Clinical trial NCT04575597
Conditions: Coronavirus Disease (COVID-19)
Sponsor: Merck Sharp & Dohme LLC
Start date: 2020-10-19; Completion date: 2022-05-05
Enrollment: 1735 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This study aims to evaluate the safety, tolerability and efficacy of molnupiravir (MK-4482) compared to placebo. The primary hypothesis is that molnupiravir is superior to placebo as assessed by the percentage of participants who are hospitalized and/or die through Day 29

Detailed description:

Arms: arm 1: 200 mg molnupiravir administered orally every 12 hours for 5 days (10 doses total) arm 2: 400 mg molnupiravir administered orally every 12 hours for 5 days (10 doses total) arm 3: 800 mg molnupiravir administered orally every 12 hours for 5 days (10 doses total) arm 4: Placebo matching molnupiravir administered orally every 12 hours for 5 days (10 doses total) arm 5: 800 mg Molnupiravir (dose to be selected) administered orally every 12 hours for 5 days (10 doses total) arm 6: Placebo matching molnupiravir administered orally every 12 hours for 5 days (10 doses total)
Interventions: intervention 1: Molnupiravir intervention 2: Placebo
Intervention descriptions: intervention 1: Molnupiravir administered orally in capsule form every 12 hours for 5 days (10 doses total) intervention 2: Placebo matching molnupiravir administered orally in capsule form every 12 hours for 5 days (10 doses total)

Protocol documents:
Prot_SAP_000.pdf: 
Official Protocol Title: 
NCT number: 
NCT04575597 
Document Date: 
15-AUG-2021
A Phase 2/3, Randomized, Placebo-Controlled, Double-Blind 
Clinical Study to Evaluate the Efficacy, Safety, and 
Pharmacokinetics of MK-4482 in Non-Hospitalized Adults with 
COVID-19


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Title Page
THIS PROTOCOL AMENDMENT AND ALL OF THE INFORMATION RELATING 
TO IT ARE CONFIDENTIAL AND PROPRIETARY PROPERTY OF MERCK 
SHARP & DOHME CORP., A SUBSIDIARY OF MERCK & CO., INC., NJ, U.S.A. 
(MSD).
Protocol Title: A Phase 2/3, Randomized, Placebo-Controlled, Double-Blind Clinical Study 
to Evaluate the Efficacy, Safety, and Pharmacokinetics of MK-4482 in Non-Hospitalized 
Adults with COVID-19.
Protocol Number: 002-04
Compound Number: MK-4482
Sponsor Name:
Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc.
(hereafter referred to as the Sponsor or MSD)
Legal Registered Address:
One Merck Drive
P.O. Box 100
Whitehouse Station, New Jersey, 08889-0100, U.S.A.
Regulatory Agency Identifying Number(s):
EudraCT
2020-003368-24
IND
147734
NCT
NCT04575597
Approval Date: 15 August 2021
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Sponsor Signatory
Typed Name:
Title:
Date
Protocol-specific Sponsor contact information can be found in the Investigator Study
File Binder (or equivalent).
Investigator Signatory
I agree to conduct this clinical study in accordance with the design outlined in this protocol 
and to abide by all provisions of this protocol.
Typed Name:
Title:
Date
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DOCUMENT HISTORY
Document
Date of Issue
Overall Rationale
Amendment 04
15-AUG-2021
To remove the enrollment target of ~50% of Part 2 participants who are >60 years of 
age and to add a new exploratory objective for detection of infectious virus from NP
swabs.
Amendment 03
22-JUN-2021
To clarify that participants can only enroll in this study if they have chosen not to 
receive a SARS-CoV-2 monoclonal antibody(ies) or SARS-CoV-2 monoclonal 
antibodies have not been authorized or approved in their country, update the benefit/risk 
assessment, add new subgroup analyses, and add a description of an unblinded team in 
the case of a positive efficacy finding noted by the eDMC at IA4.
Amendment 02
14-APR-2021
To provide the selected dose and the dose selection rationale for Part 2 (Phase 3) of the 
study, revise female and male contraception requirements, update the stratification 
factors, revise entry criteria, and increase the sample size for Part 2 (Phase 3).
Amendment 01
17-DEC-2020
To revise the dose selection process before initiation of Part 2 (Phase 3), update the 
benefit/risk assessment, clarify the key secondary efficacy objective regarding COVID-
19 signs/symptoms, and add a discontinuation criterion.
Original Protocol
14-SEP-2020
Not applicable
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PROTOCOL AMENDMENT SUMMARY OF CHANGES
Amendment: 04
Overall Rationale for the Amendments:
To remove the enrollment target of ~50% of Part 2 participants who are >60 years of age and to add a new exploratory objective for 
detection of infectious virus from NP swabs.
Summary of Changes Table:
Section # and Name
Description of Change 
Brief Rationale 
4.1 Overall Design
6.3.2 Stratification
Removed the enrollment target of
approximately 50% of Part 2 participants 
who are >60 years of age.
While the Part 2 study population will continue to be 
enriched for participants at increased risk for severe
illness from COVID-19, including those >60 years of 
age (Appendix 10), the enrollment target of ~50% of 
participants >60 years of age was removed. Based on 
observed data, events are occurring across risk factors 
and enrichment for older participants alone is not 
needed. This change was also made to support
increased feasibility of enrollment given increasing 
global vaccination rates in the older population. 
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Section # and Name
Description of Change 
Brief Rationale 
3 Hypotheses, Objectives 
and Endpoints
4.2.1.4 Virology Endpoints
4.2.5 Rationale for Other 
Exploratory Research
8.2.1 Nasopharyngeal and 
Oropharyngeal Swabs
9.4.1.1 Efficacy Endpoints
Added an exploratory objective to evaluate 
the percentage of participants with 
undetectable infectious SARS-CoV-2 in 
NP swabs at various timepoints.
Added associated changes relevant to the 
new exploratory objective.
To evaluate the antiviral activity of MK-4482 versus 
placebo via detection of infectious SARS-CoV-2.
1.3 Schedule of Activities
8.1.2 Inclusion/Exclusion 
Criteria
Added statement that laboratory testing to 
confirm SARS-CoV-2 infection may be 
performed at screening if prior results are 
not available.
To clarify that sites may perform this testing at 
screening to confirm eligibility.
7.3 Lost to Follow-up
Removed: “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 pre-
specified statistical data handling and 
analysis guidelines.”
A participant can be declared as lost to follow-up after 
the site has attempted multiple methods of contact 
rather than waiting until the last scheduled visit (ie, 
LFU Month 7). Given the length of study, it is 
considered reasonable to attempt contact to a point 
where the data that would be collected may still be 
considered meaningful instead of throughout the full 
duration of the study.
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Section # and Name
Description of Change 
Brief Rationale 
1.2 Schema
Revised footnote “a” to state that eligible 
participants will have laboratory-
confirmed infection and signs/symptoms 
of COVID-19 for ≤7 days in Part 1 and 
≤5 days in Part 2 prior to randomization.
To clarify the difference in eligibility requirements for 
each Part of the study.
Appendix 5, Section 10.5.2 
Contraception Requirements
Added “user dependent” before hormonal 
contraceptives in the text describing those 
barrier methods to be used with user 
dependent hormonal contraceptives.
To clarify that hormonal contraceptives that require 
additional barrier methods to be used are “user 
dependent” hormonal contraceptives as described in 
the preceding text.
Throughout the document
Corrected minor typographical and 
grammatical errors.
To improve clarity and consistency throughout the 
document.
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Table of Contents
DOCUMENT HISTORY ........................................................................................................3
PROTOCOL AMENDMENT SUMMARY OF CHANGES...............................................4
1
PROTOCOL SUMMARY ............................................................................................15
1.1
Synopsis.................................................................................................................15
1.2
Schema ..................................................................................................................18
1.3
Schedule of Activities...........................................................................................19
2
INTRODUCTION..........................................................................................................23
2.1
Study Rationale....................................................................................................23
2.2
Background ..........................................................................................................23
2.3
Benefit/Risk Assessment......................................................................................26
3
HYPOTHESES, OBJECTIVES, AND ENDPOINTS................................................27
4
STUDY DESIGN............................................................................................................29
4.1
Overall Design......................................................................................................29
4.2
Scientific Rationale for Study Design.................................................................31
4.2.1
Rationale for Endpoints ...............................................................................31
4.2.1.1
Efficacy Endpoints.............................................................................31
4.2.1.1.1
Primary Clinical Endpoint .......................................................31
4.2.1.1.2
Secondary Endpoints ...............................................................32
4.2.1.2
Safety Endpoints................................................................................32
4.2.1.3
Pharmacokinetic Endpoints ...............................................................33
4.2.1.4
Virology Endpoints............................................................................33
4.2.1.5
Future Biomedical Research..............................................................33
4.2.2
Rationale for the Use of Comparator/Placebo .............................................34
4.2.3
Rationale for the Selected Participant Population .......................................34
4.2.4
Rationale for Collection of Racial, Ethnic, and Gender Identity Data ........35
4.2.5
Rationale for Other Exploratory Research Samples ....................................35
4.3
Justification for Dose...........................................................................................36
4.3.1
Rationale for Dosing Duration.....................................................................36
4.3.2
Dose Range for Part 1 (Phase 2)..................................................................37
4.3.3
Dose Selection for Part 2 (Phase 3) .............................................................37
4.4
Beginning and End of Study Definition .............................................................39
4.4.1
Clinical Criteria for Early Study Termination .............................................39
5
STUDY POPULATION ................................................................................................39
5.1
Inclusion Criteria.................................................................................................39
5.2
Exclusion Criteria................................................................................................42
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5.3
Lifestyle Considerations......................................................................................43
5.4
Screen Failures.....................................................................................................44
5.5
Participant Replacement Strategy......................................................................44
6
STUDY INTERVENTION............................................................................................44
6.1
Study Intervention(s) Administered...................................................................44
6.2
Preparation/Handling/Storage/Accountability .................................................46
6.2.1
Dose Preparation..........................................................................................46
6.2.2
Handling, Storage, and Accountability........................................................46
6.3
Measures to Minimize Bias: Randomization and Blinding..............................47
6.3.1
Intervention Assignment..............................................................................47
6.3.2
Stratification.................................................................................................47
6.3.3
Blinding........................................................................................................48
6.4
Study Intervention Compliance..........................................................................48
6.5
Concomitant Therapy..........................................................................................48
6.5.1
Rescue Medications and Supportive Care ...................................................50
6.6
Dose Modification (Escalation/Titration/Other)...............................................50
6.7
Intervention After the End of the Study............................................................50
6.8
Clinical Supplies Disclosure................................................................................50
7
DISCONTINUATION OF STUDY INTERVENTION AND PARTICIPANT 
WITHDRAWAL............................................................................................................50
7.1
Discontinuation of Study Intervention...............................................................50
7.2
Participant Withdrawal From the Study...........................................................51
7.3
Lost to Follow-up .................................................................................................52
8
STUDY ASSESSMENTS AND PROCEDURES........................................................52
8.1
Administrative and General Procedures ...........................................................53
8.1.1
Informed Consent.........................................................................................53
8.1.1.1
General Informed Consent.................................................................53
8.1.1.2
Consent and Collection of Specimens for Future Biomedical 
Research.............................................................................................53
8.1.1.3
Consent for PBMC Cohort Blood Sample Collection.......................54
8.1.2
Inclusion/Exclusion Criteria ........................................................................54
8.1.3
Participant Identification Card.....................................................................54
8.1.4
Medical History ...........................................................................................55
8.1.5
Prior and Concomitant Medications Review...............................................55
8.1.5.1
Prior Medications...............................................................................55
8.1.5.2
Concomitant Medications..................................................................55
8.1.6
Assignment of Screening Number...............................................................55
8.1.7
Assignment of Treatment/Randomization Number.....................................56
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8.1.8
Study Intervention Administration ..............................................................56
8.1.8.1
Timing of Dose Administration.........................................................56
8.1.9
Discontinuation and Withdrawal .................................................................57
8.1.9.1
Withdrawal From Future Biomedical Research ................................58
8.1.10
Participant Blinding/Unblinding..................................................................58
8.1.11
Calibration of Equipment.............................................................................59
8.1.12
Collect/Update Secondary Contact Information..........................................59
8.1.13
Participant Study Supplies...........................................................................59
8.1.14
Study Medication Diary...............................................................................60
8.2
Efficacy Assessments ...........................................................................................60
8.2.1
Nasopharyngeal and Oropharyngeal Swabs ................................................60
8.2.2
Respiratory/Oxygenation Status ..................................................................60
8.2.3
Hospitalization.............................................................................................61
8.2.4
Survival Status .............................................................................................62
8.2.5
MK-4482 Symptom Diary...........................................................................62
8.2.6
Functional Status Assessments ....................................................................63
8.3
Safety Assessments...............................................................................................63
8.3.1
Physical Examinations.................................................................................63
8.3.2
Vital Signs....................................................................................................63
8.3.3
Clinical Safety Laboratory Assessments .....................................................64
8.3.4
Pregnancy Testing........................................................................................64
8.4
Adverse Events, Serious Adverse Events, and Other Reportable Safety 
Events....................................................................................................................64
8.4.1
Time Period and Frequency for Collecting AE, SAE, and Other 
Reportable Safety Event Information ..........................................................65
8.4.2
Method of Detecting AEs, SAEs, and Other Reportable Safety Events......67
8.4.3
Follow-up of AE, SAE, and Other Reportable Safety Event Information...67
8.4.4
Regulatory Reporting Requirements for SAE .............................................67
8.4.5
Pregnancy and Exposure During Breastfeeding ..........................................67
8.4.6
Disease-related Events and/or Disease-related Outcomes Not Qualifying 
as AEs or SAEs............................................................................................68
8.4.7
Events of Clinical Interest............................................................................68
8.5
Treatment of Overdose........................................................................................68
8.6
Pharmacokinetics.................................................................................................69
8.6.1
Blood Collection for Measurement of NHC in Plasma ...............................69
8.6.2
Blood Collection for Measurement of NHC-TP in PBMC..........................69
8.7
Pharmacodynamics..............................................................................................70
8.8
Exploratory Research Samples...........................................................................70
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8.9
Future Biomedical Research Sample Collection...............................................70
8.10
Medical Resource Utilization and Health Economics.......................................70
8.11
Visit Requirements...............................................................................................70
8.11.1
Infection Prevention Procedures..................................................................71
8.11.2
Types of Study Visits...................................................................................71
8.11.2.1
Screening/Rescreening Visits ............................................................71
8.11.2.2
Clinic or At-Home Visits...................................................................72
8.11.2.3
Virtual Visits......................................................................................72
8.11.3
Participants Who Discontinue or Withdraw ................................................72
8.11.4
Late Follow-up (7 Month) Visit...................................................................73
9
STATISTICAL ANALYSIS PLAN .............................................................................73
9.1
Statistical Analysis Plan Summary.....................................................................73
9.2
Responsibility for Analyses/In-house Blinding .................................................75
9.3
Hypotheses/Estimation ........................................................................................76
9.4
Analysis Endpoints...............................................................................................76
9.4.1
Efficacy/Pharmacokinetics Endpoints .........................................................76
9.4.1.1
Efficacy Endpoints.............................................................................76
9.4.1.2
Pharmacokinetics Endpoints..............................................................78
9.4.2
Safety Endpoints..........................................................................................78
9.5
Analysis Populations............................................................................................79
9.5.1
Efficacy Analysis Populations.....................................................................79
9.5.2
Safety Analysis Populations ........................................................................79
9.6
Statistical Methods...............................................................................................79
9.6.1
Statistical Methods for Efficacy Analyses...................................................80
9.6.2
Statistical Methods for Safety Analyses ......................................................83
9.6.3
Demographic and Baseline Characteristics .................................................84
9.7
Interim Analyses ..................................................................................................84
9.8
Multiplicity ...........................................................................................................88
9.9
Sample Size and Power Calculations .................................................................88
9.9.1
Sample Size and Power Calculations for Efficacy Analyses (Part 2)..........88
9.9.2
Sample Size and Power Calculations for Virology Analyses (Part 1).........89
9.9.3
Sample Size and Power Calculations for Safety Analyses (Part 2).............90
9.10
Subgroup Analyses...............................................................................................91
9.11
Compliance (Medication Adherence).................................................................92
9.12
Extent of Exposure...............................................................................................92
10
SUPPORTING DOCUMENTATION AND OPERATIONAL 
CONSIDERATIONS.....................................................................................................93
10.1
Appendix 1: Regulatory, Ethical, and Study Oversight Considerations........93
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10.1.1
Code of Conduct for Clinical Trials.............................................................93
10.1.2
Financial Disclosure.....................................................................................95
10.1.3
Data Protection.............................................................................................95
10.1.3.1
Confidentiality of Data ......................................................................96
10.1.3.2
Confidentiality of Participant Records...............................................96
10.1.3.3
Confidentiality of IRB/IEC Information............................................96
10.1.4
Committees Structure...................................................................................97
10.1.4.1
Executive Oversight Committee........................................................97
10.1.4.2
Internal Data Monitoring Committee.................................................97
10.1.4.3
External Data Monitoring Committee ...............................................97
10.1.5
Publication Policy........................................................................................97
10.1.6
Compliance with Study Registration and Results Posting Requirements ...98
10.1.7
Compliance with Law, Audit, and Debarment ............................................98
10.1.8
Data Quality Assurance ...............................................................................99
10.1.9
Source Documents .....................................................................................100
10.1.10
Study and Site Closure...............................................................................100
10.2
Appendix 2: Clinical Laboratory Tests............................................................101
10.3
Appendix 3: Adverse Events: Definitions and Procedures for Recording, 
Evaluating, Follow-up, and Reporting.............................................................105
10.3.1
Definition of AE ........................................................................................105
10.3.2
Definition of SAE ......................................................................................106
10.3.3
Additional Events Reported.......................................................................107
10.3.4
Recording AE and SAE .............................................................................107
10.3.5
Reporting of AEs, SAEs, and Other Reportable Safety Events to the 
Sponsor ......................................................................................................111
10.4
Appendix 4: Medical Device and Drug-device Combination Products: 
Product Quality Complaints/Malfunctions: Definitions, Recording, and 
Follow-up ............................................................................................................113
10.5
Appendix 5: Contraceptive Guidance..............................................................114
10.5.1
Definitions..................................................................................................114
10.5.2
Contraception Requirements......................................................................115
10.6
Appendix 6: Collection and Management of Specimens for Future 
Biomedical Research..........................................................................................116
10.7
Appendix 7: Country-specific Requirements..................................................121
10.7.1
Country-specific Request for Germany .....................................................121
10.8
Appendix 8: Ordinal Outcome Scales..............................................................122
10.8.1
World Health Organization 11-Point Scale ...............................................122
10.9
Appendix 9: COVID-19 Severity Categorization............................................123
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10.10 Appendix 10: Individuals at Increased Risk for Severe Illness from 
COVID-19...........................................................................................................126
10.11 Appendix 11: Calculation of eGFR ..................................................................127
10.12 Appendix 12: Abbreviations .............................................................................128
11
REFERENCES.............................................................................................................131
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LIST OF TABLES
Table 1
Study Interventions....................................................................................45
Table 2
Prohibited and Allowed Therapies.............................................................49
Table 3
Reporting Time Periods and Time Frames for Adverse Events and 
Other Reportable Safety Events.................................................................66
Table 4
Plasma Sample Collection Schedule for NHC Concentrations .................69
Table 5
Analysis Strategy for Key Efficacy Endpoints..........................................82
Table 6
Analysis Strategy for Safety Parameters....................................................84
Table 7
Description of Interim Analyses ................................................................86
Table 8
Study Power by Percentage Hospitalized/Dying N=1550 participants 
(775 for MK-4482 800 mg and 775 for placebo), alpha=0.025, 1-sided...89
Table 9
Power by Detectable Difference and Standard Deviation Viral RNA 
change from baseline (log10 copies/mL) N=60/group, α=0.025, 1-
sided...........................................................................................................90
Table 10
Differences in Incidence of AE Rates Between the 2 Treatment Groups 
That Can be Detected With a ~90% Probability (Assuming 2-sided 5% 
Alpha Level with 850 Participants in Each Group)...................................91
Table 11
Protocol-required Laboratory Assessments.............................................102
Table 12
Approximate Whole Blood Volumes (mL) .............................................103
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LIST OF FIGURES
Figure 1
Study Schema and Treatment Plan ............................................................18
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1
PROTOCOL SUMMARY
1.1
Synopsis
Protocol Title: A Phase 2/3, Randomized, Placebo-Controlled, Double-Blind Clinical Study 
to Evaluate the Efficacy, Safety, and Pharmacokinetics of MK-4482 in Non-Hospitalized 
Adults with COVID-19.
Short Title: MK-4482 Ph 2/3 Study in Non-Hospitalized Adults with COVID-19
Acronym: N/A
MOVe-OUT
Hypotheses, Objectives, and Endpoints:
Hypotheses are aligned with objectives in the Objectives and Endpoints table.
The following objectives will be evaluated in non-hospitalized participants ≥18 years of age 
with COVID-19.
Primary Objectives
Primary Endpoints
- To evaluate efficacy of MK-4482 compared 
to placebo as assessed by the percentage of 
participants who are hospitalized and/or die 
from randomization through Day 29.
Hypothesis: MK-4482 is superior to placebo 
as assessed by the percentage of participants 
who are hospitalized and/or die through Day 
29.
- Hospitalization or death
- To evaluate the safety and tolerability of 
MK-4482 compared to placebo.
- Adverse events
- Adverse events leading to discontinuation 
of study intervention
Secondary Objectives
Secondary Endpoints
- To evaluate the efficacy of MK-4482 
compared to placebo as assessed by time to 
sustained resolution or improvement, and 
time to progression of each targeted self-
reported sign/symptom of COVID-19 from 
randomization through Day 29.
- COVID-19 signs/symptoms
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- To evaluate the efficacy of MK-4482 
compared to placebo as assessed by the odds 
of a more favorable response on the WHO 
11-point ordinal scale on Day 3, EOT, Day 
10, Day 15, and Day 29.
- WHO 11-point scale score
Overall Design:
Study Phase
Phase 2/Phase 3
Primary Purpose
Treatment
Indication
COVID-19
Population
Participants ≥18 years of age with COVID-19 not 
requiring hospitalization
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 12 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:
A total of ~1850 participants will be randomized in the study.
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Intervention Groups and Duration:
Intervention 
Groups
Intervention Group 
Name
Drug
Dose 
Strength
Dose 
Frequency
Route of 
Administration
Treatment 
Period
Part 1 (N~300)
MK-4482 (200 mg)
MK-4482
200 mg
Q12H
Oral
5 days (10 
doses total)
MK-4482 (400 mg)
MK-4482
400 mg
Q12H
Oral
5 days (10 
doses total)
MK-4482 (800 mg)
MK-4482
800 mg
Q12H
Oral
5 days (10 
doses total)
Placebo
Placebo
0 mg
Q12H
Oral
5 days (10 
doses total)
Part 2 (N~1550)
MK-4482
MK-4482
800 mg
Q12H
Oral
5 days (10 
doses total)
Placebo
Placebo
0 mg
Q12H
Oral
5 days (10 
doses total)
N=number of participants to be enrolled in each part of the study; Q12H= once every 12 hours.
Total 
Number of 
Intervention 
Groups/ 
Arms
Part 1: 4 groups
Part 2: 2 groups
Duration of 
Participation
Each participant will be in the study for up to approximately 7 months from 
the time the participant provides documented informed consent through the 
final contact. Participants will receive 10 doses of assigned study 
intervention (administered Q12H) and will be followed for 28 days after 
randomization. In addition, participants will be contacted at approximately 
7 months after the last dose of study intervention.
Study Governance Committees:
Steering Committee
No
Executive Oversight Committee
Yes
Data Monitoring Committees
Yes
Clinical Adjudication Committee
No
Study governance considerations are outlined in Appendix 1.
Study Accepts Healthy Volunteers: No
A list of abbreviations used in this document can be found in Appendix 12.
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PRODUCT: MK-4482  
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1.2
Schema
The study design is depicted in Figure 1.
Figure 1
Study Schema and Treatment Plan
EOT=end of treatment; LFU=Late Follow-up Visit; N=total number of participants in each study part; n=number of 
participants per group; Q12H=administered once every 12 hours.
a Eligible participants will have laboratory-confirmed SARS-CoV-2 infection with signs/symptoms attributable to COVID-
19 for ≤7 days in Part 1 and ≤5 days in Part 2 prior to randomization (Section 5.1). Calculation of the 7-/5-day symptom 
onset window does not include the date of randomization (Section 5.1).
b Dose selection will be based on Part 1 interim analysis(es) in combination with the totality of data available across the 
MK-4482 clinical program prior to initiating Part 2 (Section 4.3.3 and Section 9.7). 
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1.3
Schedule of Activities
Study Period 
Screening 
Intervention
Follow-up
Notes
Visit Number/Title
1 
2
3
4
5
6
7
8
9
10
Scheduled Day 
(Window)
Screening
(≤48 hours 
before 
rand.)a
Day 
1b
Day 2
Day 
3c
Day 
4
EOT
Day 10 
(±1 
day)
Day 15 
(+3 
days)
Day 29 
(+3 
days)
LFU 
Month 7 
(±1 
month)d
Type of Visit
C
C
V/C
C
V/C
C
C
C
C
V
C = Clinic or At-home visit
V= Virtual visit (when a virtual 
visit is listed, a clinic or home visit 
is not required. Virtual visits may 
be conducted at the investigator’s
discretion)
Administrative Procedures
Informed Consent
X
Informed Consent for FBR
(Optional)
X
Informed consent for FBR should 
be presented at screening, 
however, if delayed, present at 
next possible visit as outlined in 
Appendix 6.
Informed Consent for PBMC 
Collection (Optional)
X
Only a subset of participants at 
selected sites
Register Study Visit in IRT
X
X
Inclusion/Exclusion Criteria
Xe
Xf
Including review of SARS-CoV-2 
(+) local test resultsg
Participant Identification Card
X
X
Randomization number must be 
added to card at randomization
Medical History
X
X
Including day of onset of COVID-
19 signs/symptoms 
Prior/Concomitant Medication 
Review
X
X
X
X
X
X
X
X
X
Including COVID-19 standard of 
care therapies and supportive care
Intervention Randomization
Xb
COVID-19 severity categorization 
entered in IRT at randomization 
must be based on values obtained 
on Day 1 prior to randomization
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Study Period 
Screening 
Intervention
Follow-up
Notes
Visit Number/Title
1 
2
3
4
5
6
7
8
9
10
Scheduled Day 
(Window)
Screening
(≤48 hours 
before 
rand.)a
Day 
1b
Day 2
Day 
3c
Day 
4
EOT
Day 10 
(±1 
day)
Day 15 
(+3 
days)
Day 29 
(+3 
days)
LFU 
Month 7 
(±1 
month)d
Collect/Update Secondary 
Contacts for Participant
X
X
X
X
X
MK-4482 or Placebo 
Administration
X
X
X
X
X
All efforts should be made to 
administer the first dose on Day 1
(randomization), but
administration of the first dose 
must be within 24 hours of 
randomization
MK-4482 or Placebo – Observed 
Dosing
X
The morning dose at EOT will be 
observed to facilitate PK blood 
collection.
Dispense Study Intervention and 
Participant Study Supplies
X
Including participant diaries
Completion of Study Medication 
Diary
X
X
X
X
X
Completion of MK-4482
Symptom Diary
<================= X ==================>
Completed daily from Day 1 
through Day 29. The first day of
diary completion should occur 
prior to the first dose of study 
intervention (Section 8.2.5).
Reminders for MK-4482
Symptom Diary Completion
X
X
X
X
X
X
X
Following EOT, reminders should 
be provided every other day 
through Day 29.
Study Staff Review and 
Collection of Participant’s Study 
Diaries
X
X
X
X
X
Study Medication Diary will be 
collected after the last dose of 
study intervention. Completed 
pages of MK-4482 Symptom 
Diary will be collected at all clinic 
or at-home visits.
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Study Period 
Screening 
Intervention
Follow-up
Notes
Visit Number/Title
1 
2
3
4
5
6
7
8
9
10
Scheduled Day 
(Window)
Screening
(≤48 hours 
before 
rand.)a
Day 
1b
Day 2
Day 
3c
Day 
4
EOT
Day 10 
(±1 
day)
Day 15 
(+3 
days)
Day 29 
(+3 
days)
LFU 
Month 7 
(±1 
month)d
Functional Status Assessment
X
X
X
X
X
X
Participant’s ability to 
independently perform daily 
activities will be assessed.
Efficacy Procedures
NP (Parts 1 and 2) and OP (Part 1 
only) Swabs 
X
X
X
X
X
X
Both NP and OP swabs will be 
collected in Part 1. Only NP swabs 
will be collected in Part 2.
Serum and Plasma for 
Exploratory Research 
X
X
X
X
Research samples will be stored 
for testing as described in Section 
4.2.5 and Section 8.8.
Serum for Antibody Exploratory 
Research
X
X
X
X
Respiratory/ Oxygenation Status
X
X
X
X
X
X
X
Xh
SpO2 and investigator assessment 
of shortness of breath, and if 
applicable FiO2, PaO2 and 
supplemental oxygen use.
Hospitalization, Emergency 
Room, and Other Acute Care 
Visit Status
X
X
X
X
X
X
Only hospitalization status will be 
collected at LFU (Month 7) visit.
Survival Status
X
X
Safety Procedures
Full Physical Examination 
X
Including height and weight
Directed Physical Examination
X
X
X
X
X
X
Vital Signs 
X
X
X
X
X
X
X
Heart rate, blood pressure, 
respiratory rate, temperature 
Blood Collection for Local 
Laboratory Evaluation
Xe
Local laboratory collection 
required unless 
chemistry/hematology results 
within 72 h prior to randomization 
are available
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PRODUCT: MK-4482  
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Study Period 
Screening 
Intervention
Follow-up
Notes
Visit Number/Title
1 
2
3
4
5
6
7
8
9
10
Scheduled Day 
(Window)
Screening
(≤48 hours 
before 
rand.)a
Day 
1b
Day 2
Day 
3c
Day 
4
EOT
Day 10 
(±1 
day)
Day 15 
(+3 
days)
Day 29 
(+3 
days)
LFU 
Month 7 
(±1 
month)d
Blood Collection for Central 
Laboratory Evaluation
X
X
X
X
X
X
Including hematology and 
chemistry 
Pregnancy Test (WOCBP only)
Xe
X
Confirm Contraception 
Requirements (WOCBP and male 
participants)
X
X
X
X
Confirm participant compliance 
with contraception requirements 
as outlined in inclusion criteria 
and Appendix 5
AE/SAE reviewi
X
X
X
X
X
X
X
X
X
X
Pharmacokinetics
PK Plasma Sampling
X
Part 1: pre-dose;1.5 h post-dose 
Part 2: pre-dose;1.5 h post-dose 
PK PBMC Samplingj
X
Part 1 (PBMC Cohort Only): 
Pre-dose, 1.5 h post-dose
AE=adverse event; ALT=alanine aminotransferase; AST=aspartate aminotransferase; COVID-19=coronavirus disease 2019; EOT=End of Treatment (day of last study intervention dose); 
FBR = future biomedical research; hCG=human chorionic gonadotropin; HBV=hepatitis B virus; HCV=hepatitis C virus; HIV=human immunodeficiency virus; LFU= Late Follow-Up, 
NP=nasopharyngeal; OP=oropharyngeal; PBMC=peripheral blood mononuclear cells; PK=pharmacokinetic; PSV=pregnancy status visit; rand.= randomization; RNA=ribonucleic acid; 
SAE=serious adverse event; SARS-CoV-2=severe acute respiratory syndrome coronavirus 2; SpO2 = oxygen saturation; WOCBP=women of childbearing potential.
a Screening and Day 1 (randomization) can be done in same session. Study assessments should not be duplicated if screening and Day 1 (randomization) are completed on the same day.
b Assessments required for COVID-19 severity categorization (Appendix 9) for IRT (vital signs, COVID-19 signs/symptoms assessment, respiratory measures, oxygen therapy, ongoing 
medical history) must be completed and documented on Day 1 prior to calling IRT in order to randomize. All other Day 1 assessments must be completed on Day 1 prior to first dose of 
study intervention.
c Day 3 assessments should be performed on Day 3, but if circumstances do not support performance of any procedures by study staff on Day 3, a ±24-hour window is allowed. 
d LFU (Month 7) visit is 7 months from the last dose of study intervention.
e The following local laboratory results must be available for all participants from within 72 h prior to randomization to support determination of eligibility: serum creatinine, platelets, and 
absolute neutrophil count. In participants with reported history of HBV or HCV, ALT and AST must be available from within 72 hours prior to randomization to support determination 
of eligibility. In WOCBP, a negative local pregnancy test is required within 24 hours 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 VL).
f Confirm no change in eligibility based on inclusion/exclusion criteria and/or disease severity.
g If prior results are not available, laboratory confirmation of SARS-CoV-2 infection may be performed at screening to confirm eligibility (Sections 5.1 and 8.1.2). Results must be 
available prior to randomization.
h Respiratory/Oxygenation Status collection at the LFU visit will be limited. As LFU will be a virtual visit, SpO2 will not be measured. Use of supplemental oxygen will be collected.  
i AEs, SAEs, and other reportable safety events (eg, pregnancy) will be monitored according to Section 8.4.
j A subset of ~50 participants in Part 1 will take part in the PBMC Cohort at selected sites.
06FSHF
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PRODUCT: MK-4482  
28
PROTOCOL/AMENDMENT NO.: 002-04 
MK-4482-002-04 FINAL PROTOCOL
15-AUG-2021
Objectives
Endpoints
Primary
•
To evaluate the efficacy of MK-4482
compared to placebo as assessed by the 
percentage of participants who are
hospitalized and/or die from randomization 
through Day 29.
Hypothesis: MK-4482 is superior to placebo 
as assessed by the percentage of participants 
who are hospitalized and/or die through 
Day 29.
•
Hospitalization or death
•
To evaluate the safety and tolerability of MK-
4482 compared to placebo.
•
Adverse events
•
Adverse events leading to 
discontinuation of study 
intervention
Secondary
•
To evaluate the efficacy of MK-4482 
compared to placebo as assessed by time to 
sustained resolution or improvement, and
time to progression of each targeted self-
reported sign/symptom of COVID-19 from 
randomization through Day 29.
•
COVID-19 signs/symptoms
•
To evaluate the efficacy of MK-4482 
compared to placebo as assessed by the odds 
of a more favorable response on the WHO 11-
point ordinal scale on Day 3, EOT, Day 10, 
Day 15, and Day 29.
•
WHO 11-point scale score
Tertiary/Exploratory
•
To evaluate the efficacy of MK-4482 
compared to placebo as assessed by the 
percentage of participants who have any acute 
care visit from randomization through 
Day 29.
•
Acute care visit
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Objectives
Endpoints
•
To evaluate the efficacy of MK-4482 
compared to placebo as assessed by the 
percentage of participants who have any 
COVID-19-related acute care visit from 
randomization through Day 29.
•
COVID-19-related acute care visit
•
To measure the pharmacokinetics of NHC 
(the parent nucleoside), and NHC-TP (the 
pharmacologically-active triphosphate form) 
in plasma and PBMC collected at various 
timepoints.
•
Plasma (Part 1 and Part 2) and 
PBMC (Part 1) Pharmacokinetic 
concentration (eg, Ctrough)  
•
To evaluate the antiviral activity of MK-4482 
compared to 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 
nasopharyngeal and/or oropharyngeal swabs 
separately at various timepoints.
•
SARS-CoV-2 RNA
•
To evaluate the effect of MK-4482 on viral 
RNA mutation rate and detection of 
treatment-emergent sequence variants as 
assessed by comparison of gene sequencing in 
virus isolated at baseline and post-baseline in 
samples with evaluable SARS-CoV-2 RNA. 
•
Viral RNA sequences 
•
To evaluate the antiviral activity of MK-4482 
compared to placebo as assessed by the 
percentage of participants with undetectable 
infectious SARS-CoV-2 in nasopharyngeal 
swabs at various timepoints.
•
Infectious SARS-CoV-2 
4
STUDY DESIGN
4.1
Overall Design
This study (MOVe-OUT) is a Phase 2/3, randomized, placebo-controlled, double-blind, 
multi-site study to evaluate the efficacy, safety, and PK of MK-4482 (also known as 
molnupiravir [pINN] or MOV) administered to non-hospitalized participants ≥18 years of 
age with laboratory-confirmed COVID-19 and symptom onset within 5 days prior to 
randomization.
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PRODUCT: MK-4482  
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In Part 1, participants with mild COVID-19 and at least 75% of participants overall must 
have at least 1 characteristic or underlying medical condition associated with being at 
increased risk for severe illness from COVID-19 (Appendix 10). In addition, enrollment of 
participants with moderate COVID-19 will be limited to approximately 50% of total planned 
sample size.
In Part 2, all participants must have at least 1 characteristic or underlying medical condition 
associated with being at increased risk for severe illness from COVID-19 (Appendix 10).
Age is a risk factor independent of other health conditions, so while there is no minimal 
enrollment for participants >60 years of age, every effort should be made to maximize 
enrollment of this age group.
Participants will receive assigned study intervention by oral administration Q12H for 5 days, 
for a total of 10 doses and be followed for 28 days after randomization (through Day 29). In 
addition, participants will be contacted approximately 7 months after the last dose of study 
intervention.
Part 1 (Phase 2 - Dose Ranging)
Approximately 300 participants will be randomized in a 1:1:1:1 ratio (stratified per Section 
6.3.2) into 1 of the following 4 blinded treatment groups (Figure 1):

MK-4482 200 mg (n~75)

MK-4482 400 mg (n~75)

MK-4482 800 mg (n~75)

Placebo (n~75)
The final dose selection will be based on analysis(es) of data from this study in combination 
with the totality of data available across the MK-4482 clinical program prior to initiating 
Part 2 (Section 4.3.3 and Section 9.7).
Part 2 (Phase 3 - Evaluation of Selected Dose)
In Part 2, ~1550 participants will be randomized in a 1:1 ratio (stratified per Section 6.3.2) to 
receive either of MK-4482 800 mg or placebo (Figure 1). An interim efficacy analysis is 
planned in Part 2 (Section 9.7).
Throughout the Study (Parts 1 and 2)
Participants may receive Sponsor-designated standard of care treatment of COVID-19, as 
appropriate, in addition to study intervention (Section 6.5). All participants will have plasma 
sample collection for PK assessments. The protocol will aim to enroll a subset of
~50 participants in an optional PBMC Cohort (Part 1) at select sites with capability to isolate 
PBMCs.
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Participants will be provided with a Study Medication Diary (dose administration will be 
recorded daily for 5 days) and a Symptom Diary (presence/absence and severity of a solicited 
list of signs/symptoms attributable to COVID-19 will be recorded daily for 29 days). In the 
event of hospitalization, all evaluations outlined in the SoA (Section 1.3) should be 
performed as feasible (details in Section 8.2.3). 
All participants will have a virtual visit approximately 7 months following the last dose of 
study intervention (LFU visit) to assess survival status, current supplemental oxygen use, and 
to document any hospitalizations, according to the SoA (Section 1.3).
The results of interim analyses will be reviewed by an independent eDMC (Parts 1 and 2)
and Sponsor siDMC (Part 1 only) (Section 9.7 and Section 10.1.4). In addition, participant
safety will be monitored by the independent eDMC through periodic review of accumulating
data (received from an unblinded statistician) as detailed in the eDMC charter.
Specific procedures to be performed during the study, as well as their prescribed times and 
associated visit windows, are outlined in the SoA in Section 1.3. Details of each procedure 
are provided in Section 8.
4.2
Scientific Rationale for Study Design
The randomized, placebo-controlled, double-blind superiority design and the selected 
endpoints of the study are consistent with regulatory guidance and are considered appropriate 
for non-hospitalized adult participants with COVID-19 [Food and Drug Administration 
2020] [European Commission 2020].
The primary outcome is assessed through Day 29 (for 28 days of follow-up from 
randomization) to allow for a sufficient duration to reliably assess the safety and 
effectiveness of a 5-day treatment course of MK-4482. This duration is considered 
appropriate to capture important clinically relevant efficacy endpoints (eg, hospitalization, 
death). A 28-day follow-up period also aligns with the ACTT-1 Study Group’s evaluation of 
remdesivir for treatment of COVID-19 in hospitalized adults [Beigel, J. H., et al 2020].
4.2.1
Rationale for Endpoints
4.2.1.1
Efficacy Endpoints
4.2.1.1.1
Primary Clinical Endpoint
The primary endpoint selected in this study is hospitalization or death. All-cause 
hospitalization (≥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) or death is intended to demonstrate the efficacy of MK-4482 relative to placebo 
using a clinically meaningful aspect of the disease that is relevant to non-hospitalized 
patients with COVID-19. This endpoint combines key clinical outcomes of interest, aiming 
to demonstrate the efficacy of study intervention in reducing serious complications of 
COVID-19.
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4.2.1.1.2
Secondary Endpoints
To further evaluate efficacy of MK-4482 administered to non-hospitalized participants, 
additional relevant endpoints were selected, which are based on signs/symptoms associated 
with COVID-19 infection and other aspects of clinical progression of disease that are 
expected to improve with effective antiviral therapy: 

Time to sustained resolution or improvement, and time to progression of each
targeted self-reported sign/symptom attributable to COVID-19 (Section 9.6.1) as 
reported by the participant through Day 29.

WHO 11-point ordinal outcome scale to assess COVID-19-associated symptom 
burden (severity and duration), hospitalization, and death through Day 29
(Appendix 8).
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 preclinical studies, mild hematologic toxicity was noted on Day 7, which progressed to 
more severe pancytopenia after 14-21 days of continuous exposure at 0.4-fold the NHC 
exposure at the 800 mg Q12H human dose of MK-4482. These changes were fully reversible 
(Section 2.3). Based on available unblinded data from the clinical development program for 
MK-4482, no clinically significant abnormalities in hematological laboratory tests as a 
function of either dose or treatment have been observed. 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 62-fold the NHC exposure 
at 800 mg Q12H and noted in dogs at 19-fold the NHC exposure at 800 mg Q12H. Based on 
available unblinded data from the clinical development program for MK-4482, no clinically 
significant abnormalities in liver parameters as a function of either dose or treatment were 
noted . However, elevated LFTs with a DILI pattern will be considered an ECI and closely 
monitored. 
No test-article related pathology changes in the pancreas to indicate pancreatic toxicity were 
noted in nonclinical studies and lipase and amylase were not measured. Transient elevations 
of serum lipase were observed at least 3 days after last dose in the Phase 1 study; the 
incidence of these elevations was comparable between recipients of MK-4482 and placebo. 
The occurrence and magnitude of these elevations did not appear to be dose related, and they 
were not associated with abdominal/gastrointestinal symptoms. However, as asymptomatic 
lipase elevations and clinical pancreatitis have been associated with some nucleoside analogs, 
changes in amylase or lipase were considered an ECI and closely monitored in Part 1 of this 
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study and MK-4482-001. Based on available unblinded data from the clinical development 
program for MK-4482, no clinically significant abnormalities in amylase or lipase as a 
function of either dose or treatment were noted. Thus due to the lack of preclinical findings 
and no trend noted in MK-4482 studies to date, elevated amylase, or lipase >3X the upper 
limit of normal is not considered an ECI for Part 2.
4.2.1.3
Pharmacokinetic Endpoints
Blood samples for PK assessment and concentrations of the MK-4482 nucleoside and 
triphosphate will be collected from all participants as described in the SoA (Section 1.3) and 
Section 8.6. As appropriate, PK-efficacy and PK-AE relationships for MK-4482 will also be 
evaluated. In Part 1, PBMC PK parameters (eg, Ctrough) will be estimated. In Part 2, plasma 
PK parameters (eg, Ctrough) will be summarized and in Parts 1 and 2, PK plasma parameters 
will be measured. PBMC PK samples will be used to evaluate the concentration of 
intracellular NHC-triphosphate, the active moiety resulting from dosing of MK-4482. 
Intracellular PBMC concentrations can help explain the relationship between MK-4482 dose 
and efficacy and safety.
4.2.1.4
Virology Endpoints
The study will evaluate SARS-CoV-2 RNA and infectious virus to assess the impact of 
MK-4482 on various aspects of SARS-CoV-2 viral dynamics.
Reducing SARS-CoV-2 VL and eradicating the virus are essential to recovery and has 
important implications for transmission and infection control strategies. The mechanism of 
antiviral activity of MK-4482 is viral error catastrophe predicated on increasing the viral 
mutation rate beyond a biologically-tolerable threshold resulting in impairment of viral 
fitness leading to viral elimination. These endpoints are aimed at assessing the antiviral 
activity of MK-4482 as well as evaluating the rate of viral mutagenesis with respect to 
MK-4482 treatment.
4.2.1.5
Future Biomedical Research
The Sponsor may provide samples, as described in Section 8.9, for which consent was 
provided during this study, to researchers including additional third parties (eg, a university 
investigator).
Such research is to address emergent questions not described in the protocol and will only be 
conducted on specimens as described in Section 8.9. Specimens will only be provided from 
appropriately consented participants. The objective of providing the 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.
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4.2.2
Rationale for the Use of Comparator/Placebo
This study will be placebo-controlled in order 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 may receive Sponsor-designated standard of 
care treatment (Section 6.5), as appropriate, in addition to study intervention (MK-4482 or 
matching placebo).
There are currently no orally available direct-acting antivirals approved for the treatment of 
COVID-19 to serve as an active comparator, therefore placebo will be used. 
4.2.3
Rationale for the Selected Participant Population
The rationale for the participant population selected for this study is as follows:

Participants with mild and moderate COVID-19: Participants with mild and
moderate COVID-19 (Appendix 9) are typically managed outside of the hospital and 
may benefit from administration of MK-4482 [Food and Drug Administration 2020]. 
Participants with severe and critical COVID-19 at randomization are excluded 
because they are expected to require hospitalization and would be out of scope for 
this study.

Participants at increased risk for severe illness from COVID-19: Certain 
characteristics or underlying medical conditions (Appendix 10) have been identified
that place patients at increased risk for severe illness from COVID-19, which may 
result in hospitalization, ICU-level care, ventilatory support, or death. This study 
focuses on higher risk non-hospitalized participants who may benefit from MK-4482, 
aiming to reduce the number of participants who develop severe illness from 
COVID-19 and need to be hospitalized or die. Thus, all participants must have at least 
1 characteristic or underlying medical condition associated with being at increased 
risk for severe illness from COVID-19 to ensure the drug is being evaluated in the 
non-hospitalized population at higher risk.

Participants with signs/symptoms attributable to COVID-19 for ≤5 days: Eligible
participants must have COVID-19 signs/symptoms onset no more than 5 days prior to 
randomization. SARS-CoV-2 VLs are highest early in the course of disease, present 
1-2 days prior to symptom onset, and persist for 7-12 days in moderate cases and up 
to 2 weeks in severe cases [Cevik, M., et al 2020]. Based on the viral kinetics of 
SARS-CoV-2 and the mechanism of action of MK-4482 (inhibition of viral 
replication), study participants must have signs/symptoms attributable to COVID-19 
for ≤5 days prior to randomization; all efforts should be made to administer the first 
dose on Day 1 (randomization), but administration of the first dose must occur within 
24 hours of randomization. Furthermore, as the host inflammatory response 
predominates during later stages of disease as COVID-19 progresses, treatment with 
antiviral therapy is likely to have a greater benefit with early treatment rather than 
delayed treatment >5 days after signs/symptoms onset, especially in the non-
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hospitalized setting wherein patients are often earlier in the course of their disease 
and intervention can occur sooner than in the hospital setting.
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 Other Exploratory Research Samples
Samples will be collected for other exploratory research. These samples may be utilized to 
perform evaluations related to SARS-CoV-2 and/or COVID-19 (including biomarkers), 
coinfections, or MK-4482. These samples may be tested during the course of the study or 
after study closure as the field of research evolves.
Blood for exploratory research, all residual material from NP (Parts 1 and 2) and OP (Part 1 
only) swabs, and all residual material from blood collections are intended for testing to 
address emergent questions not described elsewhere in the protocol and may be conducted on 
specimens from all participants. The objective of collecting/retaining specimens is to perform 
testing that informs the scientific understanding of SARS-CoV-2 and/or COVID-19, 
coinfections, or MK-4482. 
Exploratory research samples will not be used for human genome testing. Samples may be 
used for testing such as:
•
Determining if antibodies to SARS-CoV-2 are present and capable of neutralizing the 
virus
•
Measuring the quantity of infectious, replication-competent virus present in samples
•
Assessing if participants are coinfected with other respiratory pathogens 
•
Viral genome sequencing for determination of viral genotype (Clade) and detection of 
novel treatment-emergent variants. 
Evaluating the presence of antibodies to SARS-CoV-2 and their ability to neutralize the virus 
is critical to understanding the body’s immune response to infection with SARS-CoV-2. 
COVID-19 severity may be correlated with the timing and quantity of antibody production 
based on participant characteristics such as gender. Antibody-dependent enhancement of 
disease has also been identified as a potential rationale for increased disease severity in some 
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individuals [Ovsyannikova, I. G., et al 2020]. Antibody-related testing of participant samples 
may be used to evaluate if participants receiving MK-4482 or placebo have varying 
production of SARS-CoV-2 antibodies.
Molecular tests detecting viral RNA are capable of quantifying VLs in clinical samples; 
however, these molecular tests are incapable of quantifying infectious, replication-competent
SARS-CoV-2 [Mendoza, E. J., et al 2020]. The quantity of infectious, replication-competent 
virus in participant samples may be measured via cell-based infection assays. One such assay 
is the plaque assay, which quantifies viral titer (plaque forming unit) by counting the number 
of plaques formed in cell culture upon infection with serial dilutions of a virus specimen
[Mendoza, E. J., et al 2020]. Plaque assays performed in Vero cells will be used to assess the 
impact of MK-4482 on the presence and/or titer of replication-competent virus in NP swab 
samples.
Coinfection with other respiratory pathogens has been reported to occur to varying degrees in 
patients infected with SARS-CoV-2 and may be as high as 50% in non-survivors [Kim, D., et 
al 2020] [D'Abramo, A., et al 2020] [Wu, X., et al 2020] [Lai, C. C., et al 2020]. Participants 
enrolled may be coinfected with other pathogens. NHC has demonstrated broad antiviral 
activity against other RNA viruses including respiratory pathogens (eg, influenza, RSV, etc.) 
that have been observed in coinfection with SARS-CoV-2 [Lai, C. C., et al 2020]. Based on 
the potential for coinfection with other respiratory viruses, the potential impact of coinfection 
on outcomes, and the preclinical evidence of NHC antiviral activity against some of these 
pathogens, identifying participants coinfected with other respiratory viruses may be used to 
explore the impact of MK-4482 on coinfections. 
Since initial identification of the original SARS-CoV-2 genotype, multiple viral variants of 
concern have been identified and continue to circulate worldwide. Viral genome sequencing 
will be used to determine the SARS-CoV-2 genotype detected in study participants. 
Genotype data may be used to assess the impact of viral genotype on MK-4482 efficacy. In 
addition, viral sequence data may be used to identify treatment-emergent variants that could 
potentially impact vaccine or antiviral drug efficacy.
4.3
Justification for Dose
4.3.1
Rationale for Dosing Duration
Three doses of MK-4482 (administered every 12 hours) were sufficient to demonstrate 
efficacy in a ferret model of influenza. However, the duration of dosing of MK-4482 required 
to achieve efficacy against SARS-CoV-2 in humans is unknown. The planned treatment 
regimen of 5 days in this study is consistent with other acute antiviral treatments such as 
oseltamivir for influenza and is supported by nonclinical and clinical safety data for 
MK-4482. 
In a 28-day toxicity study of MK-4482 at 17 mg/kg/day (0.4-fold relative to the clinical NHC 
exposure at 800 mg Q12H) administered in dogs, reversible hematology changes consistent 
with bone marrow toxicity became apparent at Day 7 with increasing severity from Day 14 
onward. Dosing of MK-4482 up to 800 mg Q12H for 5.5 days has been generally well-
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tolerated by healthy participants in a Phase 1 clinical study; no clinically meaningful trends 
have been 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 MK-4482 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 MK-4482.
4.3.2
Dose Range for Part 1 (Phase 2)
The dose range planned for Part 1 was derived based on the anticipated clinically efficacious 
dose range predicted from nonclinical animal models. MK-4482 demonstrated efficacy in 
ferrets (a relevant species for virus challenge models) against H1N1 at 7 mg/kg BID (in vitro 
data demonstrated similar MK-4482 potency against H1N1 and SARS-CoV-2). The 
efficacious 7 mg/kg BID dose in ferrets scales to ~100 mg BID in humans, based on body 
surface area (assuming a 70 kg adult). This is a common scaling approach used for 
nucleosides, with some variability in the scaling of the prodrug to active triphosphate 
conversion from animals to humans.
Part 1 of the study includes evaluation of the 200 mg BID dose, as it is within the efficacious 
dose range predicted from animals, and includes higher doses in order to characterize the 
dose- and exposure-response relationship for MK-4482. The highest dose of 800 mg BID has 
a predicted steady-state mean plasma AUC0-12 exposure of ~32 µM*hr, which is 2.4-fold 
below the mean plasma AUC0-12 exposure at the highest single dose evaluated in adults of 
1600 mg. 
4.3.3
Dose Selection for Part 2 (Phase 3)
The MK-4482 dose of 800 mg Q12H for 5 days was selected for Part 2 of this study. The 
dose selection was based on data from IA2 as well as the totality of available safety, 
virology, PK, and clinical data from the MK-4482 program.
Enrollment of hospitalized participants in Part 1 (Phase 2) of MK-4482-001 has been 
completed. A total of 304 participants were randomized into 4 intervention groups: 
75 participants in the MK-4482 200 mg group, 75 participants in the MK-4482 400 mg
group, 76 participants in the MK-4482 800 mg group, and 78 participants in the placebo 
group. MK-4482 was generally well tolerated; the proportion of participants with AEs, drug-
related AEs, SAEs, and AEs leading to study intervention discontinuation during the 
protocol-specified AE safety follow-up period were comparable across the intervention
groups, with no apparent dose effect observed. There were no clinically significant 
differences in laboratory findings that met predetermined criteria, worsening Grade 3 or 4, in 
recipients of MK-4482 (any dose) compared with placebo. There was a numerically higher 
number of AEs resulting in death in participants treated with MK-4482 (14/218, 6.4%) 
compared with placebo (2/75, 2.7%) in P001. There was no apparent dose effect based on the 
incidence of death in each of the MK-4482 groups. None of the deaths was considered 
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related to study intervention by the investigator. The eDMC noted that there was no 
clustering of specific AEs resulting in death and concluded that no safety signals were seen at 
any MK-4482 dose. The most common AE resulting in death was COVID-19 and most 
deaths were associated with complications of COVID-19 (including pneumonia, sepsis, or 
thrombosis) or secondary bacterial infections. Most deaths occurred in participants who had 
severe COVID-19 at baseline, were >60 years of age, had underlying comorbidities, and/or 
had duration of symptoms >5 days prior to randomization.
Enrollment of Part 1 (Phase 2) of this study (MK-4482-002) has been completed. A total of 
302 participants were randomized into 4 intervention groups: 75 participants in the MK-4482 
200 mg group, 77 participants in the MK-4482 400 mg group, 76 participants in the 
MK-4482 800 mg group, and 74 participants in the placebo group. MK-4482 was well 
tolerated in non-hospitalized participants in MK-4482-002. The proportion of participants 
with AEs, drug-related AEs, SAEs, AEs leading to death, and AEs leading to study 
intervention discontinuation during the protocol-specified AE safety follow-up period were 
comparable across the intervention groups, with no apparent dose effect observed. No ECIs 
were reported and there were no clinically meaningful abnormalities in hematological, 
pancreatic, or hepatic parameters as a function of either dose or treatment.
The eDMC review of unblinded IA2 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, MK-4482 has been generally well-tolerated in 
other studies in the MK-4482 program at all doses studied with no dose-limiting toxicity 
observed at the highest dose (800 mg).
Virology data from IA2 in the MK-4482 program (MK-4482-001, MK-4482-002, and 
MK-4482-006) show that treatment with MK-4482 reduces the SARS-CoV-2 VL compared 
with placebo (based on change from baseline, slope of decline, and greater proportion of 
participants with a VL below the limit of quantitation within 15 or 29 days) in non-
hospitalized 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 to 200 and 
400 mg Q12H and is near the plateau of the dose-response curve. In addition, consistent with 
the proposed mechanism of action of MK-4482 of viral error catastrophe, the highest 
percentage of mutations in viral RNA post-treatment 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 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 MK-4482 intervention groups were hospitalized or 
died through Day 29 (compared to ~5% in the placebo group). All hospitalized participants 
had at least 1 risk factor for severe illness from COVID-19 including but not limited to 
obesity (n=8), >60 years of age (n=5), and diabetes (n=5). Protocol-specified subgroup 
analyses for the primary endpoint indicated potential clinical benefit from treatment with 
MK-4482 early in the course of disease (ie, symptom onset ≤5 days prior to the day of 
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randomization) as well as in individuals with risk factors for severe illness from COVID-19, 
including age >60 years. This trend is further supported by exposure-response analyses for 
the endpoint of hospitalization which suggest a trend of an increased clinical effect at 
MK-4482 800 mg Q12H dose over placebo or lower MK-4482 doses. 
Based on the totality of the observed safety profile and virologic data in the MK-4482
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. 
4.4
Beginning and End of Study Definition
The overall study begins when the first participant (or their legally acceptable representative) 
provides documented informed consent. The overall study ends when the last participant 
completes the last study-related contact, withdraws consent, or is lost to follow-up (ie, the 
participant is unable to be contacted by the investigator).
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. Early study termination may also be 
considered after review of accumulating efficacy and safety data by the eDMC (Section 9.7).
5
STUDY POPULATION
Male/female non-hospitalized participants ≥18 years of age with COVID-19 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.
5.1
Inclusion Criteria
A participant will be eligible for inclusion in the study if the participant:
Type of Participant and Disease Characteristics
1. Has documentation of laboratory-confirmed SARS-CoV-2 infection with sample 
collection ≤5 days prior to the day of randomization.
Note: PCR is the preferred method; however, with evolving approaches to laboratory 
confirmation of SARS-CoV-2 infection, other 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.
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2. Had initial onset of signs/symptoms attributable to COVID-19 for ≤5 days prior to the 
day of randomization and at least 1 of the following signs/symptoms attributable to 
COVID-19 on the day of randomization (Appendix 9): 

Cough

Sore throat

Nasal congestion

Runny nose

Shortness of breath or difficulty breathing with exertion

Muscle or body aches

Fatigue 

Fever >38.0◦C

Chills

Headache

Nausea

Vomiting

Diarrhea

Loss of smell

Loss of taste
3. Has mild or moderate COVID-19 (refer to Appendix 9 to determine disease severity at 
randomization).
4. Has at least 1 characteristic or underlying medical condition associated with an increased 
risk of severe illness from COVID-19 (refer to Appendix 10 to determine if the 
participant has a characteristic or underlying medical condition associated with an 
increased risk of severe illness from COVID-19).
5. Is willing and able to take oral medication. 
Demographics
6. Is male or female ≥18 years of age, at the time of providing informed consent.
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Male Participants
7.
Male participants are eligible to participate if they agree to the following during the 
intervention period and for at least 4 days after the last dose of study intervention:
•
Be abstinent from heterosexual intercourse as their preferred and usual lifestyle (abstinent 
on a long-term and persistent basis) and agree to remain abstinent
OR
•
Must agree to use contraception unless confirmed to be azoospermic (vasectomized or 
secondary to medical cause [Appendix 5]) as detailed below:
Agree to use a male condom plus partner use of an additional contraceptive method when 
having penile-vaginal intercourse with a WOCBP who is not currently pregnant. Note: Men 
with a pregnant or breastfeeding partner must agree to remain abstinent from penile-vaginal 
intercourse or use a male condom during each episode of penile-vaginal penetration.
•
Contraceptive use by men should be consistent with local regulations regarding the 
methods of contraception for those participating in clinical studies.
Female Participants
8. A female participant is eligible to participate if she is not pregnant or breastfeeding, and 
at least one of the following conditions applies: 
•
Is not a WOCBP
OR
•
Is a WOCBP and using a contraceptive method that is highly effective (a low user 
dependency method OR a user dependent 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 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. 
•
A WOCBP must have a negative highly sensitive pregnancy test (urine or serum as 
required by local regulations) within 24 hours before the first dose of study intervention.
•
Additional requirements for pregnancy testing during and after study intervention are 
located in Section 8.3.4.
•
The investigator is responsible for review of medical history, menstrual history, and 
recent sexual activity to decrease the risk for inclusion of a woman with an early 
undetected pregnancy.
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•
Contraceptive use by women should be consistent with local regulations regarding the 
methods of contraception for those participating in clinical studies.
•
If contraceptives are interrupted as standard of care management of COVID-19 patients 
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
9. Participant (or legally acceptable representative) has provided documented informed 
consent/assent for the study. The participant may also provide consent/assent for FBR. 
However, the participant may participate in the study without participating in FBR.
Note: As outlined in the informed consent, patients can only participate in this study if 1) 
they have chosen not to receive treatment with a SARS-CoV-2 monoclonal antibody(ies) 
and reside in the US or in other countries where SARS-CoV-2 monoclonal antibodies are 
authorized or approved, or 2) reside outside of the US in countries where SARS-CoV-2 
monoclonal antibodies are not authorized or approved.
5.2
Exclusion Criteria
The participant must be excluded from the study if the participant:
Medical Conditions
1. Is currently hospitalized or is expected to need hospitalization for COVID-19 within 
48 hours of randomization.
2. Is on dialysis or has reduced eGFR <30 mL/min/1.73 m2 (by the MDRD equation
[Appendix 11]).
3. Has any of the following conditions:

HIV with a recent VL >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.

A neutrophilic granulocyte absolute count <500/mm3
4. Has a history of HBV or HCV infection with any of the following: 

Cirrhosis 

End-stage liver disease
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
Hepatocellular carcinoma

AST and/or ALT >3X upper limit of normal at screening
5. Has a platelet count <100,000/µL or received a platelet transfusion in the 5 days prior to 
randomization.
6. Has hypersensitivity or other contraindication to any of the components of the study 
interventions as determined by the investigator.
7. 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 who are not expected to survive longer than 48 hours after 
randomization, or

Participants with a recent history of mechanical ventilation, or 

Participants with conditions that could limit gastrointestinal absorption of capsule 
contents.
Prior/Concomitant Therapy
8. Is taking or is anticipated to require any prohibited therapies as outlined in Section 6.5.
Prior/Concurrent Clinical Study Experience
9. 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
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.
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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.
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 
Formu-
lation
Unit Dose 
Strength(s)
Dosage 
Level(s)
Route of 
Adminis-
tration
Regimen/
Treatment 
Period
Use
IMP/
NIMP
Sourcing
MK-
4482
Experi-
mental
MK-4482
Drug
Capsule
200 mg
Part 1: 
200 mg, 
400 mg, 
800 mg; 
Part 2 800 mg
Oral
Q12H 5 days 
(10 doses 
total)
Experi-
mental
IMP
Central
Placebo
Placebo 
Comparator
Placebo 
Matching 
MK-4482
Drug
Capsule
0 mg
Part 1: N/A 
Part 2: N/A
Oral
Q12H 5 days 
(10 doses 
total)
Placebo
IMP
Central
N/A= not applicable; Q12H= every 12 hours.
The classification of Investigational Medicinal Product (IMP) and Non-Investigational Medicinal Product (NIMP) in this table is based on guidance issued by the European 
Commission and applies to countries in the European Economic Area (EEA). Country differences with respect to the definition/classification of IMP/NIMP may exist. In these 
circumstances, local legislation is followed.
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All supplies indicated in Table 1 will be provided per the "Sourcing" column depending upon 
local country operational requirements. If local sourcing, every attempt should be made to 
source these supplies from a single lot/batch number where possible (eg, not applicable in the 
case where multiple lots or batches may be required due to the length of the study, etc.).
Refer to Section 8.1.8 for details regarding administration of the study intervention.
6.2
Preparation/Handling/Storage/Accountability
6.2.1
Dose Preparation
There are no specific calculations or evaluations required to be performed in order to 
administer the proper dose to each participant. The rationale for selection of doses to be used 
in this study is provided in Section 4.3.
6.2.2
Handling, Storage, and Accountability
The investigator or designee must confirm appropriate temperature conditions have been 
maintained during transit for all study intervention received, and any discrepancies are 
reported and resolved before use of the study intervention.
Only participants enrolled in the study may receive study intervention, and only authorized 
site staff may supply or administer study intervention. All study interventions must be stored 
in a secure, environmentally controlled, and monitored (manual or automated) area in 
accordance with the labeled storage conditions with access limited to the investigator and 
authorized site staff.
The investigator, institution, or the head of the medical institution (where applicable) is 
responsible for study intervention accountability, reconciliation, and record maintenance (ie, 
receipt, reconciliation, and final disposition records).
For all study sites, the local country Sponsor personnel or designee will provide appropriate 
documentation that must be completed for drug accountability and return, or local discard 
and destruction if appropriate. Where local discard and destruction is appropriate, the 
investigator is responsible for ensuring that a local discard/destruction procedure is 
documented.
The study site is responsible for recording the lot number, manufacturer, and expiry date for 
any locally purchased product (if applicable) as per local guidelines unless otherwise 
instructed by the Sponsor.
The investigator shall take responsibility for and shall take all steps to maintain appropriate 
records and ensure appropriate supply, storage, handling, distribution, and usage of study 
interventions in accordance with the protocol and any applicable laws and regulations.
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6.3
Measures to Minimize Bias: Randomization and Blinding
6.3.1
Intervention Assignment
Intervention randomization will occur centrally using an IRT system. In Part 1, there are 
4 study intervention arms and participants will be assigned randomly in a 1:1:1:1 ratio to 
MK-4482 200 mg, 400 mg, 800 mg, or placebo. In Part 2, there are 2 study intervention arms 
and participants will be assigned randomly in a 1:1 ratio to MK-4482 800 mg or placebo.
6.3.2
Stratification
Intervention randomization will be stratified according to the following factors:
Part 1
1.
Time from symptom onset prior to the day of randomization (≤5 days, >5 days)
2.
At increased risk of severe illness from COVID-19 (Appendix 10) (yes, no)
Based on the viral kinetics of SARS-CoV-2 and the mechanism of action of MK-4482, 
treatment with antiviral therapy is likely to have a greater benefit with earlier treatment 
(≤5 days) rather than later treatment (>5 days). In addition, certain characteristics or 
underlying medical conditions (Appendix 10) have been identified that place patients at 
increased risk for severe illness from COVID-19, which may result in hospitalization, ICU-
level care, ventilatory support, or death. The selection of these criteria as stratification factors 
will help ensure that the treatment groups will be well balanced within each stratum and the
study results will not be confounded by factors suspected to have a potential impact on a
participant’s response to study intervention.
Of note, at least 75% of participants overall must have at least 1 characteristic or underlying
medical condition associated with being at increased risk for severe illness from COVID-19
as defined in Appendix 10. In addition, enrollment of participants with moderate COVID-19
(Appendix 9) will be limited to 50% of total planned sample size.
Part 2
1.
Time from symptom onset prior to the day of randomization (≤3 days, >3 days)
Based on updates to inclusion criterion #2 wherein the initial onset of signs/symptoms 
attributable to COVID-19 was amended to ≤5 days prior to the day of randomization to target 
participants earlier in their COVID-19 disease course, the time from symptom onset prior to 
the day of randomization stratification factor was amended to ≤3 days or >3 days. Based on 
the viral kinetics of SARS-CoV-2 and the mechanism of action of MK-4482, treatment with 
antiviral therapy is likely to have a greater benefit with earlier treatment (≤3 days) rather than 
later treatment (>3 days).
Of note, all participants must have at least 1 characteristic or underlying medical condition 
associated with being at increased risk for severe illness from COVID-19 as defined in 
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Appendix 10. Age is a risk factor independent of other health conditions, so while there is no 
minimal enrollment for participants >60 years of age, every effort should be made to 
maximize enrollment of this age group.
6.3.3
Blinding
A double-blinding technique with in-house blinding will be used. MK-4482 (all dose levels) 
and placebo will be packaged identically so 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.
To allow timely completion of dose/exposure-response analyses, select Sponsor internal or 
external personnel will be unblinded while Part 1 of the study is ongoing. No personnel 
directly associated with study conduct will be unblinded (before Part 1 database lock). Before 
granting select personnel access to unblinded Part 1 data, an official memo detailing the 
unblinding procedures and listing the personnel who will have access (before database lock) 
to the unblinded data will be generated per Sponsor SOP. Once all Part 1 participants have 
completed Day 29 (ie, achieved a final status for Day 29 endpoints), the Sponsor will initiate 
database lock/unblinding procedures for this part of the study. 
In addition, a separate, small, cross-functional unblinded team of Sponsor personnel will also 
be convened for Part 2 of the study with the purpose of supporting preparation and 
submission of applications for emergency use and/or marketing authorizations in the case of 
a positive efficacy finding noted by the eDMC at IA4. The members of this team will not 
have access to unblinded data until an eDMC decision is reached. Additional details of the 
unblinding plan will be documented in an official memo prior to eDMC review. Sponsor 
personnel responsible for ongoing blinded data review will remain blinded to data obtained 
from Part 2 participants until all Part 2 participants have completed Day 29 (ie, achieved a 
final status for Day 29 endpoints) except as documented in Section 9.7 – Interim Analyses.
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 
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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.
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 
his/her 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.
Table 2
Prohibited and Allowed Therapies
COVID-19 Vaccines

SARS-CoV-2 vaccines are prohibited any time prior to randomization 
and through Day 29.
COVID-19 Monoclonal 
Antibodies

Monoclonal antibodies are prohibited for treatment of the current SARS-
CoV-2 infection, including prior to randomization and through Day 29.
Other COVID-19 
Therapeutics

Sponsor-designated standard of care for treatment for COVID-19a is 
permitted (eg, corticosteroids) but may require additional safety 
monitoring as determined by the treating clinician.
o
If guidelines for local standard of care conflict with Sponsor-
designated standard of care, site should consult with Sponsor.
o
Unless designated by the Sponsor as acceptable standard of 
care for COVID-19, concomitant use of other therapies
intended as specific treatment for COVID-19 are prohibited 
from randomization through Day 29. If a participant is 
hospitalized during the study, other therapies intended as 
treatment for COVID-19 are permitted.

Supportive therapies (including but not limited to anti-pyretic and anti-
inflammatory agents) to manage COVID-19 signs/symptoms are 
allowed. 
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. 
a For a detailed list of Sponsor-approved treatments, refer to the MK-4482-002 Sponsor-Designated Standard of Care for 
Treatment of COVID-19 or Supportive Therapies for Management of COVID-19 document.
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6.5.1
Rescue Medications and Supportive Care
Sponsor-designated standard of care for COVID-19 is permitted.
6.6
Dose Modification (Escalation/Titration/Other)
No dose modification of MK-4482 or placebo is allowed in this study.
6.7
Intervention After the End of the Study
There is no study-specified intervention following the end of the study.
6.8
Clinical Supplies Disclosure
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 8.1.10). In the 
event that 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.
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 prior to 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 8.11.3, 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 
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.
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•
The participant has a medical condition or personal circumstance which, in the opinion of 
the investigator and/or Sponsor, places the participant at unnecessary risk from continued 
administration of study intervention.
•
An elevated AST or ALT lab value that is ≥3X the upper limit of normal and an elevated 
total bilirubin lab value that is ≥2X the upper limit of normal and, at the same time, an 
alkaline phosphatase lab value that is <2X the upper limit of normal, as determined by 
way of protocol-specified laboratory testing or unscheduled laboratory testing.
•
The participant has any platelet count of <50,000/µL, as determined by way of protocol-
specified laboratory testing or unscheduled laboratory testing.
•
The participant is no longer able to take oral medication or becomes intubated prior to 
completion of study intervention.
•
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.
If a participant discontinues from study intervention early for any reason (ie, prior to the 9th
or 10th dose), then plasma samples for PK and blood samples for PBMCs will not be 
collected for that participant (Section 8.6.1 and Section 8.6.2).
7.2
Participant Withdrawal From the Study
A participant must be withdrawn from the study if the participant or participant’s legally 
acceptable representative withdraws consent from the study.
If a participant withdraws from the study, they will no longer receive study intervention or be 
followed at scheduled protocol visits.
Both survival and hospitalization status at Day 29 and LFU are required for all randomized 
participants and should still be reported for participants who withdraw from the study where 
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 8.2.4.
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
8.11.3 and Section 8.1.9.1. 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.
8
STUDY ASSESSMENTS AND PROCEDURES
•
Study procedures and their timing are summarized in the SoA.
•
Adherence to the study design requirements, including those specified in the SoA, is 
essential and required for study conduct.
•
The investigator is responsible for ensuring that procedures are conducted by 
appropriately qualified (by education, training, and experience) staff. Delegation of study 
site personnel responsibilities will be documented in the Investigator Trial File Binder (or 
equivalent).
•
All study-related medical decisions must be made by an investigator who is a qualified 
physician.
•
All screening evaluations must be completed and reviewed to confirm that potential 
participants meet all eligibility criteria. The investigator will maintain a screening log to 
record details of all participants screened and to confirm eligibility or record reasons for 
screening failure, as applicable.
•
Procedures conducted as part of the participant’s routine clinical management (eg, blood 
count) and obtained before signing of ICF may be utilized for screening or baseline 
purposes provided the procedure met the protocol-specified criteria and were performed 
within the time frame defined in the SoA.
•
Additional evaluations/testing may be deemed necessary by the investigator and or the 
Sponsor for reasons related to participant safety. In some cases, such evaluation/testing 
may be potentially sensitive in nature (eg, HIV, Hepatitis C), and thus local regulations 
may require that additional informed consent be obtained from the participant. In these 
cases, such evaluations/testing will be performed in accordance with those regulations.
The maximum amount of blood collected from each participant over the duration of the study 
will not exceed approximately 140 mL for participants in the PBMC Cohort or 
approximately 108 mL for all other participants (Appendix 2, Table 12).
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Repeat or unscheduled samples may be taken for safety reasons or due to technical issues 
with the samples.
8.1
Administrative and General Procedures
8.1.1
Informed Consent
The investigator or medically qualified designee (consistent with local requirements) must 
obtain documented informed consent from each potential participant (or their legally 
acceptable representative) prior to participating in this clinical study or FBR. If there are 
changes to the participant’s status during the study (eg, health or age of majority 
requirements), the investigator or medically qualified designee must ensure the appropriate 
documented informed consent is in place.
For country-specific requirements see Appendix 7.
8.1.1.1
General Informed Consent
Informed consent given by the participant or their legally acceptable representative must be 
documented on a consent form. The form must include the trial protocol number, trial 
protocol title, dated signature, and agreement of the participant (or their legally acceptable 
representative) and of the person conducting the consent discussion.
A copy of the signed and dated informed consent form should be given to the participant (or 
their legally acceptable representative) before participation in the study.
The initial ICF, any subsequent revised ICF, and any written information provided to the 
participant must receive the IRB/IEC’s approval/favorable opinion in advance of use. The 
participant or their legally acceptable representative should be informed in a timely manner if 
new information becomes available that may be relevant to the participant’s willingness to 
continue participation in the study. The communication of this information will be provided 
and documented via a revised consent form or addendum to the original consent form that 
captures the participant’s or the participant’s legally acceptable representative’s dated 
signature.
Specifics about the study and the study population are to be included in the study informed 
consent form.
Informed consent will adhere to IRB/IEC requirements, applicable laws and regulations, and 
Sponsor requirements.
8.1.1.2
Consent and Collection of Specimens for Future Biomedical Research
The investigator or medically qualified designee will explain the FBR consent to the 
participant, or the participant’s legally acceptable representative, answer all of his/her 
questions, and obtain documented informed consent before performing any procedure related 
to FBR. A copy of the informed consent will be given to the participant before performing 
any procedure related to FBR.
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8.1.1.3
Consent for PBMC Cohort Blood Sample Collection
The investigator or medically qualified designee will explain the PBMC Cohort blood sample 
collection to the participant and/or the participant’s legally acceptable representative, answer 
all of their questions, and obtain documented informed consent before performing any 
procedure related to the PBMC Cohort blood sample collection. After applicable consent is 
obtained, these participants will have additional PBMC PK blood sample collection as 
specified in the SoA (Section 1.3) and Section 8.6.2. A copy of the signed informed consent 
will be given to the participant and/or participant’s legally acceptable representative.
8.1.2
Inclusion/Exclusion Criteria
All inclusion and exclusion criteria will be reviewed by the investigator, who is a qualified 
physician, to ensure that the participant qualifies for the study.
The SARS-CoV-2 test result must be reviewed for participant eligibility and data entered into 
the eCRF including date specimen collected, sample type (eg, NP swab, OP swab, 
midturbinate swab, saliva, etc.), test method (eg, RT-PCR) and result (positive result is 
required). If prior results are not available, laboratory confirmation of SARS-CoV-2 infection 
may be performed at screening to confirm eligibility. Results must be available prior to 
randomization.
Assessments required for COVID-19 severity categorization (Appendix 9) for IRT (vital 
signs, COVID-19 signs/symptoms assessment, respiratory measures, oxygen therapy, 
ongoing medical history) must be completed and documented on Day 1 prior to calling IRT 
in order to randomize. All other Day 1 assessments must be completed on Day 1 prior to first 
dose of study intervention.
The following local laboratory results must be available for all participants from within 
72 hours prior to randomization: serum creatinine, platelets, and absolute neutrophil count. In 
participants with reported history of HBV or HCV, ALT and AST must be available from 
within 72 hours prior to randomization to support determination of eligibility. In WOCBP, a 
negative local urine or serum pregnancy test is required within 24 hours 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 VL). 
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
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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. Participants will 
be asked to provide any background or concomitant conditions, drug allergies and/or 
surgeries within the last 12 months. In addition, history of smoking (tobacco or marijuana), 
including use of vaping devices, will be collected. Medical history for the following 
conditions will be collected separately on the Medical History Pre-Specified Conditions 
eCRF: chronic kidney disease, chronic obstructive pulmonary disease, immunocompromised
state from solid organ transplant (Part 1 only), obesity, active cancer (excluding minor 
cancers not associated with immunosuppression or significant morbidity/mortality), 
congestive cardiac failure, coronary artery disease, cardiomyopathies, sickle cell disease
(Part 1 only), and diabetes mellitus (Appendix 10). Any oxygen therapy needs in the 7 days 
prior to symptom onset and through randomization will be reported in the oxygen therapy 
eCRF with flow rate reported in L/min. Reporting will include supplemental oxygen 
requirements during pre-morbid/pre-COVID-19, between the onset of COVID-19 
signs/symptoms and study randomization, and any changes to oxygen therapy needs during 
the study treatment and follow-up periods.
8.1.5
Prior and Concomitant Medications Review
8.1.5.1
Prior Medications
The investigator or qualified designee will review prior medication use and record prior 
medications taken by the participant within 30 days before first dose of study intervention.
All prior therapeutics/vaccines for COVID-19 regardless of timing, must be recorded.
8.1.5.2
Concomitant Medications
The investigator or qualified designee will record medications, if any, taken by the 
participant during the study. All concomitant therapeutics/vaccines for COVID-19, including 
all supportive therapies (eg, anti-pyretic and anti-inflammatory agents) to manage COVID-19 
signs/symptoms, must be reported.
8.1.6
Assignment of Screening Number
All consented participants will be given a unique screening number that will be used to 
identify the participant for all procedures that occur prior to randomization. Each participant 
will be assigned only 1 screening number. Screening numbers must not be re-used for 
different participants.
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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 treatment randomization. Once a 
treatment/randomization number is assigned to a participant, it can never be re-assigned to 
another participant.
A single participant cannot be assigned more than 1 treatment/randomization number.
8.1.8
Study Intervention Administration
Study intervention will be provided as per Table 1 and dispensed through the IRT system at 
the Day 1 (randomization) visit. All efforts should be made to administer the first dose on 
Day 1 (randomization), but administration of the first dose must occur within 24 hours of 
randomization. If administered on the next calendar day following randomization, the day of 
administration of the first dose of study intervention in this case would be considered Day 2.
Study intervention and the Study Medication Diary will be dispensed to the participant 
according to the pharmacy manual for at home administration. Study intervention will be 
self-administered by the participant Q12H at approximately the same times each day. 
8.1.8.1
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 10 doses. Study 
intervention can be administered without regard to food. Refer to Section 8.6.1 regarding PK 
collection. 
•
For participants that begin dosing in the morning on Day 1, the EOT visit will occur on 
Day 5. PK specimens will be collected at the EOT visit in association with the 9th dose, 
and the final 10th dose will occur in the evening on Day 5.
•
For participants that begin dosing in the evening on Day 1, the EOT visit will occur on 
Day 6. PK specimens will be collected at the EOT visit in association with the 10th dose 
on Day 6. 
As outlined in the SoA, all efforts should be made to administer the first dose on Day 1 
(randomization), but administration of the first dose must occur within 24 hours of 
randomization; therefore it is possible that dosing may not begin until Day 2.
•
For participants that begin dosing in the morning on Day 2, the EOT visit will occur on 
Day 6. PK specimens will be collected at the EOT visit in association with the 9th dose, 
and the final 10th dose will occur in the evening on Day 6.
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•
For participants that begin dosing in the evening on Day 2, the EOT visit will occur on 
Day 7. PK specimens will be collected at the EOT visit in association with the 10th dose 
on Day 7.
If the EOT visit occurs on Day 6, no additional visit is required on Day 5. And if the EOT 
visit occurs on Day 7, no additional visits are required on Day 5 or Day 6.
The administration of the morning dose on the EOT visit will be observed by site
staff/delegate and should be aligned with the timing of blood collection for PK analyses at 
EOT (SoA, Section 1.3).
For all doses, the timing of dose administration should be recorded in the Study Medication 
Diary.
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 the normal dosing schedule (ie, Q12H) resumed.
•
If >10 hours from the time the missed dose should have been taken, the missed dose 
should be skipped, and the normal dosing schedule (ie, Q12H) resumed. The participant 
should not double the next dose to compensate for what has been missed.
•
In the event of an out of window dose during the treatment period, the EOT visit may 
need to be rescheduled to accommodate collection of PK samples in association with the 
9th or 10th dose. The site should communicate with the participant during the treatment 
period to discuss if any changes to the dosing schedule occurred, which might affect the 
timing of the 9th or 10th dose and thus warrant a change to the EOT visit.
If a participant's renal function deteriorates requiring dialysis during the study intervention, 
the Sponsor will not require the discontinuation of the study intervention; administration of 
the study intervention may continue at the discretion of the investigator. For participants who 
require continuous dialysis, study intervention should continue to be administered Q12H with 
no change to the timing of administration. For participants who require intermittent dialysis, 
study intervention should continue to be administered Q12H with doses administered 4 to 
6 hours prior to dialysis where possible.  
8.1.9
Discontinuation and Withdrawal
Participants who discontinue study intervention prior to completion of the treatment period
should be encouraged to continue to be followed for all remaining study visits after EOT as 
outlined in 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; Section 8.11.3) at the time of withdrawal. Any AEs that are present 
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at the time of withdrawal should be followed in accordance with the safety requirements 
outlined in Section 8.4.
Survival status at Day 29 is required for all randomized participants and should still be 
reported for participants who withdraw from the study where permitted by local guidelines.
8.1.9.1
Withdrawal From Future Biomedical Research
Participants may withdraw their consent for FBR. Participants may withdraw consent at any 
time by contacting the study investigator. If medical records for the study are still available, 
the investigator will contact the Sponsor using the designated mailbox 
(clinical.specimen.management@merck.com). Subsequently, the participant’s consent for 
FBR will be withdrawn. A letter will be sent from the Sponsor to the investigator confirming 
the withdrawal. It is the responsibility of the investigator to inform the participant of 
completion of withdrawal. Any analyses in progress at the time of request for withdrawal or 
already performed before the request being received by the Sponsor will continue to be used 
as part of the overall research study data and results. No new analyses would be generated 
after the request is received.
If the medical records for the study are no longer available (eg, if the investigator is no longer 
required by regulatory authorities to retain the study records) or the specimens have been 
completely anonymized, there will no longer be a link between the participant’s personal 
information and their specimens. In this situation, the request for specimen withdrawal 
cannot be processed.
8.1.10
Participant Blinding/Unblinding
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 
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.
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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.
8.1.11
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.
8.1.12
Collect/Update Secondary Contact Information
Sites will capture secondary contact information for 2 individuals that the site can contact if 
the participant cannot be reached (eg, spouse, friend, neighbor, etc.). Sites will also request 
healthcare provider contact information and a few hospitals that the participant is likely to go 
to if they get sick. Contact information for secondary contacts or healthcare provider will not 
be recorded on any eCRF. If participants cannot be reached after 2 attempts 24 hours apart, 
then their listed secondary contact person(s) or healthcare provider will be contacted. At
study entry only, sites will record the participant’s home address in site records (it will not be 
reported on the eCRF).
Secondary contact information will be reviewed and updated according to the SoA
(Section 1.3). 
8.1.13
Participant Study Supplies
On Day 1 of the study, participants will receive bottles of study intervention along with study 
supplies, including:
•
Copy of informed consent
•
Information about the study
•
Instructions on study procedures and how to take study intervention
•
Pocket/wallet card with site staff contact information
•
Instructions on what to do if participants have worsening symptoms/become hospitalized
•
Study Medication Diary (see Section 8.1.14) 
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•
Symptom Diary (see Section 8.2.5)
8.1.14
Study Medication Diary
A paper Study Medication Diary will be provided for documentation of doses of study 
intervention and assessment of compliance. Participants should complete the Study 
Medication Diary for each dose taken. In the event that the participant is (in the judgement of 
the investigator) unable to complete the diary, information regarding study intervention
administration may be recorded by an LAR or other close contact who witnesses 
administration of the study intervention.
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, 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 10 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. In the event that 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). 
8.2
Efficacy Assessments
8.2.1
Nasopharyngeal and Oropharyngeal Swabs 
NP (Parts 1 and 2) and OP (Part 1 only) swabs will be collected at various timepoints as 
outlined in the SoA (Section 1.3) for qualitative and quantitative SARS-CoV-2 RT-PCR 
testing, detection of infectious SARS-CoV-2, and SARS-CoV-2 genome sequencing. At 
study entry (Day 1), the samples should be collected prior to the first dose of study 
intervention. Additional information, including instructions for swab collection, storage, and 
shipping, can be found in the laboratory manual.
8.2.2
Respiratory/Oxygenation Status
SpO2 will be measured via pulse oximetry (SoA, Section 1.3) after the participant has been at 
rest for at least 5 minutes. The first recording will be on Day 1 prior to the first dose of study 
intervention and then at each in-person visit through Study Day 29. In addition, 
investigator/designee assessment of shortness of breath at rest and with exertion will be 
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performed at randomization prior to the first dose of study intervention and then at each in-
person visit through Study Day 29. FiO2, PaO2, and supplemental oxygen use if applicable
should be reported.
Use of supplemental oxygen, including type (eg, oxygen from a conventional regulator or 
high-flow heated and humidified device, non-invasive mechanical ventilation, invasive 
mechanical ventilation, ECMO) and flow rate (L/min) will be recorded on the appropriate 
eCRF. If applicable, supplemental oxygen requirements pre-morbid/pre-COVID-19 and
between the onset of COVID-19 signs and symptoms and study randomization will be 
recorded (Section 8.1.4).
New or worsening shortness of breath or difficulty breathing should be reported to the site 
clinician and referral for medical attention considered.
Note: Respiratory/Oxygenation Status collection at the LFU visit will be limited. As LFU 
will be a virtual visit, SpO2 will not be measured. Use of supplemental oxygen will be 
collected.
8.2.3
Hospitalization
Hospitalization status will be assessed as outlined in the SoA (Section 1.3). 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 in accordance with the guidance outlined in Section 8.4.6.
Participants who report worsening illness from any cause during the study may be referred to 
their healthcare 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.
Acute care visits must also be documented and recorded on the eCRF. Acute care visits are 
defined as any hospitalization (any amount of time in a hospital or similar acute care facility, 
including emergency rooms or facilities created to address hospitalization needs during the 
COVID-19 pandemic) or emergency room visit or any other acute care visit (including an 
urgent care visit or visit with any healthcare provider for acute care needs) from 
randomization through Day 29. The date and time of the acute care visit, and primary reason 
for acute care visit (including if the visit is related to COVID-19) will be recorded.
For any participants who become hospitalized during the study, all study procedures outlined 
in the SoA (Section 1.3), including study intervention administration (if applicable), should 
be continued. 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). If access to the participant by study staff is not feasible
while in hospital, use of a home healthcare professional (eg, through a home healthcare 
vendor) to perform inpatient participant visits according to the SoA (Section 1.3) should be 
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considered. Given the frequency of study intervention administration, it is recognized that 
use of nonstudy personnel may be necessary for this procedure. 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 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 COVID-19 symptoms (eg, via MK-4482 Symptom 
Diary or Sponsor-provided interview script, if completed), vital signs, supplemental 
oxygenation use, ventilation procedures, concomitant medications, and adverse events, 
including death. In addition, every effort should also be made for a visit to be scheduled after 
discharge from the hospital, providing that the visit is within 28 days of initiation of dosing. 
8.2.4
Survival Status
Survival status (ie, whether the participant is alive or dead) will be assessed per the SoA 
(Section 1.3).
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), per the SoA (Section 1.3).
Information about death should be entered in the eCRF within 24 hours of a site becoming 
aware of a death.
8.2.5
MK-4482 Symptom Diary
COVID-19 signs/symptoms will be reported daily by the participant using a paper MK-4482
Symptom Diary on Days 1 to 29. Targeted symptoms assessed in the 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 and loss of smell. If the participant is able to 
comprehend the diary questions (in the judgement of the investigator) but is unable to record 
their responses on the diary on their own per investigator discretion, collection of COVID-19 
signs/symptom data by study staff via an in-person or virtual (eg, telephone) participant 
interview using a Sponsor-provided interviewer script should be implemented.
On Day 1 (the same day as randomization), participants will complete the MK-4482
Symptom Diary prior to the first dose of study treatment. Completion of the Symptom Diary
will be observed at the site or in-home visit and documented, including time of participant 
completion, by study staff/home healthcare professional. Following Day 1, participants 
should complete the diary daily at approximately the same time every day through Day 29, 
recording and rating each symptom at its worst (reported as none, mild, moderate, or severe) 
during the prior 24 hours. 
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In the event of hospitalization, the MK-4482 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 SoA, 
Section 1.3.
The MK-4482 Symptom Diary will be reviewed by study staff with each participant at the 
visits described in the SoA (Section 1.3) to ensure compliance with completion. To further 
support compliance with completion by the participant, the study staff should provide 
participants with regular telephone or other reminders (eg, email, text messages) regarding 
diary completion. Following the EOT visit, these reminders should be provided every other 
day through Day 29. The MK-4482 Symptom Diary will be collected per the SoA, Section 
1.3, and the diary data will be recorded in the eCRF. 
8.2.6
Functional Status Assessments
Functional status assessments will be performed at all in-clinic or at-home visits per the SoA 
(Section 1.3). The participant’s ability to independently perform daily activities with minimal 
or no symptoms will be assessed and evaluated at the discretion of investigator/designee.
8.3
Safety Assessments
Details regarding specific safety procedures/assessments to be performed in this study are 
provided below. The total amount of blood to be drawn over the course of the study (from 
pre-study to post-study visits), including approximate blood volumes drawn by visit and by 
sample type per participant, can be found in Appendix 2, Table 11.
Planned time points for all safety assessments are provided in the SoA.
8.3.1
Physical Examinations
A complete physical examination will be conducted at the screening visit by a nurse or other 
qualified healthcare provider. Height and weight will also be collected and recorded. A nurse 
or other qualified healthcare provider will also conduct directed physical examination
targeted at the participant’s symptoms/complaints at all other in-person visits (in-clinic or at-
home). Details of the physical examinations will be provided to an 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.
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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 
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:
Pregnancy testing requirements for study inclusion are described in Section 5.1.
Pregnancy testing should be conducted at screening (serum or urine) and on Day 29
(serum), approximately 24 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 subject's participation in the study.
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).
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The investigator and any designees are responsible for detecting, documenting, and reporting 
events that meet the definition of an AE or SAE as well as other reportable safety events. 
Investigators remain responsible for following up AEs, SAEs, and other reportable safety 
events for outcome according to Section 8.4.3.
The investigator, who is a qualified physician, will assess events that meet the definition of 
an AE or SAE as well as other reportable safety events with respect to seriousness, 
intensity/toxicity and causality.
8.4.1
Time Period and Frequency for Collecting AE, SAE, and Other Reportable 
Safety Event Information
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 participant is receiving placebo run-in or other run-in treatment, if the 
event causes the participant to be excluded from the study, or is the result of a protocol-
specified intervention, including but not limited to washout or discontinuation of usual 
therapy, diet, or a procedure.
From the time of intervention randomization through 14 days following 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 of the 
time period specified in the previous paragraph must be reported immediately to the Sponsor 
if the event is considered related to study intervention.
Investigators are not obligated to actively seek AEs or SAEs or other reportable safety events 
in former study participants. However, if the investigator learns of any SAE, including a 
death, at any time after a participant has been discharged from the study, and he/she 
considers the event to be reasonably related to the study intervention or study participation, 
the investigator must promptly notify the Sponsor.
All initial and follow-up AEs, SAEs, and other reportable safety events will be recorded and 
reported to the Sponsor or designee within the time frames as indicated in Table 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
- participant is receiving 
placebo run-in or other 
run-in treatment
Report all
Not required
Per data entry 
guidelines
SAE
Report if:
- due to protocol-specified 
intervention
- causes exclusion
- participant is receiving 
placebo run-in or other 
run-in treatment
Report all
Report if:
- drug/vaccine 
related.
(Follow ongoing to 
outcome)
Within 24 hours of 
learning of event
Pregnancy/
Lactation 
Exposure
Report if:
- participant has been 
exposed to any protocol-
specified intervention (eg, 
procedure, washout or 
run-in treatment including 
placebo run-in)
Exception: A positive 
pregnancy test at the time 
of initial screening is not a 
reportable event.
Report all
Previously reported 
– Follow to 
completion/terminati
on; report outcome
Within 24 hours of 
learning of event
ECI (require 
regulatory 
reporting)
Report if:
- due to intervention
- causes exclusion
Report
- Potential DILI
- Require regulatory 
reporting
Not required
Within 24 hours of 
learning of event
ECI (do not 
require 
regulatory 
reporting)
Report if:
- due to intervention
- causes exclusion
Report
- non-DILI ECIs and 
those not requiring 
regulatory reporting
Not required
Within 5 calendar 
days of learning of 
event
Cancer
Report if:
- due to intervention
- causes exclusion
Report all
Not required
Within 5 calendar 
days of learning of 
event
(unless serious)
Overdose
Report if:
- receiving placebo run-in 
or other run-in medication 
Report all
Not required
Within 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. 
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 
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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). From the time of 
randomization through 14 days following 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 following 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 lab value that is greater than or equal to 3X the upper limit of 
normal and an elevated total bilirubin lab value that is greater than or equal to 2X the 
upper limit of normal and, at the same time, an alkaline phosphatase lab value that is less 
than 2X the upper limit of normal, as determined by way of protocol-specified laboratory 
testing or unscheduled laboratory testing.*
*Note: These criteria are based upon available regulatory guidance documents. The 
purpose of the criteria is to specify a threshold of abnormal hepatic tests that 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).
2. Any postbaseline platelet value <50,000/μL, as determined by protocol-specified and/or 
unscheduled laboratory testing.
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
8.6.1
Blood Collection for Measurement of NHC in Plasma
At the EOT visit, venous blood samples will be collected from all participants for the 
measurement of NHC concentrations in plasma (Table 4).
The timing of the morning dose on the EOT visit should be aligned with the timing of blood 
collection for PK analyses at EOT (Section 1.3 and Section 8.1.8.1). The EOT morning dose 
will be observed at the site or in-home visit and recorded by study staff/visiting nurse. 
Sample collection, storage, and shipment instructions for plasma samples will be provided in 
a laboratory manual. 
Table 4
Plasma Sample Collection Schedule for NHC Concentrations
Study Part
Plasma Sample Collection Time Points (Window)
Part 1 and Part 2

1 sample pre-dosea

1 sample 1.5 hours post-dose (±30 min)
a Pre-dose sample should be collected within 2 hours of dosing.
If a participant discontinues from study intervention early for any reason (ie, prior to the 9th
or 10th dose), then plasma samples for PK will not be collected for that participant.
8.6.2
Blood Collection for Measurement of NHC-TP in PBMC
At the EOT visit, venous blood samples will be collected from participants in the PBMC 
Cohort in Part 1 for the measurement of NHC-TP concentrations in PBMCs. 
Two blood samples for PBMCs will be collected at each of the following timepoints on the 
EOT visit during Part 1 only: 
•
2 tubes pre-dose
•
2 tubes post-dose at 1.5 hours (±30 min)
Pre-dose sample should be collected within 2 hours of dosing. The timing of blood collection 
will be aligned with the timing of dose administration as outlined in Section 8.1.8.1. Sample 
collection, storage, and shipment instructions for PBMC samples will be provided in a 
separate manual.
If a participant discontinues from study intervention early for any reason (ie, prior to the 9th
or 10th dose), then blood samples for PBMCs will not be collected for that participant.
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8.7
Pharmacodynamics
The virologic, clinical efficacy, and clinical safety endpoints (Section 3) will be used to 
evaluate any pharmacokinetic/pharmacodynamic relationships for MK-4482. For assessment 
of antiviral activity of MK-4482 at each study dose, baseline, and post-dose virologic 
information (eg, viral RNA) at pre-specified timepoints (Section 1.3, SoA) will be measured. 
For each participant, the baseline measurement is defined as the measurement obtained pre-
dose on the first day of dosing.
8.8
Exploratory Research Samples
Collection of samples for other exploratory research is also part of this study. These samples 
may be utilized to perform evaluations related to SARS-CoV-2 and/or COVID-19, 
coinfections, or MK-4482 as described in Section 4.2.5. These samples may be tested during 
the course of the study or after study closure as the field of research evolves. 
Serum and plasma samples for exploratory research will be collected from all participants as 
specified in the SoA (Section 1.3) for exploratory research; in addition, residual material 
from NP/OP swabs and other previously collected blood samples may also be used. Sample 
collection, storage, and shipment instructions for the exploratory research samples will be in 
the laboratory manual.
8.9
Future Biomedical Research Sample Collection
If the participant provides document informed consent, the following specimens may be used 
for exploratory research and/or FBR as outlined in Sections 8.8 and 4.2.1.5, respectively:
•
Unused isolates from NP swabs (Part 2 only)
•
Unused serum and plasma from serum and plasma for exploratory research (Part 2 only)
•
Unused serum from serum for antibody exploratory research (Part 2 only)
8.10
Medical Resource Utilization and Health Economics
Sites are to collect hospitalization status and discharge data, including acute care visit status,
per the SoA (Section 1.3) and Section 8.2.3. 
8.11
Visit Requirements
Visit requirements are outlined in Section 1.3. Specific procedure-related details are provided 
in Section 8. 
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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 LARs
•
Performing at-home and/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 will occur ≤48 hours prior to study intervention randomization. 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
If the screening window has been exceeded, participants are allowed to rescreen 1 time if the 
participant still meets all the inclusion and none of the exclusion criteria at the time of 
rescreening. Once a participant has started the rescreening process, a new screening period 
(ie, an additional 48 hour window) will begin, during which time screening procedures will 
be repeated.
The following assessments must be repeated for participants who are rescreened:
•
Vital signs and full physical examination
•
Review medical history and prior/concomitant medications for new information
•
Local laboratory assessments for inclusion/exclusion (results within 72 hours prior to 
randomization may be used for eligibility)
•
Urine or serum β-hCG (pregnancy testing for WOCBP) 
•
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. 
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8.11.2.2
Clinic or At-Home Visits
In lieu of a participant travelling to the study site, an at-home visit by a healthcare provider 
(eg, home healthcare company or visiting nurse, etc.) may be appropriate to perform study 
assessments and procedures per the SoA (Section 1.3) (where available and when permitted 
by local regulations and IRB/IEC). For any visit conducted at home, the investigator/site 
personnel may also contact the participant virtually (on the same day), Section 8.11.2.3, to 
conduct/confirm study procedures/assessments (eg, perform an investigator AE assessment).
Refer to the procedure manual and/or the Investigator Trial File Binder (or equivalent) for 
additional details. 
8.11.2.3
Virtual Visits
The investigator or designee may conduct the Day 2 and Day 4 visits with the participant 
virtually (eg, by telehealth, telephone, webcast, videoconference, etc.). Identity of each 
participant should be confirmed according to institutional procedures and/or local guidelines
prior to conduct of virtual visits. Virtual visits will consist of concomitant medication and 
AE/SAE collection only. When a virtual visit is listed in the SoA, a clinic or home visit is not 
required. Virtual visits may be conducted at the investigator’s discretion.
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. Blood samples for PK will not be collected for participants who discontinue 
study intervention prior to their 9th or 10th dose. The participant should then be encouraged to 
complete all the remaining subsequent study visits after EOT as outlined in the SoA 
(Section 1.3). In the event that an active condition requires ongoing monitoring (eg, abnormal 
laboratory results, AEs, or progression of COVID-19 signs/symptoms), unscheduled visit(s) 
may be performed prior to the next study visit on Day 10.
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. Blood samples for PK
will not be collected for participants who discontinue from study prior to their 9th or 10th dose 
of study intervention. Participants who withdraw from the study after completion of the 
treatment period should be encouraged to complete all applicable activities scheduled for the 
Day 29 visit at the time of withdrawal. This visit 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 survival and hospitalization 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.
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8.11.4
Late Follow-up (7 Month) Visit
A virtual visit (eg, by telephone, webcast, videoconference, etc.) will be conducted at 
7 months (±1 month) after the last dose of study intervention for all participants. Information 
regarding survival status, current supplemental oxygen use, and any hospitalizations that 
occurred since last contact will be collected according to the SoA (Section 1.3). 
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 a sSAP and referenced in the CSR for 
the study. Post hoc exploratory analyses will be clearly identified in the CSR. Other planned 
analyses (ie, those specific to the analysis of PK data, medical resource utilization outcomes, 
and research plasma samples) are beyond the scope of this document or will be documented 
in separate analysis plans.  
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 2/3, Randomized, Placebo-Controlled, Double-Blind 
Clinical Study to Evaluate the Efficacy, Safety, and 
Pharmacokinetics of MK-4482 in Non-Hospitalized Adults with 
COVID-19.
Treatment Assignment
Part 1: Approximately 300 participants will be randomized in a 
1:1:1:1 ratio (stratified per Section 6.3.2a) to receive 1 of the 
following 4 study interventions, Q12H for 5 days.

MK-4482 200 mg (n~75)

MK-4482 400 mg (n~75)

MK-4482 800 mg (n~75)

Placebo (n~75)
Part 2: A total of approximately 1550 participants will be 
randomized in a 1:1 ratio (stratified per Section 6.3.2) to receive 
either MK-4482 800 mg or placebo Q12H for 5 days.
Analysis Populations
Efficacy: MITT (Parts 1 and 2 separately)
Safety: APaT (Parts 1 and 2 combined)
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Primary Endpoints
Efficacy: Proportion of participants with hospitalization or death 
by Day 29.
Safety: Number of participants with AEs, and discontinuing study 
intervention due to AEs
Key Secondary Endpoints
•
Time to sustained resolution or improvement, and time to 
progression of each targeted self-reported sign/symptom of 
COVID-19 through Day 29
•
Odds of a more favorable response on the WHO 11-point 
ordinal scale on Day 3, EOT, Day 10, Day 15, and Day 29
Statistical Methods for Key 
Efficacy Analyses
For the evaluation of the primary hypothesis, superiority of 
MK-4482 compared to placebo with respect to the percentage of 
participants with hospitalization or death by Day 29 will be 
calculated using the stratified Miettinen and Nurminen method 
[Miettinen, O. 1985].
Statistical Methods for Key 
Safety Analyses
P-values (Tier 1 endpoints) and 95% CIs (Tier 1 and Tier 2 
endpoints) will be provided for between-treatment differences in 
the percentage of participants with AEs; these analyses will be 
performed using the unstratified Miettinen and Nurminen method
[Miettinen, O. 1985].
Interim Analyses
IA1 – Part 1 Dose Evaluation
This IA will be used to review data to inform dose selection 
models and analyses.
IA2 – Part 1b Dose Selection
This IA will be used to evaluate the dose/exposure-response to 
select the dose for Phase 3.
IA3 – Part 2 Sample Size Re-estimation
This IA will be an unblinded sample size re-assessment. The 
conditional power approach will be employed in which the overall 
sample size can be adjusted upwards if the interim result is 
sufficiently promising without inflation of the type I error. 
IA4 – Part 2 Futility/Early Efficacy
The purpose of this IA is to allow for early stopping in the case of 
futility and to allow for the initiation of marketing authorization 
applications in the case of a positive efficacy finding. 
Additional details about interim analyses are in Section 9.7.
Multiplicity
There are no adjustments for multiplicity other than the type I error 
control for interim analyses described in Section 9.7.
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Sample Size and Power 
The total sample size for the primary efficacy assessment (Part 2) 
will be ~1550 participants (~775 for MK-4482 800 mg and ~775
for the placebo group). The study has overall power of 97% to 
demonstrate the superiority of MK-4482 over placebo at an 
overall one-sided, 2.5% alpha level, if the underlying treatment 
difference (MK-4482 minus placebo) in the percentage of 
participants who are hospitalized and/or die through Day 29 
is -6 percentage points.  
Additional details and assumptions for sample size and power 
calculation are in Section 9.9. 
a Stratification in Part 1 included: 1) Time from symptom onset prior to the day of randomization 
(≤5 days, >5 days); and 2) At increased risk of severe illness from COVID-19 (Appendix 10) (yes, 
no)
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 has 2 distinct parts: Part 1 (Phase 2) and Part 2 (Phase 3). Part 2 will not be 
initiated until Part 1 is completed, the data have been analyzed, and a dose for Part 2 is
determined. Once all Part 1 participants have completed Day 29 (ie, achieved a final status 
for Day 29 endpoints), the Sponsor will initiate database lock/unblinding procedures for this 
part of the study. Internal blinding will be maintained for Part 2 participants until all Part 2 
participants have completed Day 29 (ie, achieved a final status for Day 29 endpoints) except 
as documented in Section 9.7. For both parts of the study, Day 1 through Day 29 will be 
conducted as a double-blind study under in-house blinding procedures. The official, final 
database for Day 1 through Day 29 will not be unblinded within each part until 
medical/scientific review has been performed, protocol deviations have been identified, and 
data have been declared final and complete. The clinical database and Sponsor personnel 
directly involved in the analysis and reporting of Day 1 through Day 29 will become 
unblinded at the time of the analyses of Part 1 and Part 2 data at Day 29, although study 
participants and site personnel will remain blinded until LFU. Results from after Day 29 
through the LFU visit may be presented separately.
PK data may be unblinded early for the purpose of preparing a population PK model. If this 
occurs, a separate team from the protocol team will be unblinded for the purpose of preparing 
the PK model. Efficacy and safety data will not be unblinded for the purpose of preparing the 
PK model. Data or results from IA1, IA2, IA3, IA4 will not be shared with the protocol team 
before unblinding of the Sponsor for the relevant part of the study.
The Clinical Biostatistics department will generate the randomized allocation schedule(s) for 
study treatment assignment.
Blinding issues related to the planned interim analyses are described in Section 9.7.
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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/Pharmacokinetics Endpoints
9.4.1.1
Efficacy Endpoints
Primary:

Proportion of participants with either hospitalization (≥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) or death by Day 29.
Secondary:

Time to sustained resolution or improvement of each targeted self-reported 
sign/symptom present at randomization (ie, Day 1), defined as the number of days 
from randomization to the first of 3 consecutive days when resolution or 
improvement is demonstrated for each targeted self-reported sign/symptom.
Participants who meet criteria for sustained resolution or improvement after 
3 consecutive days must not relapse by Day 29 (ie, have 2 or more consecutive days 
of each self-reported sign/symptom returning to the baseline severity or worse than 
baseline severity after the criteria for sustained resolution or improvement are met).
Resolution or improvement is defined as follows:
o
A symptom reported at randomization as Mild and is subsequently reported as 
None
o
A symptom reported at randomization as Moderate and is subsequently 
reported as Mild or None,
o
A symptom reported at randomization as Severe and is subsequently reported 
as Moderate, Mild or None
o
A symptom reported at randomization as Yes and is subsequently reported as 
No
NOTE: Participants without a symptom reported at randomization will not be 
included in the analysis

Time to progression of the targeted self-reported signs/symptoms present at 
randomization, defined as the number of days from randomization to the first of 
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2 consecutive days when the targeted self-reported signs/symptoms worsen. 
Worsening is defined as follows:
o
A symptom reported at randomization as None or No and is subsequently 
reported as Mild/Moderate/Severe or Yes, respectively
o
A symptom reported as Mild at randomization and is subsequently reported as 
Moderate or Severe
o
A symptom reported as Moderate at randomization and is subsequently 
reported as Severe
NOTE: Participants with symptoms reported at randomization as Severe will 
not be included in the analysis

Odds of a more favorable response on the WHO 11-point ordinal scale on Day 3, 
EOT, Day 10, Day 15, and Day 29. This scale provides a measure of illness severity 
across a range from 0 (not infected) to 10 (dead).  
Note: Relevant data (ie, central laboratory SARS-CoV-2 RNA results, supplemental 
oxygen use and methods, oxygen saturation, dialysis and vasopressor use, vital status,
and investigator assessment of the participant’s ability to independently perform daily 
activities with minimal or no symptoms) to support determination of the WHO 11-
point ordinal score will be collected in eCRFs.
Exploratory: 

Percentage of participants who have any acute care visit. Acute care visit is defined as 
any hospitalization (any amount of time in a hospital or similar acute care facility, 
including emergency rooms or facilities created to address hospitalization needs 
during the COVID-19 pandemic) or emergency room visit or any other acute care 
visit (including an urgent care visit or visit with any healthcare provider for acute care 
needs) from randomization through Day 29

Percentage of participants who have any COVID-19-related acute care visit. Acute 
care visit is defined as any hospitalization (any amount of time in a hospital or similar 
acute care facility, including emergency rooms or facilities created to address 
hospitalization needs during the COVID-19 pandemic) or emergency room visit or 
any other acute care visit (including an urgent care visit or visit with any healthcare 
provider for acute care needs) from randomization through Day 29

Change from baseline in SARS-CoV-2 RNA titer in nasopharyngeal and 
oropharyngeal swabs separately at various timepoints 

Percentage of participants with undetectable SARS-CoV-2 RNA in nasopharyngeal 
and oropharyngeal swabs separately at various timepoints
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
Viral RNA mutation rate and detection of treatment-emergent sequence variants as 
assessed by comparison of baseline and post-baseline virus sequencing

Percentage of participants with undetectable infectious SARS-CoV-2 in 
nasopharyngeal swabs on Day 3, EOT, Day 10, Day 15, and Day 29.
In addition to the endpoints listed above, survival, supplemental oxygen use, and 
hospitalization status at the LFU visit (Month 7) will also be summarized.
9.4.1.2
Pharmacokinetics Endpoints
Pharmacokinetics endpoints are exploratory endpoints in this study: 

Pharmacokinetic parameters (eg, Ctrough) (Parts 1 and 2)
9.4.2
Safety Endpoints
A description of safety measures is contained in Section 8.3 and Section 8.4. The analysis of 
safety results is described in Section 9.6.2.
The safety analysis endpoints include: 

The proportion of: 1) participants with at least 1 AE; 2) participants with at least 
1 drug-related AE; 3) participants with at least 1 SAE; 4) participants with at least 
1 serious and drug-related AE; 5) participants who discontinued study intervention 
due to AE; 6) participants who discontinued study intervention due to a drug-related 
AE; and 7) participants with AE(s) leading to death. The AE reporting period is from 
the time of randomization through 14 days following cessation of treatment. 
Additional reporting periods will be used as appropriate (eg, throughout the study for 
SAE). 

Events of Clinical Interest specified in Section 8.4.7.
Predefined Limits of Change (PDLC) in Laboratory Parameters
For the summaries of laboratory tests, participants must have both a baseline and post-
randomization 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 of 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.
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9.5
Analysis Populations
9.5.1
Efficacy Analysis Populations
The MITT population will serve as the primary population for the analysis of efficacy data 
for both parts of this study. The MITT population consists of all randomized participants who 
received at least 1 dose of study intervention. Part 1 (Phase 2) and Part 2 (Phase 3) of the 
study will be analyzed separately for efficacy endpoints. Therefore, the MITT population for 
Part 2 will not include Part 1 participants, and vice versa.
A supportive analysis using the Per-Protocol population will be performed for the primary 
efficacy endpoint(s) for Part 2. The Per-Protocol population excludes participants due to 
deviations from the protocol that may substantially affect the results of the primary efficacy 
endpoint. 
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.
Participants will be included in the treatment group to which they are randomized for the 
analysis of efficacy data using both the MITT and Per-Protocol populations.
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 treatment. Participants will be included in 
the treatment group corresponding to the study treatment they actually received for the 
analysis of safety data using the APaT population. This will be the treatment group to which 
they are randomized except for participants who take incorrect study treatment for the entire 
treatment period; such participants will be included in the treatment group corresponding to 
the study treatment actually received. Part 1 (Phase 2) and Part 2 (Phase 3) of the study will 
be combined for the final analysis of safety endpoints. The data presentations will focus on 
the selected dose group for MK-4482 and placebo.
At least 1 laboratory value or vital sign obtained subsequent to at least 1 dose of study 
treatment 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 as well as a key exploratory objective for viral RNA endpoints. Methods related to 
other exploratory objectives will be described in the sSAP. Methods related to PK analysis 
and PK/PD modeling will be described in a separate modeling and simulation plan authored 
by QP2. Methods related to dose-response analysis using MCP-MOD will be described in a 
separate dose-response analyses plan. Methods related to analyses of biomarkers and other 
exploratory samples will be described separately.
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Efficacy results that will be deemed to be statistically significant after consideration of the 
type I error control for interim analyses are discussed in Section 9.7. There are no 
adjustments for multiplicity. 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, superiority of MK-4482 compared to placebo 
with respect to the percentage of participants with either hospitalization or death by Day 29
will be assessed using the stratified Miettinen and Nurminen method [Miettinen, O. 1985]. 
Superiority will be concluded based on p-value boundaries as described in Section 9.7. 
Stratification factors include the stratification factors specified in Section 6.3.2. Geographic
region will not be used as a stratification factor in the primary analyses, but it may be 
considered as an additional stratification factor of the stratified Miettinen and Nurminen 
method for sensitivity analysis if it does not cause sparse data issues. The number of regions
along with the specific countries contained within each region will be described in the sSAP.
Every effort will be made to ascertain hospitalization and survival status for all participants. 
For the primary analysis of this endpoint in the MITT population, unknown Day 29 survival 
status will be treated as failure, and early withdrawal from the study with known Day 29 
survival status as alive but unknown Day 29 hospitalization status will not be treated as 
failure. A sensitivity analysis treating both unknown Day 29 survival status and early 
withdrawal from the study with known Day 29 survival status as alive but unknown Day 29 
hospitalization status as failure will also be provided.
A sensitivity analysis for the primary endpoint will be conducted that includes only 
COVID-19 related hospitalizations or death by Day 29 in the MITT population. This 
treatment comparison will be assessed using the stratified Miettinen and Nurminen method as 
described above. An additional sensitivity analysis excluding hospitalizations that occur early 
in the course of the study (ie, within a certain time from randomization) will also be 
performed. Details will be specified in the sSAP. 
Two additional sensitivity analyses will be performed using the endpoints of time to 
hospitalization/death and time to COVID-related hospitalization/death. These analyses will 
be performed in the MITT population. The stratified log-rank test will be used for the 
comparison of MK-4482 with placebo for these 2 endpoints. Stratification factors will be the 
same as those used for the primary endpoint. Hazard ratios will be based on the stratified Cox 
Proportional Hazards regression model. The Efron approximation will be used for handling 
ties. Hazard ratios less than 1 indicate a benefit for MK-4482. Censoring rules for these
analyses will be specified in the sSAP.
Time to sustained resolution or improvement and time to progression of each targeted self-
reported sign/symptom of COVID-19 will be summarized using data collected from a 
15-item daily paper symptom diary completed by participants (Section 8.2.5). The 
distribution of time to sustained resolution or improvement and time to progression of each
sign/symptom will be analyzed using the same method for the time to hospitalization or death 
endpoint, ie, the stratified log-rank test will be used for the comparison of MK-4482 with 
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placebo and the Cox proportional hazard model will be used to estimate the hazard ratio.
Descriptive statistics and Kaplan-Meier plots will also be provided.
The proportion of participants with each sign/symptom will be summarized by severity (or 
presence/absence for loss of taste and loss of smell) for each treatment group at Day 1, 
Day 3, EOT, Day 10, Day 15, and Day 29.
These summaries above will include comparison of each individual sign/symptom. Missing 
symptom diary data will be imputed using LOCF method. Additional details will be specified
in the sSAP. 
The viral RNA endpoints at earlier time points (Day 3 and EOT) will be important for the 
dose selection decision from Part 1 of the study. Change from baseline in SARS-CoV-2 RNA 
titer, calculated as log10 (post) minus log10 (baseline), as measured by quantitative RT-PCR 
of samples from NP (Parts 1 and 2) and OP (Part 1 only) swabs will be summarized 
separately by treatment group and time point. The DAO approach will be used to handle 
missing data for these summary statistics. In addition to summary statistics, treatment 
differences in change in SARS-CoV-2 RNA titer from baseline over time will be estimated 
using longitudinal models. Graphical presentations of the change from baseline will be 
presented and the impact of baseline viral RNA level will be explored using subgroup 
analyses (defined by level of baseline viral RNA) and analyses/summaries that exclude 
participants with low baseline levels (eg, viral RNA <106 copies/mL).
Percentage of participants with undetectable viral RNA (below limit of detection) as 
measured by qualitative RT-PCR of samples from NP (Parts 1 and 2) and OP (Part 1 only) 
swabs will be summarized separately by treatment group and time point. Between-treatment 
differences and 95% CIs will be estimated using the stratified Miettinen and Nurminen 
method [Miettinen, O. 1985].  
WHO 11-point ordinal scale score will be analyzed using the cumulative logits function and 
the proportional odds model as described by McCullagh [McCullagh, P. 1980]. This 
methodology provides an estimate of the common odds ratio for assessing differences 
between treatment groups. In addition to a term for treatment group, the model will include 
terms for the stratification factors specified Section 6.3.2. The WHO 11-point ordinal scale 
will be determined based on relevant data collected in eCRFs.
A detailed analysis strategy for key efficacy endpoints is listed in Table 5.
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Table 5
Analysis Strategy for Key Efficacy Endpoints
Endpoint/Variable
(Description, Time point)
Primary vs. 
Supportive 
Approacha
Statistical Methodb
Analysis 
Population
Missing 
Data 
Approach
Primary
Proportion of participants 
with either hospitalization 
or death by Day 29
P
Stratified Miettinen and 
Nurminenc
MITT
As 
described 
in 9.6.1
Proportion of participants 
with either hospitalization 
or death by Day 29
S
Stratified Miettinen and 
Nurminenc
PP
Observed 
data only
Proportion of participants 
with either COVID-
related hospitalization or 
death by Day 29
S
Stratified Miettinen and 
Nurminenc
MITT
M=Fd
Proportion of participants 
with either COVID-
related hospitalization or 
death by Day 29
S
Stratified Miettinen and 
Nurminenc
PP
Observed 
data only
Time to hospitalization or 
death by Day 29
S
Stratified log-rank teste;
Stratified Cox proportional 
hazard regression f
MITT, PP
Model-
based with 
censoring
Time to COVID- related 
hospitalization or death by 
Day 29
S
Stratified log-rank teste;
Stratified Cox proportional 
hazard regression f
MITT, PP
Model-
based with 
censoring
Secondary
Time to sustained 
resolution or improvement 
of each targeted self-
reported sign/symptoms of 
COVID-19
P (MITT)
S (PP)
Stratified log-rank teste;
Stratified Cox proportional 
hazard regression f
MITT
PP
Model-
based with 
censoring
Time to progression of 
each targeted self-reported 
sign/symptom of COVID-
19
P (MITT)
S (PP)
Stratified log-rank teste;
Stratified Cox proportional 
hazard regression f
MITT
PP
Model-
based with 
censoring
Odds of a more favorable 
response on the WHO 11-
point ordinal scale on Day 
3, EOT, Day 10, Day 15,
and Day 29
P (MITT)
S (PP)
Proportional odds modelg
MITT
PP
Model-
based
EOT= end of treatment; F= failure; M= missing; MITT= modified intent-to-treat; PP= per-protocol; WHO= World 
Health Organization. 
a
P=Primary approach; S=Supportive approach.
b
Statistical models are described in further detail below:
c
Miettinen and Nurminen method stratified by the factors specified in Section 6.3.2.  
dM=F is Missing equals to Failure 
e
The stratified log-rank test includes stratification factors specified in Section 6.3.2
f
Stratified Cox Proportional Hazards regression includes terms for treatment, stratification factors specified in 
Section 6.3.2 
g
Proportional odds model includes terms for treatment and stratification factors specified in Section 6.3.2.  
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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, laboratory values and vital signs.
The analysis of safety results will follow a tiered approach as shown in Table 6. The tiers 
differ with respect to the analyses that will be performed. For this protocol, only ECIs are 
considered Tier 1 events. AEs (specific terms as well as system organ class terms) and events 
that meet PDLCs in laboratory values or vital signs will be classified as belonging to "Tier 2" 
or "Tier 3" based on the number of events observed.  
Tier 1 Events
Safety parameters or AEs of special interest that are identified a priori constitute “Tier 1” 
safety endpoints that will be subject to inferential testing for statistical significance with 
p-values and 95% CIs to be provided for between-treatment differences in the proportion of 
participants with events; these analyses will be performed using the unstratified Miettinen
and Nurminen method [Miettinen, O. 1985], an unconditional, asymptotic method. Since the 
stratification factors are not considered to be related to safety endpoints, they will not be 
included as stratification factors in the safety analyses.
Tier 2 Events
Tier 2 parameters will be assessed via point estimates with 95% CIs provided for differences 
in the proportion of participants with events (also via the Miettinen and Nurminen method 
[Miettinen, O. 1985]).
Membership in Tier 2 requires that at least 4 participants in at least one treatment group 
exhibit the event. The threshold of at least 4 events was chosen because the 95% CI for the 
between-group difference in percent incidence will always include zero when treatment 
groups of equal size each have less than 4 events and thus would add little to the 
interpretation of potentially meaningful differences. Because many 95% CIs may be provided 
without adjustment for multiplicity, the CIs 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 AEs and predefined limits of change.
In addition to individual events that occur in 4 or more participants in any treatment group, 
the broad AE categories consisting of the proportion 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. 
Tier 3 Events
Safety endpoints that are not Tier 1 or 2 events are considered Tier 3 events. Only point 
estimates by treatment group are provided for Tier 3 safety parameters.
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Continuous Safety Measures 
For continuous measures such as changes from baseline in laboratory and vital signs 
parameters, summary statistics for baseline, on-treatment, and change from baseline values 
will be provided by treatment group in table format. In addition, summary statistics for the 
difference between treatment groups will also be provided.
Table 6
Analysis Strategy for Safety Parameters
Safety Tier
Safety Endpointa
p-value
95% CI for 
Treatment 
Comparison
Descriptive 
Statistics
Tier 1
ECIs
X
X
X
Tier 2
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
Discontinuation due to Drug-Related AE
X
X
Specific AEs by SOCs and PT (incidence ≥4 
participants in at least 1 of the treatment groups)
PDLCsb (incidence ≥4 participants in at least 1 of 
the treatment groups)
X
X
X
X
Tier 3
Specific AEs by SOC and PT (incidence ,<4 
participants in each of the treatment groups)
PDLCsb (incidence <4 participants in each of the 
treatment groups)
Change from Baseline Results (Labs, Vital Signs)
X
X
X
AE=adverse event; CI=confidence interval; ECI=event of clinical interest; PT=preferred term; SOC=system organ class; 
PDLC=pre-defined limit of change; X=results will be provided.
a Adverse Event references refer to both Clinical and Laboratory AEs.
b Includes only those endpoints not pre-specified as Tier 1 or not already pre-specified as Tier-2 endpoints. 
9.6.3
Demographic and Baseline Characteristics
The comparability of the treatment groups for each relevant demographic and baseline 
characteristic will be assessed by the use of tables and/or graphs. 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 treatment either by descriptive statistics or categorical 
tables.
9.7
Interim Analyses
An eDMC and Sponsor siDMC will review results of interim analyses of this study and will 
make recommendations for any actions to the Sponsor Executive Oversight Committee 
(Table 7). Recommendations by the eDMC include possible discontinuation of the study or 
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modifications to the protocol to protect the safety of participants, review of conditional 
power for potential increase to sample size, and actions resulting from the crossing of an 
efficacy or futility boundary in Phase 3. In addition to the eDMC, the Sponsor siDMC will 
review unblinded data from Phase 2 for purposes of approving the proposed MK-4482 dose 
to advance into Phase 3.
The eDMC will be supported by an unblinded statistician who will provide treatment-level 
results from the interim analyses. 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. In addition, there 
will be a small, cross-functional unblinded team of Sponsor personnel or delegates who will 
perform the exposure-response and dose-response modeling and other analyses that will be 
used to inform the dose selection decision process and the siDMC review. 
A separate, small, cross-functional unblinded team of Sponsor personnel will also be 
convened for Part 2 of the study with the purpose of supporting preparation and submission 
of applications for emergency use and/or marketing authorization in the case of a positive 
efficacy finding noted by the eDMC at IA4. The members of this team will not have access 
to unblinded data until an eDMC decision is reached.
Membership on these cross-functional unblinded teams will be documented in an unblinding 
plan and the details of the planned analyses will be outlined in the MAP document prior to 
initiation of the analyses. Sponsor personnel responsible for ongoing blinded data review and 
preparation of the final study report will not be included on the cross-functional unblinded 
team.
Following any decision to terminate or modify the protocol, the executive committee of the 
Sponsor (and potentially other limited Sponsor personnel) may be unblinded to results at the 
treatment level in order to act on these recommendations. The extent to which individuals are 
unblinded with respect to results of interim analyses will be documented in a separate 
unblinding memo. Additional logistical details will be provided in the siDMC and eDMC 
Charters.
Blinding to treatment assignment will be maintained at all investigational sites. The results of 
interim analyses will not be shared with the investigators prior to the completion of the study. 
Participant-level unblinding will be restricted to an internal (or external, as appropriate) 
unblinded cross-functional team performing the interim analyses and dose recommendation, 
who will have no other responsibilities associated with the study.
There will be 4 interim analyses during the study as shown in Table 7.
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Table 7
Description of Interim Analyses
Interim Analysis
Timing
MK-4482-002 Primary 
Data for Analysis
Committee Action
IA1 – Part 1
Dose Evaluation
Targeted to occur during Phase 2 after ~300 
participants complete EOT combined in 
MK-4482-001a and MK-4482-002. 
PK, available virologic, 
safety & efficacy data 
through EOT
eDMC recommendation for discontinuation of the study 
or protocol modifications 
Sponsor siDMC review of interim safety data and review 
of preliminary virology data
Review by an unblinded team to inform dose selection 
models and analyses
IA2 – Part 1b
Dose Selection 
Targeted to occur at the completion of Phase 2 
after ~300 participants complete Day 29 
(includes participants from IA1). 
PK, safety & efficacy 
data through Day 29 and 
available virologic data
eDMC recommendation for discontinuation of the study 
or protocol modifications 
Sponsor siDMC approval of proposed MK-4482 dose for 
Part 2
IA3 – Part 2
Sample Size Re-
estimation
Targeted to occur no earlier than at 30% of the 
full planned Part 2 enrollment and no later than 
IA4. Final timing to be based on enrollment 
timelines.  
Primary efficacy endpoint 
at Day 29
Sample size re-estimation to be assessed by eDMC 
based on review of conditional power for primary 
endpoint with potential to increase Part 2 sample size
IA4 – Part 2
Futility/Early 
Efficacy
Targeted to occur during Phase 3 after ~775
participants complete Day 29 across the 
MK-4482 group and the placebo group (~50% 
of total enrollment).  
Safety & efficacy data 
through Day 29
Futility and early efficacy to be assessed by eDMC per 
eDMC Charter and guided by statistical criteria
eDMC=external Data Monitoring Committee; EOT=End of Treatment; IA=Interim Analysis; PK=pharmacokinetics; siDMC=standing internal Data 
Monitoring Committee. 
a MK-4482-001 is a companion MK-4482 dose-ranging study in hospitalized adults with COVID-19
b IA2 represents the analysis of the full Part 1 cohort of participants through Day 29.
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Interim Analyses
IA1 – Part 1: Dose Evaluation 
IA1 is targeted to occur during Phase 2 after data is available from ~300 participants 
completing EOT combined in MK-4482-001 and MK-4482-002. This IA will be used for 
eDMC interim data review, Sponsor siDMC review of interim safety data and review of 
preliminary virology data, and for unblinded team review of data to inform dose selection 
models and analyses.
During this interim analysis, enrollment in each study will continue in the 4 intervention 
groups in Phase 2 to the targeted enrollment of 300 participants. 
IA2 – Part 1: Dose Selection
This analysis is targeted to occur at the completion of Phase 2 after ~300 participants 
(~75 per group) have completed the Day 29 visit. This IA will be used to evaluate the 
dose/exposure-response to select the dose for Phase 3.  
The relationship between dose and PK (plasma NHC and PBMC NHC-triphosphate), 
virologic endpoints (eg, rate of virologic RNA clearance, viral RNA mutation rate), safety, 
and key efficacy results will be evaluated. PK and virology data from other ongoing studies 
of MK-4482 including MK-4482-001 will also be examined at the time of this IA to inform 
the Phase 3 dose selection.
Additional details regarding dose selection criteria will be described in the siDMC Charter. 
The dose selected for Phase 3 will be communicated directly to sites in accordance with local 
regulatory requirements.
Part 2 (Phase 3) enrollment will be initiated after all participants for Part 1 of this study have
completed the Day 29 visit, and after the completion of the IA2 analysis. 
IA3 – Part 2: Sample Size Re-estimation
IA3 will include an unblinded sample size re-assessment targeted to occur no earlier than at 
30% of the full planned Part 2 enrollment and no later than IA4. Final timing should be as 
late as possible and prior to completion of enrollment based on enrollment timelines in order 
to obtain maximum study information for the sample size re-estimation. The conditional 
power approach will be employed in which the overall Part 2 sample size (see Section 9.9.1) 
can be adjusted upwards by 450 participants to a total of 2000 if the interim result is 
sufficiently promising (conditional power >51% but <80%, assuming continuing the interim 
analysis trend) without inflation of the type I error [Chen, Y. H. J., et al 2004]. The potential 
increase in total Part 2 sample size is to maintain adequate study power in the event that the 
observed treatment effect at the interim analysis is smaller than the original assumption but 
still clinical meaningful (treatment difference, MK-4482 minus placebo, in the percentage of 
participants who are hospitalized and/or die through Day 29 is between -0.037 and -0.053
percentage points).
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While there is no intention to stop the study early at the unblinded sample size re-assessment
(for the situation when this occurs before IA4) based on a positive efficacy outcome, it is
recognized that the eDMC might consider a recommendation to stop the study should
overwhelming efficacy in favor of MK-4482 be observed. To provide some guidance for the 
eDMC in this situation, a 1-sided p-value ≤0.0001 is proposed for the test of the primary 
endpoint. This conservative criterion for the superiority test will have no impact on the 
overall multiplicity strategy described in Section 9.8.
IA4 – Part 2: Futility/Early Efficacy IA 
This study will include a futility/early efficacy interim analysis when ~50% of participants in 
the selected treatment group and the placebo group have completed the Day 29 visit (Phase 3 
Interim Analysis). The purpose of this interim analysis is to allow for early stopping in the 
case of futility and to allow for the initiation of marketing authorization applications in the 
case of a positive efficacy finding. Given the expected rapid enrollment, there are no plans in 
Part 2 of the study to discontinue enrollment prior to the planned final sample size in the case 
of a positive efficacy outcome.
The Gamma family spending function with γ = -1 will be used to set both efficacy and 
futility boundaries for the primary endpoint as a guide for the eDMC in order to control 
overall type I error rate of 0.025, 1-sided. Assuming the information fraction of 50%, the 
non-binding futility boundary expressed on the absolute difference scale is -0.011. The 
boundary crossing probabilities for futility are 71% under H0 and 0.8% under H1 (absolute 
difference of -0.06). The p-value boundary for efficacy is 0.009, corresponding to an absolute 
difference of -0.048. The boundary crossing probabilities for efficacy are 0.9% under H0 and 
72% under H1 (absolute difference of -0.06).
9.8
Multiplicity 
The success of this study is based on a single primary endpoint (a composite of 
hospitalization or death) and a single treatment comparison (selected dose of MK-4482 vs. 
placebo). There are no adjustments for multiplicity other than controlling type I error for 
interim analyses described in Section 9.7. The p-value boundary for efficacy at the final 
analysis is 0.019, corresponding to an absolute difference of -0.03.
9.9
Sample Size and Power Calculations
9.9.1
Sample Size and Power Calculations for Efficacy Analyses (Part 2)
The primary analysis of the Phase 3 study endpoint will include ~1550 participants from 
Part 2 of the study (~775 for the MK-4482 800 mg group and ~775 for the placebo group)
who meet the criteria for inclusion in the MITT population. The primary endpoint is a 
composite of hospitalization or death. The study has overall power of 97% to demonstrate the 
superiority of MK-4482 800 mg over placebo at an overall one-sided, 2.5% alpha level, if the 
underlying treatment difference (MK-4482 minus placebo) in the percentage of participants 
who are hospitalized and/or die through Day 29 is -6 percentage points. 
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The power and sample size are based on the following assumptions: 1) an underlying 
percentage hospitalized/dying of 12% for placebo and 6% for MK-4482 (50% reduction in 
the relative risk) and 2) a futility/efficacy interim analysis at 50% information as outlined in 
Section 9.7. The calculation was computed using EAST. To meet the statistical criterion for 
success (one-sided p ≤0.019 at the final analysis), the observed treatment difference must be 
approximately -3.0 percentage points or lower, assuming a percentage of 12% for placebo.
The observed percentages from Part 1 of this study in the full MITT cohort were 5.4% in the 
placebo group and 4.1% in the 800 mg group, a difference of only 1.3 percentage points. 
However, higher percentages of placebo participants met this endpoint within various 
subgroups of the full study population: 21.4% in the subgroup of participants >60 years of 
age, 8.0% in the subgroup of participants with TSSO ≤5 days and 11.8% in the subgroup of 
participants with TSSO ≤5 days and who were at increased risk for severe illness. In these 
subgroups, the percentages of participants in the 800 mg group were 5.0% (difference of 16.4 
percentage points), 2.1% (difference of 5.9 percentage points) and 3.2% (difference of 8.6 
percentage points), respectively. In each of these subgroups, the observed reduction in the 
relative risk of hospitalization/death associated with 800 mg exceeded 70%. Given the 
modification to the study population for Part 2, the assumption of 12% for placebo and a 
50% reduction in the relative risk are reasonable.
Study power for different assumptions of the underlying percentage hospitalized/dying are 
presented in Table 8, all scenarios are based on a total sample size of 1550 participants and 
an overall one-sided, 2.5% alpha level [Stokes, E. K., et al 2020]. 
Table 8
Study Power by Percentage Hospitalized/Dying
N=1550 participants (775 for MK-4482 800 mg and 775 for placebo), alpha=0.025, 1-sided
Placebo Rate (%)
MK-4482 Rate (%)
Absolute Difference
(percentage points)
Power
18%
12%
6
88%
16%
10%
6
92%
14%
8%
6
95%
12%
7%
5
89%
10%
5%
5
95%
8%
4%
4
89%
6%
2%
4
97%
9.9.2
Sample Size and Power Calculations for Virology Analyses (Part 1)
The sample size for Part 1 was not determined based on a specific hypothesis for a specific 
endpoint. The selection of the dose to advance to Part 2 will be based on analyses of the 
totality of data available across the MK-4482 clinical program. Three hundred participants 
(75 per group) will be sufficient to provide reasonable precision to discriminate between 
treatment groups with regard to the virology endpoints. An important endpoint for assessing 
the dose-response relationship is viral RNA change from baseline in SARS-CoV-2 RNA 
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titer, calculated as log10 (post) minus log10 (baseline). Approximately 80% of this cohort 
(60/group) is expected to have a baseline VL of at least 106 copies/mL. A 1 log-unit 
difference between treatment groups in the population mean is considered to be clinically 
relevant. Table 9 provides power calculations for true log differences of 0.75 to 1.25 and for 
various assumptions about the true underlying standard deviation.
Table 9
Power by Detectable Difference and Standard Deviation Viral RNA change from 
baseline (log10 copies/mL) N=60/group, α=0.025, 1-sided
Between-Group Difference (log10 copies/mL)
Standard Deviation
-0.75
-1.00
-1.25
1.25
90%
99%
>99%
1.5
78%
95%
>99%
1.75
64%
87%
97%
9.9.3
Sample Size and Power Calculations for Safety Analyses (Part 2)
Part 1 (Phase 2) and Part 2 (Phase 3) of the study will be combined for the final analysis of
safety endpoints. The planned sample size for safety analysis will be 850 for each of 
MK-4482 selected dose group and placebo group. 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 an AE in the study population. If the underlying 
incidence of an AE is 1%, there is >99.9% chance of observing at least 1 AE among 
850 participants in the treatment group. If no AE of that type is observed among the 
850 participants in any treatment group, this study will provide 97.5% confidence that the 
underlying percentage of participants with the AE is <0.44 (1 of every 231 participants). 
Table 10 summarizes the percentage point differences between the 2 treatment groups that 
could be detected with 90% probability for a variety of hypothetical underlying incidences of 
an AE. These calculations assume 850 participants in each group and are based on a 2-sided 
5% alpha level. The calculations are based on Farrington and Manning [Farrington, C. P. and 
Manning, G. 1990]. No multiplicity adjustments were made.
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Table 10
Differences in Incidence of AE Rates Between the 2 Treatment Groups That Can 
be Detected With a ~90% Probability (Assuming 2-sided 5% Alpha Level with
850 Participants in Each Group)
Incidence of Adverse Event
Risk Difference
Placebo (%)
MK-4482 (%)
Percentage Points
1.0
3.3
2.3
5.0
9.1
4.1
10.0
15.3
5.3
20.0
26.7
6.7
30.0
37.5
7.5
40.0
47.8
7.8
Incidences presented here are hypothetical and do not represent actual adverse experiences in either group. 
Calculations are based on Farrington and Manning [Farrington, C. P. and Manning, G. 1990]
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: 
•
Age category (≤60 vs >60 years)
•
Sex (female, male)
•
Baseline (Day 1) disease severity (mild, moderate) per Appendix 9
•
Race (American Indian or Alaska Native, Asian, Black or African American, Native 
Hawaiian or Other Pacific Islander, White)
•
Time from symptom onset prior to the day of randomization (≤5 days, >5 days) [Part 1 
only]
•
Time from symptom onset prior to the day of randomization (≤3 days, >3 days) [Part 2 
only]
•
At increased risk for severe illness from COVID-19 (yes, no) (Appendix 10) [Part 1 only]
•
Geographic region (North America, Europe, Asia Pacific, Latin America)
•
Baseline (Day 1) SARS-CoV-2 quantitative assay VL status (undetectable
[<500 copies/mL], low VL [500 to ≤10^6 copies/mL], high VL [>10^6 copies/mL])
[Part 2 only]
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•
Baseline (Day 1) SARS-CoV-2 qualitative assay VL status (undetectable, detectable)
[Part 2 only]
•
Baseline (Day 1) SARS-CoV-2 antibody status (negative, positive) [Part 2 only]
Additional subgroups may be defined in the sSAP. Categories of the above subgroups with 
small sample sizes (<25 per treatment group) may be combined – further detail will be 
provided in the sSAP.
9.11
Compliance (Medication Adherence) 
Compliance will be calculated based on capsule counts. For a participant who is followed for 
the entire study period, the “Number of Capsules Should be Taken” is the total number of 
capsules should be taken from randomization to the last scheduled day for treatment 
administration for that participant. For a participant who discontinues from the study 
permanently, 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 
population.
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 and Dohme Corp., a subsidiary of Merck & Co., Inc. (MSD)
Code of Conduct for Interventional Clinical Trials
I. Introduction
A. Purpose
MSD, through its subsidiaries, conducts clinical trials worldwide to evaluate the safety and effectiveness of our 
products. As such, we are committed to designing, implementing, conducting, analyzing, and reporting these trials 
in compliance with the highest ethical and scientific standards. Protection of participants in clinical trials is the 
overriding concern in the design and conduct of clinical trials. In all cases, MSD clinical trials will be conducted 
in compliance with local and/or national regulations (including all applicable data protection laws and
regulations), and International Council for Harmonisation Good Clinical Practice (ICH-GCP), and also in 
accordance with the ethical principles that have their origin in the Declaration of Helsinki.
B. Scope
Highest ethical and scientific standards shall be endorsed for all clinical interventional investigations sponsored by 
MSD irrespective of the party (parties) employed for their execution (e.g., contract research organizations, 
collaborative research efforts). This Code is not intended to apply to trials that are observational in nature, or 
which are retrospective. Further, this Code does not apply to investigator-initiated trials, which are not under the 
full control of MSD.
II. Scientific Issues
A. Trial Conduct
1. Trial Design
Except for pilot or estimation trials, clinical trial protocols will be hypothesis-driven to assess safety, efficacy 
and/or pharmacokinetic or pharmacodynamic indices of MSD or comparator products. Alternatively, MSD 
may conduct outcomes research trials, trials to assess or validate various endpoint measures, or trials to 
determine patient preferences, etc.
The design (i.e., participant population, duration, statistical power) must be adequate to address the specific 
purpose of the trial and shall respect the data protection rights of all participants, trial site staff and, where 
applicable, third parties. Participants must meet protocol entry criteria to be enrolled in the trial. 
2. Site Selection
MSD selects investigative sites based on medical expertise, access to appropriate participants, adequacy of 
facilities and staff, previous performance in clinical trials, as well as budgetary considerations. Prior to trial 
initiation, sites are evaluated by MSD personnel (or individuals acting on behalf of MSD) to assess the ability 
to successfully conduct the trial.
3. Site Monitoring/Scientific Integrity
Investigative trial sites are monitored to assess compliance with the trial protocol and Good Clinical Practice 
(GCP). MSD reviews clinical data for accuracy, completeness, and consistency. Data are verified versus 
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source documentation according to standard operating procedures. Per MSD policies and procedures, if
potential fraud, scientific/research misconduct, privacy incidents/breaches or Clinical Trial-related 
Significant Quality Issues are reported, such matters are investigated. When necessary, appropriate corrective 
and/or preventative actions are defined and regulatory authorities and/or ethics review committees are 
notified.
B. Publication and Authorship
Regardless of trial outcome, MSD commits to publish the primary and secondary results of its registered trials of 
marketed products in which treatment is assigned, according to the pre-specified plans for data analysis. To the 
extent scientifically appropriate, MSD seeks to publish the results of other analyses it conducts that are important 
to patients, physicians, and payers. Some early phase or pilot trials are intended to be hypothesis-generating rather 
than hypothesis testing; in such cases, publication of results may not be appropriate since the trial may be 
underpowered and the analyses complicated by statistical issues such as multiplicity.
MSD’s policy on authorship is consistent with the recommendations published by the International Committee of 
Medical Journal Editors (ICMJE). In summary, authorship should reflect significant contribution to the design and 
conduct of the trial, performance or interpretation of the analysis, and/or writing of the manuscript. All named 
authors must be able to defend the trial results and conclusions. MSD funding of a trial will be acknowledged in 
publications.
III. Participant Protection
A. Regulatory Authority and Ethics Committee Review (Institutional Review Board [IRB]/Independent Ethics 
Committee [IEC])
All protocols and protocol amendments will be submitted by MSD for regulatory authority 
acceptance/authorization prior to implementation of the trial or amendment, in compliance with local and/or 
national regulations.
The protocol, protocol amendment(s), informed consent form, investigator’s brochure, and other relevant trial 
documents must be reviewed and approved by an IRB/IEC before being implemented at each site, in compliance 
with local and/or national regulations. Changes to the protocol that are required urgently to eliminate an 
immediate hazard and to protect participant safety may be enacted in anticipation of ethics committee approval. 
MSD will inform regulatory authorities of such new measures to protect participant safety, in compliance with 
local and/or national regulations.
B. Safety
The guiding principle in decision-making in clinical trials is that participant welfare is of primary importance. 
Potential participants will be informed of the risks and benefits of, as well as alternatives to, trial participation. At 
a minimum, trial designs will take into account the local standard of care.
All participation in MSD clinical trials is voluntary. Participants enter the trial only after informed consent is 
obtained. Participants may withdraw from an MSD trial at any time, without any influence on their access to, or 
receipt of, medical care that may otherwise be available to them.
C. Confidentiality
MSD is committed to safeguarding participant confidentiality, to the greatest extent possible, as well as all 
applicable data protection rights. Unless required by law, only the investigator, Sponsor (or individuals acting on 
behalf of MSD), ethics committee, and/or regulatory authorities will have access to confidential medical records 
that might identify the participant by name.
D. Genomic Research
Genomic research will only be conducted in accordance with a protocol and informed consent authorized by an 
ethics committee.
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IV. Financial Considerations
A. Payments to Investigators
Clinical trials are time- and labor-intensive. It is MSD’s policy to compensate investigators (or the sponsoring 
institution) in a fair manner for the work performed in support of MSD trials. MSD does not pay incentives to 
enroll participants in its trials. However, when enrollment is particularly challenging, additional payments may be 
made to compensate for the time spent in extra recruiting efforts.
MSD does not pay for participant referrals. However, MSD may compensate referring physicians for time spent 
on chart review and medical evaluation to identify potentially eligible participants.
B. Clinical Research Funding
Informed consent forms will disclose that the trial is sponsored by MSD, and that the investigator or sponsoring 
institution is being paid or provided a grant for performing the trial. However, the local ethics committee may 
wish to alter the wording of the disclosure statement to be consistent with financial practices at that institution. As 
noted above, all publications resulting from MSD trials will indicate MSD as a source of funding.
C. Funding for Travel and Other Requests
Funding of travel by investigators and support staff (e.g., to scientific meetings, investigator meetings, etc.) will be 
consistent with local guidelines and practices.
V. Investigator Commitment
Investigators will be expected to review MSD’s Code of Conduct as an appendix to the trial protocol, and in signing the 
protocol, agree to support these ethical and scientific standards.
10.1.2
Financial Disclosure
Financial Disclosure requirements are outlined in the US Food and Drug Administration 
Regulations, Financial Disclosure by Clinical Investigators (21 CFR Part 54). It is the 
Sponsor's responsibility to determine, based on these regulations, whether a request for 
Financial Disclosure information is required. It is the investigator's/subinvestigator's 
responsibility to comply with any such request.
The investigator/subinvestigator(s) agree, if requested by the Sponsor in accordance with 21 
CFR Part 54, to provide his/her financial interests in and/or arrangements with the Sponsor to 
allow for the submission of complete and accurate certification and disclosure statements. 
The investigator/subinvestigator(s) further agree to provide this information on a 
Certification/Disclosure Form, commonly known as a financial disclosure form, provided by 
the Sponsor. The investigator/subinvestigator(s) also consent to the transmission of this 
information to the Sponsor in the United States for these purposes. This may involve the 
transmission of information to countries that do not have laws protecting personal data.
10.1.3
Data Protection
The Sponsor will conduct this study in compliance with all applicable data protection 
regulations.
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Participants will be assigned a unique identifier by the Sponsor. Any participant records or 
datasets that are transferred to the Sponsor will contain the identifier only; participant names 
or any information that would make the participant identifiable will not be transferred.
The participant must be informed that his/her personal study-related data will be used by the 
Sponsor in accordance with local data protection law. The level of disclosure must also be 
explained to the participant. 
The participant must be informed that his/her medical records may be examined by Clinical 
Quality Assurance auditors or other authorized personnel appointed by the Sponsor, by 
appropriate IRB/IEC members, and by inspectors from regulatory authorities.
10.1.3.1
Confidentiality of Data
By signing this protocol, the investigator affirms to the Sponsor that information furnished to 
the investigator by the Sponsor will be maintained in confidence, and such information will 
be divulged to the IRB, IEC, or similar or expert committee; affiliated institution and 
employees, only under an appropriate understanding of confidentiality with such board or 
committee, affiliated institution and employees. Data generated by this study will be 
considered confidential by the investigator, except to the extent that it is included in a 
publication as provided in the Publications section of this protocol.
10.1.3.2
Confidentiality of Participant Records
By signing this protocol, the investigator agrees that the Sponsor (or Sponsor representative), 
IRB/IEC, or regulatory authority representatives may consult and/or copy study documents to 
verify worksheet/CRF data. By signing the consent form, the participant agrees to this 
process. If study documents will be photocopied during the process of verifying 
worksheet/CRF information, the participant will be identified by unique code only; full 
names/initials will be masked prior to transmission to the Sponsor.
By signing this protocol, the investigator agrees to treat all participant data used and 
disclosed in connection with this study in accordance with all applicable privacy laws, rules 
and regulations.
10.1.3.3
Confidentiality of IRB/IEC Information
The Sponsor is required to record the name and address of each IRB/IEC that reviews and 
approves this study. The Sponsor is also required to document that each IRB/IEC meets 
regulatory and ICH GCP requirements by requesting and maintaining records of the names 
and qualifications of the IRB/IEC members and to make these records available for 
regulatory agency review upon request by those agencies.
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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
Internal Data Monitoring Committee
A separate siDMC will review results of interim analysis(es) from Part 1 of this study. The 
siDMC is comprised of members of Sponsor Senior Management, none of whom are directly 
associated with the conduct of this study. The siDMC will review unblinded study data at the 
determined frequency (Section 9.7 Interim Analyses) for dose selection as described in 
detailed monitoring guidelines. The siDMC will make recommendations for any actions (eg,
approval of proposed dose) to the Sponsor Executive Oversight Committee.
Specific details regarding responsibilities of the siDMC will be described in a separate 
charter that is reviewed and approved by the siDMC.
10.1.4.3
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.
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If publication activity is not directed by the Sponsor, the investigator agrees to submit all 
manuscripts or abstracts to the Sponsor before submission. This allows the Sponsor to protect 
proprietary information and to provide comments.
Authorship will be determined by mutual agreement and in line with International Committee 
of Medical Journal Editors authorship requirements.
10.1.6
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 trial directive mandated trials. 
Information posted will allow participants to identify potentially appropriate studies for their 
disease conditions and pursue participation by calling a central contact number for further 
information on appropriate study locations and study site contact information.
By signing this protocol, the investigator acknowledges that the statutory obligations under 
FDAAA, the EMA clinical trials directive, or other locally mandated registries are that of the 
Sponsor and agrees not to submit any information about this study or its results to those 
registries.
10.1.7
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, International Council on Harmonisation of Technical Requirements for Registration of 
Pharmaceuticals for Human Use GCP: Consolidated Guideline and other generally accepted 
standards of GCP); and all applicable federal, state and local laws, rules and regulations 
relating to the conduct of the clinical study.
The Code of Conduct, a collection of goals and considerations that govern the ethical and 
scientific conduct of clinical investigations sponsored by MSD, is provided in this appendix 
under the Code of Conduct for Clinical Trials.
The investigator agrees not to seek reimbursement from participants, their insurance 
providers, or from government programs for procedures included as part of the study 
reimbursed to the investigator by the Sponsor.
The investigator will promptly inform the Sponsor of any regulatory authority inspection 
conducted for this study.
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 
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from regulatory authority inspection and will provide the Sponsor with a copy of the 
proposed response for consultation before submission to the regulatory authority. 
Persons debarred from conducting or working on clinical studies by any court or regulatory 
authority will not be allowed to conduct or work on this Sponsor’s studies. The investigator 
will immediately disclose in writing to the Sponsor if any person who is involved in 
conducting the study is debarred or if any proceeding for debarment is pending or, to the best 
of the investigator’s knowledge, threatened.
10.1.8
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.
•
Local laboratory test is required for initial COVID-19 SARS-CoV-2 infection 
confirmation and determination of participant eligibility.
•
All other local laboratory results are only required in the event that 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 at 
the same time; however, if it is documented for a specific participant visit that central 
sample analysis will not be possible, then the parallel collection of the sample for 
central analysis is not required. 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 CRF.
•
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 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
hs-CRP (inflammatory biomarker) 
will be tested at all visits with 
chemistry collection as the test is 
performed on the same blood sample
CK
Pregnancy Testing

Urine or Serum hCG pregnancy test (as needed for WOCBP)
Virology

SARS-CoV-2 RNA (real time PCR) OP (Part 1 only) and NP (Parts 1 and 2) swabs 
(quantitative and qualitative)

SARS-CoV-2 Gene Sequencing 
Pharmacokinetics

Plasma for NHC

PBMC for NHC- triphosphate
Exploratory 
Research Samples
Samples may be used for testing such as:

SARS-CoV-2 Antibodies 

Infectious SARS-CoV-2 presence/quantitation

Coinfection with other respiratory pathogens

Viral genotyping and treatment-emergent variant detection
ALT=alanine aminotransferase; AST=aspartate aminotransferase; BUN=blood urea nitrogen; CK=creatine kinase; 
GGT=gamma-glutamyl transferase; hCG=human chorionic gonadotropin; hs-CRP= High-sensitivity C-reactive protein;
IL-6=Interleukin 6; LDH=lactate dehydrogenase; MCH=mean corpuscular hemoglobin; MCV=mean corpuscular 
volume; NHC=N-hydroxycytidine; NP=nasopharyngeal; OP=oropharyngeal; PBMC= peripheral blood mononuclear 
cells; PCR= polymerase chain reaction; RBC=red blood cell; RDW=red cell distribution width; RNA=ribonucleic acid; 
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)
Study Period:
Specimen or Matrix Type 
(Tube Type/Additive)
Screening
Intervention
Follow-Up
Total 
Blood 
Volumes
Visit Number/Title:
1
2
3
4
5
6
7
8
9
Scheduled Day (and 
Window):
Screening 
Day 1
Day 2
Day 3
Day 4
EOT
Day 10 
(±1 day)
Day 15 
(+3 
days)
Day 29 
(+3 
days)
Nasopharyngeal Swab
flocked or polyester-
tipped swab (3 mL 
universal transport 
medium)
X
X
X
X
X
X
NA
Oropharyngeal Swab
flocked or polyester-
tipped swab (3 mL 
universal transport 
medium)
X
X
X
X
X
X
Chemistry (Day 29 
includes serum 
pregnancy)
Serum (no additive)
2.5
2.5
2.5
2.5
2.5
3.5
Hematology
Whole Blood (EDTA)
2
2
2
2
2
2
Plasma/Serum Research 
Samples
Whole Blood (clot 
activator and EDTA) 
processed to both plasma 
and serum
16
16
16
16
Serum for Antibody 
Exploratory Research
Serum (no additive)
2.5
2.5
2.5
2.5
Sub Total for all 
Participants for 
Central Laboratory 
NA
0
23.5
0
4.5
0
23.5
23.5
4.5
24
Pharmacokinetics
NA
Pharmacokinetic Plasma 
Sampling Part 1
Plasma (EDTA)
6
Pharmacokinetic Plasma 
Sampling Part 2
Plasma (EDTA)
6
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Study Period:
Specimen or Matrix Type 
(Tube Type/Additive)
Screening
Intervention
Follow-Up
Total 
Blood 
Volumes
Visit Number/Title:
1
2
3
4
5
6
7
8
9
Scheduled Day (and 
Window):
Screening 
Day 1
Day 2
Day 3
Day 4
EOT
Day 10 
(±1 day)
Day 15 
(+3 
days)
Day 29 
(+3 
days)
Pharmacokinetic PBMC 
Sampling Part 1
Whole Blood (Sodium 
Heparin) processed to 
PBMCs
32
Total For Participants 
in Part 1
NA
0
23
0
4.5
0
29
23
4.5
24
108
Total For Participants 
in Part 2
0
23
0
4.5
0
29
23
4.5
24
108
Total For PBMC 
Cohort Participants in 
Part 1
0
23
0
4.5
0
61
23
4.5
24
140
EDTA: ethylenediaminetetraacetic acid; hCG: human chorionic gonadotropin; N/A: not applicable; PBMC: peripheral blood mononuclear cells; WOCBP: 
women of childbearing potential.
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10.3
Appendix 3: Adverse Events: Definitions and Procedures for Recording, 
Evaluating, Follow-up, and Reporting
10.3.1
Definition of AE
AE definition

An AE is any untoward medical occurrence in a clinical study participant, temporally 
associated with the use of study intervention, whether or not considered related to the 
study intervention.

NOTE: An AE can therefore be any unfavorable and unintended sign (including an 
abnormal laboratory finding), symptom, or disease (new or exacerbated) temporally 
associated with the use of a study intervention.

NOTE: For purposes of AE definition, study intervention (also referred to as Sponsor’s 
product) includes any pharmaceutical product, biological product, vaccine, diagnostic 
agent, medical device, combination product, or protocol specified procedure whether 
investigational or marketed (including placebo, active comparator product, or run-in 
intervention), manufactured by, licensed by, provided by, or distributed by the Sponsor 
for human use in this study.
Events meeting the AE definition

Any abnormal laboratory test results (hematology, clinical chemistry, or urinalysis) or 
other safety assessments (eg, ECG, radiological scans, vital signs measurements), 
including those that worsen from baseline, considered clinically significant in the medical 
and scientific judgment of the investigator.

Exacerbation of a chronic or intermittent pre-existing condition including either an 
increase in frequency and/or intensity of the condition.

New conditions detected or diagnosed after study intervention administration even 
though it may have been present before the start of the study.

Signs, symptoms, or the clinical sequelae of a suspected drug-drug interaction.

Signs, symptoms, or the clinical sequelae of a suspected overdose of either study 
intervention or a concomitant medication.

For all reports of overdose (whether accidental or intentional) with an associated AE, the 
AE term should reflect the clinical symptoms or abnormal test result. An overdose 
without any associated clinical symptoms or abnormal laboratory results is reported using 
the terminology “accidental or intentional overdose without adverse effect.”

Any new cancer or progression of existing cancer.
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Events NOT meeting the AE definition

Medical or surgical procedure (eg, endoscopy, appendectomy): the condition that leads to 
the procedure is the AE.

Situations in which an untoward medical occurrence did not occur (social and/or 
convenience admission to a hospital).

Anticipated day-to-day fluctuations of pre-existing disease(s) or condition(s) present or 
detected at the start of the study that do not worsen.

Surgery planned prior to informed consent to treat a pre-existing condition that has not 
worsened.

Refer to Section 8.4.6 for protocol-specific exceptions.
10.3.2
Definition of SAE
If an event is not an AE per definition above, then it cannot be an SAE even if serious 
conditions are met.
An SAE is defined as any untoward medical occurrence that, at any dose:
a. Results in death
b. Is life-threatening
•
The term “life-threatening” in the definition of “serious” refers to an event in which 
the participant was at risk of death at the time of the event. It does not refer to an 
event, which hypothetically might have caused death, if it were more severe.
c. Requires inpatient hospitalization or prolongation of existing hospitalization
•
Hospitalization is defined as an inpatient admission, regardless of length of stay, even 
if the hospitalization is a precautionary measure for continued observation. (Note: 
Hospitalization for an elective procedure to treat a pre-existing condition that has not 
worsened is not an SAE.) A pre-existing condition is a clinical condition that is 
diagnosed prior to the use of an MSD product and is documented in the participant’s 
medical history.
d. Results in persistent or significant disability/incapacity
•
The term disability means a substantial disruption of a person’s ability to conduct 
normal life functions.
•
This definition is not intended to include experiences of relatively minor medical 
significance such as uncomplicated headache, nausea, vomiting, diarrhea, influenza, 
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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.)
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 
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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 case report forms/worksheets by 
an investigator who is a qualified physician according to his/her best clinical judgment, 
including consideration of the above elements.
•
Use the following scale of criteria as guidance (not all criteria must be present to be 
indicative of a Sponsor’s product relationship).
Yes, there is a reasonable possibility of Sponsor’s product relationship:
◦
There is evidence of exposure to the Sponsor’s product. The temporal sequence 
of the AE onset relative to the administration of the Sponsor’s product is 
reasonable. The AE is more likely explained by the Sponsor’s product than by 
another cause.
No, there is not a reasonable possibility of Sponsor’s product relationship:
◦
Participant did not receive the Sponsor’s product OR temporal sequence of the 
AE onset relative to administration of the Sponsor’s product is not reasonable 
OR the AE is more likely explained by another cause than the Sponsor’s 
product. (Also entered for a participant with overdose without an associated 
AE.)
•
For each AE/SAE, the investigator must document in the medical notes that he/she has 
reviewed the AE/SAE and has provided an assessment of causality.
•
There may be situations in which an SAE has occurred and the investigator has minimal 
information to include in the initial report to the Sponsor. However, it is very important 
that the investigator always make an assessment of causality for every event before the 
initial transmission of the SAE data to the Sponsor.
•
The investigator may change his/her opinion of causality in light of follow-up 
information and send an SAE follow-up report with the updated causality assessment.
•
The causality assessment is 1 of the criteria used when determining regulatory reporting 
requirements.
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Follow-up of AE and SAE

The investigator is obligated to perform or arrange for the conduct of supplemental 
measurements and/or evaluations as medically indicated or as requested by Sponsor to 
elucidate the nature and/or causality of the AE or SAE as fully as possible. This may 
include additional laboratory tests or investigations, histopathological examinations, or 
consultation with other health care professionals.

New or updated information will be recorded in the CRF.

The investigator will submit any updated SAE data to the Sponsor within 24 hours of 
receipt of the information.
10.3.5
Reporting of AEs, SAEs, and Other Reportable Safety Events to the Sponsor
AE, SAE, and other reportable safety event reporting to Sponsor via electronic data 
collection tool

The primary mechanism for reporting to the Sponsor will be the EDC tool.
Electronic reporting procedures can be found in the EDC data entry guidelines (or 
equivalent).
If the electronic system is unavailable for more than 24 hours, then the site will 
use the paper AE Reporting form.
◦
Reference Section 8.4.1 for reporting time requirements.

The site will enter the SAE data into the electronic system as soon as it becomes 
available.

After the study is completed at a given site, the EDC tool will be taken off-line to prevent 
the entry of new data or changes to existing data.

If a site receives a report of a new SAE from a study participant or receives updated data 
on a previously reported SAE after the EDC tool has been taken off-line, then the site can 
report this information on a paper SAE form or by telephone (see next section).

Contacts for SAE reporting can be found in the Investigator Study File Binder (or 
equivalent).
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SAE reporting to the Sponsor via paper CRF

If the EDC tool is not operational, facsimile transmission or secure e-mail of the SAE 
paper CRF is the preferred method to transmit this information to the Sponsor.

In rare circumstances and in the absence of facsimile equipment, notification by 
telephone is acceptable with a copy of the SAE data collection tool sent by overnight 
mail or courier service.

Initial notification via telephone does not replace the need for the investigator to complete 
and sign the SAE CRF pages within the designated reporting time frames.

Contacts and instructions for SAE reporting and paper reporting procedures can be found 
in the Investigator Study File Binder (or equivalent).
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10.4
Appendix 4: Medical Device and Drug-device Combination Products: Product 
Quality Complaints/Malfunctions: Definitions, Recording, and Follow-up
Not applicable.
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10.5
Appendix 5: Contraceptive Guidance
10.5.1
Definitions
Women of Childbearing Potential (WOCBP)
A woman is considered fertile following menarche and until becoming postmenopausal 
unless permanently sterile (see below):
If fertility is unclear (eg, amenorrhea in adolescents or athletes) and a menstrual cycle cannot 
be confirmed before first dose of study intervention, additional evaluation should be 
considered.
Women in the following categories are not considered WOCBP:
•
Premenarchal
•
Premenopausal female with 1 of the following:
Documented hysterectomy
Documented bilateral salpingectomy
Documented bilateral oophorectomy
For individuals with permanent infertility due to an alternate medical cause other than the 
above (eg, Mullerian agenesis, androgen insensitivity), investigator discretion should be 
applied to determining study entry.
Note: Documentation can come from the site personnel’s review of the participant’s 
medical records, medical examination, or medical history interview.
•
Postmenopausal female
A postmenopausal state is defined as no menses for 12 months without an 
alternative medical cause.
◦
A high FSH level in the postmenopausal range may be used to confirm a 
postmenopausal state in women not using hormonal contraception or HRT. 
However, in the absence of 12 months of amenorrhea, confirmation with two 
FSH measurements in the postmenopausal range is required.
Females on HRT and whose menopausal status is in doubt will be required to use 
one of the nonhormonal highly effective contraception methods if they wish to 
continue their HRT during the study. Otherwise, they must discontinue HRT to 
allow confirmation of postmenopausal status before study enrollment.
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10.5.2
Contraception Requirements
Contraceptives allowed during the study includea:
Highly Effective Contraceptive Methods That Have Low User Dependency
Failure rate of <1% per year when used consistently and correctly.
•
Progestogen-only subdermal contraceptive implantb
•
IUSc
•
Non-hormonal IUD
•
Bilateral tubal occlusion
•
Azoospermic partner (vasectomized or secondary to medical cause)
This is a highly effective contraception method provided that the partner is the sole male sexual partner of 
the WOCBP and the absence of sperm has been confirmed. If not, an additional highly effective method of 
contraception should be used. A spermatogenesis cycle is approximately 90 days.
Note: Documentation of azoospermia for a male participant can come from the site personnel’s review of 
the participant’s medical records, medical examination, or medical history interview.
Sexual Abstinence
•
Sexual abstinence is considered a highly effective method only if defined as refraining from heterosexual 
intercourse during the entire period of risk associated with the study intervention. The reliability of sexual 
abstinence needs to be evaluated in relation to the duration of the study and the preferred and usual lifestyle 
of the participant.
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 contraception b
-
Oral
-
Injectable
Barrier methods to be used with user dependent hormonal contraceptives 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 Research
The specimens consented and/or collected in this study as outlined in Section 8.9 will be 
used in various experiments to understand:
•
The biology of how drugs/vaccines work
•
Biomarkers responsible for how a drug/vaccine enters and is removed by the body
•
Other pathways with which drugs/vaccines may interact
•
The biology of disease
The specimen(s) may be used for future assay development and/or drug/vaccine 
development.
It is now well recognized that information obtained from studying and testing clinical 
specimens offers unique opportunities to enhance our understanding of how individuals 
respond to drugs/vaccines, enhance our understanding of human disease and ultimately 
improve public health through development of novel treatments targeted to populations 
with the greatest need. All specimens will be used by the Sponsor or those working for or 
with the Sponsor.
3. Summary of Procedures for Future Biomedical Research
a. Participants for Enrollment
All participants enrolled in the clinical study will be considered for enrollment in 
future biomedical research.
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b. Informed Consent
Informed consent for specimens (ie, DNA, RNA, protein, etc) will be obtained during 
screening for protocol enrollment from all participants or legal guardians, at a study 
visit by the investigator or his or her designate. Informed consent for future 
biomedical research should be presented to the participants on the visit designated in 
the SoA. If delayed, present consent at next possible Participant Visit. Consent forms 
signed by the participant will be kept at the clinical study site under secure storage for 
regulatory reasons.
A template of each study site’s approved informed consent will be stored in the 
Sponsor’s clinical document repository.
c. eCRF Documentation for Future Biomedical Research Specimens
Documentation of participant consent for future biomedical research will be captured 
in the eCRFs. Any specimens for which such an informed consent cannot be verified 
will be destroyed.
d. Future Biomedical Research Specimen(s)
Collection of specimens for future biomedical research will be performed as outlined 
in the SoA. In general, if additional blood specimens are being collected for future 
biomedical research, these will usually be obtained at a time when the participant is 
having blood drawn for other study purposes.
4. Confidential Participant Information for Future Biomedical Research
In order to optimize the research that can be conducted with future biomedical research
specimens, it is critical to link participants' clinical information with future test results. In 
fact, little or no research can be conducted without connecting the clinical study data to 
the specimen. The clinical data allow specific analyses to be conducted. Knowing 
participant characteristics like sex, age, medical history and intervention outcomes are 
critical to understanding clinical context of analytical results.
To maintain privacy of information collected from specimens obtained for future 
biomedical research, the Sponsor has developed secure policies and procedures. All 
specimens will be single-coded per ICH E15 guidelines as described below.
At the clinical study site, unique codes will be placed on the future biomedical research
specimens. This code is a random number which does not contain any personally 
identifying information embedded within it. The link (or key) between participant 
identifiers and this unique code will be held at the study site. No personal identifiers will 
appear on the specimen tube.
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5. Biorepository Specimen Usage
Specimens obtained for the Sponsor will be used for analyses using good scientific 
practices. Analyses 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 Research
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@merck.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 Specimens
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 Security
Databases containing specimen information and test results are accessible only to the 
authorized Sponsor representatives and the designated study administrator research 
personnel and/or collaborators. Database user authentication is highly secure, and is 
accomplished using network security policies and practices based on international 
standards to protect against unauthorized access.
9. Reporting of Future Biomedical Research Data to Participants
No information obtained from exploratory laboratory studies will be reported to the 
participant, family, or physicians. Principle reasons not to inform or return results to the 
participant include: lack of relevance to participant health, limitations of predictive 
capability, and concerns regarding misinterpretation.
If important research findings are discovered, the Sponsor may publish results, present 
results in national meetings, and make results accessible on a public website in order to 
rapidly report this information to doctors and participants. Participants will not be 
identified by name in any published reports about this study or in any other scientific 
publication or presentation.
10. Future Biomedical Research Study Population
Every effort will be made to recruit all participants diagnosed and treated on Sponsor 
clinical studies for future biomedical research.
11. Risks Versus Benefits of Future Biomedical Research
For future biomedical research, risks to the participant have been minimized and are
described in the future biomedical research informed consent.
The Sponsor has developed strict security, policies, and procedures to address participant 
data privacy concerns. Data privacy risks are largely limited to rare situations involving 
possible breach of confidentiality. In this highly unlikely situation, there is risk that the 
information, like all medical information, may be misused.
12. Questions
Any questions related to the future biomedical research should be emailed directly to 
clinical.specimen.management@merck.com.
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13. References
1. National Cancer Institute [Internet]: Available from 
https://www.cancer.gov/publications/dictionaries/cancer-terms?cdrid=45618
2. International Council on Harmonisation [Internet]: E15: Definitions for Genomic 
Biomarkers, Pharmacogenomics, Pharmacogenetics, Genomic Data and Sample Coding 
Categories. Available from http://www.ich.org/products/guidelines/efficacy/efficacy-
single/article/definitions-for-genomic-biomarkers-pharmacogenomics-pharmacogenetics-
genomic-data-and-sample-cod.html 
3. Industry Pharmacogenomics Working Group [Internet]: Understanding the Intent, Scope 
and Public Health Benefits of Exploratory Biomarker Research: A Guide for IRBs/IECs 
and Investigational Site Staff. Available at http://i-pwg.org/ 
4. Industry Pharmacogenomics Working Group [Internet]: Pharmacogenomics 
Informational Brochure for IRBs/IECs and Investigational Site Staff. Available at http://i-
pwg.org/
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10.7
Appendix 7: Country-specific Requirements
10.7.1
Country-specific Request for Germany
Legally Acceptable Representative
In order for a participant to be eligible to participate in Germany, he/she must be capable of 
signing the informed consent; therefore, all references to a participant’s “legally acceptable 
representative” in the protocol are not applicable for participants in Germany.
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10.8
Appendix 8: Ordinal Outcome Scales
10.8.1
World Health Organization 11-Point Scale 
The WHO 11-point ordinal scale for clinical progression is as follows, with 0 assigned to 
“Uninfected; no viral RNA detected” and 10 assigned to “Dead” [Marshall, J. C., et al 2020]:

Patient State: “Uninfected”
o
Uninfected; no viral RNA detected

Patient State: “Ambulatory Mild Disease”
o
Asymptomatic; viral RNA detected
o
Symptomatic; independent
o
Symptomatic; assistance needed

Patient State: “Hospitalized; Moderate Disease”
o
Hospitalized; no oxygen therapy*
o
Hospitalized; oxygen by mask or nasal prongs

Patient State “Hospitalized; Severe Disease”
o
Hospitalized; oxygen by non-invasive ventilation or high-flow
o
Intubation and mechanical ventilation; pO2 /FiO2 ≥150 or SpO2 /FiO2 ≥200
o
Mechanical ventilation pO2 /FiO2 <150 (SpO2 /FiO2<200) or vasopressors
o
Mechanical ventilation pO2 /FiO2 <150 and vasopressors, dialysis, or 
extracorporeal membrane oxygenation

Patient State “Dead”
o
Dead
Abbreviations: FiO2=fraction of inspired oxygen; pO2=partial pressure of oxygen; SpO2=Oxygen saturation. 
* If hospitalized for isolation only, record status as for ambulatory patient.
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10.9
Appendix 9: COVID-19 Severity Categorization
Adapted from “COVID-19: Developing Drugs and Biological Products for Treatment or 
Prevention Guidance for Industry” US Food and Drug Industry (MAY 2020), WHO 
COVID-19 case definition, and COVID-19 symptoms recognized by CDC [Food and Drug 
Administration 2020] [World Health Organization 2020] [Tenforde, M. W., et al 2020].
For inclusion in the study, the following are required of all participants:

A positive SARS-CoV-2 test result (Inclusion Criterion #1)

Signs/symptoms attributable to COVID-19 present at randomization (Inclusion 
Criterion #2), including one or more of the following: 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, loss of smell
In addition to the above criteria, the participant must be categorized into one of the following 
COVID-19 severity categories at the time of randomization: mild or moderate COVID-19
(Inclusion Criterion #3). The COVID-19 severity category that is entered in IRT at 
randomization must be based on assessments (vital signs, COVID-19 signs/symptoms, 
respiratory measures, oxygen therapy, ongoing medical history) completed and documented 
on Day 1 prior to calling IRT in order to randomize.
Vital sign measurements should be preceded by at least 5 minutes of rest for the participant 
in a quiet setting without distractions.
Mild COVID-19: 
Must have ALL of the following:

Respiratory rate <20 breaths per minute 

Heart rate <90 beats per minute

SpO2 >93% on room air or on supplemental oxygen for a reason other than COVID-19 
which HAS NOT increased since onset of COVID-19 signs/symptoms
AND 
Must NOT have shortness of breath at rest or with exertion as assessed by the investigator, 
respiratory failure, shock, or multi-organ dysfunction/failure (see definitions in Critical COVID-19 
below)
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Moderate COVID-19: 
Must have ONE or MORE of the following:

Shortness of breath with exertion as assessed by the investigator

Respiratory rate ≥20 to <30 breaths per minute

Heart rate ≥90 to <125 beats per minute
AND
Must have SpO2 >93% on room air or on supplemental oxygen for a reason other than COVID-19 
which HAS NOT increased since onset of COVID-19 signs/symptoms [or only on ≤4 liters/min 
supplemental oxygen for COVID-19 (but was not previously on supplemental oxygen), regardless 
of SpO2]
AND
Must NOT have shortness of breath at rest as assessed by the investigator, respiratory failure, 
shock, or multi-organ dysfunction/failure (see definitions in Critical COVID-19 below)
Severe COVID-19: 
Must have ONE or MORE of the following:

Shortness of breath at rest as assessed by the investigator

Respiratory rate ≥30 breaths per minute

Heart rate ≥125 beats per minute

SpO2 ≤93% on room air or on supplemental oxygen for a reason other than COVID-19 
which HAS NOT increased since onset of COVID-19 signs/symptoms

On supplemental oxygen for a reason other than COVID-19 which HAS increased since 
onset of COVID-19 signs/symptoms, regardless of SpO2

On >4 liters/min supplemental oxygen for COVID-19 (but was not previously on 
supplemental oxygen), regardless of SpO2

PaO2/FiO2 <300
AND
Must NOT have respiratory failure, shock, or multi-organ dysfunction/failure (see definitions in 
Critical COVID-19 below)
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Critical COVID-19: 
Must have ONE or MORE of the following:

Respiratory failure defined based on resource utilization requiring at least 1 of the
following:
o
Endotracheal intubation and mechanical ventilation
o
Oxygen delivered by high-flow nasal cannula (heated, humidified, oxygen delivered 
via reinforced nasal cannula at flow rates >20 L/min with fraction of delivered oxygen 
≥0.5)
o
Noninvasive positive pressure ventilation
o
ECMO
o
Clinical diagnosis of respiratory failure (ie, clinical need for 1 of the preceding 
therapies, but preceding therapies not able to be administered in setting of resource 
limitation)

Shock defined as requiring vasopressors

Multi-organ dysfunction/failure defined as participants that are acutely ill with evidence 
of either dysfunction or failure, at the discretion of the investigator, of more than 1 of the 
following organ systems: respiratory, cardiovascular, renal, hematologic, hepatic, and/or 
central nervous systems
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10.10 Appendix 10: 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] and the WHO [World 
Health Organization 2020]. Immunocompromised state from solid organ transplant and 
sickle cell disease were considered high risk conditions in Part 1; however, these conditions 
were removed for Part 2 to align with updated CDC guidance supported by meta-
analysis/systematic review rather than mostly observational studies.

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 (heart failure, coronary artery disease, or cardiomyopathies)

Diabetes mellitus
* Body mass index = weight (kg)/[height (m)]2
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10.11 Appendix 11: Calculation of eGFR
Modification of Diet in Renal Disease Study (MDRD) equation
eGFR (mL/min/1.73 m2) = 175 x (SCr)-1.154 x (age)-0.203 x 0.742 [if female] x 1.212 
[if African American]
Notes:

eGFR = estimated glomerular filtration rate

SCr = standardized serum creatinine

age = years
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10.12 Appendix 12: Abbreviations
Abbreviation
Expanded Term
ACTT 1
Adaptive COVID-19 Treatment Trial
AE
adverse event 
ALT
alanine aminotransferase
ANOVA
analysis of variance
APaT
all-participants-as-treated
AST
aspartate aminotransferase
AUC
area under the curve
BID
twice daily
BUN
blood urea nitrogen
C2hr
plasma concentration value collected at 2 hours
C12hr
plasma concentration value collected at 12 hours
CBC
complete blood count
CDC
Centers for Disease Control and Prevention
CD4
cluster of differentiation 4
CI
confidence interval
Cmax
maximum plasma concentration
CMH
Cochran–Mantel–Haenszel
CONSORT
Consolidated Standards of Reporting Trials
COVID-19
coronavirus infectious disease 2019
CRF
case report form 
CRP
C-reactive protein
CSR
clinical study report
CTFG
clinical trial facilitation group
Ctrough
lowest plasma concentration
CYP
cytochrome P450
DAIDS
Division of Acquired Immunodeficiency Syndrome
DAO
data as observed
DDI
drug-drug interaction
DILI
drug-induced liver injury
DMC
data monitoring committee
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
ePROs
electronic patient-reported outcomes
ESD
early stage development
ESR
erythrocyte sedimentation rate
EUA
emergency use authorization
FBR
future biomedical research
FDA
Food and Drug Administration
FDAAA
Food and Drug Administration Amendments Act
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Abbreviation
Expanded Term
FiO2
fraction of inspired oxygen
FSH
follicle-stimulating hormone
GCP
good clinical practice 
H1
hypothesis 1
H1N1
Hemagglutinin Type 1 and Neuraminidase Type 1 (influenza strain)
H2
hypothesis 2
HBsAg
hepatitis B surface antigen
HBV
hepatitis B virus
hCG
human chorionic gonadotropin
HCV
hepatitis C virus
HIV
human immunodeficiency virus
HRT
hormone replacement therapy
IA
interim analysis
IB
investigator’s brochure 
ICF
informed consent form
ICH
International Council for Harmonisation of Technical Requirements for 
Pharmaceuticals for Human Use
ICU
intensive care unit
IEC
Independent Ethics Committee
Ig
immunoglobulin
IgA
immunoglobulin A
IgG
immunoglobulin G
IgM
immunoglobulin M
IL-6
interleukin 6
IMP
investigational medicinal product
IRB
Institutional Review Board
IRT
intervention randomization system
IUD
intrauterine device
IUS
intrauterine hormone-releasing system
IV
intravenous
LAM
lactational amenorrhoea method
LAR
legally acceptable representative 
LFT
liver function test
LFU
late follow-up
LOCF
last observation carries forward
LSD
late stage development
MAD
multiple ascending dose
MAP
modeling analysis plan
MCH
mean corpuscular hemoglobin
MCV
mean corpuscular volume
MDRD
modification of diet in renal disease
MERS
Middle East respiratory syndrome
MHP
medical history pre-specified 
MITT
modified intent-to-treat
MOV
molnupiravir
MOVe-OUT
non-hospitalized outpatient study
MSD
Merck Sharp & Dohme
N/A
not applicable
NCT
National Clinical Trial
NEJM
New England Journal of Medicine
NHC
N-hydroxycytidine
NHC-TP
N-hydroxycytidine pharmacologically-active triphosphate
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Abbreviation
Expanded Term
NIMP
non-investigational medicinal product
NP
nasopharyngeal
NSAE
nonserious adverse event
OP
oropharyngeal
PaO2
partial pressure of oxygen
PBMC
peripheral blood mononuclear cells
PCR
polymerase chain reaction
PCT
procalcitonin
PDLC
pre-defined limit of change
pINN
proposed International Nonproprietary Name
PK
pharmacokinetic
PPE
personal protective equipment
PQC
product quality complaint
PRO
patient-reported outcome
PT
preferred term 
Q12H
administered once every 12 hours
QP2
department of quantitative pharmacology and pharmacometrics
RBC
red blood cell
RdRp
RNA-dependent RNA polymerase
RDW
red cell distribution width 
RNA
ribonucleic acid
RSV
respiratory syncytial virus
RT-PCR
real time 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
siDMC
standing internal data monitoring committee
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
TBD
to be determined
Tmax
time to maximum plasma concentration
TSSO
time since symptom onset
t1/2
half-life
ULN
upper limit of normal
US
United States
VL
viral load
WBC
white blood cell
WHO
World Health Organization
WOCBP
woman/women of childbearing potential 
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11
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PROTOCOL/AMENDMENT NO.:  002-04  
MK-4482-002-04 FINAL PROTOCOL
15-AUG-2021
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06FSHF
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PRODUCT:  MK-4482  
135
PROTOCOL/AMENDMENT NO.:  002-04  
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15-AUG-2021
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