Clinical trial NCT05386589
Conditions: Hepatic Impairment
Sponsor: Merck Sharp & Dohme LLC
Start date: 2022-06-14; Completion date: 2023-01-05
Enrollment: 14 participants; Allocation: NON_RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The purpose of this study is to evaluate the pharmacokinetics (PK) of N-hydroxycytidine (NHC) following a single oral dose of molnupiravir in participants 18 to 75 years (inclusive) with moderate hepatic impairment and healthy matched controls.

Detailed description:

Arms: arm 1: Participants with moderate hepatic impairment received a single oral dose of molnupiravir 800 mg on Day 1. arm 2: Healthy matched participants received a single oral dose of molnupiravir 800 mg on Day 1.
Interventions: intervention 1: Molnupiravir
Intervention descriptions: intervention 1: Four 200 mg capsules administered orally as a single dose

Protocol documents:
Prot_SAP_000.pdf: 
Official Protocol Title:
NCT number:                NCT05386589
Document Date:           18-Aug-2022
An Open-Label, Single-Dose Clinical Study to
Evaluate the Pharmacokinetics of Molnupiravir
(MK-4482) in Participants with Moderate
Hepatic Impairment


PRODUCT: MK-4482  
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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 Clinical Study to Evaluate the 
Pharmacokinetics of Molnupiravir (MK-4482) in Participants with Moderate Hepatic 
Impairment
Protocol Number: 016-02
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: 18 August 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
18-AUG-2022
Exclusion criterion #23 was modified to allow enrollment of participants with 
hepatic impairment (HI) who use medical marijuana and have a valid medical 
marijuana card from a licensed healthcare provider. This modification was done 
to facilitate enrollment of participants with HI due to the prevalent use of 
medical marijuana in this patient population.
Amendment 1
14-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
11-APR-2022
Not applicable
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PROTOCOL AMENDMENT SUMMARY OF CHANGES
Amendment: 02
Overall Rationale for the Amendments:
Exclusion criterion #23 was modified to allow enrollment of participants with hepatic impairment (HI) who use medical marijuana 
and have a valid medical marijuana card from a licensed healthcare provider. This modification was done to facilitate enrollment of 
participants with HI due to the prevalent use of medical marijuana in this patient population.
Summary of Changes Table:
Section # and Name
Description of Change 
Brief Rationale 
1.3 Schedule of 
Activities
The following statement was 
deleted from footnote c:
“the second CP score may be 
obtained at the time of check-in, 
but data must be available before 
dosing on Day 1 to ensure 
eligibility.” 
The timepoints for the procedures 
“Assessment of Liver Function 
Using Child-Pugh Classification”
and “PT/INR” were modified to 
be assessed only during the 
screening period and not inclusive 
of the check-in period (Day -1).
These changes are corrections of typographical errors. As per 
Amendment 01, if conducted, the second assessment of liver function 
using Child-Pugh Classification (including PT/INR assessment) is to 
be conducted prior to check-in to allow time for eligibility review and 
allocation number assignment. Therefore, these clarifications are made 
to align the text throughout the protocol.
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Section # and Name
Description of Change 
Brief Rationale 
5 Study Population
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.
This change is a correction of typographical error. This modification 
was mentioned in the previous Summary of Changes Table in 
Amendment 01, but was inadvertently not applied to the protocol 
amendment. 
5.2 Exclusion Criteria
A subheading of “All 
Participants” was added under the 
“Prior/Concurrent Clinical Study 
Experience, Diagnostic 
Assessments, and Other 
Exclusion” headings
This subheading was added as a clarification of the patient population 
for which the exclusion criteria apply. 
5.2 Exclusion Criteria
The following statement was 
removed from exclusion criterion 
#19:
“…,or is taking concomitant 
medications that prolong the 
QT/QTc interval.”
Participants with hepatic impairment may be on medications that are 
known to prolong the QT/QTc interval to manage their disease (eg, 
diuretics). This modification to exclusion criterion #19 will not 
exclude participants that are taking these medications. However, use of 
these medications during the study for enrolled participants are to be 
discussed with the Sponsor as per the addition to Section 6.5. 
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Section # and Name
Description of Change 
Brief Rationale 
6.5 Concomitant 
Therapy
The following statement was 
added:
“Medications with known effect 
on QT/QTc prolongation may be 
allowed following discussion 
with the Sponsor.”
This statement was added to align Sec. 6.5 with the modification to the 
exclusion criterion #19 and allows HI participants to continue QT/QTc
prolonging medications after discussion with the Sponsor.
5.2 Exclusion Criteria
Exclusion criterion #23 was 
modified to allow enrollment of 
participants with hepatic 
impairment (HI) who use medical 
marijuana and have a valid 
medical marijuana card from a 
licensed healthcare provider.
This modification was done to facilitate enrollment of participants 
with HI 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 24 
hours after, study intervention 
administration.”
This statement was added to provide restrictions for medical marijuana 
usage for participants with HI with regards to study intervention 
administration. 
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Section # and Name
Description of Change 
Brief Rationale 
8 Study Assessments 
and Procedures
The total maximum amount of 
blood to be collected for 
participants in Panel A was 
corrected to 116.5 mL from 
105.5 mL.
This change was a correction of a typographical error where the 
original value did not align with the Blood Volume Table in the 
finalized Study Operations Manual.
8.3.1 Physical 
Examinations
“Height and weight will also be 
measured and recorded at the 
timepoints listed in the SoA (Sec. 
1.3).”
This change was a clarification to align the requirements of the 
physical exams with the SoA (Sec. 1.3).
Throughout
Minor grammatical and 
typographical errors were 
corrected.
These changes were non-substantial editorial corrections.
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Table of Contents
DOCUMENT HISTORY ........................................................................................................3
PROTOCOL AMENDMENT SUMMARY OF CHANGES...............................................4
1
PROTOCOL SUMMARY ............................................................................................15
1.1
Synopsis.................................................................................................................15
1.2
Schema ..................................................................................................................18
1.3
Schedule of Activities...........................................................................................19
2
INTRODUCTION..........................................................................................................24
2.1
Study Rationale....................................................................................................24
2.2
Background ..........................................................................................................25
2.2.1
Pharmaceutical and Therapeutic Background .............................................25
2.2.2
Preclinical Studies........................................................................................25
2.2.3
Completed and Ongoing Clinical Studies....................................................27
2.2.3.1
Completed Clinical Studies................................................................27
2.2.3.2
Ongoing Clinical Studies...................................................................28
2.3
Benefit/Risk Assessment......................................................................................29
3
HYPOTHESES, OBJECTIVES, AND ENDPOINTS................................................30
4
STUDY DESIGN............................................................................................................32
4.1
Overall Design......................................................................................................32
4.2
Scientific Rationale for Study Design.................................................................33
4.2.1
Rationale for Endpoints ...............................................................................34
4.2.1.1
Efficacy Endpoints.............................................................................34
4.2.1.2
Safety Endpoints................................................................................34
4.2.1.3
Pharmacokinetic Endpoints ...............................................................34
4.2.1.4
Pharmacodynamic Endpoints.............................................................34
4.2.1.5
Planned Exploratory Biomarker Research.........................................35
4.2.1.5.1
Planned Genetic Analysis ........................................................35
4.2.1.6
Future Biomedical Research..............................................................35
4.2.2
Rationale for the Use of Comparator/Placebo .............................................35
4.3
Justification for Dose...........................................................................................35
4.4
Beginning and End-of-Study Definition ............................................................36
4.4.1
Clinical Criteria for Early Study Termination .............................................36
5
STUDY POPULATION ................................................................................................36
5.1
Inclusion Criteria.................................................................................................37
5.2
Exclusion Criteria................................................................................................39
5.3
Lifestyle Considerations......................................................................................43
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5.3.1
Meals and Dietary Restrictions....................................................................43
5.3.1.1
Diet Restrictions.................................................................................43
5.3.1.2
Fruit Juice Restrictions ......................................................................43
5.3.2
Caffeine, Alcohol, and Tobacco Restrictions ..............................................43
5.3.2.1
Caffeine Restrictions..........................................................................43
5.3.2.2
Alcohol Restrictions...........................................................................44
5.3.2.3
Tobacco Restrictions..........................................................................44
5.3.3
Activity Restrictions ....................................................................................44
5.4
Screen Failures.....................................................................................................44
5.5
Participant Replacement Strategy......................................................................44
6
STUDY INTERVENTION............................................................................................45
6.1
Study Intervention(s) Administered...................................................................45
6.2
Preparation/Handling/Storage/Accountability .................................................47
6.2.1
Dose Preparation..........................................................................................47
6.2.2
Handling, Storage, and Accountability........................................................47
6.3
Measures to Minimize Bias: Randomization and Blinding..............................48
6.3.1
Intervention Assignment..............................................................................48
6.3.2
Stratification.................................................................................................48
6.3.3
Blinding........................................................................................................48
6.4
Study Intervention Compliance..........................................................................48
6.5
Concomitant Therapy..........................................................................................48
6.5.1
Rescue Medications and Supportive Care ...................................................50
6.6
Dose Modification ................................................................................................50
6.6.1
Stopping Rules.............................................................................................50
6.7
Intervention After the End of the Study............................................................50
6.8
Clinical Supplies Disclosure................................................................................50
6.9
Standard Policies..................................................................................................50
7
DISCONTINUATION OF STUDY INTERVENTION AND PARTICIPANT 
WITHDRAWAL............................................................................................................51
7.1
Discontinuation of Study Intervention...............................................................51
7.2
Participant Withdrawal From the Study...........................................................51
7.3
Lost to Follow-up .................................................................................................51
8
STUDY ASSESSMENTS AND PROCEDURES........................................................52
8.1
Administrative and General Procedures ...........................................................52
8.1.1
Informed Consent.........................................................................................52
8.1.1.1
General Informed Consent.................................................................53
8.1.1.2
Consent and Collection of Specimens for Future Biomedical 
Research.............................................................................................53
8.1.2
Inclusion/Exclusion Criteria ........................................................................53
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8.1.3
Participant Identification Card.....................................................................53
8.1.4
Medical History ...........................................................................................54
8.1.5
Prior and Concomitant Medications Review...............................................54
8.1.5.1
Prior Medications...............................................................................54
8.1.5.2
Concomitant Medications..................................................................54
8.1.6
Assignment of Screening Number...............................................................54
8.1.7
Assignment of Treatment/Randomization Number.....................................54
8.1.8
Study Intervention Administration ..............................................................55
8.1.8.1
Timing of Dose Administration.........................................................55
8.1.9
Discontinuation and Withdrawal .................................................................55
8.1.9.1
Withdrawal From Future Biomedical Research ................................55
8.1.10
Participant Blinding/Unblinding..................................................................56
8.1.11
Domiciling ...................................................................................................56
8.1.12
Calibration of Equipment.............................................................................56
8.2
Efficacy/Immunogenicity Assessments ..............................................................56
8.3
Safety Assessments...............................................................................................56
8.3.1
Physical Examinations.................................................................................56
8.3.2
Vital Signs....................................................................................................57
8.3.2.1
Resting Vital Signs ............................................................................57
8.3.3
Electrocardiograms ......................................................................................58
8.3.4
Clinical Safety Laboratory Assessments .....................................................59
8.3.5
Pregnancy Testing........................................................................................59
8.3.6
Photograph of Rash......................................................................................60
8.4
Adverse Events, Serious Adverse Events, and Other Reportable Safety 
Events....................................................................................................................60
8.4.1
Time Period and Frequency for Collecting AE, SAE, and Other 
Reportable Safety Event Information ..........................................................60
8.4.2
Method of Detecting AEs, SAEs, and Other Reportable Safety Events......62
8.4.3
Follow-up of AE, SAE, and Other Reportable Safety Event Information...62
8.4.4
Regulatory Reporting Requirements for SAE .............................................63
8.4.5
Pregnancy and Exposure During Breastfeeding ..........................................63
8.4.6
Disease-related Events and/or Disease-related Outcomes Not Qualifying 
as AEs or SAEs............................................................................................63
8.4.7
Events of Clinical Interest............................................................................64
8.5
Treatment of Overdose........................................................................................64
8.6
Pharmacokinetics.................................................................................................64
8.6.1
Blood Collection for Plasma NHC Assay....................................................65
8.7
Pharmacodynamics..............................................................................................65
8.8
Biomarkers ...........................................................................................................65
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8.8.1
Planned Genetic Analysis Sample Collection..............................................65
8.9
Future Biomedical Research Sample Collection...............................................65
8.10
Visit Requirements...............................................................................................65
8.10.1
Screening......................................................................................................65
8.10.2
Treatment Period..........................................................................................66
8.10.3
Poststudy......................................................................................................66
8.10.4
Critical Procedures Based on Study Objectives: Timing of Procedure.......66
8.10.5
Study Design/Dosing/Procedures Modifications Permitted Within 
Protocol Parameters .....................................................................................67
9
STATISTICAL ANALYSIS PLAN .............................................................................68
9.1
Statistical Analysis Plan Summary.....................................................................68
9.2
Responsibility for Analyses.................................................................................69
9.3
Hypotheses/Estimation ........................................................................................69
9.4
Analysis Endpoints...............................................................................................70
9.5
Analysis Populations............................................................................................70
9.6
Statistical Methods...............................................................................................70
9.7
Interim Analyses ..................................................................................................72
9.8
Multiplicity ...........................................................................................................72
9.9
Sample Size and Power Calculations .................................................................72
10
SUPPORTING DOCUMENTATION AND OPERATIONAL 
CONSIDERATIONS.....................................................................................................73
10.1
Appendix 1: Regulatory, Ethical, and Study Oversight Considerations........73
10.1.1
Code of Conduct for Clinical Trials.............................................................73
10.1.2
Financial Disclosure.....................................................................................75
10.1.3
Data Protection.............................................................................................76
10.1.3.1
Confidentiality of Data ......................................................................76
10.1.3.2
Confidentiality of Participant Records...............................................76
10.1.3.3
Confidentiality of IRB/IEC Information............................................76
10.1.4
Publication Policy........................................................................................77
10.1.5
Compliance with Study Registration and Results Posting Requirements ...77
10.1.6
Compliance with Law, Audit, and Debarment ............................................77
10.1.7
Data Quality Assurance ...............................................................................78
10.1.8
Source Documents .......................................................................................79
10.1.9
Study and Site Closure.................................................................................79
10.2
Appendix 2: Clinical Laboratory Tests..............................................................80
10.3
Appendix 3: Adverse Events: Definitions and Procedures for Recording, 
Evaluating, Follow-up, and Reporting...............................................................82
10.3.1
Definitions of Medication Error, Misuse, and Abuse..................................82
10.3.2
Definition of AE ..........................................................................................82
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10.3.3
Definition of SAE ........................................................................................83
10.3.4
Additional Events Reported.........................................................................84
10.3.5
Recording AE and SAE ...............................................................................85
10.3.6
Reporting of AEs, SAEs, and Other Reportable Safety Events to the 
Sponsor ........................................................................................................88
10.4
Appendix 4: Medical Device and Drug-device Combination Products: 
Product Quality Complaints/Malfunctions: Definitions, Recording, and 
Follow-up ..............................................................................................................90
10.5
Appendix 5: Contraceptive Guidance................................................................91
10.5.1
Definitions....................................................................................................91
10.5.2
Contraception Requirements........................................................................93
10.6
Appendix 6: Collection and Management of Specimens for Future 
Biomedical Research............................................................................................95
10.7
Appendix 7: Country-specific Requirements..................................................100
10.8
Appendix 8: 12-Lead Electrocardiogram Abnormality Criteria ..................101
10.9
Appendix 9: Algorithm for Assessing Out of Range Laboratory Values .....103
10.10 Appendix 10: Abbreviations .............................................................................104
11
REFERENCES.............................................................................................................107
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LIST OF TABLES
Table 1
Group Assignment .....................................................................................32
Table 2
Severity of Liver Disease Classification (Child-Pugh Classification).......33
Table 3
Study Interventions....................................................................................46
Table 4
Sample Allocation Schedule of Participants to Treatment ........................48
Table 5
Reporting Time Periods and Time Frames for Adverse Events and 
Other Reportable Safety Events.................................................................61
Table 6
Pharmacokinetic (Blood for Plasma NHC Assay) Collection Windows...67
Table 7
Protocol-required Safety Laboratory Assessments....................................80
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LIST OF FIGURES
Figure 1
Study Schema.............................................................................................18
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1
PROTOCOL SUMMARY
1.1
Synopsis
Protocol Title: An Open-Label, Single-Dose Clinical Study to Evaluate the 
Pharmacokinetics of Molnupiravir (MK-4482) in Participants with Moderate Hepatic 
Impairment
Short Title: Molnupiravir (MK-4482, MOV) Hepatic Impairment Study
Acronym: Not applicable 
Hypotheses, Objectives, and Endpoints:
Hypotheses are aligned with objectives in the Objectives and Endpoints table.
The study population includes male and female participants with moderate hepatic 
impairment between the ages of 18 and 75 years (inclusive) and healthy mean-matched 
controls. 
Objectives
Endpoints
Primary
•
To evaluate the plasma pharmacokinetics of 
N-hydroxycytidine, the nucleoside 
metabolite of molnupiravir, after a single-
oral dose of 800-mg of molnupiravir in 
participants with moderate hepatic 
impairment compared to healthy mean 
matched control participants.
•
Hypothesis: In participants with moderate 
hepatic 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
(moderate hepatic impairment/healthy 
control) is less than 2.0.
•
Estimation: In participants with moderate 
hepatic 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 moderate 
hepatic impairment.
•
Adverse events
Overall Design:
Study Phase
Phase 1
Primary Purpose
Treatment
Indication
Treatment of COVID-19
Population
Participants with moderate hepatic impairment, Healthy 
participants
Study Type
Interventional
Intervention Model
Parallel
This is a multi-site study
Type of Control
Healthy-matched control participants 
Study Blinding
Unblinded Open-label
Blinding Roles
No Blinding
Estimated Duration of Study
The Sponsor estimates that the study will require 
approximately 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.
Number of Participants:
Approximately 14 to 17 participants will be allocated.
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Intervention Groups and Duration:
Intervention 
Groups
Intervention 
Group Name
Drug
Dose 
Strength
Dose 
Frequency
Route of 
Administration
Use
Moderate Hepatic 
Impairment
MK-4482 
(MOV)
800 mg
Once
Oral 
Test Product
Healthy- Matched 
Control Group
MK-4482 
(MOV)
800 mg
Once
Oral 
Test Product 
Other current or former name(s) or alias(es) for study intervention(s) are as 
follows: Molnupiravir, MOV, 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
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1.3
Schedule of Activities
All Panels
Study Period Screen-
ing
Check-
In
Intervention
Post-
study
Notes
Study Day
Up 
to -28
-1
1
2
3
4
~15
Scheduled Houra
Pre-
dose
0
0.5 1.5
2
4
6
8 12 24 48 72
Post-
studyb
Administrative/Study Procedures
Informed Consent
X
Sec. 5.1, 8.1.1.1
Informed Consent for 
FBR
X
Sec. 5.1, 8.1.1.2
Participant ID Card
X
Sec. 8.1.3
Inclusion/Exclusion 
Criteria
X
X
Review of IC/EC will occur 
at Screening and specific 
criteria after predose
procedures (if applicable) 
on Day 1.
Sec. 5.1, 5.2, and 8.1.2
Medical History
X
Includes substance abuse 
(drugs, alcohol, tobacco, 
and caffeine). 
Sec. 8.1.4
Assessment of Liver 
Function Using Child-
Pugh Classification 
Xc
To be performed in 
participants with hepatic 
impairment only. 
Sec. 4.1, 5.1
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All Panels
Study Period Screen-
ing
Check-
In
Intervention
Post-
study
Notes
Study Day
Up 
to -28
-1
1
2
3
4
~15
Scheduled Houra
Pre-
dose
0
0.5 1.5
2
4
6
8 12 24 48 72
Post-
studyb
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/Randomizati
on Number
X
To be provided within 24 
hours prior to intervention 
administration.
Sec. 5.5, 8.1.7
Participant Visit to 
CRU
X
X
X
X
X
Domiciling 
X-------------------------------------------------------X
Sec. 8.1.11
MOV Administration
X
Sec. 8.1.8.1
Standard Meals
X
Sec. 5.3.1.1
Safety Procedures
Full PE
X
X
X
Predose PE can be 
conducted up to 24 hours
prior to dosing. 
Sec. 8.3.1
Height
X
Sec. 8.3.1
Weight
X
X
BMI to be assessed only at 
Screening.
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All Panels
Study Period Screen-
ing
Check-
In
Intervention
Post-
study
Notes
Study Day
Up 
to -28
-1
1
2
3
4
~15
Scheduled Houra
Pre-
dose
0
0.5 1.5
2
4
6
8 12 24 48 72
Post-
studyb
Vital Signs (HR, BP)d
X
X
X
X
X
X
Sec. 8.3.2
Vital Signs (RR, 
Temperature)e
X
X
X
X
Sec. 8.3.2
12-lead ECG
X
Xd
X
X
Sec. 8.3.3
Serum hCG
X
Xf
X
WOCBP only. Result to be
reviewed prior to dosing on 
Day 1.
Sec. 8.3.5, Appendix 2
Serum FSH
X
Postmenopausal females 
only.
Appendix 2
Hepatitis Screen
X
Per site SOP. For healthy 
participants only.
Sec. 8.3.4, Appendix 2
HIV-1 and HIV-2 
Screen
X
Per site SOP.
Sec. 8.3.4, Appendix 2
UDS/BDS (per site 
SOP)
X
Xf
Per Site SOP.
Sec. 8.3.4, Appendix 2
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All Panels
Study Period Screen-
ing
Check-
In
Intervention
Post-
study
Notes
Study Day
Up 
to -28
-1
1
2
3
4
~15
Scheduled Houra
Pre-
dose
0
0.5 1.5
2
4
6
8 12 24 48 72
Post-
studyb
PT/INR
Xc
To be performed in 
participants with hepatic 
impairment only. 
Appendix 2
Hematology and 
Chemistry
X
Xf
X
X
Participants will fast for at 
least 8 hours prior to blood 
sample collection.
Sec. 8.3.4, Appendix 2
Urinalysis
X
Xf
X
X
Sec. 8.3.4, Appendix 2
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
Biomarkers
Blood for Genetic 
Analysis 
X
Sec. 8.8.1
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All Panels
Study Period Screen-
ing
Check-
In
Intervention
Post-
study
Notes
Study Day
Up 
to -28
-1
1
2
3
4
~15
Scheduled Houra
Pre-
dose
0
0.5 1.5
2
4
6
8 12 24 48 72
Post-
studyb
AE=adverse event; BDS=blood drug screen; ECG=electrocardiogram; FBR=future biomedical research; FSH=follicle stimulating hormone; hCG=human chorionic 
gonadotropin; HIV-1/HIV-2=human immunodeficiency virus type 1/type 2; IC/EC=inclusion and exclusion criteria; ID=identification; MOV=molnupiravir, MK-4482; NHC=N-
hydroxycytidine; PE= physical exam; PT=prothrombin time; RR=respiratory rate; SAE=serious adverse event; SOP=standard operating procedure; UDS=urine drug screen; 
VS=vital signs; WOCBP=women of childbearing potential.
a The scheduled hour is relative to the time of administration of MOV.
b The poststudy follow-up visit will have a ± 2-day window to be completed. If the visit occurs prior to 14 days postdose (Day 15), verbal contact 
should be made to assess for AEs 14 days postdose (Day 15).
c Assessment of liver function using CP classification is to be conducted for all participants with HI at screening. If a historical CP value is not 
available, a second CP assessment (including PT/INR, albumin, and bilirubin laboratory assessment) will additionally be conducted during the 
screening period (>72 hours apart) and the mean of the 2 values will be used for group assignment.
d Predose measurements will be in triplicate and screening and postdose measurements will be single measurements. 
e Assessments of RR and temperature will be collected in single measurements.
f Predose labs may be completed up to 24 hours prior to dosing.
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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 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 moderate HI compared to participants with normal 
hepatic function. 
2.1
Study Rationale
The liver is involved in drug clearance through multiple oxidative and conjugative metabolic 
pathways and through biliary excretion. For some small molecule therapeutics, HI from acute 
or chronic liver disease may affect excretion and metabolism, leading to accumulation of 
drug and metabolites. Hepatic disease can therefore alter the levels of drugs, potentially 
leading to an effect on efficacy and/or safety.
In preclinical studies, MOV undergoes rapid hydrolysis to NHC via 2 widely distributed 
high-capacity carboxylesterases during absorption/hepatic first pass metabolism leading to 
high NHC bioavailability (>50%). NHC is taken up into cells via nucleoside transporters 
where host kinases phosphorylate NHC to the pharmacologically active metabolite, NHC-TP. 
The predominate elimination pathway for NHC appears to be through metabolism to uridine 
and cytidine, which then mix with the endogenous nucleotide pool. Both cytidine deaminase 
and the mitochondrial amidoxime reducing components have capability to convert NHC to 
endogenous pyrimidines in vitro. NHC is not bound to plasma proteins and MOV absorption 
is not expected to be altered in hepatic impairment due to high solubility in buffers with and 
without bile acids. Given the totality of the preclinical data, hepatic elimination is not 
expected to be a major route of elimination for NHC.
A PopPK analysis inclusive of Phase 3 data (P002 Part 2) found minimal impact of mild HI 
on NHC exposures (5% increase in NHC AUC in participants with mild impairment) using a 
modified CP score. This modified CP score was based on reported lab values for total 
bilirubin and albumin, while encephalopathy, ascites, and INR were assumed to be normal as 
these parameters were not collected in the clinical dataset. Based on PopPK results, the GMR
(90% CI) of exposures for participants with mild HI (n=60) compared to participants with no 
HI (n=1143) was 1.05 (0.962, 1.14). Only 3 participants were classified as having moderate 
HI based on this method of classification, so a GMR was not calculated for this group.
While the existing preclinical and clinical data (based on a modified CP score) suggest that 
any degree of HI will not significantly impact metabolism and elimination of MOV, this 
study is being conducted to further evaluate the effect of HI in individuals with moderate HI
(based on CP classification) on plasma NHC PK.
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This Phase 1 study will additionally evaluate the general safety, tolerability, and PK (plasma 
NHC) of a single 800-mg dose of MOV in participants with moderate HI, compared to 
participants in good health. 
2.2
Background
Refer to the IB/approved labeling for detailed background information on MOV.
2.2.1
Pharmaceutical and Therapeutic Background
Coronaviruses are a family of enveloped positive-strand RNA viruses, which include SARS-
CoV-1 and MERS-CoV, that primarily target the respiratory system in humans and animals 
[Gorbalenya, A. E., et al 2020]. 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]. Increased risk for hospitalization with COVID-19 as 
well as increased mortality rates are associated with known risk factors, and mortality rates 
rise significantly (>50%) for patients requiring admission to the intensive care unit [Grasselli, 
G., et al 2020] [Richardson, S., et al 2020] [Docherty, A. B., et al 2020] [Guan, W., et al 
2020] [Dorjee, K., et al 2020] [Galloway, J. B., et al 2020]. There remains a need for direct-
acting antiviral agents active against SARS-CoV-2, particularly agents that are administered 
orally in medically complex populations with multiple medications or comorbidities.
MOV is the 5´-isobutyrate prodrug of the broadly active, direct-acting antiviral 
ribonucleoside analog NHC. MOV is hydrolyzed by esterases either during or after 
absorption to deliver NHC into systemic circulation. NHC inhibits replication of multiple 
viral pathogens from multiple RNA virus families including pathogenic Coronaviruses (eg, 
MERS, SARS-CoV and SARS-CoV-2), influenza viruses (seasonal, pandemic and avian 
subtypes), and respiratory syncytial virus (RSV). Inside cells, the active nucleoside 
triphosphate anabolite of MOV (NHC-TP) acts as a competitive, alternative substrate for the 
virally encoded RNA-dependent RNA polymerase that upon incorporation into nascent chain 
RNA, induces increased mutational frequency in the viral genome resulting in induction of 
viral error catastrophe [Flavell, R. A., et al 1974] [Kabinger F, Stiller C, Schmitzová J, 
Dienemann C, Kokic G, Hillen HS, et al. 2021]. Incorporation quickly results in the 
production of nonviable virus. It is anticipated that the high barrier to resistance observed 
during in vitro passaging studies will translate to slow, if any, emergence of viral resistance 
in the clinic. Results from clinical studies support the therapeutic benefit of MOV in 
nonhospitalized individuals with mild-to-moderate COVID-19.
2.2.2
Preclinical Studies
Primary pharmacology studies demonstrating the antiviral activity of MOV against SARS-
CoV-2 and other RNA viruses were conducted in vitro and in mouse, guinea pig, hamster, 
and ferret models of viral infection. In vitro, NHC shows broad-spectrum activity against 
multiple viruses including coronaviruses SARS-CoV-2, SARS-CoV, and MERS-CoV. NHC 
was equally effective against SARS-CoV-2 variants of concern, including alpha, beta, 
gamma, delta, omicron (B.1.1.529 BA.1, BA.1.1, and BA.2), as well as the variant of interest 
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(lambda) and variant being monitored (mu) compared with the WA1 isolate. NHC was active 
against coronaviruses that have mutations which reduce susceptibility to remdesivir in cell 
culture assays.
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. Based on the totality of genotoxicity data, MOV 
is not mutagenic or genotoxic in in vivo mammalian systems. 
Target organs of toxicity identified in the repeat-dose toxicity studies were limited to bone 
marrow in dogs only, and growth plate in rats only. Bone marrow toxicity/hematopoietic
finding (with resultant pancytopenia) were observed in the 28-day oral toxicity study in dogs 
at ≥17 mg/kg/day (0.4-fold the clinical NHC exposure of 75.6 µM.hr at 800 mg Q12H). The 
adverse hematopoietic findings were dose-related, affected all hematopoietic cell lines, 
caused subsequent mild hematological abnormalities on Day 7 and progressively more severe 
hematological changes after 14 to 21 days of continuous dosing, and were shown to be 
reversible. Changes in the growth plate of the long bones (femur, tibia) were observed in the 
3-month oral toxicity study in rats only, in males at ≥500 mg/kg/day (5.4-fold the clinical 
NHC AUC0-24 at the 800-mg Q12H dose) and in females at 1000 mg/kg/day (9.3-fold the 
clinical NHC AUC0-24 exposure). These growth plate findings are not considered relevant to 
adult humans, because growth plates are no longer present in the mature skeleton of adult 
humans.
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). In pregnant rats administered 
MOV during the organogenesis period, developmental toxicity including embryolethality 
(post-implantation losses) and malformations/teratogenicity was observed at 1000 mg/kg/day 
(7.5-fold the clinical NHC exposure at 800 mg Q12H), and reduced fetal growth was noted at 
≥500 mg/kg/day (≥2.9-fold the clinical NHC exposure at 800 mg Q12H). There was no 
developmental toxicity at doses up to 250 mg/kg/day (0.8-fold the clinical NHC exposure at 
800 mg Q12H). Maternal toxicity included decreased food consumption and body weight 
losses, resulting in the early sacrifice at 1000 mg/kg/day, and decreased body weight gain at 
≥500 mg/kg/day. In pregnant rabbits, developmental toxicity was limited to reduced mean 
fetal body weights at 750 mg/kg/day (18-fold the clinical NHC exposure at 800 mg Q12H). 
There was no developmental toxicity in rabbits up to 400 mg/kg/day (6.5-fold the clinical 
NHC exposure at 800 mg Q12H). Maternal toxicity included decreased food consumption 
and body weight gain, and abnormal fecal output at ≥400 mg/kg/day. In the pre- and 
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postnatal developmental study in rats, there was no F0 maternal or F1 generation toxicity up 
to the highest dose evaluated of 500 mg/kg/day (1.6-fold the clinical NHC exposure at 
800 mg Q12H). 
Further details of preclinical studies are provided in the IB. Collectively, the safety 
pharmacology and toxicology results support continued clinical development of MOV.
2.2.3
Completed and Ongoing Clinical Studies
2.2.3.1
Completed Clinical Studies
MOV has been evaluated in 3 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).
Phase 1 Studies:
MK-4482-004 was a randomized, double-blind, placebo-controlled, first in human 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 1 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. Doses of 400, 600, and 800 mg 
MOV Q12H 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 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 nonhospitalized 
adults with COVID-19. The time to undetectable SARS-CoV-2 of viral RNA in 
nasopharyngeal swabs was shorter in participants receiving 800-mg MOV (median: 14 days) 
compared with those administered placebo (median: 15 days). 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 
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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.
2.2.3.2
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).
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.
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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 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). Enrollment is complete and participants have 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. Enrollment is complete and participants are being 
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.
2.3
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 clinical studies and post
authorization surveillance demonstrate an acceptable safety and tolerability profile of MOV.
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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 
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 study population includes male and female participants with moderate hepatic 
impairment between the ages of 18 and 75 years (inclusive) and healthy mean-matched 
controls. 
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Objectives
Endpoints
Primary
•
To evaluate the plasma pharmacokinetics 
of N-hydroxycytidine, the nucleoside 
metabolite of molnupiravir, after a single-
oral dose of 800-mg of molnupiravir in 
participants with moderate hepatic 
impairment compared to healthy mean 
matched control participants.
•
Hypothesis: In participants with moderate 
hepatic 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
(moderate hepatic impairment/healthy 
control) is less than 2.0.
•
Estimation: In participants with moderate 
hepatic 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 moderate 
hepatic impairment.
•
Adverse events
Tertiary/Exploratory
•
Objective: To explore the relationship 
between genetic variation and response to 
the treatment(s) administered, and 
mechanisms of disease. Variation across 
the human genome may be analyzed for 
association with clinical data collected in 
the 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 nonrandomized, multi-site, open-label, single-dose study of MOV in adult male and 
female participants with moderate HI (Panel A; n=7) and matched healthy adult male and 
female participants (Panel B; n=7 to 10). Individual age and BMI of healthy-matched control 
participants will be within the range ± 10 years and ± 3.5 kg/m2 of the mean age and BMI of 
participants with HI, respectively. In addition, the numbers of males and females of the 
healthy participants will be generally matched to the numbers of hepatic impaired
participants within ± 1 (for the first 7 participants enrolled). Up to an additional 3 healthy 
participants may be enrolled as needed, to maintain the mean-matching of the healthy 
participant panel to the moderate HI panel. If additional healthy-matched control participants 
are enrolled (beyond the minimum 7 participants), the overall proportion of males and 
females in the healthy panel should be maintained as close as possible to the overall 
proportion of males and females in the HI panel. Assignment to a group will be as per 
[Table 1].
Table 1
Group Assignment
Panel
Impairment Stage
n
Child-Pugh Scorea
A
Moderateb
7
7-9
B
Healthy Matched
7-10c
0
CP=Child-Pugh; HI=hepatic impaired; INR=international normalized ratio; n=number of participants
CP score based on standard scoring (see below in [Table 2]). Refer to Sec. 5.1 for guidance on calculating 
the Child-Pugh score. 
At least 2 participants with a score of at least 2 on one of the laboratory parameters (reduced serum 
albumin, increased serum bilirubin, or increased INR) will be enrolled.
A minimum of 7 healthy participants will be enrolled with the ability to enroll up to 10 participants as 
needed to maintain the mean-matching of the healthy participant panel to the moderate HI panel.
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.
As noted, the CP classification will be used to categorize HI. The CP scale is utilized by 
clinicians to categorize chronic liver disease and cirrhosis and is also used to categorize 
participants with HI for PK studies. In the current study, patients with chronic, stable HI with 
features of cirrhosis due to any etiology will be enrolled, and the CP scale will be used to 
classify the severity of liver disease [Table 2]. The points from each row are summed, 
leading to the final CP score. Scores of 5 to 6, 7 to 9, and 10 to 15 are classified as having 
mild, moderate, or severe HI, respectively. Participants with a CP score of 7 to 9, 
corresponding to moderate HI, will be selected for enrollment into the current study. To 
ensure an adequate number of study participants with laboratory abnormalities consistent 
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with hepatic dysfunction, at least 2 participants will be required to have a score of at least 
2 or more on one of the following laboratory parameters: reduced serum albumin, increased 
serum bilirubin, or increased INR.
Table 2
Severity of Liver Disease Classification (Child-Pugh Classification)
Points for Increasing Abnormality
Assessment
1
2
3
Encephalopathy a
None
1 or 2
3 or 4
Ascites
Absent
Slight
Moderate
Albumin (g/dL)
>3.5
2.8 to 3.5
<2.8
INR
<1.7
1.7 to 2.3
>2.3
Bilirubin (mg/dL)—not PBCb
Bilirubin (mg/dL)—only for 
PBCb
<2
<4
2 to 3
4 to 10
>3
>10
INR= International normalized ratio; PBC=Primary Biliary Cirrhosis
aPortal-systemic encephalopathy is Staged 0 to 4.
b Select only one depending on type of cirrhosis.
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 8.10.5 for examples of modifications permitted within the protocol 
parameters.
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
An open-label, single-dose study design has been deemed optimal to evaluate the effect of HI
on the PK of NHC based on the PK properties of NHC. PK data from the completed Phase 1 
study (P004) following single oral doses of 50 to 1600 mg MOV and multiple doses of 50- to 
800-mg MOV (Q12H for 5.5 days) demonstrated Tmax for NHC occurred at ~ 1-hour
postdose for the powder in bottle formulation and between 1.50- and 1.75-hours postdose for 
the capsule formulation. Following peak plasma concentrations, NHC concentrations 
declined in a biphasic manner and PK was linear across dose ranges. 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 HI on plasma NHC PK. 
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Individuals without HI will serve as a control group. To adequately assess the impact of HI, 
enrolled participants with reasonably matched demographics to mean demographic 
parameters will be enrolled. 
4.2.1
Rationale for Endpoints
4.2.1.1
Efficacy Endpoints
There are no efficacy endpoints. 
4.2.1.2
Safety Endpoints
Based on available clinical safety data to date, evaluation of safety will be adequately 
assessed from the following standard safety assessments: VS, 12-lead ECG, laboratory safety 
tests (blood chemistry, hematology, urinalysis) and AEs. Safety evaluations will be 
conducted throughout the study at intervals dictated by NHC PK properties.
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.
The primary NHC PK parameters (AUC0-inf, Cmax) in addition to other standard NHC PK 
parameters (eg, AUC0-last, Tmax, t1/2, CL/F, Vd/F) following single-dose administration of 
MOV will sufficiently characterize the pharmacokinetic comparison between the HI group 
relative to control. Collection of blood samples up to 72-hours postdose is adequate based on 
the terminal t1/2 of NHC.
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 subpopulations 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 in this study. 
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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.
4.2.2
Rationale for the Use of Comparator/Placebo
Not applicable
4.3
Justification for Dose
A single 800-mg dose of MOV will be administered in this study, which is aligned with the 
proposed therapeutic dose of 800-mg Q12H for 5 days for adults and was the dose assessed 
in the pivotal Phase 3 portion of the Phase 2/3 study for the treatment of adults with COVID-
19 (P002 Part 2). This dose is similarly being evaluated in an ongoing clinical study for 
postexposure prophylaxis in adults (P013). Assessing the effect of moderate HI with the 
800-mg dose of MOV will ensure the data generated in this study is representative of the 
selected clinical dose level. 
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Of note, multiple doses up to 800-mg MOV Q12H for up to 10.5 days and single doses up to 
1600-mg, were generally well tolerated in healthy participants.
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 8.10.5.
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 (ie, the 
participant is unable to be contacted by the investigator).
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 EAA 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.
5
STUDY POPULATION
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.
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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
Moderate Hepatic Impairment Participants
1. The participant has a diagnosis of chronic (>6 months), stable HI with features of 
cirrhosis due to any etiology (stability of hepatic disease should correspond to no acute 
episodes of illness within the previous 2 months due to deterioration in hepatic function). 
For the purposes of this study, diagnosis of cirrhosis based on assessment on imaging 
features (ultrasound, transient elastography, or magnetic resonance elastography) 
indicative of cirrhosis in combination with clinical features of cirrhosis or biopsy-
confirmed cirrhosis will be acceptable.
Note: Individuals who have undergone a transjugular intrahepatic portosystemic shunt
procedure may be considered for inclusion upon consultation with the Sponsor.
2. The participant has a score on the CP scale ranging from 7 to 9 (moderate HI) at 
screening. At least 2 of the participants must have a score of 2 or higher on at least 1 of 
the laboratory parameters (ie, albumin, INR, and/or bilirubin) at screening on the CP 
scale.
Note: Baseline CP will be obtained by taking the mean of the CP score obtained from 
screening and from the most recent historical values within a 6-month period prior to 
screening. If no historical measurement is available, a second baseline CP will be 
assessed during the screening period (>72 hours apart) and the mean of the 2 values will 
be used for group assignment.
3. With the exception of HI, the participant is in generally good health based on medical 
history, physical examination, VS measurements and ECGs performed prior to 
randomization. Participants with stable, chronic medical or psychiatric conditions may be 
included at the discretion of the investigator and the Sponsor. Appendix 8 provides a 
table of the 12-Lead Electrocardiogram Abnormality Criteria.
4. With the exception of HI, 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.
Note: The laboratory safety test parameter values for ALT and AST must be <2X ULN
before the participant can be considered eligible for inclusion. Participants with ALT and 
AST values ≥2X ULN and <3X ULN may be enrolled at the discretion of the investigator 
following consultation with the Sponsor. 
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Healthy Participants
5. 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.
6. The participant is in good health based on laboratory safety tests obtained at the screening
visit and before administration of the initial dose of 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.
All Participants
Demographics
7. 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.
8. The participant is male or female, from 18 years to 75 years of age inclusive, at the time 
of providing informed consent.
Male Participants
9.
Male participants must agree to the following during the intervention period and for at 
least 90 days after the last 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
10. 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
11. 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:
Medical Conditions
Moderate Hepatic Impairment
1. The participant has a history of any illness that, in the opinion of the investigator, might 
confound the results of the study or poses an additional risk to the participant by their 
participation in the study.
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2. The participant is not in sufficient health, with regard to stability of hepatic impairment, 
to undergo participation in the study with anticipated survival of <3 months, in keeping 
with a MELD score of ≥25.
3. The participant is institutionalized or mentally or legally incapacitated at the time of 
prestudy (screening) visit or expected during the conduct of the study.
4. The participant is positive for HIV-1 or HIV-2 at the prestudy (screening) visit. 
5. The participant has received antiviral and/or immune modulating therapy for HBV or 
HCV within 90 days prior to study start.
6. The participant has an estimated eGFR <45 mL/min/1.73 m2 based on the CKD-EPI
equation.
CKD-EPI Equation:
eGFR = 142 × min (Scr /κ, 1)α × max(Scr /κ, 1)-1.200 × 0.994Age × 1.012 [if female] 
eGFR=estimated glomerular filtration rate (mL/min/1.73 m2); SCr=serum creatinine
(mg/dL), κ=0.7 for females and 0.9 for males, α= -0.302 for males and -0.241 for 
females, min indicates the minimum of Scr/k or 1, max indicates the maximum of Scr/k 
or 1.
At the discretion of the investigator a measured CrCl, as determined by a 24-hour urine 
collection, may be used in place of, or in conjunction with, the estimate of the eGFR.
Participants who have an eGFR or measured CrCl of up to10% below of either 
45 mL/min (for CrCl) or 45 mL/min/1.73 m2 (for eGFR) may be enrolled in the study at 
the discretion of the investigator.
Healthy Participants
7. The participant has a history of clinically significant endocrine, gastrointestinal, 
cardiovascular, hematological, hepatic, immunological, renal, respiratory, genitourinary, 
or major neurological (including stroke and chronic seizures) abnormalities or diseases. 
Participants with a remote history of uncomplicated medical events (eg, uncomplicated 
kidney stones, as defined as spontaneous passage and no recurrence in the last 5 years, or 
childhood asthma) may be enrolled in the study at the discretion of the investigator.
8. The participant is positive for HBsAg, hepatitis C antibodies or HIV-1 or HIV-2 at the 
prestudy (screening) visit.
9. The participant is mentally or legally incapacitated, has significant emotional problems at 
the time of prestudy (screening) visit or expected during the conduct of the study or has a 
history of clinically significant psychiatric disorder of the last 5 years. Participants who 
have had situational depression may be enrolled in the study at the discretion of the 
investigator.
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All Participants
10. 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).
11. 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.
12. The participant has known hypersensitivity to the active substance or any of the 
excipients of the study drug.
13. 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
Moderate Hepatic Impairment
14. The participant is taking medications to treat chronic medical conditions and has not been 
on a stable regimen for at least 1 month and/or is unable to withhold the use of the 
medication(s) within 4 hours prior to and 8 hours after administration of the study drug. 
Exceptions may be granted for participants in whom a medication regimen has been 
adjusted within the one-month window, at the discretion of the Investigator and following 
consultation with the Sponsor. See Section 5.1 for allowed medical conditions, and 
Section 6.5 for allowed medications. 
15. The participant does not agree to follow the smoking restrictions as defined by the CRU.
Healthy Participants
16. 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 the initial dose of study 
intervention, throughout the study (including washout intervals between treatment 
periods), until the poststudy visit. There may be certain medications that are permitted 
(see Section 6.5).
17. 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.
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Prior/Concurrent Clinical Study Experience
All Participants
18. The participant has participated in another investigational study within 4 weeks (or 
5 half-lives, whichever is greater) prior to the prestudy (screening) visit. The window will 
be derived from the date of the last visit in the previous study.
Diagnostic Assessments
All Participants
19. The participant meets any of the following cardiac parameters prior to study intervention 
administration: QTc interval ≥470 msec for males and ≥480 msec for females, a history 
of risk factors for Torsades de Pointes (eg, heart failure/cardiomyopathy or family history 
of long QT syndrome), uncorrected hypokalemia or hypomagnesemia.
Other Exclusions
All Participants
20. The participant is under the age of legal consent.
21. 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.
22. 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.
23. The participant is a regular user of cannabis (refer to exception below for use of cannabis 
with a medical marijuana card for HI participants) or any illicit drugs or has a history of 
drug (including alcohol) abuse within approximately 3 months. Participants must have a 
negative UDS/BDS prior to allocation. Participants with HI may be included with a 
positive UDS for opiates, benzodiazepines, or cannabanoids if they have an active 
prescription and/or medical marijuana card from a licensed health care provider.
24. The participant is unwilling to comply with the study restrictions (see Section 5.3 for a 
complete summary of study restrictions).
25. 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.
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26. 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
On Day 1, 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 initial dose of study 
intervention, 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 
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 the completion of the 
study procedures 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).
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5.3.2.2
Alcohol Restrictions
Participants will refrain from consumption of alcohol 24 hours before the prestudy and 
poststudy visits until the completion of the study procedures 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 healthy participants.
Participants in the moderate HI group will follow the smoking restrictions (and if applicable, 
the use of electronic cigarettes or nicotine/nicotine-containing products) defined by the CRU.
5.3.3
Activity Restrictions
Participants will avoid unaccustomed strenuous physical activity (ie, weightlifting, running, 
bicycling, etc) from the prestudy (screening) visit until administration of the initial dose of 
study intervention, 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 
generally receive the same intervention or intervention sequence (as appropriate) as the 
participant being replaced. The replacement participant will be assigned a unique 
treatment/randomization number.
The study site should contact the Sponsor for the replacement participant’s 
treatment/allocation number.
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6
STUDY INTERVENTION
Study intervention is defined as any investigational intervention(s), marketed product(s), 
placebo, or medical device(s) intended to be administered to a study participant according to 
the study protocol.
Clinical supplies (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 3]. Country-specific 
differences are noted in Section 10.7.
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Table 3
Study Interventions
Arm 
Name
Arm 
Type
Inter-
vention 
Name
Inter-
vention 
Type
Dose 
Formulation
Unit Dose 
Strength(s)
Dosage 
Level(s)
Route of 
Administration
Regimen/
Treatment 
Period/
Vaccination 
Regimen
Use
IMP or
NIMP/
AxMP
Sourcing
Moderate 
HI
Experi-
mental
MK-4482 
(MOV)
Drug
Capsule
200 mg
800 mg 
Oral
Panel A 
single dose
Test 
Product
IMP
Provided 
by the 
Sponsor
Healthy 
Matched
Experi-
mental
MK-4482 
(MOV)
Drug
Capsule
200 mg
800 mg
Oral
Panel B 
single dose
Test 
Product
IMP
Provided 
by the 
Sponsor
EEA=European Economic Area;IMP=investigational medicinal product; MOV=molnupiravir, MK-4482; NIMP/AxMP=noninvestigational/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 3] 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 4].
Table 4
Sample Allocation Schedule of Participants to Treatment
Panel
Hepatic Impairment Stage
n
Treatment
A
Moderate 
7
MOV 800 mg
B
Healthy Matched
7 to 10
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 randomization or intervention allocation) OR during time 
periods specified by this protocol for that medication or vaccination 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 hepatic impairment 
or up to 4 g total per day for healthy participants) may be used for minor ailments without 
prior consultation with the Sponsor.
In addition, the following concomitant medications/vaccinations are permitted:
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 Moderate Hepatic Impairment:
Participants who are taking medications to treat general medical conditions and/or conditions 
associated with hepatic disease (eg, hypertension, non-insulin dependent diabetes mellitus, 
hypercholesterolemia, hypo- or hyperthyroidism, gout, depression) will be allowed to 
participate in the study at the discretion of the Investigator and following consultation with 
the Sponsor Clinical Monitor. Participants must be on a stable regimen for at least 1 month 
prior to study intervention administration and able to withhold the use within 4 hours prior to 
and 8 hours after study drug administration. Any exceptions to this must first be discussed 
between the Investigator and Sponsor. 
Certain prescription medications used to treat manifestations of hepatic disease (eg, lactulose, 
neomycin, etc.) will be allowed during the study, but the participant must be on a steady 
dose, drug, and regimen for at least 1 month prior to dosing on Day 1. Lactulose should be 
restricted at least 6 hours prior to and 6 hours after dosing on Day 1 since it may potentially 
affect absorption.
Examples of types of medications that would be used for chronic medical conditions that 
would be allowed include (but are not limited to) the following:
•
Angiotensin converting enzyme (ACE) inhibitors, angiotensin II receptor antagonists, 
diuretics
•
Beta blockers
•
Metformin, thiazolidinediones, sulfonylureas, DPP-4 inhibitors, alpha-glucosidase 
inhibitors, incretin mimetics
•
Statins
•
Levothyroxine
•
Colchicine, allopurinol
•
Selective serotonin uptake inhibitors (SSRIs), tricyclic antidepressants
•
Proton pump inhibitors
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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 24 hours after, study intervention administration. 
Any medication (including over-the-counter) that, by the determination of the Investigator, 
might interfere with the study must be discontinued at least 2 weeks (or 5 half-lives of the 
compound, whichever is longer) prior to study intervention administration.
Medications with known effect on QT/QTc prolongation may be allowed following 
discussion with the Sponsor.
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 
(upon joint agreement with the Sponsor and investigator), an amendment will be submitted 
for approval.
1. An individual participant reports an SAE considered related to the study 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 for this study.
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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.
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.
•
Note: A participant is not considered lost to follow-up until the last scheduled visit for the 
individual participant. The missing data for the participant will be managed via the 
prespecified statistical data handling and analysis guidelines.
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8
STUDY ASSESSMENTS AND PROCEDURES
•
Study procedures and their timing are summarized in the SoA.
•
Adherence to the study design requirements, including those specified in the SoA, is 
essential and required for study conduct.
•
The investigator is responsible for ensuring that procedures are conducted by 
appropriately qualified (by education, training, and experience) staff. Delegation of 
study-site personnel responsibilities will be documented in the Investigator Trial File 
Binder (or equivalent).
•
All study-related medical decisions must be made by an investigator who is a qualified 
physician.
•
All screening evaluations must be completed and reviewed to confirm that potential 
participants meet all eligibility criteria. The investigator will maintain a screening log to 
record details of all participants screened and to confirm eligibility or record reasons for 
screening failure, as applicable.
•
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 procedure met the protocol-specified criteria and were performed within the 
time frame defined in the SoA.
•
Additional evaluations/testing may be deemed necessary by the investigator and or the 
Sponsor for reasons related to participant safety. In some cases, such evaluation/testing 
may be potentially sensitive in nature (eg, HIV, hepatitis C), and thus local regulations 
may require that additional informed consent be obtained from the participant. In these 
cases, such evaluations/testing will be performed in accordance with those regulations.
The maximum amount of blood collected from each participant over the duration of the study
will not exceed 116.5 mL for Panel A and 93.5 mL for Panel B (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 
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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 
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 
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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.
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 prior to 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.
8.1.7
Assignment of Treatment/Randomization Number
All eligible participants will be allocated, by nonrandom assignment, and will receive a 
treatment/randomization number. The treatment/randomization number identifies the 
participant for all procedures occurring after treatment allocation. Once a 
treatment/randomization number is assigned to a participant, it can never be reassigned to 
another participant.
A single participant cannot be assigned more than 1 treatment/randomization number.
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8.1.8
Study Intervention Administration
Study intervention(s) will be administered by the investigator and/or study staff. 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
Participants will be dosed according to the SoA (Section 1.3). 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.
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.
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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 after completion of the 24-hours 
postdose procedures (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 
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 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 (Sec. 1.3).
Symptom driven physical examinations may be performed at other times at the Investigator’s 
discretion.
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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.
8.3.2
Vital Signs
•
Body temperature, HR, RR, and BP will be assessed.
•
Body temperature will be assessed with an appropriate thermometer.
•
BP and pulse measurements will be assessed in a semirecumbent position with a 
completely automated device. Manual techniques will be used only if an automated 
device is not available.
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 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). Postdose VS measurements will be single measurements.
Body Temperature
Body temperature will be measured. The same method must be used for all measurements for 
each individual participant and should be the same for all participants.
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8.3.3
Electrocardiograms
•
12-lead ECG 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 are 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 a 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 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 laboratory manual and the SoA.
•
If laboratory values from nonprotocol-specified laboratory assessments performed at the 
institution’s local laboratory require a change in study participant management or are 
considered clinically significant by the investigator (eg, SAE or AE or dose 
modification), then the results must be recorded in the appropriate CRF (eg, SLAB).
•
For any laboratory tests with values considered clinically significantly abnormal during 
participation in the study or within 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.
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.
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-
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 AE and/or SAE was associated with a medication error, 
misuse, or abuse.
Investigators remain responsible for following up AEs, SAEs, and other reportable safety 
events for outcome according to Section 8.4.3.
The investigator, who is a qualified physician, will assess events that meet the definition of 
an AE or SAE as well as other reportable safety events with respect to seriousness, 
intensity/toxicity and causality.
8.4.1
Time Period and Frequency for Collecting AE, SAE, and Other Reportable 
Safety Event Information
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.
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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 .
Exception: A positive pregnancy test at the time of initial screening is not a reportable event 
unless the participant has received study intervention.
Table 5
Reporting 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
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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:
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
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,
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including pregnancy and exposure during breastfeeding, ECIs, cancer, and overdose will be 
followed until resolution, stabilization, until the event is otherwise explained, or the 
participant is lost to follow-up (as defined in Section 7.3). In addition, the investigator will 
make every attempt to follow all nonserious AEs that occur in allocated participants for 
outcome. Further information on follow-up procedures is given in Appendix 3.
8.4.4
Regulatory Reporting Requirements for SAE
Prompt notification (within 24 hours) by the investigator to the Sponsor of SAE is essential 
so that legal obligations and ethical responsibilities towards the safety of participants and the 
safety of a study intervention under clinical investigation are met.
The Sponsor has a legal responsibility to notify both the local regulatory authority and other 
regulatory agencies about the safety of a study intervention under clinical investigation. The 
Sponsor will comply with country-specific regulatory requirements and global laws and 
regulations relating to safety reporting to regulatory authorities, IRB/IECs, and investigators.
Investigator safety reports must be prepared for SUSARs according to local regulatory 
requirements and Sponsor policy and forwarded to investigators as necessary.
An investigator who receives an investigator safety report describing an SAE or other 
specific safety information (eg, summary or listing of SAE) from the Sponsor will file it 
along with the IB and will notify the IRB/IEC, if appropriate according to local requirements.
8.4.5
Pregnancy and Exposure During Breastfeeding
Although pregnancy and infant exposure during breastfeeding are not considered AEs, any 
pregnancy or infant exposure during breastfeeding in a participant (spontaneously reported to 
the investigator or their designee) that occurs during the study are reportable to the Sponsor.
All reported pregnancies must be followed to the completion/termination of the pregnancy.
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.
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8.4.7
Events of Clinical Interest
Selected serious and nonserious AEs are also known as ECIs and must be reported to the 
Sponsor.
Events of clinical interest for this study include:
1. An overdose of Sponsor's product, as defined in Section 8.5.
2. An elevated AST or ALT 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 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.
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8.6.1
Blood Collection for Plasma NHC Assay
Sample collection, storage, and shipment instructions for plasma samples will be provided in 
the Study Operations Manual.
8.7
Pharmacodynamics
Pharmacodynamic parameters will not be evaluated in this study.
8.8
Biomarkers
Collection of samples for other biomarker research is also part of this study. The following 
samples for biomarker research are required and will be collected from all participants as 
specified in the SoA:
•
Blood for genetic analysis 
8.8.1
Planned Genetic Analysis Sample Collection
The planned genetic analysis sample should be drawn for planned analysis of the association 
between genetic variants in DNA and drug response. This sample will not be collected at the 
site if there is either a local law or regulation prohibiting collection, or if the IRB/IEC does 
not approve the collection of the sample for these purposes. If the sample is collected, 
leftover extracted DNA will be stored for 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
Visit Requirements
Visit requirements are outlined in Section 1.3. Specific procedure-related details are provided 
in Section 8.
8.10.1
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.
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Participants may be rescreened after consultation with the Sponsor. Rescreening should 
include all screening procedures listed in the SoA, including consent review. Rescreen 
procedures cannot be conducted the day prior to intervention allocation if there are Day -1 
procedures planned per protocol.
8.10.2
Treatment Period
Refer to the SoA (Section 1.3) and Administrative and General Procedures (Section 8.1).
8.10.3
Poststudy
Participants will be required to return to clinic approximately 14 days (± 2 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.
8.10.4
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 6].
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Table 6
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
NHC=N-hydroxycytidine; PK=pharmacokinetic(s)
a PK collection windows are +/- relative to the time of dosing on Day 1 
•
Predose (Day 1) laboratory safety tests, serum pregnancy test (WOCBP only), UDS/BDS,
and physical exam within 24 hours prior to study intervention administration
•
Predose standard safety evaluations: VS (HR, BP, RR, BT) and ECG within 3 hours prior 
to study intervention administration
•
Postdose standard safety evaluations: VS (HR, BP, RR, BT), ECG, laboratory safety 
tests, and physical exam
-
Prior to 24-hours postdose may be obtained within 15 minutes of the theoretical time
-
24-hours postdose may be obtained within 1 hour of the theoretical time
8.10.5
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
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 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 moderate HI and healthy-matched control participants will be 
natural log-transformed and evaluated with a linear fixed effects model containing a fixed 
effect for population (participants with moderate HI and healthy-matched control 
participants). To address the primary hypothesis of comparing participants with moderate HI
to healthy control participants, the 90% CI for the true GMR (moderate HI/healthy-matched
control) will be constructed. If the 90% CI falls below 2.0, then the hypothesis that in 
participants with moderate HI, the AUC0-inf of plasma NHC is similar to that observed in 
the healthy-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 moderate HI
and healthy-matched control participants will be estimated via a similar model.
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Safety:
AEs will be tabulated by population. Summary statistics and plots will be generated for raw 
laboratory safety tests, ECGs, and/or VS 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 SD (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 7 participants in each panel, assuming the true GMR (HI/healthy-matched control) is 
1.00, there is 98.7% power to support the hypothesis that in participants with moderate HI, 
the AUC0-inf of NHC is similar to that observed in the healthy-matched control participants. 
The true GMR can be as high as 1.28 to still maintain 80% power.
With 7 participants in each panel, the half width of 90% CI for GMR for plasma NHC Cmax 
on the log scale will be 0.196. The lower and upper 90% confidence limits for the true GMRs 
will be given by OBS/1.22 and OBS*1.22 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 CSR.
9.3
Hypotheses/Estimation
Hypothesis:
In participants with moderate hepatic impairment, the GM AUC0-inf of NHC is similar to 
that observed in the healthy-matched control participants following a single dose of 800-mg 
MOV; that is, the true NHC AUC0-inf GMR (moderate hepatic impairment/healthy mean-
matched control) is less than 2.0.
Estimation:
In participants with moderate HI, plasma PK (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 Endpoint: The primary PK endpoints include AUC0-inf and Cmax of plasma
NHC
•
Secondary Endpoint: The secondary safety endpoint is AEs.
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 moderate HI and healthy-matched control participants will be 
natural log-transformed and evaluated with a linear fixed effects model containing a fixed 
effect for population (participants with moderate hepatic impairment and healthy control 
participants). 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 
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means and their corresponding 95% CIs will yield estimates for the 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 ‘moderate/normal’ population 1 -1/cl alpha=0.1;
run;
To address the primary hypothesis of comparing participants with moderate HI to healthy-
matched control participants, a two-sided 90% CI for the true difference in mean (moderate 
HI – healthy-matched 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 (moderate hepatic impairment/healthy control). If the 90% CI falls 
below 2.0, then the hypothesis that in participants with moderate HI, the AUC0-inf of plasma 
NHC is similar to that observed in the healthy-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 moderate HI
and healthy-matched control participants will be estimated via similar model.
The relationship between plasma PK of NHC and hepatic insufficiency will be examined in 
an exploratory manner via a scatter plot of PK values (NHC plasma AUC0-inf, Cmax) versus 
the CP score. Plots of PK values (NHC plasma AUC0-inf, Cmax) and the baseline laboratory 
components of the CP score (ie, bilirubin, albumin levels, and prothrombin time) will be 
provided. Plots of PK parameter values (NHC plasma AUC0-inf, Cmax) vs age and body 
weight will also be provided.
Individual values will be listed for each PK parameter including AUC0-inf, AUC0-last,
Cmax, Tmax, t1/2, CL/F, and Vd/F of plasma NHC by population, and the following (non-
model-based) descriptive statistics will be provided: N (number of participants with non-
missing data), arithmetic mean, SD, arithmetic percent CV (calculated as 100 x standard 
deviation/arithmetic mean), median, minimum, maximum, GM, and geometric percent CV 
(calculated as 100 x sqrt(exp(s2) - 1), where s2 is the observed variance on the natural log-
scale).
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).
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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 SD (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 7 participants in each panel, assuming the true GMR (moderate HI/healthy-matched
control) is 1.00, there is 98.7% power to support the hypothesis that in participants with
moderate HI, the AUC0-inf of NHC is similar to that observed in the healthy-matched 
control participants. The true GMR can be as high as 1.28 to still maintain 80% power.
With 7 participants in each panel, the half width of 90% CI for GMR for plasma NHC Cmax 
on the log scale will be 0.196. The lower and upper 90% confidence limits for the true GMRs 
will be given by OBS/1.22 and OBS*1.22 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 and 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 7] will be performed by the local laboratory.
•
Protocol-specific requirements for inclusion or exclusion of participants are detailed in 
Section 5.1 and 5.2 of the protocol.
•
Additional tests may be performed at any time during the study as determined necessary 
by the investigator or required by local regulations.
Table 7
Protocol-required Safety Laboratory Assessments
Laboratory 
Assessments
Parameters
Hematology
Platelet Count 
RBC Indices:
MCV
MCH
Reticulocytes
WBC count with 
Differential:
Neutrophils
Lymphocytes
Monocytes
Eosinophils
Basophils
RBC Count
Hemoglobin
Hematocrit
Chemistry
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 
Coagulation
•
PT/INR (International normalized ratio, for hepatic impaired participants only)
Routine 
Urinalysis
•
Specific gravity
•
pH, glucose, protein, blood, ketones, [bilirubin, urobilinogen, nitrite, leukocyte 
esterase] by dipstick
•
Microscopic examination (if blood or protein is abnormal)
Pregnancy 
Testing
•
Highly sensitive serum hCG pregnancy test for WOCBP only
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Laboratory 
Assessments
Parameters
Other Screening 
Tests
•
FSH for 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-1 and HIV-2 antibodies in all participants, HBsAg, and hepatitis C 
virus antibody in healthy participants only)
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
Notes: To the extent possible, laboratory safety tests (hematology and chemistry) will be performed after approximately 
an 8-hour fast. Predose Day 1 laboratory procedures can be conducted up to 24 hours prior to study intervention
administration.
The investigator (or medically qualified designee) must document their review of each 
laboratory safety report.
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10.3
Appendix 3: Adverse Events: Definitions and Procedures for Recording, 
Evaluating, Follow-up, and Reporting
10.3.1
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 (also referred to as Sponsor’s 
product) includes any pharmaceutical product, biological product, vaccine, diagnostic 
agent, medical device, combination product, or protocol specified procedure whether 
investigational or marketed (including placebo, active comparator product, or run-in 
intervention), manufactured by, licensed by, provided by, or distributed by the Sponsor 
for human use in this study.
Events meeting the AE definition
•
Any abnormal laboratory test results (hematology, clinical chemistry, or urinalysis) or 
other safety assessments (eg, ECG, radiological scans, vital signs measurements), 
including those that worsen from baseline, considered clinically significant in the medical 
and scientific judgment of the investigator.
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•
Exacerbation of a chronic or intermittent preexisting condition including either an 
increase in frequency and/or intensity of the condition.
•
New conditions detected or diagnosed after study intervention administration even 
though it may have been present before the start of the study.
•
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.”
Events NOT meeting the AE definition
•
Medical or surgical procedure (eg, endoscopy, appendectomy): the condition that leads to 
the procedure is the AE.
•
Situations in which an untoward medical occurrence did not occur (social and/or 
convenience admission to a hospital).
•
Anticipated day-to-day fluctuations of preexisting disease(s) or condition(s) present or 
detected at the start of the study that do not worsen.
•
Surgical procedure(s) planned prior to informed consent to treat a preexisting condition 
that has not worsened.
•
Refer to Section 8.4.6 for protocol-specific exceptions.
10.3.3
Definition of SAE
If an event is not an AE per definition above, then it cannot be an SAE even if serious 
conditions are met.
An SAE is defined as any untoward medical occurrence that, at any dose:
a.
Results in death
b. Is life-threatening
•
The term “life-threatening” in the definition of “serious” refers to an event in which 
the participant was at risk of death at the time of the event. It does not refer to an 
event, which hypothetically might have caused death, if it were more severe.
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c.
Requires inpatient hospitalization or prolongation of existing hospitalization
•
Hospitalization is defined as an inpatient admission, regardless of length of stay, even 
if the hospitalization is a precautionary measure for continued observation. (Note: 
Hospitalization for an elective procedure to treat a preexisting condition that has not 
worsened is not an SAE.) A preexisting condition is a clinical condition that is 
diagnosed prior to the use of an MSD product and is documented in the participant’s 
medical history.
d. Results in persistent or significant disability/incapacity
•
The term disability means a substantial disruption of a person’s ability to conduct 
normal life functions.
•
This definition is not intended to include experiences of relatively minor medical 
significance such as uncomplicated headache, nausea, vomiting, diarrhea, influenza, 
and accidental trauma (eg, sprained ankle) that may interfere with or prevent 
everyday life functions but do not constitute a substantial disruption.
e.
Is a congenital anomaly/birth defect
•
In offspring of participant taking the product regardless of time to diagnosis.
f.
Other important medical events
•
Medical or scientific judgment should be exercised in deciding whether SAE 
reporting is appropriate in other situations such as important medical events that may 
not be immediately life-threatening or result in death or hospitalization but may 
jeopardize the participant or may require medical or surgical intervention to prevent 1 
of the other outcomes listed in the above definition. These events should usually be 
considered serious.
•
Examples of such events include invasive or malignant cancers, intensive treatment in 
an emergency room or at home for allergic bronchospasm, blood dyscrasias or 
convulsions that do not result in hospitalization, or development of drug dependency 
or drug abuse.
10.3.4
Additional Events Reported
Additional events that require reporting
In addition to the above criteria, AEs meeting either of the below criteria, although not 
serious per ICH definition, are reportable to the Sponsor.
•
Is a cancer
•
Is associated with an overdose
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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 Sponsor’s product cause the AE?
•
The determination of the likelihood that the Sponsor’s product caused the AE will be 
provided by an investigator who is a qualified physician. The investigator’s signed/dated 
initials on the source document or worksheet that supports the causality noted on the AE 
form, ensures that a medically qualified assessment of causality was done. This initialed 
document must be retained for the required regulatory time frame. The criteria below are 
intended as reference guidelines to assist the investigator in assessing the likelihood of a 
relationship between the test product and the AE based upon the available information.
•
The following components are to be used to assess the relationship between the 
Sponsor’s product and the AE; the greater the correlation with the components and 
their respective elements (in number and/or intensity), the more likely the Sponsor’s 
product caused the AE:
- Exposure: Is there evidence that the participant was actually exposed to the 
Sponsor’s product such as: reliable history, acceptable compliance assessment (pill 
count, diary, etc), expected pharmacologic effect, or measurement of 
drug/metabolite in bodily specimen?
- Time Course: Did the AE follow in a reasonable temporal sequence from 
administration of the Sponsor’s product? Is the time of onset of the AE compatible 
with a drug-induced effect (applies to studies with investigational medicinal 
product)?
- Likely Cause: Is the AE not reasonably explained by another etiology such as 
underlying disease, other drug(s)/vaccine(s), or other host or environmental factors.
- Dechallenge: Was the Sponsor’s product discontinued or dose/exposure/frequency 
reduced?
◦If yes, did the AE resolve or improve?
◦If yes, this is a positive dechallenge.
◦If no, this is a negative dechallenge.
(Note: This criterion is not applicable if: (1) the AE resulted in death or permanent 
disability; (2) the AE resolved/improved despite continuation of the Sponsor’s 
product; (3) the study is a single-dose drug study; or (4) Sponsor’s product(s) is/are 
only used 1 time.)
- Rechallenge: Was the participant re-exposed to the Sponsor’s product in this study?
◦If yes, did the AE recur or worsen?
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◦If yes, this is a positive rechallenge.
◦If no, this is a negative rechallenge.
(Note: This criterion is not applicable if: (1) the initial AE resulted in death or 
permanent disability, or (2) the study is a single-dose drug study; or (3) Sponsor’s 
product(s) is/are used only 1 time.)
NOTE: IF A RECHALLENGE IS PLANNED FOR AN AE THAT WAS SERIOUS AND 
MAY HAVE BEEN CAUSED BY THE SPONSOR’S PRODUCT, OR IF RE-EXPOSURE 
TO THE SPONSOR’S PRODUCT POSES ADDITIONAL POTENTIAL SIGNIFICANT 
RISK TO THE PARTICIPANT THEN THE RECHALLENGE MUST BE APPROVED IN 
ADVANCE BY THE SPONSOR CLINICAL DIRECTOR, AND IF REQUIRED, THE 
IRB/IEC.
•
Consistency with study intervention profile: Is the clinical/pathological presentation of 
the AE consistent with previous knowledge regarding the Sponsor’s product or drug class 
pharmacology or toxicology?
•
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 Sponsor’s product relationship).
- Yes, there is a reasonable possibility of Sponsor’s product relationship:
◦There is evidence of exposure to the Sponsor’s product. The temporal sequence of 
the AE onset relative to the administration of the Sponsor’s product is 
reasonable. The AE is more likely explained by the Sponsor’s product than by 
another cause.
- No, there is not a reasonable possibility of Sponsor’s product relationship:
◦Participant did not receive the Sponsor’s product OR temporal sequence of the 
AE onset relative to administration of the Sponsor’s product is not reasonable 
OR the AE is more likely explained by another cause than the Sponsor’s 
product. (Also entered for a participant with overdose without an associated 
AE.)
•
The investigator must review and provide an assessment of causality for each AE/SAE 
and document this in the medical notes.
•
There may be situations in which an SAE has occurred and the investigator has minimal 
information to include in the initial report to the Sponsor. However, it is very important 
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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 Childbearing Potential (WOCBP)
A woman is considered fertile following menarche and until becoming postmenopausal 
unless permanently sterile (see below):
If fertility is unclear (eg, amenorrhea in adolescents or athletes) and a menstrual cycle cannot 
be confirmed before first dose of study intervention, additional evaluation should be 
considered.
Women in the following categories are not considered WOCBP:
•
Premenarchal
•
Premenopausal female with 1 of the following:
- Documented hysterectomy
- Documented bilateral salpingectomy
- Documented bilateral oophorectomy
For individuals with permanent infertility due to an alternate medical cause other than the 
above (eg, Mullerian agenesis, androgen insensitivity), investigator discretion should be 
applied to determining study entry.
Note: Documentation can come from the site personnel’s review of the participant’s medical 
records, medical examination, or medical history interview.
•
Postmenopausal female
- A postmenopausal state is defined as no menses for 12 months without an alternative 
medical cause.
◦A high FSH level in the postmenopausal range may be used to confirm a 
postmenopausal state in women not using hormonal contraception or HRT. 
However, in the absence of 12 months of amenorrhea, confirmation with two 
FSH measurements in the postmenopausal range is required.
- Females on HRT and whose menopausal status is in doubt will be required to use one 
of the 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.
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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) 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
-
Bilateral oophorectomy
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-
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,c
• 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
- Oral
- Intravaginal
- Transdermal
- Injectable
• Progestogen-only hormonal contraceptionc
- Oral
- Injectable
Sexual Abstinence
• Sexual abstinence is considered a highly effective method only if defined as refraining from heterosexual 
intercourse during the entire period of risk associated with the study intervention. The reliability of sexual 
abstinence needs to be evaluated in relation to the duration of the study and the preferred and usual lifestyle 
of the participant.
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.
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.
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b. Informed Consent
Informed consent for specimens (ie, DNA, RNA, protein, etc) will be obtained during 
screening for protocol enrollment from all participants or legal guardians, at a study 
visit by the investigator or his or her designate. Informed consent for future 
biomedical research should be presented to the participants on the visit designated in 
the SoA. If delayed, present consent at next possible Participant Visit. Consent forms 
signed by the participant will be kept at the clinical study site under secure storage for 
regulatory reasons.
A template of each study site’s approved informed consent will be stored in the 
Sponsor’s clinical document repository.
c. eCRF Documentation for Future Biomedical Research Specimens
Documentation of participant consent for future biomedical research will be captured 
in the eCRFs. Any specimens for which such an informed consent cannot be verified 
will be destroyed.
d. Future Biomedical Research Specimen(s)
Collection of specimens for future biomedical research will be performed as outlined 
in the SoA. In general, if additional blood specimens are being collected for future 
biomedical research, these will usually be obtained at a time when the participant is 
having blood drawn for other study purposes.
4. Confidential Participant Information for Future Biomedical 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 
identifying information embedded within it. The link (or key) between participant 
identifiers and this unique code will be held at the study site. No personal identifiers will 
appear on the specimen tube.
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5. Biorepository Specimen 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 
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 
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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 
Postrandomization 
Findings 
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
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Screen Failure Criteria
Potentially Significant 
Postrandomization 
Findings 
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
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 Ischemia
In 2 or more contiguous leads
In 2 or more contiguous 
leads
T-wave Inversions 
Suggestive of Myocardial 
Ischemia
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 Fridericia
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:
1. The participant may be excluded from the study;
a.
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).
b. 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
2. 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
ADME
absorption, distribution, metabolism, and excretion
AE
adverse event 
ALT
alanine aminotransferase
AST
aspartate aminotransferase
AUC
area under the curve
BDS
blood drug screen
BMI
body mass index
BP
blood pressure
CCU
cardiac care unit
CG
Cockcroft-Gault
CI
confidence interval
Cmax
maximum plasma concentration
CNS
central nervous system 
CKD-EPI
Chronic Kidney Disease Epidemiology Collaboration
CL
clearance
CL/F
oral clearance
COVID-19
Coronavirus disease 2019
CP
Child-Pugh 
CrCl
creatinine clearance
CRF
Case Report Form 
CRU
clinical research unit
CSR
Clinical Study Report
CTFG
Clinical Trial Facilitation Group 
CV
coefficient of variation
DILI
drug-induced liver injury
DNA
deoxyribonucleic acid 
ECG
electrocardiogram 
ECI
event of clinical interest
eCRF
electronic Case Report Form
EDC
electronic data collection 
eGFR
estimated glomerular filtration rate
EMA
European Medicines Agency
FDAAA
Food and Drug Administration Amendments Act
FSH
follicle-stimulating hormone 
GCP
Good Clinical Practice 
GM
geometric mean
GMR
geometric mean ratio
HBsAg
hepatitis B surface antigen
HBV
hepatitis B virus
hCG
human chorionic gonadotropin
HCV
hepatitis C virus
HI
hepatic impairment
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Abbreviation
Expanded Term
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
ICU
intensive care unit
IEC
Independent Ethics Committee
IND
Investigational New Drug 
INR
international normalized ratio
IRB
Institutional Review Board
IUD
intrauterine device
IUS
intrauterine hormone-releasing system
IV
intravenous
LAM
lactational amenorrhea method
MERS
Middle East respiratory syndrome
MERS-CoV
Middle East respiratory syndrome coronavirus
MOV
molnupiravir, MK-4482, EIDD-2801
NCS
not clinically significant
NHC
N-hydroxycytidine
NHC-TP
N-hydroxycytidine triphosphate
NOAEL
no observed adverse effect level 
OBS
observed GMR
P
protocol (number)
PBC
primary biliary cirrhosis 
PCL
protocol clarification letter
PCR
polymerase chain reaction
PK
pharmacokinetic
PopPK
population pharmacokinetics
Q12H
every 12 hours
RNA
ribonucleic acid
RR
respiratory rate
RSV
respiratory syncytial virus
SAE
serious adverse event 
SARS-CoV
severe acute respiratory syndrome coronavirus
SARS-CoV-2
severe acute respiratory syndrome coronavirus 2
SaO2
arterial oxygen saturation
SD
standard deviation
SLAB
supplemental laboratory test(s)
SoA
schedule of activities
SOP
standard operating procedures
SUSAR
suspected unexpected serious adverse reaction
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Abbreviation
Expanded Term
Tmax
time to maximum plasma concentration
t1/2
half life
UDS
urine drug screen
ULN
upper limit of normal
Vd
volume of distribution
Vd/F
apparent volume of distribution 
VEEV
Venezuelan equine encephalitis virus
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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