL and DOR, and ISL and 
pantoprazole demonstrated no clinically meaningful interactions.
After ISL administration to treatment-naïve participants with HIV-1 infection at doses of 
0.5 mg, 1 mg, 2 mg, 10 mg, and 30 mg, viral load reduction data show greater than 1.0 log 
drop on average at all doses tested. Pharmacokinetic data in participants infected with HIV-1 
generally were consistent with the data in healthy participants.
2.2.3
Ongoing Clinical Studies
There are ten ongoing trials involving oral ISL. 
Protocol 015 (P015) is a multiple panel double-blind placebo-controlled trial in 76 healthy 
adult Japanese males, examining PK and general safety and tolerability of ISL up to 120 mg 
and 100 mg DOR.  In P015, which remains blinded, ISL (or placebo) appears to be generally 
well tolerated at all doses examined to date.  
Protocol 026 (P026) is an open-label, single-dose trial to evaluate the pharmacokinetics of 
60 mg ISL in 6 participants with severe renal impairment and 6 control participants. This trial 
initiated in July 2020 and information on general tolerability is not yet available. 
Protocol MK-8591A 027 (P027) is an open-label clinical trial to evaluate the 
pharmacokinetics and relative bioavailability of three experimental presentations of the fixed 
dosed combination of 100 mg DOR and 0.75 mg ISL in 28 healthy participants. In this trial, 
ISL and DOR appear generally well tolerated.
Protocol MK-8558-004 is a multiple dose open label trial in 14 healthy adult participants, 
assessing the potential two-way DDI between 20 mg ISL and MK-8558, an investigational 
product that is a potential partner agent.  In this trial, ISL appears generally well tolerated.
Protocol 011 (P011) is an ongoing Phase 2b trial (NCT03272347) in treatment-naive persons 
living with HIV-1 (PLWH), examining efficacy of daily ISL (0.25 mg, 0.75 mg, or 2.25 mg) 
initially in combination with DOR and 3TC, with 3TC discontinued based on interim 
analysis at 24 weeks, compared to participants on DOR/3TC/TDF throughout the study 
period.  As of 31-Mar-2020, ISL has been administered to ~90 HIV-1 positive individuals for 
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at least 96 weeks. The 48-week analysis showed a numerically higher rate of drug-related 
AEs in participants who received DOR/3TC/TDF (19.4%) vs. participants on any dose of 
ISL (0%, 10%, 12.9% for 0.25 mg, 0.75mg, and 2.25 mg, respectively).  Among the 
90 participants who received any dose of ISL, there was no specific drug-related AE that 
occurred in more than 5% of the participants.
Protocol 016 (P016) is a double-blind, placebo-controlled Phase 2 trial (NCT04003103) in 
low-risk otherwise healthy individuals, examining general tolerability and PK of QM 
administration of oral ISL alone, to establish greater understanding of potential doses for a 
QM PrEP indication.  This trial is examining doses of 60 mg and 120 mg (and placebo); the 
first participants were dosed in November 2019.  As of 31-Mar-2020, approximately 
50 individuals considered at low risk for HIV infection have been administered at least one 
dose of ISL in this trial.
Protocols 017-020 (P017-P020) are Phase 3 trials in persons living with HIV-1 switching 
from current therapy (P017, P018), are heavily treatment experienced (P019), or are naïve to 
therapy (P020).  All four of these trials initiated in early 2020; information on general 
tolerability is limited.
2.3
Benefit/Risk Assessment
Healthy participants in clinical studies will not receive direct benefit from treatment during 
participation as clinical studies are designed to provide information about the safety and 
effectiveness of an investigational medicine.
Additional details regarding specific benefits and risks for participants participating in this 
clinical study may be found in the accompanying IB and informed consent documents.
3
HYPOTHESES, OBJECTIVES, AND ENDPOINTS
The study population includes male and female participants with moderate hepatic 
impairment between the ages of 18 and 75 years (inclusive) and healthy matched controls.
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Objectives
Endpoints
Primary
•
To evaluate the plasma pharmacokinetics 
of ISL (e.g., AUC0-∞, AUC0-last, Cmax, 
Tmax, apparent terminal t½, CL/F, and 
Vz/F) after a single oral dose of 60 mg 
ISL in participants with moderate hepatic
impairment compared to healthy control 
participants.
Estimation: In participants with moderate 
hepatic impairment, plasma 
pharmacokinetics (AUC0-∞, Cmax) of 
ISL following a single 60 mg ISL dose 
will be estimated and compared to those 
observed in healthy mean matched control 
participants.
•
AUC0-∞, AUC0-last, Cmax, Tmax, 
apparent terminal t½, CL/F, and Vz/F 
of plasma ISL
Secondary
•
To evaluate the safety and tolerability of 
ISL in participants with moderate hepatic
impairment.
•
Adverse experiences, laboratory safety 
tests, ECGs, and VSs.
•
To evaluate the intracellular 
pharmacokinetics (e.g., AUC0-∞, AUC0-
last, Cmax, C24, C168, C672, Tmax, and 
apparent terminal t½) of ISL triphosphate 
(ISL-TP) in peripheral blood mononuclear 
cells (PBMCs) after a single oral dose of 
60 mg ISL in participants with moderate 
hepatic impairment compared to healthy 
control participants.
•
AUC0-∞, AUC0-last, Cmax, C24, 
C168, C672, Tmax, and apparent 
terminal t½ of ISL-TP in PBMC 
Tertiary/Exploratory
•
To evaluate the plasma pharmacokinetics 
of the metabolite M4 (e.g., AUC0-∞, 
AUC0-last, Cmax, and Tmax,) after a 
single oral dose of 60 mg ISL in 
participants with moderate hepatic 
impairment compared to healthy control 
participants.
•
AUC0-∞, AUC0-last, Cmax, and 
Tmax, of plasma M4
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Objectives
Endpoints
•
To evaluate urinary excretion of ISL and 
M4 after a single oral dose of 60 mg ISL 
in participants with moderate hepatic 
impairment and in healthy control 
participants.
•
Ae, CLr, and fe of ISL and M4 in urine
•
To explore the relationship between 
genetic variation and response to the 
treatment(s) administered, and 
mechanisms of disease. Variation across 
the human genome may be analyzed for 
association with clinical data collected in 
this study.
•
Germline genetic variation and 
association to clinical data collected in 
this study
4
STUDY DESIGN
4.1
Overall Design
This is a nonrandomized, multi-group, open-label, single-dose study of ISL in adult male and 
female participants with moderate hepatic insufficiency (N=6) and in matched healthy adult 
male and female participants (N=6).  Once all participants with moderate hepatic
insufficiency are enrolled, the healthy matched control participants will be enrolled. 
Individual age and weight of healthy matched control participants will be within the range ± 
10 years and ± 2.0 kg/m2 of the mean age and body mass index (BMI) of participants with 
hepatic insufficiency.  In addition, the numbers of males and females of the healthy 
participants will be generally matched to the numbers of hepatic insufficient participants
within ± 1.
Assignment to a group will be as follows:
Impairment Stage 
N
Child-Pugh scorea
Moderate
6
7-9
Healthy 
6
0
a
Child-Pugh score based on standard scoring (see below). Baseline Child-Pugh will be obtained twice (at least 72 hours 
apart as part of participant screening) and the mean of the two values will be used. The second Child-Pugh score may be 
calculated at the time of check-in.
b
At least 3 participants with a score of at least 2 on one of the laboratory parameters (reduced serum albumin, increased 
serum bilirubin, or increased INR) will be enrolled.
On Day 1, participants will receive a single oral dose of 60 mg ISL, followed by PK 
sampling until 168 hours postdose (in both the healthy control group and the moderate 
hepatic impairment group).  There will be additional visits at hours 240, 336, 408, 504, 672 
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postdose for the collection of PBMCs.  Safety will be monitored throughout the study by 
repeated clinical and laboratory evaluations.
As noted, the Child-Pugh classification will be used to categorize hepatic insufficiency. The
Child-Pugh scale is utilized by clinicians to categorize chronic liver disease and cirrhosis and 
is also used to categorize participants with hepatic insufficiency for PK studies. In the current 
study, patients with chronic, stable hepatic insufficiency with features of cirrhosis due to any 
etiology will be enrolled, and the Child-Pugh scale will be used to classify the severity of 
liver disease (Table 1). The points from each row are summed, leading to the final Child-
Pugh score.  Scores of 5-6, 7-9, and 10-15 are classified as having mild, moderate, or severe 
hepatic insufficiency, respectively. To insure an adequate number of study participants with 
laboratory abnormalities consistent with hepatic dysfunction, at least 3 participants will be 
required to have a score of at least 2 on one of the laboratory parameters (reduced serum 
albumin, increased serum bilirubin, or increased INR).
Table 1
Severity of Liver Disease Classification
Points Score for Increasing Abnormality
Assessment
1
2
3
Encephalopathy†
None
1 or 2
3 or 4
Ascites
Absent
Slight
Moderate
Albumin (g/dL)
>3.5
2.8 to 3.5
<2.8
International normalized ratio (INR)
<1.7
1.7 to 2.3
>2.3
Bilirubin (mg/dL)—not PBC‡§
Bilirubin (mg/dL)—only for PBC‡§
<2
<4
2 to 3
4 to 10
>3
>10
† Portal-system encephalopathy is Staged 0 to 4.
‡ PBC=Primary Biliary Cirrhosis.
§ Select only one dependent on type of cirrhosis.
The Child-Pugh classification will be used due to its widespread use and acceptance by 
regulatory agencies, including the U.S. Food and Drug Administration and the European 
Committee for Medicinal Products for Human Use. This study design is supported by FDA 
guidelines for drugs which undergo substantial hepatic metabolism and for which an 
indication is sought for patients with hepatic insufficiency.
Because this is a Phase 1 assessment of MK-8591 in humans, the PK, pharmacodynamic, and 
safety profiles of the compound are still being elucidated. This protocol is therefore written 
with flexibility to accommodate the inherent dynamic nature of Phase 1 clinical studies. 
Refer to Section 8.11.6 for examples of modifications permitted within the protocol 
parameters.
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.
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4.2
Scientific Rationale for Study Design
An open-label study design has been selected to evaluate the effect of hepatic impairment on 
the pharmacokinetics of ISL and will adequately address the objectives of the study. 
Although hepatic elimination is unlikely to lead to marked changes in ISL levels, the 
magnitude of the preclinical and clinical safety margins supports a reduced design with an 
evaluation of patients with moderate hepatic impairment.  Individuals without hepatic 
impairment will serve as a control group. In order to adequately assess the impact of hepatic 
impairment, enrolled participants with reasonably matched demographics to mean 
demographic parameters will be enrolled.
4.2.1
Rationale for Endpoints
4.2.1.1
Efficacy Endpoints
There are no efficacy endpoints in this trial.
4.2.1.2
Safety Endpoints
Multiple trials have evaluated oral ISL in human participants, including a Phase 1 trial with 
doses as high as 400 mg, and a Phase 2 trial in which participants have received monthly 
doses of 60 mg or 120 mg.  To date, oral ISL appears generally well tolerated, and there have 
been no concerning safety signals.  A standard safety monitoring plan consisting of adverse 
event monitoring, physical examinations, vital signs (heart rate and blood pressure), 12-lead 
ECGs and laboratory tests (hematology, serum chemistry and urinalysis), obtained pre- and 
post-dosing, has been deemed adequate to assess tolerability of ISL in this trial.
4.2.1.3
Pharmacokinetic Endpoints
In order to evaluate the pharmacokinetics of ISL administered to patients with moderate 
hepatic impairment, the following pharmacokinetic parameters will be evaluated: AUC0-∞, 
AUC0-last, Cmax, Tmax, apparent terminal t½, CL/F, and Vz/F of plasma ISL. In addition to 
assessing parent ISL levels, the following ISL-TP PK parameters will be evaluated in 
PBMCs: AUC0-∞, AUC0-last, Cmax, C24, C168, C672, Tmax, and apparent terminal t½ of 
ISL-TP. This intracellular evaluation will allow a more complete understanding of ISL-TP 
levels in this population. 
Assessment of these PK parameters for both ISL and ISL-TP has been consistently 
performed throughout the entire Phase 1 clinical development program.  The relationship 
between ISL and ISL-TP levels has been well characterized in healthy study participants and 
in HIV+ study participants. This assessment, however, will allow greater understanding of 
that relationship in hepatically impaired individuals, and can therefore determine whether 
ISL-TP levels, which are key to defining the PK threshold for efficacy, will also be sufficient 
in this population.
In addition, the PK of M4, the major circulating metabolite of ISL, will be evaluated as an 
exploratory endpoint. As noted, there is a theoretical possibility that M4 levels could be 
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lower in individuals with hepatic insufficiency due to lower hepatic activity of ADA. This 
assessment, therefore, will allow determination of M4 plasma and urine concentrations in 
these participants.
4.2.1.4
Pharmacodynamic Endpoints
No pharmacodynamic endpoints will be evaluated.
4.2.1.5
Planned Exploratory Biomarker Research
4.2.1.5.1
Planned Genetic Analysis
Genetic variation may impact a participant’s response to therapy, susceptibility to, severity, 
and progression of disease. Variable response to therapy may be due to genetic determinants 
that impact drug absorption, distribution, metabolism, and excretion; mechanism of action of 
the drug; disease etiology; and/or molecular subtype of the disease being treated. Therefore, 
where local regulations and IRB/IEC allow, a sample will be collected for DNA analysis 
from consenting participants.
DNA samples may be used for research related to the study intervention(s), the disease under 
study, or related diseases. They may also be used to develop tests/assays including diagnostic 
tests related to the disease under study, related diseases, and study intervention(s). Genetic 
research may consist of the analysis of 1 or more candidate genes, the analysis of genetic 
markers throughout the genome, or analysis of the entire genome. Analysis may be 
conducted if it is hypothesized that this may help further understand the clinical data.
The samples may be analyzed as part of a multi-study assessment of genetic factors involved 
in the response to understand study disease or related conditions.
4.2.1.6
Future Biomedical Research
The Sponsor will conduct FBR on DNA specimens for which consent was provided during 
this clinical study.
Such research is for biomarker testing to address emergent questions not described elsewhere 
in the protocol (as part of the main study) and will only be conducted on specimens from 
appropriately consented participants. The objective of collecting/retaining specimens for 
FBR is to explore and identify biomarkers that inform the scientific understanding of 
diseases and/or their therapeutic treatments. The overarching goal is to use such information 
to develop safer, more effective drugs/vaccines, and/or to ensure that participants receive the 
correct dose of the correct drug/vaccine at the correct time. The details of FBR are presented 
in Appendix 6.
4.2.2
Rationale for the Use of Comparator/Placebo
Not applicable
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4.3
Justification for Dose
A dose of 60 mg has been selected to be administered as a one-time oral dose in this trial.  
This dose level is currently the highest oral dose being considered for pivotal trials, as it is 
the dose being considered for Phase 3 evaluations of QM ISL for pre-exposure prophylaxis.  
As noted, the PK for both parent ISL and ISL-TP has been dose-proportional over the entire 
dose range evaluated to date (0.25-400 mg), and thus the effects of hepatic impairment are 
not likely to vary with dose.  A one-time dose of ISL, as being performed here, will be able 
to inform on other dose administration frequencies, as the PK parameter values obtained in 
this trial can be used to model potential effects at other doses.    
As this is a Phase 1 assessment of MK-8591 in humans, and the PK, pharmacodynamic and 
safety profiles of the compound are still being evaluated, modifications to the dose or dosing 
regimen may be required to achieve the scientific goals of the study objectives and/or to 
ensure appropriate safety monitoring of the study participants. Details of allowed 
modifications are provided in Section 8.11.6.
4.4
Beginning and End of Study Definition
The overall study begins when the first participant signs the ICF. The overall study ends 
when the last participant completes the last study-related telephone-call or visit, withdraws 
from the study, or is lost to follow-up (ie, the participant is unable to be contacted by the 
investigator).
A study may be paused during review of newly available preclinical/clinical safety, PK, 
pharmacodynamic, efficacy, or biologic data or other items of interest, prior to a final 
decision on continuation or termination of the study. It may be necessary to keep the study 
open for gathering/reviewing of additional supportive data to optimally complete the 
objective(s) of the study. If necessary, the appropriate amendment(s) to the protocol and/or 
appropriate communication(s) will be generated. If the decision has been made to end the 
study following this review period, the study end will be defined as the date of the Sponsor 
decision, and this end of study date supersedes the definitions outlined above. The 
Competent Authority(ies) and IRB(s)/IEC(s) will be apprised of the maximum duration of 
the study beyond the last participant out and the justification for keeping the study open.
4.4.1
Clinical Criteria for Early Study Termination
There are no prespecified criteria for terminating the study early.
5
STUDY POPULATION
Male/Female participants with moderate hepatic impairment between the ages of 18 and 
75 years (inclusive) and healthy matched controls will be enrolled in this study.
The individual age and weight of the healthy participants is aimed to be within the
range ± 10 years and ± 10 kg of the mean age and weight of participants with hepatic
insufficiency. In addition, the numbers of males and females of the healthy participants will 
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be generally matched to the numbers of hepatic insufficient participants within ± 1; i.e., if 
there are 3 males and 3 females in the hepatic insufficient group, every effort will be made to 
ensure a 3:3 ratio in the healthy participants, but 2:4 or 4:2 would be acceptable as well.
Prospective approval of protocol deviations to recruitment and enrollment criteria, also 
known as protocol waivers or exemptions, is not permitted.
5.1
Inclusion Criteria
5.1.1
Inclusion Criteria for Healthy Participants
The following inclusion criteria apply to all healthy participants. A participant will be 
eligible for inclusion in the study if the participant:
Type of Participant and Disease Characteristics
1. Is in good health based on medical history, physical examination, VS measurements and 
ECGs performed prior to randomization.
Appendix 9 provides a table of the 12-Lead Electrocardiogram Abnormality Criteria.
2. Is in good health based on laboratory safety tests obtained at the screening visit and prior 
to administration of the initial dose of study drug. Appendix 2 provides a table of 
laboratory safety tests to be performed. Appendix 10 provides an algorithm for the 
assessment of out of range laboratory values.
3. Has a BMI ≥18.5 and ≤40 kg/m2. See Section 8.3.1 for criteria on rounding to the nearest 
whole number. BMI = weight (kg)/height (m)2.
Demographics
4. Is male or female, from 18 years to 75 years of age inclusive, at the time of signing the 
informed consent.
Male Participants
No measures are needed, but contraceptive use by men should be consistent with local 
regulations regarding the methods of contraception for those participating in clinical studies.
Female Participants
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
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•
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 [4 weeks) after study intervention. The investigator should evaluate the potential for 
contraceptive method failure (ie, noncompliance, recently initiated) in relationship to 
study intervention.
•
A WOCBP must have a negative highly sensitive pregnancy test ([urine or serum] as 
required by local regulations) within 24 hours before study intervention.
•
If a urine test cannot be confirmed as negative (eg, an ambiguous result), a serum 
pregnancy test is required. In such cases, the participant must be excluded from 
participation if the serum pregnancy result is positive.
•
Additional requirements for pregnancy testing during and after study intervention are 
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
5. Provides written informed consent/assent for the study. The participant may also provide 
consent/assent for future biomedical research. However, the participant may participate in 
the main study without participating in future biomedical research.
5.1.2
Inclusion Criteria for Hepatically Impaired Participants
The following inclusion criteria apply to all hepatically impaired participants.  A hepatically 
impaired participant will be eligible for inclusion in the study if the participant:
Type of Participant and Disease Characteristics
1. Has a diagnosis of chronic (> 6 months), stable (no acute episodes of illness within the 
previous 2 months due to deterioration in hepatic function) hepatic insufficiency with 
features of cirrhosis due to any etiology.  
2. Has a score on the Child-Pugh scale ranging from 7 to 9 (moderate hepatic insufficiency)
at screening. At least 2 of the participants must have a score of 2 or higher on at least one 
of the laboratory parameters (i.e., albumin, prothrombin time, and bilirubin) at screening 
on the Child-Pugh scale.
3. With the exception of hepatic impairment, is in generally good health based on medical 
history, physical examination, VS measurements and ECGs performed prior to 
randomization.  Participants with stable, chronic medical or psychiatric conditions may 
be included at the discretion of the investigator and the Sponsor.  Appendix 9 provides a 
table of the 12-Lead Electrocardiogram Abnormality Criteria. 
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4. With the exception of hepatic impairment, is in good health based on laboratory safety 
tests obtained at the screening visit and prior to study drug administration. Appendix 2 
provides a table of laboratory safety tests to be performed. Appendix 10 provides an 
algorithm for the assessment of out of range laboratory values.  
5. Has a BMI ≥ 18.5 and ≤ 40 kg/m2. See Section 8.3.1 for criteria on rounding to the 
nearest whole number. BMI = weight (kg)/height (m)2.
Demographics
6. Is male or female, from 18 years to 75 years of age inclusive, at the time of signing the 
informed consent.
Male Participants
No measures are needed, but 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.
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 4 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.
•
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.
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•
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
7. Provides written informed consent/assent for the study. The participant may also provide 
consent/assent for future biomedical research. However, the participant may participate in 
the main study without participating in future biomedical research.
5.2
Exclusion Criteria
5.2.1
Exclusion Criteria for Healthy Participants
The following exclusion criteria apply to all healthy participants. The participant must be 
excluded from the study if the participant:
Medical Conditions
1. Has a history of clinically significant endocrine, gastrointestinal, cardiovascular, 
hematological, hepatic, immunological, renal, respiratory, genitourinary, or major 
neurological (including stroke and chronic seizures) abnormalities or diseases. 
Participants with a remote history of uncomplicated medical events (eg, uncomplicated 
kidney stones, as defined as spontaneous passage and no recurrence in the last 5 years, or 
childhood asthma) may be enrolled in the study at the discretion of the investigator.
2. Is mentally or legally incapacitated, has significant emotional problems at the time of 
prestudy (screening) visit or expected during the conduct of the study or has a history of 
clinically significant psychiatric disorder of the last 5 years. Participants who have had 
situational depression may be enrolled in the study at the discretion of the investigator.
3. Has a history of cancer (malignancy).
Exceptions: (1) Adequately treated nonmelanomatous skin carcinoma or carcinoma in 
situ of the cervix or; (2) Other malignancies which have been successfully treated with 
appropriate follow up and therefore unlikely to recur for the duration of the study, in the 
opinion of the investigator and with agreement of the Sponsor (eg, malignancies which 
have been successfully treated ≥10 years prior to the prestudy [screening] visit).
4. Has a history of significant multiple and/or severe allergies (eg, food, drug, latex allergy), 
or has had an anaphylactic reaction or significant intolerability (ie, systemic allergic 
reaction) to prescription or non-prescription drugs or food.
5. Has known hypersensitivity to the active substance or any of the excipients of the study 
drug.
6. Is positive for hepatitis B surface antigen, hepatitis C antibodies, HIV-1 or HIV-2.
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7. Had major surgery, donated or lost 1 unit of blood (approximately 500 mL) within 
4 weeks prior to the prestudy (screening) visit.
Prior/Concomitant Therapy
8. Is unable to refrain from or anticipates the use of any medication, including prescription 
and nonprescription drugs or herbal remedies beginning approximately 2 weeks (or 5 
half-lives) prior to study drug administration, throughout the study, until the poststudy 
visit. There may be certain medications that are permitted (see Section 6.5).
Prior/Concurrent Clinical Study Experience
9. Has participated in another investigational study within 4 weeks (or 5 half-lives, 
whichever is greater) prior to the prestudy (screening) visit. The window will be derived 
from the date of the last visit in the previous study.
Diagnostic Assessments
10. Has a QTc interval >470 for males or >480 ms for females, has a history of risk factors 
for Torsades de Pointes (eg, heart failure/cardiomyopathy or family history of long QT 
syndrome), has uncorrected hypokalemia or hypomagnesemia, is taking concomitant 
medications that prolong the QT/QTc interval.
Other Exclusions
11. Is not considered low risk of having HIV infection. Low risk for HIV infection is defined 
by all of the following, within 12 months prior to the screening visit (based on self-report 
by participant or medical history [if available]):
a.
No anal or vaginal intercourse with someone known to be HIV-infected, or with 
someone of unknown HIV infection status who is at increased risk of HIV infection.
b. No stimulant use (cocaine [including crack], methamphetamine, or nonphysician 
prescribed pharmaceutical grade stimulants) or inhaled nitrous oxide.
c.
No illicit injection drug use of any kind.
d. No new diagnosis of a sexually transmitted infection (STI) such as gonorrhea (GC), 
chlamydia (CT), incident syphilis, or trichomoniasis (if assessment is available). This 
includes, but is not exclusive to, any testing performed at screening.
e.
No greater than 3 different sexual partners for receptive or insertive vaginal or anal 
sex; and
f.
No history of antiretroviral therapy for HIV-1 infection, including for PrEP or for 
post-exposure prophylaxis. Note: individuals who have participated in studies of an 
antiretroviral, including Phase 1 studies, may be eligible after Sponsor consultation.
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12. Is under the age of legal consent.
13. Is a smoker or user of electronic cigarettes and/or has used nicotine or nicotine-
containing products (eg, nicotine patch) within 3 months of screening.
14. Consumes greater than 3 glasses of alcoholic beverages (1 glass is approximately 
equivalent to: beer [354 mL/12 ounces], wine [118 mL/4 ounces], or distilled spirits 
[29.5 mL/1 ounce]) per day. Participants who consume more than the daily limit may be 
enrolled at the discretion of the investigator.
15. Consumes excessive amounts, defined as greater than 6 servings (1 serving is 
approximately equivalent to 120 mg of caffeine) of coffee, tea, cola, energy drinks, or 
other caffeinated beverages per day.
16. Is a regular user of cannabis, any illicit drugs or has a history of drug (including alcohol) 
abuse within approximately 2 years. Participants must have a negative alcohol test and 
negative drug screen prior to randomization.
17. Presents any concern by the investigator regarding safe participation in the study or for 
any other reason the investigator considers the participant inappropriate for participation 
in the study.
18. Is unwilling to comply with the study restrictions (see Section 5.3 for a complete 
summary of study restrictions).
19. Is or has an immediate family member (eg, spouse, parent/legal guardian, sibling, or 
child) who is investigational site or Sponsor staff directly involved with this study.
5.2.2
Exclusion Criteria for Hepatically Impaired Participants
The following exclusion criteria apply to all hepatically impaired participants.  
The participant must be excluded from the study if the participant:
Medical Conditions
1. Has a history of any illness that, in the opinion of the Investigator, might confound the 
results of the study or poses an additional risk to the participant by their participation in 
the study.
2. Is institutionalized or mentally or legally incapacitated at the time of prestudy (screening) 
visit or expected during the conduct of the study.
3. Has a history of cancer (malignancy).
Exceptions: (1) Adequately treated nonmelanomatous skin carcinoma or carcinoma in 
situ of the cervix or; (2) Other malignancies which have been successfully treated with 
appropriate follow up and therefore unlikely to recur for the duration of the study, in the 
opinion of the investigator and with agreement of the Sponsor (eg, malignancies which 
have been successfully treated ≥10 years prior to the prestudy [screening] visit).
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4. Has a history of significant multiple and/or severe allergies (eg, food, drug, latex allergy), 
or has had an anaphylactic reaction or significant intolerability (ie, systemic allergic 
reaction) to prescription or non-prescription drugs or food.
5. Has known hypersensitivity to the active substance or any of the excipients of the study 
drug.
6. Is positive for HIV-1 or HIV-2.
7. Had major surgery, donated or lost 1 unit of blood (approximately 500 mL) within 
4 weeks prior to the prestudy (screening) visit.
Prior/Concomitant Therapy
8. Is taking medications to treat chronic medical conditions and has not been on a stable 
regimen for at least 1 month and/or is unable to withhold the use of the medication(s) 
within 4 hours prior to and 8 hours after administration of the study drug.  Exceptions 
may be granted for participants in whom a medication regimen has been adjusted within 
the one-month window, at the discretion of the Investigator and following consultation 
with the Sponsor. See Section 5.1.2 for allowed medical conditions, and Section 6.5 for 
allowed medications. 
Prior/Concurrent Clinical Study Experience
9. Has participated in another investigational study within 4 weeks (or 5 half-lives, 
whichever is greater) prior to the prestudy (screening) visit. The window will be derived 
from the date of the last visit in the previous study.
Diagnostic Assessments
10. Has a QTc interval >470 for males or >480 ms for females, has a history of risk factors 
for Torsades de Pointes (eg, heart failure/cardiomyopathy or family history of long QT 
syndrome) or is taking concomitant medications that prolong the QT/QTc interval.
Other Exclusions
11. Is not considered low risk of having HIV infection. Low risk for HIV infection is defined 
by all of the following, within 12 months prior to the screening visit (based on self-report 
by participant or medical history [if available]):
a.
No anal or vaginal intercourse with someone known to be HIV-infected, or with 
someone of unknown HIV infection status who is at increased risk of HIV infection.
b. No stimulant use (cocaine [including crack], methamphetamine, or nonphysician
prescribed pharmaceutical grade stimulants) or inhaled nitrous oxide.
c.
No illicit injection drug use of any kind.
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d. No new diagnosis of a sexually transmitted infection (STI) such as gonorrhea (GC), 
chlamydia (CT), incident syphilis, or trichomoniasis (if assessment is available). This 
includes, but is not exclusive to, any testing performed at screening.
e.
No greater than 3 different sexual partners for receptive or insertive vaginal or anal 
sex; and
f.
No history of antiretroviral therapy for HIV-1 infection, including for PrEP or for 
post-exposure prophylaxis. Note: individuals who have participated in studies of an 
antiretroviral, including Phase 1 studies, may be eligible after Sponsor consultation.
12. Is under the age of legal consent.
13. Does not agree to follow the smoking restrictions as defined by the CRU.
14. Consumes excessive amounts, defined as greater than 6 servings (1 serving is 
approximately equivalent to 120 mg of caffeine), of coffee, tea, cola, energy drinks, or 
other caffeinated beverages per day.
15. Is a regular user of cannabis, any illicit drugs or has a history of drug abuse within 
approximately 3 months. Participants must have a negative alcohol test and negative 
UDS prior to randomization.  Participants with hepatic impairment may be allowed for 
inclusion with a positive UDS for opiates if they have an active prescription from a 
licensed health care provider.
16. Is unwilling to comply with the study restrictions (see Section 5.3 for a complete 
summary of study restrictions. 
17. Presents any concern by the investigator regarding safe participation in the study or for 
any other reason the investigator considers the participant inappropriate for participation 
in the study.
18. Is or has an immediate family member (eg, spouse, parent/legal guardian, sibling, or 
child) who is investigational site or Sponsor staff directly involved with this study.
5.3
Lifestyle Considerations
5.3.1
Meals and Dietary Restrictions
Participants will fast from all food and drinks, except water, for at least 8 hours prior to 
laboratory safety evaluations and study drug administration. Participants will fast from all 
food and drinks except water between study drug administration and the first scheduled meal, 
which will occur approximately 2 hours after dosing.  Thereafter, there will be no restrictions 
(other than those provided in Section 5.3.3.) regarding meals and snack(s). While in the 
CRU, participants will fast from all food and drinks except water between meals and snacks. 
Otherwise, there are no dietary restrictions other than those defined below.
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Water will be provided during study drug administration. Water will be restricted 1 hour 
prior to and 1 hour after study drug administration.
5.3.2
Caffeine, Alcohol, and Tobacco Restrictions
5.3.2.1
Caffeine Restrictions
Participants will refrain from consumption of caffeinated beverages or xanthine-containing 
products from 12 hours prior to the prestudy and poststudy visits and from 12 hours prior to 
and after study drug administration. At all other times, caffeinated beverages or xanthine-
containing products will be limited to no more than 6 units per day (1 unit = 120 mg of 
caffeine).
5.3.2.2
Alcohol Restrictions
Participants will refrain from consumption of alcohol 24 hours prior to the prestudy and 
poststudy visits and from 24 hours prior to and after study drug administration. At all other 
times, alcohol consumption is limited to no more than approximately 3 alcoholic beverages 
or equivalent (1 glass is approximately equivalent to: beer [354 mL/12 ounces], wine 
[118 mL/4 ounces], or distilled spirits [29.5 mL/1 ounce]) per day.
5.3.2.3
Tobacco Restrictions
Smoking or the use of electronic cigarettes, or the use of nicotine/nicotine-containing
products is not permitted for participants in the healthy control group.
Participants in the moderate hepatic impairment group will follow the smoking restrictions 
(and if applicable, the use of electronic cigarettes or nicotine/nicotine-containing products) 
defined by the CRU.
5.3.3
Activity Restrictions
Participants will avoid unaccustomed strenuous physical activity (ie, weight lifting, running, 
bicycling, etc.) from the prestudy (screening) visit until administration of the initial dose of 
study drug, throughout the study (including washout intervals between treatment periods) and 
until the poststudy visit.
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 
may be included, as outlined in the eCRF entry guidelines. Minimal information may include 
demography, screen failure details, eligibility criteria, and any AEs or SAEs meeting 
reporting requirements.
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5.5
Participant Replacement Strategy
If a participant withdraws from the study a replacement participant may be enrolled if 
deemed appropriate by the investigator and Sponsor. The replacement participant will 
generally receive the same intervention or intervention sequence (as appropriate) as the 
participant being replaced. The replacement participant will be assigned a unique 
treatment/randomization number. The study site should contact the Sponsor for the 
replacement participant’s treatment/randomization number.
The replacement participant may begin dosing at the subsequent dose level for that panel, 
based on investigator and Sponsor review and discussion.
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 and replacement participants as 
required. When a replacement participant is required, the Sponsor or designee needs to be 
contacted prior to dosing the replacement participant. Clinical supplies will be affixed with a 
clinical label in accordance with regulatory requirements.
6.1
Study Intervention(s) Administered
The study intervention(s) to be used in this study is outlined in Table 2.
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Table 2
Study Interventions
Arm 
Name
Arm 
Type
Intervention 
Name
Intervention 
Type
Dose 
Formulation
Unit Dose 
Strength(s)
Dosage 
Level(s)
Route of 
Administration
Regimen/
Treatment 
Period/
Vaccination 
Regimen
Use
IMP/
NIMP Sourcing
Healthy 
Control 
Group
Experi-
mental
MK-8591 
(ISL)
Drug
Capsule
30 mg
60 mg
Oral
Single 
Dose on 
Day 1
Experimental
IMP
Provided 
by the 
Sponsor
Moderate 
Hepatic 
Impair-
ment 
Group
Experi-
mental
MK-8591 
(ISL)
Drug
Capsule
30 mg
60 mg
Oral
Single 
Dose on 
Day 1
Experimental
IMP
Provided 
by the 
Sponsor
The classification of Investigational Medicinal Product (IMP) and Non-Investigational Medicinal Product (NIMP) in this table is based on guidance issued by the European 
Commission and applies to countries in the European Economic Area (EEA). Country differences with respect to the definition/classification of IMP/NIMP may exist. In these 
circumstances, local legislation is followed.
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All supplies indicated in Table 2 will be provided per the "Sourcing" column depending upon 
local country operational requirements. If local sourcing, every attempt should be made to 
source these supplies from a single lot/batch number where possible (eg, not applicable in the 
case where multiple lots or batches may be required due to the length of the study, etc).
Refer to Section 8.1.8 for details regarding administration of the study intervention.
6.2
Preparation/Handling/Storage/Accountability
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
Participants will be assigned an allocation number (AN) for a single open-label treatment 
using the allocation schedule shown in Table 3.
Table 3
Allocation of Participants to Treatment 
Hepatic Impairment Stage 
N
Treatment
Moderate
6
MK-8591 (ISL) 60 mg
Healthy 
6
MK-8591 (ISL) 60 mg
6.3.2
Stratification
No stratification based on age, sex, or other characteristics will be used in this study.
6.3.3
Blinding
This is an open-label study; therefore, the Sponsor, investigator, and participant will know 
the intervention administered.
6.4
Study Intervention Compliance
When the individual dose for a participant is prepared from a bulk supply, the preparation of 
the dose will be confirmed by a second member of the study site staff.
When participants are dosed at the site, they will receive study intervention directly from the 
investigator or designee, under medical supervision. The date and time of each dose 
administered in the clinic will be recorded in the source documents and recorded in the CRF. 
The dose of study intervention and study participant ID will be confirmed at the time of 
dosing by a member of the study site staff other than the person administering the study 
intervention. Study site personnel will examine each participant’s mouth to ensure that the 
study intervention was ingested.
6.5
Concomitant Therapy
If a participant does not discontinue all prior medications within 14 days or 5 half-lives of the 
first dose of study intervention (whichever is longer), they may be included in the study if the 
investigator can rationalize that the specific use of a prior medication is not clinically 
relevant within the context of the study.
Concurrent use of any prescription or nonprescription medication, or concurrent vaccination,
during the ongoing study (ie, after intervention allocation) must first be discussed between 
the investigator and Sponsor prior to administration, unless appropriate medical care 
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necessitates that therapy or vaccination should begin before the investigator and Sponsor can 
consult. The participant will be allowed to continue in the study if both the Sponsor and the 
investigator agree.
Ibuprofen may be used for minor ailments without prior consultation with the Sponsor.  
Paracetamol/acetaminophen use for minor ailments requires consultation with the Sponsor.
For Participants with Moderate Hepatic Impairment: 
Participants who are taking medications to treat general medical conditions and/or conditions 
associated with hepatic disease (e.g., hypertension, non-insulin dependent diabetes mellitus, 
hypercholesterolemia, hypo- or hyperthyroidism, gout, depression) will be allowed to 
participate in the study at the discretion of the Investigator and following consultation with 
the Sponsor Clinical Monitor. Participants must be on a stable regimen for at least 1 month 
prior to study drug administration and is able to withhold the use within 4 hours prior to and 
8 hours after study drug administration.  Any exceptions to this must first be discussed 
between the Investigator and Sponsor. 
Certain prescription medications used to treat manifestations of hepatic disease (e.g., 
lactulose, neomycin, etc.) will be allowed during the study, but the patient must be on a 
steady dose, drug, and regimen for ~1 month prior to dosing on Day 1. Lactulose should be 
restricted at least 6 hours prior to and after dosing on Day 1 since it may potentially affect 
absorption.
Examples of types of medications that would be used for chronic medical conditions that 
would be allowed include (but are not limited to) the following:

Angiotensin converting enzyme (ACE) inhibitors, angiotensin II receptor antagonists, 
diuretics

Beta blockers

Metformin, thiazolidinediones, sulfonylureas, DPP-4 inhibitors, alpha-glucosidase 
inhibitors, incretin mimetics

Statins

Levothyroxine

Colchicine, allopurinol

Selective serotonin uptake inhibitors (SSRIs), tricyclic antidepressants

Proton pump inhibitors
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Any medication (including over-the-counter) that, by the determination of the Investigator,
might interfere with the study (e.g., cimetidine) must be discontinued at least 2 weeks 
(or 5 half-lives of the compound, whichever is longer) prior to the dosing of study drug.
6.5.1
Rescue Medications and Supportive Care
No rescue or supportive medications are specified for use in this study.
6.6
Dose Modification (Escalation/Titration/Other)
Dose modifications are not applicable to this study.
6.6.1
Stopping Rules
The following stopping rules will be employed during the conduct of this study.
If any of the below stopping rules are met, the study will be paused and no further dosing 
will occur until the Sponsor has reviewed the totality of data available. In order to continue 
the study (upon joint agreement with the Sponsor and investigator), an amendment will be 
submitted for approval.
1. An individual participant reports an SAE considered related to the study drug by the 
investigator.
2. Two (2) or more participants report Severe Non-serious Adverse Events considered 
related to the study drug by the investigator.
6.7
Intervention After the End of the Study
There is no study-specified intervention following the end of the study.
6.8
Clinical Supplies Disclosure
This study is open-label; therefore, the participant, the study site personnel, the Sponsor, 
and/or designee are not blinded. Study intervention (name, strength, or potency) is included 
in the label text; random code/disclosure envelopes or lists are not provided.
7
DISCONTINUATION OF STUDY INTERVENTION AND PARTICIPANT 
WITHDRAWAL
7.1
Discontinuation of Study Intervention
In clinical studies with a single intervention, discontinuation of study intervention can only 
occur prior to the intervention and generally represents withdrawal from the study.
Participants who receive a single-dose intervention cannot discontinue study intervention.
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7.2
Participant Withdrawal From the Study
A participant must be withdrawn from the study if the participant or participant’s legally 
acceptable representative withdraws consent from the study.
If a participant withdraws from the study, they will no longer receive study intervention or be 
followed at scheduled protocol visits.
Specific details regarding procedures to be performed at the time of withdrawal from the 
study, as 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.
•
Note: A participant is not considered lost to follow-up until the last scheduled visit for the 
individual participant. The missing data for the participant will be managed via the 
prespecified statistical data handling and analysis guidelines.
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.
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•
All screening evaluations must be completed and reviewed to confirm that potential 
participants meet all eligibility criteria. The investigator will maintain a screening log to 
record details of all participants screened and to confirm eligibility or record reasons for 
screening failure, as applicable.
•
Procedures conducted as part of the participant’s routine clinical management (eg, blood 
count) and obtained before signing of ICF may be utilized for screening or baseline 
purposes provided the procedure met the protocol-specified criteria and were performed 
within the time frame defined in the SoA.
•
Additional evaluations/testing may be deemed necessary by the investigator and or the 
Sponsor for reasons related to participant safety. In some cases, such evaluation/testing 
may be potentially sensitive in nature (eg, HIV, Hepatitis C), and thus local regulations 
may require that additional informed consent be obtained from the participant. In these 
cases, such evaluations/testing will be performed in accordance with those regulations.
The maximum amount of blood collected from each participant over the duration of the study
will not exceed 382 mL (Appendix 8).
Repeat or unscheduled samples may be taken for safety reasons or for technical issues with 
the samples.
8.1
Administrative and General Procedures
8.1.1
Informed Consent
The investigator or medically qualified designee (consistent with local requirements) must 
obtain documented consent from each potential participant or each participant’s legally 
acceptable representative prior to participating in a clinical study or future biomedical 
research. If there are changes to the participant’s status during the study (eg, health or age of 
majority requirements), the investigator or medically qualified designee must ensure the 
appropriate consent is in place.
8.1.1.1
General Informed Consent
Consent must be documented by the participant’s dated signature or by the participant’s 
legally acceptable representative’s dated signature on a consent form along with the dated 
signature of the person conducting the consent discussion.
A copy of the signed and dated consent form should be given to the participant before 
participation in the study.
The initial ICF, any subsequent revised written 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 
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and documented via a revised consent form or addendum to the original consent form that 
captures the participant’s dated signature or by the participant’s legally acceptable 
representative’s dated signature.
Specifics about a study and the study population will be added to the consent form template 
at the protocol level.
The 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, answer all of his/her questions, and obtain written informed 
consent before performing any procedure related to future biomedical research. 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 written informed consent. At the time of intervention randomization,
site personnel will add the treatment/randomization number to the participant identification 
card.
The participant identification card also contains contact information for the emergency 
unblinding call center so that a health care provider can obtain information about study 
intervention in emergency situations where the investigator is not available.
8.1.4
Medical History
A medical history will be obtained by the investigator or qualified designee.
8.1.5
Prior and Concomitant Medications Review
8.1.5.1
Prior Medications
The investigator or qualified designee will review prior medication use, including any 
protocol-specified washout requirement, and record prior medication taken by the participant 
within 14 days before starting the study.
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8.1.5.2
Concomitant Medications
The investigator or qualified designee will record medication, if any, taken by the participant 
during the study.
8.1.6
Assignment of Screening Number
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.
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.
In a situation where rerandomization of the participants is planned (eg, study extension 
periods), the rerandomization will be based on a new randomization schedule; however, each 
participant will retain his/her original treatment/randomization number. Only the study 
intervention regimen associated with the rerandomization period or phase may change.
8.1.8
Study Intervention Administration
Administration of study intervention(s) will be monitored by the investigator and/or study 
staff.
Participants will fast from all food and drinks, except water, for at least 8 hours prior to study 
drug administration. Participants will remain fasted for 4 hours post dose. Approximately 240 
mL of water will be provided during study drug administration but will be restricted 1 hour 
prior to and 1 hour post dose.  
8.1.8.1
Timing of Dose Administration
Participants will be dosed according to the SoA (Section 1.3).
8.1.9
Discontinuation and Withdrawal
The investigator or study coordinator must notify the Sponsor when a participant has been 
discontinued/withdrawn from the study. If a participant discontinues for any reason at any 
time during the course of the study, the participant may be asked to return to the clinic (or be 
contacted) for a poststudy visit as per the number of days described in Section 1.3 to have the 
applicable procedures conducted. However, the investigator may decide to perform the 
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poststudy procedures at the time of discontinuation or as soon as possible after 
discontinuation. If the poststudy visit occurs prior to the safety follow-up time frame as 
specified in Section 8.4.1, the investigator should perform a follow-up telephone call at the 
end of the follow-up period (Section 8.4.1) to confirm if any AEs have occurred since the 
poststudy clinic visit. Any AEs that are present at the time of discontinuation/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
This is an open-label study; there is no blinding for this study. The emergency unblinding 
call center will be available so that a health care provider can obtain information about study 
intervention in emergency situations where the investigator is not available.
8.1.11
Domiciling
Participants will report to the CRU on Day -1 prior to the scheduled day of study intervention 
administration on Day 1 and remain in the unit until 168 hours post dose for healthy matched 
controls and participants with moderate hepatic impairment. At the discretion of the 
investigator, participants may be requested to remain in the CRU longer. Participants may be 
permitted to leave the unit, for emergency situations only, during the domiciling period at the 
discretion of the investigator after discussion with the Sponsor. The decision how to monitor 
the participant will be at the discretion of the investigator after discussion with the Sponsor.  
Domiciling of participants will facilitate PK collection and safety assessments while ISL and 
metabolite levels are expected to be highest, ensuring that these assessments are performed in 
a timely fashion.
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8.1.12
Calibration of Equipment
The investigator or qualified designee has the responsibility to ensure that any device or 
instrument used for a clinical evaluation/test during a clinical study that provides information 
about inclusion/exclusion criteria and/or safety or efficacy parameters shall be suitably 
calibrated and/or maintained to ensure that the data obtained are reliable and/or reproducible. 
Documentation of equipment calibration must be retained as source documentation at the 
study site.
8.2
Efficacy/Immunogenicity Assessments
There are no direct 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 prestudy to poststudy visits), including approximate blood/tissue volumes 
drawn/collected by visit and by sample type per participant, can be found in Section 8.
Planned time points for all safety assessments are provided in the SoA.
8.3.1
Physical Examinations
A complete physical examination will be conducted by an investigator or medically qualified 
designee (consistent with local requirements) as per institutional standard. Height and weight 
will also be measured and recorded.
A symptom driven physical examination may be performed at other times at the 
Investigator’s discretion.
BMI
Body Mass Index equals a person's weight in kilograms divided by height in meters squared 
(BMI=kg/m2). Body Mass Index will be rounded to the nearest whole number according to 
the standard convention of 0.1 to 0.4 round down and 0.5 to 0.9 round up.
Body weight and height will be obtained with the participant’s shoes off and jacket or coat 
removed.
8.3.2
Vital Signs
•
Body temperature, HR, RR, and BP will be assessed.
•
Body temperature will be measured with an appropriate thermometer.
•
Blood pressure and pulse measurements will be assessed with a completely automated 
device. Manual techniques will be used only if an automated device is not available.
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•
Vital signs will be measured in a semi-recumbent position after 10 minutes rest.
8.3.2.1
Resting Vital Signs
Vital Sign Measurements (Heart Rate and Blood Pressure)
Participants should be resting in a semirecumbent position for at least 10 minutes prior to 
having VS measurements obtained. Semirecumbent VS will include HR and BP. The correct 
size of the BP cuff and the correct positioning on the participants' arm is essential to increase 
the accuracy of BP measurements.
Predose HR and BP will be in triplicate measurements, obtained at least 1 to 2 minutes apart 
within 3 hours of study drug administration. The mean of these measurements will be used as 
the baseline to calculate change from baseline for safety evaluations (and for rechecks, if 
needed). Postdose VS measurements will be single measurements.
Body Temperature
Body temperature will be measured. The same method must be used for all measurements for 
each individual participant and should be the same for all participants.
8.3.3
Electrocardiograms
•
Triplicate and single 12-lead ECG measurements will be obtained and reviewed by an 
investigator or medically qualified designee (consistent with local requirements) as 
outlined in the SoA using an ECG machine that automatically calculates the HR and 
measures PR, QRS, QT, and QTc intervals. 
•
The model of ECG machine will remain consistent for each individual participant. 
•
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 interfering garments.
•
Participants should be resting in the semirecumbent position for at least 10 minutes prior 
to each ECG measurement.
•
The correction formula to be used for QTc is Fridericia.
•
If repeat ECGs are required, the clinical site will decide whether to leave the electrodes in 
place or mark the position of the electrodes for subsequent ECGs. To mark the position of 
the electrodes, 12-lead electrode sites will be marked on the skin of each participant with 
an ECG skin marker pen to ensure reproducible electrode placement.
•
Predose ECGs will be obtained in triplicate at least 1-2 minutes apart within 3 hours prior 
to administration of ISL. The mean of these measurements will be used as the baseline to 
calculate change from baseline for safety evaluations (and for rechecks, if needed). Post-
dose ECG measurements will be single measurements.
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•
If a participant demonstrates an increase in QTc interval ≥60 msec compared with mean 
predose baseline measurement, the ECG will be repeated twice within 5 minutes. The 
mean value of the QTc interval from the 3 ECGs will represent the value at that time 
point. If the mean QTc interval increase from baseline for any postdose time point is 
≥60 msec, the participant will continue to be monitored by repeat 12-lead ECGs every 
15 minutes for at least 1 hour or until the QTc is within 60 msec of baseline. If 
prolongation of the QTc interval ≥60 msec persists, a consultation with a study 
cardiologist may be appropriate and the Sponsor should be notified.
•
If the QTc interval is >500 msec, the Sponsor should be notified and the ECGs should be 
reviewed by a cardiologist. The participant should be telemetry-monitored (until the QTc 
is <500 msec) or should be considered for transfer to a location where closer monitoring 
and definitive care (eg, a cardiac or intensive care unit) is available.
•
If the participant has unstable hemodynamics, or has any clinically significant 
dysrhythmias noted on telemetry, the participant should be immediately transferred to an 
acute care setting for definitive therapy.
•
If prolongation of the QTc is noted, concomitant medications that prolong QTc should be 
held until the QTc is within 60 msec of baseline and the QTc is <500 msec.
•
A study cardiologist will be consulted by the investigator as needed to review ECG 
tracings with abnormalities.
8.3.4
Clinical Safety Laboratory Assessments
Refer to Appendix 2 for the list of clinical laboratory tests to be performed and to the SoA for 
the timing and frequency.
•
The investigator or medically qualified designee (consistent with local requirements) 
must review the laboratory report, document this review, and record any clinically 
relevant changes occurring during the study in the AE section of the CRF. The laboratory 
reports must be filed with the source documents. Clinically significant abnormal 
laboratory findings are those which are not associated with the underlying disease, unless 
judged by the investigator to be more severe than expected for the participant's condition.
•
All protocol-required laboratory assessments, as defined in Appendix 2, must be 
conducted in accordance with the laboratory manual and the SoA.
•
If laboratory values from nonprotocol-specified laboratory assessments performed at the 
institution’s local laboratory require a change in study participant management or are 
considered clinically significant by the investigator (eg, SAE or AE or dose 
modification), then the results must be recorded in the appropriate CRF (eg, SLAB).
•
For any laboratory tests with values considered clinically significantly abnormal during 
participation in the study or within 28 days after the last dose of study intervention, every 
attempt should be made to perform repeat assessments until the values return to normal or 
baseline or if a new baseline is established as determined by the investigator.
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8.3.5
Photograph of Rash
Photographs of any rash are highly recommended to be taken immediately, along with any 
additional information that may assist the investigator in the evaluation of the skin reaction, 
skin eruption or rash occurrence, in determining etiology and drug relationship.
8.4
Adverse Events, Serious Adverse Events, and Other Reportable Safety Events
The definitions of an AE or SAE, as well as the method of recording, evaluating, and 
assessing causality of AE and SAE and the procedures for completing and transmitting AE, 
SAE, and other reportable safety event reports can be found in Appendix 3.
Adverse events, SAEs, and other reportable safety events will be reported by the participant 
(or, when appropriate, by a caregiver, surrogate, or the participant's legally authorized 
representative).
The investigator and any designees are responsible for detecting, documenting, and reporting 
events that meet the definition of an AE or SAE as well as other reportable safety events. 
Investigators remain responsible for following up AEs, SAEs, and other reportable safety 
events for outcome according to Section 8.4.3.
The investigator, who is a qualified physician, will assess events that meet the definition of 
an AE or SAE as well as other reportable safety events with respect to seriousness, 
intensity/toxicity and causality.
8.4.1
Time Period and Frequency for Collecting AE, SAE, and Other Reportable 
Safety Event Information
AEs, SAEs, and other reportable safety events that occur after the consent form is signed but 
before intervention allocation, must be reported by the investigator for randomized 
participants only if the event is the result of a protocol-specified intervention, including but 
not limited to washout or discontinuation of usual therapy, diet, placebo, or a procedure.
From the time of intervention allocation through 28 days following cessation of intervention, 
all AEs, SAEs and other reportable safety events must be reported by the investigator.
Additionally, any SAE brought to the attention of an investigator any time outside of the time 
period specified in the previous paragraph also must be reported immediately to the Sponsor 
if the event is considered related to study intervention.
Investigators are not obligated to actively seek AEs or SAEs or other reportable safety events 
in former study participants. However, if the investigator learns of any SAE, including a
death, at any time after a participant has been discharged from the study, and he/she 
considers the event to be reasonably related to the study intervention or study participation, 
the investigator must promptly notify the Sponsor.
All initial and follow-up AEs, SAEs, and other reportable safety events will be recorded and 
reported to the Sponsor or designee within the time frames as indicated in Table 4. 
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Table 4
Reporting Time Periods and Time Frames for Adverse Events and Other 
Reportable Safety Events
Type of Event
Reporting Time 
Period:
Consent to 
Randomization/ 
Allocation
(Randomized 
participants only)
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:
NSAE
Report if:
- due to protocol-
specified 
intervention
- causes exclusion
- participant is 
receiving placebo 
run-in or other run-in 
treatment
Report all
Not required
Per data entry 
guidelines
SAE
Report if:
- due to protocol-
specified 
intervention
- causes exclusion
- participant is 
receiving placebo 
run-in or other run-in 
treatment
Report all
Report if:
- drug/vaccine related.
(Follow ongoing to 
outcome)
Within 24 hours of 
learning of event
Pregnancy/
Lactation 
Exposure
Report if:
- participant has been 
exposed to any 
protocol-specified 
intervention (eg, 
procedure, washout 
or run-in treatment 
including placebo 
run-in) 
Report all
Previously reported –
Follow to 
completion/termination; 
report outcome
Within 24 hours of 
learning of event
ECI (require 
regulatory 
reporting)
Report if:
- due to intervention
- causes exclusion
Report
- potential DILI
- require regulatory 
reporting
Not required
Within 24 hours of 
learning of event
ECI (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
(unless serious)
Overdose
Report if:
- receiving placebo 
run-in or other run-in 
medication 
Report all
Not required
Within 24 hours of 
learning of event
DILI=drug-induced liver injury; ECI=event of clinical interest; NSAE=nonserious adverse event; SAE=serious adverse 
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, ECIs, cancer, and overdose will be 
followed until resolution, stabilization, until the event is otherwise explained, or the 
participant is lost to follow-up (as defined in Section 7.3). In addition, the investigator will 
make every attempt to follow all nonserious AEs that occur in allocated participants for 
outcome. Further information on follow-up procedures is given in Appendix 3.
8.4.4
Regulatory Reporting Requirements for SAE
Prompt notification (within 24 hours) by the investigator to the Sponsor of SAE is essential 
so that legal obligations and ethical responsibilities towards the safety of participants and the 
safety of a study intervention under clinical investigation are met.
The Sponsor has a legal responsibility to notify both the local regulatory authority and other 
regulatory agencies about the safety of a study intervention under clinical investigation. The 
Sponsor will comply with country-specific regulatory requirements and global laws and 
regulations relating to safety reporting to regulatory authorities, IRB/IECs, and investigators.
Investigator safety reports must be prepared for SUSARs according to local regulatory 
requirements and Sponsor policy and forwarded to investigators as necessary.
An investigator who receives an investigator safety report describing an SAE or other 
specific safety information (eg, summary or listing of SAE) from the Sponsor will file it 
along with the IB and will notify the IRB/IEC, if appropriate according to local requirements.
8.4.5
Pregnancy and Exposure During Breastfeeding
Although pregnancy and infant exposure during breastfeeding are not considered AEs, any 
pregnancy or infant exposure during breastfeeding in a participant (spontaneously reported to 
the investigator or their designee) that occurs during the study are reportable to the Sponsor.
All reported pregnancies must be followed to the completion/termination of the pregnancy. 
Pregnancy outcomes of spontaneous abortion, missed abortion, benign hydatidiform mole, 
blighted ovum, fetal death, intrauterine death, miscarriage, and stillbirth must be reported as 
serious events (Important Medical Events). If the pregnancy continues to term, the outcome 
(health of infant) must also be reported.
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8.4.6
Disease-related Events and/or Disease-related Outcomes Not Qualifying as 
AEs or SAEs
Not applicable.
8.4.7
Events of Clinical Interest
Selected serious and nonserious AEs are also known as ECIs and must be reported to the 
Sponsor.
Events of clinical interest for this study include: 
1. An overdose of Sponsor's product, as defined in Section 8.5.
2. 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 must trigger 
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).
It may also be appropriate to conduct additional evaluation for an underlying etiology in the 
setting of abnormalities of liver blood tests including AST, ALT, bilirubin, and alkaline 
phosphatase that do not meet the criteria noted above. In these cases, the decision to proceed 
with additional evaluation will be made through consultation between the study investigators 
and the Sponsor Clinical Director. However, abnormalities of liver blood tests that do not 
meet the criteria noted above are not ECIs for this study.
8.5
Treatment of Overdose
For purposes of this study, an overdose will be defined as any dose of any drug administered 
as part of the study exceeding the dose prescribed by the protocol. It is up to the investigator 
or the reporting physician to decide whether a dose is to be considered an overdose, in 
consultation with the Sponsor.
8.6
Pharmacokinetics
The decision as to which plasma and/or urine samples collected will be assayed for 
evaluation of PK/pharmacodynamics 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 ISL and PBMC ISL-TP
Blood collection time points for plasma ISL and M4 and PBMC ISL-TP are outlined in the 
SoA (Section 1.3).  Sample collection, storage, and shipment instructions for plasma samples 
will be provided in the Study Operations Manual.
8.6.2
Urine Collection for Urinary MK-8591 and M4
Urine collection intervals for urinary ISL and M4 are outlined in the SoA (Section 1.3).  
Sample collection, storage, and shipment instructions for urine samples will be provided in 
the Study Operations manual.
8.7
Pharmacodynamics
Pharmacodynamic parameters will not be evaluated in this study.
8.8
Biomarkers
Collection of samples for other biomarker research is also part of this study. The following 
samples for biomarker research are required and will be collected from all participants as 
specified in the SoA:
•
Blood for Genetic Analysis
8.8.1
Planned Genetic Analysis Sample Collection
The planned genetic analysis sample should be 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 planned genetic 
analysis is not approved, but future biomedical research is approved, 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.
8.9
Future Biomedical Research Sample Collection
If the participant signs the future biomedical research consent, the following specimens will 
be obtained as part of future biomedical research:
•
Leftover DNA for future research 
8.10
Visit Requirements
Visit requirements are outlined in Section 1.3. Specific procedure-related details are provided 
in Section 8.
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8.10.1
Screening
Approximately 4 weeks prior to intervention randomization, potential participants will be 
evaluated to determine that they fulfill the entry requirements as set forth in Section 5.
Participants may be rescreened after consultation with the Sponsor. Rescreening should 
include all screening procedures listed in the SoA, including consent review. Rescreen 
procedures cannot be conducted the day prior to intervention allocation if there are Day -1 
procedures planned per protocol.
8.10.2
Treatment Period/Visit
Refer to the Schedule of Activities (Section 1.3).
8.10.3
Discontinued Participants Continuing to be Monitored in the Study
At any point if a participant discontinues from treatment but continues to be monitored in the 
study, all of the study procedures specified in the SoA may be completed at the discretion of 
the investigator and with Sponsor agreement. The subset of study procedures completed will 
be communicated in a PCL.
8.10.4
Poststudy
Poststudy procedures will be conducted on Day 29 of the study.  
8.10.5
Critical Procedures Based on Study Objectives: Timing of Procedure
For this study, the blood sample for ISL is the critical procedure.
At any postdose time point, the blood sample for ISL needs to be collected as close to the 
exact time point as possible. All other procedures should be completed as close to the 
prescribed/scheduled time as possible. Study procedures can be performed prior or after the 
prescribed/scheduled time.
The order of priority can be changed during the study with joint agreement of the investigator 
and the Sponsor Clinical Director.
Any nonscheduled procedures required for urgent evaluation of safety concerns take 
precedence over all routine scheduled procedures.
The following variance in procedure collection times will be permitted. 
•
PK Collection as outlined in Table 5.
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Table 5
Pharmacokinetic (Blood) Collection Windows
PK Collection
PK Collection Window
0 - <1 hr
5 min
1 - <24 hr
15 min
24 - <48 hr
1 hr
48 - ≤120 hr
2 hr
120 – 168 hr
6 hr
˃ 168 hr
24 hr
•
Predose standard safety evaluations: vital signs and ECG up to 3 hrs; laboratory safety 
tests and physical exam up to 24 hrs
•
Postdose standard safety evaluations: vital signs, ECG, laboratory safety tests, and 
physical exam
-
<24 hr postdose may be obtained within 15 min of the theoretical sampling time
-
24 hr - <48 hr postdose may be obtained within 1 hr of the theoretical sampling time
-
48 hr – ≤120 hr postdose may be obtained within 2 hr of the theoretical sampling time
-
120 – 168 hr postdose may be obtained within 6 hr of the theoretical sampling time
-
> 168 hr postdose may be obtained within 24 hr of the theoretical sampling time
8.10.6
Study Design/Dosing/Procedures Modifications Permitted Within Protocol 
Parameters
This is a Phase 1 assessment of ISL in humans, and the PK, pharmacodynamic, and safety 
profiles of the compound are still being elucidated. This protocol is written with some 
flexibility to accommodate the inherent dynamic nature of Phase 1 clinical studies. 
Modifications to the dose, dosing regimen, and/or clinical or laboratory procedures currently 
outlined may be required to achieve the scientific goals of the study objectives and/or to 
ensure appropriate safety monitoring of the study participants.
As such, some alterations from the currently outlined dose and/or dosing regimen may be 
permitted based on newly available data, but the maximum daily dose may not exceed those 
currently outlined in the protocol.
•
Decrease in the dose of the study intervention administered
•
Modification of the PK sample processing and shipping details based on newly available 
data
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The PK/pharmacodynamic sampling scheme currently outlined in the protocol may be 
modified during the study based on newly available PK or pharmacodynamic data (eg, to 
obtain data closer to the time of peak plasma concentrations). If indicated, these collected 
samples may also be assayed in an exploratory manner for metabolites and/or additional 
pharmacodynamic markers.
Up to additional 50 mL of blood may be drawn for safety, PK, and/or pharmacodynamic 
analyses. The total blood volume withdrawn from any single participant will not exceed the 
maximum allowable volume during his/her participation in the entire study (Appendix 8).
The timing of procedures for assessment of safety procedures (eg, vital signs, ECG, safety 
laboratory tests, etc.) may be modified during the study based on newly available data. 
Additional laboratory safety tests may be added to blood samples previously drawn to obtain 
additional safety information. These changes will not increase the number of study 
procedures for a given participant during his/her participation in the entire study.
It is understood that the current study may employ some or none of the alterations described 
above. Any alteration made to this protocol to meet the study objectives must be detailed by 
the Sponsor in a letter to the Study File and forwarded to the investigator for retention. The 
letter may be forwarded to the IRB/IEC at the discretion of the investigator.
9
STATISTICAL ANALYSIS PLAN
9.1
Statistical Analysis Plan Summary
This section contains a summary of the statistical analyses for this trial. Full detail is in the 
Statistical Methods (Section 9.6).
Pharmacokinetics: Separately for each of the following PK parameters, after a single dose 
administration of 60 mg ISL to participants with moderate hepatic impairment and healthy 
control participants, will be natural log-transformed and evaluated with a linear fixed effects 
model containing a fixed effect for population (participants with moderate hepatic
impairment, and healthy control participants): individual values of plasma ISL AUC0-∞, 
AUC0-last, and Cmax; PBMC ISL-TP AUC0-∞, AUC0-last, Cmax, C24, C168, and C672; 
and plasma M4 AUC0-∞, AUC0-last, and Cmax.  An unstructured covariance matrix will be 
used to allow for unequal population variances via the REPEATED and GROUP statement in 
SAS PROC MIXED.  Kenward and Roger's method will be used to calculate the 
denominator degrees of freedom for the fixed effect (DDFM=KR).  Ninety-five percent 
(95%) CIs for the least squares means for each population will be constructed on the natural 
log scale and will reference the t-distribution.  Exponentiating the least-squares means and 
their corresponding 95% CIs will yield estimates for the population geometric means and 
confidence intervals about the geometric means on the original scale.  
To address the primary estimation objective and compare participants with moderate hepatic 
impairment to participants with normal hepatic function, a two sided 90% confidence interval 
for the true difference in means (moderate hepatic impairment – normal hepatic function) 
will be calculated for each PK parameter using the mean square error from the model and 
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referencing a t-distribution.  These confidence limits will be exponentiated to obtain the 90% 
confidence interval for the true ratio of geometric means (moderate hepatic impairment/
normal hepatic function) for each PK parameter.
Safety: The safety and tolerability of ISL will be monitored by clinical assessment of adverse 
experiences and other safety measurements (e.g., labs, vital signs, ECGs).
Sample Size and Power Calculations: The between-subject standard deviations (on the 
natural log scale) for plasma ISL AUC0-∞ and Cmax, PBMC MK-8951-TP AUC0-∞ and 
Cmax after administration of ISL observed in a previous study (PN003) are 0.228 
ln(hr*nmol/L), 0.356 ln(nmol/L), 0.414 ln(hr* pmol/106 Cells) and 0.518 ln(pmol/106 Cells), 
respectively. Assuming the same variability for 60-mg ISL, with 6 moderate hepatic
impairment participants and 6 healthy participants, the half width of the 90% confidence 
intervals of geometric mean ratios (GMR)s for plasma ISL AUC0-∞ and Cmax, PBMC 
MK-8951-TP AUC0-∞ and Cmax on the log scale will be 0.239, 0.372, 0.443, and 0.542 
respectively. The lower and upper 90% confidence limits for the true GMRs will be given by 
OBS/1.27 and OBS*1.27 for plasma ISL AUC0-∞, OBS/1.45, and OBS*1.45 for plasma ISL 
Cmax, OBS/1.54 and OBS*1.54 for AUC0-∞ ISL-TP in PBMC, OBS/1.72, and OBS*1.72 
for Cmax ISL-TP in PBMC, where OBS is the observed least squares geometric mean. 
9.2
Responsibility for Analyses
The statistical analysis of the data obtained from this study will be conducted by, or under the 
direct auspices of, the Early Clinical Development Statistics Department in collaboration 
with the Quantitative Pharmacology and Pharmacometrics Department and Translational 
Pharmacology Department of the Sponsor.
If, after the study has begun, changes are made to the statistical analysis plan stated below, 
then these deviations to the plan will be listed, along with an explanation as to why they 
occurred, in the Clinical Study Report.
9.3
Hypotheses/Estimation
Estimation: In participants with moderate hepatic impairment, plasma pharmacokinetics 
(AUC0-∞, Cmax) of ISL following a single 60 mg ISL dose will be estimated and compared 
to those observed in healthy mean matched control participants.
9.4
Analysis Endpoints
Primary Endpoints
The primary PK endpoints include plasma ISL AUC0-∞, AUC0-last, Cmax, Tmax, apparent 
terminal t½, CL/F, and Vz/F. 
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Secondary Endpoints 
The secondary PK endpoints include AUC0-∞, AUC0-last, Cmax, C24, C168, C672, Tmax, 
and apparent terminal t½ of ISL-TP in PBMC. The secondary safety endpoints include 
adverse experiences, laboratory safety tests, ECGs, and VSs. 
Exploratory Endpoints: 
The exploratory endpoints include AUC0-∞, AUC0-last, Cmax, and Tmax of M4 in plasma. 
The exploratory endpoints also include Ae, CLr, and fe of ISL and M4 in urine. 
9.5
Analysis Populations
The following populations are defined for the analysis and reporting of data. All participants 
will be reported, and their data analyzed, according to the treatment(s) they actually received.
All participants as Treated (APaT): The All participants as Treated Population consists of all
participants who received at least one dose of treatment. This population will be used for
assessments of safety and tolerability.
Per-Protocol (PP): The Per-Protocol 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 considered sufficient to exhibit the effect of treatment will be included in the
Per-Protocol dataset. This population will be used for the PK analyses.
9.6
Statistical Methods
Separately for each of the following PK parameters, after a single dose administration of 60 
mg ISL to participants with moderate hepatic impairment and healthy control participants,
will be natural log-transformed and evaluated with a linear fixed effects model containing a 
fixed effect for population (participants with moderate hepatic impairment, and healthy 
control participants): individual values of plasma ISL AUC0-∞, AUC0-last, and Cmax;
PBMC ISL-TP AUC0-∞, AUC0-last, Cmax, C24, C168, and C672; and plasma M4 AUC0-
∞, AUC0-last, and Cmax.  An unstructured covariance matrix will be used to allow for 
unequal population variances via the REPEATED and GROUP statement in SAS PROC 
MIXED.  Kenward and Roger's method will be used to calculate the denominator degrees of 
freedom for the fixed effect (DDFM=KR).  Ninety-five percent (95%) CIs for the least 
squares means for each population will be constructed on the natural log scale and will 
reference the t-distribution.  Exponentiating the least-squares means and their corresponding 
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95% CIs will yield estimates for the population geometric means and confidence intervals 
about the geometric means on the original scale.  Sample SAS code is given below:
proc mixed data=data;                                                                                                                   
   class population ;                                                                                                           
   model lnpk = population /ddfm=kr;                                                                                                    
   repeated/ group= population type=UN;                                                                                 
   lsmeans population /cl alpha=0.05; 
   estimate ‘moderate/normal’ population 1 -1/cl alpha=0.1; 
run;    
To address the primary estimation objective and compare participants with moderate hepatic 
impairment to participants with normal hepatic function, a two-sided 90% confidence 
interval for the true difference in means (moderate hepatic impairment – normal hepatic 
function) will be calculated for each PK parameter using the mean square error from the 
model and referencing a t-distribution.  These confidence limits will be exponentiated to 
obtain the 90% confidence interval for the true ratio of geometric means (moderate hepatic 
impairment/normal hepatic function) for each PK parameter.
Figures showing individual PK values with GMs (95% CIs) by population, plotted on the 
natural log scale, will be provided for plasma ISL AUC0-∞, AUC0-last, and Cmax; PBMC 
ISL-TP AUC0-∞, AUC0-last, Cmax, C24, C168, and C672; and plasma M4 AUC0-∞, 
AUC0-last, and Cmax.
Individual values will be listed for each PK parameter including plasma ISL AUC0-∞, 
AUC0-last, Cmax, Tmax, apparent terminal t½, CL/F, and Vz/F, PBMC ISL-TP AUC0-∞, 
AUC0-last, Cmax, C24, C168, C672, Tmax, apparent terminal t½, plasma M4 AUC0-∞, 
AUC0-last, Cmax, Tmax , and Ae, CLr, and fe of ISL and M4 in urine by population, and the 
following (non-model-based) descriptive statistics will be provided: N (number of 
participants with non-missing data), arithmetic mean, standard deviation, arithmetic  percent 
CV (calculated as 100 x standard deviation/arithmetic mean), median, minimum, maximum, 
geometric mean, and geometric percent CV (calculated as  100 x sqrt(exp(s2) - 1), where s2 is 
the observed variance on the natural log-scale).
The relationship between ISL pharmacokinetics and hepatic insufficiency will be examined 
in an exploratory manner via a scatter plot of PK values (ISL plasma AUC0-∞, AUC0-last
and Cmax) versus the Child-Pugh score. Plots of PK values (ISL plasma AUC0-∞, AUC0-
last and Cmax) and the baseline laboratory components of the Child-Pugh score (i.e., 
bilirubin, albumin levels, and prothrombin time) will be provided.  Plots of PK parameter 
values (ISL plasma AUC0-∞, AUC0-last and Cmax) vs age and body weight will also be 
provided. 
Safety: The safety and tolerability of ISL will be monitored by clinical assessment of adverse 
experiences and other safety measurements (e.g., labs, vital signs, ECGs).
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9.7
Interim Analyses
Not applicable. 
9.8
Multiplicity
There is no pre-specified hypothesis; therefore, no multiplicity adjustment is needed.
9.9
Sample Size and Power Calculations
The between-subject standard deviations (on the natural log scale) for plasma ISL AUC0-∞ 
and Cmax, PBMC MK-8951-TP AUC0-∞ and Cmax after administration of ISL observed in 
a previous study (PN003) are 0.228 ln(hr*nmol/L), 0.356 ln(nmol/L), 0.414 ln(hr* pmol/106
Cells) and 0.518 ln(pmol/106 Cells), respectively. Assuming the same variability for 60-mg 
ISL, with 6 moderate hepatic impairment participants and 6 healthy participants, the half 
width of the 90% confidence intervals of geometric mean ratios (GMR)s for plasma ISL 
AUC0-∞ and Cmax, PBMC MK-8951-TP AUC0-∞ and Cmax on the log scale will be 0.239, 
0.372, 0.443, and 0.542 respectively. The lower and upper 90% confidence limits for the true 
GMRs will be given by OBS/1.27 and OBS*1.27 for plasma ISL AUC0-∞, OBS/1.45, and 
OBS*1.45 for plasma ISL Cmax, OBS/1.54 and OBS*1.54 for AUC0-∞ ISL-TP in PBMC, 
OBS/1.72, and OBS*1.72 for Cmax ISL-TP in PBMC, where OBS is the observed least 
squares geometric mean. 
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10
SUPPORTING DOCUMENTATION AND OPERATIONAL 
CONSIDERATIONS
10.1
Appendix 1: Regulatory, Ethical, and Study Oversight Considerations
10.1.1
Code of Conduct for Clinical Trials
Merck Sharp and Dohme Corp., a subsidiary of Merck & Co., Inc. (MSD)
Code of Conduct for Interventional Clinical Trials
I. Introduction
A. Purpose
MSD, through its subsidiaries, conducts clinical trials worldwide to evaluate the safety and effectiveness of our 
products. As such, we are committed to designing, implementing, conducting, analyzing, and reporting these trials 
in compliance with the highest ethical and scientific standards. Protection of participants in clinical trials is the 
overriding concern in the design and conduct of clinical trials. In all cases, MSD clinical trials will be conducted 
in compliance with local and/or national regulations (including all applicable data protection laws and
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 and shall respect the data protection rights of all participants, trial site staff and, where 
applicable, third parties. 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 
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source documentation according to standard operating procedures. Per MSD policies and procedures, if
potential fraud, scientific/research misconduct, privacy incidents/breaches or Clinical Trial-related 
Significant Quality Issues are reported, such matters are investigated. When necessary, appropriate corrective 
and/or preventative actions are defined and regulatory authorities and/or ethics review committees are 
notified.
B. Publication and Authorship
Regardless of trial outcome, MSD commits to publish the primary and secondary results of its registered trials of 
marketed products in which treatment is assigned, according to the pre-specified plans for data analysis. To the 
extent scientifically appropriate, MSD seeks to publish the results of other analyses it conducts that are important 
to patients, physicians, and payers. Some early phase or pilot trials are intended to be hypothesis-generating rather 
than hypothesis testing; in such cases, publication of results may not be appropriate since the trial may be 
underpowered and the analyses complicated by statistical issues such as multiplicity.
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, as well as all 
applicable data protection rights. Unless required by law, only the investigator, Sponsor (or individuals acting on 
behalf of MSD), ethics committee, and/or regulatory authorities will have access to confidential medical records 
that might identify the participant by name.
D. Genomic Research
Genomic research will only be conducted in accordance with a protocol and informed consent authorized by an 
ethics committee.
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IV. Financial Considerations
A. Payments to Investigators
Clinical trials are time- and labor-intensive. It is MSD’s policy to compensate investigators (or the sponsoring 
institution) in a fair manner for the work performed in support of MSD trials. MSD does not pay incentives to 
enroll participants in its trials. However, when enrollment is particularly challenging, additional payments may be 
made to compensate for the time spent in extra recruiting efforts.
MSD does not pay for participant referrals. However, MSD may compensate referring physicians for time spent 
on chart review and medical evaluation to identify potentially eligible participants.
B. Clinical Research Funding
Informed consent forms will disclose that the trial is sponsored by MSD, and that the investigator or sponsoring 
institution is being paid or provided a grant for performing the trial. However, the local ethics committee may 
wish to alter the wording of the disclosure statement to be consistent with financial practices at that institution. As 
noted above, all publications resulting from MSD trials will indicate MSD as a source of funding.
C. Funding for Travel and Other Requests
Funding of travel by investigators and support staff (e.g., to scientific meetings, investigator meetings, etc.) will be 
consistent with local guidelines and practices.
V. Investigator Commitment
Investigators will be expected to review MSD’s Code of Conduct as an appendix to the trial protocol, and in signing the 
protocol, agree to support these ethical and scientific standards.
10.1.2
Financial Disclosure
Financial Disclosure requirements are outlined in the US Food and Drug Administration 
Regulations, Financial Disclosure by Clinical Investigators (21 CFR Part 54). It is the 
Sponsor's responsibility to determine, based on these regulations, whether a request for 
Financial Disclosure information is required. It is the investigator's/subinvestigator's 
responsibility to comply with any such request.
The investigator/subinvestigator(s) agree, if requested by the Sponsor in accordance with 21 
CFR Part 54, to provide his/her financial interests in and/or arrangements with the Sponsor to 
allow for the submission of complete and accurate certification and disclosure statements. 
The investigator/subinvestigator(s) further agree to provide this information on a 
Certification/Disclosure Form, commonly known as a financial disclosure form, provided by 
the Sponsor. The investigator/subinvestigator(s) also consent to the transmission of this 
information to the Sponsor in the United States for these purposes. This may involve the 
transmission of information to countries that do not have laws protecting personal data.
10.1.3
Data Protection
The Sponsor will conduct this study in compliance with all applicable data protection 
regulations.
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Participants will be assigned a unique identifier by the Sponsor. Any participant records or 
datasets that are transferred to the Sponsor will contain the identifier only; participant names 
or any information that would make the participant identifiable will not be transferred.
The participant must be informed that his/her personal study-related data will be used by the 
Sponsor in accordance with local data protection law. The level of disclosure must also be 
explained to the participant. 
The participant must be informed that his/her medical records may be examined by Clinical 
Quality Assurance auditors or other authorized personnel appointed by the Sponsor, by 
appropriate IRB/IEC members, and by inspectors from regulatory authorities.
10.1.3.1
Confidentiality of Data
By signing this protocol, the investigator affirms to the Sponsor that information furnished to 
the investigator by the Sponsor will be maintained in confidence, and such information will 
be divulged to the IRB, IEC, or similar or expert committee; affiliated institution and 
employees, only under an appropriate understanding of confidentiality with such board or 
committee, affiliated institution and employees. Data generated by this study will be 
considered confidential by the investigator, except to the extent that it is included in a 
publication as provided in the Publications section of this protocol.
10.1.3.2
Confidentiality of Participant Records
By signing this protocol, the investigator agrees that the Sponsor (or Sponsor representative), 
IRB/IEC, or regulatory authority representatives may consult and/or copy study documents to 
verify worksheet/CRF data. By signing the consent form, the participant agrees to this 
process. If study documents will be photocopied during the process of verifying 
worksheet/CRF information, the participant will be identified by unique code only; full 
names/initials will be masked prior to transmission to the Sponsor.
By signing this protocol, the investigator agrees to treat all participant data used and 
disclosed in connection with this study in accordance with all applicable privacy laws, rules 
and regulations.
10.1.3.3
Confidentiality of IRB/IEC Information
The Sponsor is required to record the name and address of each IRB/IEC that reviews and 
approves this study. The Sponsor is also required to document that each IRB/IEC meets 
regulatory and ICH GCP requirements by requesting and maintaining records of the names 
and qualifications of the IRB/IEC members and to make these records available for 
regulatory agency review upon request by those agencies.
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 
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standard editorial and ethical practice, the Sponsor will generally support publication of 
multicenter studies only in their entirety and not as individual site data. In this case, a 
coordinating investigator will be designated by mutual agreement.
If publication activity is not directed by the Sponsor, the investigator agrees to submit all 
manuscripts or abstracts to the Sponsor before submission. This allows the Sponsor to protect 
proprietary information and to provide comments.
Authorship will be determined by mutual agreement and in line with International Committee 
of Medical Journal Editors authorship requirements.
10.1.5
Compliance with Study Registration and Results Posting Requirements
Under the terms of the FDAAA of 2007 and the EMA clinical trial Directive 2001/20/EC, the 
Sponsor of the study is solely responsible for determining whether the study and its results 
are subject to the requirements for submission to http://www.clinicaltrials.gov, 
www.clinicaltrialsregister.eu or other local registries. MSD, as Sponsor of this study, will 
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 Council on Harmonisation of Technical Requirements for Registration of 
Pharmaceuticals for Human Use GCP: Consolidated Guideline and other generally accepted 
standards of GCP); and all applicable federal, state and local laws, rules and regulations 
relating to the conduct of the clinical study.
The Code of Conduct, a collection of goals and considerations that govern the ethical and 
scientific conduct of clinical investigations sponsored by MSD, is provided in this appendix 
under the Code of Conduct for Clinical Trials.
The investigator agrees not to seek reimbursement from participants, their insurance 
providers, or from government programs for procedures included as part of the study 
reimbursed to the investigator by the Sponsor.
The investigator will promptly inform the Sponsor of any regulatory authority inspection 
conducted for this study.
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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 signed ICF, 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 
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the retention period without the written approval of the Sponsor. No records may be 
transferred to another location or party without written notification to the Sponsor.
10.1.8
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 6 will be performed by the local laboratory.
•
Protocol-specific requirements for inclusion or exclusion of participants are detailed in 
Section 5 of the protocol.
•
Additional tests may be performed at any time during the study as determined necessary 
by the investigator or required by local regulations.
Table 6
Protocol-required Safety Laboratory Assessments
Laboratory 
Assessments
Parameters
Hematology
Platelet Count 
RBC Indices:
MCV
MCH
%Reticulocytes
WBC count with 
Differential:
Neutrophils
Lymphocytes
Monocytes
Eosinophils
Basophils
RBC Count
Hemoglobin
Hematocrit
Chemistry
Blood Urea 
Nitrogen (BUN)
Potassium
Aspartate 
Aminotransferase
(AST)/ Serum 
Glutamic-
Oxaloacetic 
Transaminase 
(SGOT)
Total bilirubin 
(and direct 
bilirubin, if total 
bilirubin is 
elevated above 
the upper limit 
of normal)
Albumin
Bicarbonate
Chloride
Phosphorous
Creatinine
Sodium
Alanine 
Aminotransferase
(ALT)/ Serum 
Glutamic-Pyruvic 
Transaminase 
(SGPT)
Total Protein
Glucose 
(fasting)
Calcium
Alkaline 
phosphatase
Gamma 
glutamyl 
transpeptidase 
(GGT)
Coagulation
•
PT/INR (International normalized ratio, for hepatic impaired 
participants only)
Routine 
Urinalysis
•
Specific gravity
•
pH, glucose, protein, blood, ketones, [bilirubin, urobilinogen, nitrite, 
leukocyte esterase] by dipstick
•
Microscopic examination (if blood or protein is abnormal)
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Laboratory 
Assessments
Parameters
Other 
Screening 
Tests

Follicle-stimulating hormone (as needed in women of nonchildbearing 
potential only)

Serum or urine alcohol and drug screen (to include at minimum: 
amphetamines, barbiturates, cocaine, opiates, cannabinoids and 
benzodiazepines).  Alcohol breath test for alcohol screen is permitted.  

Serum or urine β human chorionic gonadotropin (β hCG) pregnancy test 
(as needed for WOCBP)

Serology (HIV-1 and HIV-2 antibodies in all participants, hepatitis B 
surface antigen [HBsAg], and hepatitis C virus antibody in healthy 
participants only

GC/CT (gonorrhea + chlamydia), Syphilis serologic, or Trichomonas 
testing may be done at screening per site SOP

HIV-1 and HIV-2 testing to be done at screening and at the Day 29 post-
trial visit.
NOTES:
Laboratory safety tests will be performed after at least an 8-hour fast. Pre-dose Day 1 
laboratory procedures can be conducted up to 24 hours prior to study drug administration.
The investigator (or medically qualified designee) must document their review of each 
laboratory safety report.
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10.3
Appendix 3: Adverse Events: Definitions and Procedures for Recording, 
Evaluating, Follow-up, and Reporting
10.3.1
Definition of AE
AE definition
    An AE is any untoward medical occurrence in a clinical study participant, temporally 
associated with the use of study intervention, whether or not considered related to the 
study intervention.
    NOTE: An AE can therefore be any unfavorable and unintended sign (including an 
abnormal laboratory finding), symptom, or disease (new or exacerbated) temporally 
associated with the use of a study intervention.
    NOTE: For purposes of AE definition, study intervention (also referred to as Sponsor’s 
product) includes any pharmaceutical product, biological product, vaccine, diagnostic 
agent, medical device, combination product, or protocol specified procedure whether 
investigational or marketed (including placebo, active comparator product, or run-in 
intervention), manufactured by, licensed by, provided by, or distributed by the Sponsor 
for human use in this study.
Events meeting the AE definition
    Any abnormal laboratory test results (hematology, clinical chemistry, or urinalysis) or 
other safety assessments (eg, ECG, radiological scans, vital signs measurements), 
including those that worsen from baseline, considered clinically significant in the medical 
and scientific judgment of the investigator.
    Exacerbation of a chronic or intermittent pre-existing condition including either an 
increase in frequency and/or intensity of the condition.
    New conditions detected or diagnosed after study intervention administration even 
though it may have been present before the start of the study.
    Signs, symptoms, or the clinical sequelae of a suspected drug-drug interaction.
    Signs, symptoms, or the clinical sequelae of a suspected overdose of either study 
intervention or a concomitant medication.
    For all reports of overdose (whether accidental or intentional) with an associated AE, the 
AE term should reflect the clinical symptoms or abnormal test result. An overdose 
without any associated clinical symptoms or abnormal laboratory results is reported using 
the terminology “accidental or intentional overdose without adverse effect.”
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Events NOT meeting the AE definition
    Medical or surgical procedure (eg, endoscopy, appendectomy): the condition that leads to 
the procedure is the AE.
    Situations in which an untoward medical occurrence did not occur (social and/or 
convenience admission to a hospital).
    Anticipated day-to-day fluctuations of pre-existing disease(s) or condition(s) present or 
detected at the start of the study that do not worsen.
    Surgery planned prior to informed consent to treat a pre-existing condition that has not 
worsened.
    Refer to Section 8.4.6 for protocol-specific exceptions.
10.3.2
Definition of SAE
If an event is not an AE per definition above, then it cannot be an SAE even if serious 
conditions are met.
An SAE is defined as any untoward medical occurrence that, at any dose:
a.   Results in death
b.   Is life-threatening
•
The term “life-threatening” in the definition of “serious” refers to an event in which 
the participant was at risk of death at the time of the event. It does not refer to an 
event, which hypothetically might have caused death, if it were more severe.
c.   Requires inpatient hospitalization or prolongation of existing hospitalization
•
Hospitalization is defined as an inpatient admission, regardless of length of stay, even 
if the hospitalization is a precautionary measure for continued observation. (Note: 
Hospitalization for an elective procedure to treat a pre-existing condition that has not 
worsened is not an SAE.) A pre-existing condition is a clinical condition that is 
diagnosed prior to the use of an MSD product and is documented in the participant’s 
medical history.
d.   Results in persistent or significant disability/incapacity
•
The term disability means a substantial disruption of a person’s ability to conduct 
normal life functions.
•
This definition is not intended to include experiences of relatively minor medical 
significance such as uncomplicated headache, nausea, vomiting, diarrhea, influenza, 
and accidental trauma (eg, sprained ankle) that may interfere with or prevent 
everyday life functions but do not constitute a substantial disruption.
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e.   Is a congenital anomaly/birth defect
•
In offspring of participant taking the product regardless of time to diagnosis.
f.   Other important medical events
•
Medical or scientific judgment should be exercised in deciding whether SAE 
reporting is appropriate in other situations such as important medical events that may 
not be immediately life-threatening or result in death or hospitalization but may 
jeopardize the participant or may require medical or surgical intervention to prevent 1 
of the other outcomes listed in the above definition. These events should usually be 
considered serious.
Examples of such events include invasive or malignant cancers, intensive treatment in 
an emergency room or at home for allergic bronchospasm, blood dyscrasias or 
convulsions that do not result in hospitalization, or development of drug dependency 
or drug abuse.
10.3.3
Additional Events Reported
Additional events that require reporting
In addition to the above criteria, AEs meeting either of the below criteria, although not 
serious per ICH definition, are reportable to the Sponsor.
•
Is a cancer
•
Is associated with an overdose
10.3.4
Recording AE and SAE
AE and SAE recording
    When an AE/SAE occurs, it is the responsibility of the investigator to review all 
documentation (eg, hospital progress notes, laboratory, and diagnostics reports) related to 
the event.
    The investigator will record all relevant AE/SAE information on the AE 
CRFs/worksheets at each examination.
·    It is not acceptable for the investigator to send photocopies of the participant’s medical 
records to the Sponsor in lieu of completion of the AE CRF page.
    There may be instances when copies of medical records for certain cases are requested by 
the Sponsor. In this case, all participant identifiers, with the exception of the participant 
number, will be blinded on the copies of the medical records before submission to the 
Sponsor.
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    The investigator will attempt to establish a diagnosis of the event based on signs, 
symptoms, and/or other clinical information. In such cases, the diagnosis (not the 
individual signs/symptoms) will be documented as the AE/SAE.
Assessment of intensity/toxicity
    An event is defined as “serious” when it meets at least 1 of the predefined outcomes as 
described in the definition of an SAE, not when it is rated as severe.
•
The investigator will make an assessment of intensity for each AE and SAE (and other 
reportable safety event) by recording the grade according to the NIH DAIDS Table for 
Grading the Severity of Adult and Pediatric Adverse Events, version 2.1. Any AE which 
changes DAIDS grade over the course of a given episode will have each change of grade 
recorded on the AE CRFs/worksheets.
-
Grade 1 Mild event: Mild symptoms causing no or minimal interference with usual 
social and functional activities with intervention not indicated.
-
Grade 2 Moderate event: Moderate symptoms causing greater than minimal 
interference with usual social and functional activities with intervention indicated.
-
Grade 3 Severe event: Severe symptoms causing inability to perform usual social and 
functional activities with intervention or hospitalization indicated.
-
Grade 4 Potentially life-threatening event: Potentially life-threatening symptoms 
causing inability to perform basic self-care funtions with intervention indicated to 
prevent permanent impairment, persistent disability, or death.
-
Grade 5 Death: Deaths related to an AE.
Assessment of causality
•
Did the Sponsor’s product cause the AE?
•
The determination of the likelihood that the Sponsor’s product caused the AE will be 
provided by an investigator who is a qualified physician. The investigator’s signed/dated 
initials on the source document or worksheet that supports the causality noted on the AE 
form, ensures that a medically qualified assessment of causality was done. This initialed 
document must be retained for the required regulatory time frame. The criteria below are 
intended as reference guidelines to assist the investigator in assessing the likelihood of a 
relationship between the test product and the AE based upon the available information.
•
The following components are to be used to assess the relationship between the 
Sponsor’s product and the AE; the greater the correlation with the components and 
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 
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count, diary, etc.), expected pharmacologic effect, or measurement of 
drug/metabolite in bodily specimen?
-
Time Course: Did the AE follow in a reasonable temporal sequence from 
administration of the Sponsor’s product? Is the time of onset of the AE compatible 
with a drug-induced effect (applies to studies with investigational medicinal 
product)?
-
Likely Cause: Is the AE not reasonably explained by another etiology such as 
underlying disease, other drug(s)/vaccine(s), or other host or environmental factors.
-
Dechallenge: Was the Sponsor’s product discontinued or dose/exposure/frequency 
reduced?
◦
If yes, did the AE resolve or improve?
◦
If yes, this is a positive dechallenge.
◦
If no, this is a negative dechallenge.
(Note: This criterion is not applicable if: (1) the AE resulted in death or permanent 
disability; (2) the AE resolved/improved despite continuation of the Sponsor’s 
product; (3) the study is a single-dose drug study; or (4) Sponsor’s product(s) is/are 
only used 1 time.)
-
Rechallenge: Was the participant re-exposed to the Sponsor’s product in this 
study?
◦
If yes, did the AE recur or worsen?
◦
If yes, this is a positive rechallenge.
◦
If no, this is a negative rechallenge.
(Note: This criterion is not applicable if: (1) the initial AE resulted in death or 
permanent disability, or (2) the study is a single-dose drug study; or (3) Sponsor’s 
product(s) is/are used only 1 time.)
NOTE: IF A RECHALLENGE IS PLANNED FOR AN AE THAT WAS SERIOUS AND 
MAY HAVE BEEN CAUSED BY THE SPONSOR’S PRODUCT, OR IF RE-EXPOSURE 
TO THE SPONSOR’S PRODUCT POSES ADDITIONAL POTENTIAL SIGNIFICANT 
RISK TO THE PARTICIPANT THEN THE RECHALLENGE MUST BE APPROVED IN 
ADVANCE BY THE SPONSOR CLINICAL DIRECTOR, AND IF REQUIRED, THE 
IRB/IEC.
•
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?
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•
The assessment of relationship will be reported on the case report forms/worksheets by 
an investigator who is a qualified physician according to his/her best clinical judgment, 
including consideration of the above elements.
•
Use the following scale of criteria as guidance (not all criteria must be present to be 
indicative of a Sponsor’s product relationship).
- Yes, there is a reasonable possibility of Sponsor’s product relationship:
◦
There is evidence of exposure to the Sponsor’s product. The temporal sequence of 
the AE onset relative to the administration of the Sponsor’s product is reasonable. 
The AE is more likely explained by the Sponsor’s product than by another cause.
- No, there is not a reasonable possibility of Sponsor’s product relationship:
◦
Participant did not receive the Sponsor’s product OR temporal sequence of the 
AE onset relative to administration of the Sponsor’s product is not reasonable OR 
the AE is more likely explained by another cause than the Sponsor’s product. 
(Also entered for a participant with overdose without an associated AE.)
•
For each AE/SAE, the investigator must document in the medical notes that he/she has 
reviewed the AE/SAE and has provided an assessment of causality.
•
There may be situations in which an SAE has occurred and the investigator has minimal 
information to include in the initial report to the Sponsor. However, it is very important 
that the investigator always make an assessment of causality for every event before the 
initial transmission of the SAE data to the Sponsor.
•
The investigator may change his/her opinion of causality in light of follow-up 
information and send an SAE follow-up report with the updated causality assessment.
•
The causality assessment is 1 of the criteria used when determining regulatory reporting 
requirements.
Follow-up of AE and SAE
    The investigator is obligated to perform or arrange for the conduct of supplemental 
measurements and/or evaluations as medically indicated or as requested by Sponsor to 
elucidate the nature and/or causality of the AE or SAE as fully as possible. This may 
include additional laboratory tests or investigations, histopathological examinations, or 
consultation with other health care professionals.
    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.
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10.3.5
Reporting of AEs, SAEs, and Other Reportable Safety Events to the Sponsor
AE, SAE, and other reportable safety event reporting to Sponsor via electronic data 
collection tool
    The primary mechanism for reporting to the Sponsor will be the EDC tool.
-
Electronic reporting procedures can be found in the EDC data entry guidelines (or 
equivalent).
-
If the electronic system is unavailable for more than 24 hours, then the site will use 
the paper AE Reporting form.
◦
Reference Section 8.4.1 for reporting time requirements.
    The site will enter the SAE data into the electronic system as soon as it becomes 
available.
    After the study is completed at a given site, the EDC tool will be taken off-line to prevent 
the entry of new data or changes to existing data.
    If a site receives a report of a new SAE from a study participant or receives updated data 
on a previously reported SAE after the EDC tool has been taken off-line, then the site can 
report this information on a paper SAE form or by telephone (see next section).
    Contacts for SAE reporting can be found in the Investigator Study File Binder (or 
equivalent).
SAE reporting to the Sponsor via paper CRF
    If the EDC tool is not operational, facsimile transmission or secure e-mail of the SAE 
paper CRF is the preferred method to transmit this information to the Sponsor.
    In rare circumstances and in the absence of facsimile equipment, notification by 
telephone is acceptable with a copy of the SAE data collection tool sent by overnight 
mail or courier service.
    Initial notification via telephone does not replace the need for the investigator to complete 
and sign the SAE CRF pages within the designated reporting time frames.
    Contacts and instructions for SAE reporting and paper reporting procedures can be found 
in the Investigator Study File Binder (or equivalent).
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10.4
Appendix 4: Medical Device and Drug-device Combination Products: Product 
Quality Complaints/Malfunctions: Definitions, Recording, and Follow-up
Not applicable.
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10.5
Appendix 5: Contraceptive Guidance
10.5.1
Definitions
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.
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 FSH level in the postmenopausal range may be used to confirm a 
postmenopausal state in women not using hormonal contraception or HRT. 
However, in the absence of 12 months of amenorrhea, confirmation with two FSH 
measurements in the postmenopausal range is required.
Females on HRT and whose menopausal status is in doubt 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,d
•
IUSc,e
•
Non-hormonal IUD
•
Bilateral tubal occlusion
•
Azoospermic partner (vasectomized or secondary to medical cause)
This is a highly effective contraception method provided that the partner is the sole male sexual partner of the WOCBP 
and the absence of sperm has been confirmed. If not, an additional highly effective method of contraception should be 
used. A spermatogenesis cycle is approximately 90 days.
Note: Documentation of azoospermia for a male participant can come from the site personnel’s review of the 
participant’s medical records, medical examination, or medical history interview.
Highly Effective Contraceptive Methods That Are User Dependentb
Failure rate of <1% per year when used consistently and correctly.
•
Combined (estrogen- and progestogen- containing) hormonal contraceptionc,d
-
Oral
-
Intravaginal
-
Transdermal
-
Injectable
•
Progestogen-only hormonal contraceptionc,d
-
Oral
-
Injectable
Sexual Abstinence
•
Sexual abstinence is considered a highly effective method only if defined as refraining from heterosexual intercourse 
during the entire period of risk associated with the study intervention. The reliability of sexual abstinence needs to be 
evaluated in relation to the duration of the study and the preferred and usual lifestyle of the participant.
Methods That Are Not Considered Highly Effective
Failure rate of >1% per year when used consistently and correctly.
•
Progesterone-only hormonal contraception where inhibition of ovulation is not the primary mode of action
•
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)f
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   Male condoms must be used in addition to female participant hormonal contraception.
d   If locally required, in accordance with CTFG guidelines, acceptable contraceptive implants are limited to those which 
inhibit ovulation. 
e   IUS is a progestin releasing IUD.
f   A combination of male condom with either cap, diaphragm, or sponge with spermicide are considered acceptable, but not 
highly effective, birth control methods. 
Note: The following are not acceptable methods of contraception:
-  Periodic abstinence (calendar, symptothermal, post-ovulation methods), withdrawal (coitus interruptus), 
spermicides only, and LAM.
-  Male and female condom should not be used together (due to risk of failure with friction).
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10.6
Appendix 6: Collection and Management of Specimens for Future Biomedical 
Research
1.  Definitions
a.   Biomarker: A biological molecule found in blood, other body fluids, or tissues that is a 
sign of a normal or abnormal process or of a condition or disease. A biomarker may be 
used to see how well the body responds to a treatment for a disease or condition.1
b   Pharmacogenomics: The investigation of variations of DNA and RNA characteristics as 
related to drug/vaccine response.2
c.   Pharmacogenetics: A subset of pharmacogenomics, pharmacogenetics is the influence of 
variations in DNA sequence on drug/vaccine response.2
d.   DNA: Deoxyribonucleic acid.
e.   RNA: Ribonucleic acid.
2.  Scope of Future Biomedical Research
The specimens consented and/or collected in this study as outlined in Section 8.9 will be 
used in various experiments to understand:
◦
The biology of how drugs/vaccines work
◦
Biomarkers responsible for how a drug/vaccine enters and is removed by the body
◦
Other pathways with which drugs/vaccines may interact
◦
The biology of disease
The specimen(s) may be used for future assay development and/or drug/vaccine 
development.
It is now well recognized that information obtained from studying and testing clinical 
specimens offers unique opportunities to enhance our understanding of how individuals 
respond to drugs/vaccines, enhance our understanding of human disease and ultimately 
improve public health through development of novel treatments targeted to populations 
with the greatest need. All specimens will be used by the Sponsor or those working for or 
with the Sponsor.
3.  Summary of Procedures for Future Biomedical Research
a.   Participants for Enrollment
All participants enrolled in the clinical study will be considered for enrollment in future 
biomedical research.
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b.   Informed Consent
Informed consent for specimens (ie, DNA, RNA, protein, etc.) will be obtained during 
screening for protocol enrollment from all participants or legal guardians, at a study visit 
by the investigator or his or her designate. Informed consent for future biomedical 
research should be presented to the participants on the visit designated in the SoA. If 
delayed, present consent at next possible Participant Visit. Consent forms signed by the 
participant will be kept at the clinical study site under secure storage for regulatory 
reasons.
A template of each study site’s approved informed consent will be stored in the Sponsor’s 
clinical document repository.
c.   eCRF Documentation for Future Biomedical Research Specimens
Documentation of participant consent for future biomedical research will be captured in 
the eCRFs. Any specimens for which such an informed consent cannot be verified will be 
destroyed.
d.   Future Biomedical Research Specimen(s)
Collection of specimens for future biomedical research will be performed as outlined in 
the SoA. In general, if additional blood specimens are being collected for future 
biomedical research, these will usually be obtained at a time when the participant is 
having blood drawn for other study purposes.
4.  Confidential Participant Information for Future Biomedical Research
In order to optimize the research that can be conducted with future biomedical research 
specimens, it is critical to link participants' clinical information with future test results. In 
fact, little or no research can be conducted without connecting the clinical study data to 
the specimen. The clinical data allow specific analyses to be conducted. Knowing 
participant characteristics like sex, age, medical history and intervention outcomes 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 Harmonisation [Internet]: E15: Definitions for Genomic 
Biomarkers, Pharmacogenomics, Pharmacogenetics, Genomic Data and Sample Coding 
Categories. Available from http://www.ich.org/products/guidelines/efficacy/efficacy-
single/article/definitions-for-genomic-biomarkers-pharmacogenomics-pharmacogenetics-
genomic-data-and-sample-cod.html 
3.   Industry Pharmacogenomics Working Group [Internet]: Understanding the Intent, Scope 
and Public Health Benefits of Exploratory Biomarker Research: A Guide for IRBs/IECs 
and Investigational Site Staff. Available at http://i-pwg.org/ 
4.  Industry Pharmacogenomics Working Group [Internet]: Pharmacogenomics 
Informational Brochure for IRBs/IECs and Investigational Site Staff. Available at 
http://i-pwg.org/
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10.7
Appendix 7: Country-specific Requirements
Not applicable
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10.8
Appendix 8: Blood Volume Table
All Participants 
Pre-study
Treatment 
Period
Post-
study
Total 
Collections
mL Per 
Collection
Total 
mL/ Test
Laboratory Safety Tests (all 
participants; includes FSH if 
applicable, β-hCG if applicable, 
and HIV/Hepatitis screen)
2
2
1
5
17
85b
Blood for Genetic Analysis 
0
1
0
1
8.5
8.5
Blood for PBMC ISL-TP
0
11
0
11
16
176
Blood for Plasma ISL
0
16
0
16
4
64
Blood for plasma M4
0
16
0
16
3
48
Total Blood Volume per Participant a
381.5 mL
a. If additional pharmacokinetic/pharmacodynamic and/or safety analysis is necessary, additional blood (up to 50 mL) 
may be obtained. Note: never to exceed 50 mL.
b Total blood volume for laboratory safety tests (including screening tests) throughout the study but may be a lower
volume based on site’s SOP.  Additionally, HIV-1 and HIV-2 and syphilis serologic tests will be done at screening.   
HIV-1 and HIV-2 tests will be done on Day 29. Hepatitis screen is for healthy participants only.
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10.9
Appendix 9: 12-Lead Electrocardiogram Abnormality Criteria
12-Lead Electrocardiogram Abnormality Criteria 
Screen Failure Criteria
Potentially Significant 
Postrandomization Findings 
(clarification on action to take)
RHYTHM
Sinus Tachycardia
110 bpm
HR >110 bpm and HR increase 
of ≥25 bpm from baseline
Sinus Bradycardia
<40 bpm
HR <40 bpm and HR decrease of 
≥5 bpm from baseline
Sinus Pause/Arrest
>2.0 seconds
>2.0 seconds
Atrial Premature Complex
1 beat
3 beats
Ventricular Premature 
Complex
All
3 beats
Ectopic Atrial Rhythm 
None
None
Junctional Rhythm
Junctional Rhythm with HR 
<40 bpm
Junctional Rhythm with HR <40 
bpm
Idioventricular Rhythm
All
All
Atrial Fibrillation
All
All
Atrial Flutter
All
All
Supraventricular Tachycardia
All
All
Ventricular Tachycardia
All
All
AXIS
Left Axis Deviation
RBBB With Left Anterior 
Hemiblock (LAHB)
New Onset LAHB
Right Axis Deviation
RBBB With Left Posterior 
Hemiblock (LPHB)
New Onset LPHB
CONDUCTION
1st Degree AV Block
PR 230 ms
PR 230 ms  + Increase of 15 
ms; or PR Increase of >25%
2nd Degree AV Block
Mobitz Type II
Mobitz Type II
3rd Degree AV Block
All
All
LBBB
All
All
RBBB
RBBB With LAHB/LPHB as 
Defined Above
New Onset RBBB (Not 
Including Rate-related)
Incomplete Right BBB 
(ICRBBB) (QRS <120 ms)
No Exclusion
Nothing
Short PR/ Preexcitation 
Syndrome
Delta Wave + PR <120 ms
Delta Wave + PR <120 ms
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12-Lead Electrocardiogram Abnormality Criteria 
Screen Failure Criteria
Potentially Significant 
Postrandomization Findings 
(clarification on action to take)
Other Intra-Ventricular 
Conduction Delay
QRS 130 ms
QRS 130 ms + Increase of 10 
ms
QTc (B or F)
Male
QTc 470 ms
QTc 500 ms or Increase of 60 
ms From Baseline
Female
QTc 480 ms
QTc 500 ms or Increase of 60 
ms From Baseline
HYPERTROPHY
Atrial Abnormalities
Definite Evidence of P Mitrale 
or P Pulmonale
Definite Evidence of P Mitrale or 
P Pulmonale
Ventricular Abnormalities
Voltage Criteria for LVH Plus 
Strain Pattern
Voltage Criteria  for LVH Plus 
Strain Pattern
MYOCARDIAL INFARCTION
Acute or Recent
All
All
Old
All
All
ST/T MORPHOLOGY
ST Elevation Suggestive of 
Myocardial Injury 
In 2 or more contiguous leads
In 2 or more contiguous leads
ST Depression Suggestive of
Myocardial Ischaemia 
In 2 or more contiguous leads
In 2 or more contiguous leads
T-wave Inversions 
Suggestive of Myocardial 
Ischaemia 
In 2 or more contiguous leads
In 2 or more contiguous leads
Non-specific ST-T Changes 
(In 2 or More Leads)
No exclusion
In 2 or more contiguous leads
PACEMAKER
All
All
Baseline is defined as Predose Day 1; ms=milliseconds, mm=millimeter
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10.10 Appendix 10: Algorithm for Assessing Out of Range Laboratory Values
For all laboratory values obtained at prestudy (screening) visit and/or predose evaluation:
A. If all protocol-specified laboratory values are normal, the participant may enter the study.
B. If a protocol specified laboratory value is outside of the parameter(s) outlined in the 
inclusion/exclusion criteria (including a repeat if performed), the participant will be 
excluded from the study.
C. If ≥1 protocol-specified laboratory value not specified in the inclusion/exclusion criteria 
is outside the normal range, the following choices are available:
1. The participant may be excluded from the study;
2. The participant may be included in the study if the abnormal value(s) is NCS (the 
investigator must annotate the laboratory value “NCS” on the laboratory safety test 
source document).
3. The participant may be included in the study if the abnormality is consistent with a 
pre-existing medical condition which is not excluded per protocol (eg, elevated 
eosinophil count in a participant with asthma or seasonal allergies), the medical
condition should be annotated on the laboratory report.
OR
4. The abnormal test may be repeated (refer items a. and b. below for continuation of 
algorithm for repeated values).
a.   If the repeat test value is within the normal range, the participant may enter the 
study.
b.   If the repeat test value is still abnormal, the study investigator will evaluate the 
potential participant with a complete history and physical examination, looking 
especially for diseases that could result in the abnormal laboratory value in 
question. If such diseases can be ruled out, and if the abnormal laboratory value is 
not clinically relevant, then the participant may enter the study.
D. If there is any clinical uncertainty regarding the significance of an abnormal value, the 
participant will be excluded from the study.
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10.11 Appendix 11: Abbreviations
Abbreviation
Expanded Term
3TC
Lamivudine
ADA
adenosine deaminase
Ae
Amount excreted in urine
AE
adverse event 
AIDS
Acquired immunodeficiency syndrome
ALT 
Alanine aminotransferase
AN
Allocation number
APaT
All participants as Treated
AR
adverse reaction
ART
Anti-retroviral therapy
ARV
Antiretroviral
AST
Aspartate aminotransferase
ATP
adenosine triphosphate
AUC
Area under the concentration-time curve
AUC0-24
Area Under the Curve from time 0 to 24 hours post dose
AUC0-inf
Area Under the Curve from time 0 to infinity
AUC0-last
Area Under the Curve from time 0 to last sampling time post dose
BDS
blood drug screen
β-hCG
β-human chorionic gonadotropin
BMI
body mass index
BP
blood pressure
C24
Concentration at 24 hours post dose
C168
Concentration at 168 hours post dose
C672
Concentration at 672 hours post dose
Cmax
Maximum concentration
CI
confidence interval
CLr
Renal clearance
CL/F
Apparent clearance after extravascular administration
CRF
Case Report Form 
CRU
clinical research unit
CV
coefficient of variation
DAIDS
Division of AIDS
DDI
Drug-drug interaction
DILI
drug-induced liver injury
DOR
Doravirine 
DP
Diphosphate 
DTG
Dolutegravir 
DNA
deoxyribonucleic acid 
ECG
electrocardiogram 
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Abbreviation
Expanded Term
ECI
event of clinical interest
eCRF
electronic Case Report Form
eCTA
exploratory Clinical Trial Application
EDC
electronic data collection 
EMA
European Medicines Agency
FBR
Future biomedical research
FDA
Food and Drug Administration 
FDC
Fixed dose combination
fe
fraction of dose excreted in urine
FSH
follicle stimulating hormone 
GC/CT
Gonorrhea/chlamydia
GCP
Good Clinical Practice 
GCV
geometric coefficient of variation
GGT
Gamma glutamyl transpeptidase
GLP
good laboratory practice
GM
geometric mean
HBsAg
Hepatitis B surface antigen
HBV
Hepatitis B virus
HCV
Hepatitis C virus 
HIV
human immunodeficiency virus
HR
heart rate
HRT
hormone replacement therapy
IB
Investigator’s Brochure 
IC50
50% inhibitory concentration 
ICC
intraclass correlation
ICF
Informed Consent Form
ICH
International Council on Harmonization
IEC
Independent Ethics Committee
I/E
Inclusion/Exclusion
IMP
investigational medicinal product
IND
Investigational New Drug 
INR
International normalized ratio 
IRB
Institutional Review Board
LNG/EE
Levonorgestrel/ethinyl estradiol
ISL
Islatravir
ISL-DP
Islatravir- diphosphate
ISL-TP
Islatravir- triphosphate
MedDRA
Medical Dictionary for Regulatory Activities
M4
metabolite M4
MCV
Mean corpuscular volume
MCH
Mean corpuscular hemoglobin
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Abbreviation
Expanded Term
NIMP
non-investigational medicinal product
NCS
not clinically significant
NOAEL
no observed adverse effect level 
NOEL
No observed effect level
NRTI
Nucleoside reverse transcriptase inhibitor
NNRTI
Non-nucleoside reverse transcriptase inhibitor
NRTTI
Nucleoside reverse transcriptase translocation inhibitor
PBC
Primary Biliary Cirrhosis
PBMC
Peripheral blood mononuclear cell
PK
pharmacokinetic
PP
Per-protocol
PrEP
Pre-exposure prophylaxis
QD
once-daily
QW
once-weekly
QM
Once-monthly
RBC
red blood cell 
RR
Respiratory rate
SAC
Scientific Advisory Committee
SAE
serious adverse event 
SAP
Statistical Analysis Plan
SD
standard deviation 
SGOT
Serum glutamic-oxaloacetic transaminase
SGPT
Serum glutamic-pyruvic transaminase 
SoA
schedule of activities
SOP
Standard operating procedure 
STI
sexually transmitted infection
t1/2
Half-life
TDF
Tenofovir disoproxil fumarate
TK
toxicokinetic
Tmax
time of maximum concentration
TP
Triphosphate
UDS
urine drug screen
VS
vital sign
Vz/F
Apparent volume of distribution during the terminal phase
WBC
white blood cell 
WOCBP
woman/women of childbearing potential 
WONCBP
woman/women of non-childbearing potential
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11
REFERENCES
Not applicable.
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