Clinical trial NCT04303156
Conditions: Human Immunodeficiency Virus (HIV) Infection
Sponsor: Merck Sharp & Dohme LLC
Start date: 2020-06-18; Completion date: 2020-10-19
Enrollment: 12 participants; Allocation: NON_RANDOMIZED; Intervention model: SINGLE_GROUP

Brief summary:
This study will evaluate the general tolerability and pharmacokinetics (PK) of a single 60 mg dose of MK-8591 (Islatravir) in participants with severe renal insufficiency, compared to participants in good health.

Detailed description:

Arms: arm 1: Participants with severe renal impairment received a single oral dose of 60 mg MK-8591 (Islatravir) administered in capsule form. arm 2: Healthy participants received a single oral dose of 60 mg Islatravir administered in capsule form.
Interventions: intervention 1: Islatravir
Intervention descriptions: intervention 1: Single oral dose of 60 mg Islatravir administered in capsule form

Protocol documents:
Prot_SAP_000.pdf: 
Official Protocol Title: 
NCT number: 
NCT04303156  
Document Date: 
24-JUN-2020
An Open-Label, Single-Dose Study to Evaluate the 
Pharmacokinetics of Islatravir (MK-8591) in Subjects with Severe 
Renal Impairment


PRODUCT: MK-8591  
1
PROTOCOL/AMENDMENT NO.: 026-02 
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24-JUN-2020
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 Subjects with Severe Renal Impairment
This protocol amendment is applicable only to Germany.
Protocol Number: 026-02
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
EudraCT
2020-000153-27
Approval Date: 24 June 2020
 
 
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Sponsor Signatory
Typed Name:
Title:
Date
Protocol-specific Sponsor contact information can be found in the Investigator Study
File Binder (or equivalent).
Investigator Signatory
I agree to conduct this clinical study in accordance with the design outlined in this protocol 
and to abide by all provisions of this protocol.
Typed Name:
Title:
Date
 
 
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DOCUMENT HISTORY
Document
Date of Issue
Overall Rationale
Amendment -02
24-Jun-2020
Inclusion criteria were clarified to define ‘good health’ with respect to blood pressure 
limits and laboratory values for healthy and renally impaired participants (country 
specific, Germany only).
Amendment -01 
19-May-2020
Exclusion criteria and ECG abnormality criteria to adjust the threshold value of QTc for 
all participants and adjust the upper limit of heart rate for healthy participants were 
modified. The eGFR threshold for healthy participants was also adjusted to align with 
the European guidance and the CKD-EPI equation will be used for all participants.  
Exclusion criteria was also added to ensure enrolled subjects are at low risk for HIV 
infection (country specific, US only).  
Original Protocol
10-Feb-2020
Not applicable
 
 
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PROTOCOL AMENDMENT SUMMARY OF CHANGES 
Amendment: 02
Overall Rationale for the Amendments:
Inclusion criteria were clarified to define ‘good health’ with respect to blood pressure limits and laboratory values for healthy and 
renally impaired participants (country specific, Germany only).
Summary of Changes Table:
Section # and Name
Description of Change 
Brief Rationale 
Section 5.1.1 Inclusion 
Criteria for Healthy 
Participants,
Section 5.1.2 Inclusion 
Criteria for Renally 
Impaired Participants
Clarify that the inclusion criteria apply to all healthy or 
renally impaired participants and additional inclusion 
criteria that apply to Germany only can be found in 
Appendix 7 Country Specific Requirements.
Country specific requirements have been 
added for Germany only.
Section 10.7 Country 
Specific Requirements
Define good health in inclusion # 1 and #2 for healthy
participants as follows: 
With respect to blood pressure, “good health” is defined 
as systolic blood pressure not more than 139 mm Hg and 
the diastolic blood pressure not more than 89 mm Hg.
With respect to specific laboratory results, “good health” 
is defined so that ALT, AST, and bilirubin values (except 
if consistent with Gilbert’s disease) should not exceed the 
upper limit of normal (ULN); any other abnormal 
laboratory parameters must be considered not clinically 
significant.
Inclusion criteria was clarified to define 
‘good health’ with respect to blood pressure 
limits and laboratory values for healthy and 
renally impaired participants (country 
specific, Germany only).
 
 
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Section # and Name
Description of Change 
Brief Rationale 
Define good health in inclusion # 1 and #2 for renally 
impaired participants as follows: 
With respect to blood pressure, “good health” is defined 
as systolic blood pressure not more than 160 mm Hg and 
diastolic blood pressure not more than 100 mm Hg.
With respect to specific laboratory results, “good health” 
is defined so that only clinically significant lab 
abnormalities associated with renal disease are acceptable; 
any other abnormal laboratory parameters must be 
considered not clinically significant for inclusion.
 
 
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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..........................................................................................................21
2.1
Study Rationale....................................................................................................21
2.2
Background ..........................................................................................................21
2.2.1
Pharmaceutical and Therapeutic Background .............................................21
2.2.2
Preclinical and Clinical Studies ...................................................................22
2.2.3
Ongoing Clinical Studies.............................................................................23
2.3
Benefit/Risk Assessment......................................................................................24
3
HYPOTHESES, OBJECTIVES, AND ENDPOINTS................................................24
4
STUDY DESIGN............................................................................................................25
4.1
Overall Design......................................................................................................25
4.2
Scientific Rationale for Study Design.................................................................26
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 .............................................29
4.3
Justification for Dose...........................................................................................29
4.4
Beginning and End of Study Definition .............................................................29
4.4.1
Clinical Criteria for Early Study Termination .............................................30
5
STUDY POPULATION ................................................................................................30
5.1
Inclusion Criteria.................................................................................................30
5.1.1
Inclusion Criteria for Healthy Participants ..................................................30
5.1.2
Inclusion Criteria for Renally Impaired Participants...................................32
5.2
Exclusion Criteria................................................................................................34
5.2.1
Exclusion Criteria for Healthy Participants .................................................34
 
 
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5.2.2
Exclusion Criteria for Renally Impaired Participants..................................36
5.3
Lifestyle Considerations......................................................................................38
5.3.1
Meals and Dietary Restrictions....................................................................38
5.3.2
Caffeine, Alcohol, and Tobacco Restrictions ..............................................38
5.3.2.1
Caffeine Restrictions..........................................................................38
5.3.2.2
Alcohol Restrictions...........................................................................39
5.3.2.3
Smoking Restrictions.........................................................................39
5.3.3
Activity Restrictions ....................................................................................39
5.4
Screen Failures.....................................................................................................39
5.5
Participant Replacement Strategy......................................................................39
6
STUDY INTERVENTION............................................................................................40
6.1
Study Intervention(s) Administered...................................................................40
6.2
Preparation/Handling/Storage/Accountability .................................................42
6.2.1
Dose Preparation..........................................................................................42
6.2.2
Handling, Storage, and Accountability........................................................42
6.3
Measures to Minimize Bias: Randomization and Blinding..............................43
6.3.1
Intervention Assignment..............................................................................43
6.3.2
Stratification.................................................................................................43
6.3.3
Blinding........................................................................................................43
6.4
Study Intervention Compliance..........................................................................43
6.5
Concomitant Therapy..........................................................................................43
6.5.1
Rescue Medications and Supportive Care ...................................................44
6.6
Dose Modification (Escalation/Titration/Other)...............................................45
6.6.1
Stopping Rules.............................................................................................45
6.7
Intervention After the End of the Study............................................................45
6.8
Clinical Supplies Disclosure................................................................................45
7
DISCONTINUATION OF STUDY INTERVENTION AND PARTICIPANT 
WITHDRAWAL............................................................................................................45
7.1
Discontinuation of Study Intervention...............................................................45
7.2
Participant Withdrawal From the Study...........................................................45
7.3
Lost to Follow-up .................................................................................................46
8
STUDY ASSESSMENTS AND PROCEDURES........................................................46
8.1
Administrative and General Procedures ...........................................................47
8.1.1
Informed Consent.........................................................................................47
8.1.1.1
General Informed Consent.................................................................47
8.1.1.2
Consent and Collection of Specimens for Future Biomedical 
Research.............................................................................................47
8.1.2
Inclusion/Exclusion Criteria ........................................................................48
 
 
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8.1.3
Participant Identification Card.....................................................................48
8.1.4
Medical History ...........................................................................................48
8.1.5
Prior and Concomitant Medications Review...............................................48
8.1.5.1
Prior Medications...............................................................................48
8.1.5.2
Concomitant Medications..................................................................48
8.1.6
Assignment of Screening Number...............................................................48
8.1.7
Assignment of Treatment/Randomization Number.....................................49
8.1.8
Study Intervention Administration ..............................................................49
8.1.8.1
Timing of Dose Administration.........................................................49
8.1.9
Discontinuation and Withdrawal .................................................................49
8.1.9.1
Withdrawal From Future Biomedical Research ................................50
8.1.10
Participant Blinding/Unblinding..................................................................50
8.1.11
Domiciling ...................................................................................................50
8.1.12
Calibration of Equipment.............................................................................50
8.2
Efficacy/Immunogenicity Assessments ..............................................................51
8.3
Safety Assessments...............................................................................................51
8.3.1
Physical Examinations.................................................................................51
8.3.2
Vital Signs....................................................................................................51
8.3.2.1
Resting Vital Signs ............................................................................52
8.3.3
Electrocardiograms ......................................................................................52
8.3.4
Clinical Safety Laboratory Assessments .....................................................53
8.4
Adverse Events, Serious Adverse Events, and Other Reportable Safety 
Events....................................................................................................................54
8.4.1
Time Period and Frequency for Collecting AE, SAE, and Other 
Reportable Safety Event Information ..........................................................54
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...56
8.4.4
Regulatory Reporting Requirements for SAE .............................................56
8.4.5
Pregnancy and Exposure During Breastfeeding ..........................................56
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............................................................................57
8.5
Treatment of Overdose........................................................................................57
8.6
Pharmacokinetics.................................................................................................57
8.6.1
Blood Collection for Plasma ISL and PBMC ISL-TP.................................57
8.7
Pharmacodynamics..............................................................................................58
8.8
Biomarkers ...........................................................................................................58
8.8.1
Planned Genetic Analysis Sample Collection..............................................58
 
 
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8.9
Future Biomedical Research Sample Collection...............................................58
8.10
Visit Requirements...............................................................................................58
8.10.1
Screening......................................................................................................58
8.10.2
Treatment Period..........................................................................................59
8.10.3
Discontinued Participants Continuing to be Monitored in the Study ..........59
8.10.4
Poststudy......................................................................................................59
8.10.5
Critical Procedures Based on Study Objectives: Timing of Procedure.......59
8.10.6
Study Design/Dosing/Procedures Modifications Permitted Within 
Protocol Parameters .....................................................................................60
9
STATISTICAL ANALYSIS PLAN .............................................................................61
9.1
Statistical Analysis Plan Summary.....................................................................61
9.2
Responsibility for Analyses.................................................................................62
9.3
Hypotheses/Estimation ........................................................................................62
9.4
Analysis Endpoints...............................................................................................62
9.5
Analysis Populations............................................................................................63
9.6
Statistical Methods...............................................................................................63
9.7
Interim Analyses ..................................................................................................65
9.8
Multiplicity ...........................................................................................................65
9.9
Sample Size and Power Calculations .................................................................65
10
SUPPORTING DOCUMENTATION AND OPERATIONAL
CONSIDERATIONS.....................................................................................................66
10.1
Appendix 1: Regulatory, Ethical, and Study Oversight Considerations........66
10.1.1
Code of Conduct for Clinical Trials.............................................................66
10.1.2
Financial Disclosure.....................................................................................68
10.1.3
Data Protection.............................................................................................68
10.1.3.1
Confidentiality of Data ......................................................................69
10.1.3.2
Confidentiality of Participant Records...............................................69
10.1.3.3
Confidentiality of IRB/IEC Information............................................69
10.1.4
Publication Policy........................................................................................69
10.1.5
Compliance with Study Registration and Results Posting Requirements ...70
10.1.6
Compliance with Law, Audit, and Debarment ............................................70
10.1.7
Data Quality Assurance ...............................................................................71
10.1.8
Source Documents .......................................................................................72
10.1.9
Study and Site Closure.................................................................................72
10.2
Appendix 2: Clinical Laboratory Tests..............................................................73
10.3
Appendix 3: Adverse Events: Definitions and Procedures for Recording, 
Evaluating, Follow-up, and Reporting...............................................................74
10.3.1
Definition of AE ..........................................................................................74
 
 
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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: Device Events, Adverse Device Events, and Medical Device 
Incidents: Definitions, Collection, and Documentation....................................82
10.5
Appendix 5: Contraceptive Guidance................................................................83
10.5.1
Definitions....................................................................................................83
10.5.2
Contraception Requirements........................................................................84
10.6
Appendix 6: Collection and Management of Specimens for Future 
Biomedical Research............................................................................................85
10.7
Appendix 7: Country-specific Requirements....................................................90
10.7.1
Country-specific Requirements - Germany .................................................90
10.7.2
Country-specific Requirements – US ..........................................................91
10.8
Appendix 8: Blood Volume Table ......................................................................93
10.9
Appendix 9: 12-Lead Electrocardiogram Abnormality Criteria ....................94
10.10 Appendix 10: Algorithm for Assessing Out of Range Laboratory Values .....96
10.11 Appendix 11: Abbreviations ...............................................................................97
11
REFERENCES.............................................................................................................100
 
 
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LIST OF TABLES
Table 1
Population PK Modeling Projections for ISL Levels After 60 mg............27
Table 2
Population PK Modeling Projection of ISL Levels After 0.75 mg QD 
Dosing ......................................................................................................29
Table 3
Study Interventions....................................................................................41
Table 4
Allocation of Subjects to Treatment ..........................................................43
Table 5
Reporting Time Periods and Time Frames for Adverse Events and 
Other Reportable Safety Events ...............................................................55
Table 6
Pharmacokinetic (Blood) Collection Windows .........................................59
Table 7
Protocol-required Safety Laboratory Assessments....................................73
 
 
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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 Subjects with Severe Renal Impairment
Short Title: Islatravir (MK-8591, ISL) Renal Impairment Study 
Acronym: Not applicable 
Hypotheses, Objectives, and Endpoints:
Hypotheses are aligned with objectives in the Objectives and Endpoints table.
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 subjects with severe renal impairment 
compared to healthy control subjects.
Estimation: In subjects with severe renal 
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 subjects.
- 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 subjects with severe renal 
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 subjects with renal 
impairment compared to healthy control 
subjects.
- AUC0-∞, AUC0-last, Cmax, C24, C168, 
C672, Tmax, and apparent terminal t½ of 
ISL-TP in PBMC 
 
 
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Tertiary/Exploratory Objectives
Tertiary/Exploratory Endpoints
- To evaluate the plasma pharmacokinetics 
of the metabolite M4 (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 subjects with 
severe renal impairment compared to 
healthy control subjects.
- AUC0-∞, AUC0-last, Cmax, Tmax, 
apparent terminal t½, CL/F, and Vz/F of 
plasma M4
- To explore the relationship between 
genetic variation and response to the 
treatment administered. Variation across 
the human genome will be analyzed for 
association with clinical data collected in 
this study.
- Germline genetic variation
Overall Design:
Study Phase
Phase 1
Primary Purpose
Treatment
Indication
Treatment of HIV Infection
Population
Participants with Severe Renal Impairment and Healthy 
Participants 
Study Type
Interventional
Intervention Model
Single Group
This is a multi-site study.
Type of Control
Healthy matched control subjects
Study Blinding
Unblinded Open-label
Blinding Roles
No Blinding
Estimated Duration of Study
The Sponsor estimates that the study will require 
approximately 5 months from the time the first participant 
signs the informed consent until the last participant’s last 
study-related telephone call or visit.
 
 
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Number of Participants:
Approximately 12 participants will be randomized.
Intervention Groups and Duration:
Interven-
tion Groups
Intervention 
Group Name
Drug
Dose 
Strength
Dose 
Frequency
Route of 
Administration
Use
Severe Renal 
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
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
Insert Other Oversight 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
3
4
5
6
8
Scheduled Hour
Screening 
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
X
Prior/Concomitant Medication Review
X
X
X --------------------------------------------------------------------X
Assignment of Screening Number 
X
Assignment of Treatment Number
X
Site will follow local 
SOP for the timing of 
treatment allocation.
Domiciling 
X---------------------------------------------------------------------X
Refer to Section 8.1.11
MK-8591 (ISL) Administration
X
Safety Procedures
Full physical examination (PE)
X
Xa
Symptom-driven PE 
may be performed at 
other times, at the 
Investigator’s 
discretion.
Height
X
Weight
X
Vital Signs (heart rate, blood pressure)
X
X
X
X
Refer to Section 8.3.2
Respiratory Rate
X
X
Body Temperature
X
X
 
 
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All Participants
Intervention
Notes
Scheduled Day 
1
2
3
4
5
6
8
Scheduled Hour
Screening 
Pre-
dose 0 0.25 0.5 1
2
4
6
8 12 24 36 48 72 96 120 168
12-lead ECG
X
X
X
X
Refer to Section 8.3.3
HIV, hepatitis B and C screen (per site 
SOP)
X
Serum/urine β-Human Chorionic 
Gonadotropin (β-hCG)
X
X
Required for WOCBP.  
Serum or urine β-hCG 
at predose (per site 
SOP). Serum β-hCG 
required at Screening.
Serum Follicle Stimulating Hormone 
(FSH)
X
For WONCBP.
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.  
Hematology, urinalysis, and chemistry
X
Xa
X
X
AE/SAE review
X
X
X---------------------------------------------------------------------X
Pharmacokinetics/Biomarkers 
Blood Collection for Plasma ISL in Severe 
Renal Impairment Group
Xa
X
X
X X X X X X
X
X
X
X
X
X
X
Blood collection for M4 metabolite in 
Severe Renal Impairment Group
Xa
X
X
X X X X X X
X
X
X
X
X
X
X
Blood for PBMC ISL-TP in Severe Renal 
Impairment Group
Xa
X
X
X
X
X
Blood Collection for Plasma ISL in 
Healthy Control Group
Xa
X
X
X X X X X X
X
X
X
X
X
X
Blood collection for M4 metabolite in 
Healthy Control Group
Xa
X
X
X X X X X X
X
X
X
X
X
X
Blood for PBMC ISL-TP in Healthy 
Control Group
Xa
X
X
X
X
X
Blood for Genetic Analysisb
X
 
 
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All Participants
Intervention
Notes
Scheduled Day 
1
2
3
4
5
6
8
Scheduled Hour
Screening 
Pre-
dose 0 0.25 0.5 1
2
4
6
8 12 24 36 48 72 96 120 168
a. Pre-dose PE, urine drug screen, safety labs, and blood sample for plasma ISL/M4 metabolite/PBMC ISL-TP can be conducted 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. This sample should be drawn for planned analysis of the association between genetic variants in DNA and drug response. This sample will not be collected at the site if there is 
either a local law or regulation prohibiting collection, or if the IRB/IEC does not approve the collection of the sample for these purposes. If the sample is collected, leftover 
extracted DNA will be stored for future biomedical research if the participant signs the future biomedical research consent. If the planned genetic analysis is not approved, but 
future biomedical research is approved and consent is given, this sample will be collected for the purpose of future biomedical research.  
*Please refer to Appendix 7 Country Specific Requirements for screening tests that are applicable to the US only.
 
 
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Intervention 
Notes 
Scheduled Day 
11
15
18
22
Post-
trial 
visit/D
ay 29 c
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
Pharmacokinetics 
Blood for PBMC ISL-TP PK in Severe Renal Impairment 
Group
X
X
X
X
X
Blood for PBMC ISL-TP PK in Healthy Control Group
X
X
X
X
X
c. Post-trial study procedures will be conducted on Day 29 of the study
*Please refer to Appendix 7 Country Specific Requirements for screening tests that are applicable to the US only.
 
 
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PRODUCT: MK-8591  
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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 who are at 
high risk of becoming infected. Currently, ISL is being evaluated in a Phase 2 trial at a dose 
of 0.75 mg QD (in combination with 100 mg doravirine, DOR; NCT03272347), 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
This Phase 1 study will evaluate the general tolerability and pharmacokinetics (PK) of a 
single 60 mg dose of ISL in participants with severe renal insufficiency, compared to 
participants in good health.
2.2
Background
Refer to the IB for detailed background information on 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 
regimens and long-acting formulations that potentially allow for less frequent dosing, are 
attempting to address these needs in order to improve adherence and outcomes for patients.
Islatravir is differentiated from other ARVs because of its high potency, long half-life, 
favorable drug resistance profile and broad pharmacological distribution.  Because of these 
properties, ISL is well-suited as a compound to be delivered in less frequent dosing regimens.  
Understanding the effect of intrinsic factors, such as renal insufficiency, on ISL is an 
important aspect of clinical development of the compound.
2.2.1
Pharmaceutical and Therapeutic Background
Islatravir is a highly potent HIV-1 NRTTI. Unlike conventional NRTIs, ISL acts via 
multiple mechanisms, leading to both immediate and delayed chain termination.  The 
inactive parent is phosphorylated to the active ISL-TP in PBMCs and other cells.  In in vitro
studies in PBMCs, ISL-TP demonstrated antiviral activity, with an IC50 of 0.21 nM, while 
other NRTIs demonstrated IC50s ranging from 10.1 to 144 nM.  ISL demonstrates a favorable 
mutant selection profile compared to other NRTIs, selecting only for the M184V/I mutant, 
against which ISL is active but with a decrease in sensitivity of 7.3- to 9.5-fold.
 
 
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CCI


PRODUCT: MK-8591  
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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.
Urine samples were collected for the PK assessment of ISL and to evaluate urinary excretion 
of intact ISL in healthy subjects in three Phase I studies (P002, P003, P009). Following 
multiple-dose administration with increasing dose from 0.75 mg to 5 mg ISL QD (P009), 
GM Ae and fe of urine ISL increased with repeated administration within the 0.75 and 5 mg 
dose levels, whereas GM CLr values appeared similar. Urine fe (fraction excreted) levels 
ranged from 27-40% at steady state.
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 three ongoing studies involving oral ISL.  
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 subjects were dosed in November 2019.
Protocol 015 (P015) is a multiple panel double-blind placebo-controlled trial in 64 healthy 
adult Japanese males, examining PK and general safety and tolerability of ISL up to 30 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 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 subjects on DOR/3TC/TDF throughout the study period.  
As of 30-Sep-2019, ISL has been administered to ~90 HIV-1 positive individuals for at least 
48 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 
 
 
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who received any dose of ISL, there was no specific drug-related AE that occurred in more 
than 5% of the participants.  
Five participants reported 7 SAEs, of which only one was considered drug-related.  This was 
in a subject who received DOR/3TC/TDF (therefore not receiving ISL), who had a 
worsening of congenital long QT syndrome; this subject withdrew from the study and the 
event resolved.  Two additional subjects discontinued study medication due to a drug-related 
AE.  Both of these subjects initially received ISL (2.25 mg)/DOR/3TC; one subject 
discontinued because of diarrhea, nausea and vomiting, and the other discontinued due to 
Hepatitis B reactivation.
Of note, enrollment in P011 is open to PLWH with mild renal impairment (CrCL >50 
mL/min).  Five individuals receiving ISL had screening eGFRs ranging from 50-90 mL/min.  
In exploratory analysis of potential covariates on PK from P011, CrCL does not appear to be 
a significant covariate.  Given the low number of participants with mild renal insufficiency in 
P011, no conclusions can be drawn yet regarding safety and tolerability in this population.
2.3
Benefit/Risk Assessment
Participants in this clinical study 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
Hypotheses are aligned with objectives in the Objectives and Endpoints table.
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 subjects with severe renal impairment 
compared to healthy control subjects.
Estimation: In subjects with severe renal 
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 subjects.
•
AUC0-∞, AUC0-last, Cmax, Tmax, 
apparent terminal t½, CL/F, and 
Vz/F of plasma ISL
 
 
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Objectives
Endpoints
Secondary
•
To evaluate the safety and tolerability of ISL
in subjects with severe renal 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 subjects with renal impairment 
compared to healthy control subjects.
•
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, Tmax, apparent terminal t½, 
CL/F, and Vz/F) after a single oral dose of 
60 mg ISL in subjects with severe renal 
impairment compared to healthy control 
subjects.
•
AUC0-∞, AUC0-last, Cmax, Tmax, 
apparent terminal t½, CL/F, and 
Vz/F of plasma M4
•
To explore the relationship between genetic 
variation and response to the treatment 
administered. Variation across the human 
genome will be analyzed for association with 
clinical data collected in this study.
•
Germline genetic variation
4
STUDY DESIGN
4.1
Overall Design
This is an open-label, single-dose, multi-site study in subjects with severe renal impairment 
(N=6) and healthy mean matched controls (N=6).  Once all subjects with severe renal 
impairment are enrolled, the healthy matched control subjects will be enrolled. Individual age 
and weight of healthy matched control subjects will be within the range ± 10 years and ± 10 
kg of the mean age and weight of subjects with severe renal impairment.  In addition, the 
numbers of males and females of the healthy subjects will be generally matched to the 
numbers of renal insufficient subjects within ± 1.
 
 
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Assignment to a renal function group will be as follows:
Impairment Stage 
N
eGFR (mL/min/1.73 m2)a
Severe
6
< 30, not on dialysisb
Healthy 
6
≥ 90
a
eGFR based on the CKD-EPI equation. Baseline eGFR will be obtained twice (at least 72 hours apart as part of 
subject screening) and the mean of the two values will be used. The second baseline eGFR sample may be 
obtained at the time of check-in.
b
Reasonable efforts will be made to enroll 1-2 subjects in the severe renal impairment group who have eGFR 
values of 10 - 20 mL/min/1.73 m2.
On Day 1, subjects will receive a single oral dose of 60 mg (6 x 10 mg capsules) ISL, 
followed by PK sampling until 120 hours postdose (healthy control group) or 168 hours 
postdose (severe renal impairment group).  There will be additional visits at hours 168, 240, 
336, 408, 504, 672 postdose for the collection of PBMCs.  Safety will be monitored 
throughout the study by repeated clinical and laboratory evaluations.
Because this is a Phase 1 assessment of ISL 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 8.10.6 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.
4.2
Scientific Rationale for Study Design
As the HIV+ population ages, more persons living with HIV (PLWH) will accumulate co-
morbidities, including chronic medical conditions such as diabetes and hypertension that can 
lead to renal insufficiency.  Existing preclinical and clinical data suggest that renal excretion
of unchanged parent is a major mode of elimination for ISL, and therefore it seems likely that 
individuals with renal insufficiency may have higher levels of ISL and perhaps ISL-TP as 
well.  Given the wide dose ranges throughout development noted above (0.25-400 mg), along 
with favorable preclinical toxicity studies and an excellent clinical tolerability profile to date, 
a potential increase in ISL in renally insufficient subjects is not anticipated to be clinically 
meaningful.
In this trial, PK of ISL in subjects with severe renal insufficiency are being compared to the 
PK in generally healthy study participants.  Confirmation of the expected elevation in ISL 
levels, along with adequate tolerability, in subjects with severe renal insufficiency would 
support not assessing subjects with mild and moderate renal insufficiency in this trial.  Based 
on preclinical and clinical PK to date, it is expected that ISL parent levels will increase only 
modestly (5% for Cmax, ~50% for AUC) in subjects with severe renal insufficiency relative 
 
 
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to healthy study participants (see Table 1 for levels projected using population PK modeling), 
while ISL-TP levels will increase as well.  For comparison, the NOAEL from preclinical 
chronic toxicity studies is 118 µM*hr (0-168hr), which provides a ~10x exposure margin to 
the levels expected in subjects with severe renal insufficiency.  As noted, doses up to 400 mg 
(which leads to an AUC of 47.1 µM*hr, or a 4x exposure margin) have been generally well 
tolerated, and to date no dose-related AEs have been observed; thus, a modest increase in ISL 
levels is not likely to lead to clinically significant effects.  In addition, any increase in ISL-TP 
is not expected to have an adverse effect on efficacy. Such relatively modest increases in ISL 
and ISL-TP in subjects with severe renal insufficiency would suggest that there would be an 
even more modest effect in subjects with mild or moderate renal insufficiency.
Table 1
Population PK Modeling Projections for ISL Levels After 60 mg.
Dose
Cmax (µM)
AUC (µM*hr)
60 mg x1
1.01
7.42 (0-inf)
60 mg (severe renal insufficiency)
1.06
11.19 (0-inf)
4.2.1
Rationale for Endpoints
4.2.1.1
Efficacy Endpoints
No efficacy endpoints will be evaluated.
4.2.1.2
Safety Endpoints
Multiple trials have evaluated oral ISL in human subjects, including a Phase 1 trial with 
single doses as high as 400 mg and Phase 2 trial in which subjects have received daily doses 
of up to 2.25 mg ISL for at least 48 weeks.  To date, oral ISL appears generally well 
tolerated, and there have been no concerning safety signals from oral ISL administration.  As 
such, standard safety monitoring of adverse events, 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, should be adequate to assess tolerability of 
ISL in this trial.
4.2.1.3
Pharmacokinetic Endpoints
The primary endpoints for this study will include the pharmacokinetic parameters of AUC0-
∞, AUC0-last, Cmax, Tmax, apparent terminal t½, CL/F, and Vz/F of plasma ISL.  The
pharmacokinetic parameters AUC0-∞, AUC0-last, Cmax, C24, C168, C672, Tmax, and 
apparent terminal t½ of ISL-TP in PBMC will be included as secondary endpoints. These 
parameters correspond to the systemic PK of ISL and ISL-TP, respectively, following a 
single dose of ISL.  Assessment of these PK parameters for both ISL and ISL-TP has been 
consistently performed throughout the entire Phase 1 clinical development program.
As ISL is subject to renal clearance, the plasma concentration may be higher in renally
impaired subjects. Plasma PK parameters included in the primary endpoints will be evaluated
 
 
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and compared between healthy and renally impaired subjects, using geometric mean ratio 
(GMR) and confidence interval (CI) to assess differences between the two groups. 
In addition to assessing parent ISL levels, ISL-TP PK parameters will be evaluated as 
secondary endpoints in healthy and renally impaired subjects. This will allow a more 
complete understanding of ISL-TP levels in this population.  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 renally 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, PK parameters of M4, the major circulating metabolite of ISL, will be evaluated 
as exploratory endpoints in healthy study participants and in the renally impaired subjects.  
As with ISL-TP, there is no a priori reason to expect M4 levels to not continue to track at 
~30-40% of ISL levels in plasma in healthy subjects.  This assessment, however, will allow 
determination of M4 plasma concentrations in renally insufficient subjects.
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 future biomedical research on DNA specimens for which consent 
was provided during this clinical study.
 
 
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Such research is for biomarker testing to address emergent questions not described elsewhere 
in the protocol (as part of the main study) and will only be conducted on specimens from 
appropriately consented participants. The objective of collecting/retaining specimens for 
future biomedical research is to explore and identify biomarkers that inform the scientific 
understanding of diseases and/or their therapeutic treatments. The overarching goal is to use 
such information to develop safer, more effective drugs/vaccines, and/or to ensure that 
participants receive the correct dose of the correct drug/vaccine at the correct time. The 
details of future biomedical research are presented in Appendix 6.
4.2.2
Rationale for the Use of Comparator/Placebo
Not applicable 
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.  As 
noted above, doses of 60 mg and 120 mg are being evaluated in the Phase 2 general 
tolerability and PK trial.  A dose of 60 mg is being considered for future 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 renal insufficiency are not likely to vary with dose.  Based on the 
assessment of urine excretion to date, an increase of ~50% is expected in ISL plasma levels
in subjects with severe renal insufficiency.  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.  As shown below (Table 2), the 
expected effect of severe renal insufficiency after QD dosing would lead to increases in ISL 
levels similar in magnitude to those expected after single dose administration (Table 1).
Table 2
Population PK Modeling Projection of ISL Levels After 0.75 mg QD Dosing
Dose
Cmax (µM)
AUC (µM*hr)
0.75 mg QD (steady state)
0.013
0.094 (0-24hr)
0.75 mg QD (steady state, severe renal insufficiency)
0.017
0.146 (0-24hr)
As this is a Phase 1 assessment of ISL 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 8.10.6.
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).
 
 
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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 severe renal impairment between the ages of 18 and 75
(inclusive) and healthy matched controls will be enrolled in this study.
The individual age and weight of the healthy subjects is aimed to be within the
range ± 10 years and ± 10 kg of the mean age and weight of subjects with renal impairment.  
In addition, the numbers of males and females of the healthy subjects will be generally 
matched to the numbers of renal insufficient subjects within ± 1; i.e., if there are 3 males and 
3 females in the renal insufficient group, every effort will be made to ensure a 3:3 ratio in the 
healthy subjects, 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.  Additional inclusion 
criteria that apply to Germany only can be found in Appendix 7 Country Specific 
Requirements.  
Type of Participant and Disease Characteristics 
A participant will be eligible for inclusion in the study if the participant: 
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 study drug administration. Appendix 2 provides a table of laboratory safety tests to be 
 
 
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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.
4. Have a baseline eGFR ≥ 90 mL/min/1.73 m2 based on eGFR equation from CKD-EPI at 
screening:
The CKD-EPI equation is defined as follows:
CKD-EPI Equation:
eGFR = 141 × min (Scr /κ, 1)α × max(Scr /κ, 1)-1.209 × 0.993Age × 1.018 [if female] × 1.159 
[if African American]
Baseline eGFR will be obtained twice (at least 72 hours apart as part of subject
screening), and the mean of the two values will be used. The second baseline eGFR 
sample may be obtained at the time of check-in.
Participants who have an eGFR of up to 10% below 90 mL/min/1.73m2 may be enrolled 
in the study at the discretion of the investigator.
Demographics 
5. 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
 
 
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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 drug administration. 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].
•
The investigator is responsible for review of medical history, menstrual history, and 
recent sexual activity to decrease the risk for inclusion of a woman with an early 
undetected pregnancy.
Informed Consent
6. The participant 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 Renally Impaired Participants
The following inclusion criteria apply to all renally impaired participants.  Additional 
inclusion criteria that apply to Germany only can be found in Appendix 7 Country Specific 
Requirements.
A participant will be eligible for inclusion in the study if the participant:
Type of Participant and Disease Characteristics
1. With the exception of renal 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, 
including but not limited to hypertension, hypercholesterolemia, non-insulin dependent 
diabetes mellitus, hyper- or hypothyroidism, gout, and chronic anxiety or depression 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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2. With the exception of renal 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.  
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.
4. Have a baseline eGFR < 30 mL/min/1.73 m2 based on eGFR equation from CKD-EPI at 
screening.
The CKD-EPI equation is defined as follows:
CKD-EPI Equation:
eGFR = 141 × min (Scr /κ, 1)α × max(Scr /κ, 1)-1.209 × 0.993Age × 1.018 [if female] × 1.159 
[if African American]
Baseline eGFR will be obtained twice (at least 72 hours apart as part of subject
screening), and the mean of the two values will be used. The second baseline eGFR 
sample may be obtained at the time of check-in.
Reasonable efforts will be made to enroll an adequate number of subjects (1-2 subjects) 
in the severe renal impairment group who have eGFR values of 10 - 20 mL/min/1.73 m2
Demographics
5. 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
 
 
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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 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].
•
The investigator is responsible for review of medical history, menstrual history, and 
recent sexual activity to decrease the risk for inclusion of a woman with an early 
undetected pregnancy.
Informed Consent
6.
The participant 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.  Additional exclusion
criteria that apply to the US only can be found in Appendix 7 Country Specific 
Requirements. 
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.
 
 
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2. Is institutionalized or 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 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.
4. Has known hypersensitivity to the active substance or any of the excipients of the study 
drug.
5. Is positive for hepatitis B surface antigen, hepatitis C antibodies or HIV.
6. 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
7. 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
8. 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 
9. Has a QTc interval >450 for males or >460 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 
10. Is under the age of legal consent.
11. Is a smoker or user of electronic cigarettes, or has used nicotine or nicotine-containing 
products (eg, nicotine patch) within 3 months of screening.
 
 
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12. Consumes greater than 1 glass of alcoholic beverage or equivalent per day (12 g/d) for 
females and 2 glasses of alcoholic beverages or equivalent per day (24 g/d) for males
(Note - 1 glass is approximately equivalent to: beer [354 mL/12 ounces], wine [118 mL/4 
ounces], or distilled spirits [29.5 mL/1 ounce]). Participants who consume more than the 
daily limit may be enrolled at the discretion of the investigator.
13. 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.
14. Is a regular user of cannabis or any illicit drugs or has a history of drug (including 
alcohol) abuse within approximately 2 years. Participants must have a negative drug 
screen prior to randomization.
15. 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.
16. Is unwilling to comply with the study restrictions (see Section 5.3 for a complete 
summary of study restrictions).
17. 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 Renally Impaired Participants
The following exclusion criteria apply to all renally impaired participants.  Additional 
exclusion criteria that apply to the US only can be found in Appendix 7 Country Specific 
Requirements.
The participant must be excluded from the study if the participant:
Medical Conditions
1. Has a history or presence of renal artery stenosis.
2. Has had a renal transplant or nephrectomy.
3. Has rapidly fluctuating renal function as determined by historical measurements. Rapidly 
fluctuating renal function is defined as > 30% difference between two measurements of 
eGFR taken at least 72 hour apart as part of subject screening.
4. 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 subject by their participation in the 
study.
5. Is institutionalized or mentally or legally incapacitated at the time of prestudy (screening) 
visit or expected during the conduct of the study.
 
 
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6. 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).
7. 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.
8. Has known hypersensitivity to the active substance or any of the excipients of the study 
drug.
9. Is positive for hepatitis B surface antigen, hepatitis C antibodies or HIV.
10. 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
11. Is taking medications to treat chronic medical conditions and/or conditions associated 
with renal disease and has not been on a stable regimen 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 subjects in 
whom a medication regimen has been adjusted within the three-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
12. 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
13. Has a QTc interval >450 for males or >460 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
14. Is under the age of legal consent.
15. Does not agree to follow the smoking restrictions as defined by the CRU.
 
 
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16. Consumes greater than 1 glass of alcoholic beverage or equivalent per day (12 g/d) for 
females and 2 glasses of alcoholic beverages or equivalent per day (24 g/d) for males
(Note - 1 glass is approximately equivalent to: beer [354 mL/12 ounces], wine [118 mL/4 
ounces], or distilled spirits [29.5 mL/1 ounce]). Participants who consume more than the 
daily limit may be enrolled at the discretion of the investigator.
17. 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.
18. Is a regular user of cannabis, any illicit drugs or has a history of drug (including alcohol) 
abuse within approximately 3 months. Participants must have a negative UDS prior to 
randomization.  Participants with severe renal impairment will be allowed for inclusion 
with a positive UDS for opiates if they have an active prescription from a licensed health 
care provider.
19. Is unwilling to comply with the study restrictions (see Section 5.3 for a complete 
summary of study restrictions. 
20. 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.
20. 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 4 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.
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-
 
 
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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 1 glass of alcoholic 
beverage or equivalent per day (12 g/d) for females and 2 glasses of alcoholic beverages or 
equivalent per day (24 g/d) for males (Note - 1 glass is approximately equivalent to: beer 
[354 mL/12 ounces], wine [118 mL/4 ounces], or distilled spirits [29.5 mL/1 ounce]). .
5.3.2.3
Smoking 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 severe renal 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 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.
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.
 
 
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6
STUDY INTERVENTION
Study intervention is defined as any investigational intervention(s), marketed product(s), 
placebo, or medical device(s) intended to be administered to a study participant according to 
the study protocol.
Clinical supplies will be packaged to support enrollment and replacement participants as 
required. When a replacement participant is required, the Sponsor or designee needs to be 
contacted prior to dosing the replacement supplies. 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 3.
 
 
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Table 3
Study Interventions
Arm Name
Arm 
Type
Inter-
vention 
Name
Type
Dose 
Formu-
lation
Unit Dose 
Strength(s)
Dosage 
Level(s)
Route of 
Adminis-
tration
Regimen/
Treatment 
Period
Use
IMP/
NIMP
Sourcing
Severe 
Renal 
Impair-
ment 
Group 
Experi-
mental
MK-8591 
(ISL)
Drug
Capsule
10 mg
60 mg
Oral
Single 
Dose on 
Day 1
Experi-
mental
IMP
Provided by 
the Sponsor 
Healthy 
Control 
Group
Experi-
mental
MK-8591
(ISL)
Drug
Capsule
10 mg
60 mg
Oral
Single 
Dose on 
Day 1
Experi-
mental
IMP
Provided by 
the Sponsor 
Definition Investigational Medicinal Product (IMP) and Non-Investigational Medicinal Product (NIMP) is based on guidance issued by the European 
Commission. Regional and/or Country differences of the definition of IMP/NIMP may exist. In these circumstances, local legislation is followed.
 
 
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All supplies indicated in Table 3 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
Subjects will be assigned an allocation number (AN) for a single open-label treatment using 
the allocation schedule shown in Table 4.
Table 4
Allocation of Subjects to Treatment 
Impairment Stage 
N
Treatment
Severe
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 identification 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, he/she 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, intervention allocation) must first be discussed between the 
investigator and Sponsor prior to administration, unless appropriate medical care necessitates 
that therapy or vaccination should begin before the investigator and Sponsor can consult. The 
 
 
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participant will be allowed to continue in the study if both the Sponsor and the investigator 
agree.
Paracetamol/acetaminophen may be used for minor ailments without prior consultation with 
the Sponsor.
For Participants with Severe Renal Impairment: 
Participants who are taking medications to treat general medical conditions and/or conditions 
associated with renal 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. Subjects 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. Examples of types of medications 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

Synthroid

Colchicine, allopurinol

Selective serotonin uptake inhibitors (SSRIs), tricyclic antidepressants

Proton pump inhibitors
Any medication (including over-the-counter) that would significantly alter eGFR, which, 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 first dosing of study drug. 
6.5.1
Rescue Medications and Supportive Care
No rescue or supportive medications are specified for use in this study.
 
 
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6.6
Dose Modification (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 a Serious Adverse Event 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.
7.2
Participant Withdrawal From the Study
A participant must be withdrawn from the study if the participant 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.
 
 
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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.
•
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.
 
 
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•
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 296.5 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 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 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 should be informed in a timely manner if new information becomes available that 
may be relevant to the participant’s willingness to continue participation in the study. The 
communication of this information will be provided and documented via a revised consent 
form or addendum to the original consent form that captures the participant’s 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 
 
 
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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.
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.
 
 
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Any participant who is screened multiple times will retain the original screening number 
assigned at the initial screening visit. Specific details on the screening/rescreening visit 
requirements are provided in Section 8.10.1.
8.1.7
Assignment of Treatment/Randomization Number
All eligible participants will be randomly allocated and will receive a 
treatment/randomization number. The treatment/randomization number identifies the 
participant for all procedures occurring after treatment allocation. 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. 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 
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.
 
 
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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.
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 120 hours post dose for healthy matched 
controls and 120 hours post dose for participants with severe renal 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.
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.
 
 
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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 full physical examination will be conducted by an investigator or medically qualified 
designee (consistent with local requirements) as per institutional standard per SoA. 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.
•
Vital signs will be measured in a semi-recumbent position after 10 minutes rest. 
 
 
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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).
 
 
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•
For any laboratory tests with values considered clinically significantly abnormal during 
participation in the study or within 14 days after study drug administration, every attempt 
should be made to perform repeat assessments until the values return to normal or 
baseline or if a new baseline is established as determined by the investigator.
8.4
Adverse Events, 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 or surrogate).
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 study drug, 
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 5.
 
 
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Table 5
Reporting Time Periods and Time Frames for Adverse Events and Other 
Reportable Safety Events
Type of Event
Reporting Time 
Period:
Consent to 
Randomization/ 
Allocation
Reporting Time 
Period:
Randomization/ 
Allocation through 
Protocol-specified 
Follow-up Period
Reporting Time 
Period:
After the Protocol-
specified Follow-up 
Period
Time Frame to 
Report Event and 
Follow-up 
Information to 
Sponsor:
Nonserious 
Adverse Event 
(NSAE) 
Report if:
- due to protocol-
specified intervention
- causes exclusion
- participant is 
receiving placebo run-
in or other run-in 
treatment
Report all
Not required
Per data entry 
guidelines
Serious Adverse 
Event (SAE)
Report if:
- due to protocol-
specified intervention
- causes exclusion
- participant is 
receiving placebo run-
in or other run-in 
treatment
Report all
Report if:
- drug/vaccine related.
(Follow ongoing to 
outcome)
Within 24 hours of 
learning of event
Pregnancy/
Lactation 
Exposure
Report if:
- due to intervention
- causes exclusion
Report all
Previously reported –
Follow to 
completion/termination; 
report outcome
Within 24 hours of 
learning of event
Event of 
Clinical Interest 
(require 
regulatory 
reporting)
Report if:
- due to intervention
- causes exclusion
Report
- potential drug-
induced liver injury 
(DILI)
- require regulatory 
reporting
Not required
Within 24 hours of 
learning of event
Event of 
Clinical Interest 
(do not require 
regulatory 
reporting)
Report if:
- due to intervention
- causes exclusion
Report
- non-DILI ECIs and 
those not requiring 
regulatory reporting
Not required
Within 5 calendar days 
of learning of event
Cancer
Report if:
- due to intervention
- causes exclusion
Report all
Not required
Within 5 calendar days 
of learning of event
Overdose
Report if:
- receiving placebo 
run-in or other run-in 
medication 
Report all
Not required
Within 24 hours of 
learning of event
8.4.2
Method of Detecting AEs, SAEs, and Other Reportable Safety Events
Care will be taken not to introduce bias when detecting AEs and/or SAEs and other 
reportable safety events. Open-ended and nonleading verbal questioning of the participant is 
the preferred method to inquire about AE occurrence.
 
 
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8.4.3
Follow-up of AE, SAE, and Other Reportable Safety Event Information
After the initial AE/SAE report, the investigator is required to proactively follow each 
participant at subsequent visits/contacts. All AEs, SAEs, and other reportable safety events,
including pregnancy and exposure during breastfeeding, ECIs, cancer, and overdose will be 
followed until resolution, stabilization, until the event is otherwise explained, or the 
participant is lost to follow-up (as defined in Section 7.3). In addition, the investigator will 
make every attempt to follow all nonserious AEs that occur in allocated participants for 
outcome. Further information on follow-up procedures is given in Appendix 3.
8.4.4
Regulatory Reporting Requirements for SAE
Prompt notification (within 24 hours) by the investigator to the Sponsor of SAE is essential 
so that legal obligations and ethical responsibilities towards the safety of participants and the 
safety of a study intervention under clinical investigation are met.
The Sponsor has a legal responsibility to notify both the local regulatory authority and other 
regulatory agencies about the safety of a study intervention under clinical investigation. The 
Sponsor will comply with country-specific regulatory requirements and global laws and 
regulations relating to safety reporting to regulatory authorities, IRB/IECs, and investigators.
Investigator safety reports must be prepared for SUSARs according to local regulatory 
requirements and Sponsor policy and forwarded to investigators as necessary.
An investigator who receives an investigator safety report describing an SAE or other 
specific safety information (eg, summary or listing of SAE) from the Sponsor will file it 
along with the IB and will notify the IRB/IEC, if appropriate according to local requirements.
8.4.5
Pregnancy and Exposure During Breastfeeding
Although pregnancy and infant exposure during breastfeeding are not considered AEs, any 
pregnancy or infant exposure during breastfeeding in a participant (spontaneously reported to 
the investigator or their designee) that occurs during the study are reportable to the Sponsor.
All reported pregnancies must be followed to the completion/termination of the pregnancy. 
Pregnancy outcomes of spontaneous abortion, missed abortion, benign hydatidiform mole, 
blighted ovum, fetal death, intrauterine death, miscarriage, and stillbirth must be reported as 
serious events (Important Medical Events). If the pregnancy continues to term, the outcome 
(health of infant) must also be reported.
8.4.6
Disease-related Events and/or Disease-related Outcomes Not Qualifying as 
AEs or SAEs
Not applicable.
 
 
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8.4.7
Events of Clinical Interest
Selected nonserious and SAEs are also known as ECIs and must be reported to the Sponsor.
Events of clinical interest for this study include: 
1. An 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 samples collected will be assayed for evaluation of PK will 
be collaboratively determined by the Sponsor (eg, samples at lower doses may not be assayed 
if samples at higher doses reveal undetectable drug concentrations). If indicated, these 
samples may also be assayed and/or pooled for assay in an exploratory manner for 
metabolites and/or additional pharmacodynamic markers.
8.6.1
Blood Collection for Plasma ISL and PBMC ISL-TP
Blood collection time points for plasma ISL 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.
 
 
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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 participant signs 
the future biomedical research consent. If the planned genetic analysis is not approved, but 
future biomedical research is approved and consent is given, this sample will be collected for 
the purpose of future biomedical research.
Sample collection, storage, and shipment instruction for planned genetic analysis samples 
will be provided in the operations/laboratory manual.
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.
8.10.1
Screening
Approximately 3 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 randomization if there are Day -
1 procedures planned per protocol.
 
 
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8.10.2
Treatment Period
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 6.
Table 6
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
 
 
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•
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
The PK 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 
 
 
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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).
Safety: The safety and tolerability of ISL will be evaluated by clinical assessment of adverse 
events and other safety measurements. Summary statistics for the laboratory safety tests, 
ECGs, and/or vital signs may also be computed and provided, as deemed clinically 
appropriate.
Pharmacokinetics: Separately for each PK parameter and analyte, individual values of
plasma ISL AUC0-∞, AUC0-last, Cmax, CL/F, and Vz/F, PBMC ISL-TP AUC0-∞, AUC0-last, 
Cmax, C24, C168, C672, plasma M4 AUC0-∞, AUC0-last, Cmax, CL/F, and Vz/F after a single 
dose administration of 60 mg ISL to subjects with severe renal impairment and healthy
subjects will be natural log-transformed and evaluated with a linear fixed effects model
containing a categorical effect for population (subjects with severe renal impairment, healthy 
subjects).  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%) confidence intervals 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% 
confidence limits 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 subjects with severe renal impairment to subjects with normal renal 
function, a two-sided 90% confidence interval for the true difference in means (subjects with 
severe renal impairment – healthy subjects) 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 (subjects with severe renal impairment/healthy subjects) for each PK 
parameter.  
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, 0.356, 
0.414 and 0.518, respectively. Assuming the same variability for 60-mg ISL, with 6 severe 
renal impairment subjects and 6 healthy subjects, the half width of the 90% confidence 
 
 
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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 subjects with severe renal 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 subjects.
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. 
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, Tmax, apparent terminal t½, 
CL/F, and Vz/F of M4 in plasma. The exploratory endpoints also include genetic variation 
and response to the treatment administered. 
 
 
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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 Subjects as Treated (ASaT): The All Subjects 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
No value for AUC0-∞, apparent terminal t½, CL/F, or Vz/F will be reported for cases that do 
not exhibit a terminal log-linear phase in the concentration versus time profile. 
Pharmacokinetics: Separately for each PK parameter and analyte, individual values of
plasma ISL AUC0-∞, AUC0-last, Cmax, CL/F, and Vz/F, PBMC ISL-TP AUC0-∞, AUC0-last, 
Cmax, C24, C168, C672, plasma M4 AUC0-∞, AUC0-last, Cmax, CL/F, and Vz/F after a single 
dose administration of 60 mg ISL to subjects with severe renal impairment and healthy
subjects will be natural log-transformed and evaluated with a linear fixed effects model
containing a categorical effect for population (subjects with severe renal impairment, healthy 
subjects).  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%) confidence intervals 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% 
confidence limits 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; 
run;
 
 
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To address the primary estimation objective and compare subjects with severe renal 
impairment to subjects with normal renal function, a two-sided 90% confidence interval for 
the true difference in means (subjects with severe renal impairment – healthy subjects) 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 (subjects with severe renal 
impairment/healthy subjects) for each PK parameter.  
Individual values will be listed for each PK parameter (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, and apparent terminal t½, plasma M4 AUC0--∞, AUC0-
last, Cmax, Tmax, apparent terminal t½, CL/F, and Vz/F) by population, and the following 
(non-model-based) descriptive statistics will be provided: N (number of subjects 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).
Figures showing individual PK values with GMs (95% CIs) by population, plotted on the 
natural log scale, will be provided for ISL plasma AUC0-∞, AUC0-last and Cmax. Individual 
subject PK values will also be plotted against BSA normalized eGFR and against BSA un-
normalized eGFR, using different symbols to identify subjects from each population. For this 
analysis, eGFR will be calculated as the mean of the two values determined at screening.  
Plots of PK parameters versus CLcr using the C-G equation will also be provided.  
Additionally, plots of PK parameter values vs age and body mass index (BMI) may be 
provided. 
Summary Statistics using BSA un-normalized eGFR  The subjects will be re-categorized into 
different renal categories based on their BSA un-normalized eGFR and non -model based 
summary statistics by population will be provided for plasma ISL AUC0-∞, AUC0-last, Cmax, 
CL/F, and Vz/F, PBMC ISL-TP AUC0-∞, AUC0-last, Cmax, C24, C168, C672, plasma M4 
AUC0-∞, AUC0-last, Cmax, CL/F, and Vz/F.
Analysis using CLcr (C-G equation):  The subjects will be re-categorized into different renal 
categories based on their CLcr obtained from C-G equation and non-model based summary 
statistics by population will be provided for plasma ISL AUC0-∞, AUC0-last, Cmax, CL/F, and 
Vz/F, PBMC ISL-TP AUC0-∞, AUC0-last, Cmax, C24, C168, C672, plasma M4 AUC0-∞, 
AUC0-last, Cmax, CL/F, and Vz/F. 
Safety: The safety and tolerability of ISL will be evaluated by clinical assessment of adverse 
events and other safety measurements. Summary statistics for the laboratory safety tests, 
ECGs, and/or vital signs may also be computed and provided, as deemed clinically 
appropriate.
 
 
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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/10^6 
Cells) and 0.518 ln(pmol/10^6 Cells), respectively. Assuming the same variability for 60-mg 
ISL, with 6 severe renal impairment subjects and 6 healthy subjects, 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 regulations), and 
International Council for Harmonisation Good Clinical Practice (ICH-GCP), and also in accordance with the 
ethical principles that have their origin in the Declaration of Helsinki.
B. Scope
Highest ethical and scientific standards shall be endorsed for all clinical interventional investigations sponsored by 
MSD irrespective of the party (parties) employed for their execution (e.g., contract research organizations, 
collaborative research efforts). This Code is not intended to apply to trials that are observational in nature, or 
which are retrospective. Further, this Code does not apply to investigator-initiated trials, which are not under the 
full control of MSD.
II. Scientific Issues
A. Trial Conduct
1. Trial Design
Except for pilot or estimation trials, clinical trial protocols will be hypothesis-driven to assess safety, efficacy 
and/or pharmacokinetic or pharmacodynamic indices of MSD or comparator products. Alternatively, MSD 
may conduct outcomes research trials, trials to assess or validate various endpoint measures, or trials to 
determine patient preferences, etc.
The design (i.e., participant population, duration, statistical power) must be adequate to address the specific 
purpose of the trial. Participants must meet protocol entry criteria to be enrolled in the trial. 
2. Site Selection
MSD selects investigative sites based on medical expertise, access to appropriate participants, adequacy of 
facilities and staff, previous performance in clinical trials, as well as budgetary considerations. Prior to trial 
initiation, sites are evaluated by MSD personnel (or individuals acting on behalf of MSD) to assess the ability 
to successfully conduct the trial.
3. Site Monitoring/Scientific Integrity
Investigative trial sites are monitored to assess compliance with the trial protocol and Good Clinical Practice 
(GCP). MSD reviews clinical data for accuracy, completeness, and consistency. Data are verified versus 
source documentation according to standard operating procedures. Per MSD policies and procedures, if fraud, 
 
 
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scientific/research misconduct or serious GCP-non-compliance is suspected, the issues are investigated. 
When necessary, the clinical site will be closed, the responsible regulatory authorities and ethics review 
committees notified.
B. Publication and Authorship
Regardless of trial outcome, MSD commits to publish the primary and secondary results of its registered trials of 
marketed products in which treatment is assigned, according to the pre-specified plans for data analysis. To the 
extent scientifically appropriate, MSD seeks to publish the results of other analyses it conducts that are important 
to patients, physicians, and payers. Some early phase or pilot trials are intended to be hypothesis-generating rather 
than hypothesis testing; in such cases, publication of results may not be appropriate since the trial may be 
underpowered and the analyses complicated by statistical issues such as multiplicity.
MSD’s policy on authorship is consistent with the recommendations published by the International Committee of 
Medical Journal Editors (ICMJE). In summary, authorship should reflect significant contribution to the design and 
conduct of the trial, performance or interpretation of the analysis, and/or writing of the manuscript. All named 
authors must be able to defend the trial results and conclusions. MSD funding of a trial will be acknowledged in 
publications.
III. Participant Protection
A. Regulatory Authority and Ethics Committee Review (Institutional Review Board [IRB]/Independent Ethics 
Committee [IEC])
All protocols and protocol amendments will be submitted by MSD for regulatory authority 
acceptance/authorization prior to implementation of the trial or amendment, in compliance with local and/or 
national regulations.
The protocol, protocol amendment(s), informed consent form, investigator’s brochure, and other relevant trial 
documents must be reviewed and approved by an IRB/IEC before being implemented at each site, in compliance 
with local and/or national regulations. Changes to the protocol that are required urgently to eliminate an 
immediate hazard and to protect participant safety may be enacted in anticipation of ethics committee approval.  
MSD will inform regulatory authorities of such new measures to protect participant safety, in compliance with 
local and/or national regulations.
B. Safety
The guiding principle in decision-making in clinical trials is that participant welfare is of primary importance. 
Potential participants will be informed of the risks and benefits of, as well as alternatives to, trial participation. At 
a minimum, trial designs will take into account the local standard of care.
All participation in MSD clinical trials is voluntary. Participants enter the trial only after informed consent is 
obtained. Participants may withdraw from an MSD trial at any time, without any influence on their access to, or 
receipt of, medical care that may otherwise be available to them.
C. Confidentiality
MSD is committed to safeguarding participant confidentiality, to the greatest extent possible. Unless required by 
law, only the investigator, Sponsor (or individuals acting on behalf of MSD), ethics committee, and/or regulatory 
authorities will have access to confidential medical records that might identify the participant by name.
D. Genomic Research
Genomic research will only be conducted in accordance with a protocol and informed consent authorized by an 
ethics committee.
 
 
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IV. Financial Considerations
A. Payments to Investigators
Clinical trials are time- and labor-intensive. It is MSD’s policy to compensate investigators (or the sponsoring 
institution) in a fair manner for the work performed in support of MSD trials. MSD does not pay incentives to 
enroll participants in its trials. However, when enrollment is particularly challenging, additional payments may be 
made to compensate for the time spent in extra recruiting efforts.
MSD does not pay for participant referrals. However, MSD may compensate referring physicians for time spent 
on chart review and medical evaluation to identify potentially eligible participants.
B. Clinical Research Funding
Informed consent forms will disclose that the trial is sponsored by MSD, and that the investigator or sponsoring 
institution is being paid or provided a grant for performing the trial. However, the local ethics committee may 
wish to alter the wording of the disclosure statement to be consistent with financial practices at that institution. As 
noted above, all publications resulting from MSD trials will indicate MSD as a source of funding.
C. Funding for Travel and Other Requests
Funding of travel by investigators and support staff (e.g., to scientific meetings, investigator meetings, etc.) will be 
consistent with local guidelines and practices.
V. Investigator Commitment
Investigators will be expected to review MSD’s Code of Conduct as an appendix to the trial protocol, and in signing the 
protocol, agree to support these ethical and scientific standards.
10.1.2
Financial Disclosure
Financial Disclosure requirements are outlined in the US Food and Drug Administration 
Regulations, Financial Disclosure by Clinical Investigators (21 CFR Part 54). It is the 
Sponsor's responsibility to determine, based on these regulations, whether a request for 
Financial Disclosure information is required. It is the investigator's/subinvestigator's 
responsibility to comply with any such request.
The investigator/subinvestigator(s) agree, if requested by the Sponsor in accordance with 21 
CFR Part 54, to provide his/her financial interests in and/or arrangements with the Sponsor to 
allow for the submission of complete and accurate certification and disclosure statements. 
The investigator/subinvestigator(s) further agree to provide this information on a 
Certification/Disclosure Form, commonly known as a financial disclosure form, provided by 
the Sponsor. The investigator/subinvestigator(s) also consent to the transmission of this 
information to the Sponsor in the United States for these purposes. This may involve the 
transmission of information to countries that do not have laws protecting personal data.
10.1.3
Data Protection
The Sponsor will conduct this study in compliance with all applicable data protection 
regulations.
 
 
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Participants will be assigned a unique identifier by the Sponsor. Any participant records or 
datasets that are transferred to the Sponsor will contain the identifier only; participant names 
or any information that would make the participant identifiable will not be transferred.
The participant must be informed that his/her personal study-related data will be used by the 
Sponsor in accordance with local data protection law. The level of disclosure must also be 
explained to the participant. 
The participant must be informed that his/her medical records may be examined by Clinical 
Quality Assurance auditors or other authorized personnel appointed by the Sponsor, by 
appropriate IRB/IEC members, and by inspectors from regulatory authorities.
10.1.3.1
Confidentiality of Data
By signing this protocol, the investigator affirms to the Sponsor that information furnished to 
the investigator by the Sponsor will be maintained in confidence, and such information will 
be divulged to the IRB, IEC, or similar or expert committee; affiliated institution and 
employees, only under an appropriate understanding of confidentiality with such board or 
committee, affiliated institution and employees. Data generated by this study will be 
considered confidential by the investigator, except to the extent that it is included in a 
publication as provided in the Publications section of this protocol.
10.1.3.2
Confidentiality of Participant Records
By signing this protocol, the investigator agrees that the Sponsor (or Sponsor representative), 
IRB/IEC, or regulatory authority representatives may consult and/or copy study documents to 
verify worksheet/CRF data. By signing the consent form, the participant agrees to this 
process. If study documents will be photocopied during the process of verifying 
worksheet/CRF information, the participant will be identified by unique code only; full 
names/initials will be masked prior to transmission to the Sponsor.
By signing this protocol, the investigator agrees to treat all participant data used and 
disclosed in connection with this study in accordance with all applicable privacy laws, rules 
and regulations.
10.1.3.3
Confidentiality of IRB/IEC Information
The Sponsor is required to record the name and address of each IRB/IEC that reviews and 
approves this study. The Sponsor is also required to document that each IRB/IEC meets 
regulatory and ICH GCP requirements by requesting and maintaining records of the names 
and qualifications of the IRB/IEC members and to make these records available for 
regulatory agency review upon request by those agencies.
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 7 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 7
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
Magnesium 
Routine 
Urinalysis
•
Specific gravity
•
pH, glucose, protein, blood, ketones, [bilirubin, urobilinogen, nitrite, leukocyte 
esterase] by dipstick
•
Microscopic examination (if blood or protein is abnormal)
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 antibody, hepatitis B surface antigen [HBsAg], and hepatitis C virus 
antibody)]
*Please refer to Appendix 7 Country Specific Requirements for screening tests that are 
applicable to the US only.
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, or protocol specified procedure whether investigational or marketed (including 
placebo, active comparator product, or run-in intervention), manufactured by, licensed 
by, provided by, or distributed by the Sponsor for human use in this study.
Events meeting the AE definition

Any abnormal laboratory test results (hematology, clinical chemistry, or urinalysis) or 
other safety assessments (eg, ECG, radiological scans, vital signs measurements), 
including those that worsen from baseline, considered clinically significant in the medical 
and scientific judgment of the investigator.

Exacerbation of a chronic or intermittent pre-existing condition including either an 
increase in frequency and/or intensity of the condition.

New conditions detected or diagnosed after study intervention administration even 
though it may have been present before the start of the study.

Signs, symptoms, or the clinical sequelae of a suspected drug-drug interaction.

Signs, symptoms, or the clinical sequelae of a suspected overdose of either study 
intervention or a concomitant medication.

For all reports of overdose (whether accidental or intentional) with an associated AE, the 
AE term should reflect the clinical symptoms or abnormal test result. An overdose 
without any associated clinical symptoms or abnormal laboratory results is reported using 
the terminology “accidental or intentional overdose without adverse effect.”
•
Any new cancer or progression of existing cancer.
 
 
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Events NOT meeting the AE definition
·
Medical or surgical procedure (eg, endoscopy, appendectomy): the condition that leads to 
the procedure is the AE.

Situations in which an untoward medical occurrence did not occur (social and/or 
convenience admission to a hospital).

Anticipated day-to-day fluctuations of pre-existing disease(s) or condition(s) present or 
detected at the start of the study that do not worsen.

Surgery planned prior to informed consent to treat a pre-existing condition that has not 
worsened.

Refer to Section 8.4.6 for protocol-specific exceptions.
10.3.2
Definition of SAE
If an event is not an AE per definition above, then it cannot be an SAE even if serious 
conditions are met.
An SAE is defined as any untoward medical occurrence that, at any dose:
a.
Results in death
b. Is life-threatening
•
The term “life-threatening” in the definition of “serious” refers to an event in which 
the participant was at risk of death at the time of the event. It does not refer to an 
event, which hypothetically might have caused death, if it were more severe.
c.
Requires inpatient hospitalization or prolongation of existing hospitalization
•
Hospitalization is defined as an inpatient admission, regardless of length of stay, even 
if the hospitalization is a precautionary measure for continued observation. (Note: 
Hospitalization for an elective procedure to treat a pre-existing condition that has not 
worsened is not an SAE.) A pre-existing condition is a clinical condition that is 
diagnosed prior to the use of an MSD product and is documented in the participant’s 
medical history.
d. Results in persistent or significant disability/incapacity
•
The term disability means a substantial disruption of a person’s ability to conduct 
normal life functions.
 
 
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•
This definition is not intended to include experiences of relatively minor medical 
significance such as uncomplicated headache, nausea, vomiting, diarrhea, influenza, 
and accidental trauma (eg, sprained ankle) that may interfere with or prevent 
everyday life functions but do not constitute a substantial disruption.
e.
Is a congenital anomaly/birth defect
•
In offspring of participant taking the product regardless of time to diagnosis.
f.
Other important medical events
•
Medical or scientific judgment should be exercised in deciding whether SAE 
reporting is appropriate in other situations such as important medical events that may 
not be immediately life-threatening or result in death or hospitalization but may 
jeopardize the participant or may require medical or surgical intervention to prevent 1 
of the other outcomes listed in the above definition. These events should usually be 
considered serious.
Examples of such events include invasive or malignant cancers, intensive treatment in 
an emergency room or at home for allergic bronchospasm, blood dyscrasias or 
convulsions that do not result in hospitalization, or development of drug dependency 
or drug abuse.
10.3.3
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.
 
 
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
There may be instances when copies of medical records for certain cases are requested by 
the Sponsor. In this case, all participant identifiers, with the exception of the participant 
number, will be blinded on the copies of the medical records before submission to the 
Sponsor.

The investigator will attempt to establish a diagnosis of the event based on signs, 
symptoms, and/or other clinical information. In such cases, the diagnosis (not the 
individual signs/symptoms) will be documented as the AE/SAE.
Assessment of intensity/toxicity

An event is defined as “serious” when it meets at least 1 of the predefined outcomes as 
described in the definition of an SAE, not when it is rated as severe.
•
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.
 
 
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•
The following components are to be used to assess the relationship between the 
Sponsor’s product and the AE; the greater the correlation with the components and 
their respective elements (in number and/or intensity), the more likely the Sponsor’s 
product caused the AE:
- Exposure: Is there evidence that the participant was actually exposed to the 
Sponsor’s product such as: reliable history, acceptable compliance assessment (pill 
count, diary, etc.), expected pharmacologic effect, or measurement of 
drug/metabolite in bodily specimen?
- Time Course: Did the AE follow in a reasonable temporal sequence from 
administration of the Sponsor’s product? Is the time of onset of the AE compatible 
with a drug-induced effect (applies to studies with investigational medicinal 
product)?
- Likely Cause: Is the AE not reasonably explained by another etiology such as 
underlying disease, other drug(s)/vaccine(s), or other host or environmental factors.
- Dechallenge: Was the Sponsor’s product discontinued or dose/exposure/frequency 
reduced?
◦
If yes, did the AE resolve or improve?
◦
If yes, this is a positive dechallenge.
◦
If no, this is a negative dechallenge.
(Note: This criterion is not applicable if: (1) the AE resulted in death or permanent 
disability; (2) the AE resolved/improved despite continuation of the Sponsor’s 
product; (3) the study is a single-dose drug study; or (4) Sponsor’s product(s) is/are 
only used 1 time.)
- Rechallenge: Was the participant re-exposed to the Sponsor’s product in this study?
◦
If yes, did the AE recur or worsen?
◦
If yes, this is a positive rechallenge.
◦
If no, this is a negative rechallenge.
(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 
 
 
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ADVANCE BY THE SPONSOR CLINICAL DIRECTOR, AND IF REQUIRED, THE 
IRB/IEC.
•
Consistency with study intervention profile: Is the clinical/pathological presentation of 
the AE consistent with previous knowledge regarding the Sponsor’s product or drug class 
pharmacology or toxicology?
•
The assessment of relationship will be reported on the case report forms/worksheets by 
an investigator who is a qualified physician according to his/her best clinical judgment, 
including consideration of the above elements.
•
Use the following scale of criteria as guidance (not all criteria must be present to be 
indicative of a Sponsor’s product relationship).
- Yes, there is a reasonable possibility of Sponsor’s product relationship:
◦
There is evidence of exposure to the Sponsor’s product. The temporal sequence 
of the AE onset relative to the administration of the Sponsor’s product is 
reasonable. The AE is more likely explained by the Sponsor’s product than by 
another cause.
- No, there is not a reasonable possibility of Sponsor’s product relationship:
◦
Participant did not receive the Sponsor’s product OR temporal sequence of the 
AE onset relative to administration of the Sponsor’s product is not reasonable 
OR the AE is more likely explained by another cause than the Sponsor’s 
product. (Also entered for a participant with overdose without an associated 
AE.)
•
For each AE/SAE, the investigator must document in the medical notes that he/she has 
reviewed the AE/SAE and has provided an assessment of causality.
•
There may be situations in which an SAE has occurred and the investigator has minimal 
information to include in the initial report to the Sponsor. However, it is very important 
that the investigator always make an assessment of causality for every event before the 
initial transmission of the SAE data to the Sponsor.
•
The investigator may change his/her opinion of causality in light of follow-up 
information and send an SAE follow-up report with the updated causality assessment.
•
The causality assessment is 1 of the criteria used when determining regulatory reporting 
requirements.
 
 
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Follow-up of AE and SAE

The investigator is obligated to perform or arrange for the conduct of supplemental 
measurements and/or evaluations as medically indicated or as requested by Sponsor to 
elucidate the nature and/or causality of the AE or SAE as fully as possible. This may 
include additional laboratory tests or investigations, histopathological examinations, or 
consultation with other health care professionals.

New or updated information will be recorded in the CRF.

The investigator will submit any updated SAE data to the Sponsor within 24 hours of 
receipt of the information.
10.3.5
Reporting of AEs, SAEs, and Other Reportable Safety Events to the Sponsor
AE, SAE, and other reportable safety event reporting to Sponsor via electronic data 
collection tool

The primary mechanism for reporting to the Sponsor will be the EDC tool.
-
Electronic reporting procedures can be found in the EDC data entry guidelines (or 
equivalent).
-
If the electronic system is unavailable for more than 24 hours, then the site will 
use the paper AE Reporting form.
◦
Reference Section 8.4.1 for reporting time requirements.

The site will enter the SAE data into the electronic system as soon as it becomes 
available.

After the study is completed at a given site, the EDC tool will be taken off-line to prevent 
the entry of new data or changes to existing data.

If a site receives a report of a new SAE from a study participant or receives updated data 
on a previously reported SAE after the EDC tool has been taken off-line, then the site can 
report this information on a paper SAE form or by telephone (see next section).

Contacts for SAE reporting can be found in the Investigator Study File Binder (or 
equivalent).
 
 
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SAE reporting to the Sponsor via paper CRF
·
If the EDC tool is not operational, facsimile transmission or secure e-mail of the SAE 
paper CRF is the preferred method to transmit this information to the Sponsor.

In rare circumstances and in the absence of facsimile equipment, notification by 
telephone is acceptable with a copy of the SAE data collection tool sent by overnight 
mail or courier service.

Initial notification via telephone does not replace the need for the investigator to 
complete and sign the SAE CRF pages within the designated reporting time frames.

Contacts and instructions for SAE reporting and paper reporting procedures can be found 
in the Investigator Study File Binder (or equivalent).
 
 
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10.4
Appendix 4: Device Events, Adverse Device Events, and Medical Device 
Incidents: Definitions, Collection, and Documentation
Not applicable. 
 
 
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10.5
Appendix 5: Contraceptive Guidance
10.5.1
Definitions
Women of 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 can come from the site personnel’s review of the participant’s 
medical records, medical examination, or medical history interview.
Highly Effective Contraceptive Methods That Are User Dependentb
Failure rate of <1% per year when used consistently and correctly.
•
Combined (estrogen- and progestogen- containing) hormonal contraceptionc,d
- Oral
- Intravaginal
- Transdermal
- Injectable
•
Progestogen-only hormonal contraceptionc,d
- Oral
- Injectable
Sexual Abstinence
•
Sexual abstinence is considered a highly effective method only if defined as refraining from heterosexual 
intercourse during the entire period of risk associated with the study intervention. The reliability of sexual 
abstinence needs to be evaluated in relation to the duration of the study and the preferred and usual lifestyle 
of the participant.
Acceptable Contraceptive Methods
Failure rate of >1% per year when used consistently and correctly.
•
Progesterone-only hormonal contraception where inhibition of ovulation is not the primary mode of action
•
Male or female condom with or without spermicide
•
Cervical cap, diaphragm, or sponge with spermicide
•
A combination of male condom with either cervical cap, diaphragm, or sponge with spermicide (double 
barrier methods)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 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
 
 
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All participants enrolled in the clinical study will be considered for enrollment in 
future biomedical research.
b.
Informed Consent
Informed consent for specimens (ie, DNA, RNA, protein, etc.) will be obtained 
during screening for protocol enrollment from all participants or legal guardians, 
at a study visit by the investigator or his or her designate. Informed consent for 
future biomedical research should be presented to the participants on the visit 
designated in the SoA. If delayed, present consent at next possible Participant 
Visit. Consent forms signed by the participant will be kept at the clinical study 
site under secure storage for regulatory reasons.
A template of each study site’s approved informed consent will be stored in the 
Sponsor’s clinical document repository.
c.
eCRF Documentation for Future Biomedical Research Specimens
Documentation of participant consent for future biomedical research will be 
captured in the eCRFs. Any specimens for which such an informed consent 
cannot be verified will be destroyed.
d.
Future Biomedical Research Specimen(s)
Collection of specimens for future biomedical research will be performed as 
outlined in the SoA. In general, if additional blood specimens are being collected 
for future biomedical research, these will usually be obtained at a time when the 
participant is having blood drawn for other study purposes.
4.
Confidential Participant Information for Future Biomedical Research
In order to optimize the research that can be conducted with future biomedical research 
specimens, it is critical to link participant' clinical information with future test results. 
In fact little or no research can be conducted without connecting the clinical study data 
to the specimen. The clinical data allow specific analyses to be conducted. Knowing 
participant characteristics like gender, age, medical history and intervention outcomes 
are critical to understanding clinical context of analytical results.
To maintain privacy of information collected from specimens obtained for future 
biomedical research, the Sponsor has developed secure policies and procedures. All 
specimens will be single-coded per ICH E15 guidelines as described below.
At the clinical study site, unique codes will be placed on the future biomedical research 
specimens. This code is a random number which does not contain any personally 
identifying information embedded within it. The link (or key) between participant 
identifiers and this unique code will be held at the study site. No personal identifiers 
will appear on the specimen tube.
 
 
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5.
Biorepository Specimen Usage
Specimens obtained for the Sponsor will be used for analyses using good scientific 
practices. Analyses utilizing the future biomedical research specimens may be 
performed by the Sponsor, or an additional third party (eg, a university investigator) 
designated by the Sponsor. The investigator conducting the analysis will follow the 
Sponsor’s privacy and confidentiality requirements. Any contracted third party analyses 
will conform to the specific scope of analysis outlined in future biomedical research 
protocol and consent. Future biomedical research specimens remaining with the third 
party after specific analysis is performed will be reported to the Sponsor.
6.
Withdrawal From Future Biomedical Research
Participants may withdraw their consent for future biomedical research and ask that 
their biospecimens not be used for future biomedical research. Participants may 
withdraw consent at any time by contacting the investigator for the main study. If 
medical records for the main study are still available, the investigator will contact the 
Sponsor using the designated mailbox (clinical.specimen.management@merck.com). 
Subsequently, the participant's specimens will be flagged in the biorepository and 
restricted to main study use only. If specimens were collected from study participants 
specifically for future biomedical research, these specimens will be removed from the 
biorepository and destroyed. Documentation will be sent to the investigator confirming 
withdrawal and/or destruction, if applicable. It is the responsibility of the investigator to 
inform the participant of completion of the withdrawal and/or destruction, if applicable. 
Any analyses in progress at the time of request for withdrawal/destruction or already 
performed prior to the request being received by the Sponsor will continue to be used as 
part of the overall research study data and results. No new analyses would be generated 
after the request is received.
In the event that the medical records for the main study are no longer available (eg, if 
the investigator is no longer required by regulatory authorities to retain the main study 
records) or the specimens have been completely anonymized, there will no longer be a 
link between the participant’s personal information and their specimens. In this 
situation, the request for withdrawal of consent and/or destruction cannot be processed.
7.
Retention of Specimens
Future biomedical research specimens will be stored in the biorepository for potential 
analysis for up to 20 years from the end of the main study. Specimens may be stored for 
longer if a regulatory or governmental authority has active questions that are being 
answered. In this special circumstance, specimens will be stored until these questions 
have been adequately addressed.
Specimens from the study site will be shipped to a central laboratory and then shipped 
to the Sponsor-designated biorepository. If a central laboratory is not utilized in a 
particular study, the study site will ship directly to the Sponsor-designated 
biorepository. The specimens will be stored under strict supervision in a limited access 
 
 
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facility which operates to assure the integrity of the specimens. Specimens will be 
destroyed according to Sponsor policies and procedures and this destruction will be 
documented in the biorepository database.
8.
Data 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
10.7.1
Country-specific Requirements - Germany
The following specifies “good health” with respect to the inclusion criteria.
Section 5.1.1 Inclusion Criteria for Healthy Participants 
Inclusion criterion #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”
In this Inclusion Criterion, with respect to blood pressure, “good health” is defined as systolic 
blood pressure not more than 139 mm Hg and the diastolic blood pressure not more than 89 
mm Hg.
Inclusion criterion #2: 
“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.”
In this Inclusion Criterion, with respect to specific laboratory results, “good health” is 
defined so that ALT, AST, and bilirubin values (except if consistent with Gilbert’s disease)
should not exceed the upper limit of normal (ULN); any other abnormal laboratory
parameters must be considered not clinically significant.
Section 5.1.2 Inclusion Criteria for Renally Impaired Participants
Inclusion criterion #1:
“With the exception of renal 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, including 
but not limited to hypertension, hypercholesterolemia, non-insulin dependent diabetes 
mellitus, hyper- or hypothyroidism, gout, and chronic anxiety or depression may be included 
at the discretion of the investigator and the Sponsor.  Appendix 9 provides a table of the 12-
Lead Electrocardiogram Abnormality Criteria.”
In this Inclusion Criterion, with respect to blood pressure, “good health” is defined as systolic 
blood pressure not more than 160 mm Hg and diastolic blood pressure not more than 100 mm
Hg.
 
 
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Inclusion criterion #2:
“With the exception of renal 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.”
In this Inclusion Criterion, with respect to specific laboratory results, “good health” is 
defined so that only clinically significant lab abnormalities associated with renal disease are 
acceptable; any other abnormal laboratory parameters must be considered not clinically 
significant for inclusion.
10.7.2
Country-specific Requirements – US
Section 1.3 Schedule of Activities 
The following safety procedures are applicable to the United States (US) only.  Please refer 
to Section 1.3 Schedule Activities for other safety procedures required for all participants.
Participants in the US only 
Intervention
Notes
Scheduled Day 
1
2
3
4
5
6
8
Scheduled Hour
Screening Pre-
dose 0 0.25 0.5 1 2 4 6 8 12 24 36 48 72 96 120 168
Safety Procedures
HIV, hepatitis B and C 
screen. HIV-2 
included for the US 
only
X
GC/CT (gonorrhea + 
chlamydia) screen –
US only
X
Per site 
SOP 
Syphilis serologic 
screening – US only
X
Per site 
SOP
Trichomonas testing –
US only
X
If 
available, 
per site 
SOP 
Intervention 
Notes 
Scheduled Day 
11
15
18
22
Post-trial 
visit/Day 
29 c
Scheduled Hour
240
336
408
504
672
Safety Procedures
HIV Screen (including HIV-2) – US only 
X
c. Post-trial study procedures will be conducted on Day 29 of the study.
 
 
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Section 5.2 Exclusion Criteria 
The following exclusion criteria apply to healthy and renally impaired participants in the US 
only.  Please refer to Section 5.2 Exclusion Criteria for other exclusion criteria required for 
all participants. 
1. 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.
Section 10.2 Clinical Laboratory Tests 
The following Clinical Laboratory Tests are applicable to the US only.  Please refer to 
Appendix 2 Clinical Laboratory Tests for other screening tests required for all participants.
Other Screening 
Tests
•
HIV-2 included in HIV screen at screening and HIV screen (HIV-1/HIV-2) 
on Day 29 – US only
•
Syphilis serologic testing - US only
•
GC/CT testing per site SOP - US only
•
Trichomonas testing, if available, per site SOP – US only
 
 
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10.8
Appendix 8: Blood Volume Table
All Participants 
Pre-study
Treatment Periods
Post-study
Total 
Collections
mL Per 
Collection
Total mL/ 
Test
Laboratory Safety Tests (all 
subjects; includes FSH if 
applicable, β-hCG if 
applicable, and 
HIV/Hepatitis screen)
2
2
1
5
17
85c
Blood for Genetic Analysis 
1
0
0
1
8.5
8.5
Blood for PBMC ISL-TP
0
11
0
11
16
176
Blood for Plasma ISL
1
14-15b
0
15-16
4
60 – 64
Blood for plasma M4
1
14-15b
0
15-16
3
45-48
Total Blood Volume per participant: 
374.5 to 
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
During the treatment period, 15 blood collections for plasma ISL and M4 in healthy control group and 16 blood 
collections for plasma ISL and M4 in severe renal impaired group.
c. 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 screen will include HIV-2 in the US only, syphilis serologic testing 
will be conducted in the US only, and an HIV screen will be conducted on Day 29 in the US only.  Please refer to 
Appendix 7 Country Specific Requirements.
 
 
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10.9
Appendix 9: 12-Lead Electrocardiogram Abnormality Criteria
12-Lead Electrocardiogram Abnormality Criteria 
Screen Failure Criteria
Potentially Significant 
Post-randomization Findings 
(clarification on action to take)
RHYTHM
Sinus Tachycardia
110 bpm for renally impaired 
participants 
>90 bpm for healthy participants
HR >110 bpm for renally impaired 
participants and >90 bpm for 
healthy participants
AND HR increase of ≥25 bpm 
from baseline
Sinus Bradycardia
<50 bpm
HR <50 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
Other Intra-Ventricular 
Conduction Delay
QRS 130 ms
QRS 130 ms + Increase of 10 
ms
QTc F
Male
QTc 450 ms
QTc 500 ms or Increase of 60 
ms From Baseline
Female
QTc 460 ms
QTc 500 ms or Increase of 60 
ms From Baseline
 
 
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12-Lead Electrocardiogram Abnormality Criteria 
Screen Failure Criteria
Potentially Significant 
Post-randomization Findings 
(clarification on action to take)
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
AE
adverse event 
APaT
All-Participants-as-Treated
AR
adverse reaction
ART
anti-retroviral therapy
ATP
adenosine triphosphate
AIDS
Acquired immunodeficiency syndrome
ALT 
Alanine aminotransferase
ART
Anti-retroviral therapy
ARV
Antiretroviral
AST
Aspartate aminotransferase
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
Bx
biopsy
C24
Concentration at 24 hours post dose
C168
Concentration at 168 hours post dose
C672
Concentration at 672 hours post dose
Cmax
Maximum concentration
CCC
concordance correlation
CI
confidence interval
CKD-EPI
Chronic Kidney Disease Epidemiology Collaboration
CL
clearance
CL/F
Apparent clearance after extravascular administration
CrCl
creatinine clearance
CRF
Case Report Form 
CRU
clinical research unit
CV
coefficient of variation
DAIDS
Division of AIDS
DILI
drug-induced liver injury
DOR
Doravirine 
DP
Diphosphate 
DTG
Dolutegravir 
DNA
deoxyribonucleic acid 
ECG
electrocardiogram 
ECI
event of clinical interest
eCRF
electronic Case Report Form
eCTA
exploratory Clinical Trial Application
EDC
electronic data collection 
eGFR
estimated glomerular filtration rate
EMA
European Medicines Agency
FBR
Future biomedical research
FDA
Food and Drug Administration 
FDC
Fixed dose combination
FSH
follicle stimulating hormone 
 
 
05JCP2


PRODUCT: MK-8591  
98
PROTOCOL/AMENDMENT NO.: 026-02 
MK-8591-026-02 FINAL PROTOCOL
24-JUN-2020
Abbreviation
Expanded Term
FTC
Emtricitabine
GCP
Good Clinical Practice 
GCV
geometric coefficient of variation
GLP
good laboratory practice
GM
geometric mean
HBsAg
Hepatitis B surface antigen
HBV
Hepatitis B 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 
IRB
Institutional Review Board
LNG/EE
Levonorgestrel/ethinyl estradiol
MedDRA
Medical Dictionary for Regulatory Activities
M4
metabolite M4
MCV
Mean corpuscular volume
MCH
Mean corpuscular hemoglobin
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
PBMC
Peripheral blood mononuclear cell
PK
pharmacokinetic
PP
Per-protocol
PrEP
Pre-exposure prophylaxis
QD
once-daily
QW
once-weekly
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 
t1/2
Half-life
TDF
Tenofovir disoproxil fumarate
TK
toxicokinetic
Tmax
time of maximum concentration
 
 
05JCP2


PRODUCT: MK-8591  
99
PROTOCOL/AMENDMENT NO.: 026-02 
MK-8591-026-02 FINAL PROTOCOL
24-JUN-2020
Abbreviation
Expanded Term
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
 
 
05JCP2


PRODUCT: MK-8591  
100
PROTOCOL/AMENDMENT NO.: 026-02 
MK-8591-026-02 FINAL PROTOCOL
24-JUN-2020
11
REFERENCES
Not Applicable.
 
 
05JCP2