Conditions: Renal Impairment
Allocation: NON_RANDOMIZED | Intervention model: PARALLEL
Enrollment: 16
Healthy volunteers: yes

Brief summary:
This purpose of this study is to evaluate the plasma pharmacokinetics (PK) of N-hydroxycytidine (NHC), the nucleoside metabolite of molnupiravir, after a single oral dose of 800 mg molnupiravir in participants with severe renal impairment compared to healthy mean matched control participants. This study will also assess the safety and tolerability of molnupiravir in participants with severe renal impairment and the urinary excretion of NHC after a single oral dose of 800 mg molnupiravir in participants with severe renal impairment compared to healthy mean matched control participants. The primary hypothesis is that the plasma PK participants with severe renal impairment will be similar to that observed in the healthy mean matched control participants.

Detailed description:

Arms:
arm 1: Participants with severe renal impairment will receive a single oral 800 mg dose of molnupiravir. arm 2: Participants in the healthy mean matched control group will receive a single oral 800 mg dose of molnupiravir.

Interventions: intervention 1: Molnupiravir
Intervention descriptions: intervention 1: Four 200 mg capsules administered orally as a single dose

Protocol document:
Prot_SAP_000.pdf: 
Official Protocol Title:
NCT number:                 NCT05386758
Document Date:            27-Oct-2022
An Open-Label, Single-Dose Study to Evaluate
the Pharmacokinetics of Molnupiravir (MK-
4482; MOV) in Participants with Severe Renal
Impairment


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Title Page
THIS PROTOCOL AMENDMENT AND ALL OF THE INFORMATION RELATING 
TO IT ARE CONFIDENTIAL AND PROPRIETARY PROPERTY OF MERCK 
SHARP & DOHME LLC, RAHWAY, NJ, USA (MSD).
Protocol Title: An Open-Label, Single-Dose Study to Evaluate the Pharmacokinetics of 
Molnupiravir (MK-4482; MOV) in Participants with Severe Renal Impairment 
Protocol Number: 003-02
Compound Number: MK-4482
Sponsor Name:
Merck Sharp & Dohme LLC
(hereafter called the Sponsor or MSD)
Legal Registered Address:
126 East Lincoln Avenue
P.O. Box 2000
Rahway, NJ 07065 USA
Regulatory Agency Identifying Number(s):
IND
147734
Approval Date: 27 October 2022
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Sponsor Signatory
Typed Name:
Title:
Date
Protocol-specific Sponsor contact information can be found in the Investigator Study
File Binder (or equivalent).
Investigator Signatory
I agree to conduct this clinical study in accordance with the design outlined in this protocol 
and to abide by all provisions of this protocol.
Typed Name:
Title:
Date
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DOCUMENT HISTORY
Document
Date of Issue
Overall Rationale
Amendment 2
27-OCT-2022
Modifications were made to the medical history and diagnostic exclusion criteria 
for study participants with severe renal impairment to facilitate recruitment of 
these participants, provided they are otherwise considered clinically stable.
Amendment 1
30-JUN-2022
The definition of nonparticipant women of childbearing potential (WOCBP) 
partners of male participants was added as well as acceptable contraceptive 
methods to be used by nonparticipant WOCBP partners during the study.
Original Protocol
14-APR-2022
Not applicable
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PROTOCOL AMENDMENT SUMMARY OF CHANGES
Amendment: 02
Overall Rationale for the Amendments:
Modifications were made to the medical history and diagnostic exclusion criteria for study participants with severe renal impairment 
to facilitate recruitment of these participants, provided they are otherwise considered clinically stable
Summary of Changes Table:
Section # and Name
Description of Change 
Brief Rationale 
4.4 Beginning and End-of-
Study Definition
Removed example text in this section 
that referred to a participant that is 
unable to be contacted by the 
investigator.
To clarify definition of lost-to-follow-up by referring to 
Section 7.3 Lost to Follow-up
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Section # and Name
Description of Change 
Brief Rationale 
5.1.2 Inclusion Criteria for 
Severe Renally Impaired 
Participants
Inclusion Criterion #1 – removed the 
following sentence, “Appendix 8 
provides a table of the 12-Lead 
Electrocardiogram Abnormality 
Criteria.”
Appendix 8 still applies for the healthy 
participant population
Individuals with advanced CKD have a very high 
prevalence of cardiovascular disease, including 
hypertension, coronary artery disease and left ventricular 
hypertrophy (LVH). As a result, ECG abnormalities such 
as evidence of prior myocardial infarction and LVH are 
highly common in this patient population where ECG 
evidence of LVH is present in well over half of patients 
with stage IV CKD. The standard ECG exclusion criteria 
listed in Appendix 8 are generally designed for healthy 
participants in clinical trials. Therefore, the ECG inclusion 
and exclusion criteria for study participants with severe 
renal impairment is being modified to facilitate 
recruitment of these participants if they are otherwise 
clinically stable with no active cardiac disease, such as 
myocardial ischemia or uncompensated heart failure. The 
administration of a single dose of molnupiravir would not 
be expected to lead to cardiovascular complications, based 
on clinical trials and post marketing studies. There were 
no study intervention-related changes in ECGs observed 
in clinical trials. Furthermore, in MK-4482-004 a 
concentration-QTc analysis conducted on ECG from 
dedicated Holter ECGs showed no clinically meaningful 
effect of molnupiravir on the QT/QTc interval (see Sec. 
5.4.1 of Investigator’s Brochure). The changes in ECG 
criteria are therefore highly unlikely to lead to cardiac 
ischemia or conduction defects in this study.  
5.2.2 Exclusion Criteria for 
Severe Renally Impaired 
Participants
Exclusion Criterion #13 - removed prior 
Diagnostic Assessment criterion for 
ECG and replaced it with ECG criterion 
that allows increased flexibility for the 
severe renal impairment participant 
population
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Section # and Name
Description of Change 
Brief Rationale 
5.2.1 Exclusion Criteria for 
Healthy Participants, 5.5 
Participant Replacement 
Strategy, Appendix 8
Changed all reference to 
“treatment/randomization number” to 
“treatment/allocation number”
To align wording for nonrandom treatment assignment
5.2.2 Exclusion Criteria for 
Severe Renally Impaired 
Participants
Exclusion Criterion #2 - removed 
nephrectomy from exclusionary medical 
history
A history of previous nephrectomy in an individual with 
otherwise stable kidney function would not be expected to 
be associated with any higher risk in this study than in 
non-nephrectomized individuals with equivalent eGFR. 
There are no study interventions, such as renal biopsy, that 
necessitate exclusion of participants with previous 
nephrectomy if screening eGFR values demonstrate stable 
renal function.
5.2.2 Exclusion Criteria for 
Severe Renally Impaired 
Participants
Exclusion Criterion #18 – was modified 
to allow enrollment of participants with 
renal impairment who use medical 
marijuana and have a valid medical 
marijuana card from a licensed 
healthcare provider.
To facilitate enrollment of participants with RI due to the 
prevalent use of medical marijuana in this patient 
population. However, participants must refrain from 
medical marijuana use for the protocol-specified time 
before and after study intervention administration
6.5 Concomitant Therapy
The following statement was added, 
“Participants with a valid medical 
marijuana card will be allowed to 
participate in the study at the discretion 
of the investigator, however, use of 
medical marijuana should be restricted at 
least 24 hours prior to, and for 24 hours 
after, study intervention administration.” 
To provide restrictions for medical marijuana usage for 
participants with severe RI with regards to study 
intervention administration.
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Section # and Name
Description of Change 
Brief Rationale 
7.3 Lost to Follow-up
Removed note in this section.
To allow a participant to be considered “lost to follow-up” 
as appropriate for the study
8.1.6 Assignment of 
Screening Number
Added the following statements, “Pre-
trial screening logs may be collected for 
review by the Sponsor. If applicable, any 
information that would make the 
participant identifiable will be 
removed.”
To allow collection of participant screening logs
8.1.7 Assignment of 
Treatment/Allocation 
Number
Changed all reference to 
“treatment/randomization number” to 
“treatment/allocation number”
To correct wording for nonrandom treatment assignment
8.1.8 Study Intervention 
Administration
Replaced “study staff” with 
“appropriately qualified designee”
To allow qualified designee who may not be “study staff” 
to administer study intervention
8.4.7 Events of Clinical 
Interest
Modified the beginning of bullet #2 to 
state, “Potential DILI events defined as 
an elevated AST…”
Clarity for the investigator/site to define what potential 
DILI is and to align with this acronym being used in the 
reporting table
10.3 Appendix 3: Adverse 
Events: Definitions and 
Procedures for Recording, 
Evaluating, Follow-up, and 
Reporting
Changed “Sponsor’s product” to “study 
intervention” throughout the subsections
To be consistent with the rest of the protocol (ie, Study 
Intervention Table)
10.3.2 Definition of AE
Removed the following text, “(also 
referred to as Sponsor’s product)”
To be consistent with the rest of the protocol (ie, Study 
Intervention Table)
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Section # and Name
Description of Change 
Brief Rationale 
Throughout Document
Minor administrative, formatting, 
grammatical, and typographical changes 
were made throughout the document.
To ensure clarity and accurate interpretation of the intent 
of the protocol.
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Table of Contents
DOCUMENT HISTORY ........................................................................................................3
PROTOCOL AMENDMENT SUMMARY OF CHANGES...............................................4
1
PROTOCOL SUMMARY ............................................................................................16
1.1
Synopsis.................................................................................................................16
1.2
Schema ..................................................................................................................19
1.3
Schedule of Activities...........................................................................................20
2
INTRODUCTION..........................................................................................................23
2.1
Study Rationale....................................................................................................23
2.2
Background ..........................................................................................................23
2.2.1
Pharmaceutical and Therapeutic Background .............................................23
2.2.2
Preclinical and Clinical Studies ...................................................................24
2.2.2.1
Preclinical Studies..............................................................................24
2.2.2.2
Completed Clinical Studies................................................................25
2.2.2.3
Ongoing Clinical Studies...................................................................26
2.2.3
Information on Other Study-related Therapy ..............................................28
2.3
Benefit/Risk Assessment......................................................................................28
3
HYPOTHESES, OBJECTIVES, AND ENDPOINTS................................................29
4
STUDY DESIGN............................................................................................................31
4.1
Overall Design......................................................................................................31
4.2
Scientific Rationale for Study Design.................................................................32
4.2.1
Rationale for Endpoints ...............................................................................33
4.2.1.1
Efficacy Endpoints.............................................................................33
4.2.1.2
Safety Endpoints................................................................................33
4.2.1.3
Pharmacokinetic Endpoints ...............................................................33
4.2.1.4
Pharmacodynamic Endpoints.............................................................34
4.2.1.5
Planned Exploratory Biomarker Research.........................................34
4.2.1.5.1
Planned Genetic Analysis ........................................................34
4.2.1.6
Future Biomedical Research..............................................................34
4.3
Justification for Dose...........................................................................................35
4.4
Beginning and End-of-Study Definition ............................................................35
4.4.1
Clinical Criteria for Early Study Termination .............................................35
5
STUDY POPULATION ................................................................................................36
5.1
Inclusion Criteria.................................................................................................36
5.1.1
Inclusion Criteria for Healthy Participants ..................................................36
5.1.2
Inclusion Criteria for Severe Renally Impaired Participants .......................39
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5.2
Exclusion Criteria................................................................................................40
5.2.1
Exclusion Criteria for Healthy Participants.................................................41
5.2.2
Exclusion Criteria for Severe Renally Impaired Participants......................43
5.3
Lifestyle Considerations......................................................................................45
5.3.1
Meals and Dietary Restrictions....................................................................45
5.3.1.1
Diet Restrictions.................................................................................45
5.3.1.2
Fruit Juice Restrictions ......................................................................45
5.3.2
Caffeine, Alcohol, and Tobacco Restrictions ..............................................46
5.3.2.1
Caffeine Restrictions..........................................................................46
5.3.2.2
Alcohol Restrictions...........................................................................46
5.3.2.3
Tobacco Restrictions..........................................................................46
5.3.3
Activity Restrictions ....................................................................................46
5.4
Screen Failures.....................................................................................................46
5.5
Participant Replacement Strategy......................................................................46
6
STUDY INTERVENTION............................................................................................47
6.1
Study Intervention(s) Administered...................................................................47
6.2
Preparation/Handling/Storage/Accountability .................................................49
6.2.1
Dose Preparation..........................................................................................49
6.2.2
Handling, Storage, and Accountability........................................................49
6.3
Measures to Minimize Bias: Randomization and Blinding..............................50
6.3.1
Intervention Assignment..............................................................................50
6.3.2
Stratification.................................................................................................50
6.3.3
Blinding........................................................................................................50
6.4
Study Intervention Compliance..........................................................................50
6.5
Concomitant Therapy..........................................................................................50
6.5.1
Rescue Medications and Supportive Care ...................................................52
6.6
Dose Modification ................................................................................................52
6.6.1
Stopping Rules.............................................................................................52
6.7
Intervention After the End of the Study............................................................52
6.8
Clinical Supplies Disclosure................................................................................52
6.9
Standard Policies..................................................................................................52
7
DISCONTINUATION OF STUDY INTERVENTION AND PARTICIPANT 
WITHDRAWAL............................................................................................................52
7.1
Discontinuation of Study Intervention...............................................................52
7.2
Participant Withdrawal From the Study...........................................................53
7.3
Lost to Follow-up .................................................................................................53
8
STUDY ASSESSMENTS AND PROCEDURES........................................................53
8.1
Administrative and General Procedures ...........................................................54
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8.1.1
Informed Consent.........................................................................................54
8.1.1.1
General Informed Consent.................................................................54
8.1.1.2
Consent and Collection of Specimens for Future Biomedical 
Research.............................................................................................55
8.1.2
Inclusion/Exclusion Criteria ........................................................................55
8.1.3
Participant Identification Card.....................................................................55
8.1.4
Medical History ...........................................................................................55
8.1.5
Prior and Concomitant Medications Review...............................................56
8.1.5.1
Prior Medications...............................................................................56
8.1.5.2
Concomitant Medications..................................................................56
8.1.6
Assignment of Screening Number...............................................................56
8.1.7
Assignment of Treatment/Allocation Number.............................................56
8.1.8
Study Intervention Administration ..............................................................56
8.1.8.1
Timing of Dose Administration.........................................................56
8.1.9
Discontinuation and Withdrawal .................................................................57
8.1.9.1
Withdrawal From Future Biomedical Research ................................57
8.1.10
Participant Blinding/Unblinding..................................................................57
8.1.11
Domiciling ...................................................................................................57
8.1.12
Calibration of Equipment.............................................................................58
8.2
Efficacy/Immunogenicity Assessments ..............................................................58
8.3
Safety Assessments...............................................................................................58
8.3.1
Physical Examinations.................................................................................58
8.3.2
Vital Signs....................................................................................................59
8.3.2.1
Resting Vital Signs ............................................................................59
8.3.3
Electrocardiograms ......................................................................................60
8.3.4
Clinical Safety Laboratory Assessments .....................................................61
8.3.5
Pregnancy Testing........................................................................................62
8.3.6
Photograph of Rash......................................................................................62
8.4
Adverse Events, Serious Adverse Events, and Other Reportable Safety 
Events....................................................................................................................62
8.4.1
Time Period and Frequency for Collecting AE, SAE, and Other 
Reportable Safety Event Information ..........................................................63
8.4.2
Method of Detecting AEs, SAEs, and Other Reportable Safety Events......65
8.4.3
Follow-up of AE, SAE, and Other Reportable Safety Event Information...65
8.4.4
Regulatory Reporting Requirements for SAE .............................................65
8.4.5
Pregnancy and Exposure During Breastfeeding ..........................................66
8.4.6
Disease-related Events and/or Disease-related Outcomes Not Qualifying 
as AEs or SAEs............................................................................................66
8.4.7
Events of Clinical Interest............................................................................66
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8.5
Treatment of Overdose........................................................................................67
8.6
Pharmacokinetics.................................................................................................67
8.6.1
Blood Collection for Plasma NHC and/or Metabolites Assay.....................67
8.6.2
Urine Collection for Urinary NHC and/or Metabolites Assay ....................67
8.7
Pharmacodynamics..............................................................................................68
8.8
Biomarkers ...........................................................................................................68
8.8.1
Planned Genetic Analysis Sample Collection..............................................68
8.9
Future Biomedical Research Sample Collection...............................................68
8.10
Health Economics Medical Resource Utilization and Health Economics.......68
8.11
Visit Requirements...............................................................................................68
8.11.1
Screening......................................................................................................68
8.11.2
Treatment Period..........................................................................................69
8.11.3
Poststudy......................................................................................................69
8.11.4
Critical Procedures Based on Study Objectives: Timing of Procedure.......69
8.11.5
Study Design/Dosing/Procedures Modifications Permitted Within 
Protocol Parameters .....................................................................................70
9
STATISTICAL ANALYSIS PLAN .............................................................................71
9.1
Statistical Analysis Plan Summary.....................................................................71
9.2
Responsibility for Analyses.................................................................................72
9.3
Hypotheses/Estimation ........................................................................................72
9.4
Analysis Endpoints...............................................................................................73
9.5
Analysis Populations............................................................................................73
9.6
Statistical Methods...............................................................................................73
9.7
Interim Analyses ..................................................................................................75
9.8
Multiplicity ...........................................................................................................75
9.9
Sample Size and Power Calculations .................................................................75
10
SUPPORTING DOCUMENTATION AND OPERATIONAL 
CONSIDERATIONS.....................................................................................................76
10.1
Appendix 1: Regulatory, Ethical, and Study Oversight Considerations........76
10.1.1
Code of Conduct for Clinical Trials.............................................................76
10.1.2
Financial Disclosure.....................................................................................78
10.1.3
Data Protection.............................................................................................79
10.1.3.1
Confidentiality of Data ......................................................................79
10.1.3.2
Confidentiality of Participant Records...............................................79
10.1.3.3
Confidentiality of IRB/IEC Information............................................79
10.1.4
Publication Policy........................................................................................80
10.1.5
Compliance with Study Registration and Results Posting Requirements ...80
10.1.6
Compliance with Law, Audit, and Debarment ............................................80
10.1.7
Data Quality Assurance ...............................................................................81
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10.1.8
Source Documents .......................................................................................82
10.1.9
Study and Site Closure.................................................................................82
10.2
Appendix 2: Clinical Laboratory Tests..............................................................83
10.3
Appendix 3: Adverse Events: Definitions and Procedures for Recording, 
Evaluating, Follow-up, and Reporting...............................................................85
10.3.1
Definitions of Medication Error, Misuse, and Abuse..................................85
10.3.2
Definition of AE ..........................................................................................85
10.3.3
Definition of SAE ........................................................................................86
10.3.4
Additional Events Reported.........................................................................87
10.3.5
Recording AE and SAE ...............................................................................88
10.3.6
Reporting of AEs, SAEs, and Other Reportable Safety Events to the 
Sponsor ........................................................................................................91
10.4
Appendix 4: Medical Device and Drug-device Combination Products: 
Product Quality Complaints/Malfunctions: Definitions, Recording, and 
Follow-up ..............................................................................................................93
10.5
Appendix 5: Contraceptive Guidance................................................................94
10.5.1
Definitions....................................................................................................94
10.5.2
Contraception Requirements........................................................................96
10.6
Appendix 6: Collection and Management of Specimens for Future 
Biomedical Research............................................................................................98
10.7
Appendix 7: Country-specific Requirements..................................................103
10.8
Appendix 8: 12-Lead Electrocardiogram Abnormality Criteria ..................104
10.9
Appendix 9: Algorithm for Assessing Out of Range Laboratory Values .....106
10.10 Appendix 10: Abbreviations .............................................................................107
11
REFERENCES.............................................................................................................111
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LIST OF TABLES
Table 1
Renal Function Group......................................................................................31
Table 2
Study Interventions..........................................................................................48
Table 3
Sample Allocation Schedule............................................................................50
Table 4
Reporting Time Periods and Time Frames for Adverse Events and Other 
Reportable Safety Events.................................................................................64
Table 5
Pharmacokinetic (Blood for Plasma NHC Assay) Collection Windows.........70
Table 6
Protocol-required Safety Laboratory Assessments..........................................83
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LIST OF FIGURES
Figure 1
Study Schema...................................................................................................19
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1
PROTOCOL SUMMARY
1.1
Synopsis
Protocol Title: An Open-Label, Single-Dose Study to Evaluate the Pharmacokinetics of 
Molnupiravir (MK-4482; MOV) in Participants with Severe Renal Impairment 
Short Title: Molnupiravir (MK-4482; MOV) Renal Impairment Study
Acronym: Not applicable
Hypotheses, Objectives, and Endpoints:
Hypotheses are aligned with objectives in the Objectives and Endpoints table.
The following objectives will be evaluated in adult male and female participants with severe 
renal impairment between the ages of 18 to 75 (inclusive) and healthy mean matched 
controls. 
Objectives
Endpoints
Primary
•
To evaluate the plasma pharmacokinetics of 
the N-hydroxycytidine, the nucleoside 
metabolite of molnupiravir, after a 
single-oral dose of 800-mg molnupiravir in 
participants with severe renal impairment 
compared to healthy mean matched control 
participants.
•
Hypothesis: In participants with severe 
renal impairment, the geometric mean 
AUC0-inf of N-hydroxycytidine is similar 
to that observed in the healthy mean 
matched control participants following a 
single dose of 800 mg molnupiravir; that is, 
the true AUC0-inf geometric mean ratio 
(severe renal impairment/healthy control) is 
less than 2.0.
•
Estimation: In participants with severe renal 
impairment, plasma pharmacokinetics 
(Cmax) of N-hydroxycytidine following a 
single 800 mg molnupiravir dose will be 
estimated and compared to those observed 
in healthy mean matched control 
participants.
•
AUC0-inf and Cmax of plasma N-
hydroxycytidine.
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Objectives
Endpoints
Secondary
•
To evaluate the safety and tolerability of 
molnupiravir in participants with severe 
renal impairment.
•
Adverse events
•
To evaluate urinary excretion of 
N-hydroxycytidine after a single oral dose 
of 800 mg molnupiravir in participants with 
severe renal impairment compared to 
healthy mean matched control participants.
Ae and Fe of N-hydroxycytidine in 
urine and CLr of N-hydroxycytidine
Overall Design:
Study Phase
Phase 1
Primary Purpose
Treatment
Indication
Treatment of COVID-19
Population
Participants with Severe Renal Impairment and Healthy 
Participants
Study Type
Interventional
Intervention Model
Parallel
This is a multi-site study.
Type of Control
Healthy mean matched control participants
Study Blinding
Unblinded Open-label
Blinding Roles
No Blinding
Estimated Duration of Study
The Sponsor estimates that the study will require 
approximately 5 months from the time the first participant 
(or their legally acceptable representative) provides 
documented informed consent until the last participant’s 
last study-related contact.
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Number of Participants:
Approximately 16 to 18 participants will be allocated.
Intervention Groups and Duration:
Intervention 
Groups
Intervention 
Group Name
Drug
Dose 
Strength
Dose 
Frequency
Route of 
Administration
Regimen
Use
Severe Renal 
Impairment 
Group
MK-4482 
(MOV)
800 mg
Single 
Dose
Oral
Single 
Dose on 
Day 1
Test 
Product
Healthy Mean
Matched 
Control 
Group
MK-4482
(MOV)
800 mg
Single 
Dose
Oral
Single 
Dose on 
Day 1
Test 
Product
Other current or former name(s) or alias(es) for study intervention(s) are as 
follows: MK-4482; Molnupiravir, MOV; formerly known as EIDD-2801
Total 
Number of 
Intervention 
Groups/
Arms
2
Duration of 
Participation
Each participant will participate in the study for approximately 6 weeks from 
the time the participant provides documented informed consent through the 
final contact.
Study Governance Committees:
Executive Oversight Committee
No
Data Monitoring Committee
No
Clinical Adjudication Committee
No
There are no governance committees in this study. Regulatory, ethical, and study oversight 
considerations are outlined in Appendix 1.
Study Accepts Healthy Volunteers: Yes
A list of abbreviations is in Appendix 10.
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1.2
Schema
The study design is depicted in Figure 1.
Figure 1
Study Schema
NHC=N-hydroxycytidine
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1.3
Schedule of Activities
All Participants
Study Period:
Screening 
Visit 1
Screening 
Visit 2
Check-In
Intervention
Post-
studya
Notes
Scheduled Day
Up to -28
-1
1
1
2
3
4
~15
Scheduled Hour
Pre-
dose
0
0.5
1.5
2
4
6
8
12
24
48
72
Administrative and Study Procedures
Informed Consent
X
Sec. 5.1, 8.1.1
Informed Consent for FBR
X
Sec. 5.1, 8.1.1.2
Inclusion/Exclusion Criteria
Xb
Xb
Review to occur at 
Screening and after 
predose procedures. 
Sec. 5.1, 5.2, and 8.1.2
Participant ID Card
X
Sec. 8.1.3
Medical History
X
X
X
Includes history of
illicit drug, alcohol, 
tobacco, and caffeine 
use. Sec. 8.1.4
Prior/Concomitant Medication 
Review
X-------------------------------------------------------------------------------------------------X
Sec. 5.2, 6.5 and 8.1.5
Assignment of Screening Number
X
Sec. 8.1.6
Assignment of Treatment/
Allocation Number
X
To be assigned within 
24 hours prior to study 
intervention 
administration.
Sec. 5.5, 8.1.7
Participant Visit to CRU
X
Xb
X
X
X
X
Domicilingc
X---------------------------------------------------X
Sec. 8.1.11
Standard Mealsd
X
Sec. 5.3.1
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All Participants
Study Period:
Screening 
Visit 1
Screening 
Visit 2
Check-In
Intervention
Post-
studya
Notes
Scheduled Day
Up to -28
-1
1
1
2
3
4
~15
Scheduled Hour
Pre-
dose
0
0.5
1.5
2
4
6
8
12
24
48
72
MOV Administration
X 
Sec. 8.1.8.
Safety Procedures
Full physical examination
X
Xe
X
Sec. 8.3.1
Height
X
Sec. 8.3.1
Weight
X
X
BMI and BSA will be 
assessed only at 
Screening. Sec. 8.3.1
VS (HR, BP)
X
Xf
X
X
X
X
Sec. 8.3.2
VS (RR, BT)
X
Xf
X
X
Sec. 8.3.2
12-lead ECG
X
Xf
X
X
Sec. 8.3.3
Serum
(hCG; WOCBP only)
X
Xe
X
Result to be reviewed 
prior to dosing on 
Day 1. Sec. 8.3.5 and 
Appendix 2
Serum FSH -
(postmenopausal WONCBP only)
X
Appendix 2
HIV, hepatitis B and C screen 
(per site SOP)
X
Sec 8.3.4, Appendix 2
UDS/BDS (per site SOP)
X
Xe
Sec 8.3.4, Appendix 2
Hematology/Chemistry
X
Xb,e
X
X
Fast for at least 8 hours 
prior to sample 
collection. Sec. 8.3.4 
and Appendix 2
Serum Cystatin C
X
Xe
Appendix 2
Urinalysis
X
Xe
X
X
Sec. 8.3.4
AE/SAE review
X---------------------------------------------------------------------------------------------X
Sec. 8.4
Pharmacokinetics
Blood for Plasma NHC Assay
X
X
X
X X X X
X
X
X
X
Sec. 8.6.1
Urine for NHC Assayg
X
X----------------X----X--X--X
Sec. 8.6.2
Biomarkers
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All Participants
Study Period:
Screening 
Visit 1
Screening 
Visit 2
Check-In
Intervention
Post-
studya
Notes
Scheduled Day
Up to -28
-1
1
1
2
3
4
~15
Scheduled Hour
Pre-
dose
0
0.5
1.5
2
4
6
8
12
24
48
72
Blood for Genetic Analysis
X
Collect predose from 
enrolled participants 
only. Sec. 8.8
AE=adverse event; BDS=blood drug screen; BMI=body mass index; BP=blood pressure; BT=body temperature; CRU=clinical research unit; ECG=electrocardiogram; FBR=future biomedical research; 
FSH=follicle stimulating hormone; hCG=human chorionic gonadotropin; HIV=human immunodeficiency virus; HR=heart rate; ID=identification; MOV=molnupiravir; NHC=N-hydroxycytidine; 
RR=respiratory rate; SAE=serious adverse event; SOP=standard operating procedure; UDS=urine drug screen; VS=vital signs; WOCBP=women of childbearing potential; WONCBP=women of non-
childbearing potential.
a Poststudy visit should occur approximately 14 days postdose. If the visit occurs prior to 14 days postdose, verbal contact should be made to assess for AEs 14 days postdose.
b Baseline eGFR will be obtained twice (at least 72 hours apart as part of participant screening) based on the 2021 CKD-EPI Creatinine (CKD-EPIcr_R) equation. The second baseline eGFR may be 
obtained at the time of Day -1 check-in but data must be available before dosing on Day 1 to ensure eligibility.
c Participants will report to the CRU on Day -1, at the time indicated by the CRU (~24 hours prior to dosing on Day 1). Participants will be discharged after completion of the 24-hour postdose 
procedures on Day 2.
d A standard meal will be provided as follows relative to dosing: lunch at approximately 4 hours postdose. After the 4-hour postdose standard meal has been completed, subsequent meals and snacks 
will be unrestricted in terms of caloric content, composition, and timing.
e Predose full physical examination, serum pregnancy test (WOCBP only), UDS/BDS, hematology/chemistry (including serum cystatin C), and urinalysis may be conducted/collected upon admission 
to the CRU but within 24 hours of study drug administration.
f Predose VS and 12-lead ECG to be measured within 3 hours prior to study drug administration. Predose VS (HR and BP) and ECG measurements will be done in triplicate and all other 
measurements, including Predose RR and BT, will be single measurements.
g Urine samples will be collected at predose (baseline) and at the following intervals postdose: 0 to 4 hours, 4 to 8 hours, 8 to 12 hours, and 12 to 24 hours.
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2
INTRODUCTION
Molnupiravir (also known as MK-4482 and EIDD-2801; hereafter referred to as MOV) is a 
novel ribonucleoside analog prodrug with broad-spectrum antiviral activity against a range of 
RNA viruses, including coronaviruses. MOV has been developed as an oral treatment for the 
treatment of mild-to-moderate COVID-19 (laboratory-confirmed SARS-CoV-2 infection 
with symptoms) in those who are at risk to progress to severe disease. MOV is additionally 
being evaluated for prophylaxis for COVID-19 in initially asymptomatic individuals ≥18 
years of age residing with a person with COVID. This study will evaluate the tolerability and 
PK of a single 800 mg dose of MOV in participants with severe renal impairment compared 
to participants with normal renal function.
2.1
Study Rationale
Following administration of MOV, MOV is rapidly converted to NHC, its active metabolite; 
MOV is only detected at very low levels systemically. Preclinical and clinical data indicate 
that renal excretion is a minor route of elimination of MOV and NHC. Minimal renal 
elimination of NHC was observed in healthy adults. Only 3% of the 800-mg dose was 
excreted renally as NHC at steady-state over the 12-hour dosing interval. 
The impact of renal impairment on NHC exposures has been evaluated in a PopPK analysis 
of a total of 1207 participants with data on renal function (evaluated based on MDRD) from a 
Phase 2/Phase 3 trial. Renal impairment was not identified as a statistically significant 
covariate in the model. Compared to participants with normal renal function, the GMR (90% 
CI) of NHC AUC was 1.01 (0.975, 1.05) and 1.18 (1.09, 1.28) in participants with mild and 
moderate renal impairment, respectively. Individuals with severe renal impairment (eGFR 
<30 mL/min/1.73 m2) were excluded from these clinical studies. Extrapolation of NHC 
exposures from mild and moderate populations to eGFR values associated with severe renal 
impairment suggests a small potential increase in NHC exposures in this population. 
While the existing preclinical and clinical data suggest that any degree of renal impairment 
will not meaningfully impact metabolism and elimination of MOV and/or NHC, this study is 
being conducted to further evaluate the effect of renal impairment in individuals with severe 
renal insufficiency (eGFR < 30) on plasma NHC PK. A reduced PK study design is proposed 
consistent with FDA guidelines for drugs that are predominantly eliminated though nonrenal 
routes.
2.2
Background
Refer to the IB/approved labeling for detailed background information on MOV.
2.2.1
Pharmaceutical and Therapeutic Background
MOV is a novel, broadly active, direct-acting antiviral that inhibits replication of enveloped 
positive strand RNA viruses, including the highly pathogenic coronaviruses (SARS-CoV-2, 
MERS-CoV). Following MOV oral administration, MOV is rapidly absorbed in the gut 
where it is hydrolyzed to the parent nucleoside analog NHC, which is widely distributed to 
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tissues (including lungs and brain) and metabolized to the pharmacologically active 
triphosphate form (NHC-TP). NHC-TP is incorporated into the viral RNA by viral RNA 
polymerase, leading to an inhibition of viral replication due to the accumulation of errors in 
the viral genome. Viral error catastrophe, a concept that is predicated on increasing the viral 
mutation rate beyond a biologically tolerable threshold, results in impairment of viral fitness 
leading to viral extinction. This mechanism is distinct from that of remdesivir where its 
incorporation into nascent RNA results in premature termination of RNA synthesis, halting 
growth of the RNA strand after a few more nucleotides are added [Gordon, C. J., et al 2020].
NHC demonstrated a high barrier to the development of resistance in vitro and is anticipated 
to slow or prevent emergence of viral resistance in humans. NHC has also demonstrated in 
vitro activity against remdesivir-resistant SARS-CoV-2 and a related coronavirus (mouse 
hepatitis virus) with F476L and V553L mutations in the viral RNA polymerase. Given the 
unique mechanism of action, NHC is expected to be active against viruses resistant to other 
antiviral agents as well as emerging SARS-CoV-2 variants of concern with spike protein 
mutations.
MOV is unlikely to be a victim or perpetrator of CYP-related DDIs based on its anticipated 
metabolic pathways and lack of CYP inhibition/induction in vitro. A DDI between MOV and 
remdesivir is also not expected, given these 2 prodrugs are cleaved in distinct locations (gut 
versus target cells) and the exposure of their active triphosphate metabolites in cells are 
regulated by different enzymes in 2 distinct nucleotide pathways (pyrimidine versus purine). 
To evaluate possible interactions of approved antiviral drugs on the activity of MOV, in vitro 
drug-drug combination studies were performed. SARS-CoV-2 infected Vero cells were 
treated with NHC (MOV parent) in combination with other antiviral drugs including 
remdesivir, tenofovir, lamivudine, emtricitabine, abacavir, nelfinavir, ribavirin, sofosbuvir, 
and hydroxychloroquine, and antiviral activity and cellular toxicity were assessed. Results 
demonstrated no significant interaction (synergistic or antagonistic) of any drug tested on the 
antiviral activity or toxicity profile of NHC in this culture system.
COVID-19, the disease caused by the novel SARS-CoV-2 virus, can produce a range of 
clinical manifestations, from an asymptomatic carrier state to critical illness, characterized 
primarily by acute respiratory failure [Wu, Z. 2020] [Grasselli, G., et al 2020] [Guan, W., et 
al 2020]. There remains a need for additional direct-acting antiviral agents active against 
SARS-CoV-2, particularly agents that are administered orally in medically complex 
populations with multiple medications or comorbidities. Results from clinical studies support 
the therapeutic benefit of MOV in non-hospitalized individuals with mild-to-moderate 
COVID-19.
2.2.2
Preclinical and Clinical Studies
2.2.2.1
Preclinical Studies
Primary pharmacology studies have demonstrated antiviral activity of MOV and NHC 
against SARS-CoV-2 and other RNA viruses that were conducted in vitro and in vivo (ie, 
mouse, guinea pig, hamster, and ferret) models of viral infection. NHC has shown antiviral 
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activity against SARS-Cov-2 variants of concern, the Alpha, Beta, Gamma, Delta, and 
Omicron, and remdesivir-resistant strains.
MOV was evaluated in nonclinical safety studies, including a standard battery of in vitro and 
in vivo safety pharmacology studies, genotoxicity assays (including Ames assays, in vitro 
and in vivo micronucleus assays, an in vivo Pig-a assay in rats, and an in vivo mutation assay 
in Big Blue® [BioReliance] transgenic rats), tolerability/dose-range-finding studies in mice, 
rats, and dogs, repeat-dose toxicity studies of up to 3 months in rats and 1 month in mice and 
dogs, fertility studies in male and female rats, embryo-fetal developmental toxicity studies in 
rats and rabbits, a pre- and post-natal developmental toxicity study in rats, and toxicity 
studies in juvenile rats. Additional nonpivotal short-term tolerability and/or toxicokinetic 
studies were conducted in mice, rats, rabbits, and monkeys.
MOV was devoid of effects on CNS, respiratory, or cardiovascular functions in 
well-characterized safety pharmacology models. The integrated assessment of the mutagenic 
and genotoxic potential of MOV indicates that MOV is not mutagenic or genotoxic in in vivo 
mammalian systems.
In the 1-month repeat-dose toxicity study in dogs (doses of 6, 17, and 50 mg/kg/day), mild 
dose-related hematologic findings affecting all cell lines were observed following 7 days of 
dosing. More severe hematologic changes were apparent after 14 to 21 days of continuous 
dosing leading to pancytopenia, including severe thrombocytopenia and associated 
hemorrhage at 17 mg/kg/day (0.4-fold the clinical NHC AUC0-24 exposure) and 
50 mg/kg/day (2-fold the clinical NHC AUC0-24 exposure). This resulted in early 
termination of treatment at 50 mg/kg/day after 2 weeks and at 17 mg/kg/day after 3 weeks. 
These hematologic changes were secondary to decreased cellularity of the bone marrow 
hematopoietic precursors (bone marrow depletion) observed at postmortem examinations. 
The hematopoietic changes were fully reversible at 17 mg/kg/day with essentially normal 
bone marrow and hematologic parameter values following a 1-month recovery period. 
Animals in the 50 mg/kg/day group were euthanized approximately 10 days after treatment 
termination; hematopoietic changes were partially reversible during the shortened recovery 
period. Only minor, reversible, non-adverse hematopoietic changes were seen in animals 
administered 6 mg/kg/day for 28 days. The NOAEL in dogs was therefore 6 mg/kg/day 
(0.1-fold the NHC AUC0-24 exposure at the 800 mg Q12H human dose).
Refer to the IB for additional information on preclinical and clinical studies conducted with 
MOV.
2.2.2.2
Completed Clinical Studies
MOV has been evaluated in three completed Phase 1 studies (P004, P008, P012) and 1
completed Phase 2a study (P006) (Refer to the IB Section 5 for the detailed study designs on 
each study).
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Phase 1 Studies:
MK-4482-004 was a randomized, double-blind, placebo-controlled, FIH study designed to 
evaluate the safety, tolerability, and PK of MOV following oral administration to healthy 
participants. Oral doses (50 to 1600 mg as a single dose, including 200 mg with a high fat 
meal, and 50 to 800 mg as multiple doses [Q12H for 5.5 days]) of MOV or placebo 
administered to 130 healthy participants were generally well tolerated. Out of these 
130 participants, 100 received at least one dose of MOV. No deaths or SAEs were reported.
MK-4482-008 was a single and multiple-dose, randomized, placebo-controlled, double-blind 
study of MOV in healthy Japanese adult male participants. Single doses of MOV up to 
1600 mg, including 800 mg with a high fat meal, and multiple doses of MOV 400 mg and 
800 mg Q12H for 5.5 days were generally well tolerated in healthy Japanese male adult 
participants. Out of 79 randomized participants, 51 received at least one dose of MOV. No 
SAEs, deaths or ECIs were reported. 
MK-4482-012 was a randomized, double-blind, placebo-controlled, multiple ascending dose 
study to evaluate the safety, tolerability, and PK of MOV. Daily Q12H doses of 400, 600, 
and 800 mg MOV for 10.5 days were generally well tolerated in healthy adult study 
participants. Out of 32 randomized participants, 24 received at least 1 dose of MOV. No 
SAEs, deaths or ECIs were reported and no study intervention-related clinically meaningful 
changes in vital sign values, ECGs, or safety laboratory values (including hematology) were 
observed as a function of dose or treatment.
Phase 2/2a Study:
MK-4482-006 was a Phase 2a, randomized, double-blind, placebo-controlled study to 
evaluate the safety, tolerability, and efficacy of MOV (Q12H for 5 days) in non-hospitalized 
adults with COVID-19. Time to clearance of viral RNA in nasopharyngeal swabs was the 
primary endpoint of this study and was shorter in participants receiving 800 mg MOV 
(median: 14 days) compared with those administered placebo (log-rank p = 0.0128). MOV 
200 mg (n=23), 400 mg (n=62) or 800 mg (n=55) or placebo (n=62) was generally 
well-tolerated with a comparable incidence of AEs across the intervention groups. Four 
SAEs were reported (3 participants in the MOV groups combined, 1 in the placebo group); 
none were considered related to study intervention by the investigator. No participants died 
while enrolled in the study.
2.2.2.3
Ongoing Clinical Studies
MOV is being evaluated in 1 ongoing Phase 1 study (P010), 1 ongoing Phase 1/2 study 
(P005), 1 ongoing Phase 2a study (P007), 2 ongoing Phase 2/3 studies (P001, P002), and 
1 ongoing Phase 3 study (P013) (Refer to the IB Section 5 for the detailed study designs on 
each study).
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Phase 1 or 1/2 Studies:
MK-4482-010 is a randomized, 4-treatment, 4-period crossover, single site, open-label, 
relative bioavailability study of MOV oral granules and MOV reference capsule formulations 
in healthy adult participants. A total of 16 participants were randomized into 4 treatment 
sequences consisting of a single 800-mg dose of MOV administered as oral granules in 
water, apple sauce or pudding or as the reference capsule formulation with water. Relative 
bioavailability was assessed through repeat evaluations of plasma NHC PK. The study is 
clinically complete, and the clinical study report is being authored.
MK-4482-005 is a Phase 1/2 randomized, multicenter, seamless, adaptive study to determine 
the optimal dose, safety, and efficacy of MOV for the treatment of COVID-19. The primary 
efficacy objective is to determine the ability of MOV to reduce serious complications of 
COVID-19 including hospitalization, reduction in SaO2 <92%, or death. As of 
14-MAR-2022, 18 participants enrolled in Phase 1 (12 received MOV; 300 mg n=4; 600 mg 
n=4; 800 mg n=4), and 178 participants enrolled in Phase 2. Enrollment is complete and 
patient activity is ongoing. Based on preliminary review of blinded safety data, 5 SAEs were 
reported, 1 of which (vomiting) was considered related to study intervention by the 
investigator. No deaths were reported.
Phase 2a Study:
MK-4482-007 is a Phase 2a randomized, placebo-controlled, double-blind clinical study of 
MOV in adults who have tested positive for SARS-CoV-2 infection via PCR and are 
hospitalized with a diagnosis of COVID-19 with symptoms of ≤8 days. The primary efficacy 
objective is to measure the proportion of nasopharyngeal swabs and saliva from recipients 
becoming undetectable for SARS-CoV-2 RNA at Day 5 of MOV administration compared 
with placebo. As of 14-MAR-2022, 71 participants were enrolled in the study and enrollment 
is closed as of 15-FEB-2022. Based on preliminary review of blinded safety data, SAEs were 
reported for 4 participants, none were considered related to study intervention by the 
investigator. Of the 4 participants who had SAE, one had SAE of hypovolemic shock on 
Day 12 and died of respiratory failure on Day 28, and one had SAE of worsening bradycardia 
and hypotension that required discontinuation of study intervention. No other deaths or other 
AEs requiring discontinuation of study intervention have been reported.
Phase 2/3 or 3 Studies:
MK-4482-001 is a Phase 2/3 randomized, placebo-controlled, double-blind clinical study to 
evaluate the efficacy, safety, and PK of MOV in hospitalized adults with COVID-19. In the 
Phase 2 portion of the study (Part 1) a total of 218 hospitalized participants with COVID-19 
received at least 1 dose of MOV (72 participants received MOV 800 mg) and 75 participants 
received placebo. MOV was generally well-tolerated with a comparable incidence of AEs 
across the intervention groups. SAEs were reported for 15.4% participants (15.1% MOV 
groups, 16.0% placebo), with 1 SAE deemed related to study intervention by the investigator 
(Grade 3 urticaria) for 1 participant in the MOV 200 mg treatment group. A total of 16 
participants had AEs leading to death (6.4% MOV groups combined, 2.7% placebo), none of 
which were considered study intervention-related by investigator assessment. The study was 
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stopped due to lack of clinical benefit in this population (participants already hospitalized 
prior to randomization) and did not proceed to the Phase 3 portion of the study (Part 2). All
participants have now completed the 7-month poststudy visit.
MK-4482-002 is a Phase 2/3, randomized, placebo-controlled, double-blind, multisite study 
to evaluate the efficacy, safety, and PK of MOV administered to non-hospitalized adults with 
laboratory-confirmed COVID-19 and symptom onset within 7 days (Part 1, Phase 2) or 
within 5 days (Part 2, Phase 3) prior to randomization, and all participants must have at least 
one risk factor for progressing to severe illness from COVID-19. Enrollment into the study is 
complete and the study conduct is clinically complete up to Day 29 in Part 2 (Phase 3). 
Participants are in the 7-month follow up period. MOV 200 mg (n=74), 400 mg (n=77), 
800 mg (n=74) or placebo (n=74) Q12H for 5 days in Part 1 and MOV 800 mg (n=710) or 
placebo (n=701) Q12H for 5 days in Part 2 were generally well tolerated. In Part 2 (Phase 3), 
the proportion of participants with AEs, drug-related AEs (per investigator assessment), AEs 
leading to death, SAEs, and AEs leading to study intervention discontinuation, were 
comparable for the intervention groups. AEs leading to death occurred in a higher proportion 
of participants who received placebo. All participants will be followed until the 7-month 
poststudy visit.
MK-4482-013 is a Phase 3, multicenter, randomized, double-blind, placebo-controlled study 
to evaluate the efficacy and safety of MOV for the prevention of COVID-19 
(laboratory-confirmed SARS-CoV-2 infection with symptoms) in adults residing with a 
person with COVID-19. As of 14-MAR-2022, 798 household participants were randomized 
out of a planned total of 1500 participants.
2.2.3
Information on Other Study-related Therapy
There is no other study-related therapy in this protocol.
2.3
Benefit/Risk Assessment
Participants in clinical studies will not receive direct benefit from treatment during 
participation as clinical studies are designed to provide information about the safety and 
properties of an investigational medicine. 
The totality of the safety data from Phase 1 through Phase 3 studies and post authorization 
surveillance demonstrate an acceptable safety and tolerability profile of MOV.
There were no effects on cardiovascular, neurological, and respiratory function in several 
well-characterized safety pharmacology experimental models. The integrated assessment of 
the mutagenic and genotoxic potential of MOV indicates that MOV is not mutagenic or 
genotoxic in in vivo mammalian systems.
As described in Section 2.2.2, in a 28-day repeat dose toxicity study with MOV in dogs, 
reversible hematologic toxicities were noted after Day 7 at exposures 0.4-fold those of the 
anticipated clinical exposures at the 800-mg Q12H dose. However, to date no clinically 
meaningful hematological changes have been observed in healthy participants up to 800-mg 
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MOV Q12H for up to 10.5 days or in participants with COVID-19 at multiple doses up to 
800 mg Q12H for 5 days.
Histopathology results from the 3-month rat toxicity study demonstrated an increase in the 
thickness of the growth plate/physis, a finding not observed in 1-month studies in rats, dogs, 
or mice. These findings are not considered to represent a significant new risk to human 
adults. 
In fertility studies in rats, there were no MOV-related effects on female or male fertility, or 
on early embryonic development up to the highest dose tested, 500 mg/kg/day, (2.1/6.1-fold 
[female/male] the clinical NHC exposure at 800 mg Q12H). While embryolethality 
(post-implantation losses) and teratogenicity were limited to rats exposed to 7.5-fold the 
clinical NHC exposure at 800 mg Q12H during the organogenesis period, and these 
developmental findings were not observed in rats up to 2.9-fold the clinical NHC exposure at 
800 mg Q12H and rabbits up to 18-fold the clinical NHC exposure at 800 mg Q12H, 
WOCBP will be required to use effective contraception for the duration of treatment and for 
at least 4 days postdose.
It is important to note that the animal/human AUC0-24 exposure multiples are expected to be 
approximately 2-fold higher when human participants are dosed only once at 800 mg.
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.
The following objectives will be evaluated in adult male and female participants with severe 
renal impairment between the ages of 18 to 75 (inclusive) and healthy mean matched 
controls. 
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Objectives
Endpoints
Primary
•
To evaluate the plasma pharmacokinetics of 
the N-hydroxycytidine, the nucleoside 
metabolite of molnupiravir, after a single-oral 
dose of 800-mg molnupiravir in participants 
with severe renal impairment compared to 
healthy mean matched control participants.
•
Hypothesis: In participants with severe renal 
impairment, the geometric mean AUC0-inf of 
N-hydroxycytidine is similar to that observed 
in the healthy mean matched control 
participants following a single dose of 800 mg 
molnupiravir; that is, the true AUC0-inf 
geometric mean ratio (severe renal 
impairment/healthy control) is less than 2.0.
•
Estimation: In participants with severe renal 
impairment, plasma pharmacokinetics (Cmax) 
of N-hydroxycytidine following a single 
800 mg molnupiravir dose will be estimated 
and compared to those observed in healthy 
mean matched control participants.
•
AUC0-inf and Cmax of plasma N-
hydroxycytidine.
Secondary
•
To evaluate the safety and tolerability of 
molnupiravir in participants with severe renal 
impairment.
•
Adverse events
•
To evaluate urinary excretion of 
N-hydroxycytidine after a single oral dose of 
800 mg molnupiravir in participants with 
severe renal impairment compared to healthy 
mean matched control participants.
Ae and Fe of N-hydroxycytidine in 
urine and CLr of N-hydroxycytidine
Tertiary/Exploratory
•
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 and 
association to clinical data 
collected in this study.
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4
STUDY DESIGN
4.1
Overall Design
This is a non-randomized, open-label, single-dose, multi-site study of MOV in adult male 
and female participants with severe renal impairment (Panel A; n=8) and healthy mean 
matched controls (Panel B; n = 8 to 10). Healthy control participants will be matched for 
mean age (± 10 years) and BMI (± 3.5 kg/m2) of participants with severe renal impairment. 
In addition, the numbers of males and females of the healthy participants will be generally 
matched to the numbers of renal impairment participants within ± 1, for the first 
8 participants enrolled. Up to an additional 2 healthy participants may be enrolled as needed, 
to maintain the mean-matching of the healthy participant panel to the severe renal 
impairment panel. If additional healthy matched control participants are enrolled (beyond the 
minimum 8 participants), the total number of males and females in the healthy panel should 
be as close as possible to the overall proportion of males and females in the renal impairment 
panel.
Assignment to a renal function group will be as shown in Table 1:
Table 1
Renal Function Group
Panel
Renal Impairment Stage
n
eGFR (mL/min)a,b
A
Severe
8
< 30, not on dialysisc
B
Healthy
8 to 10d
≥ 90
BSA=body surface area; cr=creatinine; eGFR=estimated glomerular filtration rate; CKD-EPI Chronic Kidney Disease 
Epidemiology Collaboration
a eGFR based on the 2021 CKD-EPI Creatinine (CKD-EPIcr_R) equation that does not require use of race. Baseline 
eGFR will be obtained twice (at least 72 hours apart as part of participant screening) and the mean of the 2 values will 
be used. The second baseline eGFR sample may be obtained at the time of check-in as long as data are available in time 
to confirm eligibility.
b eGFR criteria will use de-indexed values to correct for participant BSA. To convert indexed eGFR expressed as 
mL/min/1.73 m2, this value will be divided by 1.73 and multiplied by participant BSA.
c Reasonable efforts will be made to enroll at least 1 to 2 participants in the severe renal impairment group who have 
eGFR values of 10 to 20 mL/min.
d May need to enroll more than 8 to enable mean matching of the healthy match controls to the participants with severe 
renal impairment
On Day 1, participants will receive a single oral dose of 800 mg (4 x 200 mg capsules) MOV, 
followed by PK sampling until 24 hours postdose in the clinic. There will be additional 
outpatient visits on Day 3 and Day 4 for the collection of 48- and 72-hour postdose PK 
samples and a follow-up visit approximately 14 days postdose. Safety will be monitored 
throughout the study by repeated clinical and laboratory evaluations.
Because this is a Phase 1 assessment of MOV in humans, the PK, pharmacodynamic, and 
safety profiles of the compound are still being elucidated. This protocol is therefore written 
with flexibility to accommodate the inherent dynamic nature of Phase 1 clinical studies. 
Refer to Section 8.11.5 for examples of modifications permitted within the protocol 
parameters.
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Specific procedures to be performed during the study, including prescribed times and 
associated visit windows, are outlined in Section 1.3 of the SoA. Details of each procedure 
are provided in Section 8.
4.2
Scientific Rationale for Study Design
This open-label, single dose study will investigate the PK of NHC following a single 800-mg 
dose of MOV in participants with severe renal impairment compared to participants with 
normal renal function. Phase 1 studies of MOV with doses ranging from 50 to 800 mg 
indicated that there was minimal renal elimination of MOV or active metabolite NHC with 
≤3% renal excretion at steady state with 800 mg Q12H dosing. PopPK analyses were 
performed using data from protocols MK-4482-001, MK-4482-002, MK-4482-004, and 
MK-4482-006 that included 1207 participants, including 580 participants with mild renal 
impairment and 84 participants with moderate renal impairment. Compared to participants 
with normal renal function, the GMR (90% CI) of NHC AUC was 1.01 (0.975, 1.05) and 
1.18 (1.09, 1.28) in participants with mild and moderate renal impairment, respectively. 
Extrapolation of these exposures to eGFR values associated with severe renal impairment 
(22.5 mL/min) resulted in a predicted GMR of 1.28 in this subpopulation. These findings 
suggest that severe renal impairment is unlikely to impact NHC PK to an extent that is 
clinically meaningful. However, it is possible that severe renal impairment may alter 
absorption, hepatic metabolism, plasma protein binding, and drug distribution. Based on the 
ADME and PopPK analysis, this study is proposed using a “reduced study design” in 
keeping with FDA guidance for studies of drug PK and dosing in renal impairment.
As NHC exhibits linear PK with minimal to no accumulation and single dose PK is 
predictive of multiple dose PK, administration of a single dose of MOV in this study is 
considered adequate to evaluate the effect of renal impairment on plasma NHC PK. In this 
protocol, we will obtain baseline eGFR using the most recent 2021 CKD-EPI equations that 
do not utilize race in accordance with recent recommendations from a joint NKF/ASN Task 
Force. Multi-investigator studies using numerous cohorts in diverse populations led to the 
formulation of improved eGFR equations that did not require use of race that were shown to 
be accurate with minimal bias. The most accurate equation used both creatinine and serum 
cystatin C (CKD-EPIcr-cys_R), whereas a new improved equation using creatinine without 
cystatin C was also developed (CKD-EPIcr_R)[Inker, L. A., et al 2021]. Guidance from the 
NKF/ASN taskforce strongly recommended immediate implementation of the new 2021 
CKD-EPI equations. Because of more limited availability of routine cystatin C testing, this 
study will utilize the 2021 CKD-EPI Creatinine equation (CKD-EPIcr_R) for assessment of 
eGFR in accordance with Task Force recommendations [Delgado, C., et al 2021]. The Task
Force also recommended efforts to make cystatin C levels routinely available and use of the 
2021 CKD-EPI Creatinine-Cystatin C as a more accurate confirmatory and future first-line 
test. Cystatin C levels will therefore also be collected in order to facilitate calculation of 
eGFR using the 2021 CKD-EPI Creatinine-Cystatin C (CKD-EPIcr-cys_R) equation for 
future comparisons with other studies that include cystatin C levels as this test becomes more 
routinely used to estimate GFR. The 2021 CKD-EPI Creatinine-Cystatin C equation will not 
be used for calculation of eGFR to determine participant eligibility. Finally, in alignment 
with the FDA draft guidance on “Pharmacokinetics in Patients with Impaired Renal Function 
(September 2020)”, we will apply a correction for participant BSA (de-indexed or 
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nonindexed eGFR) with the use of the CKD-EPIcr_R equation for calculation of eGFR to 
determine participant eligibility.
Individuals without renal impairment (eGFR ≥90) will serve as a control group. To 
adequately assess the impact of renal impairment, enrolled participants with reasonably 
matched demographics to mean demographic parameters (age and BMI) will be enrolled.
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 studies have evaluated oral MOV in human participants, including single doses as 
high as 1600 mg and multiple doses up to 800 mg Q12H. Overall, MOV has been generally 
well tolerated, and there have been no concerning safety signals from oral MOV
administration. As such, standard safety monitoring of AEs, PEs, VSs, 12-lead ECGs, and 
laboratory safety tests (hematology, serum chemistry, and urinalysis), obtained pre- and 
post-dosing, should be adequate to assess tolerability of a single dose of MOV in this study.
4.2.1.3
Pharmacokinetic Endpoints
Following oral administration of MOV (the prodrug), MOV is only detected at very low 
levels in systemic circulation due to rapid conversion to NHC (the circulating nucleoside 
analogue). NHC exposures in plasma have been shown to be well correlated with NHC-TP 
exposures in PBMCs, with plasma NHC AUC being a consistent strong correlate of NHC-TP 
exposures. Furthermore, the t1/2 of NHC-TP in PBMCs was consistent with the terminal t1/2 
of NHC in plasma. Based on this, the more readily available plasma NHC exposures are 
considered an appropriate surrogate for the pharmacologically active NHC-TP, and therefore 
plasma NHC will be measured in this study for the evaluation of the primary PK objective.
In Phase 1 SAD and MAD studies, the median NHC Tmax at doses up to 800 mg with a DFC 
formulation, which represents the FMI, was approximately 1.5 hours. Following peak plasma 
concentrations, NHC concentrations declined in a biphasic manner with an effective t1/2 of 
3.3 hours for doses. Increases in NHC AUC0-inf and Cmax were dose-proportional across 
the range of doses evaluated. The majority of NHC elimination occurred during the first 4 
hours post-dose. 
The primary plasma NHC PK parameters (AUC0-inf, Cmax) in addition to other standard 
plasma NHC PK parameters for NHC (eg, AUC0-last, Tmax, t1/2, CL/F, Vd/F) following 
single dose administration of MOV will sufficiently characterize the pharmacokinetic 
comparison between the renal impairment group relative to control. Urine NHC PK 
parameters (eg, Ae and Fe over the 24-hour time interval and CLr) will be evaluated and 
compared between the renal impairment group and healthy mean matched control group.
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The GMR value of 2.0 included in the hypothesis for the primary endpoint was chosen based 
on the upper clinical comparability bound for the program. This estimate was derived based 
on exposure-response modeling and corresponds to plasma NHC AUC0-12 of approximately 
2 times the geometric mean of model predicted AUC0-12 for patients with COVID-19 at the 
800 mg dose level. This upper bound ensures that sub populations are maintained within the 
range of clinical experience at 800 mg, as an adequate number of participants have achieved 
plasma NHC AUC0-12 values greater than this threshold in clinical studies without notable 
alteration in the safety and tolerability profile seen in subgroup analyses of higher exposures.
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 ADME; mechanism of action of the drug; disease etiology; and/or 
molecular subtype of the disease being treated. Therefore, where local regulations and 
IRB/IEC allow, a sample will be collected for DNA analysis from consenting participants.
DNA samples may be used for research related to the study intervention(s), the disease under 
study, or related diseases. They may also be used to develop tests/assays including diagnostic 
tests related to the disease under study, related diseases, and study intervention(s). Genetic 
research may consist of the analysis of 1 or more candidate genes, the analysis of genetic 
markers throughout the genome, or analysis of the entire genome. Analysis may be 
conducted if it is hypothesized that this may help further understand the clinical data.
The samples may be analyzed as part of a multistudy assessment of genetic factors involved 
in the response to understand study disease or related conditions.
4.2.1.6
Future Biomedical Research
The Sponsor will conduct FBR on DNA specimens for which consent was provided during 
this clinical study.
Such research is for biomarker testing to address emergent questions not described elsewhere 
in the protocol and will only be conducted on specimens from appropriately consented 
participants. The objective of collecting/retaining specimens for FBR is to explore and 
identify biomarkers that inform the scientific understanding of diseases and/or their 
therapeutic treatments. The overarching goal is to use such information to develop safer, 
more effective drugs/vaccines, and/or to ensure participants receive the correct dose of the 
correct drug/vaccine at the correct time. The details of FBR are presented in Appendix 6.
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4.3
Justification for Dose
A single dose of 800 mg has been chosen to be administered in this study. Single doses up to 
1600 mg and multiple doses up to 800 mg Q12H (for up to 10.5 days) were generally 
well-tolerated in healthy participants (MK-4482-004, MK-4482-008, and MK-4482-012). An 
800 mg dose was assessed in the pivotal Phase 2/3 study for the treatment of adults with 
COVID-19 (MK-4482-002) and is the proposed therapeutic dose. This dose is similarly 
being evaluated in an ongoing clinical study for postexposure prophylaxis in adults (P013).
Therefore, PK studies using the 800 mg dose in participants with severe renal impairment 
will inform any need for dose and/or regimen alterations for treatment of COVID-19 in this 
patient group.
As this is a Phase 1 assessment of MOV in humans, and the PK, pharmacodynamic and 
safety profiles of the compound are still being evaluated, modifications to the dose or dosing 
regimen may be required to achieve the scientific goals of the study objectives and/or to 
ensure appropriate safety monitoring of the study participants. Details of allowed 
modifications are provided in Section 8.11.5.
4.4
Beginning and End-of-Study Definition
The overall study begins when the first participant (or their legally acceptable representative) 
provides documented informed consent. The overall study ends when the last participant 
completes the last study-related contact, withdraws consent, or is lost to follow-up (Section 
7.3).
For purposes of analysis and reporting, the overall study ends when the Sponsor receives the 
last laboratory result or at the time of final contact with the last participant, whichever comes 
last.
If the study includes countries in the European Economic Area (EEA), the local start of the 
study in the EEA is defined as First Site Ready (FSR) in any Member State.
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.
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5
STUDY POPULATION
Male/female participants with severe renal impairment between the ages of 18 and 75
(inclusive) and healthy mean matched controls will be enrolled in this study.
Healthy control participants will be matched for mean age (± 10 years) and BMI (± 
3.5 kg/m2) of participants with severe renal impairment. In addition, the numbers of males 
and females of the healthy participants will be generally matched to the numbers of renal 
impairment participants within ± 1.
As stated in the Code of Conduct for Clinical Trials (Appendix 1.1), this study includes 
participants of varying age (as applicable), race, ethnicity, and sex (as applicable). The 
collection and use of these demographic data will follow all local laws and participant 
confidentiality guidelines while supporting the study of the disease, its related factors, and 
the IMP under investigation. Prospective approval of protocol deviations to recruitment and 
enrollment criteria, also known as protocol waivers or exemptions, is not permitted.
5.1
Inclusion Criteria
A participant will be eligible for inclusion in the study if the participant meets all of the 
following criteria:
Type of Participant and Disease Characteristics
5.1.1
Inclusion Criteria for Healthy Participants
1. The participant is in good health based on medical history, physical examination, VS 
measurements, and ECGs performed before allocation. Appendix 8 provides a table of 
the 12-Lead Electrocardiogram Abnormality Criteria.
2. The participant is in good health based on laboratory safety tests obtained at the screening 
visit and before administration of the study intervention. Appendix 2 provides a table of 
laboratory safety tests to be performed. Appendix 9 provides an algorithm for the 
assessment of out-of-range laboratory values.
3. The participant has a BMI ≥18.5 and ≤35 kg/m2. See Section 8.3.1 for criteria on 
rounding to the nearest whole number. BMI = weight (kg)/height (m)2.
4. The participant has a baseline eGFR ≥90 mL/min based on 2021 CKD-EPI Creatinine 
equation [Inker, L. A., et al 2021][Delgado, C., et al 2021]:
2021 CKD-EPI Creatinine (CKD-EPIcr_R) Equation:
eGFR = 142 X min(Scr/k,1)α X max(Scr/k,1)-1.200 X 0.994age  X 1.012 [if female]
where Scr is serum creatinine, k is 0.7 for females and 0.9 males, α is  -0.241 for females 
and -0.302 for males, min indicates the minimum of Scr/k or 1, max indicates the 
maximum of Scr/k or 1.
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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 as long as the result is available in time to 
determine eligibility.
eGFR values indexed to BSA 1.73 m2 will be de-indexed by dividing the value obtained 
from the equation by 1.73 and then multiplying by participant BSA.
Healthy control participants who have an eGFR of 80-89 mL/min may be enrolled in the 
study at the discretion of the investigator.
Demographics
5. The participant is male or female, from 18 years to 75 years of age inclusive, at the time 
of providing informed consent.
Male Participants
6.
If male, agrees to the following during the intervention period and for at least 90 days 
after the dose of study intervention:
•
Abstains from heterosexual intercourse as their preferred and usual lifestyle (abstinent on 
a long-term and persistent basis) and agrees to remain abstinent
OR
•
Uses contraception unless confirmed to be azoospermic (vasectomized or secondary to 
medical cause, documented from the site personnel’s review of the participant’s medical 
records, medical examination, or medical history interview) as detailed below:
-
Uses a male condom plus partner use of an additional contraceptive method when 
having penile-vaginal intercourse with a WOCBP who is not currently pregnant. 
Note: Men with a pregnant or breastfeeding partner must agree to remain abstinent 
from penile-vaginal intercourse or use a male condom during each episode of penile-
vaginal penetration.
-
Contraceptive use by men should be consistent with local regulations regarding the 
methods of contraception for those participating in clinical studies.
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Female Participants
7. A female participant is eligible to participate if she is not pregnant or breastfeeding, and 
at least one of the following conditions applies: 
•
Not a WOCBP
OR
•
A WOCBP and:
-
Uses a contraceptive method that is highly effective (with a failure rate of <1% per 
year), with low user dependency, 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 days after 
the last dose of study intervention. The investigator should evaluate the potential for 
contraceptive method failure (ie, noncompliance, recently initiated) in relationship to 
the first dose of study intervention. Contraceptive use by women should be consistent 
with local regulations regarding the methods of contraception for those participating 
in clinical studies.
-
Has a negative highly sensitive pregnancy test (serum) as required by local 
regulations) within 24 hours before the first dose of study intervention. Additional 
requirements for pregnancy testing during and after study intervention are in Section 
8.3.5.
-
Medical history, menstrual history, and recent sexual activity has been reviewed by 
the investigator to decrease the risk for inclusion of a woman with an early undetected 
pregnancy.
Informed Consent
8. The participant (or legally acceptable representative) has provided documented informed 
consent/assent for the study. The participant may also provide consent/assent for FBR. 
However, the participant may participate in the study without participating in FBR.
A severe renally impaired participant will be eligible for inclusion in the study if the 
participant meets all of the following criteria:
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Type of Participant and Disease Characteristics
5.1.2
Inclusion Criteria for Severe Renally Impaired Participants 
1. With the exception of renal impairment, the participant is in generally good health based 
on medical history, physical examination, VS measurements and ECGs performed prior 
to dosing. 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.
2. With the exception of renal impairment, the participant 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 9 provides an algorithm for the assessment of out-of-range laboratory values.
3. The participant has a BMI ≥18.5 and ≤35 kg/m2. See Section 8.3.1 for criteria on 
rounding to the nearest whole number. BMI = weight (kg)/height (m)2.
4. The participant has a baseline eGFR < 30 mL/min based on 2021 CKD-EPI Creatinine 
(CKD-EPIcr_R) equation at screening [Delgado, C., et al 2021]; see formula in Section 
5.1.1 Inclusion Criterion #4.
Demographics
5. The participant is male or female, from 18 years to 75 years of age inclusive, at the time 
of signing the informed consent.
Male Participants
6.
If male, agrees to the following during the intervention period and for at least 90 days 
after the dose of study intervention:
•
Abstains from heterosexual intercourse as their preferred and usual lifestyle (abstinent on 
a long-term and persistent basis) and agrees to remain abstinent
OR
•
Uses contraception unless confirmed to be azoospermic (vasectomized or secondary to 
medical cause, documented from the site personnel’s review of the participant’s medical 
records, medical examination, or medical history interview) as detailed below:
-
Uses a male condom plus partner use of an additional contraceptive method when 
having penile-vaginal intercourse with a WOCBP who is not currently pregnant. 
Note: Men with a pregnant or breastfeeding partner must agree to remain abstinent 
from penile-vaginal intercourse or use a male condom during each episode of penile-
vaginal penetration.
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Contraceptive use by men should be consistent with local regulations regarding the methods 
of contraception for those participating in clinical studies.
Female Participants
Female Participants
7. A female participant is eligible to participate if she is not pregnant or breastfeeding, and 
at least one of the following conditions applies: 
•
Not a WOCBP
OR
•
A WOCBP and:
-
Uses a contraceptive method that is highly effective (with a failure rate of <1% per 
year), with low user dependency, 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 days after 
the last dose of study intervention. The investigator should evaluate the potential for 
contraceptive method failure (ie, noncompliance, recently initiated) in relationship to 
the first dose of study intervention. Contraceptive use by women should be consistent 
with local regulations regarding the methods of contraception for those participating 
in clinical studies.
-
Has a negative highly sensitive pregnancy test (serum) as required by local 
regulations) within 24 hours before the first dose of study intervention. Additional 
requirements for pregnancy testing during and after study intervention are in Section 
8.3.5.
-
Medical history, menstrual history, and recent sexual activity has been reviewed by 
the investigator to decrease the risk for inclusion of a woman with an early undetected 
pregnancy.
Informed Consent
8. The participant (or legally acceptable representative) has provided documented informed 
consent/assent for the study. The participant may also provide consent/assent for FBR. 
However, the participant may participate in the study without participating in FBR.
5.2
Exclusion Criteria
The participant must be excluded from the study if the participant meets any of the following 
criteria:
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5.2.1
Exclusion Criteria for Healthy Participants
Medical Conditions
1. The participant has a history of clinically significant endocrine, GI, cardiovascular, 
hematological, hepatic, immunological, renal, respiratory, genitourinary, or major 
neurological (including stroke and chronic seizures) abnormalities or diseases. 
Participants with a remote history of uncomplicated medical events (eg, uncomplicated 
kidney stones, as defined as spontaneous passage and no recurrence in the last 5 years, or 
childhood asthma) may be enrolled in the study at the discretion of the investigator.
2. The participant 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. The participant has a history of cancer (malignancy).
Exceptions: (1) Adequately treated nonmelanomatous skin carcinoma or carcinoma in 
situ of the cervix or; (2) Other malignancies that 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 
that have been successfully treated ≥ 10 years prior to the prestudy [screening] visit).
4. The participant has a history of significant multiple and/or severe allergies (eg, food, 
drug, latex allergy), or has had an anaphylactic reaction or significant intolerability (ie, 
systemic allergic reaction) to prescription or non-prescription drugs or food.
5. The participant has a known hypersensitivity to the active substance or any of the 
excipients of the study drug.
6. The participant tests positive for HBsAg, hepatitis C antibodies or HIV.
7. The participant had a major surgery and/or donated or lost 1 unit of blood (approximately 
500 mL) within 4 weeks prior to the prestudy (screening) visit.
Prior/Concomitant Therapy
8. The participant 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 administration of study intervention, 
throughout the study, until the poststudy visit. There may be certain medications that are 
permitted (see Section 6.5).
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Prior/Concurrent Clinical Study Experience
9. The participant participated in another investigational study within 4 weeks (or 
5 half-lives, whichever is greater) prior to the prestudy (screening) visit. The window will 
be derived from the date of the last visit in the previous study.
Diagnostic Assessments
10. The participant meets any of the following cardiac parameters prior to study intervention 
administration: QTc interval ≥470 msec (for males) or ≥480 msec (for females), has a 
history of risk factors for Torsades de Pointes (eg, heart failure/cardiomyopathy or family 
history of long QT syndrome), has uncorrected hypokalemia or hypomagnesemia, is 
taking concomitant medications that prolong the QT/QTc interval.
Other Exclusions
11. The participant is under the age of legal consent.
12. The participant is a smoker and/or has used nicotine or nicotine-containing products (eg, 
nicotine patch and electronic cigarette) within 3 months of screening. 
13. The participant consumes greater than 3 servings of alcoholic beverages (1 serving is 
approximately equivalent to: beer [354 mL/12 ounces], wine [118 mL/4 ounces], or 
distilled spirits [29.5 mL/1 ounce]) per day. Participants who consume 4 servings of 
alcoholic beverages per day may be enrolled at the discretion of the investigator.
14. The participant consumes excessive amounts, defined as greater than 6 servings 
(1 serving is approximately equivalent to 120 mg of caffeine) of coffee, tea, cola, energy 
drinks, or other caffeinated beverages per day.
15. The participant 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 
UDS prior to allocation.
16. The participant is unwilling to comply with the study restrictions (see Section 5.3 for a 
complete summary of study restrictions).
17. The investigator has any concern regarding safe participation in the study or for any other 
reason the investigator considers the participant inappropriate for participation in the 
study.
18. Is or has an immediate family member (eg, spouse, parent/legal guardian, sibling, or 
child) who is investigational site or Sponsor staff directly involved with this study.
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5.2.2
Exclusion Criteria for Severe Renally Impaired Participants
The participant must be excluded from the study if the participant meets any of the following 
criteria:
Medical Conditions
1. The participant has a history or presence of renal artery stenosis.
2. The participant had a renal transplant.
3. The participant 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 hours apart as part of participant screening.
4. The participant has a history of any illness, other than severe renal impairment, that, in 
the opinion of the Investigator, might confound the results of the study or poses an 
additional risk to the participant by their participation in the study.
5. The participant 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.
6. The participant has a history of cancer (malignancy).
Exceptions: (1) Adequately treated nonmelanomatous skin carcinoma or carcinoma in 
situ of the cervix or; (2) Other malignancies that 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 that have 
been successfully treated ≥10 years prior to the prestudy [screening] visit).
7. The participant 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. The participant has a known hypersensitivity to the active substance or any of the 
excipients of the study drug.
9. The participant tests positive for HBsAg, hepatitis C antibodies or HIV.
10. The participant had a major surgery and/or donated or lost 1 unit of blood 
(approximately 500 mL) within 4 weeks prior to the prestudy (screening) visit.
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Prior/Concomitant Therapy
11. The participant is taking medications to treat chronic medical conditions and/or 
conditions associated with renal disease, if participant has not been on a stable regimen 
for at least 1 month and/or is unable to withhold the use of the medication(s) within 
4 hours prior to and 8 hours after administration of the study drug. Exceptions may be 
granted for participants in whom a medication regimen has been adjusted within the 
one-month window, at the discretion of the Investigator and following consultation with 
the Sponsor. See Section 5.1.2 for allowed medical conditions, and Section 6.5 for 
allowed medications.
Prior/Concurrent Clinical Study Experience
12. The participant 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. The participant meets the following exclusion criteria for ECG:
•
Heart rate < 40 or > 110 bpm
•
QTc interval > 500 msec
•
Any significant arrhythmia or conduction abnormality, (including but not specific to 
atrioventricular block [2nd degree or higher], Wolff Parkinson White syndrome 
[unless curative radio ablation therapy]), which, in the opinion of the investigator and 
Sponsor, could interfere with the safety for the individual participant.
•
Non-sustained or sustained ventricular tachycardia (> 2 consecutive ventricular 
ectopic beats at a rate of > 1.7/second).
Other Exclusions
14. The participant is under the age of legal consent.
15. The participant does not agree to follow the smoking restrictions as defined by the CRU.
16. The participant consumes greater than 3 servings of alcoholic beverage (1 serving is 
approximately equivalent to: beer [354 mL/12 ounces], wine [118 mL/4 ounces], or 
distilled spirits [29.5 mL/1 ounce]) per day. Participants who consume 4 servings of 
alcoholic beverages per day may be enrolled at the discretion of the investigator.
17. The participant 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.
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18. The participant is a regular user of cannabis (refer to exception below for use of cannabis 
with a medical marijuana card) or any illicit drugs or has a history of drug (including 
alcohol) abuse within approximately 3 months. Participants must have a negative UDS 
prior to allocation. Participants with severe renal impairment will be allowed for 
inclusion with a positive UDS for opiates or cannabinoids if they have an active 
prescription and/or medical marijuana card from a licensed healthcare provider.
19. The participant is unwilling to comply with the study restrictions (see Section 5.3 for a 
complete summary of study restrictions).
20. The investigator has any concern regarding safe participation in the study or for any other 
reason the investigator considers the participant inappropriate for participation in the 
study.
21. The participant 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
5.3.1.1
Diet Restrictions
Participants will fast from all food and drinks, except water, for at least 8 hours before study 
intervention administration. Participants will fast from all food and drinks, except water,
between study intervention administration and the first scheduled meal (approximately 4-
hours postdose). After the 4-hour postdose standard meal has been completed, subsequent 
meals and snacks will be unrestricted in caloric content, composition, and timing.
To the extent possible, laboratory safety tests (hematology and chemistry) will be performed 
after approximately an 8-hour fast.
The study intervention will be administered with approximately 240 mL of water. Additional 
water in approximately 50 mL increments may be provided, if needed. Water will be 
restricted 1 hour before and 1 hour after study intervention administration.
Instructions on whether to take MOV with or without food and/or drink may be modified 
during the study based on newly available data.
5.3.1.2
Fruit Juice Restrictions
Participants will refrain from the consumption of grapefruit juice, grapefruits, and grapefruit 
products beginning approximately 2 weeks before administration of the study intervention, 
throughout the study and until the poststudy visit.
Participants also will refrain from the consumption of all fruit juices 24 hours before and 
after study intervention administration. On all other days during the study, consumption of 
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fruits and fruit juices (except for grapefruit, grapefruit juices, and grapefruit products) is 
allowed.
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 before the prestudy and poststudy visits until completion of the visit 
requirements and from 12 hours before and after study intervention administration. At all 
other times, caffeinated beverages or xanthine-containing products will be limited to no more 
than 6 units per day (1 unit = 120 mg of caffeine).
5.3.2.2
Alcohol Restrictions
Participants will refrain from consumption of alcohol 24 hours before the prestudy and 
poststudy visits until completion of the visit requirements and from 24 hours before and after 
study intervention administration. At all other times, alcohol consumption is limited to no 
more than approximately 3 alcoholic beverages or equivalent servings (1 serving is 
approximately equivalent to: beer [354 mL/12 ounces], wine [118 mL/4 ounces], or distilled 
spirits [29.5 mL/1 ounce]) per day.
5.3.2.3
Tobacco Restrictions
Smoking (and/or the use of nicotine/nicotine-containing products) is not permitted during the 
study 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 nicotine/nicotine-containing products) defined by the CRU.
5.3.3
Activity Restrictions
Participants will avoid unaccustomed strenuous physical activity (ie, weightlifting, running, 
bicycling, etc) from the prestudy (screening) visit, throughout the study, 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 entered 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 
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generally receive the same intervention or intervention sequence (as appropriate) as the 
participant being replaced. The replacement participant will be assigned a unique 
treatment/allocation number.
The study site should contact the Sponsor for the replacement participant’s 
treatment/allocation number.
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 (MOV 200-mg capsules) 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 before dosing the replacement participant. Clinical supplies 
will be affixed with a clinical label in accordance with regulatory requirements.
6.1
Study Intervention(s) Administered
The study intervention to be used in this study is outlined in Table 2.
Country-specific differences are noted in Appendix 7.
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Table 2
Study Interventions
Arm 
Name
Arm Type
Intervention 
Name
Interven-
tion Type
Dose 
Formulation
Unit Dose 
Strength(s)
Dosage 
Level(s)
Route of 
Administration
Regimen/Treatment 
Period/Vaccination 
Regimen
Use
IMP or
NIMP/
AxMP
Sourcing
Severe 
Renal 
Impairm-
ent Group
Experimental
MK-4482
Drug
Capsule
200 mg
800 mg
Oral
Panel A: Single 
Dose on Day 1
Test 
Product
IMP
Provided 
centrally 
by the 
sponsor
Healthy 
Control 
Group
Experimental
MK-4482
Drug
Capsule
200 mg
800 mg
Oral
Panel B: Single 
Dose on Day 1
Test 
Product
IMP
Provided 
centrally 
by the 
sponsor
EEA=European Economic Area; IMP=investigational medicinal product; NIMP/AxMP=non-investigational/auxiliary medicinal product.
The classification of IMP and NIMP/AxMP in this table is based on guidance issued by the European Commission and applies to countries in the EEA. Country differences with respect to the 
definition/classification of IMP and NIMP/AxMP may exist. In these circumstances, local legislation is followed.
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All supplies indicated in Table 2 will be provided per the “Sourcing” column depending on 
local country operational requirements. If local sourcing, every attempt should be made to 
source these supplies from a single lot/batch number 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 to administer the 
proper dose to each participant. The rationale for selection of doses to be used in this study is 
in Section 4.3.
6.2.2
Handling, Storage, and Accountability
The investigator or designee must confirm appropriate temperature conditions have been 
maintained during transit for all study intervention received, and any discrepancies are 
reported and resolved before use of the study intervention.
Only participants enrolled in the study may receive study intervention, and only authorized 
site staff may supply or administer study intervention. All study interventions must be stored 
in a secure, environmentally controlled, and monitored (manual or automated) area in 
accordance with the labeled storage conditions with access limited to the investigator and 
authorized site staff.
The investigator, institution, or the head of the medical institution (where applicable) is 
responsible for study intervention accountability, reconciliation, and record maintenance (ie, 
receipt, reconciliation, and final disposition records).
For all study sites, the local country Sponsor personnel or designee will provide appropriate 
documentation that must be completed for drug accountability and return, or local discard 
and destruction if appropriate. Where local discard and destruction is appropriate, the 
investigator is responsible for ensuring that a local discard/destruction procedure is 
documented.
The study site is responsible for recording the lot number, manufacturer, and expiry date for 
any locally purchased product (if applicable) as per local guidelines unless otherwise 
instructed by the Sponsor.
The investigator shall take responsibility for and shall take all steps to maintain appropriate 
records and ensure appropriate supply, storage, handling, distribution, and usage of study 
interventions in accordance with the protocol and any applicable laws and regulations.
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6.3
Measures to Minimize Bias: Randomization and Blinding
6.3.1
Intervention Assignment
Participants in this study will be allocated by nonrandom assignment.
A sample allocation schedule is shown in Table 3.
Table 3
Sample Allocation Schedule
Panel
Renal Impairment Stage
N
Treatment
A
Severe
8
MK-4482 (MOV) 800 mg
B
Healthy
8 to 10
MK-4482 (MOV) 800 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
Participants will be 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 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 
dose of study intervention, they may be included in the study if the investigator can 
rationalize that the specific use of a prior medication is not clinically relevant within the 
context of the study.
Concurrent use of any prescription or nonprescription medication, or concurrent vaccination,
during the ongoing study (ie, after intervention allocation) must first be discussed between 
the investigator and Sponsor before administration, unless appropriate medical care 
necessitates that therapy or vaccination should begin before the investigator and Sponsor can 
consult. The participant will be allowed to continue in the study if both the Sponsor and the 
investigator agree.
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Paracetamol/acetaminophen (up to 2 g total per day for participants with severe renal 
impairment or up to 4 g total per day for healthy participants) may be used for minor 
ailments without prior consultation with the Sponsor.
Nonsteroidal anti-inflammatory drugs (NSAIDs) are not to be used without prior consultation 
with the Sponsor.
COVID-19 vaccine may be administered. Study intervention must be given at least 72 hours 
following or at least 48 hours prior to any COVID-19 vaccination.
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. Participants must be on a stable regimen for at least 1 month prior to study 
intervention administration and able to withhold the use within 4 hours prior to and 8 hours 
after study intervention administration. Any exceptions to this must first be discussed 
between the Investigator and Sponsor. Examples of the 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
Participants with a valid medical marijuana card will be allowed to participate in the study at 
the discretion of the investigator, however, use of medical marijuana should be restricted at 
least 24 hours prior to, and for 24 hours after, study intervention administration. 
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 
study intervention administration.
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6.5.1
Rescue Medications and Supportive Care
No rescue or supportive medications are specified for use in this study.
6.6
Dose Modification
Dose modifications are not applicable to this study.
6.6.1
Stopping Rules
The following stopping rules will be used 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. To continue the study 
(on joint agreement with the Sponsor and investigator), a substantial amendment will be 
submitted for approval.
1. An individual participant reports an SAE considered related to the study intervention by 
the investigator.
2. Two (2) or more participants report Severe Nonserious AEs considered related to the 
study intervention by the investigator.
6.7
Intervention After the End of the Study
There is no study-specified intervention after 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.
6.9
Standard Policies
Not applicable.
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 before the intervention. Therefore, participants who receive a single-dose intervention 
cannot discontinue study intervention.
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7.2
Participant Withdrawal From the Study
Participants may withdraw from the study at any time for any reason. If a participant 
withdraws from the study, they will no longer receive study intervention or be followed at 
scheduled protocol visits.
A participant must be withdrawn from the study if:
•
The participant or participant’s legally acceptable representative withdraws consent from 
the study.
Specific details regarding procedures to be performed at the time of withdrawal from the 
study, as well as specific details regarding withdrawal from FBR, are outlined in Section 
8.1.9. The procedures to be performed should a participant repeatedly fail to return for 
scheduled visits and/or if the study site is unable to contact the participant are outlined in
Section 7.3.
7.3
Lost to Follow-up
If a participant fails to return to the clinic for a required study visit and/or if the site is unable 
to contact the participant, the following procedures are to be performed:
•
The site must attempt to contact the participant and reschedule the missed visit. If the 
participant is contacted, the participant should be counseled on the importance of 
maintaining the protocol-specified visit schedule.
•
The investigator or designee must make every effort to regain contact with the participant 
at each missed visit (eg, telephone calls and/or a certified letter to the participant’s last 
known mailing address or locally equivalent methods). These contact attempts should be 
documented in the participant’s medical record.
8
STUDY ASSESSMENTS AND PROCEDURES
•
Study procedures and their timing are summarized in the SoA.
•
Adherence to the study design requirements, including those specified in the SoA, is 
essential and required for study conduct.
•
The investigator is responsible for ensuring that procedures are conducted by 
appropriately qualified (by education, training, and experience) staff. Delegation of 
study-site personnel responsibilities will be documented in the Investigator Trial File 
Binder (or equivalent).
•
All study-related medical decisions must be made by an investigator who is a qualified 
physician.
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•
All screening evaluations must be completed and reviewed to confirm that potential 
participants meet all eligibility criteria. The investigator will maintain a screening log to 
record details of all participants screened and to confirm eligibility or record reasons for 
screening failure, as applicable.
•
Procedures conducted as part of the participant’s routine clinical management (eg, blood 
count) and obtained before signing of ICF may be used for screening or baseline purposes 
provided the procedures meet the protocol-specified criteria and were performed within 
the time frame defined in the SoA.
•
Additional evaluations/testing may be deemed necessary by the investigator and or the 
Sponsor for reasons related to participant safety. In some cases, such evaluation/testing 
may be potentially sensitive in nature (eg, HIV, hepatitis C), and thus local regulations 
may require that additional informed consent 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 132.5 mL (refer to Study Operations Manual for Blood Volume 
Table). If additional pharmacokinetic and/or safety analysis is necessary, additional blood 
(no more than 50 mL in total) may be obtained.
•
Repeat or unscheduled samples may be taken for safety reasons or for technical issues 
with the samples.
8.1
Administrative and General Procedures
8.1.1
Informed Consent
The investigator or medically qualified designee (consistent with local requirements) must 
obtain documented informed consent from each potential participant (or their legally 
acceptable representative) prior to participating in this clinical study or FBR. If there are 
changes to the participant’s status during the study (eg, health or age of majority 
requirements), the investigator or medically qualified designee must ensure the appropriate 
documented informed consent is in place.
8.1.1.1
General Informed Consent
Informed consent given by the participant or their legally acceptable representative must be 
documented on a consent form. The form must include the study protocol number, study 
protocol title, dated signature, and agreement of the participant (or his/her legally acceptable 
representative) and of the person conducting the consent discussion.
A copy of the signed and dated informed consent form should be given to the participant (or 
their legally acceptable representative) before participation in the study.
The initial ICF, any subsequent revised ICF, and any written information provided to the 
participant must receive the IRB/IEC’s approval/favorable opinion in advance of use. The 
participant or his/her legally acceptable representative should be informed in a timely manner 
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if new information becomes available that may be relevant to the participant’s willingness to 
continue participation in the study. The communication of this information will be provided 
and documented via a revised consent form or addendum to the original consent form that 
captures the participant’s or the participant’s legally acceptable representative’s dated 
signature.
Specifics about the study and the study population are to be included in the study informed
consent form.
Informed consent will adhere to IRB/IEC requirements, applicable laws and regulations, and 
Sponsor requirements.
8.1.1.2
Consent and Collection of Specimens for Future Biomedical Research
The investigator or medically qualified designee will explain the FBR consent to the 
participant, or the participant’s legally acceptable representative, answer all of his/her 
questions, and obtain documented informed consent before performing any procedure related 
to FBR. A copy of the informed consent will be given to the participant before performing 
any procedure related to FBR.
8.1.2
Inclusion/Exclusion Criteria
All inclusion and exclusion criteria will be reviewed by the investigator, who is a qualified 
physician, to ensure that the participant qualifies for the study.
8.1.3
Participant Identification Card
All participants will be given a participant identification card identifying them as participants 
in a research study. The card will contain study-site contact information (including direct 
telephone numbers) to be used in the event of an emergency. The investigator or qualified 
designee will provide the participant with a participant identification card immediately after 
the participant provides documented informed consent. At the time of intervention allocation,
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.
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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 administration of study intervention.
8.1.5.2
Concomitant Medications
The investigator or qualified designee will record medication, if any, taken by the participant 
during the study.
8.1.6
Assignment of Screening Number
All consented participants will be given a unique screening number that will be used to 
identify the participant for all procedures that occur before intervention allocation. Each 
participant will be assigned only 1 screening number. Screening numbers must not be reused 
for different participants.
Any participant who is screened multiple times will retain the original screening number 
assigned at the initial Screening Visit. Specific details on the screening/rescreening visit 
requirements are in Section 8.11.1. Pre-trial screening logs may be collected for review by 
the Sponsor. If applicable, any information that would make the participant identifiable will 
be removed.
8.1.7
Assignment of Treatment/Allocation Number
All eligible participants will be allocated, by nonrandom assignment, and will receive a 
treatment/allocation number. The treatment/allocation number identifies the participant for 
all procedures occurring after treatment/allocation. Once a treatment/allocation number is 
assigned to a participant, it can never be reassigned to another participant.
A single participant cannot be assigned more than 1 treatment/allocation number.
8.1.8
Study Intervention Administration
Study intervention(s) will be administered by the investigator and/or appropriately qualified 
designee. A hand and mouth check will be performed immediately after drug administration 
to ensure that the study drug has been swallowed.
8.1.8.1
Timing of Dose Administration
On Day 1, participants will receive a single oral dose of 800 mg MOV (4 x 200-mg capsules)
at Hour 0, following an overnight fast of at least 8 hours. Dosing of MOV will take place in 
the morning.
The exact clock time of study intervention administration will be recorded.
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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.
8.1.9.1
Withdrawal From Future Biomedical Research
Participants may withdraw their consent for FBR. Participants may withdraw consent at any 
time by contacting the study investigator. If medical records for the study are still available, 
the investigator will contact the Sponsor using the designated mailbox 
(clinical.specimen.management@MSD.com). Subsequently, the participant’s consent for 
FBR will be withdrawn. A letter will be sent from the Sponsor to the investigator confirming 
the withdrawal. It is the responsibility of the investigator to inform the participant of 
completion of withdrawal. Any analyses in progress at the time of request for withdrawal or 
already performed before the request being received by the Sponsor will continue to be used 
as part of the overall research study data and results. No new analyses would be generated 
after the request is received.
If the medical records for the study are no longer available (eg, if the investigator is no longer 
required by regulatory authorities to retain the study records) or the specimens have been 
completely anonymized, there will no longer be a link between the participant’s personal 
information and their specimens. In this situation, the request for specimen withdrawal 
cannot be processed.
8.1.10
Participant Blinding/Unblinding
This is an open-label study; there is no blinding for this study. The emergency unblinding 
call center will be available so that a health care provider can obtain information about study 
intervention in emergency situations where the investigator is not available.
8.1.11
Domiciling
Participants will report to the CRU on Day -1 before the scheduled day of study intervention 
administration on Day 1 and remain in the unit until the 24-hour postdose procedures have 
been performed (Day 2). 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 
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decision how to monitor the participant will be at the discretion of the investigator after 
discussion with the Sponsor.
8.1.12
Calibration of Equipment
The investigator or qualified designee has the responsibility to ensure that any device or 
instrument used for a clinical evaluation/test during a clinical study that provides information 
about inclusion/exclusion criteria and/or safety or efficacy parameters shall be suitably 
calibrated and/or maintained to ensure that the data obtained are reliable and/or reproducible. 
Documentation of equipment calibration must be retained as source documentation at the 
study site.
8.2
Efficacy/Immunogenicity Assessments
There are no direct efficacy or immunogenicity assessments in this study.
8.3
Safety Assessments
Details regarding specific safety procedures/assessments to be performed in this study are 
provided. The total amount of blood to be drawn over the course of the study (from prestudy 
[screening] to poststudy [follow-up] visits), including approximate blood volumes drawn by 
visit and by sample type per participant, can be found in the Study Operations Manual.
Planned time points for all safety assessments are provided in the SoA.
8.3.1
Physical Examinations
A complete physical examination will be conducted by an investigator or medically qualified 
designee (consistent with local requirements) per institutional standard. Height and weight 
will also be measured and recorded at the timepoints listed in the SoA (Section 1.3).
Symptom-driven physical examinations may be performed at other times, if deemed 
necessary by the investigator or designee.
Investigators should pay special attention to clinical signs related to previous serious 
illnesses.
BMI
BMI equals a person's weight in kilograms divided by height in meters squared 
(BMI=kg/m2). BMI 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.
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BSA
In order to correct eGFR for individual BSA, the DuBois formula will be used to calculate 
BSA:
BSA (m2) = Weight (kg)0.425 x Height (cm)0.725 x 0.007184
8.3.2
Vital Signs
•
Body temperature, HR, RR, and BP will be assessed.
•
Body temperature will be measured with an appropriate thermometer.
•
BP and HR measurements will be assessed with a completely automated device. Manual 
techniques will be used only if an automated device is not available.
•
VS measurements should be taken before blood collection for laboratory tests.
8.3.2.1
Resting Vital Signs
Vital Sign Measurements (Heart Rate and Blood Pressure)
Participants should be resting in a quiet setting without distractions in a semirecumbent
position for at least 10 minutes before having VS measurements obtained. Semirecumbent
VS will include HR, systolic and diastolic BP, RR, and body temperature at timepoints 
indicated in the SoA. The correct size of the BP cuff and the correct positioning on the 
participants' arm is essential to increase the accuracy of BP measurements.
The screening HR and BP will be single measurements. This may be repeated on a second 
screening day at the discretion of the study investigator.
The predose (baseline) HR and BP will be in triplicate measurements, obtained at least 1 to 2 
minutes apart within 3 hours of dosing MOV. The median of these measurements will be 
used as the baseline to calculate change from baseline for safety evaluations (and for 
rechecks, if needed). All other VS measurements, including all postdose assessments and 
poststudy 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.
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8.3.3
Electrocardiograms
•
All 12-lead ECGs will be obtained and reviewed by an investigator or medically qualified 
designee (consistent with local requirements) as outlined in the SoA (Section 1.3) using 
an ECG machine that automatically calculates the HR and measures PR, QRS, QT, and 
QTc intervals. Refer to Appendix 8 for evaluation and potentially significant findings.
•
At each time point when triplicate ECG is required, 3 individual ECG tracings should be 
obtained at least 1 to 2 minutes apart, but no more than 2 minutes apart. The full set of 
triplicates should be completed in no more than 6 minutes.
Special care must be taken for proper lead placement by qualified personnel. Skin should be 
clean and dry before 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 before 
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 to 2 minutes apart within 3 hours before 
dosing MOV. The median of these measurements will be used as the baseline to calculate 
change from baseline for safety evaluations (and for rechecks, if needed).
All other ECG measurements, including screening, all postdose assessments and poststudy 
ECG measurements will be single measurements.
During the treatment period, if a participant demonstrates an increase in QTc interval 
≥60 msec compared with median predose baseline measurement, the ECG will be repeated 
twice within 5 minutes. The median value of the QTc interval from the 3 ECGs will represent 
the value at that time point. If the median 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.
During the treatment period, if a participant demonstrates a QTc interval ≥500 msec on a 
postdose ECG, the ECG will be repeated twice within 5 minutes. The median value of the 
QTc interval from the 3 ECGs will represent the value at that time point. If the median 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 CCU or ICU) is available.
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If at any time the QRS duration is prolonged ≥200 msec (and change is not considered rate 
related or pacing induced), then the Sponsor should be notified. The ECGs should be 
reviewed by a cardiologist and the participant should be considered for transfer to a location 
where closer monitoring and definitive care (eg, a CCU or ICU) 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 cardiologist will be consulted by the investigator as needed to review ECG tracings with 
significant 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 SoA.
•
If laboratory values from nonprotocol-specified laboratory assessments performed at the 
institution’s local laboratory require a change in study participant management or are 
considered clinically significant by the investigator (eg, SAE or AE or dose 
modification), then the results must be recorded in the appropriate CRF (eg, SLAB).
•
For any laboratory tests with values considered clinically significantly abnormal during 
participation in the study or within 14 days after the last dose of study intervention, every 
attempt should be made to perform repeat assessments until the values return to normal or 
baseline or if a new baseline is established as determined by the investigator.
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8.3.5
Pregnancy Testing
•
Pregnancy testing:
-
Pregnancy testing requirements for study inclusion are described in Section 5.1.
-
Pregnancy testing (serum) should be conducted at the poststudy visit.
-
Additional serum or urine pregnancy tests may be performed, as determined 
necessary by the investigator or required by local regulation, to establish the absence 
of pregnancy at any time during the participant's participation in the study.
8.3.6
Photograph of Rash
Photographs of the rash are highly recommended to be taken immediately, along with any 
additional information that may assist the investigator to evaluate the skin reaction, skin 
eruption or rash occurrence in determining etiology and drug relationship.
8.4
Adverse Events, Serious Adverse Events, and Other Reportable Safety Events
The definitions of an AE or SAE, as well as the method of recording, evaluating, and 
assessing causality of AE and SAE and the procedures for completing and transmitting AE, 
SAE, and other reportable safety event reports can be found in Appendix 3.
Adverse events, SAEs, and other reportable safety events will be reported by the participant 
(or, when appropriate, by a caregiver, surrogate, or the participant's legally authorized 
representative).
The investigator and any designees are responsible for detecting, documenting, and reporting 
events that meet the definition of an AE or SAE as well as other reportable safety events.
Investigators need to document if an SAE was associated with a medication error, misuse, or 
abuse. 
Investigators remain responsible for following up AEs, SAEs, and other reportable safety 
events for outcome according to Section 8.4.3.
The investigator, who is a qualified physician, will assess events that meet the definition of 
an AE or SAE as well as other reportable safety events with respect to seriousness, 
intensity/toxicity and causality.
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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 participant provides 
documented informed consent, but before intervention allocation, must be reported by the 
investigator under any of the following circumstances:
•
if the participant is receiving placebo run-in or other run-in treatment,
•
if the event causes the participant to be excluded from the study,
•
if it 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 14 days after cessation of intervention, all 
AEs, SAEs and other reportable safety events must be reported by the investigator.
Additionally, any SAE brought to the attention of an investigator any time outside the 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 the investigator 
considers the event to be reasonably related to the study intervention or study participation, 
the investigator must promptly notify the Sponsor.
All initial and follow-up AEs, SAEs, and other reportable safety events will be recorded and 
reported to the Sponsor or designee within the time frames as indicated in Table 4.
Exception: A positive pregnancy test at the time of initial screening is not a reportable event 
unless the participant has received study intervention.
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Table 4
Reporting Time Periods and Time Frames for Adverse Events and Other 
Reportable Safety Events
Type of Event
Reporting Time 
Period:
Consent to 
Randomization/ 
Allocation
Reporting Time 
Period:
Randomization/ 
Allocation 
through 
Protocol-
specified Follow-
up Period
Reporting Time 
Period:
After the Protocol-
specified Follow-up 
Period
Time Frame to 
Report Event 
and Follow-up 
Information to 
Sponsor:
NSAE
Report if:
- due to protocol-
specified intervention
- causes exclusion
- participant is 
receiving placebo 
run-in or other run-in 
treatment
Report all
Not required
Per data entry 
guidelines
SAE
Report if:
- due to protocol-
specified intervention
- causes exclusion
- participant is 
receiving placebo 
run-in or other run-in 
treatment
Report all
Report if:
- drug/vaccine related.
(Follow ongoing to 
outcome)
Within 24 hours 
of learning of 
event
Pregnancy/
Lactation 
Exposure
Report if:
- participant has been 
exposed to any
protocol-specified 
intervention (eg, 
procedure, washout 
or run-in treatment 
including placebo 
run-in)
Exception: A 
positive pregnancy 
test at the time of 
initial screening is 
not a reportable 
event.
Report all
Previously reported –
Follow to completion/
termination; report 
outcome
Within 24 hours 
of learning of 
event
ECI (require 
regulatory 
reporting)
Report if:
- due to intervention
- causes exclusion
Report
- potential DILI
- require 
regulatory 
reporting
Not required
Within 24 hours 
of learning of 
event
ECI (do not 
require 
regulatory 
reporting)
Report if:
- due to intervention
- causes exclusion
Report
- non-DILI ECIs 
and those not 
requiring 
regulatory 
reporting
Not required
Within 5 calendar 
days of learning 
of event
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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:
Cancer
Report if:
- due to intervention
- causes exclusion
Report all
Not required
Within 5 calendar 
days of learning 
of event
(unless serious)
Overdose
Report if:
- receiving placebo 
run-in or other run-in 
medication 
Report all
Not required
Within 24 hours 
of learning of 
event
DILI=drug-induced liver injury; ECI=event of clinical interest; NSAE=nonserious adverse event; SAE=serious adverse 
event.
8.4.2
Method of Detecting AEs, SAEs, and Other Reportable Safety Events
Care will be taken not to introduce bias when detecting AEs and/or SAEs and other 
reportable safety events. Open-ended and nonleading verbal questioning of the participant is 
the preferred method to inquire about AE occurrence.
8.4.3
Follow-up of AE, SAE, and Other Reportable Safety Event Information
After the initial AE/SAE report, the investigator is required to proactively follow each 
participant at subsequent visits/contacts. All AEs, SAEs, and other reportable safety events,
including pregnancy and exposure during breastfeeding, ECIs, cancer, and overdose will be 
followed until resolution, stabilization, until the event is otherwise explained, or the 
participant is lost to follow-up (as defined in Section 7.3). In addition, the investigator will 
make every attempt to follow all nonserious AEs that occur in allocated participants for 
outcome. Further information on follow-up procedures is given in Appendix 3.
8.4.4
Regulatory Reporting Requirements for SAE
Prompt notification (within 24 hours) by the investigator to the Sponsor of SAE is essential 
so that legal obligations and ethical responsibilities towards the safety of participants and the 
safety of a study intervention under clinical investigation are met.
The Sponsor has a legal responsibility to notify both the local regulatory authority and other 
regulatory agencies about the safety of a study intervention under clinical investigation. The 
Sponsor will comply with country-specific regulatory requirements and global laws and 
regulations relating to safety reporting to regulatory authorities, IRB/IECs, and investigators.
Investigator safety reports must be prepared for SUSARs according to local regulatory 
requirements and Sponsor policy and forwarded to investigators as necessary.
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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.
Any pregnancy complication will be reported as an AE or SAE.
The medical reason (example: maternal health or fetal disease) for an elective termination of 
a pregnancy will be reported as an AE or SAE. Prenatal testing showing fetus will be born 
with severe abnormalities/congenital anomalies that leads to an elective termination of a 
pregnancy will be reported as an SAE for the fetus.
Pregnancy outcomes of ectopic pregnancy, spontaneous abortion, missed abortion, benign 
hydatidiform mole, blighted ovum, fetal death, intrauterine death, miscarriage, and stillbirth 
must be reported as serious events (Important Medical Events). If the pregnancy continues to 
term, the outcome (health of infant) must also be reported.
8.4.6
Disease-related Events and/or Disease-related Outcomes Not Qualifying as 
AEs or SAEs
Not applicable to this study.
8.4.7
Events of Clinical Interest
Selected serious and nonserious AEs are also known as ECIs and must be reported to the 
Sponsor.
Events of clinical interest for this study include:
1. An overdose of Sponsor's product, as defined in Section 8.5.
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2. Potential DILI events defined as an elevated AST or ALT laboratory value that is greater 
than or equal to 3X the ULN and an elevated total bilirubin laboratory value that is 
greater than or equal to 2X the ULN and, at the same time, an alkaline phosphatase 
laboratory value that is less than 2X the ULN, as determined by way of protocol-
specified laboratory testing or unscheduled laboratory testing.*
*Note: These criteria are based on available regulatory guidance documents. The purpose 
of the criteria is to specify a threshold of abnormal hepatic tests that may require an 
additional evaluation for an underlying etiology. The study-site guidance for assessment 
and follow up of these criteria can be found in the Investigator Study File Binder (or 
equivalent).
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.
There is no specific guidance available regarding overdose due to the lack of clinical 
experience with overdosing. In case of acute overdosage, specific medical therapy should be 
performed as clinically appropriate and supportive care provided through local acute care 
facilities as needed. Additional measures such as emptying the stomach may be considered. 
The Sponsor Clinical Director should be contacted immediately.
8.6
Pharmacokinetics
The decision as to which plasma and urine samples collected will be measured for evaluation 
of PK will be collaboratively determined by the Sponsor. If indicated, these samples may 
also be measured and/or pooled for assay in an exploratory manner for metabolites and/or 
additional pharmacodynamic markers.
8.6.1
Blood Collection for Plasma NHC and/or Metabolites Assay
Sample collection, storage, and shipment instructions for plasma samples will be provided in 
the Study Operations Manual.
8.6.2
Urine Collection for Urinary NHC and/or Metabolites Assay
Sample collection, storage, and shipment instructions for urine 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 FBR if the participant provides documented 
informed consent for FBR. If the planned genetic analysis is not approved, but future 
biomedical research is approved, this sample will be collected for the purpose of FBR.
Sample collection, storage, and shipment instructions for planned genetic analysis samples 
will be in the Operations/Laboratory Manual.
8.9
Future Biomedical Research Sample Collection
If the participant provides documented informed consent for FBR, the following specimens 
will be obtained as part of FBR:
•
Leftover DNA for future research
8.10
Health Economics Medical Resource Utilization and Health Economics
Health Economics, Medical Resource Utilization and Health Economics are not evaluated in 
this study.
8.11
Visit Requirements
Visit requirements are outlined in Section 1.3. Specific procedure-related details are provided 
in Section 8.
8.11.1
Screening
Approximately 28 days before intervention allocation, 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 
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procedures cannot be conducted the day prior to intervention allocation if there are Day -1 
procedures planned per protocol.
8.11.2
Treatment Period
Refer to the Schedule of Activities (Section 1.3) and Administrative and General Procedures 
(Section 8.1).
8.11.3
Poststudy
Participants will be required to return to clinic approximately 14 days after the last dose of 
study intervention for the poststudy visit. If the poststudy visit occurs less than 14 days after 
the last dose of study intervention, a subsequent follow-up verbal contact should be made at 
14 days post the last dose of study intervention to determine if any AEs have occurred since 
the poststudy clinic visit.
8.11.4
Critical Procedures Based on Study Objectives: Timing of Procedure
For this study, the blood sample for plasma NHC assay is the critical procedure.
At any postdose time point, the blood sample for plasma NHC assay 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 before or 
after the prescribed/scheduled time.
The order of priority can be changed during the study with joint agreement of the investigator 
and the Sponsor Clinical Director.
Any nonscheduled procedures required for urgent evaluation of safety concerns take 
precedence over all routine scheduled procedures.
The following variance in procedure collection times will be permitted.
•
PK Collection as outlined in Table 5.
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Table 5
Pharmacokinetic (Blood for Plasma NHC Assay) Collection Windows
Plasma NHC PK Collection
PK Collection Windowa
Predose
Within 3 h prior to dosing
0 to <1 h
5 min
1 to <12 h
10 min
12 to <24 h
15 min
24 to <48 h
1 h
48 to 72 h
2 h
h=hour; min=minute; NHC=N-hydroxycytidine; PK=pharmacokinetic(s)
a PK collection windows are +/- relative to time of dosing on Day 1
•
Predose standard safety evaluations: VS (HR, BP, RR, BT) and ECG within 3 hours prior 
to intervention administration; laboratory safety tests, serum pregnancy test (WOCBP 
only), UDS/BDS and physical exam within 24 hours prior to study intervention 
administration
•
Postdose standard safety evaluations: VS, ECG, laboratory safety tests, and physical 
exam
-
Prior to 24-hours postdose may be obtained within 15 minutes of the theoretical 
sampling time
-
24-hours postdose may be obtained within 1 hour of the theoretical sampling time
8.11.5
Study Design/Dosing/Procedures Modifications Permitted Within Protocol 
Parameters
This is a Phase 1 assessment of MOV 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 in any given panel
•
Instructions to take study intervention with or without food or drink may also be modified 
based on newly available data
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•
Modification of the plasma NHC PK sample processing and shipping details based on 
newly available data
•
Modification of urine sample collection 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 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 an additional 50 mL of blood may be drawn for safety and/or PK 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 (refer to the Study Operations 
Manual).
The timing of procedures for assessment of safety procedures (eg, vital signs, ECG, safety 
laboratory tests, etc) may be modified during the study based on newly available data. 
Additional laboratory safety tests may be added to blood samples previously drawn to obtain 
additional safety information. These changes will not increase the number of study 
procedures for a given participant during his/her participation in the entire study.
It is understood that the current study may use 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 study. Full detail is in the
Statistical Methods (Section 9.6).
Pharmacokinetics:
Individual values of plasma NHC AUC0-inf after a single dose administration of 800-mg 
MOV to participants with severe renal impairment and healthy control participants will be 
natural log-transformed and evaluated with a linear fixed effects model containing a fixed 
effect for population (participants with severe renal impairment and healthy control 
participants). To address the primary hypothesis of comparing participants with severe renal 
impairment to healthy control participants, the 90% CI for the true GMR (severe renal 
impairment /healthy control) will be constructed. If the 90% CI falls below 2.0, then the 
hypothesis that in participants with severe renal impairment, the AUC0-inf of plasma NHC is 
similar to that observed in the healthy mean matched control participants following a single 
dose of 800 mg will be supported.
Plasma Cmax of NHC after a single dose of 800-mg MOV to participants with severe renal 
impairment and healthy control participants will be estimated via similar model.
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Safety:
AEs will be tabulated. Summary statistics and plots will be generated for raw laboratory 
safety tests, ECGs, and/or vital signs as well as for change from baseline, as deemed 
clinically appropriate. Depending on the safety parameter, the difference from baseline will 
either be computed on the original scale (raw change from baseline) or on the log scale and 
back-transformed for reporting (percent change from baseline).
Sample Size and Power Calculations:
The between-subject standard deviation (on the natural log scale) for plasma NHC AUC0-inf 
and Cmax after administration of 800 mg MOV are 0.314 ln(hr*nmol/L) and 
0.206 ln(nmol/L), respectively, based on the MK-4482 P004 study (1600 mg single dose 
group). The true GMR for participants with severe renal impairment is assumed to be 1.28 
based on extrapolation of exposures in participants eGFR >30 mL/min (see Section 4.2).
With 8 participants in each panel, assuming the true GMR (renal impairment/healthy control) 
is 1.28, there is 85.5% power to support the hypothesis that in participants with severe renal 
impairment, the AUC0-inf of NHC is similar to that observed in the healthy mean matched 
control participants. The true GMR can be as high as 1.33 to still maintain 80% power.
With 8 participants in each panel, the half width of 90% CI for GMR for plasma NHC Cmax 
on the log scale will be 0.181. The lower and upper 90% confidence limits for the true GMRs 
will be given by OBS/1.2 and OBS*1.2 for plasma NHC Cmax, where OBS is the observed 
GMR.
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
Medicine 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
Hypothesis: In participants with severe renal impairment, the AUC0-inf of NHC is similar to 
that observed in the healthy mean matched control participants following a single dose of 800 
mg MOV; that is, the true AUC0-inf GMR (severe renal impairment/healthy control) is less 
than 2.0.
Estimation: In participants with severe renal impairment, plasma pharmacokinetics (Cmax) 
of NHC following a single 800-mg MOV dose will be estimated and compared to those 
observed in healthy mean matched control participants.
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9.4
Analysis Endpoints
Primary Endpoints:
•
The primary PK endpoints include AUC0-inf and Cmax of plasma N-hydroxycytidine.
Secondary Endpoints:
The secondary safety endpoint is AEs. Secondary PK endpoints include:
Ae and Fe of N-hydroxycytidine in urine and CLr of N-hydroxycytidine
9.5
Analysis Populations
The following populations are defined for the analysis and reporting of data. All participants
will be reported, and their data analyzed, according to the treatment(s) they actually received.
All Participants as Treated: The All Participants as Treated Population consists of all
participants who received at least one dose of treatment. This population will be used for
assessments of safety and tolerability.
Per-Protocol: The Per-Protocol Population consists of the subset of participants who comply 
with the protocol sufficiently to ensure that generated data will likely 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 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
Pharmacokinetics:
Individual values of plasma NHC AUC0-inf after a single dose administration of 800-mg 
MOV to participants with severe renal impairment and healthy control participants will be 
natural log-transformed and evaluated with a linear fixed effects model containing a fixed 
effect for population (participants with severe renal impairment and healthy control 
participants). 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). Covariates including age, BMI, and gender may be considered. 
Ninety-five percent (95%) CIs for the least squares means for each population will be 
constructed on the natural log scale and will reference the t-distribution. Exponentiation of 
the least-squares means and their corresponding 95% CIs will yield estimates for the 
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population GMs and CIs about the GMs on the original scale. Sample SAS code is given 
below:
proc mixed data=data;
class population;
model lnpk=population /ddfm=kr;
repeated/group=population type=UN;
lsmeans population /cl alpha=0.05;
estimate ‘severe/normal’ population 1 -1/cl alpha=0.1;
run;
To address the primary hypothesis of comparing participants with severe renal impairment to 
healthy control participants, a two-sided 90% CI for the true difference in mean (severe renal 
impairment – healthy control) will be calculated using the mean square error from the model 
and referencing a t-distribution. These confidence limits will be exponentiated to obtain the 
90% CI for the true GMR (severe renal impairment/healthy control). If the 90% CI falls 
below 2.0, then the hypothesis that in participants with severe renal impairment, the 
AUC0-inf of plasma NHC is similar to that observed in the healthy mean matched control 
participants following a single dose of 800 mg will be supported.
Plasma Cmax of NHC after a single dose of 800 mg MOV to participants with severe renal 
impairment and healthy control participants will be estimated via similar model.
Individual values will be listed for each PK parameter (plasma NHC: AUC0-inf, Cmax, 
Tmax, AUC0-last, t1/2, CL/F, and Vd/F; urine NHC: Ae and Fe of N-hydroxycytidine in urine 
and CLr of N-hydroxycytidine) 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 AUC0-inf and Cmax. Individual subject PK values will 
also be plotted against BSA indexed eGFR and against BSA de-indexed eGFR, using 
different symbols to identify participants 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 eGFR obtained from the 2021 CKD-EPI Creatinine equation will also be provided. 
Additionally, plots of PK parameter values vs age and BMI may be provided. 
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Summary Statistics using BSA de-indexed eGFR: The participants will be re-categorized into 
different renal categories based on their BSA de-indexed eGFR and non-model based 
summary statistics by population will be provided for AUC0-inf and Cmax.
Analysis using the eGFR 2021 CKD-EPI Creatinine equation: The participants will be re-
categorized into different renal categories based on their eGFR obtained from the 2021 CKD-
EPI Creatinine equation and non-model based summary statistics by population will be 
provided for AUC0-inf and Cmax.
Safety:
AEs will be tabulated. Summary statistics and plots will be generated for raw laboratory 
safety tests, ECGs, and/or vital signs as well as for change from baseline, as deemed 
clinically appropriate. Depending on the safety parameter, the difference from baseline will 
either be computed on the original scale (raw change from baseline) or on the log scale and 
back-transformed for reporting (percent change from baseline).
9.7
Interim Analyses
Not applicable.
9.8
Multiplicity
Since there is only 1 hypothesis in the primary objective, no multiplicity adjustment is 
needed.
9.9
Sample Size and Power Calculations
The between-subject standard deviation (on the natural log scale) for plasma NHC AUC0-inf 
and Cmax after administration of 800 mg MOV are 0.314 ln(hr*nmol/L) and 
0.206 ln(nmol/L), respectively, based on the MK-4482 P004 study (1600-mg single dose 
group). 
With 8 participants in each panel, assuming the true GMR (severe renal impairment /healthy 
control) is 1.28, there is 85.5% power to support the hypothesis that in participants with 
severe renal impairment, the AUC0-inf of NHC is similar to that observed in the healthy 
mean matched control participants. The true GMR can be as high as 1.33 to still maintain 
80% power.
With 8 participants in each panel, the half width of 90% CI for GMR for plasma NHC Cmax 
on the log scale will be 0.181. The lower and upper 90% confidence limits for the true GMRs 
will be given by OBS/1.2 and OBS*1.2 for plasma NHC Cmax, where OBS is the observed 
GMR.
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10
SUPPORTING DOCUMENTATION AND OPERATIONAL 
CONSIDERATIONS
10.1
Appendix 1: Regulatory, Ethical, and Study Oversight Considerations
10.1.1
Code of Conduct for Clinical Trials
Merck Sharp & Dohme LLC, Rahway, NJ, USA (MSD)
Code of Conduct for Interventional Clinical Trials
I. Introduction
A. Purpose
MSD, through its subsidiaries, conducts clinical trials worldwide to evaluate the safety and effectiveness of our 
products. As such, we are committed to designing, implementing, conducting, analyzing, and reporting these trials 
in compliance with the highest ethical and scientific standards. Protection of participants in clinical trials is the 
overriding concern in the design and conduct of clinical trials. In all cases, MSD clinical trials will be conducted 
in compliance with local and/or national regulations (including all applicable data protection laws and
regulations), and International Council for Harmonisation Good Clinical Practice (ICH-GCP), and also in 
accordance with the ethical principles that have their origin in the Declaration of Helsinki.
B. Scope
Highest ethical and scientific standards shall be endorsed for all clinical interventional investigations sponsored by 
MSD irrespective of the party (parties) employed for their execution (e.g., contract research organizations, 
collaborative research efforts). This Code is not intended to apply to trials that are observational in nature, or 
which are retrospective. Further, this Code does not apply to investigator-initiated trials, which are not under the 
full control of MSD.
II. Scientific Issues
A. Trial Conduct
1. Trial Design
Except for pilot or estimation trials, clinical trial protocols will be hypothesis-driven to assess safety, efficacy 
and/or pharmacokinetic or pharmacodynamic indices of MSD or comparator products. Alternatively, MSD 
may conduct outcomes research trials, trials to assess or validate various endpoint measures, or trials to 
determine patient preferences, etc.
The design (i.e., participant population, duration, statistical power) must be adequate to address the specific 
purpose of the trial and shall respect the data protection rights of all participants, trial site staff and, where 
applicable, third parties. All trial protocols are and will be assessed for the need and capability to enroll 
underrepresented groups. Participants must meet protocol entry criteria to be enrolled in the trial. 
2. Site Selection
MSD’s clinical trials are conducted globally in many different countries and in diverse populations, including 
people of varying age, race, ethnicity, gender, and accounting for other potential disease related factors. MSD 
selects investigative sites based on medical expertise, access to appropriate participants, adequacy of facilities 
and staff, previous performance in clinical trials, as well as budgetary considerations. Prior to trial initiation, 
sites are evaluated by MSD personnel (or individuals acting on behalf of MSD) to assess the ability to 
successfully conduct the trial.
Where appropriate, and in accordance with regulatory authority guidance, MSD will make concerted efforts 
to raise awareness of clinical trial opportunities in various communities. MSD will seek to engage 
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underrepresented groups and those disproportionately impacted by the disease under study. MSD will support 
clinical trial investigators to enroll underrepresented groups and expand access to those who will ultimately 
use the products under investigation.
3. Site Monitoring/Scientific Integrity
Investigative trial sites are monitored to assess compliance with the trial protocol and Good Clinical Practice 
(GCP). MSD reviews clinical data for accuracy, completeness, and consistency. Data are verified versus 
source documentation according to standard operating procedures. Per MSD policies and procedures, if
potential fraud, scientific/research misconduct, privacy incidents/breaches or Clinical Trial-related 
Significant Quality Issues are reported, such matters are investigated. When necessary, appropriate corrective 
and/or preventative actions are defined and regulatory authorities and/or ethics review committees are 
notified.
B. Publication and Authorship
Regardless of trial outcome, MSD commits to publish the primary and secondary results of its registered trials of 
marketed products in which treatment is assigned, according to the pre-specified plans for data analysis. To the 
extent scientifically appropriate, MSD seeks to publish the results of other analyses it conducts that are important 
to patients, physicians, and payers. Some early phase or pilot trials are intended to be hypothesis-generating rather 
than hypothesis testing; in such cases, publication of results may not be appropriate since the trial may be 
underpowered and the analyses complicated by statistical issues such as multiplicity.
MSD’s policy on authorship is consistent with the recommendations published by the International Committee of 
Medical Journal Editors (ICMJE). In summary, authorship should reflect significant contribution to the design and 
conduct of the trial, performance or interpretation of the analysis, and/or writing of the manuscript. All named 
authors must be able to defend the trial results and conclusions. MSD funding of a trial will be acknowledged in 
publications.
III. Participant Protection
A. Regulatory Authority and Ethics Committee Review (Institutional Review Board [IRB]/Independent Ethics 
Committee [IEC])
All protocols and protocol amendments will be submitted by MSD for regulatory authority 
acceptance/authorization prior to implementation of the trial or amendment, in compliance with local and/or 
national regulations.
The protocol, protocol amendment(s), informed consent form, investigator’s brochure, and other relevant trial 
documents must be reviewed and approved by an IRB/IEC before being implemented at each site, in compliance 
with local and/or national regulations. Changes to the protocol that are required urgently to eliminate an 
immediate hazard and to protect participant safety may be enacted in anticipation of ethics committee approval. 
MSD will inform regulatory authorities of such new measures to protect participant safety, in compliance with 
local and/or national regulations.
B. Safety
The guiding principle in decision-making in clinical trials is that participant welfare is of primary importance. 
Potential participants will be informed of the risks and benefits of, as well as alternatives to, trial participation. At 
a minimum, trial designs will take into account the local standard of care.
All participation in MSD clinical trials is voluntary. Participants enter the trial only after informed consent is 
obtained. Participants may withdraw from an MSD trial at any time, without any influence on their access to, or 
receipt of, medical care that may otherwise be available to them.
C. Confidentiality
MSD is committed to safeguarding participant confidentiality, to the greatest extent possible, as well as all 
applicable data protection rights. Unless required by law, only the investigator, Sponsor (or individuals acting on 
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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.
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, frequently known as a financial disclosure form, provided by 
the Sponsor. The investigator/subinvestigator(s) also consent to the transmission of this 
information to the Sponsor in the United States for these purposes. This may involve the 
transmission of information to countries that do not have laws protecting personal data.
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10.1.3
Data Protection
The Sponsor will conduct this study in compliance with all applicable data protection 
regulations.
Participants will be assigned a unique identifier by the Sponsor. Any participant records or 
datasets that are transferred to the Sponsor will contain the identifier only; participant names 
or any information that would make the participant identifiable will not be transferred.
The participant must be informed that his/her personal study-related data will be used by the 
Sponsor in accordance with local data protection law. The level of disclosure must also be 
explained to the participant. 
The participant must be informed that his/her medical records may be examined by Clinical 
Quality Assurance auditors or other authorized personnel appointed by the Sponsor, by 
appropriate IRB/IEC members, and by inspectors from regulatory authorities.
10.1.3.1
Confidentiality of Data
By signing this protocol, the investigator affirms to the Sponsor that information furnished to 
the investigator by the Sponsor will be maintained in confidence, and such information will 
be divulged to the IRB, IEC, or similar or expert committee; affiliated institution and 
employees, only under an appropriate understanding of confidentiality with such board or 
committee, affiliated institution and employees. Data generated by this study will be 
considered confidential by the investigator, except to the extent that it is included in a 
publication as provided in the Publications section of this protocol.
10.1.3.2
Confidentiality of Participant Records
By signing this protocol, the investigator agrees that the Sponsor (or Sponsor representative), 
IRB/IEC, or regulatory authority representatives may consult and/or copy study documents to 
verify worksheet/CRF data. By signing the consent form, the participant agrees to this 
process. If study documents will be photocopied during the process of verifying 
worksheet/CRF information, the participant will be identified by unique code only; full 
names/initials will be masked before transmission to the Sponsor.
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.
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10.1.4
Publication Policy
The results of this study may be published or presented at scientific meetings. The Sponsor 
will comply with the requirements for publication of study results. In accordance with 
standard editorial and ethical practice, the Sponsor will generally support publication of 
multicenter studies only in their entirety and not as individual site data. In this case, a 
coordinating investigator will be designated by mutual agreement.
If publication activity is not directed by the Sponsor, the investigator agrees to submit all 
manuscripts or abstracts to the Sponsor before submission. This allows the Sponsor to protect 
proprietary information and to provide comments.
Authorship will be determined by mutual agreement and in line with ICMJE authorship 
requirements.
10.1.5
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 trials 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, ICH GCP: Consolidated Guideline and other generally accepted standards of GCP); and 
all applicable federal, state and local laws, rules and regulations relating to the conduct of the 
clinical study.
The Code of Conduct, a collection of goals and considerations that govern the ethical and 
scientific conduct of clinical investigations sponsored by MSD, is provided in this appendix 
under the Code of Conduct for Clinical Trials.
The investigator agrees not to seek reimbursement from participants, their insurance 
providers, or from government programs for procedures included as part of the study 
reimbursed to the investigator by the Sponsor.
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The investigator will promptly inform the Sponsor of any regulatory authority inspection 
conducted for this study.
The investigator agrees to provide the Sponsor with relevant information from inspection 
observations/findings to allow the Sponsor to assist in responding to any citations resulting 
from regulatory authority inspection and will provide the Sponsor with a copy of the 
proposed response for consultation before submission to the regulatory authority. 
Persons debarred from conducting or working on clinical studies by any court or regulatory 
authority will not be allowed to conduct or work on this Sponsor’s studies. The investigator 
will immediately disclose in writing to the Sponsor if any person who is involved in 
conducting the study is debarred or if any proceeding for debarment is pending or, to the best 
of the investigator’s knowledge, threatened.
10.1.7
Data Quality Assurance
All participant data relating to the study will be recorded on printed or electronic CRF unless 
transmitted to the Sponsor or designee electronically (eg, laboratory data). The investigator 
or qualified designee is responsible for verifying that data entries are accurate and correct by 
physically or electronically signing the CRF.
Detailed information regarding Data Management procedures for this protocol will be 
provided separately.
The investigator must maintain accurate documentation (source data) that supports the 
information entered in the CRF.
The investigator must permit study-related monitoring, audits, IRB/IEC review, and 
regulatory agency inspections and provide direct access to source data documents.
Study documentation will be promptly and fully disclosed to the Sponsor by the investigator 
upon request and also shall be made available at the study site upon request for inspection, 
copying, review, and audit at reasonable times by representatives of the Sponsor or any 
regulatory authorities. The investigator agrees to promptly take any reasonable steps that are 
requested by the Sponsor or any regulatory authorities as a result of an audit or inspection to 
cure deficiencies in the study documentation and worksheets/CRFs.
The Sponsor or designee is responsible for the data management of this study including 
quality checking of the data.
Study monitors will perform ongoing source data review and verification to confirm that data 
entered into the CRF by authorized site personnel are accurate, complete, and verifiable from 
source documents; that the safety and rights of participants are being protected; and that the 
study is being conducted in accordance with the currently approved protocol and any other 
study agreements, ICH GCP, and all applicable regulatory requirements.
Records and documents, including participants’ documented informed consent, pertaining to 
the conduct of this study must be retained by the investigator for 15 years after study 
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completion unless local regulations or institutional policies require a longer retention period. 
No records may be destroyed during the retention period without the written approval of the 
Sponsor. No records may be transferred to another location or party without written 
notification to the Sponsor.
10.1.8
Source Documents
Source documents provide evidence for the existence of the participant and substantiate the 
integrity of the data collected. The investigator/institution should maintain adequate and 
accurate source documents and study records that include all pertinent observations on each 
of the site’s participants. Source documents and data should be attributable, legible, 
contemporaneous, original, accurate, and complete. Changes to source data should be 
traceable, should not obscure the original entry, and should be explained if necessary (eg, via 
an audit trail). Source documents are filed at the investigator’s site.
Data reported on the CRF or entered in the eCRF that are transcribed from source documents 
must be consistent with the source documents or the discrepancies must be explained. The 
investigator/institution may need to request previous medical records or transfer records, 
depending on the study. Also, current medical records must be available.
10.1.9
Study and Site Closure
The Sponsor or its designee may stop the study or study-site participation in the study for 
medical, safety, regulatory, administrative, or other reasons consistent with applicable laws, 
regulations, and GCP.
In the event the Sponsor prematurely terminates a particular study site, the Sponsor or 
designee will promptly notify that study site’s IRB/IEC as specified by applicable regulatory 
requirement(s).
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10.2
Appendix 2: Clinical Laboratory Tests
•
The tests detailed in Table 6 will be performed by the local laboratory.
•
Protocol-specific requirements for inclusion or exclusion of participants are detailed in 
Section 5 of the protocol.
•
Additional tests may be performed at any time during the study as determined necessary 
by the investigator or required by local regulations.
Table 6
Protocol-required Safety Laboratory Assessments
Laboratory 
Assessments
Parameters
Hematology
Platelet Count 
RBC Indices:
MCV
MCH
Reticulocytes
WBC count with 
Differential:
Neutrophils
Lymphocytes
Monocytes
Eosinophils
Basophils
RBC Count
Hemoglobin
Hematocrit
Chemistry
BUN
Potassium
AST/SGOT
Total bilirubin 
(and direct 
bilirubin, if total 
bilirubin is 
above the ULN)
Albumin
Bicarbonate
Chloride
Phosphorous
Creatinine
Sodium
ALT/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)
Pregnancy 
Testing
•
Highly sensitive serum hCG pregnancy test (as needed for WOCBP)
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Laboratory 
Assessments
Parameters
Other 
Screening 
Tests
•
FSH (as needed in postmenopausal WONCBP only)
•
Serum or urine alcohol and drug screen (to include at minimum: 
amphetamines, barbiturates, cocaine, opiates, cannabinoids and 
benzodiazepines) per site SOP
•
Serology (HIV antibody, HBsAg, and hepatitis C virus antibody)
•
Serum Cystatin C (for use in the CKD-EPIcr-cys_R equation; see Section 4.2)
and below:
The 2021 CKD-EPI Creatinine-Cystatin C (CKD-EPIcr-cys_R) equation 
including serum cystatin C that also does not use race will also be calculated 
as follows:
2021 CKD-EPI Creatinine-Cystatin C (CKD-EPIcr-cys_R) Equation:
eGFR = 135 × min(Scr /κ, 1)α × max(Scr /κ, 1)-0.544 × min(Scys /0.8, 1)-0.323 × 
max(Scys /0.8, 1)-0.778 × 0.9961Age × 0.963 [if female]
where Scr is serum creatinine, Scys is serum cystatin C, k is 0.7 for females and 
0.9 males, α is -0.219 for females and -0.144 for males, min indicates the 
minimum of Scr/k or 1, max indicates the maximum of Scr/k or 1.
eGFR values indexed to BSA 1.73 m2 will be de-indexed by dividing the 
value obtained from either formula by 1.73 and then multiplying by 
participant BSA.
ALT=alanine aminotransferase; AST=aspartate aminotransferase; BUN=blood urea nitrogen; FSH=follicle-stimulating 
hormone; HBsAg=hepatitis B surface antigen; hCG=human chorionic gonadotropin; HIV=human immunodeficiency 
virus; MCH=mean corpuscular hemoglobin; MCV=mean corpuscular volume; RBC=red blood cell; SGOT=serum 
glutamic-oxaloacetic transaminase; SGPT=serum glutamic-pyruvic transaminase; ULN=upper limit of normal; 
WBC=white blood cell; WOCBP=women of childbearing potential; WONCBP=women of nonchildbearing potential
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
Definitions of Medication Error, Misuse, and Abuse
Medication Error
This is an unintended failure in the drug treatment process that leads to or has the potential to 
lead to harm to the patient.
Misuse
This refers to situations where the medicinal product is intentionally and inappropriately used 
not in accordance with the terms of the product information.
Abuse
This corresponds to the persistent or sporadic, intentional excessive use of a medicinal 
product for a perceived psychological or physiological reward or desired non-therapeutic 
effect.
10.3.2
Definition of AE
AE definition
•
An AE is any untoward medical occurrence in a clinical study participant, temporally 
associated with the use of study intervention, whether or not considered related to the 
study intervention.
•
Note: An AE can therefore be any unfavorable and unintended sign (including an 
abnormal laboratory finding), symptom, or disease (new or exacerbated) temporally 
associated with the use of a study intervention.
•
Note: For purposes of AE definition, study intervention includes any pharmaceutical 
product, biological product, vaccine, diagnostic agent, medical device, combination 
product, or protocol specified procedure whether investigational or marketed (including 
placebo, active comparator product, or run-in intervention), manufactured by, licensed 
by, provided by, or distributed by the Sponsor for human use in this study.
Events meeting the AE definition
•
Any abnormal laboratory test results (hematology, clinical chemistry, or urinalysis) or 
other safety assessments (eg, ECG, radiological scans, vital signs measurements), 
including those that worsen from baseline, considered clinically significant in the medical 
and scientific judgment of the investigator.
•
Exacerbation of a chronic or intermittent preexisting condition including either an 
increase in frequency and/or intensity of the condition.
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•
New conditions detected or diagnosed after study intervention administration even 
though it may have been present before the start of the study.
•
Signs, symptoms, or the clinical sequelae of a suspected drug-drug interaction.
•
Signs, symptoms, or the clinical sequelae of a suspected overdose of either study 
intervention or a concomitant medication.
•
For all reports of overdose (whether accidental or intentional) with an associated AE, the 
AE term should reflect the clinical symptoms or abnormal test result. An overdose 
without any associated clinical symptoms or abnormal laboratory results is reported using 
the terminology “accidental or intentional overdose without adverse effect.”
•
Any new cancer or progression of existing cancer.
Events NOT meeting the AE definition
•
Medical or surgical procedure (eg, endoscopy, appendectomy): the condition that leads to 
the procedure is the AE.
•
Situations in which an untoward medical occurrence did not occur (social and/or 
convenience admission to a hospital).
•
Anticipated day-to-day fluctuations of preexisting disease(s) or condition(s) present or 
detected at the start of the study that do not worsen.
•
Surgical procedure(s) planned prior to informed consent to treat a preexisting condition 
that has not worsened.
•
Refer to Section 8.4.6 for protocol-specific exceptions.
10.3.3
Definition of SAE
If an event is not an AE per definition above, then it cannot be an SAE even if serious 
conditions are met.
An SAE is defined as any untoward medical occurrence that, at any dose:
1. Results in death
2. 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.
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3. Requires inpatient hospitalization or prolongation of existing hospitalization
•
Hospitalization is defined as an inpatient admission, regardless of length of stay, even 
if the hospitalization is a precautionary measure for continued observation. (Note: 
Hospitalization for an elective procedure to treat a preexisting condition that has not 
worsened is not an SAE.) A preexisting condition is a clinical condition that is 
diagnosed prior to the use of an MSD product and is documented in the participant’s 
medical history.
4. Results in persistent or significant disability/incapacity
•
The term disability means a substantial disruption of a person’s ability to conduct 
normal life functions.
•
This definition is not intended to include experiences of relatively minor medical 
significance such as uncomplicated headache, nausea, vomiting, diarrhea, influenza, 
and accidental trauma (eg, sprained ankle) that may interfere with or prevent 
everyday life functions but do not constitute a substantial disruption.
5. Is a congenital anomaly/birth defect
•
In offspring of participant taking the product regardless of time to diagnosis.
6. Other important medical events
•
Medical or scientific judgment should be exercised in deciding whether SAE 
reporting is appropriate in other situations such as important medical events that may 
not be immediately life-threatening or result in death or hospitalization but may 
jeopardize the participant or may require medical or surgical intervention to prevent 1 
of the other outcomes listed in the above definition. These events should usually be 
considered serious.
•
Examples of such events include invasive or malignant cancers, intensive treatment in 
an emergency room or at home for allergic bronchospasm, blood dyscrasias or 
convulsions that do not result in hospitalization, or development of drug dependency 
or drug abuse.
10.3.4
Additional Events Reported
Additional events that require reporting
In addition to the above criteria, AEs meeting either of the below criteria, although not 
serious per ICH definition, are reportable to the Sponsor.
•
Is a cancer
•
Is associated with an overdose
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10.3.5
Recording AE and SAE
AE and SAE recording
•
When an AE/SAE occurs, it is the responsibility of the investigator to review all 
documentation (eg, hospital progress notes, laboratory, and diagnostics reports) related to 
the event.
•
The investigator will record all relevant AE/SAE information on the AE 
CRFs/worksheets at each examination.
•
It is not acceptable for the investigator to send photocopies of the participant’s medical 
records to the Sponsor in lieu of completion of the AE CRF page.
•
There may be instances when copies of medical records for certain cases are requested by 
the Sponsor. In this case, all participant identifiers, with the exception of the participant 
number, will be blinded on the copies of the medical records before submission to the 
Sponsor.
•
The investigator will attempt to establish a diagnosis of the event based on signs, 
symptoms, and/or other clinical information. In such cases, the diagnosis (not the 
individual signs/symptoms) will be documented as the AE/SAE.
Assessment of intensity
•
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) reported during the study and assign it to 1 of the following
categories:
-
Mild: An event that is easily tolerated by the participant, causing minimal discomfort, 
and not interfering with everyday activities (for pediatric studies, awareness of 
symptoms, but easily tolerated).
-
Moderate: An event that causes sufficient discomfort to interfere with normal 
everyday activities (for pediatric studies, definitely acting like something is wrong).
-
Severe: An event that prevents normal everyday activities. An AE that is assessed as 
severe should not be confused with an SAE. Severe is a category used for rating the 
intensity of an event; and both AE and SAE can be assessed as severe (for pediatric 
studies, extremely distressed or unable to do usual activities).
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Assessment of causality
•
Did the study intervention cause the AE?
•
The determination of the likelihood that the study intervention caused the AE will be 
provided by an investigator who is a qualified physician. The investigator’s signed/dated 
initials on the source document or worksheet that supports the causality noted on the AE 
form, ensures that a medically qualified assessment of causality was done. This initialed 
document must be retained for the required regulatory time frame. The criteria below are 
intended as reference guidelines to assist the investigator in assessing the likelihood of a 
relationship between the test product and the AE based upon the available information.
•
The following components are to be used to assess the relationship between the 
study intervention and the AE; the greater the correlation with the components and 
their respective elements (in number and/or intensity), the more likely the study 
intervention caused the AE:
-
Exposure: Is there evidence that the participant was actually exposed to the study 
intervention such as: reliable history, acceptable compliance assessment (pill count, 
diary, etc), expected pharmacologic effect, or measurement of drug/metabolite in 
bodily specimen?
-
Time Course: Did the AE follow in a reasonable temporal sequence from 
administration of the study intervention? Is the time of onset of the AE compatible 
with a drug-induced effect (applies to studies with 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 study intervention discontinued or dose/exposure/frequency 
reduced?
◦
If yes, did the AE resolve or improve?
◦
If yes, this is a positive dechallenge.
◦
If no, this is a negative dechallenge.
(Note: This criterion is not applicable if: (1) the AE resulted in death or permanent 
disability; (2) the AE resolved/improved despite continuation of the study 
intervention; (3) the study is a single-dose drug study; or (4) study intervention(s) 
is/are only used 1 time.)
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-
Rechallenge: Was the participant re-exposed to the study intervention in this study?
◦
If yes, did the AE recur or worsen?
◦
If yes, this is a positive rechallenge.
◦
If no, this is a negative rechallenge.
(Note: This criterion is not applicable if: (1) the initial AE resulted in death or 
permanent disability, or (2) the study is a single-dose drug study; or (3) study 
intervention(s) is/are used only 1 time.)
NOTE: IF A RECHALLENGE IS PLANNED FOR AN AE THAT WAS SERIOUS AND 
MAY HAVE BEEN CAUSED BY THE STUDY INTERVENTION, OR IF RE-
EXPOSURE TO THE STUDY INTERVENTION POSES ADDITIONAL POTENTIAL 
SIGNIFICANT RISK TO THE PARTICIPANT THEN THE RECHALLENGE MUST BE 
APPROVED IN ADVANCE BY THE SPONSOR CLINICAL DIRECTOR, AND IF 
REQUIRED, THE IRB/IEC.
•
Consistency with study intervention profile: Is the clinical/pathological presentation of 
the AE consistent with previous knowledge regarding the study intervention or drug class 
pharmacology or toxicology?
•
The assessment of relationship will be reported on the CRFs/worksheets by an 
investigator who is a qualified physician according to their best clinical judgment, 
including consideration of the above elements.
•
Use the following scale of criteria as guidance (not all criteria must be present to be 
indicative of a study intervention relationship).
-
Yes, there is a reasonable possibility of study intervention relationship:
◦
There is evidence of exposure to the study intervention. The temporal sequence of 
the AE onset relative to the administration of the study intervention is reasonable. 
The AE is more likely explained by the study intervention than by another cause.
-
No, there is not a reasonable possibility of study intervention relationship:
◦
Participant did not receive the study intervention OR temporal sequence of the AE 
onset relative to administration of the study intervention is not reasonable OR the 
AE is more likely explained by another cause than the study intervention. (Also 
entered for a participant with overdose without an associated AE.)
•
The investigator must review and provide an assessment of causality for each AE/SAE 
and document this in the medical notes.
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•
There may be situations in which an SAE has occurred and the investigator has minimal 
information to include in the initial report to the Sponsor. However, it is very important 
that the investigator always make an assessment of causality for every event before the 
initial transmission of the SAE data to the Sponsor.
•
The investigator may change their opinion of causality in light of follow-up information 
and send an SAE follow-up report with the updated causality assessment.
•
The causality assessment is 1 of the criteria used when determining regulatory reporting 
requirements.
Follow-up of AE and SAE
•
The investigator is obligated to perform or arrange for the conduct of supplemental 
measurements and/or evaluations as medically indicated or as requested by Sponsor to 
elucidate the nature and/or causality of the AE or SAE as fully as possible. This may 
include additional laboratory tests or investigations, histopathological examinations, or 
consultation with other health care professionals.
•
New or updated information will be recorded in the CRF.
•
The investigator will submit any updated SAE data to the Sponsor within 24 hours of 
receipt of the information.
10.3.6
Reporting of AEs, SAEs, and Other Reportable Safety Events to the Sponsor
AE, SAE, and other reportable safety event reporting to Sponsor via electronic data 
collection tool
•
The primary mechanism for reporting to the Sponsor will be the EDC tool.
-
Electronic reporting procedures can be found in the EDC data entry guidelines (or 
equivalent).
-
If the electronic system is unavailable for more than 24 hours, then the site will use 
the paper AE Reporting form.
◦
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).
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•
Contacts for SAE reporting can be found in the Investigator Study File Binder (or 
equivalent).
SAE reporting to the Sponsor via paper CRF
•
If the EDC tool is not operational, facsimile transmission or secure e-mail of the SAE 
paper CRF is the preferred method to transmit this information to the Sponsor.
•
In rare circumstances and in the absence of facsimile equipment, notification by 
telephone is acceptable with a copy of the SAE data collection tool sent by overnight 
mail or courier service.
•
Initial notification via telephone does not replace the need for the investigator to 
complete and sign the SAE CRF pages within the designated reporting time frames.
•
Contacts and instructions for SAE reporting and paper reporting procedures can be found 
in the Investigator Study File Binder (or equivalent).
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10.4
Appendix 4: Medical Device and Drug-device Combination Products: Product 
Quality Complaints/Malfunctions: Definitions, Recording, and Follow-up
Not applicable.
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10.5
Appendix 5: Contraceptive Guidance
10.5.1
Definitions
Women of Nonchildbearing Potential (WONCBP)
Women in the following categories are considered WONCBP:
•
Premenopausal female with 1 of the following:
-
Documented hysterectomy
-
Documented bilateral salpingectomy
-
Documented bilateral oophorectomy
For individuals with permanent infertility due to an alternate medical cause other than 
the above (eg, Mullerian agenesis, androgen insensitivity), investigator discretion 
should be applied to determining study entry.
Note: Documentation can come from the site personnel’s review of the participant’s 
medical records, medical examination, or medical history interview.
•
Postmenopausal female
-
A postmenopausal state is defined as no menses for 12 months without an alternative 
medical cause. 
◦
A high 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 must discontinue HRT to 
allow confirmation of postmenopausal status before study enrollment.
Women of Childbearing Potential (WOCBP)
A woman is considered fertile following menarche and until becoming postmenopausal 
unless permanently sterile (see below):
If fertility is unclear (eg, amenorrhea in adolescents or athletes) and a menstrual cycle cannot 
be confirmed before first dose of study intervention, additional evaluation should be 
considered.
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Women in the following categories are not considered WOCBP:
•
Premenarchal
•
Premenopausal female with 1 of the following:
-
Documented hysterectomy
-
Documented bilateral salpingectomy
-
Documented bilateral oophorectomy
For individuals with permanent infertility due to an alternate medical cause other than the 
above (eg, Mullerian agenesis, androgen insensitivity), investigator discretion should be 
applied to determining study entry.
Note: Documentation can come from the site personnel’s review of the participant’s medical 
records, medical examination, or medical history interview.
•
Postmenopausal female
-
A postmenopausal state is defined as no menses for 12 months without an alternative 
medical cause.
◦
A high 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 non-hormonal highly effective contraception methods if they wish to continue 
their HRT during the study. Otherwise, they must discontinue HRT to allow 
confirmation of postmenopausal status before study enrollment.
Women of Childbearing Potential (WOCBP) Nonparticipant Only
A woman is considered fertile following menarche and until becoming postmenopausal 
unless permanently sterile (see below):
•
Women in the following categories are not considered WOCBP:
-
Premenarchal
-
Premenopausal female with 1 of the following:
-
Hysterectomy
-
Bilateral salpingectomy
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-
Bilateral oophorectomy
-
Permanent infertility due to an alternate medical cause other than the above (eg, 
Mullerian agenesis, androgen insensitivity.
•
Postmenopausal female
-
A postmenopausal state is defined as no menses for 12 months without an alternative 
medical cause.
10.5.2
Contraception Requirements
The following contraceptive methods should be used by WOCBP participants in the study 
(Section 5.1)
Contraceptives allowed during the study includea:
Highly Effective Contraceptive Methods That Have Low User Dependency
Failure rate of <1% per year when used consistently and correctly.
•
Progestogen-only subdermal contraceptive implantb
•
IUSc
•
Non-hormonal IUD
•
Bilateral tubal occlusion
•
Azoospermic partner (vasectomized or secondary to medical cause)
This is a highly effective contraception method provided that the partner is the sole male sexual partner of 
the WOCBP and the absence of sperm has been confirmed. If not, an additional highly effective method of 
contraception should be used. A spermatogenesis cycle is approximately 90 days.
Note: Documentation of azoospermia for a male participant can come from the site personnel’s review of 
the participant’s medical records, medical examination, or medical history interview. 
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.
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
If locally required, in accordance with CTFG guidelines, acceptable contraceptive implants are limited to 
those which inhibit ovulation.
  c IUS is a progestin releasing IUD.
Note: The following are not acceptable methods of contraception:
- Periodic abstinence (calendar, symptothermal, post-ovulation methods), withdrawal (coitus 
interruptus), spermicides only, and LAM.
- Male condom with cap, diaphragm, or sponge with spermicide.
- Male and female condom should not be used together (due to risk of failure with friction).
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The following contraceptive methods should be used by nonparticipant WOCBP partners of 
male participants in the study (Section 5.1)
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 subdermal contraceptive implantc
•
IUSd
•
Non-hormonal IUD
•
Bilateral tubal occlusion
•
Azoospermic partner (vasectomized or secondary to medical cause)
This is a highly effective contraception method provided that the partner is the sole male sexual partner of 
the WOCBP and the absence of sperm has been confirmed. If not, an additional highly effective method of 
contraception should be used. A spermatogenesis cycle is approximately 90 days.
Note: Documentation of azoospermia for a male participant can come from the site personnel’s review of 
the participant’s medical records, medical examination, or medical history interview. 
Highly Effective Contraceptive Methods That Are User Dependentb
Failure rate of <1% per year when used consistently and correctly.
•
Combined (estrogen- and progestogen- containing) hormonal contraceptionc,d
- Oral
- Intravaginal
- Transdermal
- Injectable
•
Progestogen-only hormonal contraceptionc,d
- Oral
- Injectable
Sexual Abstinence
•
Sexual abstinence is considered a highly effective method only if defined as refraining from heterosexual 
intercourse during the entire period of risk associated with the study intervention. The reliability of sexual 
abstinence needs to be evaluated in relation to the duration of the study and the preferred and usual lifestyle 
of the participant.
a Contraceptive use by men or women should be consistent with local regulations regarding the use of 
contraceptive methods for participants of clinical studies.
b Typical use failure rates are higher than perfect-use failure rates (ie, when used consistently and correctly).
c If locally required, in accordance with CTFG guidelines, acceptable hormonal contraceptives are limited to 
those which inhibit ovulation.
d IUS is a progestin releasing IUD.
Note: The following are not acceptable methods of contraception:
- Periodic abstinence (calendar, symptothermal, post-ovulation methods), withdrawal (coitus 
interruptus), spermicides only, and LAM.
- Male condom with cap, diaphragm, or sponge with spermicide.
- 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 Research3, 4
The specimens consented and/or collected in this study as outlined in Section 8.9 will be 
used in various experiments to understand:

The biology of how drugs/vaccines work

Biomarkers responsible for how a drug/vaccine enters and is removed by the body

Other pathways with which drugs/vaccines may interact

The biology of disease
The specimen(s) may be used for future assay development and/or drug/vaccine 
development.
It is now well recognized that information obtained from studying and testing clinical 
specimens offers unique opportunities to enhance our understanding of how individuals 
respond to drugs/vaccines, enhance our understanding of human disease and ultimately 
improve public health through development of novel treatments targeted to populations 
with the greatest need. All specimens will be used by the Sponsor or those working for or 
with the Sponsor.
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3. Summary of Procedures for Future Biomedical Research3, 4
a. Participants for Enrollment
All participants enrolled in the clinical study will be considered for enrollment in 
future biomedical research.
b. Informed Consent
Informed consent for specimens (ie, DNA, RNA, protein, etc) will be obtained during 
screening for protocol enrollment from all participants or legal guardians, at a study 
visit by the investigator or his or her designate. Informed consent for future 
biomedical research should be presented to the participants on the visit designated in 
the SoA. If delayed, present consent at next possible Participant Visit. Consent forms 
signed by the participant will be kept at the clinical study site under secure storage for 
regulatory reasons.
A template of each study site’s approved informed consent will be stored in the 
Sponsor’s clinical document repository.
c. eCRF Documentation for Future Biomedical Research Specimens
Documentation of participant consent for future biomedical research will be captured 
in the eCRFs. Any specimens for which such an informed consent cannot be verified 
will be destroyed.
d. Future Biomedical Research Specimen(s)
Collection of specimens for future biomedical research will be performed as outlined 
in the SoA. In general, if additional blood specimens are being collected for future 
biomedical research, these will usually be obtained at a time when the participant is 
having blood drawn for other study purposes.
4. Confidential Participant Information for Future Biomedical Research3, 4
In order to optimize the research that can be conducted with future biomedical research
specimens, it is critical to link participants' clinical information with future test results. In 
fact, little or no research can be conducted without connecting the clinical study data to 
the specimen. The clinical data allow specific analyses to be conducted. Knowing 
participant characteristics like sex, age, medical history and intervention outcomes 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 
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identifying information embedded within it. The link (or key) between participant 
identifiers and this unique code will be held at the study site. No personal identifiers will 
appear on the specimen tube.
5. Biorepository Specimen Usage3, 4
Specimens obtained for the Sponsor will be used for analyses using good scientific 
practices. Analyses using the future biomedical research specimens may be performed by 
the Sponsor, or an additional third party (eg, a university investigator) designated by the 
Sponsor. The investigator conducting the analysis will follow the Sponsor’s privacy and 
confidentiality requirements. Any contracted third party analyses will conform to the 
specific scope of analysis outlined in future biomedical research protocol and consent. 
Future biomedical research specimens remaining with the third party after specific 
analysis is performed will be reported to the Sponsor.
6. Withdrawal From Future Biomedical Research3, 4
Participants may withdraw their consent for FBR and ask that their biospecimens not be 
used for FBR. Participants may withdraw consent at any time by contacting the study 
investigator. If medical records for the study are still available, the investigator will 
contact the Sponsor using the designated mailbox 
(clinical.specimen.management@MSD.com). Subsequently, the participant's specimens 
will be flagged in the biorepository and restricted to study use only. If specimens were 
collected from study participants specifically for FBR, these specimens will be removed 
from the biorepository and destroyed. Documentation will be sent to the investigator 
confirming withdrawal and/or destruction, if applicable. It is the responsibility of the 
investigator to inform the participant of completion of the withdrawal and/or destruction, 
if applicable. Any analyses in progress at the time of request for withdrawal/destruction 
or already performed before the request being received by the Sponsor will continue to be 
used as part of the overall research study data and results. No new analyses would be 
generated after the request is received.
If the medical records for the study are no longer available (eg, if the investigator is no 
longer required by regulatory authorities to retain the study records) or the specimens 
have been completely anonymized, there will no longer be a link between the 
participant’s personal information and their specimens. In this situation, the request for 
withdrawal of consent and/or destruction cannot be processed.
7. Retention of Specimens3, 4
Future biomedical research specimens will be stored in the biorepository for potential 
analysis for up to 20 years from the end of the study. Specimens may be stored for longer 
if a regulatory or governmental authority has active questions that are being answered. In 
this special circumstance, specimens will be stored until these questions have been 
adequately addressed.
Specimens from the study site will be shipped to a central laboratory and then shipped to 
the Sponsor-designated biorepository. If a central laboratory is not utilized in a particular 
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study, the study site will ship directly to the Sponsor-designated biorepository. The 
specimens will be stored under strict supervision in a limited access facility which 
operates to assure the integrity of the specimens. Specimens will be destroyed according 
to Sponsor policies and procedures and this destruction will be documented in the 
biorepository database.
8. Data Security3, 4
Databases containing specimen information and test results are accessible only to the 
authorized Sponsor representatives and the designated study administrator research 
personnel and/or collaborators. Database user authentication is highly secure, and is 
accomplished using network security policies and practices based on international 
standards to protect against unauthorized access.
9. Reporting of Future Biomedical Research Data to Participants3, 4
No information obtained from exploratory laboratory studies will be reported to the 
participant, family, or physicians. Principle reasons not to inform or return results to the 
participant include: lack of relevance to participant health, limitations of predictive 
capability, and concerns regarding misinterpretation.
If important research findings are discovered, the Sponsor may publish results, present 
results in national meetings, and make results accessible on a public website in order to
rapidly report this information to doctors and participants. Participants will not be 
identified by name in any published reports about this study or in any other scientific 
publication or presentation.
10. Future Biomedical Research Study Population3, 4
Every effort will be made to recruit all participants diagnosed and treated on Sponsor 
clinical studies for future biomedical research.
11. Risks Versus Benefits of Future Biomedical Research3, 4
For future biomedical research, risks to the participant have been minimized and are 
described in the future biomedical research informed consent.
The Sponsor has developed strict security, policies, and procedures to address participant 
data privacy concerns. Data privacy risks are largely limited to rare situations involving 
possible breach of confidentiality. In this highly unlikely situation, there is risk that the 
information, like all medical information, may be misused.
12. Questions
Any questions related to the future biomedical research should be emailed directly to 
clinical.specimen.management@MSD.com.
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13. References
1. National Cancer Institute [Internet]: Available from 
https://www.cancer.gov/publications/dictionaries/cancer-terms?cdrid=45618
2. International Council on Harmonisation [Internet]: E15: Definitions for Genomic 
Biomarkers, Pharmacogenomics, Pharmacogenetics, Genomic Data and Sample 
Coding Categories. Available from 
http://www.ich.org/products/guidelines/efficacy/efficacy-single/article/definitions-
for-genomic-biomarkers-pharmacogenomics-pharmacogenetics-genomic-data-and-
sample-cod.html 
3. Industry Pharmacogenomics Working Group [Internet]: Understanding the Intent, 
Scope and Public Health Benefits of Exploratory Biomarker Research: A Guide for 
IRBs/IECs and Investigational Site Staff. Available at http://i-pwg.org/ 
4. Industry Pharmacogenomics Working Group [Internet]: Pharmacogenomics 
Informational Brochure for IRBs/IECs and Investigational Site Staff. Available at 
http://i-pwg.org/
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10.7
Appendix 7: Country-specific Requirements
Not applicable.
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10.8
Appendix 8: 12-Lead Electrocardiogram Abnormality Criteria
Screen Failure Criteria
Potentially Significant Post-
allocation Findings 
(clarification on action to take)
RHYTHM
Sinus Tachycardia
110 bpm
HR >110 bpm and HR increase of 
≥25 bpm from baseline
Sinus Bradycardia
<40 bpm
HR <40 bpm and HR decrease of 
≥5 bpm from baseline
Sinus Pause/Arrest
>2.0 seconds
>2.0 seconds
Atrial Premature Complex
1 beat
3 beats
Ventricular Premature Complex
All
3 beats
Ectopic Atrial Rhythm 
None
None
Junctional Rhythm
Junctional Rhythm with HR 
<40 bpm
Junctional Rhythm with HR 
<40 bpm
Idioventricular Rhythm
All
All
Atrial Fibrillation
All
All
Atrial Flutter
All
All
Supraventricular Tachycardia
All
All
Ventricular Tachycardia
All
All
AXIS
Left Axis Deviation
RBBB With LAHB
New Onset LAHB
Right Axis Deviation
RBBB With 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)
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 (B or F)
Male
QTc 470 ms
QTc 500 ms or Increase of 60 
ms From Baseline
Female
QTc 480 ms
QTc 500 ms or Increase of 60 
ms From Baseline
HYPERTROPHY
Atrial Abnormalities
Definite Evidence of P Mitrale or 
P Pulmonale
Definite Evidence of P Mitrale or P 
Pulmonale
Ventricular Abnormalities
Voltage Criteria for LVH Plus 
Strain Pattern
Voltage Criteria for LVH Plus 
Strain Pattern
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Screen Failure Criteria
Potentially Significant Post-
allocation Findings 
(clarification on action to take)
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
AV=atrioventricular; bpm=beats per minute; HR=heart rate: ICRBBB=incomplete right bundle branch block; LAHB=left 
anterior hemiblock; LPHB=left posterior hemiblock; LVH=left ventricular hypertrophy; mm=millimeter; 
ms=milliseconds, PR=pulse rate; QTcB=QT correction using Bazett’s formula; QTcF=QT correction using Fredericia 
formula; RBBB=right bundle branch block; ST/T=ST-segment/T wave.
Baseline is defined as Predose Day 1
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10.9
Appendix 9: 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:
a.
The participant may be excluded from the study;
b. 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).
c.
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
d. 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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10.10 Appendix 10: Abbreviations
Abbreviation
Expanded Term
ACE
angiotensin converting enzyme
ADME
absorption, distribution, metabolism, and excretion
AE
adverse event 
Ae
Amount of dose administered excreted in urine
ALT
alanine aminotransferase
APaT
All-Participants-as-Treated
ASN
American Society of Nephrology
AST
aspartate aminotransferase
AUC
area under the curve
AUC0-24
area under the concentration-time curve (0 to 24 hours)
AUC0-inf
area under the concentration-time curve (0 to infinity)
AUC0-last
Area under curve from time 0 to last measured concentration
AV
atrioventricular
BDS
blood drug screen
BMI
body mass index
BP
blood pressure
bpm
beats per minute
BSA
body surface area
BT
body temperature
BUN
blood urea nitrogen
C12
concentration at 12 hours after dosing
CCU
Cardiac care unit
CI
confidence interval
CKD-EPI
Chronic Kidney Disease Epidemiology Collaboration
CL
clearance
CL/F
apparent total clearance from plasma after oral administration
Cmax
maximum plasma concentration
CNS
central nervous system 
COVID-19
Coronavirus Disease 2019
CRF
Case Report Form 
cr
creatinine
CRU
clinical research unit
CSR
Clinical Study Report
CTCAE
Common Terminology Criteria for Adverse Events
CTCAE 5.0
Common Terminology Criteria for Adverse Events, Version 5.0
CTFG
Clinical Trial Facilitation Group 
CV
Coefficient of variation
CYP
cytochrome P450
cys
cystatin C
DDFM=KR
denominator degrees of freedom for fixed effects using the Kenward-
Roger calculation
DDI
drug-drug interaction
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Abbreviation
Expanded Term
DFC
dry fill capsule
DILI
drug-induced liver injury
DNA
deoxyribonucleic acid 
DPP-4
dipeptidyl peptidase-4
ECG
electrocardiogram 
ECI
event of clinical interest
eCRF
electronic Case Report Form
EDC
electronic data collection 
EEA
European Economic Area
eGFR
estimated glomerular filtration rate
EIDD
Emory Institute of Drug Development
EMA
European Medicines Agency
FBR
future biomedical research
FDA
Food and Drug Administration
FDAAA
Food and Drug Administration Amendments Act
Fe
fraction of the dose administered excreted in urine
FIH
first in human
FMI
final market image
FSH
follicle-stimulating hormone 
FSR
First Site Ready
GCP
Good Clinical Practice 
GI
gastrointestinal
GM
geometric mean
GMR
geometric mean ratio
HBcAb
hepatitis B core antibody
HBsAg
hepatitis B surface antigen
HBV
hepatitis B virus
hCG
human chorionic gonadotropin
HCV
hepatitis C virus
HIV
human immunodeficiency virus
HR
heart rate
HRT
hormone replacement therapy
IB
Investigator’s Brochure 
ICF
Informed Consent Form
ICH
International Council for Harmonisation of Technical Requirements for 
Pharmaceuticals for Human Use
ICMJE
International Committee of Medical Journal Editors
ICRBBB
incomplete right bundle branch block
ICU
intensive care unit
ID
identification
IEC
Independent Ethics Committee
IMP
investigational medicinal product
IND
Investigational New Drug 
IRB
Institutional Review Board
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Abbreviation
Expanded Term
IUD
intrauterine device
IUS
intrauterine hormone-releasing system
IV
intravenous
LAHB
left anterior hemiblock
LAM
lactational amenorrhea method
LPHB
left posterior hemiblock
LVH
left ventricular hypertrophy
MAD
multiple ascending dose
MCH
mean corpuscular hemoglobin
MCV
mean corpuscular volume
MDRD
Modification of Diet in Renal Disease
MERS-CoV
Middle East respiratory syndrome coronavirus
mm
millimeter
MOV
molnupiravir, MK-4482, EIDD-2801
ms
milliseconds
NCS
not clinically significant
NHC
N-hydroxycytidine
NHC-TP
N-hydroxycytidine triphosphate
NIMP
non-investigational medicinal product
NKF
National Kidney Foundation
NOAEL
no observed adverse effect level 
NSAE
nonserious adverse event
OBS
observed GMR
PCL
Protocol Clarification Letter
PCR
polymerase chain reaction
pEFD
prenatal embryo fetal development
PK
pharmacokinetic
PopPK
population pharmacokinetic
PR
pulse rate
Q12H
every 12 hours
QP2
Department of Quantitative Pharmacology and Pharmacometrics
QTcB
QT correction using Bazett’s formula
QTcF
QT correction using Fredericia formula
RBBB
right bundle branch block
RBC
red blood cell
RI
renal impairment
RNA
ribonucleic acid
RR
respiratory rate
RSV
respiratory syncytial virus
SAD
single ascending dose
SAE
serious adverse event 
SaO2
oxygen saturation
SARS-CoV-2
severe acute respiratory syndrome coronavirus 2
SAS
Statistical Analysis Software
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Abbreviation
Expanded Term
Scr
serum creatinine
Scys
serum cystatin C
SGOT
serum glutamic oxaloacetic transaminase
SGPT
Serum glutamic pyruvic transaminase
SLAB
Supplemental laboratory test(s)
SoA
schedule of activities
SOP
Standard Operating Procedures
SSRIs
selective serotonin uptake inhibitors
ST/T
ST-segment/T wave
SUSAR
suspected unexpected serious adverse reaction
Tmax
Time to maximum plasma concentration
t1/2
half life
UDS
urine drug screen
ULN
upper limit of normal
US
United States of America
Vd/F
apparent volume of distribution
VS
vital signs
WBC
white blood cell
WOCBP
woman/women of childbearing potential
WONCBP
woman/women of nonchildbearing potential
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11
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Delgado C, Baweja M, Crews DC, Eneanya ND, 
Gadegbeku CA, Inker LA, et al. A unifying 
approach for GFR estimation: recommendations 
of the NKF-ASN Task Force on reassessing the 
inclusion of race in diagnosing kidney disease. J 
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[Gordon, C. J., et al 
2020]
Gordon CJ, Tchesnokov EP, Woolner E, Perry 
JK, Feng JY, Porter DP, et al. Remdesivir is a 
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[Grasselli, G., et al 2020]
Grasselli G, Pesenti A, Cecconi M. Critical care 
utilization for the COVID-19 outbreak in 
Lombardy, Italy: early experience and forecast 
during an emergency response. JAMA. 2020 Apr 
28;323(16):1545-6.
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[Guan, W., et al 2020]
Guan W, Ni Z, Hu Y, Liang W, Ou C, He J, et 
al. Clinical characteristics of coronavirus disease 
2019 in China. N Engl J Med. 2020 Apr 
30;382(18):1708-20.
[05H4S0]
[Inker, L. A., et al 2021]
Inker LA, Eneanya ND, Coresh J, Tighiouart H, 
Wang D, Sang Y, et al. New creatinine- and 
cystatin C-based equations to estimate GFR 
without race. N Engl J Med. 2021 Nov 
4;385(19):1737-49. Supplemental material; 87 p.
[07ZRQ6]
[Wu, Z. 2020]
Wu Z, McGoogan JM. Characteristics of and 
important lessons from the coronavirus disease 
2019 (COVID-19) outbreak in China: summary 
of a report of 72 314 cases from the Chinese 
Center for Disease Control and Prevention. 
JAMA. 2020 Apr 7;323(13):1239-42.
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