Clinical trial NCT04939428
Conditions: Coronavirus Disease (COVID-19)
Sponsor: Merck Sharp & Dohme LLC
Start date: 2021-08-11; Completion date: 2022-11-16
Enrollment: 2441 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The purpose of the study is to assess if the study medication (molnupiravir, MK-4482) will prevent symptomatic coronavirus disease 2019 (COVID-19) in adults who live with someone with confirmed COVID-19 infection. This is a phase 3, multicenter, randomized, double-blind, placebo-controlled study; half of the study participants will receive molnupiravir twice daily by mouth and the other half will receive a placebo. The primary objectives of the study are to determine if molnupiravir prevents symptomatic COVID-19 disease and to evaluate its safety and tolerability. All participants who develop COVID-19 during the study are still eligible for any COVID-19 treatment recommended by their doctor.

Detailed description:

Arms: arm 1: Participants take molnupiravir 800 mg every 12 hours (Q12H) on Days 1 to 5. arm 2: Participants take placebo Q12H on Days 1 to 5.
Interventions: intervention 1: Molnupiravir intervention 2: Placebo
Intervention descriptions: intervention 1: Four molnupiravir 200 mg capsules taken by mouth. intervention 2: Placebo capsule matched to molnupiravir 200 mg capsules taken by mouth.

Protocol documents:
Prot_SAP_000.pdf: 
Official Protocol Title:
NCT number: 
NCT04939428
Document Date: 
16-Oct-2022
A Phase 3, Multicenter, Randomized, Double-blind, 
Placebo-controlled Study to Evaluate the Efficacy and 
Safety of MK-4482 for the Prevention of COVID-19 
(Laboratory-confirmed SARS-CoV-2 Infection With 
Symptoms) in Adults Residing With a Person With 
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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: A Phase 3, Multicenter, Randomized, Double-blind, Placebo-controlled 
Study to Evaluate the Efficacy and Safety of MK-4482 for the Prevention of COVID-19 
(Laboratory-confirmed SARS-CoV-2 Infection With Symptoms) in Adults Residing With a 
Person With COVID-19.
Protocol Number: 013-05
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):
EudraCT
2021-000904-39
IND
155588
Approval Date: 16 October 2022
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Sponsor Signatory
Typed Name:
Title:
Date
Protocol-specific Sponsor contact information can be found in the Investigator Study
File Binder (or equivalent).
Investigator Signatory
I agree to conduct this clinical study in accordance with the design outlined in this protocol 
and to abide by all provisions of this protocol.
Typed Name:
Title:
Date
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DOCUMENT HISTORY
Document
Date of Issue
Overall Rationale
Amendment 5
16-OCT-2022
The rationale for this amendment is 1) to update the anti-SARS-CoV-2 
neutralizing antibody testing method and 2) to allow use of qualitative OP swab 
data, under extenuating circumstances where NP swab data are not available, 
for baseline viral status categorization (ie, to establish whether they are in the 
primary analysis population, mITT-VN) and for clinical outcome assessment.
Amendment 4
15-MAY-2022
The rationale for this amendment is 1) to update the interim analysis to remove 
the assessment of early efficacy; only safety and futility will be assessed at the 
interim analysis 2) to revise the power calculation and sample size as a result of 
removing the assessment of early efficacy at the interim analysis and 3) to 
correct errors mistakenly introduced in the prior amendment in the third 
secondary objective and second exploratory objective.
Amendment 3
05-APR-2022
The rationale for this amendment is 1) to add as a secondary objective and 
associated hypothesis for the prevention of laboratory-confirmed COVID-19 
through Day 14 in participants regardless of SARS-CoV-2 results (detectable or 
undetectable) in baseline NP swabs, and 2) to align male contraception 
requirements across the study with the requirements in the US EUA Fact Sheet 
for MOV even if not required locally.
Amendment 2
07-JAN-2022
The primary rationale for this amendment was to revise the primary efficacy 
objective to include only those participants with undetectable SARS-CoV-2 in 
baseline nasopharyngeal swabs, and to update the interim analysis to include an 
assessment of early efficacy. These changes required an increase in the sample 
size (from 1332 to 1500) and an update of the timing of the interim analysis.
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Document
Date of Issue
Overall Rationale
Amendment 1
23-AUG-2021
The key reasons for this amendment are to 1) make the evaluation of 
laboratory-confirmed COVID-19 through Day 14 in participants with 
undetectable SARS-CoV-2 in baseline nasopharyngeal (NP) swabs a key 
secondary endpoint; 2) align the windows (5-days) for COVID-19 symptoms 
and SARS-CoV-2 testing in the index; and 3) to collect symptom diaries in all 
participants through Day 29.
Original Protocol
14-JUN-2021
Not applicable
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PROTOCOL AMENDMENT SUMMARY OF CHANGES
Amendment: 05
Overall Rationale for the Amendments:
The rationale for this amendment is 1) to update the anti-SARS-CoV-2 neutralizing antibody testing method and 2) to allow use of 
qualitative OP swab data, under extenuating circumstances where NP swab data are not available, for baseline viral status 
categorization (ie, to establish whether they are in the primary analysis population, mITT-VN) and for clinical outcome assessment.
Summary of Changes Table:
Section # and 
Name
Description of Change 
Brief Rationale 
8.8 Anti-SARS-
CoV-2 Antibody 
Serology Testing
Updated the anti-SARS-
CoV-2 neutralizing 
antibody testing method.
The assay to be used to test for SARS-CoV-2 neutralization antibodies has 
been revised due to technical and timing issues with the original method. The 
updated assay is a validated assay which works by a method similar to the 
original method (a spike-protein pseudotyped VSV neutralization assay) and 
has an additional luciferase reporter system that enables higher throughput.
8.2.5 SARS-CoV-2 
RT-PCR Assay
9.5.1 Efficacy 
Analysis 
Populations
Added a statement to allow 
for OP swab results to be 
used for baseline qualitative 
virology testing in the 
absence of NP swab results.
Clarified that in some instances, only OP swab results may be available. In 
light of good concordance between OP and NP swab results observed in prior 
studies, use of OP swab results is an acceptable alternative to support efficacy 
endpoints including the primary outcome assessment and baseline viral status.
NP swabs remain the required procedure, and OP results will only be used in 
the event that NP swab results are not available. 
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Section # and 
Name
Description of Change 
Brief Rationale 
10.5.2
Contraception 
Requirements
Added that tubal occlusion 
includes tubal ligation.
To clarify that tubal ligation is considered a contraception method, not a 
sterilization method as per company guidance.
Throughout 
Document
Minor formatting, editorial, 
and typographical changes 
were made throughout the 
document.
To ensure clarity and accuracy.
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Table of Contents
DOCUMENT HISTORY ........................................................................................................3
PROTOCOL AMENDMENT SUMMARY OF CHANGES...............................................5
1
PROTOCOL SUMMARY ............................................................................................15
1.1
Synopsis.................................................................................................................15
1.2
Schema ..................................................................................................................19
1.3
Schedule of Activities...........................................................................................20
1.3.1
Schedule of Activities for Randomized Participants ...................................20
1.3.2
Schedule of Activities for Index Cases........................................................29
2
INTRODUCTION..........................................................................................................30
2.1
Study Rationale....................................................................................................30
2.2
Background ..........................................................................................................31
2.2.1
Pharmaceutical and Therapeutic Background .............................................31
2.2.2
Preclinical and Clinical Studies ...................................................................32
2.2.3
Clinical Studies............................................................................................32
2.2.3.1
Completed Clinical Studies................................................................32
2.2.3.2
Ongoing Clinical Studies...................................................................34
2.3
Benefit/Risk Assessment......................................................................................35
3
HYPOTHESES, OBJECTIVES, AND ENDPOINTS................................................37
4
STUDY DESIGN............................................................................................................40
4.1
Overall Design......................................................................................................40
4.2
Scientific Rationale for Study Design.................................................................42
4.2.1
Rationale for Endpoints ...............................................................................43
4.2.1.1
Efficacy Endpoints.............................................................................43
4.2.1.2
Safety Endpoints................................................................................44
4.2.1.3
Virology Endpoints............................................................................44
4.2.1.4
Serology Endpoints............................................................................45
4.2.1.5
Health Care Utilization and Health Outcomes...................................45
4.2.1.6
Future Biomedical Research..............................................................45
4.2.2
Rationale for the Use of Comparator/Placebo .............................................46
4.2.3
Rationale for the Selected Participant Population .......................................46
4.2.4
Rationale for Collection of Racial, Ethnic, and Gender Identity Data ........47
4.2.5
Rationale for Selected Stratification Factors ...............................................47
4.3
Justification for Dose...........................................................................................47
4.3.1
Rationale for Dose .......................................................................................47
4.3.2
Rationale for Dosing Duration.....................................................................48
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4.4
Beginning and End-of-Study Definition ............................................................49
4.4.1
Clinical Criteria for Early Study Termination .............................................49
5
STUDY POPULATION ................................................................................................49
5.1
Inclusion Criteria.................................................................................................50
5.2
Exclusion Criteria................................................................................................52
5.3
Lifestyle Considerations......................................................................................53
5.4
Screen Failures.....................................................................................................53
5.5
Participant Replacement Strategy......................................................................54
6
STUDY INTERVENTION............................................................................................54
6.1
Study Intervention(s) Administered...................................................................54
6.2
Preparation/Handling/Storage/Accountability .................................................56
6.2.1
Dose Preparation..........................................................................................56
6.2.2
Handling, Storage, and Accountability........................................................56
6.3
Measures to Minimize Bias: Randomization and Blinding..............................57
6.3.1
Intervention Assignment..............................................................................57
6.3.2
Stratification.................................................................................................57
6.3.3
Blinding........................................................................................................57
6.4
Study Intervention Compliance..........................................................................57
6.5
Concomitant Therapy..........................................................................................57
6.5.1
Rescue Medications and Supportive Care ...................................................59
6.6
Dose Modification (Escalation/Titration/Other)...............................................59
6.7
Intervention After the End of the Study............................................................59
6.8
Clinical Supplies Disclosure................................................................................59
6.9
Standard Policies..................................................................................................59
7
DISCONTINUATION OF STUDY INTERVENTION AND PARTICIPANT 
WITHDRAWAL............................................................................................................59
7.1
Discontinuation of Study Intervention...............................................................59
7.2
Participant Withdrawal From the Study...........................................................60
7.3
Lost to Follow-up .................................................................................................61
8
STUDY ASSESSMENTS AND PROCEDURES........................................................61
8.1
Administrative and General Procedures ...........................................................62
8.1.1
Informed Consent.........................................................................................62
8.1.1.1
General Informed Consent.................................................................62
8.1.1.2
Consent and Collection of Specimens for Future Biomedical 
Research.............................................................................................63
8.1.1.3
Consent/Assent for Data Collection and Viral 
Testing/Quantification for Index Cases .............................................63
8.1.2
Inclusion/Exclusion Criteria ........................................................................63
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8.1.3
Participant Identification Card.....................................................................64
8.1.4
Medical History ...........................................................................................64
8.1.5
Prior and Concomitant Medications Review...............................................64
8.1.5.1
Prior Medications...............................................................................64
8.1.5.2
Concomitant Medications..................................................................65
8.1.6
Assignment of Screening Number...............................................................65
8.1.7
Assignment of Treatment/Randomization Number.....................................65
8.1.8
Participant Study Supplies...........................................................................66
8.1.9
Study Intervention Administration ..............................................................66
8.1.9.1
Timing of Dose Administration.........................................................66
8.1.10
Study Medication Diary...............................................................................67
8.1.11
Discontinuation and Withdrawal .................................................................68
8.1.11.1
Withdrawal From Future Biomedical Research ................................68
8.1.12
Participant Blinding/Unblinding..................................................................68
8.1.13
Calibration of Equipment.............................................................................69
8.2
Efficacy Assessments ...........................................................................................69
8.2.1
Completing the Symptom Diary and Monitoring for Symptoms of 
COVID-19....................................................................................................69
8.2.2
Qualifying Symptoms of Suspected COVID-19..........................................71
8.2.3
Scheduling Requirements and Procedures at a COVID-19 Confirmation 
Visit..............................................................................................................72
8.2.4
Nasopharyngeal Swab Collection for Viral Testing/Quantification............73
8.2.5
SARS-CoV-2 RT-PCR Assay......................................................................74
8.2.6
Assessment of Prophylaxis Outcome...........................................................75
8.2.7
Hospitalization.............................................................................................76
8.2.8
Survival Status .............................................................................................77
8.2.9
Health Care Utilization for COVID-19........................................................77
8.2.10
Assessment for Severity of COVID-19 .......................................................77
8.2.11
EuroQoL EQ-5D-5L Questionnaire.............................................................78
8.3
Safety Assessments...............................................................................................78
8.3.1
Physical Examinations.................................................................................78
8.3.2
Vital Signs....................................................................................................78
8.3.3
Clinical Safety Laboratory Assessments .....................................................78
8.3.4
Pregnancy Testing........................................................................................79
8.3.5
Pregnancy Follow-up...................................................................................79
8.4
Adverse Events, Serious Adverse Events, and Other Reportable Safety 
Events....................................................................................................................79
8.4.1
Time Period and Frequency for Collecting AE, SAE, and Other 
Reportable Safety Event Information ..........................................................80
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8.4.2
Method of Detecting AEs, SAEs, and Other Reportable Safety Events......82
8.4.3
Follow-up of AE, SAE, and Other Reportable Safety Event Information...82
8.4.4
Regulatory Reporting Requirements for SAE .............................................82
8.4.5
Pregnancy and Exposure During Breastfeeding ..........................................82
8.4.6
Disease-related Events and/or Disease-related Outcomes Not Qualifying 
as AEs or SAEs............................................................................................83
8.4.7
Events of Clinical Interest............................................................................83
8.5
Treatment of Overdose........................................................................................83
8.6
Pharmacokinetics.................................................................................................84
8.7
Pharmacodynamics..............................................................................................84
8.8
Anti-SARS-CoV-2 Antibody Serology Testing .................................................84
8.9
Biomarkers ...........................................................................................................84
8.10
Future Biomedical Research Sample Collection...............................................84
8.11
Visit Requirements...............................................................................................85
8.11.1
Infection Prevention Procedures..................................................................85
8.11.2
Types of Study Visits...................................................................................85
8.11.2.1
Screening/Rescreening Visits ............................................................85
8.11.2.2
Clinic Visits, Home Visits, or Visits to an Alternate Site..................86
8.11.2.3
Virtual Visits......................................................................................86
8.11.3
Participants Who Discontinue or Withdraw ................................................86
9
STATISTICAL ANALYSIS PLAN .............................................................................87
9.1
Statistical Analysis Plan Summary.....................................................................88
9.2
Responsibility for Analyses/In-house Blinding .................................................90
9.3
Hypotheses/Estimation ........................................................................................90
9.4
Analysis Endpoints...............................................................................................90
9.4.1
Efficacy Endpoints.......................................................................................90
9.4.2
Safety Endpoints..........................................................................................91
9.5
Analysis Populations............................................................................................92
9.5.1
Efficacy Analysis Populations.....................................................................92
9.5.2
Safety Analysis Populations ........................................................................92
9.6
Statistical Methods...............................................................................................93
9.6.1
Statistical Methods for Efficacy Analyses...................................................93
9.6.2
Statistical Methods for Safety Analyses ......................................................97
9.6.3
Demographic and Baseline Characteristics .................................................98
9.7
Interim Analyses ..................................................................................................98
9.8
Multiplicity ...........................................................................................................99
9.9
Sample Size and Power Calculations ...............................................................100
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9.9.1
Sample Size and Power Calculations for Efficacy Analyses (Primary 
Objective)...................................................................................................100
9.9.2
Sample Size and Power Calculations for Efficacy Analyses (Secondary 
Objective)...................................................................................................102
9.9.3
Sample Size and Power Calculations for Safety Analyses ........................103
9.10
Subgroup Analyses.............................................................................................105
9.11
Compliance (Medication Adherence)...............................................................105
9.12
Extent of Exposure.............................................................................................105
10
SUPPORTING DOCUMENTATION AND OPERATIONAL 
CONSIDERATIONS...................................................................................................106
10.1
Appendix 1: Regulatory, Ethical, and Study Oversight Considerations......106
10.1.1
Code of Conduct for Clinical Trials...........................................................106
10.1.2
Financial Disclosure...................................................................................108
10.1.3
Data Protection...........................................................................................109
10.1.3.1
Confidentiality of Data ....................................................................109
10.1.3.2
Confidentiality of Participant Records.............................................109
10.1.3.3
Confidentiality of IRB/IEC Information..........................................109
10.1.4
Committees Structure.................................................................................110
10.1.4.1
Executive Oversight Committee......................................................110
10.1.4.2
External Data Monitoring Committee .............................................110
10.1.5
Publication Policy......................................................................................110
10.1.6
Compliance with Study Registration and Results Posting Requirements .111
10.1.7
Compliance with Law, Audit, and Debarment ..........................................111
10.1.8
Data Quality Assurance .............................................................................112
10.1.9
Source Documents .....................................................................................113
10.1.10
Study and Site Closure...............................................................................113
10.2
Appendix 2: Clinical Laboratory Tests............................................................114
10.3
Appendix 3: Adverse Events: Definitions and Procedures for Recording, 
Evaluating, Follow-up, and Reporting.............................................................117
10.3.1
Definition of AE ........................................................................................117
10.3.2
Definition of SAE ......................................................................................118
10.3.3
Additional Events Reported.......................................................................119
10.3.4
Recording AE and SAE .............................................................................119
10.3.5
Reporting of AEs, SAEs, and Other Reportable Safety Events to the 
Sponsor ......................................................................................................123
10.4
Appendix 4: Medical Device and Drug-device Combination Products: 
Product Quality Complaints/Malfunctions: Definitions, Recording, and 
Follow-up ............................................................................................................125
10.5
Appendix 5: Contraceptive Guidance..............................................................126
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10.5.1
Definitions..................................................................................................126
10.5.2
Contraception Requirements......................................................................127
10.6
Appendix 6: Collection and Management of Specimens for Future 
Biomedical Research..........................................................................................128
10.7
Appendix 7: Country-specific Requirements..................................................133
10.7.1
Country-specific Requirements for Argentina...........................................133
10.7.2
Country-specific Requirements for France................................................133
10.8
Appendix 8: Individuals at Increased Risk for Severe Illness from 
COVID-19...........................................................................................................134
10.9
Appendix 9: Calculation of eGFR ....................................................................135
10.10 Appendix 10: Abbreviations .............................................................................136
11
REFERENCES.............................................................................................................139
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LIST OF TABLES
Table 1
Study Interventions....................................................................................55
Table 2
Prohibited and Allowed Therapies for Participating Household 
Contacts......................................................................................................58
Table 3
Reporting Time Periods and Time Frames for Adverse Events and 
Other Reportable Safety Events.................................................................81
Table 4
Imputation for Indeterminate Prophylaxis Outcomes................................94
Table 5
Analysis Strategy for Key Efficacy Endpoints..........................................95
Table 6
Analysis Strategy for Safety Parameters....................................................98
Table 7
Power Analysis to Assess the Primary Objective in Participants With 
Undetectable SARS-CoV-2 in Baseline NP Swabs; N=1100 
Participants, Overall Alpha=0.025, One-sided ........................................101
Table 8
Power Analysis to Assess the Secondary Objective Participants; 
N=1376 Overall Alpha=0.025, One-Sided ..............................................103
Table 9
Difference in Percentage of Participants With AEs (MOV Minus 
Placebo) That Can be Ruled Out With 688 Participants in Each Group .104
Table 10
Percentage of Participants with AEs and 95% Upper Confidence 
Bound Based on Hypothetical Numbers of Participants with AEs (688 
Participants per Group)............................................................................104
Table 11
Protocol-required Clinical Laboratory Assessments ...............................115
Table 12
Approximate Whole Blood Volumes (mL) for Clinical Laboratory 
Assessments.............................................................................................116
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LIST OF FIGURES
Figure 1
MK-4482-013 Study Design......................................................................19
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1
PROTOCOL SUMMARY
1.1
Synopsis
Protocol Title: A Phase 3, Multicenter, Randomized, Double-blind, Placebo-controlled 
Study to Evaluate the Efficacy and Safety of MK-4482 for the Prevention of COVID-19 
(Laboratory-confirmed SARS-CoV-2 Infection With Symptoms) in Adults Residing With a 
Person With COVID-19.
Short Title: MK-4482 Phase 3 Study for Prevention of COVID-19 in Adults
Acronym: N/A 
MOVe-AHEAD
Hypotheses, Objectives, and Endpoints:
Hypotheses are aligned with objectives in the Objectives and Endpoints table.
Objectives will be evaluated in participants ≥18 years of age who do not have confirmed or 
suspected COVID-19 at the time of screening and randomization and are residing with an 
individual (of any age) with COVID-19 (laboratory-confirmed SARS-CoV-2 infection with 
symptoms), defined as the index case.
Objectives
Endpoints
Primary
•
To evaluate the efficacy of molnupiravir 
(MOV) compared with placebo for the 
prevention of laboratory-confirmed 
COVID-19 through Day 14 in participants 
with undetectable SARS-CoV-2 in 
baseline nasopharyngeal (NP) swabs.
•
Hypothesis: MOV is superior to placebo 
for the prevention of laboratory-confirmed 
COVID-19 through Day 14 in participants 
with undetectable SARS-CoV-2 in baseline 
NP swabs.
•
COVID-19 (laboratory-confirmed 
SARS-CoV-2 infection with 
symptoms)
•
To evaluate the safety and tolerability of 
MOV compared with placebo.
•
Adverse events
•
Adverse events leading to 
discontinuation of study intervention
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Objectives
Endpoints
Secondary
•
To evaluate the efficacy of MOV
compared with placebo for the prevention 
of laboratory-confirmed COVID-19 
through Day 14 in participants regardless 
of SARS-CoV-2 results in baseline NP 
swabs.
•
Hypothesis: MOV is superior to placebo 
for the prevention of laboratory-confirmed 
COVID-19 through Day 14 in all 
participants regardless of SARS-CoV-2 
results in baseline NP swabs.
•
COVID-19 (laboratory-confirmed 
SARS-CoV-2 infection with 
symptoms)
•
To evaluate the efficacy of MOV 
compared with placebo for the prevention 
of laboratory-confirmed COVID-19 
through Day 29 in participants with 
undetectable SARS-CoV-2 in baseline NP 
swabs.
•
COVID-19 (laboratory-confirmed 
SARS-CoV-2 infection with 
symptoms)
•
To evaluate prevention of viral 
transmission through Day 14 for MOV 
compared with placebo in participants 
with undetectable SARS-CoV-2 in 
baseline NP swabs.
•
SARS-CoV-2 RNA
•
To evaluate the efficacy of MOV 
compared with placebo for the prevention
of laboratory-confirmed COVID-19 
through Day 14 in participants with 
detectable SARS-CoV-2 in baseline NP 
swabs.
•
COVID-19 (laboratory-confirmed 
SARS-CoV-2 infection with 
symptoms)
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Overall Design:
Study Phase
Phase 3
Primary Purpose
Prevention
Indication
Prophylaxis of COVID-19 in adults
Population
Participants ≥18 years of age
Study Type
Interventional
Intervention Model
Parallel
This is a multi-site study.
Type of Control
Placebo-controlled
Study Blinding
Double-blind with in-house blinding
Blinding Roles
Participants or Subjects
Investigator
Sponsor
Estimated Duration of Study
The Sponsor estimates that the study will require 
approximately 9 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:
Participants in this study are adult household contacts of index cases. Approximately 1376
participants will be randomized in a 1:1 ratio to receive either blinded MOV or blinded 
placebo. Index cases will not be randomized to receive intervention in the study.
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Intervention Groups and Duration:
Intervention 
Groups
Intervention 
Group Name
Drug
Dose 
Strength
Dose 
Frequency
Route of 
Admin.
Regimen/ 
Treatment 
Period
Use
Group 1
MOV
(MK-4482)
800 mg
Q12H
Oral
5 days
(10 doses 
total)
Test 
Product
Group 2
Matching 
Placebo
0 mg
Q12H
Oral
5 days
(10 doses 
total)
Placebo
Admin.=administration; MOV=molnupiravir; Q12H=once every 12 hours
Total 
Number of 
Intervention 
Groups/
Arms
2 groups (1 active and 1 control)
Duration of 
Participation
Each participant will be in the study for ~35 days from the time the 
participant provides documented informed consent through the final 
contact. Participants will be randomized on Day 1 and receive 10 doses of 
assigned blinded study intervention (administered Q12H). Participants will 
be followed through Day 29 after randomization.
Study Governance Committees:
Steering Committee
No
Executive Oversight Committee
Yes
Data Monitoring Committee
Yes
Clinical Adjudication Committee
No
Study governance 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
MK-4482-013 Study Design
COVID-19=coronavirus infectious disease 2019; EOT=end of treatment; LFU=Late Follow-up Visit; MOV=molnupiravir; 
Q12H=administered once every 12 hours; SARS-CoV-2=severe acute respiratory syndrome coronavirus 2
a Eligible participants (household contacts of index cases) who do not have confirmed or suspected COVID-19 at the time 
of screening and randomization will be randomized within 5 days of both the time of sample collection for the index 
case’s first detectable SARS-CoV-2 test result and time of onset of the index case’s COVID-19 symptoms. Index cases 
will not be randomized to receive study intervention; however, these individuals will be requested to provide documented 
informed consent/assent to allow for the collection of information related to COVID-19.
b Active surveillance will be conducted in this study for onset of symptoms attributable to COVID-19. Participants will be 
instructed to contact study personnel if they develop 1 or more symptoms of suspected COVID-19 (listed in the Symptom 
Diary) at any time through Day 29. If a participant reports qualifying symptoms of suspected COVID-19, a COVID-19 
Confirmation Visit should be scheduled to occur as soon as possible, but within 3 days of symptom onset.
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1.3
Schedule of Activities
1.3.1
Schedule of Activities for Randomized Participants
Study Period:
Screening
Intervention
Follow-up
Notes
Visit Number/Name:
1 a,b
2 a,b
3
4
5
6
COVID-19 
Confirmation 
Visit c
Scheduled Day (Window)
(≤5 days prior 
to rand)
Day 1
Day 5
(+2 days)
EOT
Day 14
(+3 days)
Day 21
(+3 days)
Day 29
(+3 days)
LFU
Type of Visit
C d
C d
C d
C d
V e
C d
C d
C = Clinic Visit
V = Virtual Visit
Administrative Procedures
Informed Consent
X
Documented informed consent 
must be provided. See Section 
8.1.1.
Informed Consent for Future 
Biomedical Research
X
Participation in Future 
Biomedical Research is 
optional. See Section 8.1.1.2.
Register Study Visit in IRT
X
X
Inclusion/Exclusion Criteria
X
X
Participants must not have 
confirmed or suspected 
COVID-19 at the time of 
screening and randomization.
Participant Identification Card
X
X
Add randomization number to 
the card at randomization.
Medical History
X
X
Includes prior medical history 
of COVID-19. See Section 
8.1.4 for all reporting criteria.
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Study Period:
Screening
Intervention
Follow-up
Notes
Visit Number/Name:
1 a,b
2 a,b
3
4
5
6
COVID-19 
Confirmation 
Visit c
Scheduled Day (Window)
(≤5 days prior 
to rand)
Day 1
Day 5
(+2 days)
EOT
Day 14
(+3 days)
Day 21
(+3 days)
Day 29
(+3 days)
LFU
Type of Visit
C d
C d
C d
C d
V e
C d
C d
C = Clinic Visit
V = Virtual Visit
Prior/Concomitant 
Medication Review
X
X
X
X
X
X
X
Record the following:
Prior or concomitant 
COVID-19 vaccine.
Concomitant COVID-19 
medication for participants 
with laboratory-confirmed 
COVID-19.
See Section 8.1.5 for all 
reporting criteria.
Study Intervention 
Randomization
X
Dispense Study Intervention 
and Participant Study 
Supplies
X
Includes Study Medication 
Diary and Symptom Diary.
MOV or Placebo 
Administration
<=== X ===>
All efforts should be made to 
administer the first dose on 
Day 1 (randomization).
Administration of the first 
dose must be within 24 hours 
after randomization.
Completion of Study 
Medication Diary
<=== X ===>
Complete Study Medication 
Diary daily.
Reminder for Study 
Medication Diary Completion
<=== X ===>
Reminders from site personnel 
should be performed daily 
during the treatment period.
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Study Period:
Screening
Intervention
Follow-up
Notes
Visit Number/Name:
1 a,b
2 a,b
3
4
5
6
COVID-19 
Confirmation 
Visit c
Scheduled Day (Window)
(≤5 days prior 
to rand)
Day 1
Day 5
(+2 days)
EOT
Day 14
(+3 days)
Day 21
(+3 days)
Day 29
(+3 days)
LFU
Type of Visit
C d
C d
C d
C d
V e
C d
C d
C = Clinic Visit
V = Virtual Visit
Study Medication 
Reconciliation
X
X
Study medication reconciliation 
is required at the Day 14 visit if 
EOT is completed after the 
Day 5 visit.
Study Staff Review and 
Collection of Study 
Medication Diary
X
X
Study Medication Diary will be 
collected after the last dose of 
study intervention (either Day 5 
or Day 14 visit, if EOT is 
completed after the Day 5 
visit). 
Efficacy Procedures
Completion of Symptom 
Diary
<=============== X===============>
X
Complete daily from Day 1 
(predose) through Day 29 to 
confirm the presence/absence 
and severity of targeted 
COVID-19 symptoms. See 
Section 8.2.1.
Reminders for Symptom 
Diary Completion
<====== X======>
X
X
Reminders from site personnel 
should be performed:
Daily during treatment period
and every other day from 
EOT through Day 14 to a 
participant or 1 participant 
who represents the 
household.
Weekly after Day 14.
See Section 8.2.1.
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Study Period:
Screening
Intervention
Follow-up
Notes
Visit Number/Name:
1 a,b
2 a,b
3
4
5
6
COVID-19 
Confirmation 
Visit c
Scheduled Day (Window)
(≤5 days prior 
to rand)
Day 1
Day 5
(+2 days)
EOT
Day 14
(+3 days)
Day 21
(+3 days)
Day 29
(+3 days)
LFU
Type of Visit
C d
C d
C d
C d
V e
C d
C d
C = Clinic Visit
V = Virtual Visit
Investigator Assessed Signs
X
X
X
X
X
Investigator or designee will
assess the participant’s ability 
to undertake personal usual 
activities (ie, activities of daily 
living) and assess shortness of 
breath at rest and with exertion.
Study Staff Review and 
Collection of Symptom Diary
X
X
X
X
X
X
Completed pages of 
Symptom Diary will be 
collected at clinic visits.
Symptom Diaries completed 
after Day 29 will be returned 
to the site as allowed per 
local guidelines.
Monitoring for Symptoms for 
COVID-19
X
X
X
X
X
Participants should be reminded 
at all visits to contact the site if 
they develop symptoms of 
suspected COVID-19.
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Study Period:
Screening
Intervention
Follow-up
Notes
Visit Number/Name:
1 a,b
2 a,b
3
4
5
6
COVID-19 
Confirmation 
Visit c
Scheduled Day (Window)
(≤5 days prior 
to rand)
Day 1
Day 5
(+2 days)
EOT
Day 14
(+3 days)
Day 21
(+3 days)
Day 29
(+3 days)
LFU
Type of Visit
C d
C d
C d
C d
V e
C d
C d
C = Clinic Visit
V = Virtual Visit
NP Swabsf for Viral 
Testing/Quantification
X
X
X
X
X
NP swabs at the Day 1, 
Day 5, Day 14, and Day 29 
visits should be collected 
from all participants.
NP swabs for confirmation of 
COVID-19 should be 
collected from all 
participants who develop 
qualifying symptoms of 
COVID-19 through Day 29.
NP swab must be collected 
by site personnel or 
medically qualified designee.
If an additional sample is 
collected for testing per local 
guidelines, the swab sample 
for central laboratory testing 
should be collected first.
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Study Period:
Screening
Intervention
Follow-up
Notes
Visit Number/Name:
1 a,b
2 a,b
3
4
5
6
COVID-19 
Confirmation 
Visit c
Scheduled Day (Window)
(≤5 days prior 
to rand)
Day 1
Day 5
(+2 days)
EOT
Day 14
(+3 days)
Day 21
(+3 days)
Day 29
(+3 days)
LFU
Type of Visit
C d
C d
C d
C d
V e
C d
C d
C = Clinic Visit
V = Virtual Visit
Prophylaxis Outcome 
Assessment
X
X
X
Assess for all participants 
whether a clinical success (no 
laboratory-confirmed 
COVID-19), failure 
(laboratory-confirmed 
COVID-19), or indeterminate. 
At the COVID-19 Confirmation 
Visit, assess only for 
participants who develop 
laboratory-confirmed COVID-
19 with symptoms. See Section 
8.2.6.
Hospitalization Status
X
X
X
X
Collect from all participants.
Survival Status
X
Collect from all participants.
Health care Utilization for 
COVID-19
X
X
X
X
X
Collect only from participants 
with laboratory-confirmed 
COVID-19.
Assessment for Severity of 
COVID-19 (NIAID Scale)
X
X
X
X
X
Collect only from participants 
with laboratory-confirmed 
COVID-19.
EuroQoL EQ-5D-5L
Questionnaire
X
X
X
X
Collect from all participants.
Safety Procedures
Directed Physical 
Examination
X
X
X
X
Including height and weight at 
screening only
Vital Signs
X
X
X
X
X
Heart rate, blood pressure, 
respiratory rate, temperature.
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Study Period:
Screening
Intervention
Follow-up
Notes
Visit Number/Name:
1 a,b
2 a,b
3
4
5
6
COVID-19 
Confirmation 
Visit c
Scheduled Day (Window)
(≤5 days prior 
to rand)
Day 1
Day 5
(+2 days)
EOT
Day 14
(+3 days)
Day 21
(+3 days)
Day 29
(+3 days)
LFU
Type of Visit
C d
C d
C d
C d
V e
C d
C d
C = Clinic Visit
V = Virtual Visit
Blood Collection for Local 
Laboratory Evaluation
X g
Blood Collection for Central 
Laboratory Evaluationh
(Hematology and Chemistry)
X
X
X
Any laboratory test with a 
result considered abnormal and 
clinically significant should be 
repeated until the result returns 
to normal or baseline, or a new 
baseline is established, as 
determined by the investigator. 
See Section 8.3.3.
Pregnancy Test
(WOCBP only)
X g, h
X
Pregnancy test at screening 
may be a urine or serum test. If 
it is a urine test, it should be 
sensitive enough to detect 
25 mIU/mL hCG. Day 14 (Visit 
4) test must be a serum 
pregnancy test.
Confirm Contraception 
Requirements (WOCBP and 
Male Participants)
X
X
X
X
X
X
X
Pregnancy Follow-up
X
Request pregnancy status of 
female participant or female 
partner of male participants. 
See Section 8.3.5.
AE/SAE Review
X
X
X
X
X
X
x
AEs, SAEs, and other 
reportable events (eg, 
pregnancy) will be reported 
according to Section 8.4.
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Study Period:
Screening
Intervention
Follow-up
Notes
Visit Number/Name:
1 a,b
2 a,b
3
4
5
6
COVID-19 
Confirmation 
Visit c
Scheduled Day (Window)
(≤5 days prior 
to rand)
Day 1
Day 5
(+2 days)
EOT
Day 14
(+3 days)
Day 21
(+3 days)
Day 29
(+3 days)
LFU
Type of Visit
C d
C d
C d
C d
V e
C d
C d
C = Clinic Visit
V = Virtual Visit
Pharmacodynamics/ Biomarkers
Anti-SARS-CoV-2 Antibody 
Serology Testingi
X
X
X
Collect predose at the Day 1 
visit from enrolled participants 
only.
Blood (DNA) for Future 
Biomedical Research
X
Collect predose from enrolled 
participants only. See 
Section 8.10
AE=adverse event; ALT=alanine aminotransferase; AST=aspartate aminotransferase; COVID-19=coronavirus disease 2019; CRF=case report form; 
DNA=deoxyribonucleic acid; EOT=end of treatment (day of last study intervention dose); HBV=hepatitis B virus; HCV=hepatitis C virus; HIV=human 
immunodeficiency virus; IRT=intervention randomization system; LFU=Late Follow-Up; MOV=molnupiravir; NIAID=National Institute of Allergy and 
Infectious Diseases; NP=nasopharyngeal; rand=randomization; RNA=ribonucleic acid; RT-PCR=reverse transcription polymerase chain reaction; 
SAE=serious adverse event; SARS-CoV-2=severe acute respiratory syndrome coronavirus 2; WOCBP=women of childbearing potential.
a
Eligible participants (household contacts of index cases) who do not have confirmed or suspected COVID-19 at the time of screening and randomization 
will be randomized within 5 days of both the time of sample collection for the index case’s first detectable SARS-CoV-2 test result and time of onset of the 
index case’s COVID-19 symptoms.
b
Screening and Day 1 (randomization) may occur on the same day. Study assessments should not be duplicated if screening and Day 1 (randomization) are 
completed on the same day. Blood collection for central laboratory evaluation is still required if local laboratory evaluation is conducted.
c
Participants should contact study personnel if they develop 1 or more symptoms of suspected COVID-19 (as listed in the Symptom Diary) at any time 
through Day 29. If a participant reports qualifying symptoms of suspected COVID-19 (see Section 8.2.2), a COVID-19 Confirmation Visit should be 
scheduled to occur as soon as possible, but within 3 days of symptom onset (see Section 8.2.3). A participant may have more than one COVID-19 
Confirmation Visit.
d
If circumstances do not support a clinic visit, a home visit or visit to an alternate site may be performed, if allowed by local regulations. In the case of a 
home visit or visit to an alternate site, all indicated study procedures should be completed, including NP swab collection for SARS-CoV-2 RT-PCR testing
and blood collections. The procedures may be conducted by site personnel or their medically qualified designee, as applicable.
e
When a virtual visit is designated, a clinic or home visit/visit to alternate site is not required. The choice to conduct a virtual visit, rather than a clinic or 
home visit/visit to an alternate site, is at the investigator’s discretion.
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Study Period:
Screening
Intervention
Follow-up
Notes
Visit Number/Name:
1 a,b
2 a,b
3
4
5
6
COVID-19 
Confirmation 
Visit c
Scheduled Day (Window)
(≤5 days prior 
to rand)
Day 1
Day 5
(+2 days)
EOT
Day 14
(+3 days)
Day 21
(+3 days)
Day 29
(+3 days)
LFU
Type of Visit
C d
C d
C d
C d
V e
C d
C d
C = Clinic Visit
V = Virtual Visit
f
Leftover isolates from NP swab will be stored for future biomedical research if the participant provides documented informed consent; see Section 8.10.
g
In participants with reported history of HBV or HCV, ALT and AST must be available within 5 days prior to administration of the first dose of study 
intervention to support determination of eligibility. In WOCBP, a negative local pregnancy test is required within 24 hours prior to administration of the 
first dose of study intervention per inclusion criteria. All other inclusion/exclusion criteria determination (eg, HIV status) can be based on participant-
reported medical history, available medical records, and the most recently available laboratory results for the participant (eg, HIV RNA viral load). See 
Appendix 7 for country-specific requirements.
h
Local laboratory assessment of protocol-required safety laboratory assessments (chemistry, hematology, and pregnancy) may be permissible under 
extenuating circumstances. Sponsor approval must be obtained, and results must be recorded in the appropriate case report form. Blood collection should 
take place predose at Day 1 visit.
i
Leftover serum will be stored for future biomedical research if the participant provides documented informed consent; see Section 8.10.
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1.3.2
Schedule of Activities for Index Cases
Study Period:
Screening
Intervention
Notes
Visit Number/Name:
1
2
Scheduled Day (Window)
(≤5 days prior to 
randomization of 
participant[s] a)
Day 1
Type of Visit
C b/V c
N/A
C = Clinic Visit
V = Virtual Visit
Administrative Procedures
Informed Consent/Assent
X
Documented informed consent/assent must be provided. See Section 8.1.1.
Register Study Visit in IRT
X
Study Allocation
X
Each index case will receive an allocation number. They will not be 
randomized to receive study intervention.
Report Current (and Any Prior) 
COVID-19 Diagnosis Information and 
Date of COVID-19 Onset
X
See Section 8.1.2 and Section 8.1.4.
Report Prior COVID-19 Vaccination 
and All COVID-19 Medications
X
See Section 8.1.5.1.
NP or OP Swabs for Viral 
Testing/Quantification
X
Optional NP or OP swab may be collected at the time of screening. Note: 
Test is separate from the first detectable SARS-CoV-2 test result required 
for index cases prior to randomization of participants (Section 5.1).
NP swab is preferred; however, OP swabs are acceptable for index cases 
only.
COVID-19=coronavirus disease 2019; IRT=intervention randomization system; N/A=not applicable; NP=nasopharyngeal; OP=oropharyngeal; 
rand=randomization; SARS-CoV-2=severe acute respiratory syndrome coronavirus 2
a
The participant(s) is the household contact(s) of the index case.
b
If circumstances do not support a clinic visit, a home visit or visit to an alternate site may be performed, if allowed by local regulations. In the case of a 
home visit or visit to an alternate site, all indicated study procedures should be completed. The procedures may be conducted by site personnel or their 
medically qualified designee, as applicable.
c
For index cases who do not provide documented informed consent/assent for the optional NP or OP swab for viral testing/quantification, a virtual visit may 
be conducted. Documented informed consent/assent (as indicated in the Schedule of Activities) must be provided for data collection from these individuals.
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2
INTRODUCTION
MOV (also known as molnupiravir [rINN] or MK-4482; formerly EIDD-2801) is a novel 
ribonucleoside analog prodrug with broad-spectrum antiviral activity against a range of RNA 
viruses, including coronaviruses. MOV is being developed as an oral prophylactic for 
COVID-19 (laboratory-confirmed SARS-CoV-2 infection with symptoms) in initially 
asymptomatic individuals ≥18 years of age residing with a person with COVID-19 (defined 
as the index case).
2.1
Study Rationale
COVID-19, a disease resulting from SARS-CoV-2 infection, was declared a global pandemic 
by the WHO on 11-MAR-2020. Within 4 months of that declaration, there were over 11 
million cases of COVID-19 reported globally and more than 500,000 associated deaths 
[World health Organization 2020]. As of early JUN 2021, more than 170 million confirmed 
cases of SARS-CoV-2 infection and over 3.5 million COVID-19-related deaths have been 
reported globally [Johns Hopkins University & Medicine 2021]. SARS-CoV-2 variants of 
concern (ie, B.1.1.7, B.1.351, or P1) have been associated with gradual increase in the 
frequency of global COVID-19 cases and hospitalizations observed since late 2020 in 
Western Europe and South Africa, and early 2021 in the US [Kirby, T. 2021] [Lauring, A. S. 
2021]. There is a high unmet medical need for new, effective therapies and prophylactics.
Household contacts living with a SARS-CoV-2-infected individual are at elevated risk of 
developing COVID-19 due to their extended close proximity with this individual who is 
shedding virus. Estimates of the secondary attack rate (ie, risk of onset of COVID-19) for 
household contacts vary widely between individual studies, but 2 meta analyses have 
generated pooled estimates of approximately 17.1% and 18.1% [Fung, H. F., et al 2020] 
[Koh, W. C., et al 2020]. This relatively high secondary attack rate, combined with the 
known risks of poor outcome associated with COVID-19 [Richardson, S., et al 2020], 
supports the development of drugs for postexposure prophylaxis for close contacts of an 
index case.
Notably, while asymptomatic index patients have been documented to contribute to SARS-
CoV-2 spread, estimates of secondary attack rates for symptomatic individuals are markedly 
higher than for asymptomatic individuals as demonstrated by a relative risk of 3.23 (95% CI: 
1.46, 7.14) [Luo, L., et al 2020] [Koh, W. C., et al 2020]. Data also suggest a higher 
vulnerability among the elderly population compared with other household members 
[Madewell, Z. J., et al 2020]. Emerging evidence on secondary attack rates in the 
transmission of SARS-CoV-2 infection presents a compelling case that asymptomatic and 
presymptomatic individuals are the major drivers of the COVID-19 pandemic and argues for 
reassessment of public health strategies. Targeted antiviral prophylaxis for household 
residents of the index case, with the aim to lessen human-to-human transmission, is one 
prevention strategy that has not been fully explored in reducing the public health burden 
associated with SARS-CoV-2 infection. For these reasons, the population selected for this 
study comprises asymptomatic housemates of individuals with COVID-19.
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Although multiple vaccines are currently being distributed and a global effort is underway to 
vaccinate the population as rapidly as possible, chemoprophylaxis is anticipated to remain an 
ongoing need. Clinical data have suggested very high rates (>90%) of efficacy for at least 
some of the available vaccines, whereas others have shown lower efficacy rates, particularly 
for preventing mild disease [Baden, L. R., et al 2021] [Voysey, M., et al 2021] [Polack, F. P., 
et al 2020]. Additionally, emerging variants are appearing, such as the B.1.351 variant 
identified in South Africa, which has been shown to be poorly neutralized by antispike 
monoclonal antibodies and convalescent serum [Wibmer, C. K., et al 2021]. Recent evidence 
has suggested that vaccine protection may be reduced, perhaps substantially, against this 
variant [Kustin, T., et al 2021]. Based on its mechanism of action (Section 2.2.1), MOV is 
expected to remain active against emerging SARS-CoV-2 spike protein variants capable of 
evading monoclonal antibodies and vaccine-induced immunity. Therefore, MOV may be an 
effective means to prevent illness after exposure to SARS-CoV-2, including SARS-CoV-2 
variants with spike gene mutations for which current vaccines may not provide protection.
MOV is a novel drug candidate with demonstrated activity against SARS-CoV-2 in vitro, 
efficacy against coronaviruses in animal models, and a high barrier to viral resistance. MOV 
has been generally safe and well tolerated to date in completed and ongoing clinical studies 
for treatment of COVID-19 in adults. In this study, the safety and efficacy of MOV for 
prophylaxis against COVID-19 in participants residing in the same household with 
individuals with COVID-19 will be evaluated.
2.2
Background
Refer to the IB for detailed background information on MOV.
2.2.1
Pharmaceutical and Therapeutic Background
MOV is a novel, broadly active, direct-acting antiviral that has been shown to inhibit 
replication of viral pathogens from multiple RNA virus families in vitro, including the highly 
pathogenic coronaviruses (SARS-CoV-2, MERS-CoV), as well as influenza virus, RSV, 
filoviruses, flaviviruses, chikungunya virus, and alphaviruses. The prodrug is orally 
administered and rapidly absorbed in the gut where it is hydrolyzed to the parent nucleoside 
analog β-D-N4-hydroxycytidine (NHC), which is widely distributed to tissues (including 
lungs and brain) and metabolized to the pharmacologically active triphosphate form 
(NHC-TP). The NHC-TP is incorporated into the viral RNA by the viral RNA polymerase, 
leading to an inhibition of viral replication by error catastrophe. Viral error catastrophe, a 
concept that is predicated on increasing the viral mutation rate beyond a 
biologically tolerable threshold, results in impairment of viral fitness leading to viral 
extinction. This mechanism is distinct from that of remdesivir where its incorporation into 
nascent RNA results in premature termination of RNA synthesis, halting growth of the RNA 
strand after a few more nucleotides are added [Gordon, C. J., et al 2020].
NHC has demonstrated a high barrier to the development of resistance in vitro that is 
anticipated to slow or prevent emergence of viral resistance in humans. NHC has also 
demonstrated in vitro activity against remdesivir-resistant SARS-CoV-2 and a related
coronavirus (mouse hepatitis virus) with F476L and V553L mutations in the viral RNA 
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polymerase (RdRp). Given the unique mechanism of action, NHC is expected to be active 
against viruses resistant to other antiviral agents as well as emerging SARS-CoV-2 variants 
of concern with spike protein mutations.
MOV is unlikely to be a victim or perpetrator of CYP-related DDIs based on its anticipated 
metabolic pathways and lack of CYP inhibition/induction in vitro. A DDI between MOV and 
remdesivir is also not expected, given these 2 prodrugs are cleaved in distinct locations (gut 
versus target cells) and the exposure of their active triphosphate metabolites in cells are 
regulated by different enzymes in 2 distinct nucleotide pathways (pyrimidine versus purine).
To evaluate possible interactions of approved antiviral drugs on the activity of MOV, in vitro 
drug-drug combination studies were performed. SARS-CoV-2 infected Vero cells were 
treated with NHC (MOV parent) in combination with other antiviral drugs including 
remdesivir, tenofovir, lamivudine, emtricitabine, abacavir, nelfinavir, ribavirin, sofosbuvir, 
and hydroxychloroquine, and antiviral activity and cellular toxicity were assessed. Results 
demonstrated no significant interaction (synergistic or antagonistic) of any drug tested on the 
antiviral activity or toxicity profile of NHC in this culture system.
2.2.2
Preclinical and Clinical Studies
Refer to the IB for information on preclinical and clinical studies conducted with MOV.
2.2.3
Clinical Studies
2.2.3.1
Completed Clinical Studies
The following clinical studies are either complete or clinically complete; further details are 
provided in the IB.

MK-4482-004 (EIDD-2801-1001; NCT04392219) was a Phase 1, randomized, double-
blind, placebo-controlled SAD/MAD study to evaluate the safety, tolerability, and PK of 
MOV in healthy adult male and female (nonchildbearing potential) participants [Painter, 
W. P., et al 2021]. This study is complete; a total of 130 healthy participants were 
enrolled, of whom 100 received at least 1 dose of MOV orally (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). MOV was generally well tolerated. No deaths or SAEs were 
reported. One participant discontinued from study treatment after receiving 
MOV 800 mg Q12H for 3 days (6 doses) due to an AE of mild rash, considered related to 
study treatment by the investigator. No clinically meaningful hematological laboratory 
test result abnormalities were observed. Overall, no clinically meaningful trends were 
observed for changes in clinical laboratory values, vital signs, or ECGs as a function of 
dose or treatment.
Results indicate linear PK that is dose-proportional, with single-dose PK exposure 
predictive of multidose exposure. No accumulation was observed following multiple 
doses. The nucleoside metabolite (NHC) has a short effective plasma half-life (~1 hour), 
which results in minimal accumulation after multiple dosing with a longer terminal phase 
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characterized by a half-life of up to ~19 hours. MOV can be dosed without regard to
food; no significant food effect was observed with a single MOV 200-mg dose.

MK-4482-006 (EIDD-2801-2003; NCT04405570) 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 study is complete. A 
total 204 participants were randomized; of these participants, 140 received at least 1 dose 
of MOV (23 in the 200 mg BID group, 62 in the 400 mg BID group, and 55 in the 
800 mg BID group) and 62 received placebo. Virology data from this study showed a 
reduction in recovery of infectious virus in MOV-treated participants compared with 
placebo recipients at Day 5. MOV was generally well tolerated with a comparable
incidence of AEs across the intervention groups. The most frequently reported AEs
(>2%) in the MOV groups combined were headache (4.3%), ALT increased (2.9%),
insomnia (2.9%), dizziness (2.1%), and AST increased (2.1%). The most frequently 
reported AEs (>2%) in the placebo group were insomnia (6.5%), headache (4.8%), and 
ALT increased (3.2%). There were no drug-related AEs leading to study intervention 
discontinuation, no deaths, no drug-related SAEs, and no drug-related Grade 3 or higher 
AEs.

Two Phase 2/3 randomized, double-blind, placebo-controlled studies are now clinically 
complete in hospitalized (MK-4482-001; MOVe-IN) and nonhospitalized (MK-4482-
002; MOVe-OUT) adults with COVID-19 to evaluate the efficacy, safety, and PK of 
MOV (Q12H for 5 days). Enrollment in Part 1 (Phase 2) of each of these studies has been 
completed, as well as Part 2 (Phase 3) of study MK-4482-002. A summary of interim 
data from MK-4482-001 and MK-4482-002 that supports dose selection for MK-4482-
013 is provided in Section 4.3.1 of this protocol. Summaries of safety data for MK-4482-
001 and MK-4482-002 are provided below.

MK-4482-001 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. The overall safety profiles observed in P001 were generally 
comparable for MOV doses and placebo. No trends in AEs or changes in clinical 
laboratory values were observed as a function of dose or study intervention. The most 
frequently reported AEs (≥5%) in any MOV group were COVID-19, AST/ALT
elevations, constipation, bacterial pneumonia, hyperglycemia, and respiratory failure. The 
most frequently reported AEs (≥5%) in the placebo group were constipation, COVID-19, 
COVID-19 pneumonia, ALT increased, and respiratory failure. SAEs were reported for 
15.4% participants (15.1% participants in the MOV groups combined and 16.0% in the 
placebo group). One drug-related (as per investigator) SAE (Grade 3 urticaria) was 
reported for 1 participant (MOV 200 mg). A total of 16 participants had AEs leading to 
death (6.4% in the MOV groups combined and 2.7% in the placebo group). Most deaths 
occurred in participants who had severe COVID-19 at baseline (12 of 16), were >60 
years of age (13 of 16), had underlying comorbidities (14 of 16), and/or had duration of 
COVID-19 symptoms >5 days before randomization (12 of 16). None of the deaths were 
considered drug-related per investigator assessment. The study was stopped due to lack 
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of clinical benefit in this population (participants already hospitalized prior to 
randomization) and did not proceed to Part 2.

MK-4482-002 Part 1: A total of 225 nonhospitalized participants with COVID-19 
received at least 1 dose of MOV (74 received at least 1 dose of MOV 800 mg) and 74 
participants received placebo in the APaT population. The safety profiles for MOV (all 
doses) and placebo were comparable. No trends in AEs or changes in clinical laboratory 
values were observed as a function of dose or study intervention. The most frequently 
reported AEs (≥5%) were COVID-19 pneumonia in any MOV group and diarrhea and 
COVID-19 in the placebo group. The percentage of participants with drug-related AEs 
per the investigator was comparable across all intervention groups. SAEs were reported 
for 3.6% participants in the MOV combined group and for 5.4% participants in the 
placebo group. No SAEs were considered drug-related per investigator. Efficacy data are 
summarized in Section 4.3.1.

MK-4482-002 Part 2: a total of 1411 nonhospitalized participants with COVID-19 
received at least 1 dose of study intervention and were included in the APaT population 
(710 participants in the MOV group and 701 in the placebo group). The percentage of 
participants with at least 1 AE was comparable between the MOV and placebo groups 
(30.4% and 33.0% participants, respectively). The observed percentages of participants 
with SAEs, SAEs leading to discontinuation of study intervention, and AEs leading to 
death were lower in the MOV group compared with the placebo group. AEs leading to 
death were reported for 2 (0.3%) participants in the MOV group and 12 (1.7%) 
participants in the placebo group. No participant in the MOV group had laboratory values 
that met the predefined ECI criteria for potential DILI or for platelet count of <50,000 
cells/μL). In this study, treatment with MOV was shown to significantly reduce the risk 
of hospitalization or death through Day 29. These results are described in Section 2.3.
2.2.3.2
Ongoing Clinical Studies
The following clinical studies are ongoing; further details are provided in the IB.

MK-4482-005 (AGILE-ACCORD CST-2 EIDD-2801) is an ongoing Phase 1/2 
randomized, adaptive design study to evaluate the safety, and efficacy of MOV for the 
treatment of adults with COVID-19. Enrollment in the Phase 1 component of the study is 
complete; 18 participants were randomized in a 4:2 ratio in 3 dosing cohorts
(6 participants each) and received MOV 300, 600 or 800 mg or control (standard of care)
Q12H for 5 days. The incidence of AEs in participants who received MOV across the 3 
cohorts was low. As of 18-SEP-2021, 114 of 180 participants have been enrolled in the 
Phase 2 component of the study and received MOV (800 mg) or placebo Q12H for 5 
days. Five participants (4.4%) had SAEs (considered related to study intervention by the 
investigator for 2 participants). No deaths were reported.
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
MK-4482-007 (EIDD-2801-2004; NCT04405739) is an ongoing Phase 2a, randomized, 
double-blind, placebo-controlled study to evaluate the safety, tolerability, and efficacy of 
5 days of MOV in hospitalized adults with COVID-19. As of 18-SEP-2021, 65 of 
80 participants were enrolled and received 200 mg or 400 mg MOV or placebo Q12H for 
5 days. Ongoing Sponsor review of blinded clinical and laboratory data indicate that 
MOV is generally well tolerated. No significant safety concerns were observed based on 
the second interim analysis (n=52). There was 1 AE leading to discontinuation which was 
considered related to study medication. SAEs were reported for 4.6% of participants; 
none were considered related to study intervention by the investigator. One participant 
had an AE leading to death (not related to study intervention per investigator assessment). 
No participant experienced a Grade 3 elevation of lipase or a platelet count <50,000 
cells/µL.
2.3
Benefit/Risk Assessment
MOV has demonstrated activity against SARS-CoV-2 in vitro, efficacy against coronaviruses 
in animal models, and a high barrier to viral resistance in vitro. Data from Phase 2 studies in 
participants with COVID-19 have shown that treatment with MOV results in an antiviral 
effect, including reduction in viral load and in infectious virus as well as a higher percentage 
of mutations in viral RNA posttreatment consistent with the mechanism of action (ie, viral 
error catastrophe). An interim analysis (IA4) for study MK-4482-002 evaluated efficacy in 
762 nonhospitalized participants with mild to moderate COVID-19, with at least 1 risk factor 
for severe disease. These results showed that the percentage of participants who were 
hospitalized or died through Day 29 in the MOV group (7.3%) was statistically significantly 
lower than in the placebo group (14.1%). Treatment with MOV resulted in a 6.8 percentage 
point reduction [95% CI: -11.3, -2.4; p=0.0012] in the risk of hospitalization or death through 
Day 29 compared with placebo (approximately 50% relative risk reduction). MOV met the 
protocol-defined criterion (one-sided p-value boundary <0.0092 at the IA4 timepoint) for 
demonstration of superiority to placebo for the primary efficacy endpoint. All 8 participants 
who died through Day 29 were in the placebo group and were hospitalized prior to their 
death. No participants in the MOV group died. In adults with mild to moderate COVID-19, 
treatment with MOV 800 mg Q12H for 5 days is superior to placebo in reducing 
hospitalization or death within 29 days of initiating study intervention. The study was 
stopped due to early efficacy at the interim analysis, but additional participants already 
enrolled were followed up to completion. An efficacy analysis that included the full 
randomized population (N=1408) was supportive of the earlier results, with the percentage of 
participants who were hospitalized or died through Day 29 in the MOV group being lower 
than in the placebo group (6.8% vs 9.7%, difference -3.0%, 95% CI: -5.9, -0.1; p=0.0218). 
Of the 10 participants who died through Day 29, 9 were in the placebo group versus 1 in the 
MOV group.
As noted in Section 2.1, individuals living with a person with COVID-19 are at elevated risk 
of becoming infected with SARS-CoV-2 and developing symptoms, which can range from 
mild to severe or even life-threatening disease. Although this study is designed to evaluate 
efficacy for prevention of COVID-19 and no clinical benefit can be guaranteed, preclinical 
and clinical data support the hypothesis that a short prophylactic regimen of MOV may 
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provide benefit to asymptomatic household members by reducing their likelihood of 
developing COVID-19.
The integrated assessment of the mutagenic and genotoxic potential of MOV detailed in the 
IB indicates that MOV is not mutagenic or genotoxic in in vivo mammalian systems. Based 
on the totality of the genotoxicity data, MOV is of low risk of genotoxicity in clinical use. 
MOV was devoid of effects on CNS, respiratory, or cardiovascular functions in well-
characterized safety pharmacology models. Key target organs of toxicity identified in the 
GLP repeat-dose toxicity studies were limited to bone marrow in dogs only, and bone and 
cartilage in rats only.
In a 28-day repeat-dose toxicity study of MOV in dogs, mild hematologic toxicity was noted 
after Day 7 at exposures with a NOAEL (6 mg/kg/day) 0.13-fold the anticipated clinical 
exposure of the 800 mg Q12H dose. These changes were fully reversible. No clinically 
significant abnormalities in hematological laboratory tests as a function of either dose or 
treatment were observed in available unblinded data from the clinical development program 
for MOV. For the treatment and prevention of COVID-19 in clinical studies, MOV duration 
is limited to 5 days.
In a 3-month toxicity study in rats, increased thickness of physeal and epiphyseal cartilage
was observed, with the exposure at the lowest observed effect level of 500 mg/kg/day being 
approximately 5.4-fold above the 800 mg Q12H clinical exposure. These findings do not 
represent a risk for adult humans 18 years of age or older because physeal/epiphyseal growth 
cartilage in growing rats is not present in adult humans.
No bone findings were observed in rats dosed for 1 month up to 500 mg/kg/day (female/male 
~4/8-fold above the 800 mg Q12H dose), dogs dosed for up to 14 days at 50 mg/kg/day (1.6-
fold above the human AUC exposure at 800 mg Q12H), or rasH2 wild-type mice dosed at 
2000 mg/kg/day (18-fold above the human AUC exposure at 800 mg Q12H).
EFD studies in rats with MOV demonstrated test article-related postimplantation losses; fetal 
abnormalities (malformations and variations) and evidence of growth delay at 
1000 mg/kg/day (7.5-fold relative to the human AUC exposure at 800 mg Q12H); and 
reduced fetal growth at 500 mg/kg/day (2.9-fold relative to human AUC exposure at 800 mg
Q12H). In the definitive EFD study in rabbits, MOV-related developmental toxicity occurred 
at 750 mg/kg/day (18-fold relative to the human AUC exposure at 800 mg Q12H) and was 
limited to reduced mean fetal body weights. In WOCBP, a sensitive test will be used to rule 
out pregnancy prior to study enrollment, and adherence to highly effective contraceptive 
measures will be required for 4 days (5 plasma half-lives of NHC) after receiving the last 
dose of study intervention.
A total of 1393 adults received at least 1 dose of MOV in P002 (Parts 1 and 2), P006, P001, 
and P004. Of these, 917 participants received at least 1 dose of MOV 800 mg in a dosing 
regimen of Q12H for 5 days. MOV (800 mg Q12H for 5 days) was generally well tolerated 
with no major safety concerns identified. There was no evidence of hematologic toxicity for 
MOV doses ranging between 200 mg and 800 mg Q12H for 5 days based on laboratory 
evaluations.
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Additional details regarding specific benefits and risks for participants in this clinical study 
may be found in the IB and informed consent documents. It cannot be guaranteed that 
participants in clinical studies will directly benefit from treatment during participation 
because clinical studies are designed to provide information about the safety and 
effectiveness of an investigational medicine.
Given the antiviral activity of MOV, the anticipated short duration of treatment (5 days), and 
the totality of available preclinical and clinical data, MOV is considered to have a 
benefit/risk profile that supports further clinical development as a potential prophylactic for 
laboratory-confirmed COVID-19.
3
HYPOTHESES, OBJECTIVES, AND ENDPOINTS
Hypotheses are aligned with objectives in the Objectives and Endpoints table.
Objectives will be evaluated in participants ≥18 years of age who do not have confirmed or 
suspected COVID-19 at the time of screening and randomization and are residing with an 
individual (of any age) with COVID-19 (laboratory-confirmed SARS-CoV-2 infection with 
symptoms), defined as the index case.
Objectives
Endpoints
Primary
•
To evaluate the efficacy of molnupiravir 
(MOV) compared with placebo for the 
prevention of laboratory-confirmed 
COVID-19 through Day 14 in 
participants with undetectable 
SARS-CoV-2 in baseline nasopharyngeal 
(NP) swabs.
•
Hypothesis: MOV is superior to placebo 
for the prevention of laboratory-
confirmed COVID-19 through Day 14 in 
participants with undetectable SARS-
CoV-2 in baseline NP swabs.
•
COVID-19 (laboratory-confirmed 
SARS-CoV-2 infection with 
symptoms)
•
To evaluate the safety and tolerability of 
MOV compared with placebo.
•
Adverse events
•
Adverse events leading to 
discontinuation of study intervention
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Objectives
Endpoints
Secondary
•
To evaluate the efficacy of MOV
compared with placebo for the prevention 
of laboratory-confirmed COVID-19 
through Day 14 in participants regardless 
of SARS-CoV-2 results in baseline NP 
swabs.
•
Hypothesis: MOV is superior to placebo 
for the prevention of laboratory-
confirmed COVID-19 through Day 14 in 
all participants regardless of SARS-CoV-
2 results in baseline NP swabs.
•
COVID-19 (laboratory-confirmed 
SARS-CoV-2 infection with 
symptoms)
•
To evaluate the efficacy of MOV 
compared with placebo for the prevention 
of laboratory-confirmed COVID-19 
through Day 29 in participants with 
undetectable SARS-CoV-2 in baseline 
NP swabs.
•
COVID-19 (laboratory-confirmed 
SARS-CoV-2 infection with 
symptoms)
•
To evaluate prevention of viral 
transmission through Day 14 for MOV 
compared with placebo in participants 
with undetectable SARS-CoV-2 in 
baseline NP swabs.
•
SARS-CoV-2 RNA
•
To evaluate the efficacy of MOV 
compared with placebo for the prevention 
of laboratory-confirmed COVID-19 
through Day 14 in participants with 
detectable SARS-CoV-2 in baseline NP 
swabs.
•
COVID-19 (laboratory-confirmed 
SARS-CoV-2 infection with 
symptoms)
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Objectives
Endpoints
Exploratory
•
To evaluate the efficacy of MOV 
compared with placebo for the prevention 
and laboratory-confirmed COVID-19 
through Day 29 in participants regardless
of SARS-CoV-2 results in baseline NP 
swabs.
•
COVID-19 (laboratory-confirmed 
SARS-CoV-2 infection with 
symptoms)
•
To evaluate the prevention of viral 
transmission through Day 29 for MOV 
compared with placebo in participants 
with undetectable SARS-CoV-2 in 
baseline NP swabs.
•
SARS-CoV-2 RNA
•
To evaluate the development of anti-
SARS-CoV-2 antibodies through Day 29 
in MOV recipients compared with
placebo in baseline seronegative 
participants with undetectable SARS-
CoV-2 RNA in baseline NP swabs.
•
Anti-SARS-CoV-2 antibodies
•
To evaluate the severity of laboratory-
confirmed COVID-19 through Day 29 for 
MOV recipients compared with placebo 
recipients.
•
NIAID ordinal scale criteria for 
COVID-19 severity
•
For participants who develop laboratory-
confirmed COVID-19 on or before Day 
14, to describe the severity and/or 
presence of COVID-19 symptoms for 
MOV recipients compared with placebo 
recipients through resolution of 
symptoms or Day 29, whichever is first.
•
Participant-reported symptoms severity 
(for specified COVID-19 symptoms)
•
For participants with detectable 
SARS-CoV-2 in NP swabs at baseline, to 
evaluate the antiviral activity of MOV 
compared with placebo as assessed by the 
change from baseline in SARS-CoV-2 
RNA titer and percentage of participants 
with undetectable SARS-CoV-2 RNA in 
NP swabs at Day 14.
•
Quantitative SARS-CoV-2 RNA
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Objectives
Endpoints
•
For participants who develop laboratory-
confirmed COVID-19 on or before Day 
14, to evaluate the effect of MOV on 
viral RNA mutation rate and detection of 
treatment-emergent sequence variants as 
assessed by comparison of viral gene 
sequencing in virus isolated at baseline 
and post-baseline in samples with 
evaluable SARS-CoV-2 RNA.
•
Viral RNA Sequences
•
For participants who develop laboratory-
confirmed COVID-19 on or before Day 
14, to evaluate the prevention or 
reduction of health care utilization related 
to COVID-19 through Day 29 for MOV 
recipients compared with placebo 
recipients.
•
Medically attended COVID-19
•
To evaluate the impact of MOV on 
generic health-related quality-of-life 
through Day 29 in participants who do 
not have confirmed or suspected COVID-
19 at the time of screening and 
randomization and are residing with an 
individual with COVID-19.
•
EuroQoL Five Dimension 
Questionnaire (EQ-5D-5L) score
4
STUDY DESIGN
4.1
Overall Design
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.
This is a Phase 3, randomized, placebo-controlled, double-blind, multi-site study
(MOVe-AHEAD) to evaluate the efficacy and safety of MOV to prevent COVID-19 in 
participants ≥18 years of age residing with an individual (no age requirement) with 
COVID-19 (defined as the index case). Eligible participants who do not have confirmed or 
suspected COVID-19 at the time of screening and randomization will be randomized within 
5 days of both the time of sample collection for the index case’s first detectable (ie, positive) 
SARS-CoV-2 test result and time of onset of the index case’s COVID-19 symptoms.
All index cases will be requested to provide documented informed consent/assent for the 
collection of specific data regarding the diagnosis and time of onset of COVID-19 as well as 
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demographics, history of prior COVID-19 vaccination, and medication for COVID-19 at the 
time of screening. Index cases will not be randomized to receive study intervention nor have 
any study specific assessments or procedures conducted other than an NP or OP swab 
collected at the time of screening for viral testing/quantification and SARS-CoV-2 genome 
sequencing for genetic lineage identification. This NP or OP swab is not required for 
participation of the household contacts; however, it is highly encouraged for complete 
virologic assessment.
Approximately 1376 participants will be randomized in a 1:1 ratio to receive blinded MOV 
(800 mg) or blinded placebo by oral administration Q12H (±2 hours) for 5 days (Figure 1). 
The primary objective of the study will be assessed in participants who have undetectable 
SARS-CoV-2 in NP swabs at baseline. Assuming approximately 80% of the 1376
participants will have no detectable SARS-CoV-2 at baseline (see Section 4.2.3), 
approximately 1100 participants will have undetectable SARS-CoV-2 at baseline.
Randomization will be stratified by 1) age category (≤60 vs >60 years) and 2) household size 
(≤3 vs >3 household residents; all residents, including the index case, are counted regardless 
of whether they are participating in the study.
All participants will be provided with a Study Medication Diary in which dose administration 
will be recorded daily for 5 days.
Active surveillance will be conducted in this study for onset of symptoms attributable to 
COVID-19 as follows:
•
Participants will monitor themselves for new onset or marked worsening of symptoms 
attributable to COVID-19 through the duration of the study. Participants should be 
reminded by study personnel at weekly visits indicated in the SoA (Section 1.3.1) to 
actively monitor for symptoms.
•
Participants will receive a Symptom Diary in which the presence/absence and severity of 
a solicited list of symptoms attributable to COVID-19 should be recorded daily through 
Day 29 (see Section 8.2.1).
•
Participants will be instructed to contact study personnel if they develop 1 or more
symptoms of suspected COVID-19 (listed in the Symptom Diary) at any time through 
Day 29. If a participant reports qualifying symptoms of suspected COVID-19 (see 
Section 8.2.2), a COVID-19 Confirmation Visit that includes NP swab collection for 
RT-PCR testing at the central laboratory should be scheduled, to occur as soon as 
possible, but within 3 days of symptom onset (see Section 8.2.3).
Participants with an onset of symptoms of COVID-19 during the study may receive standard 
of care treatment for COVID-19, as appropriate, in addition to study intervention 
(Section 6.5). Treatment with MOV, should it become approved for use in the participant’s 
jurisdiction and available for administration, is not permitted for any participant in this study.
(This restriction pertains to participants receiving study intervention, not index cases.)
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The following will also be collected from participants at time points indicated in the SoA 
(Section 1.3.1):
•
Any hospitalizations, for all participants. In the event of hospitalization, all evaluations 
outlined in the SoA (Section 1.3.1) should be performed as feasible.
•
Survival status, for all participants.
•
Health care utilization (ie, medically attended COVID-19) due to COVID-19, for 
participants with laboratory-confirmed COVID-19. Medically attended COVID-19 refers 
to COVID-19 for which medical attention is received during an unscheduled, nonroutine 
visit, such as a telemedicine visit, emergency room visit, an in-person physician office 
visit, an urgent care or emergency department visit, or hospitalization.
•
The EQ-5D-5L questionnaire, for all participants at the Day 1, Day 5, Day 14, and 
Day 29 visits. The EQ-5D-5L is a standardized instrument for measuring health outcome
and will be used in this study to assess the impact of MOV on participant general health 
status.
All AEs, SAEs, and other reportable events (eg, ECI and pregnancy) will be reported 
according to the time period and procedures specified in Section 8.4 and Appendix 3.
Interim Analyses
This study will include an interim analysis when approximately 55% (or approximately 600
across the MOV and placebo groups) of the participants with undetectable SARS-CoV-2 in 
baseline NP swabs have either completed the Day 14 visit or discontinued from the study 
prior to the Day 14 visit. See Section 9.7 for details of the interim analysis. An eDMC will 
review the data at this interim analysis. A description of the structure and function of the
eDMC, along with the timing and content of the interim analysis and any other study data 
review, is provided in the eDMC charter. Information regarding the composition of the 
eDMC is provided in Appendix 1.
4.2
Scientific Rationale for Study Design
Antivirals for prevention of COVID-19 are urgently needed during this unprecedented global 
pandemic. This randomized, placebo-controlled, double-blind, superiority study is designed 
to evaluate the efficacy and safety of MOV compared with placebo for the prevention of 
COVID-19 in household contacts of an individual with COVID-19, in accordance with 
available regulatory guidance [Food and Drug Administration 2021].
The primary outcome is assessed through Day 14 to allow for a sufficient duration to reliably 
assess the efficacy of 5 days of MOV for prophylaxis of COVID-19. This duration of the 
primary outcome assessment is considered appropriate to capture important clinically 
relevant efficacy endpoints (eg, laboratory-confirmed COVID-19), as the reported duration 
of the SARS-CoV-2 incubation period is 2 to 14 days [Guan, W., et al 2020] [Li, Q., et al 
2020] [Lauer, S. A., et al 2020].
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AEs, SAEs, and other reportable safety events will be monitored according to Section 8.4. 
Final Per-Protocol laboratory assessments occur on Day 14 (9 days after the last dose of 
study intervention), which allows for the resolution of any abnormal laboratory values 
identified at the EOT (Day 5). The follow-up time period for the evaluation of safety 
adequately assesses treatment-emergent AEs, as there is no preclinical or clinical evidence 
suggesting delayed toxicity for MOV. 
4.2.1
Rationale for Endpoints
4.2.1.1
Efficacy Endpoints
The primary efficacy endpoint for the study, COVID-19 (laboratory-confirmed SARS-CoV-2 
infection with symptoms), was selected in accordance with the US FDA guidance on 
development of drug and biological products for treatment or prevention of COVID-19 [Food 
and Drug Administration 2021]. Development of symptomatic disease represents a clinically 
meaningful endpoint for participants since it demonstrates the onset of deleterious effects 
they can directly perceive. A COVID-19 case for the study is defined as a participant with 
qualifying symptoms of COVID-19 with onset through Day 14 (for the primary endpoint)
and SARS-CoV-2 detected by central laboratory RT-PCR testing from a sample collected at 
the COVID-19 Confirmation Visit. Laboratory-confirmed COVID-19 with onset through 
Day 29 will also be assessed as an exploratory endpoint. The onset of COVID-19 is 
determined by the day of onset of symptoms, rather than the day of the COVID-19 
Confirmation Visit. Therefore, the day of onset of COVID-19 symptoms supports the 
primary endpoint, even if the day of the COVID-19 Confirmation Visit is later than Day 14. 
The qualifying symptoms of COVID-19 are provided in Section 8.2.2.
The study will evaluate SARS-CoV-2 RNA as a secondary endpoint through Day 14 (and as 
an exploratory endpoint through Day 29) to assess the impact of MOV on preventing viral 
transmission in participants with undetectable SARS-CoV-2 in baseline NP swabs. Viral 
transmission, even in the absence of symptoms, represents an important outcome with 
regards to infection control. This is best evaluated via RT-PCR detection of SARS-CoV-2 
RNA since nucleic acid amplification offers the most sensitive method for assessment of 
viral transmission. For this reason, SARS-CoV-2 RNA has been selected as the appropriate 
endpoint.
For participants with laboratory-confirmed COVID-19, the severity of disease will be 
assessed using the NIAID ordinal scale for COVID-19 severity [Beigel, J. H., et al 2020]; see 
Section 8.2.10. The severity endpoint (exploratory) is included since it is conceivable that 
prophylactic treatment may be more effective at preventing onset of more severe disease than 
preventing the onset of symptomatic disease of any severity, particularly as some participants 
will enter the study with a detectable test for SARS-CoV-2 at baseline that is identified 
postrandomization. While most severity scales include criteria (eg, oxygen saturation criteria) 
that are not readily ascertained in an outpatient population living at home, the criteria for 
severe disease described in the NIAID ordinal scale include hospitalization as a basic 
criterion for moderate to severe disease, with an additional set of criteria (eg, supplemental 
oxygen requirements) to further delineate severity. These features of the NIAID ordinal scale 
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criteria for defining disease severity are readily applicable to a population that is mostly
outpatient.
In addition to severity of disease, severity of symptoms will be collected from participants in 
the Symptom Diary to examine potential differences between prophylaxis with MOV or 
placebo, since prophylaxis may be more effective in preventing severe symptoms than in 
preventing the onset of any symptoms at all.
4.2.1.2
Safety Endpoints
Safety evaluations include AE collection, physical examinations (including vital signs), and 
laboratory tests (hematology and chemistry) performed per the SoA (Section 1.3). AEs will 
be evaluated and assessed according to the guidelines in Section 8.4 and Appendix 3. 
Participants may be asked to return for unscheduled visits to perform additional safety
monitoring.
In the 28-day toxicity study of MOV at 17 mg/kg/day (0.4-fold relative to the clinical NHC 
exposure at 800 mg Q12H) administered to dogs, reversible hematologic changes consistent 
with bone marrow toxicity were noted on Day 7, which progressed to more severe 
pancytopenia after 14 to 21 days of continuous exposure. No clinically significant 
abnormalities in hematological laboratory tests as a function of either dose or treatment were
observed in available unblinded data from the clinical development program for MOV. 
However, based on preclinical findings, participants in this study will be monitored for any 
signs of bone marrow toxicity, including monitoring of CBC and platelets after initiating 
study intervention.
In preclinical studies, elevated liver enzymes were noted in rats at 61-fold (female) and 
91-fold (male) over the clinical NHC exposure at 800 mg Q12H and dogs at 19-fold over the 
clinical NHC exposure at 800 mg Q12H. No clinically significant abnormalities in liver 
parameters as a function of either dose or treatment were observed in available unblinded 
data from the clinical development program for MOV. However, elevated LFTs meeting 
criteria for potential DILI will be considered an ECI and closely monitored.
4.2.1.3
Virology Endpoints
The proposed exploratory virologic endpoints are aimed at assessing the antiviral activity of 
MOV as well as evaluating the rate of viral mutagenesis with respect to MOV treatment.
Reducing SARS-CoV-2 viral load or eradicating the virus is essential to recovery and has 
important implications for transmission and infection control strategies. As a direct-acting 
antiviral, the inclusion of an exploratory endpoint evaluating the change in viral RNA titer 
from baseline after treatment with MOV is meaningful and consistent with the mechanism of 
action. Note that after randomization, some participants may be identified to have been 
detectable for SARS-CoV-2 at baseline; analyzing a transition to viral positivity is only 
meaningful in the subset of the population that is undetectable at baseline. For participants 
who are virus-detectable at baseline, viral quantitation can only be used to demonstrate and 
compare changes in viral titer after treatment.
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In addition to a means of assessing the rate of viral mutagenesis, viral genome sequencing 
will be used to identify SARS-CoV-2 genetic lineage. Since initial identification of the 
original SARS-CoV-2 genotype, multiple viral variants of concern have been identified and 
continue to circulate worldwide. SARS-CoV-2 genotype data may be used to assess the 
impact of viral genotype on MOV efficacy. In addition, viral sequence data may be used to 
identify treatment-emergent variants that could potentially impact vaccine or antiviral drug 
efficacy and to further characterize the mechanism of action (viral error catastrophe) of 
MOV.
4.2.1.4
Serology Endpoints
Although samples for virologic testing are collected at baseline and multiple timepoints 
post-baseline, there is potential, especially in the case of asymptomatic infection, that 
transient infections with SARS-CoV-2 may occur in between planned sampling timepoints. 
These infections can be inferred from development of antibodies toward SARS-CoV-2. For 
this reason, in addition to virologic endpoints, an exploratory serologic endpoint is included.
4.2.1.5
Health Care Utilization and Health Outcomes
Health care utilization and health outcomes will be measured as exploratory endpoints in this 
study. Health care utilization information (ie, medically attended COVID-19, as defined in 
Section 4.1) will be assessed both as an indirect marker of severity (with hospitalization as 
part of the criteria in the NIAID ordinal scale for severity assessment in Section 8.2.10), and 
for a potential reduction in health care resource utilization from prophylaxis to asymptomatic 
individuals at high risk of acquiring COVID-19.
The EuroQoL EQ-5D-5L is a validated, standardized, 5-item health-state questionnaire 
applicable to a wide range of health conditions and treatments and used to assess health 
outcomes [The EuroQol Group 1990] [Brooks, R. 1995] [Herdman, M., et al 2011]. The 5 
health-state dimensions include: mobility, self-care, usual activities, pain/discomfort, and 
anxiety/depression. Each dimension has 5 levels: no problems, slight problems, moderate 
problems, severe problems, and extreme problems. The recall period is today. The EuroQoL
EQ-5D-5L also includes a graded (0 to 100) 20 centimeter vertical visual analog scale (EQ 
VAS) on which subjects rate their current general state of health, from “the worst health you 
can imagine” to “the best health you can imagine.” The EuroQoL EQ-5D-5L provides a 
simple descriptive profile and a single index value for health status that can be used to 
develop health utilities or ”quality adjusted life years” for health economic analyses.
4.2.1.6
Future Biomedical Research
The Sponsor will conduct FBR on specimens for which consent was provided during this 
study. This research may include genetic analyses (DNA), gene expression profiling (RNA), 
proteomics, metabolomics (serum, plasma), and/or the measurement of other analytes, 
depending on which specimens are consented for FBR.
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 
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participants. The objective of collecting/retaining specimens for FBR is to explore and 
identify biomarkers that inform the scientific understanding of diseases and/or their 
therapeutic treatments. The overarching goal is to use such information to develop safer, 
more effective drugs/vaccines, and/or to ensure that participants receive the correct dose of 
the correct drug/vaccine at the correct time. The details of FBR research are presented in
Appendix 6.
4.2.2
Rationale for the Use of Comparator/Placebo
This study will be placebo-controlled to avoid bias in the collection/evaluation of data during 
study conduct and to assess whether any observed effects are treatment-related or an impact 
of study participation. Participants who develop symptoms attributable to COVID-19 may
receive standard of care treatment (as specified in Section 6.5), as appropriate, in addition to 
study intervention (blinded MOV or matching placebo).
There are currently no agents approved for the prevention of COVID-19 to serve as an active 
comparator; therefore, placebo will be used.
4.2.3
Rationale for the Selected Participant Population
Household contacts living with a SARS-CoV-2-infected individual will comprise the 
participant population in this study. As noted in Section 2.1, household contacts are at 
elevated risk of developing COVID-19 due to their extended close proximity with this 
individual who is shedding virus and therefore, are potential candidates for prophylaxis with 
MOV.
In this study, a household is defined as a unit with shared living space(s) with no more than 
10 inhabitants (ie, large communal living arrangements such as dormitories, hostels, 
barracks, and long-term care facilities do not qualify as households). There is no requirement 
that the household residents share a familial relationship.
The primary endpoint is analyzed in those without detectable SARS-CoV-2 virus at baseline
(ie, the Day 1 NP swab; those with detectable virus prior to randomization are ineligible). 
Recent data from a study of household prophylaxis with casirivimab and imdevimab 
[O'Brien, M. P., et al 2021] showed that COVID-19 incidence rates are substantially higher 
in the population that has detectable virus via PCR at baseline than in the population that 
does not have detectable virus at baseline. The viral status is not known at the time of 
randomization due to the duration required for RT-PCR testing. Since randomization cannot
therefore be stratified to assure balance between the arms, the 2 populations will be analyzed 
both separately and together for onset of disease. It is assumed that up to 20% of the enrolled 
population may have detectable virus at baseline, in consideration of the virus-positive (or 
viral status unknown) percentage (16.5%) reported by O’Brien [O'Brien, M. P., et al 2021]
and a conservative adjustment to 20% based on the higher infectivity of more recently 
reported viral variants.
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4.2.4
Rationale for Collection of Racial, Ethnic, and Gender Identity Data
The differential effect on the safety and efficacy based on any demographic parameter, 
including race, ethnicity, or gender identity, cannot be predicted when evaluating a new 
investigational drug. Therefore, it is important to collect race, ethnicity, and gender identity
data to ensure that there is not a differential effect based on these parameters. These data will 
also provide assurance that the results observed in the clinical study will be representative of 
the drug’s use in a broader patient population, including transgender people whose gender 
identities and/or expressions differ from the sex assigned to them at birth. Also, subgroup 
analyses on race and ethnicity will be performed to better understand how these parameters 
may influence clinical outcome and toxicity.
4.2.5
Rationale for Selected Stratification Factors
Household size has a recognized influence on secondary attack rate. Multiple studies have 
demonstrated a decreasing secondary attack rate observed with increasing household size 
[Grijalva, C. G., et al 2020] [Li, F., et al 2021] [Wu, J., et al 2020]. There is some variability 
between studies in whether there is an inflection point in the household size and at what 
household size that inflection point is; however, most show that secondary attack rates drop 
from 30 to 50% or more between small, 2-person households and larger households of 4 or 
more. Therefore, a household size of 3 has been selected as the threshold in this study for 
stratifying the randomization (ie, ≤3 or >3 people).
Advancing age has been noted as a risk factor for COVID-19 incidence as well as severity 
[Li, F., et al 2021] [Luo, L., et al 2020] [Wu, J., et al 2020], with individuals over 55 or 60 
years of age having markedly higher (at least 70% higher) likelihood of acquiring COVID-19 
in household or close contact settings with infected individuals than younger adults. For this 
reason, participant age has been selected as a second stratification variable (ie, ≤60 years or 
>60 years).
4.3
Justification for Dose
4.3.1
Rationale for Dose
The MOV dose for this Phase 3 study (800 mg MOV Q12H for 5 days) was selected based 
on interim data from other studies evaluating MOV for treatment as well as the totality of 
available safety, virology, PK, and clinical data from the MOV program.
The eDMC review of unblinded interim data from MK-4482-001 and MK-4482-002 
concluded that there were no safety signals seen at any dose, and no dose-limiting toxicity 
was observed at the highest dose (800 mg). Furthermore, MOV has been generally well
tolerated in other studies in the MOV program at all doses studied with no dose-limiting 
toxicity observed at the highest dose (800 mg).
Virology data from completed dose-ranging studies in the MOV program (MK-4482-001, 
MK-4482-002, and MK-4482-006) show that treatment with MOV reduces the SARS-CoV-2 
viral load compared with placebo (based on change from baseline, slope of decline, and 
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greater percentage of participants with a viral load below the limit of quantitation within 15 
or 29 days) in nonhospitalized participants enrolled in MK-4482-002 and participants with 
symptom onset ≤5 days in both MK-4482-001 and MK-4482-002. The exposure-response 
analyses for various virologic endpoints based on MK-4482-001 and MK-4482-002 suggest 
that the 800 mg Q12H dose provides a larger magnitude of virologic effect compared with
200 mg and 400 mg Q12H and is near the plateau of the dose response curve. In addition, 
consistent with the proposed mechanism of action of MOV of viral error catastrophe, the 
highest percentage of mutations in viral RNA posttreatment at Day 5 were observed in the 
800 mg Q12H intervention group from MK-4482-001 and MK-4482-002.
Evaluation of the primary clinical efficacy endpoint for the Phase 2 portion of MK-4482-002
showed that 11 of 299 participants were hospitalized through Day 29 (including 1 participant 
treated with placebo who died); ~3% of participants in the MOV intervention groups were 
hospitalized or died through Day 29 (compared with ~5% in the placebo group). Notably, an
exposure-response analyses for the endpoint of hospitalization suggested a trend of an 
increased clinical effect at MOV 800 mg Q12H dose over placebo or lower MOV doses.
Based on the totality of the observed safety profile and virologic data in the MOV program, 
and trends in clinical efficacy in MK-4482-002, the 800 mg Q12H dose was selected as the 
dose for further evaluation in Phase 3.
The expectation of both treatment and prophylaxis of COVID-19 using an antiviral is to 
prevent propagation of the virus; thus, the dose level to be used for both indications is 
proposed as the dose selected for treatment of symptomatic disease.
4.3.2
Rationale for Dosing Duration
A 5-day duration of dosing of MOV is currently under evaluation for the treatment of 
COVID-19 in adults in clinical studies. The planned treatment regimen of 5 days in these 
studies is consistent with other acute antiviral treatments such as oseltamivir for influenza 
and is supported by nonclinical and clinical safety data for MOV. A 5-day duration is 
proposed in MK-4482-013 for prophylaxis of household contacts.
In the 28-day toxicity study of MOV at 17 mg/kg/day (0.4-fold relative to the clinical NHC 
exposure at 800 mg Q12H) administered to dogs, reversible hematology changes consistent 
with bone marrow toxicity became apparent on Day 7 with increasing severity from Day 14 
onward. In a Phase 1 clinical study (MK-4482-004), dosing of MOV up to 800 mg Q12H for 
5.5 days was generally well tolerated by healthy participants. No clinically meaningful trends 
were observed for changes in clinical laboratory values, vital signs, or ECGs as a function of 
dose or treatment. Specifically, there were no clinically significant abnormalities observed in 
the hematological laboratory tests. Furthermore, unblinded data obtained from participants 
treated in the Phase 2 program indicate that MOV has been generally well tolerated across all 
doses studied. Overall, preclinical and Phase 1 and 2 clinical observations to date support a 
~5-day dosing duration for treatment with MOV.
A 5-day duration of dosing of MOV for prophylaxis in household contacts of an individual 
with COVID-19 is further supported from data evaluating viral shedding and symptom onset 
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after SARS-CoV-2 infection. Estimates of the duration of viral shedding (and likely 
infectiousness) have varied widely, and estimation is complicated by the methods used to 
detect and measure viral load. The most facile method is quantitative RT-PCR; however, it is 
recognized that the presence of viral nucleic acid does not correspond directly to presence of 
infectious virus, although high quantities of viral RNA generally correlate with a higher 
likelihood of viable virus [Wolfel, R., et al 2020]. In mild to moderate cases of COVID-19, 
1 small study that evaluated viable virus in 9 patients showed that viral shedding concluded 
within 8 days after the onset of symptoms [Wolfel, R., et al 2020]. Other studies evaluating 
viral RNA loads showed a dramatic drop within the first 5 days after onset of symptoms 
[Kim, S. E., et al 2020], while others showed a more prolonged course [Vetter, P., et al 2020] 
[Yilmaz, A., et al 2021]. A study of COVID-19 infected health care workers, which 
evaluated shedding from symptom onset and 14 days thereafter, found that only 1 of 118 of 
these health care workers was still shedding viable virus 14 days after symptom onset. Of 
note, these studies provide no indication of changes in relative infectiousness with time. 
While virus is still detectable in some cases for more than a week past the onset of 
symptoms, viral RNA titers drop by multiple logs over that time frame and thus may be 
present in insufficient quantities to be effectively transmitted. 
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/assent. The overall study ends when the last 
participant completes the last study-related contact, withdraws consent/assent, or is lost to 
follow-up (ie, the participant is unable to be contacted by the investigator).
4.4.1
Clinical Criteria for Early Study Termination
The clinical study may be terminated early if the extent (incidence and/or severity) of 
emerging effects/clinical endpoints is such that the risk/benefit ratio to the study population 
as a whole is unacceptable. In addition, further recruitment in the study or at (a) particular 
study site(s) may be stopped due to insufficient compliance with the protocol, GCP, and/or 
other applicable regulatory requirements, procedure-related problems or the number of 
discontinuations for administrative reasons is too high.
5
STUDY POPULATION
Male and female participants ≥18 years of age will be enrolled in this study.
Prospective approval of protocol deviations to recruitment and enrollment criteria, also 
known as protocol waivers or exemptions, is not permitted.
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5.1
Inclusion Criteria
A participant will be eligible for inclusion in the study if the participant meets all of the 
following criteria:
Type of Participant and Disease Characteristics
1. The participant is a household contact of an index case. An index case is a person with 
documented COVID-19 (laboratory-confirmed SARS-CoV-2 infection with symptoms 
case) and must have:
a)
A first detectable SARS-CoV-2 test result from a sample collected ≤5 days
prior to randomization of the participant(s), AND
b)
At least 1 of the following symptoms attributable to COVID-19: fever 
≥38.0ºC, chills, cough, sore throat, shortness of breath or difficulty breathing 
with exertion, fatigue, nasal congestion, runny nose, headache, muscle or 
body aches, nausea, vomiting, diarrhea, loss of taste, or loss of smell, with 
symptom onset no earlier than 5 days prior to randomization of the 
participant(s).
Note:

To be considered a household contact, the individual must be currently residing with 
an index case and expect to continue residing with the index case through the 
duration of the study. Thus, the index case should not be hospitalized at the time of 
randomization.

For the SARS-CoV-2 test for the index case, molecular or antigen tests that detect 
viral RNA or protein are allowed if authorized for use in the country. Serological 
tests that detect host antibodies generated in response to recent or prior infection are 
not allowed.

A household may have more than one individual with documented COVID-19 
(laboratory-confirmed SARS-CoV-2 infection with symptoms); however, the 
individual with the earliest evidence of COVID-19 (onset of symptoms or detectable 
SARS-CoV-2 test) is considered the “Index case.” If this criterion does not 
distinguish a single index (ie, more than one individual developed COVID-19 on the 
same day), either individual can consent to participate as the index. As noted in 
Exclusion Criterion 1, other individuals within the household with suspected or 
confirmed COVID-19 cannot be considered household contacts and are ineligible to 
participate in the study.
2. The participant does not have confirmed or suspected COVID-19.
3. The participant is willing and able to take oral medication.
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Demographics
4. The participant is male or female ≥18 years of age, at the time of providing documented 
informed consent.
Male Participants
5. Male participants must agree to be abstinent from penile-vaginal intercourse OR agree to 
use a highly effective contraceptive method while receiving study drug and for at least 3 
months after the last dose of study drug.
Female Participants
6. A female participant is eligible to participate if she is not pregnant or breastfeeding, and 
at least one of the following conditions applies:
•
Is not a WOCBP
OR
•
Is a WOCBP and:
-
Uses a contraceptive method that is highly effective (a low user dependency method 
OR a user dependent hormonal method in combination with barrier method), or be 
abstinent from heterosexual intercourse as their preferred and usual lifestyle 
(abstinent on a long-term and persistent basis), as described in Appendix 5 during the 
intervention period and for at least 4 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 (urine or 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 
8.3.4.
Note: If using a urine pregnancy test, it should be sensitive enough to measure 
25 mIU/mL hCG.
-
Has had her medical history, menstrual history, and recent sexual activity reviewed 
by the investigator to decrease the risk for inclusion of a woman with an early 
undetected pregnancy.
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-
If contraceptives are interrupted in case of standard of care management of 
COVID-19 and resumed at a later time point, such as at hospital discharge, then 
abstinence must be practiced for the defined period of back-up contraception per the 
contraceptive product labeling. After this period, contraceptive use must adhere to 
Appendix 5.
Informed Consent
7. The participant’s index case (or legally acceptable representative of the index case) has 
provided documented informed consent/assent for the collection of COVID-19 
documentation requirements.
Note: There is no age requirement for index cases, and they may be less than 18 years of 
age. Index cases will be offered optional SARS-CoV-2 testing. An index case who opts in 
for this additional test must have had prior documented, laboratory-confirmed 
COVID-19 for eligibility of the household contacts (see Inclusion Criterion #1). Informed 
consent/assent for SARS-CoV-2 testing will be documented.
8. The participant (or legally acceptable representative) has provided documented informed 
consent to participate in the study. The participant may also provide consent for 
participation in FBR, but 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
1. The participant has a prior history of laboratory-confirmed SARS-CoV-2 infection (with 
or without symptoms), within 6 months prior to randomization.
2. The participant has either of the following conditions:

HIV with a recent viral load >50 copies/mL (regardless of CD4 count) or an AIDS-
defining illness in the past 6 months
Note: Participants with HIV may only be enrolled if on a stable antiretroviral therapy
regimen.
3. The participant has a history of HBV or HCV infection with any of the following:

Cirrhosis

End-stage liver disease

Hepatocellular carcinoma
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
AST and/or ALT >3X upper limit of normal at screening
4. The participant has hypersensitivity or other contraindication to any of the components of 
the study interventions as determined by the investigator.
5. The participant has any condition for which, in the opinion of the investigator, 
participation would not be in the best interest of the participant or that could prevent, 
limit, or confound the protocol-specified assessments including, but not limited to
participants with conditions that could limit gastrointestinal absorption of capsule 
contents.
Prior/Concomitant Therapy
6. The participant has received, is taking, or is anticipated to require any prohibited 
therapies as outlined in Section 6.5.
7. The participant has received a COVID-19 vaccine with the first dose 7 days or more prior
to randomization.
Prior/Concurrent Clinical Study Experience
8. The participant is unwilling to abstain from participating in another interventional clinical 
study through Day 29 with an investigational compound or device, including those for 
COVID-19 therapeutics.
Diagnostic Assessments
Not applicable.
Other Exclusions
9. The participant is living in a household of more than 10 people.
10. Is or has an immediate family member (eg, spouse, parent/legal guardian, sibling, or 
child) who is investigational site or Sponsor staff directly involved with this study.
5.3
Lifestyle Considerations
There are no lifestyle restrictions for the study.
5.4
Screen Failures
Screen failures are defined as participants who consent to participate in the clinical study, but 
are not subsequently randomized in the study. A minimal set of screen-failure information is 
required to ensure transparent reporting of screen-failure participants to meet the CONSORT 
publishing requirements and to respond to queries from regulatory authorities. Minimal 
information includes demography, screen-failure details, eligibility criteria, and any AEs or 
SAEs meeting reporting requirements as outlined in the data entry guidelines.
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5.5
Participant Replacement Strategy
A participant who discontinues from study intervention OR withdraws from the study will 
not be replaced.
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 (study intervention[s] provided by the Sponsor) will be packaged to support 
enrollment. Clinical supplies will be affixed with a clinical label in accordance with 
regulatory requirements.
6.1
Study Intervention(s) Administered
The study intervention(s) to be used in this study are outlined in Table 1.
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Table 1
Study Interventions
Arm 
Name
Arm Type
Intervention 
Name
Inter-
vention 
Type
Dose 
Formulation
Unit Dose 
Strength(s)
Dosage 
Level(s)
Route of 
Admin.
Regimen/
Treatment 
Period 
Use
IMP
or
NIMP/
AxMP
Sourcing
Group 1
Experimental
MOV
(MK-4482)
Drug
Capsule
200 mg
800 mg
Oral
Q12H
(+/-2 hours)
for 5 days
(10 doses 
total)
Test 
Product
IMP
Central
Group 2
Placebo 
Comparator
Matching 
Placebo
Drug
Capsule
0 mg
N/A
Oral
Q12H
(+/-2 hours)
for 5 days
(10 doses 
total)
Placebo
IMP
Central
Admin=administration; AxMP=Auxiliary Medical Product; EEA=European Economic Area; IMP=investigational medicinal product; MOV=molnupiravir; N/A=not applicable;
NIMP=noninvestigational medicinal product; Q12H=every 12 hours.
The classification of IMP and NIMP 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/NIMP may exist. In these circumstances, local legislation is followed.
Note: Participants will be randomized 1:1 to receive either blinded MOV (Group 1) or blinded placebo (Group 2).
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All supplies indicated in Table 1 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 8.1.9 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 will be randomized in a 1:1 ratio to either MOV (800 mg, Group 1) or placebo
(Group 2). Randomization will occur centrally using an IRT system.
6.3.2
Stratification
Intervention randomization will be stratified according to the following factors:
1. Age category (≤60 vs >60 years)
2. Household size (≤3 vs >3 household residents. All residents, including the index case, 
are counted regardless of whether they are participating in the study.)
6.3.3
Blinding
A double-blinding technique with in-house blinding will be used. MOV and placebo capsules 
are identical in appearance and will be packaged identically so that the blind is maintained. 
The participant, the investigator, and Sponsor personnel or delegate(s) who are involved in 
the study intervention administration or clinical evaluation of the participants are unaware of 
the intervention assignments.
6.4
Study Intervention Compliance
When participants self-administer study intervention(s) at home, compliance with study 
intervention will be assessed at each visit. Compliance will be assessed by review of a Study 
Medication Diary during the site visits and documented in the source documents and CRF.
A record of the number of capsules dispensed to and taken by each participant must be 
maintained and reconciled with study intervention and compliance records. Intervention start 
and stop dates, including dates for intervention delays and/or dose reductions will also be 
recorded in the CRF. Deviation(s) from the prescribed dosage regimen should be recorded in 
the CRF.
6.5
Concomitant Therapy
Medications or vaccinations specifically prohibited in the exclusion criteria are not allowed
during time periods specified by this protocol for those medications or vaccinations. If there 
is a clinical indication for any medications or vaccinations specifically prohibited, 
discontinuation from study intervention may be required. The investigator should discuss any 
questions regarding this with the Sponsor Clinical Director. The final decision on any
supportive therapy or vaccination rests with the investigator and/or the participant’s primary 
physician. However, the decision to continue the participant on study intervention requires 
the mutual agreement of the investigator, the Sponsor, and the participant.
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Any medication or vaccine (including over-the-counter or prescription medicines, vitamins, 
and/or herbal supplements or other specific categories of interest) that the participant is 
receiving at the time of enrollment or receives during the study must be recorded per data 
entry guidelines.
Prior and concomitant therapies listed as prohibited in Table 2 are not permitted for the 
specific time frames listed. Table 2 is not comprehensive, and the investigator should use 
their medical judgment when assessing whether a participant’s prior and concomitant 
therapy(ies) are prohibited. The Sponsor Clinical Director or designee should be contacted if 
there are any questions about a therapy not listed or regarding potential DDIs with a specific 
treatment that the participant may plan to receive. Of note, if a participant is hospitalized 
during the study, other medications intended as treatment for COVID-19 are permitted.
The Sponsor Clinical Director should be contacted if there are any questions regarding 
concomitant or prior therapy.
There are no restrictions for treatment of the index cases for this study as they will not 
receive intervention provided by this study. Index cases may receive treatment outside this 
study.
Table 2
Prohibited and Allowed Therapies for Participating Household Contacts
COVID-19 Vaccines

COVID-19 vaccines are prohibited with the first dose 7 days or more 
prior to randomization and from the time of randomization through Day 
14.
COVID-19 Monoclonal 
Antibodies

Monoclonal antibodies are prohibited for prevention of SARS-CoV-2 
infection at any time prior to randomization and through Day 29.
Note: This includes approved, authorized, or investigational anti-SARS-
CoV-2 monoclonal antibodies, COVID-19 convalescent plasma, or other 
anti-SARS-CoV-2 biologic products with a long (eg, >1 week) half-life.

Monoclonal antibodies are permitted as rescue treatment for participants 
who develop COVID-19 in accordance with local standard of care.
COVID-19 Therapeutics

Sponsor-designateda treatment or preventative agents targeting 
SARS-CoV-2 should not be used in asymptomatic participants.

Standard of care treatment for COVID-19 is permitted as rescue treatment 
for participants who develop COVID-19 (eg, remdesivir, corticosteroids, 
etc).

Treatment with MOV, if approved for use in the participant’s jurisdiction 
and available for administration, is not permitted.
Non-COVID-19 
Investigational Agents 
All non-COVID-19 investigational agents including devices are prohibited 
within 30 days prior to randomization and through Day 29. 
COVID-19=coronavirus disease 2019; MOV=molnupiravir; SARS-CoV-2=severe acute respiratory syndrome 
coronavirus 2
a Refer to the MK-4482-013 Sponsor-Designated Treatment or Preventative Agents Targeting SARS-CoV-2 document.
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6.5.1
Rescue Medications and Supportive Care
Standard of care for COVID-19 is permitted as rescue treatment for participants who develop 
COVID-19 (eg, remdesivir, corticosteroids, etc). Monoclonal antibodies are permitted as 
rescue treatment for participants who develop COVID-19 in accordance with local standard 
of care.
6.6
Dose Modification (Escalation/Titration/Other)
No dose modification of MOV or placebo is allowed in this study.
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
The emergency unblinding call center will use the intervention/randomization schedule for 
the study to unblind participants and to unmask study intervention identity. The emergency 
unblinding call center should only be used in cases of emergency (see Section 8.1.12). If the 
emergency unblinding call center is not available for a given site in this study, the central 
electronic intervention randomization system (IRT) should be used to unblind participants 
and to unmask study intervention identity. The Sponsor will not provide random 
code/disclosure envelopes or lists with the clinical supplies.
6.9
Standard Policies
This section is not applicable.
7
DISCONTINUATION OF STUDY INTERVENTION AND PARTICIPANT 
WITHDRAWAL
7.1
Discontinuation of Study Intervention
Discontinuation of study intervention does not represent withdrawal from the study.
As certain data on clinical events beyond study intervention discontinuation may be 
important to the study, they must be collected through the participant’s last scheduled follow-
up, even if the participant has discontinued study intervention. Therefore, all participants 
who discontinue study intervention before completion of the protocol-specified treatment 
period will still continue to be monitored in the study and participate in the study visits and 
procedures as specified in Section 1.3.1 and Section 8.11.2. unless the participant has 
withdrawn from the study (Section 7.2).
Participants may discontinue study intervention at any time for any reason or be discontinued 
from the study intervention at the discretion of the investigator should any untoward effect 
occur. In addition, a participant may be discontinued from study intervention by the 
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investigator or the Sponsor if study intervention is inappropriate, the study plan is violated, or 
for administrative and/or other safety reasons.
A participant must be discontinued from study intervention, but continue to be monitored in 
the study for any of the following reasons:
•
The participant or participant’s legally acceptable representative requests to discontinue 
study intervention.
•
The participant has a medical condition or personal circumstance, which in the opinion of 
the investigator and/or Sponsor, placed the participant at unnecessary risk from continued 
administration of study intervention.
•
The participant is no longer able to take oral medication or becomes intubated prior to 
completion of study intervention.
•
The participant receives concomitant treatment with MOV that is provided outside this 
study (see Section 6.5).
•
A female participant becomes pregnant.
For participants who are discontinued from study intervention, but continue to be monitored 
in the study, all visits and procedures, as outlined in the SoA, should be completed.
Discontinuation from study intervention is “permanent.” Once a participant is discontinued
from study intervention, they shall not be allowed to restart study intervention.
7.2
Participant Withdrawal From the Study
A participant must be withdrawn from the study if the participant or participant’s legally 
acceptable representative withdraws consent/assent from the study.
If a participant withdraws from the study, they will no longer receive study intervention or be 
followed at scheduled protocol visits.
Hospitalization and survival status at Day 29 are required for all randomized participants and 
should still be reported for participants who withdraw from the study where it is permitted by 
local guidelines. Site personnel should attempt to obtain information regarding vital status 
(including date last known to be alive, hospitalization, date of death, primary cause of death, 
and COVID-19 contribution to death) as outlined in Section 8.2.8.
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 
8.1.11 and 8.11.3. 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.
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7.3
Lost to Follow-up
If a participant fails to return to the clinic for a required study visit and/or if the site is unable 
to contact the participant, the following procedures are to be performed:
•
The site must attempt to contact the participant and reschedule the missed visit. If the 
participant is contacted, the participant should be counseled on the importance of 
maintaining the protocol-specified visit schedule.
•
The investigator or designee must make every effort to regain contact with the participant 
at each missed visit (eg, telephone calls and/or a certified letter to the participant’s last 
known mailing address or locally equivalent methods). These contact attempts should be 
documented in the participant’s medical record.
•
Note: A participant is not considered lost to follow-up until the last scheduled visit for the 
individual participant. The missing data for the participant will be managed via the 
prespecified statistical data handling and analysis guidelines.
8
STUDY ASSESSMENTS AND PROCEDURES
•
Study procedures and their timing are summarized in the SoA.
•
Adherence to the study design requirements, including those specified in the SoA, is 
essential and required for study conduct.
•
The investigator is responsible for ensuring that procedures are conducted by 
appropriately qualified (by education, training, and experience) staff. Delegation of 
study-site personnel responsibilities will be documented in the Investigator Trial File 
Binder (or equivalent).
•
All study-related medical decisions must be made by an investigator who is a qualified 
physician.
•
All screening evaluations must be completed and reviewed to confirm that potential 
participants meet all eligibility criteria. The investigator will maintain a screening log to 
record details of all participants screened and to confirm eligibility or record reasons for 
screening failure, as applicable.
•
Procedures conducted as part of the participant’s routine clinical management (eg, blood 
count) and obtained before signing of ICF may be 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.
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The maximum amount of blood collected from each participant for clinical laboratory 
assessments over the duration of the study is approximately 33.0 mL (Appendix 2, Table 12).
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
Potential participants who will be requested to provide documented informed consent/assent 
are index cases and household contacts of each index case, as per study eligibility 
requirements described in Section 5.1. The informed consent/assent activities are described 
in Section 1.3.
For the information provided in Section 8.1.1 and Section 8.1.1.1, the term “participant” 
refers to index cases and household contacts of each index case.
The investigator or medically qualified designee (consistent with local requirements) must 
obtain documented informed consent/assent from each potential participant (or their legally 
acceptable representative) prior to participating in this clinical study or FBR (only household 
contacts will participate in FBR). If there are changes to the participant’s status during the 
study (eg, health or age of majority requirements), the investigator or medically qualified 
designee must ensure the appropriate documented informed consent/assent is in place.
8.1.1.1
General Informed Consent
Informed consent/assent given by the participant or their legally acceptable representative 
must be documented on a consent/assent 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/assent discussion.
A copy of the signed and dated informed consent/assent 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/assent form or addendum to the original consent/assent
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/assent form.
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Informed consent/assent 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.
Index cases will not participate in FBR in this study.
8.1.1.3
Consent/Assent for Data Collection and Viral Testing/Quantification for 
Index Cases
The investigator or medically qualified designee will explain the collection of data and 
optional swab collection for viral testing/quantification to all index cases and/or their legally 
acceptable representative, answer all of their questions, and obtain documented informed 
consent/assent before performing the collection of data or swab from the index case. The 
COVID-19 data include COVID-19 diagnostic test information (Section 8.1.2), date of onset 
for prior and current COVID-19 diagnoses (Section 8.1.4), prior COVID-19 vaccine 
information (Section 8.1.5.1), and medication for COVID-19 at the time of screening
(Section 8.1.5.1). The NP or OP swab collection and viral testing/quantification are described 
in Section 1.3.2 and Section 8.2.4. A copy of the signed informed consent/assent will be 
given to the index case and/or the index case’s legally acceptable representative.
8.1.2
Inclusion/Exclusion Criteria
All inclusion and exclusion criteria (Section 5.1 and Section 5.2) will be reviewed by the 
investigator, who is a qualified physician, to ensure that a participant qualifies for the study.
The first detectable SARS-CoV-2 test result for the index case must be from a sample 
collected within 5 days prior to randomization of the potential participant(s) in the study. The 
index case’s SARS-CoV-2 test result must be confirmed for the participant(s) to be eligible 
for the study. Data pertaining to the index case’s SARS-CoV-2 sample and test must be
entered into the eCRF including date specimen collected, sample type (eg, NP swab), test 
method (eg, RT-PCR), and result (detectable result is required).
For participants with reported history of HBV or HCV, ALT and AST must be available 
from within 5 days prior to randomization to support determination of eligibility. In 
WOCBP, a negative local urine or serum pregnancy test is required within 24 hours prior to 
the first dose of study intervention per inclusion criteria.
All other inclusion/exclusion criteria determination (eg, HIV status) can be based on 
participant-reported medical history, available medical records, and the most recently 
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available laboratory results for the participant (eg, HIV RNA viral load or CD4 count). See 
Appendix 7 for country-specific requirements.
8.1.3
Participant Identification Card
All participants will be given a participant identification card identifying them as participants 
in a research study. The card will contain study-site contact information (including direct 
telephone numbers) to be used in the event of an emergency. The investigator or qualified 
designee will provide the participant with a participant identification card immediately after 
the participant provides documented informed consent. At the time of intervention
randomization, site personnel will add the treatment/randomization number to the participant 
identification card.
The participant identification card also contains contact information for the emergency 
unblinding call center so that a healthcare provider can obtain information about study 
intervention in emergency situations where the investigator is not available.
8.1.4
Medical History
A medical history will be obtained by the investigator or qualified designee as follows:
•
Participants will provide any prior medical history of COVID-19, background or 
concomitant conditions, drug allergies and/or surgical procedures within the last 12 
months. Medical history for the following conditions will also be collected separately on 
the Medical History Pre-Specified Conditions eCRF: chronic kidney disease, chronic 
obstructive pulmonary disease, obesity, active cancer (excluding minor cancers not 
associated with immunosuppression or significant morbidity/mortality), congestive 
cardiac failure, coronary artery disease, cardiomyopathies, and diabetes mellitus
(Appendix 8).
•
All index cases will provide information pertaining to COVID-19 diagnostic test (as 
described in Section 8.1.2) and date of COVID-19 onset for the current COVID-19 
diagnosis, as well as any prior COVID-19 diagnosis.
8.1.5
Prior and Concomitant Medications Review
8.1.5.1
Prior Medications
The investigator or qualified designee will review and record prior medications taken by 
participants as follows:
•
Participants will provide prior medications taken within 30 days before the first dose of 
study intervention and prior COVID-19 vaccine, regardless of the time period.
•
All index cases will be asked to provide all medications being taken for COVID-19 (at 
the time of screening) and any prior COVID-19 vaccine.
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8.1.5.2
Concomitant Medications
The investigator or qualified designee will record medication and vaccines, if any, taken by 
participants during the study.
In addition, the following concomitant medications and vaccines will be recorded on the 
appropriate eCRF:
•
Medication(s) for the treatment of COVID-19. This includes all supportive therapies (eg, 
antipyretic and anti-inflammatory agents) to manage COVID-19 symptoms. See 
Section 6.5 for prohibited and allowed therapies.
•
COVID-19 vaccine(s) at any time during the study. Note: COVID-19 vaccine(s) are 
prohibited from the time of randomization through Day 14; see Section 6.5.
Treatment with MOV, if approved for use in the participant’s jurisdiction and available for 
administration, is not permitted for any participant in this study. (This restriction pertains to 
participants receiving study intervention, not index cases.)
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 randomization. Each participant 
will be assigned only 1 screening number. Screening numbers must not be reused for 
different participants.
Participants may be rescreened. Specific details on the screening/rescreening visit 
requirements are provided in Section 8.11.2.1.
8.1.7
Assignment of Treatment/Randomization Number
All eligible participants will be randomly allocated and will receive a 
treatment/randomization number. The treatment/randomization number identifies the 
participant for all procedures occurring after intervention randomization. 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.
Index cases will not be randomized to receive study intervention, but will receive an 
allocation number for the collection of data and optional NP or OP swab.
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8.1.8
Participant Study Supplies
On Day 1 of the study, participants will receive bottles of study intervention and the 
following study supplies:
•
Copy of informed consent
•
Information about the study
•
Instructions on study procedures and how to take study intervention
•
Participant identification card with study contact information
•
Instructions on what to do if participants develop symptoms of COVID-19 or become 
hospitalized
•
Study Medication Diary (see Section 8.1.10)
•
Symptom Diary (see Section 8.2.1)
•
EuroQoL EQ-5D-5L questionnaire (see Section 8.2.11)
8.1.9
Study Intervention Administration
Study intervention will be provided as per Table 1 and dispensed through the IRT system at 
the Day 1 (randomization) visit. Study intervention and the Study Medication Diary will be 
dispensed according to the pharmacy manual for at home administration. Study intervention 
will be self-administered by the participants according to the study intervention period in the 
SoA (Section 1.3.1) and timing described in Section 8.1.9.1.
8.1.9.1
Timing of Dose Administration
Participants will take the appropriate number of capsules of study intervention (as described 
in the study intervention administration instructions) Q12H (±2 hours) for 5 days. Study 
intervention may be administered without regard to food.
As outlined in the SoA (Section 1.3.1), all efforts should be made to administer the first dose 
of study intervention on Day 1, but administration of the first dose must be within 24 hours 
of randomization; therefore, it is possible that dosing may not begin until Day 2. Thus, the 
final dose could occur on the evening of Day 6, if dosing initiated in the morning; or the 
morning of Day 7, if dosing initiated in the evening.
For all doses, the timing of dose administration should be recorded in the Study Medication 
Diary.
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If a participant misses a dose of the study intervention, then the following guidance should be 
followed:
•
If ≤10 hours from the time the missed dose should have been taken, the missed dose 
should be taken, and a Q12H dosing schedule resumed. Each subsequent dose should be 
taken 12 hours after its preceding dose.
•
If >10 hours from the time the missed dose should have been taken, the missed dose 
should be skipped, and Q12H dosing schedule resumed. In this case, the subsequent dose 
should be taken 12 hours after the time that the missed dose should have been taken 
(which would be 24 hours after the last dose consumed). The participant should not 
double the next dose to compensate for what has been missed.
8.1.10
Study Medication Diary
A paper Study Medication Diary will be provided for the documentation of doses of study 
intervention and assessment of compliance. Participants should complete the Study 
Medication Diary for each dose taken. If the participant is (in the judgment of the 
investigator) unable to complete the diary, information regarding study intervention
administration may be recorded by a legally acceptable representative or other close contact 
who witnesses administration of the study intervention.
To further support compliance with completion of the Study Medication Diary by the 
participant, the study staff should provide daily telephone or other reminders (eg, email, text 
messages) during the treatment period (see SoA, Section 1.3.1).
The Study Medication Diary will be reviewed in conjunction with capsule counts by study 
staff with each participant at the visits described in the SoA, Section 1.3.1, to ensure 
compliance with completion and consistency with capsule counts. Capsule counts will be 
performed by study staff (expected versus actual) for each study intervention bottle according 
to the pharmacy manual.
The Study Medication Diary will be collected as soon as possible after the last dose 
(ie, 10th dose) of study intervention. If the EOT visit is performed prior to the last dose of 
study intervention, the Study Medication Diary should be collected no later than the Day 14 
visit. The study intervention data as recorded in the participant’s Study Medication Diary will 
be entered in the eCRF.
In the event of hospitalization, the Study Medication Diary will be completed by the 
participant as feasible. If the participant is unable to complete the diary during 
hospitalization, the individual administering the study intervention (eg, study or nonstudy 
staff) will collect information corresponding to study intervention administration in the 
participant’s Study Medication Diary or other source notes (documentation should be 
maintained as part of participant records at the site).
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8.1.11
Discontinuation and Withdrawal
Participants who discontinue study intervention before completion of the treatment period
should be encouraged to continue to be followed for all remaining study visits after EOT as 
outlined in the SoA (Section 1.3.1) and Section 8.11.3.
Participants who withdraw from the study should be encouraged to complete all applicable 
activities scheduled for the Day 29 visit (or the EOT visit if withdrawing prior to completion 
of the treatment period or the Day 14 visit if withdrawing after the EOT visit and prior to the 
Day 14 visit; see Section 8.11.3) at the time of withdrawal. Any AEs that are present at the 
time of withdrawal should be followed in accordance with the safety requirements outlined in
Section 8.4.
Hospitalization and survival status at Day 29 are required for all randomized participants and 
should still be reported for participants who withdraw from the study where permitted by 
local guidelines.
8.1.11.1
Withdrawal From Future Biomedical Research
Participants may withdraw their consent for FBR. Participants may withdraw consent at any 
time by contacting the study investigator. If medical records for the study are still available, 
the investigator will contact the Sponsor using the designated mailbox 
(clinical.specimen.management@MSD.com). Subsequently, the participant’s consent for 
FBR will be withdrawn. A letter will be sent from the Sponsor to the investigator confirming 
the withdrawal. It is the responsibility of the investigator to inform the participant of 
completion of withdrawal. Any analyses in progress at the time of request for withdrawal or 
already performed before the request being received by the Sponsor will continue to be used 
as part of the overall research study data and results. No new analyses would be generated 
after the request is received.
If the medical records for the study are no longer available (eg, if the investigator is no longer 
required by regulatory authorities to retain the study records) or the specimens have been 
completely anonymized, there will no longer be a link between the participant’s personal 
information and their specimens. In this situation, the request for specimen withdrawal 
cannot be processed.
8.1.12
Participant Blinding/Unblinding
STUDY INTERVENTION IDENTIFICATION INFORMATION IS TO BE UNMASKED 
ONLY IF NECESSARY FOR THE WELFARE OF THE PARTICIPANT. EVERY 
EFFORT SHOULD BE MADE NOT TO UNBLIND.
For emergency situations where the investigator or medically qualified designee (consistent 
with local requirements) needs to identify the intervention used by a participant and/or the 
dosage administered, he/she will contact the emergency unblinding call center by telephone 
and make a request for emergency unblinding. As requested by the investigator or medically 
qualified designee, the emergency unblinding call center will provide the information to 
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him/her promptly and report unblinding to the Sponsor. Before contacting the emergency 
unblinding call center to request unblinding of a participant’s intervention assignment, the 
investigator who is a qualified physician should make reasonable attempts to enter the 
toxicity grade of the AEs observed, the relation to study intervention, the reason thereof, etc, 
in the medical record. If it is not possible to record this assessment in the medical record 
before the unblinding, the unblinding should not be delayed.
If unblinding has occurred, the circumstances around the unblinding (eg, date, reason, and 
person performing the unblinding) must be documented promptly, and the Sponsor Clinical 
Director notified as soon as possible.
Once an emergency unblinding has taken place, the investigator, site personnel, and Sponsor 
personnel may be unblinded so that the appropriate follow-up medical care can be provided 
to the participant.
Participants whose treatment assignment has been unblinded by the investigator or medically 
qualified designee and/or nonstudy treating physician should continue to be monitored in the 
study.
Additionally, the investigator or medically qualified designee must go into the IRT system 
and perform the unblind in the IRT system to update drug disposition. If the emergency 
unblinding call center is not available for a given site in this study, the IRT system should be 
used for emergency unblinding if this is required for participant safety.
8.1.13
Calibration of Equipment
The investigator or qualified designee has the responsibility to ensure that any device or 
instrument used for a clinical evaluation/test during a clinical study that provides information 
about inclusion/exclusion criteria and/or safety or efficacy parameters shall be suitably 
calibrated and/or maintained to ensure that the data obtained are reliable and/or reproducible. 
Documentation of equipment calibration must be retained as source documentation at the 
study site.
8.2
Efficacy Assessments
8.2.1
Completing the Symptom Diary and Monitoring for Symptoms of COVID-19
Completing the Symptom Diary
Participants will self-report COVID-19 symptoms daily, if any, using a paper Symptom 
Diary. The Symptom Diary contains 15 targeted COVID-19 symptoms for which 13 will be 
assessed for absence/presence as well as severity (mild, moderate, or severe). Two other 
symptoms (loss of taste and loss of smell) will be assessed for absence/presence only. The 
recall period is “during the past 24 hours.”
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Targeted symptoms for COVID-19 assessed in the Symptom Diary include:
•
Cough
•
Sore throat
•
Nasal congestion (stuffy nose)
•
Runny nose
•
Shortness of breath or difficulty breathing
•
Muscle or body aches
•
Fatigue (tiredness)
•
Feeling hot or feverish
•
Chills
•
Headache
•
Nausea
•
Vomiting
•
Diarrhea
•
Loss of taste
•
Loss of smell
The Symptom Diary will be completed by participants as follows:
•
Participants will begin to complete the Symptom Diary on Day 1 (the same day as 
randomization), prior to the first dose of study intervention. Completion of the Day 1
Symptom Diary will be observed at the site (or a home visit, or visit to an alternate site) 
and documented, including time of participant completion, by study staff/qualified health
care provider.
•
After Day 1, participants should complete the Symptom Diary daily at approximately the 
same time every day through Day 29, recording the absence/presence of each symptom 
and highest severity (mild, moderate, or severe) for 13 of the 15 symptoms during the 
past 24 hours.
If the participant is able to comprehend the Symptom Diary questions (in the judgment of the 
investigator), but is unable to record their responses on the diary on their own per 
investigator judgment, collection of COVID-19 symptom data by study staff via an in-person 
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or virtual (eg, telephone) participant interview using a Sponsor-provided interviewer script 
should be implemented.
In the event of hospitalization, the Symptom Diary should be completed during 
hospitalization if possible. If the participant is unable to record their responses on the diary 
on their own, the Sponsor-provided interviewer script should be implemented by study staff.
Completion of the diary should be resumed by the participant after discharge per the SoA, 
Section 1.3.1.
The Symptom Diary will be reviewed by study staff with each participant at the visits 
described in the SoA (Section 1.3.1) to ensure compliance with completion. To further 
support compliance with completion by the participant, the study staff should provide the 
following reminders for Symptom Diary completion:
•
Daily telephone or other reminders (eg, email, text messages) during the treatment period
and every other day from EOT through Day 14 to a participant or 1 participant who 
represents multiple participants from the same household.
•
After Day 14, weekly telephone or other reminders (eg, email, text messages).
The Symptom Diary will be collected per the SoA, Section 1.3.1, and the diary data will be 
recorded in the eCRF.
In addition to the participant-recorded symptoms, the Investigator or designee will assess the 
participant’s ability to undertake personal usual activities (ie, activities of daily living) and 
assess shortness of breath at rest and with exertion at scheduled visits per the SoA, Section 
1.3.1.
All participants should be reminded at weekly visits (as specified in the SoA, Section 1.3.1) 
to contact the site if they develop symptoms of suspected COVID-19 (through Day 29) for 
assessment at a COVID-19 Confirmation Visit.
Monitoring for Qualifying Symptoms of COVID-19
Participants will be instructed to contact study personnel if they develop 1 or more symptoms 
of suspected COVID-19 (listed above and in the Symptom Diary) at any time through 
Day 29. If a participant reports qualifying symptoms of suspected COVID-19 (described in 
Section 8.2.2) at any time during the study, a COVID-19 Confirmation Visit that includes 
NP swab collection for RT-PCR testing at the central laboratory should be scheduled, to 
occur as soon as possible, but within 3 days of symptom onset (see Section 8.2.3).
8.2.2
Qualifying Symptoms of Suspected COVID-19
To identify suspected cases of COVID-19, prespecified symptoms as well as time criteria 
will be elicited from participants. Any participant who presents with a new onset or marked 
worsening of any one of the 15 targeted COVID-19 symptoms listed in the Symptom Diary 
(described in Section 8.2.1) persisting or recurring over a period of at least 24 hours (except 
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the symptoms of feeling hot or feverish, cough, shortness of breath, loss of taste, or loss of 
smell, which can be present for any duration) should be assessed by the investigator or 
medically qualified designee at a COVID-19 Confirmation Visit (see Section 8.2.3).
8.2.3
Scheduling Requirements and Procedures at a COVID-19 Confirmation Visit
The COVID-19 Confirmation Visit should be scheduled to occur as soon as possible, but
within 3 days of symptom onset. If the 3-day window is exceeded, then the Confirmation 
Visit should be scheduled to be conducted as soon as possible. Every attempt should be made 
to assess the participant. If circumstances do not support a clinic visit, a home visit or visit to 
an alternate study site may be used, if allowed by local regulations. In the case of a home 
visit or visit to an alternate study site, all indicated study procedures should be performed, 
including NP swab collection (Section 8.2.4) for SARS-CoV-2 RT-PCR testing at the central 
laboratory. A participant may have more than one COVID-19 Confirmation Visit.
The COVID-19 Confirmation Visit must be performed by the investigator or medically 
qualified designee.
The following procedures are to be performed at a COVID-19 Confirmation Visit in any 
setting (eg, clinic, home, or alternate site visit) to assess the participant for COVID-19:
1. Confirm the presence or absence of symptoms of COVID-19. All COVID-19 
symptoms that prompted the COVID-19 Confirmation Visit and/or are observed 
during the visit will be recorded on the appropriate eCRF.
2. An NP swab will be collected from the participant for central laboratory RT-PCR 
testing (see Section 8.2.4). If an additional sample is collected for local testing per 
local guidelines, the NP swab for central laboratory testing should be collected first.
3. A directed physical examination, vital signs measurement (including heart rate, blood 
pressure, respiratory rate, and temperature), and SpO2 (if device to measure SpO2 is 
available) to assess the participant’s symptoms and severity of COVID-19.
4. Assess the participant for severity of COVID-19. See Section 8.2.10 for COVID-19
severity criteria.
5. Determine if further triage or clinical evaluation is needed, consistent with standard
of care and local guidelines, and in conjunction with the participant’s primary 
physician (if applicable).
6. The COVID-19 Confirmation Visit may be performed separately from the scheduled 
study visits in the SoA (Section 1.3.1) per the scheduling requirements described 
above. However, if a scheduled visit (Section 1.3.1) overlaps with the COVID-19 
Confirmation Visit, all applicable procedures can be performed at the same visit.
If a participant was assessed for COVID-19 symptoms in a nonstudy outpatient or inpatient 
clinical setting (eg, outpatient clinic, Emergency Department, urgent care center, or hospital), 
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attempts should be made to obtain medical records from the outpatient facility or hospital for 
review by the investigator (or medically qualified designee). Relevant information 
(COVID-19 symptoms, local COVID-19 testing results, etc) should be recorded on the 
appropriate eCRF.
Study sites will follow infection control practices for encounters with participants presenting 
with suspected COVID-19 per local guidelines.
8.2.4
Nasopharyngeal Swab Collection for Viral Testing/Quantification
Study site personnel or their medically qualified designee will collect the NP swabs from 
participants and NP or OP swabs from index cases.
Swabs will be collected and tested as follows:
•
For participants, NP swabs will be collected at the Day 1, Day 5, Day 14, and Day 29
study visits and at a COVID-19 Confirmation Visit (see below). At study entry (Day 1), 
the samples should be collected prior to the first dose of study intervention. Qualitative 
and quantitative SARS-CoV-2 RT-PCR testing at the central laboratory and SARS-CoV-
2 genome sequencing for genetic lineage identification will be performed on the NP 
swabs. Testing for coinfection with other respiratory pathogens is also planned for the NP 
swabs collected from participants.
•
For index cases, NP or OP swabs may be collected at screening (see Section 1.3.2). NP 
swabs are preferred; however, OP swabs are also acceptable for index cases only. This 
swab is separate from the sample for the first detectable SARS-CoV-2 test required for 
the index case prior to randomization of the participant(s) in the study (see Section 5.1).
The swab is not required for study participation of household contacts; however, it is 
highly encouraged for complete virologic assessment. Qualitative and quantitative 
SARS-CoV-2 RT-PCR testing at the central laboratory and SARS-CoV-2 genome 
sequencing for genetic lineage identification will be performed on the NP or OP swabs 
collected at screening.
The swabs for collecting NP and OP samples will be provided by the central laboratory. The 
NP and OP swab sample collection, storage, and shipment instructions are provided in the 
laboratory manual.
Nasopharyngeal Swab Collection at a COVID-19 Confirmation Visit
NP swab samples should be collected from participants by study site personnel or their 
medically qualified designee within the time requirements for the COVID-19 Confirmation 
Visit (see Section 8.2.3). If an additional sample is collected for testing per local guidelines, 
the swab sample for central laboratory testing should be collected first.
If it is not possible to conduct the COVID-19 Confirmation Visit at the study site, as 
described in Section 8.2.3, the investigator may designate staff caring for the participant in an 
alternate nonstudy outpatient or inpatient clinical setting to obtain the samples.
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The following procedures should be followed for obtaining an NP swab sample during a 
nonstudy outpatient or inpatient visit in a clinical setting (eg, outpatient clinic, Emergency 
Department, urgent care center, or hospital) other than the study site:
1. If a participant first visits a nonstudy outpatient or inpatient clinical setting other than 
the study site and is confirmed to have symptoms of COVID-19, the study staff 
should make every effort to obtain an NP sample using the study-supplied swab, as 
permitted, and the site should send this sample to the central laboratory for analysis.
2. If site staff are not permitted to access the outpatient facility or hospital to obtain an 
NP sample, they should coordinate with providers caring for the participant to use the 
study-supplied NP swab or equivalent to collect the sample for central laboratory 
testing, if possible.
3. If it is not possible to collect the NP swab sample with study-supplied NP swabs for 
central laboratory testing, the local SARS-CoV-2 test result should be collected.
4. If an NP sample cannot be collected at a nonstudy outpatient or inpatient clinical 
setting other than the study site, the sample should be collected using the 
study-supplied swab as soon as possible postvisit or postdischarge. The local 
SARS-CoV-2 test result and medical records should also be obtained from the 
outpatient facility or hospital.
8.2.5
SARS-CoV-2 RT-PCR Assay
NP swab samples collected from participants and NP or OP swab samples collected from
index cases (Section 8.2.4) will be tested for the presence of SARS-CoV-2 RNA using the 
Roche Cobas SARS-CoV-2 PCR assay, which has been approved under EUA, at the central 
laboratory. This is a qualitative dual target assay that specifically amplifies a region in the 
SARS-CoV-2 ORF1 a/b as well as a conserved region in the E-gene for pan Sarbecovirus 
detection. The lower limit of detection for this assay is 1.8 × 103 NDU/mL (RNA NAAT 
detectable units/mL). In addition, a second research-use only PCR assay, developed at 
Q-squared Genomics Laboratories, will be used to quantify SARS-CoV-2 RNA titers in 
NP samples. The SARS-CoV-2 Viral Load Quantitation Assay utilizes the MagMAX™ 
Viral/Pathogen Nucleic Acid Isolation Kit on the KingFisher system and reagents from the 
TaqPath™ COVID-19 Combo Kit to amplify 2 unique regions in the ORF1ab, N protein, and 
S protein genes. The lower limit of quantification is 500 RNA copies/mL and the upper limit 
of quantification is 500,000,000 RNA copies/mL.
Central laboratory RT-PCR assay results from NP swabs will be used for the analysis of 
efficacy. If extenuating circumstances impact the ability to use the central laboratory, results 
from a local laboratory will be used if available. If only OP swabs are available, the RT-PCR 
results will be used to support clinical endpoints and establish baseline viral status (ie, to 
establish whether they are in the primary analysis population, mITT-VN) but will not be used 
to assess virologic endpoints. 
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8.2.6
Assessment of Prophylaxis Outcome
The clinical outcome of prophylaxis will be assessed at the Day 14 and Day 29 visits for all 
participants and at the COVID-19 Confirmation Visit for participants who develop 
laboratory-confirmed COVID-19 with symptoms (see Section 1.3.1). Assessments should be 
made according to the following definitions:
Term
Definition
Clinical Success
The participant does not develop laboratory-confirmed COVID-19 with 
onset within the window of interest (ie, symptom onset on or before Day 
14 for the Visit 4 assessment; and on or before Day 29 for Visit 6 
assessment).
Note: Participants who remain asymptomatic through Day 14 (or Day 29, 
for the Day 29 endpoint) are also considered clinical successes regardless 
of SARS-CoV-2 results (positive, negative, or missing).
Clinical Failure
The participant develops laboratory-confirmed COVID-19 with onset 
within the window of interest (ie, symptom onset on or before Day 14 for 
the Visit 4 assessment; and on or before Day 29 for Visit 6 assessment).
The date of onset is considered the date of onset of symptoms.
Note: An assessment of “Clinical Failure” on or before Day 14/Visit 4 
will also be carried forward to the Day 29/Visit 6 assessment.
Indeterminate 
The outcome is indeterminate if any of the following apply:

The participant is lost to follow-up during or has discontinued from 
the study prior to the window of interest (ie, prior to Visit 4 or Visit 6 
for the outcome assessments conducted at those visits).
Note: This definition does not apply to participants who developed 
laboratory-confirmed COVID-19 with symptoms prior to leaving the 
study. For those participants, prophylaxis outcome should be 
assessed as “Clinical Failure” per the definition above.

Death unrelated to COVID-19.

The participant is symptomatic and missing the required viral test for 
confirmation of COVID-19.
Note: A virus-detectable NP swab collected within +/-5 days of 
symptom onset is considered to be within an acceptable window to 
confirm onset of COVID-19. A virus-undetectable NP swab that is 
collected within 5 days after symptom onset is considered to be 
within an acceptable window to rule out COVID-19.
NP swabs collected outside these windows are considered missing.

There are other extenuating circumstances that preclude classification 
as a clinical success or failure, such as:
-
The participant receives Sponsor-designated treatment or 
preventative agents targeting SARS-CoV-2 for reasons other 
than rescue treatment for participants who develop COVID-19; 
see Section 6.5.
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Term
Definition
-
Clinical observations and diagnostic tests cannot distinguish 
COVID-19 from another confirmed diagnosis (eg, influenza like 
symptoms with detectable results for both influenza and SARS-
CoV-2 diagnostic tests).
8.2.7
Hospitalization
Hospitalization status will be assessed for all participants as outlined in the SoA
(Section 1.3.1). Hospitalization is defined as ≥24 hours of acute care in a hospital or similar 
acute care facility, including emergency rooms or facilities created to address hospitalization 
needs during the COVID-19 pandemic. The date and time of hospital admission, date and 
time of discharge, and primary reason for hospitalization (including if the admission is 
related to COVID-19) will be recorded. The Sponsor must be notified within 24 hours of 
site’s awareness of a participant’s hospitalization.
Participants who report worsening illness from any cause during the study may be referred to 
their health care provider or a medical facility. Such instances will be recorded at the time of 
the notification, and during follow-up to assess study endpoints, ie, hospitalization or death.
For any participants who become hospitalized during the study, all study procedures outlined 
in the SoA (Section 1.3.1), including study intervention administration (if applicable), should 
be continued if possible. If the hospitalized participant has not completed study intervention 
and is unable to swallow the capsules or is intubated during hospitalization, then study 
intervention should be discontinued (Section 7.1).
It is recognized that use of nonstudy personnel may be necessary for some procedures in the 
study. In such cases, documentation of these responsibilities and source documentation of 
study intervention administration must be maintained in the site's source documentation as 
appropriate. If in-person visits are not permitted by the institution in which the participant is 
hospitalized, a virtual visit (eg, telehealth, telephone) may be performed to collect data per 
the SoA (Section 1.3.1) that does not require in-person collection. Every attempt should be 
made to obtain equivalent data from hospital records.
In addition to information regarding hospitalization details, available pertinent information 
will be collected, including assessment of participant self-reported COVID-19 symptoms 
(eg, based on Symptom Diary via self-recording or Sponsor-provided interview script, if 
completed), local COVID-19 testing results, vital signs, supplemental oxygenation use, 
ventilation procedures, concomitant medications and AEs, including death.
In addition, every effort should also be made for a visit to be scheduled after discharge from 
the hospital, provided that the visit is within 28 days of initiation of dosing.
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8.2.8
Survival Status
Survival status (ie, whether the participant is alive or deceased) will be assessed for
participants per the SoA (Section 1.3.1).
Site personnel should attempt to obtain information regarding vital status (including date last 
known to be alive, hospitalization, date of death, primary cause of death, and COVID-19 
contribution to death) from the participant or other sources (eg, family members, other 
designated secondary contacts, hospital the participant stated they would most likely go to, 
clinic/hospital/medical records, and local or national databases).
Information about death should be entered in the eCRF within 24 hours of a site becoming 
aware of a death.
8.2.9
Health Care Utilization for COVID-19
Medically attended COVID-19 (as defined in Section 4.1) will be collected for participants 
with laboratory-confirmed COVID-19 per the SoA (Section 1.3.1) and entered on the 
appropriate eCRF. The investigator or qualified designee will assess participant reports to 
determine if COVID-19 required medical care per the protocol definition of medically 
attended COVID-19.
8.2.10
Assessment for Severity of COVID-19
The severity of COVID-19 will be assessed for participants who develop laboratory-
confirmed COVID-19 at study visits specified in the SoA and the COVID-19 Confirmation 
Visit (Section 1.3.1). COVID-19 severity assessments will be performed using the NIAID 
ordinal scale criteria for COVID-19 severity [Beigel, J. H., et al 2020], as follows:
1. Not hospitalized and no limitations of activities
2. Not hospitalized with limitation of activities, home oxygen requirement, or both
3. Hospitalized, not requiring supplemental oxygen and no longer requiring ongoing 
medical care (used if hospitalization was extended for infection control or other 
nonmedical reasons)
4. Hospitalized, not requiring supplemental oxygen, but requiring ongoing medical care 
(related to COVID-19 or to other medical conditions)
5. Hospitalized, requiring any supplemental oxygen
6. Hospitalized, requiring noninvasive ventilation or use of high-flow oxygen devices
7. Hospitalized, receiving invasive mechanical ventilation or extracorporeal membrane 
oxygenation (ECMO)
8. Death
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The participant’s worst severity experienced since the prior visit should be entered on the 
appropriate eCRF.
8.2.11
EuroQoL EQ-5D-5L Questionnaire
A quality-of-life assessment will be conducted using the paper EuroQoL EQ-5D-5L 
questionnaire (as described in Section 4.2.1.5) for participants at study visits specified in the 
SoA (Section 1.3.1). The questionnaire should be self-administered by participants. If a 
participant is unable to record responses on the questionnaire on their own, the Sponsor-
provided EQ-5D-5L Interviewer Administered Script should be implemented by study staff.
If a validated Interviewer Administered Script is unavailable in a language understood by a 
participant who is unable to record responses on the questionnaire on their own, the quality-
of-life assessment does not need to be performed. The EuroQoL EQ-5D-5L questionnaire
assessments should be entered on the appropriate eCRF.
8.3
Safety Assessments
Details regarding specific safety procedures/assessments to be performed in this study are 
provided in the subsections that follow.
Planned time points for all safety assessments are provided in the SoA. The volume of blood 
to be drawn for clinical laboratory assessments over the course of the study is provided in 
Appendix 2, Table 12.
8.3.1
Physical Examinations
A directed physical examination will be conducted at the screening visit by a nurse or other 
qualified health care provider. Height and weight will also be collected and recorded. A nurse 
or other qualified health care provider will also conduct directed physical examinations
targeted at the participant’s symptoms/complaints at visits indicated in the SoA
(Section 1.3.1). Details of the physical examinations will be provided to the investigator or 
medically qualified designee (consistent with local requirements) for review and assessment 
per institutional standard.
8.3.2
Vital Signs
Body temperature, heart rate, respiratory rate, and blood pressure will be assessed. Vital sign
measurements should be preceded by at least 5 minutes of rest for the participant in a quiet 
setting without distractions.
8.3.3
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 
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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), 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.
8.3.4
Pregnancy Testing
Pregnancy testing requirements for study inclusion are described in Section 5.1. Pregnancy 
testing should be conducted at screening (may use either serum or urine test; if using a urine
test, the test should be sensitive enough to measure 25 mIU/mL hCG) and on Day 14
(serum), approximately 9 days after the last dose of study intervention.
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.
8.3.5
Pregnancy Follow-up
Pregnancy status (eg, estimated date of conception and delivery date) for female participants 
of childbearing potential and, female partners of male participants will be collected at the 
Day 29 (LFU) visit (Section 1.3.1). Collection of pregnancy data for female partners of male 
participants is not required if the male participant is confirmed to be azoospermic 
(vasectomized or secondary to medical cause) as documented in medical history.
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. 
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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
For participating household contacts, all AEs, SAEs, and other reportable safety events that 
occur after the participant provides documented informed consent, but before intervention 
randomization, must be reported by the investigator if the event causes the participant to be 
excluded from the study, or is the result of a protocol-specified intervention.
From the time of intervention randomization, through 14 days after cessation of study 
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 at any time outside the 
period specified in the previous paragraph must be reported immediately to the Sponsor if the 
event is considered related to study intervention.
For participating index cases, all AEs, SAEs, and other reportable safety events that occur 
after the participant provides documented informed consent, but before allocation, must be 
reported by the investigator if the event causes the participant to be excluded from the study, 
or is the result of a protocol-specified 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 (index or household contact) has been discharged from 
the study, and the investigator considers the event to be reasonably related to the study 
intervention or study participation, the investigator must promptly notify the Sponsor.
All initial and follow-up AEs, SAEs, and other reportable safety events will be recorded and 
reported to the Sponsor or designee within the time frames as indicated in Table 3.
Exception: A positive pregnancy test at the time of initial screening is not a reportable event 
unless the participant has received study intervention.
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Table 3
Reporting Time Periods and Time Frames for Adverse Events and Other 
Reportable Safety Events
Type of Event
Reporting Time 
Period:
Consent to 
Randomization/ 
Allocation
Reporting Time 
Period:
Randomization/ 
Allocation 
through 
Protocol-
specified Follow-
up Period
Reporting Time 
Period:
After the Protocol-
specified Follow-up 
Period
Time Frame to 
Report Event 
and Follow-up 
Information to 
Sponsor:
NSAE
Report if:
- due to protocol-
specified 
intervention
- causes 
exclusion
Report all
Not required
Per data entry 
guidelines
SAE
Report if:
- due to protocol-
specified 
intervention
- causes 
exclusion
Report all
Report if:
- drug/vaccine related.
(Follow ongoing to 
outcome)
Within 24 hours 
of learning of 
event
Pregnancy/
Lactation Exposure
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
Not applicable
Report all
Not required
Within 5 
calendar days of 
learning of event
DILI=drug-induced liver injury; ECI=event of clinical interest; NSAE=nonserious adverse event; SAE=serious adverse 
event.
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8.4.2
Method of Detecting AEs, SAEs, and Other Reportable Safety Events
Care will be taken not to introduce bias when detecting AEs and/or SAEs and other 
reportable safety events. Open-ended and nonleading verbal questioning of the participant is 
the preferred method to inquire about AE occurrence.
8.4.3
Follow-up of AE, SAE, and Other Reportable Safety Event Information
After the initial AE/SAE report, the investigator is required to proactively follow each 
participant at subsequent visits/contacts. All AEs, SAEs, and other reportable safety events,
including pregnancy and exposure during breastfeeding, ECIs, cancer, and overdose will be 
followed until resolution, stabilization, until the event is otherwise explained, or the 
participant is lost to follow-up (as defined in Section 7.3). In addition, the investigator will 
make every attempt to follow all nonserious AEs that occur in randomized participants for 
outcome. Further information on follow-up procedures is given in Appendix 3.
8.4.4
Regulatory Reporting Requirements for SAE
Prompt notification (within 24 hours) by the investigator to the Sponsor of SAE is essential 
so that legal obligations and ethical responsibilities towards the safety of participants and the 
safety of a study intervention under clinical investigation are met.
The Sponsor has a legal responsibility to notify both the local regulatory authority and other 
regulatory agencies about the safety of a study intervention under clinical investigation. The 
Sponsor will comply with country-specific regulatory requirements and global laws and 
regulations relating to safety reporting to regulatory authorities, IRB/IECs, and investigators.
Investigator safety reports must be prepared for 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), including the pregnancy of a male participant’s female 
partner, that occurs during the study are reportable to the Sponsor as described in 
Section 8.4.1.
All reported pregnancies must be followed to the completion/termination of the pregnancy.
Any pregnancy complication will be reported as an AE or SAE.
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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 lead 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
Certain efficacy endpoints including hospitalizations and mortality must be collected 
throughout the study (ie, during both treatment and follow-up periods). From the time of 
randomization through 14 days after cessation of study intervention, these events must be 
reported as described in Section 8.4.1. New hospitalizations and/or deaths that occur after 
14 days after cessation of treatment must continue to be assessed for seriousness and 
causality. However, they must only be reported to the Sponsor within 24 hours as new SAEs 
if there is evidence to suggest a causal relationship between the study intervention and the 
SAE.
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 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).
8.5
Treatment of Overdose
In this study, an overdose is the receipt of any number of capsules greater than the number of 
capsules to be taken as outlined in the pharmacy manual.
No specific information is available on the treatment of overdose.
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Decisions regarding dose interruptions or modifications will be made by the investigator in 
consultation with the Sponsor Clinical Director based on the clinical evaluation of the 
participant.
8.6
Pharmacokinetics
PK parameters will not be evaluated in this study.
8.7
Pharmacodynamics
Virologic, clinical efficacy, and clinical safety endpoints (Section 3) will be summarized. For 
assessment of antiviral activity of MOV, baseline and postdose virologic information 
(eg, viral RNA) from NP swabs of participants will be measured at prespecified timepoints in 
the SoA (Section 1.3.1). For each participant, the baseline measurement is defined as the 
measurement obtained predose on the first day of dosing.
8.8
Anti-SARS-CoV-2 Antibody Serology Testing
Participants will have serologic testing performed for the presence of anti-SARS-CoV-2 
nucleocapsid (N) protein and neutralizing antibodies in serum at time points indicated in the 
SoA (Section 1.3.1).
Anti-nucleocapsid antibodies will be measured at the central laboratory using the Roche 
Elecsys Anti-SARS-CoV-2 test that is currently available under EUA. This assay is a 
qualitative test yielding a positive versus negative result for anti-nucleocapsid antibodies.
Anti-SARS-CoV-2 neutralizing antibody titers will be measured at a centralized testing
laboratory using a VSV pseudotype containing a luciferase reporter and bearing a 
cytoplasmic domain-truncated SARS-CoV-2 spike protein. This assay, validated at Nexelis 
Laval Canada (a Q2 Solutions Company), measures the ability of antibodies in serum to 
neutralize infection of a VSV reporter virus pseudotyped with the SARS-CoV-2 spike protein
[Bewley, K. R., et al 2021].
8.9
Biomarkers
Biomarkers will not be evaluated in this study.
8.10
Future Biomedical Research Sample Collection
If the participant provides documented informed consent for FBR, the following specimens 
will be obtained as part of FBR:
•
DNA for future research
•
Leftover isolates from NP swab for viral testing/quantification stored for future research
•
Leftover serum from anti-SARS-CoV-2 antibody serology testing stored for future 
research
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8.11
Visit Requirements
Visit requirements are outlined in Section 1.3. Specific procedure-related details are provided 
in Section 8.
8.11.1
Infection Prevention Procedures
Each site will follow their institutional procedures and/or local requirements to protect study 
staff and other patients from infectious exposure to SARS-CoV-2. These procedures may 
include, but are not limited to:
•
Provision of PPE to site staff, participants, and legally acceptable representatives
•
Performing home visits, visits to alternate sites, or virtual visits (as allowed per the SoA)
•
Designating special entry points for study participants for clinic visits
8.11.2
Types of Study Visits
8.11.2.1
Screening/Rescreening Visits
Screening
Screening of potential participants and index cases will occur within 5 days prior to 
randomization of the participants. The sample for the first detectable SARS-CoV-2 test for 
the index case must have been collected within 5 days prior to randomization of the 
participants. In addition, COVID-19 symptom onset for the index case may be no earlier than 
5 days prior to randomization of the participants.
Prior to randomization, potential participants will be evaluated to determine that they fulfill 
the entry requirements as set forth in Section 5. Participants are expected to enroll as soon as 
possible after eligibility is confirmed.
Rescreening
Participants are allowed to rescreen 1 time. Rescreening procedures must be completed 
within 5 days from the time of sample collection for the first detectable SARS-CoV-2 test 
result of the index case and also within 5 days from the time of onset of symptoms for the 
index case. The following assessments must be repeated for participants who are rescreened:
•
Vital signs and directed physical examination
•
Review medical history and prior/concomitant medications for new information
•
Local laboratory assessments for inclusion/exclusion (results within 5 days prior to 
randomization may be used for eligibility)
•
Urine or serum β-hCG (pregnancy testing for WOCBP)
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•
Review of AEs
If the informed consent form has been updated, participants should be reconsented before 
rescreening. If no updates have been made, the informed consent from the original screening 
period should be reviewed with the participant and a verbal reconsent to continue in the study 
should be documented.
8.11.2.2
Clinic Visits, Home Visits, or Visits to an Alternate Site
If circumstances do not support a clinic visit, a home visit by the site personnel or a qualified 
health care provider (eg, home health care company, visiting nurse, etc) or a visit to an 
alternate site may be appropriate to perform study assessments and procedures per the SoA 
(where available and when permitted by local regulations and IRB/IEC). All study 
procedures indicated in the SoAs (Section 1.3.1 and Section 1.3.2) should be completed. The 
documentation from the visit will be provided to the investigator or medically qualified 
designee (consistent with local requirements) for review and assessment per institutional 
standards.
Every attempt should be made to assess the participant for a COVID-19 Confirmation Visit.
See Section 8.2.3 for scheduling and visit requirements for a COVID-19 Confirmation Visit.
Refer to the procedure manual and/or the Investigator Trial File Binder (or equivalent) for 
additional details.
8.11.2.3
Virtual Visits
For participants, the investigator or designee may conduct a virtual visit (eg, by telehealth, 
telephone, webcast, videoconference, etc) for the Day 21 visit. When a virtual visit is listed 
in the SoA (Section 1.3.1), a clinic or home visit is not required. The choice to conduct a 
virtual visit, rather than a clinic or home visit/visit to an alternate site, is at the investigator’s 
discretion. All study procedures indicated in the SoA (Section 1.3.1) should be completed.
For index cases who do not provide documented informed consent/assent for the optional NP 
or OP swab for viral testing/quantification, a virtual visit may be conducted for screening 
(Visit 1) procedures in the SoA (Section 1.3.2).
Identity of each participant and index case should be confirmed according to institutional 
procedures and/or local guidelines prior to conduct of virtual visits.
8.11.3
Participants Who Discontinue or Withdraw
Participants who discontinue study intervention prior to completion of the treatment period 
should complete the activities for the EOT visit at the time of discontinuing study 
intervention. The participant should then be encouraged to complete all the remaining 
subsequent study visits after EOT as outlined in the SoA (Section 1.3.1). If an active 
condition requires ongoing monitoring (eg, abnormal laboratory results, AEs, or progression 
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of COVID-19 symptoms), unscheduled visit(s) may be performed prior to the next study visit 
on Day 14.
Study activities for participants who withdraw from the study depend on the time of 
withdrawal, as follows:
•
Participants who withdraw from the study prior to completion of the treatment period 
should complete the activities for the EOT visit at the time of withdrawal.
•
Participants who withdraw from the study after the EOT visit, but prior to the Day 14 
visit should complete all activities scheduled for the Day 14 visit, including the NP swab 
collection for RT-PCR testing at the central laboratory, at the time of withdrawal.
•
Participants who withdraw from the study after the Day 14 visit should be encouraged to 
complete all applicable activities scheduled for the Day 29 visit at the time of withdrawal.
This visit at the time of study withdrawal should be conducted at the clinic or as a home visit 
if possible. If circumstances do not support an in-person visit, a virtual visit may be used; in 
this case, laboratory or other in-person measures would not be collected. Return of 
participant diaries and reconciliation of any study intervention should be coordinated if 
relevant. Any AEs that are present at the time of withdrawal should be followed in 
accordance with the safety requirements outlined in Section 8.4.
Both hospitalization and survival status at Day 29 are required for all randomized 
participants and should still be reported for participants who withdraw from the study where 
permitted by local guidelines.
9
STATISTICAL ANALYSIS PLAN
This section outlines the statistical analysis strategy and procedures for the study. If after the 
study has begun, but prior to any unblinding/final database lock, changes are made to the 
primary hypothesis, or the statistical methods related to this hypothesis, then the protocol will 
be amended (consistent with ICH Guideline E-9). Changes to exploratory or other 
non-confirmatory analyses made after the protocol has been finalized, but prior to 
unblinding/final database lock, will be documented in an sSAP and referenced in the CSR for 
the study. Post hoc exploratory analyses will be clearly identified in the CSR. Other planned 
analyses (ie, medical resource utilization outcomes and research plasma samples) are beyond 
the scope of this document or will be documented in separate analysis plans.
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9.1
Statistical Analysis Plan Summary
Key elements of the statistical analysis plan are summarized below; the comprehensive plan 
is provided in Section 9.2 to Section 9.12.
Study Design Overview
A Phase 3, Multicenter, Randomized, Double-blind, Placebo-
controlled Study to Evaluate the Efficacy and Safety of MK-4482 
for the Prevention of COVID-19 (Laboratory-confirmed SARS-
CoV-2 Infection With Symptoms) in Adults Residing With a 
Person With COVID-19.
Treatment Assignment
Approximately 1376 participants (regardless of SARS-CoV-2 
results in baseline NP swabs) will be randomized in a 1:1 ratio 
(stratified per Section 6.3.2) to receive either MOV or placebo,
Q12H for 5 days.

MOV 800 mg (n~688)

Placebo (n~688)
Analysis Populations
Efficacy: mITT
Safety: APaT
Primary Endpoint(s)
Efficacy: Percentage of participants with undetectable 
SARS-CoV-2 in baseline NP swabs developing COVID-19 
through Day 14.
Safety: AEs, and AEs leading to discontinuation of study 
intervention.
Secondary Endpoints
1.
Percentage of participants (regardless of SARS-CoV-2 results
in baseline NP swabs) developing COVID-19 through Day 14
2.
Percentage of participants with undetectable SARS-CoV-2 in 
baseline NP swabs developing COVID-19 through Day 29.
3.
Percentage of participants with undetectable SARS-CoV-2 in 
baseline NP swabs having viral transmission through Day 14.
4.
Percentage of participants with detectable SARS-CoV-2 in 
baseline NP swabs developing COVID-19 through Day 14
Statistical Methods for Key 
Efficacy Analyses
The primary objective and hypothesis, superiority of MOV 
compared with placebo with respect to the percentage of 
participants with undetectable SARS-CoV-2 in baseline NP 
swabs developing COVID-19 through Day 14, will be evaluated 
using a 2-sided 95% CI. The CI will be calculated based on the 
stratified Miettinen and Nurminen method [Miettinen, O. and 
Nurminen, M. 1985] with Cochran-Mantel-Haenszel weights 
(stratified by age and household size).
Statistical Methods for Key 
Safety Analyses
95% CIs (Tier 2 endpoints) will be provided for between
treatment differences in the percentage of participants with 
events; these analyses will be performed using the Miettinen and 
Nurminen method [Miettinen, O. and Nurminen, M. 1985].
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Interim Analyses
One IA will be performed to evaluate safety and futility with 
respect to the primary efficacy hypothesis. Results will be 
reviewed by an eDMC. A summary of the IA is provided below. 
Further details are provided in Section 9.7.

Timing: To be conducted when approximately 55% of the 
participants with undetectable SARS-CoV-2 in baseline NP 
swabs have either completed the Day 14 visit or discontinued 
from the study prior to the Day 14 visit.

Testing: The primary efficacy hypothesis will be tested.
Multiplicity
A gatekeeping strategy will be used to control the overall FWER 
associated with the primary and secondary analyses.
The following efficacy hypotheses will be tested sequentially at a 
one-sided 2.49% Type I error rate at final analyses:
1.
Primary efficacy hypothesis (H1) testing superiority of 
MOV compared with placebo in participants with 
undetectable SARS-CoV-2 in baseline NP swabs through 
Day 14
2.
Secondary hypothesis (H2) testing superiority of MOV 
compared with placebo in participants regardless of 
SARS-CoV-2 results in baseline NP swabs through Day 14
The primary hypothesis (H1) will be tested first. The secondary 
hypothesis (H2) will be tested only if H1 is rejected. If H1 fails to 
reach statistical significance, then H2 will not be tested.
Although there is no plan to stop the study early for efficacy at the 
interim analysis, a small statistical penalty (α=0.0001) will be applied 
for this interim analysis. The final analysis will be conducted at 
0.0249 alpha-level to preserve the type I error level.
Sample Size and Power 
The study will enroll approximately 1376 participants (regardless 
of SARS-CoV-2 results in baseline NP swabs; approximately 688 
each in MOV 800 mg and in the placebo group). Assuming 
approximately 20% of the 1376 participants will have detectable 
SARS-CoV-2 at baseline [O'Brien, M. P., et al 2021], this will 
result in approximately 1100 participants with undetectable 
SARS-CoV-2 at baseline.
The primary objective will be assessed on the approximately 1100 
participants with undetectable SARS-CoV-2 in baseline NP 
swabs.
Assume:

A background secondary attack rate of 8% and an underlying 
treatment difference (MOV minus placebo) in percentage of 
participants developing COVID-19 through Day 14 of -4.8
percentage points (a 60% relative reduction in attack rate).

At least 10% of the approximately 276 participants with 
detectable SARS-CoV-2 in baseline NP swabs are 
randomized to the MOV group.
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The study has at least 90% power to demonstrate that MOV is 
superior to placebo for prevention of confirmed COVID-19 in 
household contacts (with undetectable SARS-CoV-2 in baseline 
NP swabs) of an index case through Day 14 at an overall 
one-sided 2.5% alpha-level.
Details are provided in Section 9.9.1.
9.2
Responsibility for Analyses/In-house Blinding
The statistical analysis of the data obtained from this study will be the responsibility of the 
Clinical Biostatistics department of the Sponsor or designee.
This study will be conducted as a double-blind study under in-house blinding procedures. 
The official, final database will not be unblinded until medical/scientific review has been 
performed, protocol deviations have been identified, and data have been declared final and 
complete.
The Clinical Biostatistics department will generate the randomized allocation schedule(s) for 
study intervention assignment.
Blinding issues related to the planned interim analysis are described in Section 9.7.
9.3
Hypotheses/Estimation
Objectives and hypotheses of the study are stated in Section 3.
9.4
Analysis Endpoints
Efficacy and safety endpoints that will be evaluated for within- and/or between treatment 
differences are listed below.
9.4.1
Efficacy Endpoints
The primary efficacy endpoint is the percentage of participants with undetectable 
SARS-CoV-2 in baseline NP swabs developing COVID-19 (laboratory-confirmed SARS-
CoV-2 infection with symptoms) through Day 14.
The secondary efficacy endpoints are:

Percentage of participants (regardless of SARS-CoV-2 results in baseline NP swabs) 
developing COVID-19 through Day 14

Percentage of participants with undetectable SARS-CoV-2 in baseline NP swabs 
developing COVID-19 through Day 29

Percentage of participants with undetectable SARS-CoV-2 in baseline NP swabs having 
viral transmission through Day 14
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
Percentage of participants with detectable SARS-CoV-2 in baseline NP swabs developing 
COVID-19 through Day 14
The exploratory efficacy endpoints are:

Percentage of participants (regardless of SARS-CoV-2 results in baseline NP swabs) 
developing COVID-19 through Day 29

Percentage of participants with detectable SARS-CoV-2 in baseline NP swabs developing
COVID-19 through Day 29

Percentage of participants with undetectable SARS-CoV-2 in baseline NP swabs having 
viral transmission through Day 29

Percentage of baseline seronegative participants with undetectable SARS-CoV-2 in 
baseline NP swabs developing anti-SARS-CoV-2 antibodies through Day 29

Severity of laboratory-confirmed COVID-19 through Day 29 using NIAID ordinal scale 
criteria

Participant-reported symptoms severity (for specified COVID-19 symptoms) in 
participants who develop laboratory-confirmed COVID-19 on or before Day 14

Change from baseline in SARS-CoV-2 RNA titer and percentage of participants with 
undetectable SARS-CoV-2 RNA in NP swabs at Day 14 in participants with detectable 
SARS-CoV-2 in NP swabs at baseline

Viral RNA mutation rate and detection of treatment-emergent sequence variants as 
assessed by comparison of viral gene sequencing at baseline and postbaseline in 
participants who develop laboratory-confirmed COVID-19 on or before Day 14

Percentage of participants who develop laboratory-confirmed COVID-19 on or before 
Day 14 utilizing health care related to COVID-19 through Day 29

Generic health-related quality-of-life in participants through Day 29 via EuroQoL Five 
Dimension Questionnaire (EQ-5D-5L)
9.4.2
Safety Endpoints
An initial description of safety measures is provided in Section 4.
Safety and tolerability will be assessed by clinical review of all relevant parameters including
AEs and laboratory tests.
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PDLC in Laboratory Parameters
For the summaries of laboratory tests, participants must have both a baseline and 
postrandomization on-treatment measurement to be included. Participants’ laboratory values 
(based on their most abnormal laboratory test values, in the direction of interest, while on 
study intervention) will be classified as to whether or not they fall outside the PDLC and are 
worse in grade (ie, more abnormal in the direction of interest) than at baseline. The criteria 
will be adapted from the DAIDS Table for Grading the Severity of Adult and Pediatric 
Adverse Events, JUL-2017, version 2.1. A listing of the participants who meet the criteria 
will also be provided.
9.5
Analysis Populations
9.5.1
Efficacy Analysis Populations
The mITT will serve as the primary population for the analysis of efficacy data in this study. 
The mITT consists of all randomized participants who received at least 1 dose of study 
intervention. The primary objective will be assessed in the mITT-VN population, which 
consists of the subset of the participants in the mITT with undetectable SARS-CoV-2 in 
baseline NP swabs (ie, virus negative/undetectable at baseline). The mITT-VP population, 
consisting of the subset of the participants in the mITT with detectable SARS-CoV-2 in 
baseline NP swabs (ie, virus-positive/detectable at baseline) will be used in some of the 
exploratory analyses. Under certain extenuating circumstances (Section 8.2.5), eg, when only 
qualitative OP swab results are available from the central laboratory, qualitative OP swab 
results can be used to derive the baseline viral status.
A supportive analysis using the Per-Protocol population will be performed for the primary 
efficacy endpoint. The Per-Protocol population excludes participants from the mITT due to 
deviations from the protocol that may substantially affect the results of the primary efficacy 
endpoints. Participants with prophylaxis outcomes of “indeterminate” (Section 8.2.6) will be 
excluded from the Per-Protocol population. Moreover, participants who took <80% of the 
required doses will be excluded from the Per-Protocol population.
The final determination on protocol deviations, and thereby the composition of the 
Per-Protocol population, will be made prior to the final unblinding of the database and will 
be documented in a separate memo.
Due to the conflict in Ukraine, participants in Ukraine who were randomized in FEB-2022 
with incomplete data for the primary endpoint (ie, no clinical outcome assessment on Day 
14) will be excluded from the efficacy analyses in the mITT population.
9.5.2
Safety Analysis Populations
Safety Analyses will be conducted in the APaT population, which consists of all randomized
participants who received at least 1 dose of study intervention. Participants will be included
in the intervention group corresponding to the study intervention they actually received for 
the analysis of safety data using the APaT population. For most participants, this will be the 
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intervention group to which they are randomized. Participants who take incorrect study 
intervention for the entire treatment period will be included in the intervention group 
corresponding to the study intervention actually received.
At least 1 laboratory or vital sign measurement obtained subsequent to at least 1 dose of 
study intervention is required for inclusion in the analysis of the respective safety parameter. 
To assess change from baseline, a baseline measurement is also required.
9.6
Statistical Methods
This section describes the statistical methods that address the primary and secondary
objectives. Methods related to exploratory objectives will be described in the sSAP. Methods 
related to analyses of biomarkers and other exploratory samples (Section 8.10) will be 
described separately.
Efficacy results that will be deemed to be statistically significant after consideration of the
type I error control strategy are discussed in Section 9.8 and a description of the interim 
analysis is in 9.7. Statistical testing and inference for safety analyses are described in Section 
9.6.2.
9.6.1
Statistical Methods for Efficacy Analyses
For the evaluation of the primary hypothesis, the superiority of MOV compared with placebo
with respect to the percentage of participants with undetectable SARS-CoV-2 in baseline NP 
swabs developing COVID-19 by Day 14 will be assessed using the stratified Miettinen and 
Nurminen method with CMH weights [Miettinen, O. and Nurminen, M. 1985]. Stratification
factors include age and household size as specified in Section 6.3.2. The primary hypothesis 
will be addressed by testing the null hypothesis pt ≥ pc versus the alternative hypothesis pt < 
pc, where pt and pc refer to event rates in MOV and placebo groups in participants with 
undetectable SARS-CoV-2 in baseline NP swabs, respectively. The null hypothesis will be 
rejected if the 1-sided p-value is less than 0.0249 (see Section 9.8 for alpha adjustment) and 
the superiority of MOV relative to placebo will be demonstrated for the primary endpoint.
For the analysis of this primary endpoint in the mITT-VN population, the following Table 
shows how to handle the indeterminate clinical outcomes of prophylaxis presented in Section 
8.2.6 (Table 4).
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Table 4
Imputation for Indeterminate Prophylaxis Outcomes
Indeterminate Prophylaxis Outcomes
Imputation 
Lost to follow-up during or discontinued from the study prior to the 
window of interest (ie, prior to Visit 4 or Visit 6 for the outcome 
assessments conducted at those visits). This does not include 
participants who were already determined to be clinical failures prior 
to being lost to follow-up or discontinued.
Considered a case 
of COVID-19
Death unrelated to COVID-19
Considered a case 
of COVID-19
Missing the required viral test for confirmation of COVID-19 (see 
also Section 8.2.6 for details around acceptable windows)
Considered a case 
of COVID-19
Other extenuating circumstances that preclude classification as a 
clinical success or failure (such as the participant receives another 
agent for the prevention of COVID-19)
Considered a case 
of COVID-19
Participants in Ukraine who were randomized in FEB-2022 without clinical outcome assessment on Day 14 
will be excluded from the efficacy analysis.
Moreover, a participant without a Day 14 clinical outcome assessment, but assessed as a 
clinical success through Day 29 will be treated as a clinical success through Day 14. A 
participant without a Day 29 clinical outcome assessment, but assessed as a clinical failure 
through Day 14 will be treated as a clinical failure through Day 29. If a participant 
discontinued from the study prior to the Day 14 or the Day 29 visit, but was assessed as a 
clinical failure from the COVID-19 Confirmation Visit, then the clinical failure should be 
carried forward to the Day 14 and/or the Day 29 visit after the COVID-19 Confirmation 
Visit. All other missing clinical outcome assessments will be imputed as clinical failures.
For the evaluation of the secondary hypothesis, the superiority of MOV compared with
placebo with respect to the percentage of participants (regardless of SARS-CoV-2 results in 
baseline NP swabs) developing COVID-19 by Day 14 will be assessed using the same 
method in the primary hypothesis, ie, the stratified Miettinen and Nurminen method with 
CMH weights [Miettinen, O. and Nurminen, M. 1985] (stratified by age and household size 
as described in Section 6.3.2, and SARS-CoV-2 status in baseline NP swab). The secondary 
hypothesis will be evaluated by testing the null hypothesis pts ≥pcs versus the alternative 
hypothesis pts < pcs, where pts and pcs refer to event rates (percentages of participants 
developing COVID-19 by Day 14) in MOV and placebo groups, respectively. The null 
hypothesis will be rejected if the 1-sided p-value is less than 0.0249 (see Section 9.8 for 
alpha adjustment) and the superiority of MOV relative to placebo will be concluded for this
secondary endpoint.
The efficacy of MOV compared with placebo for the prevention of COVID-19 with respect 
to the percentage of participants with undetectable SARS-CoV-2 in baseline NP swabs
developing COVID-19 through Day 29 will be evaluated. The difference in percentages
between treatment groups (MOV minus placebo) and the associated 95% CI will be 
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calculated using the stratified Miettinen and Nurminen method with CMH weights 
[Miettinen, O. and Nurminen, M. 1985] (stratified by age and household size as described in 
Section 6.3.2).
For the evaluation of the prevention of viral transmission using MOV compared with placebo 
through Day 14 among participants with undetectable SARS-CoV-2 in NP swabs at baseline, 
the percentage of participants in the 2 intervention groups who have positive/detectable
SARS-CoV-2 RNA through Day 14 will also be compared using the stratified Miettinen and 
Nurminen method [Miettinen, O. and Nurminen, M. 1985] (stratified by age and household 
size as described in Section 6.3.2).
The efficacy of MOV compared with placebo for the prevention of COVID-19 with respect 
to the percentage of participants with detectable SARS-CoV-2 in baseline NP swabs
developing COVID-19 through Day 14 will be evaluated. The difference in percentages 
between treatment groups (MOV minus placebo) and the associated 95% CI will be 
calculated using the Miettinen and Nurminen method with CMH weights [Miettinen, O. and 
Nurminen, M. 1985].
A detailed analysis strategy for key efficacy endpoints is listed in Table 5.
Table 5
Analysis Strategy for Key Efficacy Endpoints
Endpoint/Variable
(Description, Time Point)
Primary vs 
Supportive 
Approacha
Statistical Method
Analysis 
Population
Missing 
Data 
Approach
Primary
Percentage of participants with 
undetectable SARS-CoV-2 in 
baseline NP swabs developing 
COVID-19 by Day 14
P 
Stratified M&N method 
with CMH weightsb
mITT-VN
As 
described 
in 9.6.1
Percentage of participants with 
undetectable SARS-CoV-2 in 
baseline NP swabs developing 
COVID-19 by Day 14
S
Stratified M&N method 
with CMH weightsb
PP
Observed 
data only
Secondary
Percentage of participants
(regardless of SARS-CoV-2
results in baseline NP swabs) 
developing COVID-19 by Day 
14
P 
Stratified M&N method 
with CMH weightsb
mITT
As 
described 
in 9.6.1
Percentage of participants
(regardless of SARS-CoV-2
results in baseline NP swabs) 
developing COVID-19 by Day 
14
S
Stratified M&N method 
with CMH weightsb
PP
Observed 
data only
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Endpoint/Variable
(Description, Time Point)
Primary vs 
Supportive 
Approacha
Statistical Method
Analysis 
Population
Missing 
Data 
Approach
Percentage of participants with 
undetectable SARS-CoV-2 in 
baseline NP swabs developing 
COVID-19 by Day 29
P 
Stratified M&N method 
with CMH weightsb
mITT-VN
As 
described 
in 9.6.1
Percentage of participants with 
undetectable SARS-CoV-2 in 
baseline NP swabs developing 
COVID-19 by Day 29
S
Stratified M&N method 
with CMH weightsb
PP
Observed 
data only
Percentage of participants who 
develop positive/detectable 
SARS-CoV-2 through Day 14 
among those with undetectable 
SARS-CoV-2 in NP swabs at 
baseline
P 
Stratified M&N method 
with CMH weightsb
mITT-VN
M=Cc
Percentage of participants who 
develop positive/detectable 
SARS-CoV-2 through Day 14 
among those with undetectable 
SARS-CoV-2 in NP swabs at 
baseline
S
Stratified M&N method 
with CMH weightsb
PP
Observed 
data only
Percentage of participants with 
detectable SARS-CoV-2 in 
baseline NP swabs developing 
COVID-19 by Day 14
P 
Stratified M&N method 
with CMH weightsb
mITT-VN
As 
described 
in 9.6.1
Percentage of participants with 
detectable SARS-CoV-2 in 
baseline NP swabs developing 
COVID-19 by Day 14
S
Stratified M&N method 
with CMH weightsb
PP
Observed 
data only
C=case of COVID-19; CMH=Cochran-Mantel-Haenszel; M=missing; M&N=Miettinen and Nurminen; mITT-
VN=modified intent-to-treat population with undetectable SARS-CoV-2 in baseline NP swabs; 
NP=nasopharyngeal; PP=per-protocol.
a
P=Primary approach; S=Supportive approach.
b
Miettinen and Nurminen method with CMH weights stratified by age and household size.
c
M=C is Missing considered as a case of COVID-19.
Participants in Ukraine who were randomized in FEB 2022 without clinical outcome assessment on Day 14 will be 
excluded from the efficacy analysis.
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9.6.2
Statistical Methods for Safety Analyses
Safety and tolerability will be assessed by clinical review of all relevant parameters including 
AEs and laboratory tests.
The analysis of safety results for participants will follow a tiered approach (Table 6). The 
tiers differ with respect to the analyses that will be performed. Adverse events (specific terms 
as well as system organ class terms) and events that meet PDLCs in laboratory will be 
classified as belonging to “Tier 2” or “Tier 3” based on the number of events observed.
Safety parameters or adverse events of special interest that are identified a priori constitute 
“Tier 1” safety endpoints that will be subject to inferential testing for statistical significance. 
No a priori clinical events of concern have been identified for this study.
Tier 2 parameters will be assessed via point estimates with 95% confidence intervals 
provided for differences in the percentage of participants with events (via the unstratified 
Miettinen and Nurminen method (1985) [Miettinen, O. and Nurminen, M. 1985]).
Because many 95% confidence intervals for Tier 2 events may be provided without 
adjustment for multiplicity, the confidence intervals should be regarded as a helpful 
descriptive measure to be used in review, not a formal method for assessing the statistical 
significance of the between-group differences in adverse events and safety parameters that 
meet predefined limits of change.
ECIs identified in Section 8.4.7 are considered Tier 2 events, as well as the broad AE 
categories consisting of the percentage of participants with any AE, a drug-related AE, a 
serious AE, an AE, which is both drug-related and serious, and discontinuation due to an AE 
will be considered Tier 2 endpoints. In addition, individual AEs observed in ≥1% of 
participants in any intervention group will be categorized as a Tier 2 event. Events reported 
less frequently than in 1% of participants would obscure the assessment of the overall safety 
profile and add little to the interpretation of potentially meaningful differences.
Safety endpoints that are not Tier 2 events are considered Tier 3 events. Only point estimates 
by treatment group are provided for Tier 3 safety parameters.
Continuous Safety Measures
For continuous measures such as changes from baseline in laboratory parameters, summary 
statistics for baseline, on-treatment, and change from baseline values will be provided by 
treatment group in Table format.
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Table 6
Analysis Strategy for Safety Parameters
Safety Tier
Safety Endpoint
95% CI for 
Treatment 
Comparisona
Descriptive 
Statistics
Tier 2
ECIs
X
X
Any AE
X
X
Any Serious AE
X
X
Any Drug-Related AE
X
X
Any Serious and Drug-Related AE
X
X
Discontinuation due to AE
X
X
Specific AEs, SOCs, or PDLCs (incidence ≥1% of 
participants in one of the intervention groups)
X
X
Tier 3
Specific AEs, SOCs or PDLCs (incidence <1% of 
participants in all of the intervention groups)
X
Change from Baseline Results in selected laboratory 
test results
X
AE=adverse event; CI=confidence interval; PDLC=predefined limit of change; SOC=system organ class; 
X=results will be provided.
a
95% CIs will be based on the method of Miettinen and Nurminen [Miettinen, O. and Nurminen, M. 1985].
9.6.3
Demographic and Baseline Characteristics
The comparability of the intervention groups for each relevant demographic and baseline 
characteristic will be assessed by the use of tables. No statistical hypothesis tests will be 
performed on these characteristics. The number and percentage of participants screened and 
randomized and the primary reasons for screening failure and discontinuation will be 
displayed. Demographic variables, baseline characteristics, and prior and concomitant 
therapies will be summarized by intervention either by descriptive statistics or categorical 
tables.
9.7
Interim Analyses
Study enrollment is likely to be ongoing at the time of the interim analysis. Blinding to 
treatment assignment will be maintained at all investigational sites. The results of the interim 
analysis will not be shared with the investigators prior to the completion of the study. 
Participant-level unblinding will be restricted to an external unblinded statistician and 
scientific programmer performing the interim analysis, who will have no other 
responsibilities associated with the study.
An eDMC will serve as the primary reviewer of the interim data and will make 
recommendations for discontinuation of the study or protocol modifications to an executive 
committee of the Sponsor. If the eDMC recommends modifications to the design of the 
protocol or discontinuation of the study, this executive committee (and potentially other 
limited Sponsor personnel) may be unblinded to results at the treatment level to act on these 
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recommendations. The extent to which individuals are unblinded with respect to results of 
interim analyses will be documented. Additional details for this interim analysis and any 
other study data review will be provided in the eDMC Charter.
Results from the interim analysis will be provided to the eDMC by the unblinded statistician.
Prior to final study unblinding, the unblinded statistician will not be involved in any
discussions regarding modifications to the protocol, statistical methods, identification of
protocol deviations, or data validation efforts after the interim analyses.
This study will include an interim analysis when approximately 55% (or approximately 600
across the MOV and the placebo groups) of the participants with undetectable SARS-CoV-2 
in baseline NP swabs have either completed the Day 14 visit or discontinued from the study 
prior to the Day 14 visit. The purpose of this interim analysis is to review safety and allow 
for early stopping in the case of futility. There is no plan to stop the study early for efficacy. 
However, a small statistical penalty (α=0.0001) will be applied for this interim analysis using 
a Haybittle-Peto type adjustment [Haybittle, J. L. 1971] [Peto, R, et al 1976]. The final 
analysis will be conducted at a 0.0249 alpha-level to preserve the overall type I error level.
The allocation of the approximately 1100 participants with undetectable SARS-CoV-2 in 
baseline NP swabs randomized to the 2 intervention groups may not be in a 1:1 ratio, since 
SARS-CoV-2 in baseline NP swabs will not be available before randomization so that the 
number of participants in each group may vary. As an example, the case when approximately
660 participants with undetectable SARS-CoV-2 in baseline NP swabs and approximately
440 participants with undetectable SARS-CoV-2 in baseline NP swabs are randomized to
MOV and placebo groups, respectively, will be discussed in this section.
The Gamma family spending function with γ = -4 will be used to set the futility boundary for 
the primary endpoint as a guide for the eDMC to control overall type I error rate of 0.025, 
one-sided. Assuming the information fraction of 55%, the nonbinding futility boundary 
expressed on the risk difference (MOV minus placebo) is -0.0049. The boundary crossing 
probabilities for futility are 59.8% under H0 and 1.4% under H1 (risk difference of -0.048). 
Power assessments for additional scenarios where the number of participants with 
undetectable SARS-CoV-2 in baseline NP swabs may be different from the scenario 
described above are presented in Section 9.9.1.
9.8
Multiplicity
Two main objectives will be evaluated in this study. A gatekeeping procedure that controls 
the overall FWER associated with the primary and secondary analyses will be used. The 
primary hypothesis (H1) is that MOV is superior to placebo for the prevention of laboratory-
confirmed COVID-19 in participants with undetectable SARS-CoV-2 in baseline NP swabs
through Day 14. As stated in Section 9.6.1, the null hypothesis pt ≥ pc will be tested versus 
the alternative hypothesis pt < pc. The secondary hypothesis (H2) is that MOV is superior to 
placebo for the prevention of laboratory-confirmed COVID-19 in participants regardless of 
SARS-CoV-2 results in baseline NP swabs through Day 14. As stated in Section 9.6.1, this 
will be evaluated by testing the null hypothesis pts ≥ pcs versus the alternative hypothesis pts < 
pcs.
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As stated in Section 9.7, although there is no plan to stop the study early for efficacy, a small 
statistical penalty (α=0.0001) will be applied for this interim analysis using a Haybittle-Peto 
type adjustment [Haybittle, J. L. 1971] [Peto, R, et al 1976]. The final analysis will be 
conducted at a 0.0249 alpha-level to preserve the overall type I error level.
Testing begins with the primary hypothesis (H1). The secondary hypothesis (H2) will be 
tested only if H1 is rejected. Both tests will be performed at the same one-sided 2.49% 
alpha-level. If H1 fails to reach statistical significance, then H2 will not be tested. In this 
way, the overall one-sided 2.5% type I error rate is controlled.
9.9
Sample Size and Power Calculations
9.9.1
Sample Size and Power Calculations for Efficacy Analyses (Primary 
Objective)
The study will enroll approximately 1376 participants (regardless of SARS-CoV-2 results in 
baseline NP swabs) in a 1:1 ratio to MOV and placebo groups. Assuming approximately 80% 
of the 1376 participants will have undetectable SARS-CoV-2 at baseline (see Section 4.2.3), 
approximately 1100 participants will have undetectable SARS-CoV-2 at baseline and 276 
participants will have detectable SARS-CoV-2 at baseline.
The primary endpoint of this study is the percentage of participants with undetectable SARS-
CoV-2 in baseline NP swabs developing COVID-19 through Day 14. Thus, the primary 
analysis population consists of the approximately 1100 participants with undetectable 
SARS-CoV-2 at baseline, which is a subset of the 1376 participants randomized that is based 
on a factor (SARS-CoV-2 results in baseline NP swabs) that will not be available before 
randomization.
Moreover, because this factor cannot be used for stratification at randomization, the 
allocation of the participants with undetectable SARS-CoV-2 in baseline NP swabs
randomized to the 2 intervention groups may not be in a 1:1 ratio. If at least 10% of the 
approximately 276 participants with detectable SARS-CoV-2 in baseline NP swabs are 
randomized to the MOV group, the study has at least 90% power to demonstrate the 
superiority of MOV over placebo for participants with undetectable SARS-CoV-2 in baseline 
NP swabs at an overall one-sided 2.5% alpha-level. The power and sample size calculation 
for the primary objective were computed using EAST and based on the following 
assumptions:
•
The percentage of participants with undetectable SARS-CoV-2 in baseline NP swabs is 
assumed to be 80% among the 1376 participants (see Section 4.2.3), resulting in 
approximately 1100 participants with undetectable SARS-CoV-2 in baseline NP swabs.
•
The background secondary attack rate, in the absence of MOV, for participants with 
undetectable SARS-CoV-2 in baseline NP swabs, is assumed to be ~8% [Regeneron 
Pharmaceuticals, Inc. 2021].
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•
MOV is assumed to reduce the background secondary attack rate for participants with 
undetectable SARS-CoV-2 in baseline NP swabs by 60%, resulting in a secondary attack 
rate of ~3.2% in the MOV group.
•
A futility interim analysis at 55% information as outlined in Section 9.7. The 
Haybittle-Peto type adjustment [Haybittle, J. L. 1971] [Peto, R, et al 1976] with a small 
amount of alpha (α=0.0001) will be applied to this interim analysis.
Some selected power and sample size calculations are presented in Table 7, including the 
extreme cases where all participants with detectable SARS-CoV-2 in baseline NP swabs are 
either in the MOV or the placebo group, and some less-extreme scenarios:
1. In the scenario where the approximately 276 participants with detectable SARS-CoV-2 in 
baseline NP swabs are balanced between the 2 intervention groups (allocation ratio of 1), 
approximately 550 participants with undetectable SARS-CoV-2 in baseline NP swabs 
would be randomized to each group.
2. In the scenario where the approximately 276 participants are all randomized to the MOV 
group, there would be approximately 412 participants with undetectable SARS-CoV-2 in 
baseline NP swabs in this group versus approximately 688 in the placebo group, with an 
allocation ratio (MOV versus placebo) of 0.6.
3. In the scenario where the approximately 276 participants are all randomized to the 
placebo group, there would be approximately 688 participants with undetectable SARS-
CoV-2 in baseline NP swabs in the MOV group versus approximately 412 in the placebo
group with an allocation ratio of 1.67.
4. Two additional scenarios with allocation ratios of 1.5 and 0.85 are also provided.
All scenarios are based on a total sample size of 1100 participants with undetectable SARS-
CoV-2 in baseline NP swabs and an overall one-sided, 2.5% alpha-level.
Table 7
Power Analysis to Assess the Primary Objective in Participants With 
Undetectable SARS-CoV-2 in Baseline NP Swabs; N=1100 Participants, Overall 
Alpha=0.025, One-sided
Sample Size
Allocation Ratio
Sample Size in 
MOV
Sample Size in 
Placebo
Power (%)
1100
1.67
688
412
89
1100
1.5
660
440
90
1100
1
550
550
93
1100
0.85
505
595
94
1100
0.6
412
688
94
MOV=molnupiravir; NP=nasopharyngeal
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As shown in Table 7, the power in the first scenario (the extreme case where all 
approximately 276 participants with detectable SARS-CoV-2 in baseline NP swabs are in the 
placebo group) is approximately 89%. In scenarios where at least 10% of the participants 
with detectable SARS-CoV-2 in baseline NP swabs are in the MOV group, there is at least 
90% power.
Moreover, as long as the event rate reduction is at least 54%, the study has over 80% power 
in the most extreme scenario (when all participants with detectable SARS-CoV-2 in baseline 
NP swabs, expected to be approximately 276, are in the placebo group).
9.9.2
Sample Size and Power Calculations for Efficacy Analyses (Secondary 
Objective)
The secondary endpoint associated with a hypothesis of this study is the percentage of 
participants developing COVID-19 through Day 14, regardless of SARS-CoV-2 results in 
baseline NP swabs. The related analysis population will consist of participants in the mITT 
population (see Section 9.5.1), approximately 1376 participants.
The power and sample size calculation for the secondary objective were computed using 
EAST and based on the following assumptions in addition to the assumptions listed in the 
previous section:
•
The percentage of participants with detectable SARS-CoV-2 in baseline NP swabs is 
assumed to be 20% among the 1376 participants (see Section 4.2.3), resulting in 
approximately 276 participants with detectable SARS-CoV-2 in baseline NP swabs.
•
The background secondary attack rate, in the absence of MOV, for participants with 
detectable SARS-CoV-2 in baseline NP swabs, is assumed to be ~40% based on the 
secondary attack rate calculated for the virus-positive participants in the REGEN-COV™ 
prophylaxis study [O'Brien, M. P., et al 2021] [Food and Drug Administration 2021].
•
The secondary attack rate for participants in the MOV group with detectable SARS-CoV-
2 in baseline NP swabs is ~28% (with a risk reduction of 30% relative to the placebo 
group based on the reduction observed with REGEN-COV™ in this population)
[O'Brien, M. P., et al 2021] [Food and Drug Administration 2021].
Since the SARS-CoV-2 viral status at baseline will not be available before randomization, 
there is a potential imbalance in the 2 study intervention groups for participants with 
undetectable and detectable SARS-CoV-2 in baseline NP swabs. This also leads to different 
potential allocation ratios of participants with undetectable versus detectable SARS-CoV-2 in 
baseline NP swabs in the 2 study intervention groups. Assessment of power for this 
comparison is presented under 3 selected scenarios in Table 8:
•
Scenario with more participants with detectable SARS-CoV-2 in baseline NP swabs in 
the MOV group (as listed in Table 7). There are approximately 188 participants with 
detectable SARS-CoV-2 in baseline NP swabs and 500 participants with undetectable 
SARS-CoV-2 in baseline NP swabs randomized to the MOV group. Approximately 88
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participants with detectable SARS-CoV-2 in baseline NP swabs and 600 participants with 
undetectable SARS-CoV-2 in baseline NP swabs are randomized to the placebo group.
•
Equal allocation scenario: There are approximately 138 participants with detectable 
SARS-CoV-2 in baseline NP swabs and 550 participants with undetectable SARS-CoV-2 
in baseline NP swabs randomized to in each of the 2 intervention groups.
•
Scenario with more participants with detectable SARS-CoV-2 in baseline NP swabs in 
the placebo group (as listed in Table 7 and described in Section 9.7). There are
approximately 28 participants with detectable SARS-CoV-2 in baseline NP swabs and 
660 participants with undetectable SARS-CoV-2 in baseline NP swabs randomized to the 
MOV group. Approximately 248 participants with detectable SARS-CoV-2 in baseline 
NP swabs and 440 participants with undetectable SARS-CoV-2 in baseline NP swabs are 
randomized to the placebo group.
All scenarios below are based on a total sample size of 1376 participants and an overall one-
sided, 2.5% alpha-level.
Table 8
Power Analysis to Assess the Secondary Objective Participants; N=1376 Overall 
Alpha=0.025, One-Sided
Sample 
Size
Sample Size
Power (%)
V-
V+
Total
MOV
Placebo
MOV
Placebo
MOV
Placebo
1376
500
600
188
88
688
688
24
1376
550
550
138
138
688
688
95
1376
660
440
28
248
688
688
>99
MOV=molnupiravir; NP=nasopharyngeal; V- = undetectable SARS-CoV-2 in baseline NP swabs; V+ = detectable SARS-CoV-2 in 
baseline NP swabs
As shown in Table 8, the power for the secondary objective analysis is greater than 90% in 
second and third scenarios, given the stated assumptions. There is substantially less power in 
the first scenario where there is a marked and unfavorable imbalance in randomization of the 
participants with detectable SARS-CoV-2 in NP swabs, causing the difference in the overall
secondary attack rates between the 2 intervention groups to be smaller.
9.9.3
Sample Size and Power Calculations for Safety Analyses
There will be approximately 1376 participants in total (approximately 688 participants in 
each intervention group) included for the analysis of safety endpoints.
Table 9 demonstrates the difference in the percentage of participants with an AE (MOV
minus placebo) that can be ruled out with different power levels and 95% confidence when 
there are approximately 688 participants in each intervention group. The underlying 
percentage of participants with the AE is assumed to be the same for the 2 intervention 
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groups. For example, for an AE that occurs in 10% of participants in both groups, the study 
has 80% power to show with 95% confidence that the true difference between the treatment 
groups is no more than 5.0% percentage points. The calculations are based on an asymptotic 
method proposed by Miettinen and Nurminen [Miettinen, O. and Nurminen, M. 1985].
Table 9
Difference in Percentage of Participants With AEs (MOV Minus Placebo) That 
Can be Ruled Out With 688 Participants in Each Group
Target Power
Underlying Percentage of Participants With AE
1%
5%
10%
20%
80
2.2%
3.8%
5.0%
6.4%
85
2.4%
4.1%
5.4%
6.8%
90
2.6%
4.5%
5.9%
7.4%
AE=adverse event; CI=confidence interval; MOV=molnupiravir.
Note: The upper bound of the 2-sided 95% CI (Miettinen and Nurminen method [Miettinen, O. and 
Nurminen, M. 1985]) for the difference in percentages of participants with AEs (MOV minus placebo) 
assuming the percentages are the same.
The probability of observing at least 1 of a particular type of AE in this study depends on the
number of participants treated and the underlying percentage of participants with that AE in
the study population. If the underlying percentage of participants with a particular AE is 
0.1%, there is 49.8% chance of observing at least 1 AE among 688 participants in an 
intervention group. If no AE of that type is observed among the 688 participants in an 
intervention group, this study will provide 97.5% confidence that the underlying percentage 
of participants with that particular AE is <0.6% (1 of approximately every participants).
The estimate of, and the upper bound of the 95% CI for, the underlying percentage of
participants with an AE given various hypothetical observed numbers of participants with the
AE within each treatment group are provided in Table 10. These calculations are based on
the exact binomial method proposed by Clopper and Pearson [Clopper, C. J. 1934].
Table 10
Percentage of Participants with AEs and 95% Upper Confidence Bound Based on 
Hypothetical Numbers of Participants with AEs (688 Participants per Group)
Hypothetical Numbers of 
Participants with AEs
Percentage
95% Upper Confidence Bounda
0
0.0%
0.5%
14
2.0%
3.4%
40
5.8%
7.8%
55
8.0%
10.3%
69
10.0%
12.5%
AE=adverse event; CI=confidence interval
a Based on the 2-tailed exact CI for a binomial proportion (Clopper and Pearson method [Clopper, C. J. 
1934]). 
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9.10
Subgroup Analyses
To determine whether the treatment effect is consistent across various subgroups, the 
estimate of the between-group treatment effect (with a nominal 95% CI) for the primary 
endpoint will be estimated and plotted within each category of each subgroup. The following 
are examples of classification variables:
•
Baseline SARS-CoV-2 NP swab result (undetectable, detectable)
•
Baseline serology result for anti-SARS-CoV-2 antibodies (positive, negative)
•
Age category (≤60, >60 years)
•
Household size (≤3, >3 household residents)
•
Sex (female, male)
•
Race (American Indian or Alaska Native, Asian, Black or African American, White)
•
Geographic region (North America, Europe, Asia Pacific, Latin America, Africa)
9.11
Compliance (Medication Adherence)
Compliance will be calculated based on capsule counts. For a participant who is followed up
for the entire study treatment period, the “Number of Capsules Should be Taken” is the total 
number of capsules that should be taken from randomization to the last scheduled day for 
treatment administration for that participant. For a participant who discontinues from the 
study treatment, the “Number of Capsules Should be Taken” is the total Number of Capsules 
should be taken from randomization to the date of the last dose of study intervention. The 
“Number of Capsules Taken” will be based on data reported in the eCRF.
For each participant, percent compliance will then be calculated using the following formula:
Summary statistics will be provided on percent compliance by treatment group for the mITT.
9.12
Extent of Exposure
The Extent of Exposure to study treatment will be evaluated by summary statistics (N, mean, 
median, standard deviation) for the “Number of Capsules Taken” by treatment group.
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10
SUPPORTING DOCUMENTATION AND OPERATIONAL 
CONSIDERATIONS
10.1
Appendix 1: Regulatory, Ethical, and Study Oversight Considerations
10.1.1
Code of Conduct for Clinical Trials
Merck Sharp & Dohme LLC, Rahway, NJ, USA (MSD)
Code of Conduct for Interventional Clinical Trials
I. Introduction
A. Purpose
MSD, through its subsidiaries, conducts clinical trials worldwide to evaluate the safety and effectiveness of our 
products. As such, we are committed to designing, implementing, conducting, analyzing, and reporting these trials 
in compliance with the highest ethical and scientific standards. Protection of participants in clinical trials is the 
overriding concern in the design and conduct of clinical trials. In all cases, MSD clinical trials will be conducted 
in compliance with local and/or national regulations (including all applicable data protection laws and
regulations), and International Council for Harmonisation Good Clinical Practice (ICH-GCP), and also in 
accordance with the ethical principles that have their origin in the Declaration of Helsinki.
B. Scope
Highest ethical and scientific standards shall be endorsed for all clinical interventional investigations sponsored by 
MSD irrespective of the party (parties) employed for their execution (e.g., contract research organizations, 
collaborative research efforts). This Code is not intended to apply to trials that are observational in nature, or 
which are retrospective. Further, this Code does not apply to investigator-initiated trials, which are not under the 
full control of MSD.
II. Scientific Issues
A. Trial Conduct
1. Trial Design
Except for pilot or estimation trials, clinical trial protocols will be hypothesis-driven to assess safety, efficacy 
and/or pharmacokinetic or pharmacodynamic indices of MSD or comparator products. Alternatively, MSD 
may conduct outcomes research trials, trials to assess or validate various endpoint measures, or trials to 
determine patient preferences, etc.
The design (i.e., participant population, duration, statistical power) must be adequate to address the specific 
purpose of the trial and shall respect the data protection rights of all participants, trial site staff and, where 
applicable, third parties. All trial protocols are and will be assessed for the need and capability to enroll 
underrepresented groups. Participants must meet protocol entry criteria to be enrolled in the trial. 
2. Site Selection
MSD’s clinical trials are conducted globally in many different countries and in diverse populations, including 
people of varying age, race, ethnicity, gender, and accounting for other potential disease related factors. MSD 
selects investigative sites based on medical expertise, access to appropriate participants, adequacy of facilities 
and staff, previous performance in clinical trials, as well as budgetary considerations. Prior to trial initiation, 
sites are evaluated by MSD personnel (or individuals acting on behalf of MSD) to assess the ability to 
successfully conduct the trial.
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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 
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.
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C. Confidentiality
MSD is committed to safeguarding participant confidentiality, to the greatest extent possible, as well as all 
applicable data protection rights. Unless required by law, only the investigator, Sponsor (or individuals acting on 
behalf of MSD), ethics committee, and/or regulatory authorities will have access to confidential medical records 
that might identify the participant by name.
D. Genomic Research
Genomic research will only be conducted in accordance with a protocol and informed consent authorized by an 
ethics committee.
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 
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information to the Sponsor in the United States for these purposes. This may involve the 
transmission of information to countries that do not have laws protecting personal data.
10.1.3
Data Protection
The Sponsor will conduct this study in compliance with all applicable data protection 
regulations.
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 
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and qualifications of the IRB/IEC members and to make these records available for 
regulatory agency review upon request by those agencies.
10.1.4
Committees Structure
10.1.4.1
Executive Oversight Committee
The EOC is comprised of members of Sponsor Senior Management. The EOC will receive 
and decide on any recommendations made by the eDMC regarding the study.
10.1.4.2
External Data Monitoring Committee
To supplement the routine study monitoring outlined in this protocol, an external DMC will 
monitor the interim data from this study. The voting members of the committee are external 
to the Sponsor. The members of the DMC must not be involved with the study in any other 
way (eg, they cannot be study investigators) and must have no competing interests that could 
affect their roles with respect to the study.
The DMC will make recommendations to the EOC regarding steps to ensure both participant 
safety and the continued ethical integrity of the study. Also, the DMC will review interim 
study results, consider the overall risk and benefit to study participants (Section 9.7 [Interim 
Analysis]) and recommend to the EOC whether the study should continue in accordance with 
the protocol.
Specific details regarding composition, responsibilities, and governance, including the roles 
and responsibilities of the various members and the Sponsor protocol team; meeting 
facilitation; the study governance structure; and requirements for and proper documentation 
of DMC reports, minutes, and recommendations will be described in the DMC charter that is 
reviewed and approved by all the DMC members.
10.1.5
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.
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10.1.6
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.
10.1.7
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.
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.
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10.1.8
Data Quality Assurance
All participant data relating to the study will be recorded on printed or electronic CRF unless 
transmitted to the Sponsor or designee electronically (eg, laboratory data). The investigator 
or qualified designee is responsible for verifying that data entries are accurate and correct by 
physically or electronically signing the CRF.
Detailed information regarding Data Management procedures for this protocol will be 
provided separately.
The investigator must maintain accurate documentation (source data) that supports the 
information entered in the CRF.
The investigator must permit study-related monitoring, audits, IRB/IEC review, and 
regulatory agency inspections and provide direct access to source data documents.
Study documentation will be promptly and fully disclosed to the Sponsor by the investigator 
upon request and also shall be made available at the study site upon request for inspection, 
copying, review, and audit at reasonable times by representatives of the Sponsor or any 
regulatory authorities. The investigator agrees to promptly take any reasonable steps that are 
requested by the Sponsor or any regulatory authorities as a result of an audit or inspection to 
cure deficiencies in the study documentation and worksheets/CRFs.
The Sponsor or designee is responsible for the data management of this study including 
quality checking of the data.
Study monitors will perform ongoing source data review and verification to confirm that data 
entered into the CRF by authorized site personnel are accurate, complete, and verifiable from 
source documents; that the safety and rights of participants are being protected; and that the 
study is being conducted in accordance with the currently approved protocol and any other 
study agreements, ICH GCP, and all applicable regulatory requirements.
Records and documents, including participants’ documented informed consent, pertaining to 
the conduct of this study must be retained by the investigator for 15 years after study 
completion unless local regulations or institutional policies require a longer retention period. 
No records may be destroyed during the retention period without the written approval of the 
Sponsor. No records may be transferred to another location or party without written 
notification to the Sponsor.
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10.1.9
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.
10.1.10
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 11 will be performed by the central laboratory. (Note: Local 
laboratory assessment of protocol-required safety laboratory assessments [chemistry, 
hematology, and pregnancy] may be permissible under extenuating circumstances. 
Sponsor approval must be obtained, and results must be recorded in the appropriate 
eCRF).
•
Documentation of the index’s first detectable SARS-CoV-2 local laboratory test result 
from a sample collected within 5 days prior to randomization of the potential 
participant(s) in the study is required.
•
Other local laboratory results are only required if the central laboratory results are not 
available in time for participant management, or for either study intervention 
administration and/or response evaluation. If a collection of a local sample is required, it 
is important that the sample for central analysis is obtained first (eg, NP swab). 
Additionally, if the local laboratory results are used for participant management, or to 
make either a study intervention decision or response evaluation, the results must be 
entered into the eCRF.
•
Protocol-specific requirements for inclusion or exclusion of participants are detailed in 
Section 5 of the protocol.
•
Additional tests may be performed at any time during the study as determined necessary 
by the investigator or required by local regulations.
•
The investigator (or medically qualified designee) must document their review of each 
laboratory safety report (eg, hematology, chemistry, pregnancy).
•
Laboratory/analyte results that could unblind the participant’s intervention group will not 
be reported to blinded site and Sponsor personnel. These laboratory results include, but
may not be limited to virology results with the exception of screening results and error 
reports.
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Table 11
Protocol-required Clinical Laboratory Assessments
Laboratory 
Assessments
Parameters
Hematology
Platelet Count 
RBC Indices:
MCV
MCH
RDW
WBC count with Differential:
Neutrophils
Lymphocytes
Monocytes
Eosinophils
Basophils
Calculation of: 
Neutrophil/lymphocyte ratio
Absolute Neutrophil Count
RBC Count
Hemoglobin
Hematocrit
Chemistry
BUN
Chloride
AST/SGOT
Albumin
Calcium
ALT/SGPT
Creatinine
Phosphorous
Alkaline phosphatase
Glucose 
(nonfasting)
Amylase
GGT
Potassium
Lipase
LDH
Bicarbonate
Total Protein
Total bilirubin (and direct bilirubin if 
total bilirubin is elevated above the 
ULN)
Sodium
Magnesium
CK
Pregnancy Testing

Urine or Serum hCG pregnancy test (as needed for WOCBP)
Serology

SARS-CoV-2 Antibodies
Virology

SARS-CoV-2 RNA (RT-PCR; qualitative and quantitative) from NP swab samples

SARS-CoV-2 Gene Sequencing
Other Laboratory 
Assessments

Testing for other respiratory pathogens is planned from NP swab samples.
ALT=alanine aminotransferase; AST=aspartate aminotransferase; BUN=blood urea nitrogen; CK=creatine kinase; 
GGT=gamma-glutamyl transferase; hCG=human chorionic gonadotropin; LDH=lactate dehydrogenase; MCH=mean 
corpuscular hemoglobin; MCV=mean corpuscular volume; NP=nasopharyngeal; RBC=red blood cell; RDW=red cell 
distribution width; RNA=ribonucleic acid; RT-PCR=reverse transcription polymerase chain reaction; 
SARS-CoV-2=severe acute respiratory syndrome coronavirus 2; SGOT=serum glutamic-oxaloacetic transaminase; 
SGPT=serum glutamic-pyruvic transaminase; ULN=upper limit of normal; WBC=white blood cell; WOCBP=women of 
childbearing potential.
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Table 12
Approximate Whole Blood Volumes (mL) for Clinical Laboratory Assessments
Study Period:
Screening
Intervention
Follow-up
Visit Number/Name:
1
2
3
4
5
6
COVID-19 
Confirmation 
Visit
Total Blood 
Volume
Scheduled Day (Window)
(≤5 days prior 
to rand)
Day 1
Day 5
(+ 2 days)
EOT
Day 14
(+3 days)
Day 21 
(+3 days)
Day 29 (+3 
days)
LFU
Laboratory Assessment
Chemistrya (Day 14 includes 
serum pregnancy)
Per Local 
Requirements
2.5
2.5
2.5
N/A
N/A
N/A
10.0
Hematologya
N/A
2.0
2.0
2.0
N/A
N/A
N/A
8.0
Anti-SARS-CoV-2 Antibody 
Serology Testing
N/A
5.0
N/A
5.0
N/A
5.0
N/A
15.0
Total
N/A
9.5
4.5
9.5
N/A
5.0
N/A
33.0
COVID-19=coronavirus infectious disease 2019; EOT=end of treatment (day of last study intervention dose); LFU=Late Follow-Up; N/A=not applicable; SARS-CoV-2=severe 
acute respiratory syndrome coronavirus 2
a
Where local safety laboratories are permitted on days other than screening (see Appendix 2), volumes will be per local requirements.
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10.3
Appendix 3: Adverse Events: Definitions and Procedures for Recording, 
Evaluating, Follow-up, and Reporting
10.3.1
Definition of AE
AE definition
•
An AE is any untoward medical occurrence in a clinical study participant, temporally 
associated with the use of study intervention, whether or not considered related to the 
study intervention.
•
Note: An AE can therefore be any unfavorable and unintended sign (including an 
abnormal laboratory finding), symptom, or disease (new or exacerbated) temporally 
associated with the use of a study intervention.
•
Note: For purposes of AE definition, study intervention (also referred to as Sponsor’s 
product) includes any pharmaceutical product, biological product, vaccine, diagnostic 
agent, medical device, combination product, or protocol specified procedure whether 
investigational or marketed (including placebo, active comparator product, or run-in 
intervention), manufactured by, licensed by, provided by, or distributed by the Sponsor 
for human use in this study.
Events meeting the AE definition
•
Any abnormal laboratory test results (hematology, clinical chemistry, or urinalysis) or 
other safety assessments (eg, ECG, radiological scans, vital signs measurements), 
including those that worsen from baseline, considered clinically significant in the medical 
and scientific judgment of the investigator.
•
Exacerbation of a chronic or intermittent 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.”
•
Any new cancer or progression of existing cancer.
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Events NOT meeting the AE definition
•
Medical or surgical procedure (eg, endoscopy, appendectomy): the condition that leads to 
the procedure is the AE.
•
Situations in which an untoward medical occurrence did not occur (social and/or 
convenience admission to a hospital).
•
Anticipated day-to-day fluctuations of 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.
10.3.2
Definition of SAE
If an event is not an AE per definition above, then it cannot be an SAE even if serious 
conditions are met.
An SAE is defined as any untoward medical occurrence that, at any dose:
a.
Results in death
b.
Is life-threatening
•
The term “life-threatening” in the definition of “serious” refers to an event in which 
the participant was at risk of death at the time of the event. It does not refer to an 
event, which hypothetically might have caused death, if it were more severe.
c.
Requires inpatient hospitalization or prolongation of existing hospitalization
•
Hospitalization is defined as an inpatient admission, regardless of length of stay, even 
if the hospitalization is a precautionary measure for continued observation. (Note: 
Hospitalization for an elective procedure to treat a 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.
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•
This definition is not intended to include experiences of relatively minor medical 
significance such as uncomplicated headache, nausea, vomiting, diarrhea, influenza, 
and accidental trauma (eg, sprained ankle) that may interfere with or prevent 
everyday life functions but do not constitute a substantial disruption.
e.
Is a congenital anomaly/birth defect
•
In offspring of participant taking the product regardless of time to diagnosis.
f.
Other important medical events
•
Medical or scientific judgment should be exercised in deciding whether SAE 
reporting is appropriate in other situations such as important medical events that may 
not be immediately life-threatening or result in death or hospitalization but may 
jeopardize the participant or may require medical or surgical intervention to prevent 1 
of the other outcomes listed in the above definition. These events should usually be 
considered serious.
•
Examples of such events include invasive or malignant cancers, intensive treatment in 
an emergency room or at home for allergic bronchospasm, blood dyscrasias or 
convulsions that do not result in hospitalization, or development of drug dependency 
or drug abuse.
10.3.3
Additional Events Reported
Additional events that require reporting
In addition to the above criteria, AEs meeting either of the below criteria, although not 
serious per ICH definition, are reportable to the Sponsor.
•
Is a cancer
•
Is associated with an overdose
10.3.4
Recording AE and SAE
AE and SAE recording
•
When an AE/SAE occurs, it is the responsibility of the investigator to review all 
documentation (eg, hospital progress notes, laboratory, and diagnostics reports) related to 
the event.
•
The investigator will record all relevant AE/SAE information on the AE 
CRFs/worksheets at each examination.
•
It is not acceptable for the investigator to send photocopies of the participant’s medical 
records to the Sponsor in lieu of completion of the AE CRF page.
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•
There may be instances when copies of medical records for certain cases are requested by 
the Sponsor. In this case, all participant identifiers, with the exception of the participant 
number, will be blinded on the copies of the medical records before submission to the 
Sponsor.
•
The investigator will attempt to establish a diagnosis of the event based on signs, 
symptoms, and/or other clinical information. In such cases, the diagnosis (not the 
individual signs/symptoms) will be documented as the AE/SAE.
Assessment of intensity/toxicity
•
An event is defined as “serious” when it meets at least 1 of the predefined outcomes as 
described in the definition of an SAE, not when it is rated as severe.
•
The investigator will make an assessment of intensity for each AE and SAE (and other 
reportable safety event) by recording the grade according to the NIH DAIDS Table for 
Grading the Severity of Adult and Pediatric Adverse Events, version 2.1. Any AE which 
changes DAIDS grade over the course of a given episode will have each change of grade 
recorded on the AE CRFs/worksheets.
- Grade 1 Mild event: Mild symptoms causing no or minimal interference with usual 
social and functional activities with intervention not indicated.
- Grade 2 Moderate event: Moderate symptoms causing greater than minimal 
interference with usual social and functional activities with intervention indicated.
- Grade 3 Severe event: Severe symptoms causing inability to perform usual social and 
functional activities with intervention or hospitalization indicated.
- Grade 4 Potentially life-threatening event: Potentially life-threatening symptoms 
causing inability to perform basic self-care functions with intervention indicated to 
prevent permanent impairment, persistent disability, or death.
- Grade 5 Death: Deaths related to an AE.
Assessment of causality
•
Did the Sponsor’s product cause the AE?
•
The determination of the likelihood that the Sponsor’s product caused the AE will be 
provided by an investigator who is a qualified physician. The investigator’s signed/dated 
initials on the source document or worksheet that supports the causality noted on the AE 
form, ensures that a medically qualified assessment of causality was done. This initialed 
document must be retained for the required regulatory time frame. The criteria below are 
intended as reference guidelines to assist the investigator in assessing the likelihood of a 
relationship between the test product and the AE based upon the available information.
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•
The following components are to be used to assess the relationship between the 
Sponsor’s product and the AE; the greater the correlation with the components and 
their respective elements (in number and/or intensity), the more likely the Sponsor’s 
product caused the AE:
- Exposure: Is there evidence that the participant was actually exposed to the 
Sponsor’s product such as: reliable history, acceptable compliance assessment (pill 
count, diary, etc), expected pharmacologic effect, or measurement of 
drug/metabolite in bodily specimen?
- Time Course: Did the AE follow in a reasonable temporal sequence from 
administration of the Sponsor’s product? Is the time of onset of the AE compatible 
with a drug-induced effect (applies to studies with investigational medicinal 
product)?
- Likely Cause: Is the AE not reasonably explained by another etiology such as 
underlying disease, other drug(s)/vaccine(s), or other host or environmental factors.
- Dechallenge: Was the Sponsor’s product discontinued or dose/exposure/frequency 
reduced?
◦
If yes, did the AE resolve or improve?
◦
If yes, this is a positive dechallenge.
◦
If no, this is a negative dechallenge.
(Note: This criterion is not applicable if: (1) the AE resulted in death or permanent 
disability; (2) the AE resolved/improved despite continuation of the Sponsor’s 
product; (3) the study is a single-dose drug study; or (4) Sponsor’s product(s) is/are 
only used 1 time.)
- Rechallenge: Was the participant re-exposed to the Sponsor’s product in this study?
◦
If yes, did the AE recur or worsen?
◦
If yes, this is a positive rechallenge.
◦
If no, this is a negative rechallenge.
(Note: This criterion is not applicable if: (1) the initial AE resulted in death or 
permanent disability, or (2) the study is a single-dose drug study; or (3) Sponsor’s 
product(s) is/are used only 1 time.)
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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 
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.
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Follow-up of AE and SAE
•
The investigator is obligated to perform or arrange for the conduct of supplemental 
measurements and/or evaluations as medically indicated or as requested by Sponsor to 
elucidate the nature and/or causality of the AE or SAE as fully as possible. This may 
include additional laboratory tests or investigations, histopathological examinations, or 
consultation with other healthcare professionals.
•
New or updated information will be recorded in the CRF.
•
The investigator will submit any updated SAE data to the Sponsor within 24 hours of 
receipt of the information.
10.3.5
Reporting of AEs, SAEs, and Other Reportable Safety Events to the Sponsor
AE, SAE, and other reportable safety event reporting to Sponsor via electronic data 
collection tool
•
The primary mechanism for reporting to the Sponsor will be the EDC tool.
-
Electronic reporting procedures can be found in the EDC data entry guidelines (or 
equivalent).
-
If the electronic system is unavailable for more than 24 hours, then the site will 
use the paper AE Reporting form.
◦
Reference Section 8.4.1 for reporting time requirements.
•
The site will enter the SAE data into the electronic system as soon as it becomes 
available.
•
After the study is completed at a given site, the EDC tool will be taken off-line to prevent 
the entry of new data or changes to existing data.
•
If a site receives a report of a new SAE from a study participant or receives updated data 
on a previously reported SAE after the EDC tool has been taken off-line, then the site can 
report this information on a paper SAE form or by telephone (see next section).
•
Contacts for SAE reporting can be found in the Investigator Study File Binder (or 
equivalent).
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SAE reporting to the Sponsor via paper CRF
•
If the EDC tool is not operational, facsimile transmission or secure e-mail of the SAE 
paper CRF is the preferred method to transmit this information to the Sponsor.
•
In rare circumstances and in the absence of facsimile equipment, notification by 
telephone is acceptable with a copy of the SAE data collection tool sent by overnight 
mail or courier service.
•
Initial notification via telephone does not replace the need for the investigator to 
complete and sign the SAE CRF pages within the designated reporting time frames.
•
Contacts and instructions for SAE reporting and paper reporting procedures can be found 
in the Investigator Study File Binder (or equivalent).
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10.4
Appendix 4: 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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10.5.2
Contraception Requirements
Contraceptives allowed during the study includea:
Highly Effective Contraceptive Methods That Have Low User Dependency
Failure rate of <1% per year when used consistently and correctly.
•
Progestogen-only subdermal contraceptive implantb
•
IUSc
•
Non-hormonal IUD
•
Bilateral tubal occlusion (tubal occlusion includes tubal ligation)
•
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.
Highly Effective Contraceptive Methods That Are User Dependentd (must be used in combination with a barrier 
method)
•
Combined (estrogen- and progestogen-containing) hormonal contraceptionb
-
Oral
-
Intravaginal
-
Transdermal
-
Injectable
•
Progestogen-only hormonal contraceptionb
-
Oral
-
Injectable
Barrier methods to be used with user dependent hormonal methods above (male condoms are preferred method)
•
Male or female condom with or without spermicide
•
Cervical cap, diaphragm, or sponge with spermicide 
A combination of male condom with either cervical cap, diaphragm, or sponge with spermicide (double barrier methods)
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.
d
Failure rate of <1% per year when used consistently and correctly (and not in combination with barrier method). Typical 
use failure rates are higher than perfect-use failure rates (ie, when used consistently and correctly).
Note: The following are not acceptable methods of contraception alone or in combination:
- Periodic abstinence (calendar, symptothermal, post-ovulation methods), withdrawal (coitus interruptus), 
spermicides only, and LAM.
- Male and female condom should not be used together (due to risk of failure with friction).
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10.6
Appendix 6: Collection and Management of Specimens for Future Biomedical 
Research
1. Definitions
a.
Biomarker: A biological molecule found in blood, other body fluids, or tissues that is
a sign of a normal or abnormal process or of a condition or disease. A biomarker may
be used to see how well the body responds to a treatment for a disease or condition.1
b. Pharmacogenomics: The investigation of variations of DNA and RNA characteristics 
as related to drug/vaccine response.2
c.
Pharmacogenetics: A subset of pharmacogenomics, pharmacogenetics is the influence 
of variations in DNA sequence on drug/vaccine response.2
d. DNA: Deoxyribonucleic acid.
e.
RNA: Ribonucleic acid.
2. Scope of Future Biomedical Research3,4
The specimens consented and/or collected in this study as outlined in Section 8.10 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
10.7.1
Country-specific Requirements for Argentina
Section 1.3.1 Schedule of Activities
HBV, HCV, and HIV testing at screening is mandatory.
Section 8.1.2 Inclusion/Exclusion Criteria
HBV, HCV, and HIV testing at screening is mandatory.
10.7.2
Country-specific Requirements for France
Section 1.3.1 Schedule of Activities
Footnote g: In France and associated territories, the following laboratory results must also be 
available for all participants within 5 days prior to administration of the first dose of study 
intervention to support determination of eligibility: serum creatinine, platelets, and absolute 
neutrophil count.
Section 8.1.2 Inclusion/Exclusion Criteria
For participants enrolled in France and associated territories, participants with any of the 
following conditions are excluded:

A neutrophilic granulocyte absolute count <500/mm3

A platelet count <100,000/µL or received a platelet transfusion in the 5 days prior to 
randomization

On dialysis or has reduced eGFR <30 mL/min/1.73 m2 by the MDRD equation
(Appendix 9):
eGFR (mL/min/1.73 m2) = 175 × (SCr)-1.154 × (age)-0.203 × 0.742 [if female] × 1.212 
[if African American]
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10.8
Appendix 8: Individuals at Increased Risk for Severe Illness from COVID-19
Individuals with at least 1 of the following characteristics or underlying medical conditions 
are at increased risk for severe illness from COVID-19, as adapted from the US CDC 
[Centers for Disease Control and Prevention 2020] [Centers for Disease Control and 
Prevention 2021] [Centers for Disease Control and Prevention 2020] [Centers for Disease 
Control and Prevention 2021] and the WHO [World Health Organization 2020]:

Age >60 years

Active cancer (excluding minor cancers not associated with immunosuppression or 
significant morbidity/mortality [eg, basal cell carcinomas])

Chronic kidney disease (excluding participants on dialysis or has reduced eGFR 
<30 mL/min/1.73 m2; See Section 5.2)

Chronic obstructive pulmonary disease

Obesity (body mass index* of 30 or higher)

Serious heart conditions such as heart failure, coronary artery disease, or 
cardiomyopathies

Diabetes mellitus
* Body mass index = weight (kg)/[height (m)]2
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10.9
Appendix 9: Calculation of eGFR
Modification of Diet in Renal Disease Study (MDRD) equation
eGFR (mL/min/1.73 m2) = 175 × (SCr)-1.154 × (age)-0.203 × 0.742 [if female] × 1.212 
[if African American]
Notes:

eGFR = estimated glomerular filtration rate

SCr = standardized serum creatinine

Age = years
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10.10 Appendix 10: Abbreviations
Abbreviation
Expanded Term
AE
adverse event 
AIDS
acquired immunodeficiency syndrome
ALT
alanine aminotransferase
APaT
all-participants-as-treated
AST
aspartate aminotransferase
AUC
area under the curve
BUN
blood urea nitrogen
CBC
complete blood count
CDC
Centers for Disease Control and Prevention
CD4
cluster of differentiation 4
CHMP
Committee for Medicinal Products for Human Use
CI
confidence interval
CMH
Cochran-Mantel-Haenszel
CNS
central nervous system
CONSORT
Consolidated Standards of Reporting Trials
COVID-19
coronavirus disease 2019
CRF
case report form 
CSR
clinical study report
CTFG
clinical trial facilitation group
CYP
Cytochrome P450
DAIDS
Division of Acquired Immunodeficiency Syndrome
DDI
drug-drug interaction
DILI
drug-induced liver injury
DMC
data monitoring committee
DNA
deoxyribonucleic acid
EAST
software platform for the statistical design, simulation and monitoring of clinical trials
ECG
electrocardiogram 
ECI
event of clinical interest
ECMO
extracorporeal membrane oxygenation
eCRF
electronic Case Report Form
EDC
electronic data collection 
eDMC
external data monitoring committee
EEA
European Economic Area
EFD
embryo-fetal development
eGFR
estimated glomerular filtration rate
EMA
European Medicines Agency
EOC
executive oversight committee
EOT
end of treatment
EUA
emergency use authorization
FBR
future biomedical research
FDA
Food and Drug Administration
FDAAA
Food and Drug Administration Amendments Act
FSH
follicle-stimulating hormone
FWER
family wise error rate
GCP
good clinical practice 
GLP
good laboratory practice
H1
hypothesis 1
H2
hypothesis 2
HBV
hepatitis B virus
hCG
human chorionic gonadotropin
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Abbreviation
Expanded Term
HCV
hepatitis C virus
HIV
human immunodeficiency virus
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
IEC
Independent Ethics Committee
IMP
investigational medicinal product
IND
investigational new drug
IRB
Institutional Review Board
IRT
intervention randomization system
IUD
intrauterine device
IUS
intrauterine hormone-releasing system
LAM
lactational amenorrhoea method
LFT
liver function test
LFU
late follow-up
MAD
multiple ascending dose
MCH
mean corpuscular hemoglobin
MCV
mean corpuscular volume
MDRD
modification of diet in renal disease
MERS
Middle East respiratory syndrome
mITT
modified intent-to-treat
mITT-VN
subset of modified intent-to-treat population with undetectable SARS-CoV-2 in 
baseline nasal swabs
mITT-VP
subset of modified intent-to-treat population with detectable SARS-CoV-2 in baseline 
nasal swabs
MOV
Molnupiravir (MK-4482)
N/A
not applicable
NCT
National Clinical Trial
NEJM
New England Journal of Medicine
NHC
β-D-N4-hydroxycytidine
NHC-TP
N-hydroxycytidine pharmacologically active triphosphate
NIAID
National Institute of Allergy and Infectious Diseases
NIMP
noninvestigational medicinal product
NOAEL
no-observed-adverse-effect-level
NP
nasopharyngeal
NSAE
nonserious adverse event
OP
oropharyngeal
PCR
polymerase chain reaction
PDLC
predefined limit of change
PK
pharmacokinetic
PPE
personal protective equipment
PRO
patient reported outcome
Q12H
administered once every 12 hours
RBC
red blood cell
RdRp
RNA-dependent RNA polymerase
RDW
red cell distribution width 
rINN
recommended International Nonproprietary Name
RNA
ribonucleic acid
RSV
respiratory syncytial virus
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Abbreviation
Expanded Term
RT-PCR
reverse transcription polymerase chain reaction
SAD
single ascending dose
SAE
serious adverse event 
SAP
statistical analysis plan
SARS
severe acute respiratory syndrome
SARS-CoV-2
severe acute respiratory syndrome coronavirus 2
SCr
standardized serum creatinine
SGOT
serum glutamic-oxaloacetic transaminase
SGPT
serum glutamic-pyruvic transaminase
SLAB
supplemental laboratory test(s)
SoA
schedule of activities
SOC
system organ class
SOP
standard operating procedure
SpO2
oxygen saturation
sSAP
supplemental statistical analysis plan
SUSAR
suspected unexpected serious adverse reaction
ULN
upper limit of normal
US
United States
VSV
vesicular stomatitis virus
WBC
white blood cell
WHO
World Health Organization
WOCBP
woman/women of childbearing potential 
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11
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