A Phase 2/3, Randomized, Placebo-Controlled, Double-Blind Clinical Study to Evaluate the Efficacy, Safety, and Pharmacokinetics of MK-4482 in Hospitalized Adults With COVID-19
Phase: PHASE2
Conditions: Coronavirus Disease (COVID-19)
Sponsor: Merck Sharp & Dohme LLC

Official Protocol Title: 
NCT number: 
NCT04575584
Document Date: 
17-DEC-2020
A Phase 2/3, Randomized, Placebo-Controlled, Double-Blind 
Clinical Study to Evaluate the Efficacy, Safety, and 
Pharmacokinetics of MK-4482 in Hospitalized Adults with 
COVID-19

PRODUCT: MK-4482  
1
PROTOCOL/AMENDMENT NO.: 001-01 
MK-4482-001-01 FINAL PROTOCOL
17-DEC-2020
Title Page
THIS PROTOCOL AMENDMENT AND ALL OF THE INFORMATION RELATING 
TO IT ARE CONFIDENTIAL AND PROPRIETARY PROPERTY OF MERCK 
SHARP & DOHME CORP., A SUBSIDIARY OF MERCK & CO., INC., NJ, U.S.A. 
(MSD).
Protocol Title: A Phase 2/3, Randomized, Placebo-Controlled, Double-Blind Clinical Study 
to Evaluate the Efficacy, Safety, and Pharmacokinetics of MK-4482 in Hospitalized Adults 
with COVID-19
Protocol Number: 001-01
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
2020-003367-26
IND
147734
Approval Date: 17 December 2020
 
 
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PRODUCT: MK-4482  
2
PROTOCOL/AMENDMENT NO.: 001-01 
MK-4482-001-01 FINAL PROTOCOL
17-DEC-2020
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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PRODUCT: MK-4482  
3
PROTOCOL/AMENDMENT NO.: 001-01 
MK-4482-001-01 FINAL PROTOCOL
17-DEC-2020
DOCUMENT HISTORY
Document
Date of Issue
Overall Rationale
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 primary efficacy endpoint 
definition, and add a new inclusion criterion and discontinuation 
criterion
Original Protocol
14-SEP-2020
Not applicable
 
 
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PRODUCT: MK-4482  
4
PROTOCOL/AMENDMENT NO.: 001-01 
MK-4482-001-01 FINAL PROTOCOL
17-DEC-2020
PROTOCOL AMENDMENT SUMMARY OF CHANGES
Amendment: 01
Overall Rationale for the Amendments:
To revise the dose selection process before initiation of Part 2 (Phase 3), update the benefit/risk assessment, clarify the primary 
efficacy endpoint definition, and add a new inclusion criterion and discontinuation criterion.
Summary of Changes Table:
Section # and Name
Description of Change 
Brief Rationale 
1.1 Synopsis
4.1 Overall Design 
4.2 Scientific Rationale for 
Study Design 
8.1.8 Study Intervention 
Administration
References to ‘Day 1’ and/or ‘first dose’ 
were revised to ‘randomization’ and 
clarification regarding study day 
numbering (ie, randomization = Day 1)
was provided
To add clarity and consistency
1.2 Schema
5.1 Inclusion Criteria
Clarified that 10-day window for 
assessment of COVID-19 sign/symptoms 
does not include the day of randomization 
To clarify the timing of symptom onset prior to 
randomization for study eligibility
1.3 Schedule of Activities
-Included an option for clinic or at-home 
visit in lieu of virtual visits on Days 2 and 
4. Corresponding update in Section 
8.11.2.4.
-To increase flexibility for visit scheduling
 
 
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PRODUCT: MK-4482  
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PROTOCOL/AMENDMENT NO.: 001-01 
MK-4482-001-01 FINAL PROTOCOL
17-DEC-2020
Section # and Name
Description of Change 
Brief Rationale 
-Added a footnote to clarify that LFU visit 
will occur 7 months after the last dose of 
study intervention.
-Visit Window for LFU visit changed to 
±1 Month. 
-Review of inclusion/exclusion criteria 
added to Day 1 in SoA and Section 8.1.2
-COVID-19 severity must be based on 
Day 1 pre randomization values. 
Corresponding updates to Section 8.1.2.
-Clarified that the first dose of study 
intervention is preferably administered on 
Day 1. Corresponding updates in Section 
8.1.8.
-Revised note for Serum and Plasma for 
Exploratory Research to provide the 
correct cross-reference.
-Added a separate line to the SoA for 
collection of serum for antibody 
exploratory research
-Text revised to indicate that discharge 
readiness will be assessed daily while 
hospitalized.
-To add clarity 
-To increase flexibility for visit scheduling 
-To add clarity for the timing of certain screening 
activities in relation to randomization through the IRT 
system.
-To add clarity.
-To add clarity.
-To correct an error. 
-To add clarity as a separate laboratory collection kit is 
needed to collect this sample. 
-To add clarity.
 
 
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PRODUCT: MK-4482  
8
PROTOCOL/AMENDMENT NO.: 001-01 
MK-4482-001-01 FINAL PROTOCOL
17-DEC-2020
Section # and Name
Description of Change 
Brief Rationale 
5.1 Inclusion Criteria
-Clarified use of molecular or antigen tests 
are allowed if authorized for use in the 
country. Serological tests that detect host 
antibodies are not allowed to confirm 
study eligibility.
-Inclusion Criterion #4 added to indicate 
that participants with mild, moderate, or 
severe COVID-19 (per Appendix 9) are 
eligible for study entry.
-To clarify appropriate diagnostic testing that can be 
used for study eligibility
-To add clarity
5.2 Exclusion Criteria
8.1.2 Inclusion/Exclusion 
Criteria
Revised exclusion criterion related to 
HBV or HCV infection.
To allow participants with stable and/or well-controlled 
HBV/HCV participation in the study.
5.2 Exclusion Criteria
Mechanical ventilation criterion edited.
To broaden this criterion since participants with a 
recent history of mechanical ventilation for any reason 
(not just due to COVID-19) are a higher risk for re-
intubation.
6.1 Study Intervention(s)
Administered 
Changed the placebo comparator use from 
experimental to placebo
To add clarity
6.3.1 Intervention 
Assignment
Added text describing study intervention 
assignments. 
Inadvertently omitted in original protocol.
6.3.2 Stratification 
Revised wording of stratification criteria.
Repeated text present in Section 4.1 
regarding planned sample size.
To add clarity and consistency. 
 
 
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PRODUCT: MK-4482  
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17-DEC-2020
Section # and Name
Description of Change 
Brief Rationale 
6.4 Study Intervention 
Compliance 
Study intervention compliance 
requirements clarified. 
To allow increased flexibility in the event that local 
infection-control restrictions do not allow for direct 
medical supervision of study intervention 
administration or for confirmation at the time of dosing 
by a member of the study site staff other than the 
person administering the study intervention.
6.5 Concomitant Therapy
Updated ‘Investigational Agents” to “Non-
Covid-19 Investigational Agents” and 
“medications” to “therapies” in the 
Prohibited and Allowed Therapies table
To clarify that this row refers to Investigational Agents 
not intended for COVID-19 treatment and for wording 
consistency.
7.1 Discontinuation of Study 
Intervention 
-Added criteria for participants who meet 
liver enzyme ECI criteria
-Revised criterion for participants with a 
platelet count <50,000 µL that repeat 
confirmatory testing is needed.
-Added a discontinuation criterion for 
participants who become pregnant
-Repeated discontinuation text present in 
Sections 8.6.1 and 8.6.2. 
-To align with ECI criteria for participant safety
-To align with the ECI criterion
-To add criterion for participant and fetal safety
-To add clarity and consistency 
8.1.8 Study Intervention 
Administration 
Added text describing study intervention 
administration.
To provide text inadvertently omitted in original 
protocol
 
 
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PRODUCT: MK-4482  
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17-DEC-2020
Section # and Name
Description of Change 
Brief Rationale 
8.1.8.1 Timing of Dose 
Administration 
-Timing of dosing and EOT visit was 
added
-Clarified that if a participant’s renal 
function deteriorates requiring dialysis, 
discontinuation is not required
-To clarify details regarding the EOT visit requirements 
-To add clarity
8.1.14 Study Medication 
Diary 
-Added options for recording study 
intervention in the Study Medication diary.
-Included option for collection of the 
Study Medication Diary at the Day 10 
visit if collection at EOT is not feasible.
-Clarified capsule count definition. 
Corresponding updates made in Section 
9.11. 
-To increase flexibility for appropriate methods of 
recording study intervention administration 
-To provide flexibility
-To provide clarification that capsule count should be 
recorded on the eCRF
8.3.1 Physical Examinations
Revised to indicate the height and weight 
data will be collected (not measured).
To allow increased flexibility for collection of height 
and weight data. 
8.3.3 Electrocardiograms
Revised text to indicate that ECG 
parameters may be either calculated 
manually during review by a qualified 
physician or obtained via an ECG machine 
that automatically calculates such 
parameters.
To allow increased flexibility for ECG data collection. 
8.6.1 Blood Collection for 
Measurement of NHC in 
Plasma
Footnote added to clarify timing of pre-
dose samples in Part 2. 
To provide text inadvertently omitted from original 
protocol
 
 
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Section # and Name
Description of Change 
Brief Rationale 
8.6.2 Blood Collection for 
Measurements of NHC-TP 
in PBMCs
PBMC requirements clarified. 
To allow flexibility if PBMC collection is not possible 
due to infection control restrictions. 
8.11.2.2 Hospitalized Visits
Removed text indicating that participants 
require ≥24 hours of medical care in the 
hospital.
To clarify specific duration of medical care in the 
hospital required for study eligibility.
9.1 Statistical Analysis Plan 
Summary
9.5.1 Efficacy Analysis 
Populations
9.5.2 Safety Analysis 
Populations
9.9.3 Sample Size and 
Power Calculations for 
Safety Analyses (Part 2)
-Clarified that Part 1 (Phase 2) and Part 2 
(Phase 3) efficacy endpoints will be 
analyzed separately
-Clarified that Part 1 (Phase 2) and Part 2 
(Phase 3) will be combined for the final 
analysis of safety endpoints  
To provide additional details regarding the analysis of 
efficacy and safety in Part 1 (Phase2) and Part 2 (Phase 
3).
 
 
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Section # and Name
Description of Change 
Brief Rationale 
9.1 Statistical Analysis Plan 
Summary 
9.7 Interim Analyses
Revised to state that dose evaluation will 
occur after 300 participants complete 
EOT, MK-4482-001 and MK-4482-002 
combined, during IA1
Modifications made to IA1 and IA2 to 
indicate that dose selection for Phase 3 
will not occur until IA2
To clarify the timing for dose evaluation 
9.2 Responsibility for 
Analyses/In-house Blinding 
9.7 Interim Analyses
Clarified that Part 2 of the study will not 
be initiated until Part 1 of the study is 
completed
To add clarity
9.4.1.1
Efficacy/Pharmacokinetics 
Endpoints 
Description of WHO 11-point ordinal 
scale was added
To provide more detail about the significance of the 
WHO 11-point ordinal scale
9.6.1 Statistical Methods for 
Efficacy Analyses
-Removed geographic region as 
stratification factor for the primary 
analysis.
-Text added to describe sensitivity 
analyses. 
-Text added to clarify impact of lost to 
follow up and other discontinuations on 
primary endpoint.
To clarify primary analysis methodology
 
 
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Section # and Name
Description of Change 
Brief Rationale 
9.6.1 Statistical Methods for 
Efficacy Analyses
9.9.2 Sample Size and 
Power Calculations for 
Virology Analyses (Part 1)
-Statistical methods for viral RNA 
endpoints added
-Section added to describe sample size and 
power calculations for viral RNA 
endpoints. 
To provide additional description for the analyses of  
virology endpoints 
9.6.2 Statistical Methods for 
Safety Analyses
Updated Tier 3 safety endpoint description To align table with text
9.7 Interim Analyses
Revised Sponsor siDMC review of IA1 
data
To revise purpose of siDMC review of IA1 data
9.10 Subgroup Analyses
-Revised subgroup related to remdesivir 
use.
-Added a subgroup for corticosteroid use 
at baseline. 
-To add clarity
-To add a subgroup factor
10.2 Appendix 2: Clinical 
Laboratory Tests
Updated approximate whole blood 
volumes and visit windows. 
Corresponding updates in Section 8.
To revise the specimen collection volumes and to
clarify windows for specimen collection time points 
10.7 Appendix 7: Country-
specific Requirements 
Text added to indicate that participants in 
South Korea whose renal function 
deteriorates requiring dialysis must be 
discontinued. 
To provide country-specific requirement for South 
Korea 
 
 
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Section # and Name
Description of Change 
Brief Rationale 
10.9 Appendix 9: COVID-
19 Severity Categorization
Table format was modified. Clarified that 
participants with new oxygen needs not 
previously on supplemental oxygen are 
considered to have severe COVID-19.
To add clarity
Throughout the document 
Corrected minor typographical and 
grammatical errors
To improve clarity and consistency throughout the 
document. 
 
 
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PRODUCT: MK-4482  
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Table of Contents
DOCUMENT HISTORY ........................................................................................................3
PROTOCOL AMENDMENT SUMMARY OF CHANGES...............................................4
1
PROTOCOL SUMMARY ............................................................................................23
1.1
Synopsis.................................................................................................................23
1.2
Schema ..................................................................................................................27
1.3
Schedule of Activities...........................................................................................28
2
INTRODUCTION..........................................................................................................33
2.1
Study Rationale....................................................................................................33
2.2
Background ..........................................................................................................33
2.3
Benefit/Risk Assessment......................................................................................35
3
HYPOTHESES, OBJECTIVES, AND ENDPOINTS................................................36
4
STUDY DESIGN............................................................................................................38
4.1
Overall Design......................................................................................................38
4.2
Scientific Rationale for Study Design.................................................................39
4.2.1
Rationale for Endpoints ...............................................................................40
4.2.1.1
Efficacy Endpoints.............................................................................40
4.2.1.1.1
Primary Clinical Endpoint .......................................................40
4.2.1.1.2
Secondary Endpoint (Mortality) ..............................................41
4.2.1.1.3
Secondary Endpoints (Ordinal Scales) ....................................41
4.2.1.2
Safety Endpoints................................................................................41
4.2.1.3
Pharmacokinetic Endpoints ...............................................................42
4.2.1.4
Virology Endpoints............................................................................42
4.2.1.5
Inflammatory Biomarkers..................................................................43
4.2.2
Rationale for the Use of Comparator/Placebo .............................................43
4.2.3
Rationale for the Selected Participant Population .......................................43
4.2.4
Rationale for Collection of Racial, Ethnic, and Gender Identity Data ........44
4.2.5
Rationale for Other Exploratory Research Samples ....................................44
4.3
Justification for Dose...........................................................................................45
4.3.1
Rationale for Dosing Duration.....................................................................45
4.3.2
Dose Range for Part 1 (Phase 2)..................................................................46
4.3.3
Dose Selection for Part 2 (Phase 3) .............................................................46
4.4
Beginning and End of Study Definition .............................................................46
4.4.1
Clinical Criteria for Early Study Termination .............................................46
5
STUDY POPULATION ................................................................................................46
5.1
Inclusion Criteria.................................................................................................47
 
 
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5.2
Exclusion Criteria................................................................................................49
5.3
Lifestyle Considerations......................................................................................51
5.4
Screen Failures.....................................................................................................51
5.5
Participant Replacement Strategy......................................................................51
6
STUDY INTERVENTION............................................................................................51
6.1
Study Intervention(s) Administered...................................................................51
6.2
Preparation/Handling/Storage/Accountability .................................................53
6.2.1
Dose Preparation..........................................................................................53
6.2.2
Handling, Storage, and Accountability........................................................53
6.3
Measures to Minimize Bias: Randomization and Blinding..............................54
6.3.1
Intervention Assignment..............................................................................54
6.3.2
Stratification.................................................................................................54
6.3.3
Blinding........................................................................................................54
6.4
Study Intervention Compliance..........................................................................55
6.5
Concomitant Therapy..........................................................................................55
6.5.1
Rescue Medications and Supportive Care ...................................................56
6.6
Dose Modification (Escalation/Titration/Other)...............................................57
6.7
Intervention After the End of the Study............................................................57
6.8
Clinical Supplies Disclosure................................................................................57
7
DISCONTINUATION OF STUDY INTERVENTION AND PARTICIPANT 
WITHDRAWAL............................................................................................................57
7.1
Discontinuation of Study Intervention...............................................................57
7.2
Participant Withdrawal From the Study...........................................................58
7.3
Lost to Follow-up .................................................................................................58
8
STUDY ASSESSMENTS AND PROCEDURES........................................................59
8.1
Administrative and General Procedures ...........................................................60
8.1.1
Informed Consent.........................................................................................60
8.1.1.1
General Informed Consent.................................................................60
8.1.1.2
Consent for PBMC Cohort Blood Sample Collection.......................60
8.1.2
Inclusion/Exclusion Criteria ........................................................................61
8.1.3
Participant Identification Card.....................................................................61
8.1.4
Medical History ...........................................................................................61
8.1.5
Prior and Concomitant Medications Review...............................................62
8.1.5.1
Prior Medications...............................................................................62
8.1.5.2
Concomitant Medications..................................................................62
8.1.6
Assignment of Screening Number...............................................................62
8.1.7
Assignment of Treatment/Randomization Number.....................................62
8.1.8
Study Intervention Administration ..............................................................63
 
 
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8.1.8.1
Timing of Dose Administration.........................................................63
8.1.9
Discontinuation and Withdrawal .................................................................64
8.1.10
Participant Blinding/Unblinding..................................................................64
8.1.11
Domiciling ...................................................................................................65
8.1.12
Calibration of Equipment.............................................................................65
8.1.13
Collect/Update Secondary Contact Information..........................................65
8.1.14
Study Medication Diary...............................................................................66
8.2
Efficacy Assessments ...........................................................................................66
8.2.1
Nasopharyngeal and Oropharyngeal Swabs ................................................66
8.2.2
Assessment of COVID-19 Signs, Symptoms, and Functional Status..........67
8.2.3
Assessment of Level of Consciousness .......................................................67
8.2.4
Respiratory/Oxygenation Status ..................................................................67
8.2.5
Hospitalization Status ..................................................................................67
8.2.6
Survival Status .............................................................................................68
8.3
Safety Assessments...............................................................................................68
8.3.1
Physical Examinations.................................................................................68
8.3.2
Vital Signs....................................................................................................69
8.3.3
Electrocardiograms ......................................................................................69
8.3.4
Clinical Safety Laboratory Assessments .....................................................69
8.3.5
Pregnancy Testing........................................................................................70
8.4
Adverse Events, Serious Adverse Events, and Other Reportable Safety 
Events....................................................................................................................70
8.4.1
Time Period and Frequency for Collecting AE, SAE, and Other 
Reportable Safety Event Information ..........................................................70
8.4.2
Method of Detecting AEs, SAEs, and Other Reportable Safety Events......73
8.4.3
Follow-up of AE, SAE, and Other Reportable Safety Event Information...73
8.4.4
Regulatory Reporting Requirements for SAE .............................................73
8.4.5
Pregnancy and Exposure During Breastfeeding ..........................................73
8.4.6
Disease-related Events and/or Disease-related Outcomes Not Qualifying 
as AEs or SAEs............................................................................................74
8.4.7
Events of Clinical Interest............................................................................74
8.5
Treatment of Overdose........................................................................................75
8.6
Pharmacokinetics.................................................................................................75
8.6.1
Blood Collection for Measurement of NHC in Plasma ...............................75
8.6.2
Blood Collection for Measurement of NHC-TP in PBMCs........................76
8.7
Pharmacodynamics..............................................................................................76
8.8
Biomarkers and Exploratory Research Samples..............................................77
8.8.1
Biomarkers...................................................................................................77
 
 
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8.8.2
Exploratory Research Samples ....................................................................77
8.9
Future Biomedical Research Sample Collection...............................................77
8.10
Medical Resource Utilization and Health Economics.......................................77
8.11
Visit Requirements...............................................................................................77
8.11.1
Infection Prevention Procedures..................................................................77
8.11.2
Types of Study Visits...................................................................................78
8.11.2.1
Screening/Rescreening Visits ............................................................78
8.11.2.2
Hospitalized Visits.............................................................................78
8.11.2.3
Clinic or At-Home Visits...................................................................79
8.11.2.4
Virtual Visits......................................................................................79
8.11.3
Participants who Discontinue or Withdraw .................................................79
8.11.4
Late Follow-up (7 month) Visit...................................................................80
9
STATISTICAL ANALYSIS PLAN .............................................................................80
9.1
Statistical Analysis Plan Summary.....................................................................81
9.2
Responsibility for Analyses/In-house Blinding .................................................83
9.3
Hypotheses/Estimation ........................................................................................83
9.4
Analysis Endpoints...............................................................................................83
9.4.1
Efficacy/Pharmacokinetics Endpoints .........................................................84
9.4.1.1
Efficacy Endpoints.............................................................................84
9.4.1.2
Pharmacokinetics Endpoints..............................................................86
9.4.2
Safety Endpoints..........................................................................................86
9.5
Analysis Populations............................................................................................86
9.5.1
Efficacy Analysis Populations.....................................................................86
9.5.2
Safety Analysis Populations ........................................................................87
9.6
Statistical Methods...............................................................................................87
9.6.1
Statistical Methods for Efficacy Analyses...................................................88
9.6.2
Statistical Methods for Safety Analyses ......................................................92
9.6.3
Demographic and Baseline Characteristics .................................................93
9.7
Interim Analyses ..................................................................................................94
9.8
Multiplicity ...........................................................................................................97
9.9
Sample Size and Power Calculations .................................................................97
9.9.1
Sample Size and Power Calculations for Efficacy Analyses (Part 2)..........97
9.9.2
Sample Size and Power Calculations for Virology Analyses (Part 1).........98
9.9.3
Sample Size and Power Calculations for Safety Analyses (Part 2).............98
9.10
Subgroup Analyses...............................................................................................99
9.11
Compliance (Medication Adherence)...............................................................100
9.12
Extent of Exposure.............................................................................................100
 
 
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10
SUPPORTING DOCUMENTATION AND OPERATIONAL 
CONSIDERATIONS...................................................................................................101
10.1
Appendix 1: Regulatory, Ethical, and Study Oversight Considerations......101
10.1.1
Code of Conduct for Clinical Trials...........................................................101
10.1.2
Financial Disclosure...................................................................................103
10.1.3
Data Protection...........................................................................................103
10.1.3.1
Confidentiality of Data ....................................................................104
10.1.3.2
Confidentiality of Participant Records.............................................104
10.1.3.3
Confidentiality of IRB/IEC Information..........................................104
10.1.4
Committees Structure.................................................................................105
10.1.4.1
Executive Oversight Committee......................................................105
10.1.4.2
Internal Data Monitoring Committee...............................................105
10.1.4.3
External Data Monitoring Committee .............................................105
10.1.5
Publication Policy......................................................................................105
10.1.6
Compliance with Study Registration and Results Posting Requirements .106
10.1.7
Compliance with Law, Audit, and Debarment ..........................................106
10.1.8
Data Quality Assurance .............................................................................107
10.1.9
Source Documents .....................................................................................108
10.1.10
Study and Site Closure...............................................................................108
10.2
Appendix 2: Clinical Laboratory Tests............................................................109
10.3
Appendix 3: Adverse Events: Definitions and Procedures for Recording, 
Evaluating, Follow-up, and Reporting.............................................................113
10.3.1
Definition of AE ........................................................................................113
10.3.2
Definition of SAE ......................................................................................114
10.3.3
Additional Events Reported.......................................................................115
10.3.4
Recording AE and SAE .............................................................................115
10.3.5
Reporting of AEs, SAEs, and Other Reportable Safety Events to the 
Sponsor ......................................................................................................119
10.4
Appendix 4: Medical Device and Drug-device Combination Products: 
Product Quality Complaints/Malfunctions: Definitions, Recording, and 
Follow-up ............................................................................................................121
10.5
Appendix 5: Contraceptive Guidance..............................................................122
10.5.1
Definitions..................................................................................................122
10.5.2
Contraception Requirements......................................................................123
10.6
Appendix 6: Collection and Management of Specimens for Future 
Biomedical Research..........................................................................................124
10.7
Appendix 7: Country-specific Requirements..................................................125
10.7.1
Country-specific Request for South Korea................................................125
10.8
Appendix 8: Ordinal Outcome Scales..............................................................126
 
 
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10.8.1
Pulmonary and Pulmonary+ ......................................................................126
10.8.2
National Early Warning Score...................................................................127
10.8.3
World Health Organization 11-Point Scale ...............................................128
10.9
Appendix 9: COVID-19 Severity Categorization............................................129
10.10 Appendix 10: Calculation of eGFR ..................................................................132
10.11 Appendix 11: Abbreviations .............................................................................133
11
REFERENCES.............................................................................................................137
 
 
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LIST OF TABLES
Table 1
Study Interventions....................................................................................52
Table 2
Prohibited and Allowed Therapies.............................................................56
Table 3
Reporting Time Periods and Time Frames for Adverse Events and 
Other Reportable Safety Events.................................................................72
Table 4
Plasma Sample Collection Schedule for NHC Concentrations .................75
Table 5
Analysis Strategy for Key Efficacy Endpoints..........................................90
Table 6
Analysis Strategy for Safety Parameters....................................................93
Table 7
Description of Interim Analyses ................................................................95
Table 8
Power by Detectable Difference and Standard Deviation Viral RNA 
Change from Baseline (log10 copies/mL) N=60/group, α=0.025, 1-
sided...........................................................................................................98
Table 9
Differences in Incidence of AE Rates Between the 2 Treatment Groups 
That Can be Detected With an ~90% Probability (Assuming 2-sided 
5% Alpha Level with 575 Participants in Each Group).............................99
Table 10
Protocol-required Laboratory Assessments.............................................109
Table 11
Approximate Whole Blood Volumes (mL) .............................................111
 
 
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LIST OF FIGURES
Figure 1
Study Schema and Treatment Plan ............................................................27
 
 
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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 Hospitalized Adults 
with COVID-19
Short Title: MK-4482 Ph 2/3 Study in Hospitalized Adults with COVID-19
Acronym: N/A
Hypotheses, Objectives, and Endpoints:
Hypotheses are aligned with objectives in the Objectives and Endpoints table.
The following objectives will be evaluated in hospitalized participants ≥18 years of age with 
COVID-19. 
Primary Objectives
Primary Endpoints
- To evaluate the efficacy of MK-4482 
compared to placebo as assessed by the rate 
of sustained recovery from randomization 
through Day 29.
Hypothesis (H1): MK-4482 is superior to 
placebo as assessed by the rate of sustained 
recovery through Day 29.
- Time-to-sustained recovery
- 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 the 
percentage of participants who die through 
Day 29.
Hypothesis (H2): MK-4482 is superior to 
placebo as assessed by the percentage of 
participants who die through Day 29.
- All-cause mortality 
 
 
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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 
selected ordinal outcome scales at Day 3, 
EOT, Day 10, Day 15, and Day 29.
- Pulmonary score 
- Pulmonary+ score
- To evaluate the efficacy of MK-4482 
compared to placebo as assessed by the 
odds of a more favorable response in the 
clinical risk of mortality category from the 
National Early Warning Score at EOT.
- National Early Warning Score
- 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 hospitalized with COVID-19
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.
 
 
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Number of Participants:
A total of ~1300 participants will be randomized in the study.
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~1000)
MK-4482
MK-4482
TBD 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; TBD=to be 
determined based on dose selected in Part 1 of the study.
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 approximately
7 months after the last dose of study intervention. 
 
 
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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 11.
 
 
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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; TBD=to be determined based on dose selection in Part 1 
of the study
a Eligible participants will have PCR-confirmed SARS-CoV-2 infection with signs/symptoms attributable to 
COVID-19 for ≤10 days prior to randomization (Section 5.1). Calculation of the 10-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 (Sections 4.3.3 and 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 (and 
Window):
Screening 
(≤24 hours 
before
rand.)a
Day 
1b
Day 
2
Day 
3
Day 
4
EOT 
Day 10 
(±1 
day)
Day 15 
(+3 
days)
Day 29 
(+3 
days)
LFU
Month 
7 (±1 
Month)c
Type of Visit
H = Hospitalized
C = Clinic or At-home visit
V= Virtual Visit
H
H
H/C/
V
H/C
H/C/
V
H/C
H/C
H/C
H/C
V
Virtual, Clinic, and At-home 
visits are only allowed after 
discharge. Virtual visits (Day 2 
and Day 4) will consist of 
Concomitant Medication and 
AE/SAE collection only. 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 
PBMC Collection
(Optional)
X
Only a subset of participants at 
selected sites
Register Study Visit in IRT
X
X
Inclusion/Exclusion 
Criteria
Xd
Xe
Including review of SARS-CoV-
2 (+) local test results. 
Participant Identification 
Card
X
X
Randomization number must be 
added to card at randomization.
Medical History
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
 
 
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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 (and 
Window):
Screening 
(≤24 hours 
before
rand.)a
Day 
1b
Day 
2
Day 
3
Day 
4
EOT 
Day 10 
(±1 
day)
Day 15 
(+3 
days)
Day 29 
(+3 
days)
LFU
Month 
7 (±1 
Month)c
Intervention Randomization 
Xb
COVID-19 severity 
categorization entered in IRT at 
randomization must be based on 
values obtained on Day 1 prior 
to randomization
Collect/Update Secondary 
Contacts for Participant
X
X
X
X
Also to occur upon discharge 
MK-4482 or Placebo 
Administrationf
X
X
X
X
X
First dose is preferably 
administered on Day 1
(randomization), but 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.
Efficacy Procedures
NP and OP Swabs
X
X
X
X
X
X
Based on Part 1 data, NP and OP 
swab collection may be adapted 
to remove one method or 
timepoints throughout the life of 
the study; this will be 
communicated via Protocol 
Clarification Letters. 
Serum and Plasma for 
Exploratory Research 
X
X
X
X
Research samples will be stored 
for testing as described in 
Sections 4.2.5 and 8.8.
Serum for Antibody 
Exploratory Research
X
X
X
X
 
 
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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 (and 
Window):
Screening 
(≤24 hours 
before
rand.)a
Day 
1b
Day 
2
Day 
3
Day 
4
EOT 
Day 10 
(±1 
day)
Day 15 
(+3 
days)
Day 29 
(+3 
days)
LFU
Month 
7 (±1 
Month)c
Assessment of COVID-19 
Signs, Symptoms, 
Functional Status
X
X
X
X
X
X
X
X
Assess signs and symptoms 
daily while hospitalized and 
only at study visits after 
discharge. Functional status only 
assessed at Day 1, Day 3, EOT, 
Days 10, 15, and 29. Assessment 
will not be done at virtual visits. 
Assessment of Level of 
Consciousness (AVPU)
X
X
Respiratory/ Oxygenation 
Status
X
X
X
X
X
X
X
X
Xg
SpO2 measured daily while 
hospitalized via pulse oximetry. 
If applicable: FiO2, PaO2, and 
supplemental oxygen use. SpO2
will not be done at virtual visits.
Hospitalization Status
X
X
X
X
X
X
X
X
X
Discharge readiness will be 
assessed daily while 
hospitalized. 
Survival Status
X
X
Safety Procedures
Full Physical Examination
X
Including height and weight
Directed Physical Exam 
X
X
X
X
X
X
Vital Signs
X
X
X
X
X
X
X
X
X
Heart rate, blood pressure, 
respiratory rate, temperature. 
Assess vitals daily while 
hospitalized and only on study 
visits after discharge.
 
 
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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 (and 
Window):
Screening 
(≤24 hours 
before
rand.)a
Day 
1b
Day 
2
Day 
3
Day 
4
EOT 
Day 10 
(±1 
day)
Day 15 
(+3 
days)
Day 29 
(+3 
days)
LFU
Month 
7 (±1 
Month)c
Blood Collection for Local 
Laboratory Evaluation 
Xd
Local laboratory collection 
required unless
chemistry/hematology results 
within 72h prior to 
randomization are available.
Blood Collection for 
Central Laboratory 
Evaluation 
X
X
X
X
X
X
Hematology and Chemistry at 
all indicated time points. 
Inflammatory biomarkers at 
Day 1 and EOT only.
12-lead ECG
X
X
If ECG is conducted at 
Screening, then do not repeat on 
Day 1. 
Serum Pregnancy Test 
(hCG; WOCBP only)
Xd
X
Confirm Contraception 
Requirements (WOCBP 
and male participants)
X
X
X
X
X
X
X
Confirm participant compliance 
with contraception requirements 
as outlined in inclusion criteria 
and Appendix 5
Urinalysis
X
AE/SAE Reviewh
X
X
X
X
X
X
X
X
X
X
Pharmacokinetics
PK Plasma Sampling
X
Part 1:
Pre-dose, 1, 3, 5, 8 hours post-
dose
Part 2: 
Pre-dose, 1, 5 hours post-dose
 
 
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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 (and 
Window):
Screening 
(≤24 hours 
before
rand.)a
Day 
1b
Day 
2
Day 
3
Day 
4
EOT 
Day 10 
(±1 
day)
Day 15 
(+3 
days)
Day 29 
(+3 
days)
LFU
Month 
7 (±1 
Month)c
PK PBMC Samplingi
X
Part 1 (PBMC Cohort only):
Pre-dose, 1, 3, 5, 8 hours post-
dose
AE=adverse event; ALT=alanine aminotransferase; AST=aspartate aminotransferase; AVPU=Alert, Voice, Pain, Unresponsive; COVID-19=coronavirus 
disease 2019; ECG=electrocardiogram; EOT=End of Treatment (day of last study intervention dose); FiO2=fraction of inspired oxygen; hCG=human chorionic 
gonadotropin; HBV=hepatitis B virus; HCV=hepatitis C virus; HIV=human immunodeficiency virus; LFU= Late Follow-Up; IRT=intervention randomization 
system; NP=nasopharyngeal; OP=oropharyngeal; PaO2=partial pressure of oxygen; PBMC=peripheral blood mononuclear cells; PSV= Pregnancy Status Visit; 
PK=pharmacokinetic; rand.=randomization; RNA=ribonucleic acid; SARS-CoV-2=severe acute respiratory syndrome coronavirus 2; SAE=serious adverse 
event; SpO2 = oxygen saturation; WOCBP=women of childbearing potential.
a Screening and Day1 (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 LFU (Month 7) visit is 7 months from the last dose of study intervention. 
d The following local laboratory results must be available for all participants from within 72 hours prior to randomization to support determination of 
eligibility: serum creatinine, platelets, and absolute neutrophil count (segmented neutrophils and bands). 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 serum 
pregnancy test is required within 24 hours of the first dose of study drug per inclusion criteria. All other inclusion/exclusion criteria determination (eg, HIV 
status, pancreatitis, etc.) can be based on participant-reported medical history, available medical records, and the most recently available laboratory results for 
the participant (eg, HIV RNA viral load or CD4 count).
e Confirm no change in eligibility based on inclusion/exclusion criteria and/or disease severity.
f If participant is discharged prior to study intervention completion, study intervention and the Study Medication Diary will be dispensed to the participant 
according to the pharmacy manual.
g 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.  
h AEs, SAEs, and other reportable safety events (eg, pregnancy) will be monitored according to Section 8.4.
i A subset of ~100 participants will take part in the PBMC Cohort at selected sites.
 
 
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PRODUCT: MK-4482  
37
PROTOCOL/AMENDMENT NO.: 001-01 
MK-4482-001-01 FINAL PROTOCOL
17-DEC-2020
Objectives
Endpoints
Secondary
•
To evaluate the efficacy of MK-4482 compared 
to placebo as assessed by the percentage of 
participants who die through Day 29.
Hypothesis (H2): MK-4482 is superior to 
placebo as assessed by the percentage of 
participants who die through Day 29.
•
All-cause mortality 
•
To evaluate the efficacy of MK-4482 compared 
to placebo as assessed by the odds of a more 
favorable response on selected ordinal outcome 
scales at Day 3, EOT, Day 10, Day 15, and Day 
29.
•
Pulmonary score
•
Pulmonary+ score
•
To evaluate the efficacy of MK-4482 compared 
to placebo as assessed by the odds of a more 
favorable response in the clinical risk of 
mortality category from the National Early 
Warning Score at EOT.
•
National Early Warning Score
•
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 measure the pharmacokinetics of NHC (the 
parent nucleoside), and NHC-TP (the 
pharmacologically-active triphosphate form) in 
plasma and PBMC at various timepoints.
•
Plasma and PBMC 
pharmacokinetic parameters 
(eg, Ctrough, Cmax, tmax, t1/2, 
AUC0-12) (Part 1)
•
Plasma (Part 1 and Part 2) and 
PBMC (Part 1) 
pharmacokinetic concentrations 
(eg, C8hr)
 
 
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Objectives
Endpoints
•
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 as assessed by comparison of gene 
sequencing in virus isolated at baseline and post-
baseline samples with evaluable SARS-CoV-2 
RNA (Part 1). 
•
Viral RNA sequences
4
STUDY DESIGN
4.1
Overall Design
This 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 hospitalized participants ≥18 years of age with PCR-confirmed 
COVID-19 and symptom onset within 10 days prior to randomization.
Enrollment of participants with severe COVID-19 (Appendix 9) will be limited to 50% of the 
total planned sample size in both Parts 1 and 2.
Participants will receive 10 doses of assigned study intervention by oral administration Q12H
(±2 hours) 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)
 
 
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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 (Sections 4.3.3 and 9.7).
Part 2 (Phase 3 - Evaluation of Selected Dose)
In Part 2, ~1000 participants will be randomized in a 1:1 ratio (stratified per Section 6.3.2) to 
receive either the selected dose of MK-4482 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 
~100 participants in an optional PBMC Cohort (Part 1) at select sites with capability to 
isolate PBMCs. 
In the event of hospital discharge, study evaluations should be performed as described in 
Section 8. For participants who are discharged prior to end of treatment, a study intervention
diary will be used to record dose administration. 
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). In addition, pregnancy 
status for female participants of childbearing potential and female partners of male 
participants will be collected at this visit (Section 8.11.4).
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 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 
 
 
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appropriate to capture important clinically relevant efficacy endpoints (eg, time-to-sustained 
recovery, mortality). 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, time-to-sustained recovery, is intended to 
demonstrate the efficacy of MK-4482 relative to placebo using a clinically meaningful aspect 
of the disease relevant to hospitalized patients with COVID-19. 
Sustained recovery is defined as:
1. Participant is alive and not hospitalized through Day 29 (including those re-hospitalized 
and discharged again before Day 29). Includes those discharged to home, home with nursing 
care, a rehabilitation facility, a long-term care facility, or a non-hospital intermediate care 
facility.  
OR
2. Participant is alive and medically ready for discharge through Day 29 as determined by the 
investigator. Includes those hospitalized or re-hospitalized participants who no longer require 
ongoing medical care but remain hospitalized for infection-control reasons or due to delay in 
identifying living accommodation outside the hospital.
The following events do not meet the definition of sustained recovery:

Died

Discharged to hospice care

Remains in facility receiving ongoing medical care

Transferred to a general hospital unit or another hospital for ongoing medical care

Re-hospitalized and not discharged or not medically ready for discharge again before 
Day 29

Initially discharged to home, home with nursing care, a rehabilitation facility, a long-term 
care facility, or a non-hospital intermediate care facility, but subsequently transferred by 
Day 29 to hospice care or to a medical care facility due to worsening condition.

Discharged but lost to follow-up through Day 29
 
 
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4.2.1.1.2
Secondary Endpoint (Mortality)
All-cause mortality was selected as a relevant secondary endpoint to further evaluate efficacy 
of MK-4482 when administered to participants hospitalized with COVID-19. All-cause 
mortality is of particular interest in this study population, given the significant mortality 
caused by COVID-19 and the need for therapeutic agents to demonstrate rapid attenuation 
early in disease progression.
4.2.1.1.3
Secondary Endpoints (Ordinal Scales)
The Pulmonary and Pulmonary+ scales (Appendix 8) are ordinal categorical endpoints that 
assess intermediate measures of activity as indicators of disease progression and recovery. 
The Pulmonary ordinal scale focuses on the respiratory sequalae of COVID-19 and is defined 
based on oxygen requirements using 7 well-defined mutually exclusive categories. The 
Pulmonary+ ordinal scale is a 7-category assessment that captures the range of disease 
severity, including coagulation-related complications and respiratory dysfunction, 
experienced by hospitalized patients with COVID-19. The Pulmonary+ scale recognizes that 
non-pulmonary events are emerging as significant contributors to the overall morbidity of the 
disease. Of note, the Pulmonary+ scale was adapted to remove the use of the NIHSS in 
assessing stroke-related neurologic deficits due to challenges in implementing the NIHSS 
tool at all participating clinical sites. While the Pulmonary and Pulmonary+ scales are 
correlated, it is yet to be determined which of these 2 scales better represents clinical benefit 
and the impact of study intervention. Therefore, both scales will be used to assess benefit.
In addition, the National Early Warning Score will be used to assess a participant’s degree of 
illness as assessed by clinical risk prediction categories for poor clinical outcomes including 
mortality within 24 hours of a set of vital sign measurements; the National Early Warning 
Score will be used as supportive evidence of the efficacy of MK-4482 when administered in 
hospitalized participants with COVID-19 (Appendix 8).
To further evaluate efficacy of MK-4482, the WHO 11-point ordinal outcome scale will also 
be used 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 2.2-fold and 0.5-fold 
the NHC exposure at the 200 mg Q12H and 800 mg Q12H human dose of MK-4482 
respectively. These changes were fully reversible (Section 2.3). There have been no clinically 
significant abnormalities observed in hematological laboratory tests in the Phase 1 study
 
 
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(MK-4482-004). However, based on pre-clinical 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 72-fold the NHC exposure 
at 800 mg Q12H and not noted in dogs at 22-fold the NHC exposure at 800 mg Q12H. No 
clinically significant abnormalities in liver parameters were noted in the Phase 1 study at any 
dose. 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 
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/lipase will be considered an ECI and closely monitored.
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. 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. 
In Part 1, plasma and PBMC PK parameters such as Ctrough, Cmax, tmax, t1/2, AUC0-12 
will be estimated. In Part 2, plasma concentration values at each timepoint collected (eg, 
C8hr) will be summarized. 
4.2.1.4
Virology Endpoints
The study will evaluate SARS-CoV-2 RNA to assess the impact of MK-4482 on various 
aspects of SARS-CoV-2 viral dynamics.
Reducing SARS-CoV-2 viral load or eradicating the virus is 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 extinction. These endpoints are aimed at assessing the antiviral 
activity of MK-4482 as well as evaluating the rate of viral mutagenesis with MK-4482 
treatment.
 
 
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4.2.1.5
Inflammatory Biomarkers
Inflammatory biomarkers have been shown to be correlated with the severity of COVID-19 
and may provide insight on the progression of the disease [Zeng, F., et al 2020] [Velavan, T. 
P. 2020]. The study will explore the impact of MK-4482 on inflammatory response by 
evaluating select biomarkers (eg, CRP, IL-6, PCT, D-dimer, and ESR) at baseline and at 
EOT. 
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. Remdesivir is an antiviral agent administered intravenously for treatment of 
patients with severe COVID-19 under conditional marketing authorization by the European 
Commission and Emergency Use Authorization by the US FDA. However, with blinding 
consideration between IV and oral administration and access limitations for sourcing in a 
global clinical study during the pandemic, it was not feasible to include remdesivir as the
comparator for this study.
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, moderate, and severe COVID-19: Participants with mild, 
moderate, and severe COVID-19 (Appendix 9) may all require hospitalization and 
may benefit from administration of MK-4482. Participants in this study must require 
medical care in the hospital for ongoing clinical manifestations of COVID-19 (not 
just for public health or quarantine purposes). Participants with critical COVID-19 
will be excluded as antiviral therapy may have less impact on patients who have 
progressed to advanced critical illness due to the robust host inflammatory response
that may confound antiviral treatment at this later stage in the disease. Furthermore, 
patients with critical COVID-19 demonstrated no difference in mortality or median 
time to recovery comparing placebo to remdesivir [Beigel, J. H., et al 2020].

Participants with signs/symptoms attributable to COVID-19 for ≤10 days:
Eligible participants must have COVID-19 signs/symptom onset no more than 
10 days prior to randomization. SARS-CoV-2 viral loads 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 ≤10 days prior to randomization with administration of 
 
 
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the first dose occurring 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 >10 days after sign/symptoms onset.
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 and OP 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, co-infections, 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 co-infected with other respiratory pathogens
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 
individuals [Ovsyannikova, I. G., et al 2020]. Antibody-related testing of participant samples 
 
 
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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 viral loads 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 infectivity assays. One such 
assay is the plaque assay which quantifies the plaques formed in cell culture upon infection 
with serial dilutions of a virus specimen [Mendoza, E. J., et al 2020]. These infectivity assays 
may be used to evaluate the impact of MK-4482 on the quantity and/or presence of 
replication-competent virus.
Co-infection 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 co-infection with SARS-CoV-2 [Lai, C. C., et al 
2020]. Based on the potential for co-infection 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 co-infections.
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 (2.2-fold the predicted NHC 
exposure of 13.27 μM*hr at a dose of 200 mg BID) 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 tolerated by healthy participants in a Phase 1 clinical study; 
on review of preliminary blinded safety data, 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 have been no clinically significant abnormalities observed in 
the hematological laboratory tests. Overall, preclinical and Phase 1 clinical observations to 
date support a ~5-day dosing duration for MK-4482.
 
 
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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 Phase 3 dose will be selected based on evaluation of Phase 2 data and will not exceed a 
dose of 800 mg Q12H. Interim analyses will be conducted as outlined in Section 9.7 to 
support dose selection. 
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 hospitalized participants ≥18 years of age with COVID-19 will be enrolled in 
this study.
 
 
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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 PCR-confirmed SARS-CoV-2 infection with sample collection 
≤10 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.
2. Had initial onset of signs/symptoms attributable to COVID-19 for ≤10 days prior to the 
day of randomization and ≥1 sign/symptom attributable to COVID-19 present at 
randomization.
3. Requires medical care in the hospital for ongoing clinical manifestations of COVID-19 
(not just for public health or quarantine purposes).
4. Has mild, moderate, or severe COVID-19 (Appendix 9).
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.
Male Participants
7. Male participants are eligible to participate if they agree to the following during the 
intervention period and for at least 90 days after the last dose of study intervention:
•
Refrain from donating sperm
PLUS either:
•
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
 
 
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•
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 28 days from the start 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 (serum test is 
required) within 24 hours before the first dose of study intervention.
•
Additional requirements for pregnancy testing during and after study intervention are 
located in Section 8.3.5.
•
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.
•
Contraceptive use by women should be consistent with local regulations regarding the 
methods of contraception for those participating in clinical studies.
•
Given the elevated risk of venous thrombotic events in patients hospitalized with 
COVID-19 [Benson, L. S., et al 2020] [Spratt, D. I. 2020], estrogen-containing
contraceptives must not be started to fulfill the contraceptive requirement of this 
study at any time during participant’s hospitalization. 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 
 
 
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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 for the study.
5.2
Exclusion Criteria
The participant must be excluded from the study if the participant:
Medical Conditions
1. Has critical COVID-19 (Appendix 9) with any of the following:

Respiratory failure defined based on resource utilization requiring at least one of 
the following:
o
Endotracheal intubation and mechanical ventilation, 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), noninvasive positive pressure ventilation, 
ECMO, or clinical diagnosis of respiratory failure (i.e., clinical need 
for one of the preceding therapies, but preceding therapies not able to 
be administered in setting of resource limitation)

Shock (defined by systolic blood pressure <90 mm Hg, or diastolic blood pressure 
<60 mm Hg or requiring vasopressors)

Multi-organ dysfunction/failure
2. Is on dialysis or has reduced eGFR <30 mL/min/1.73m2 by the MDRD equation
(Appendix 10).
3. Has any of the following conditions:

HIV with a recent viral load >50 copies/mL or CD4 <200 cell/mm³

Chemotherapy required within 6 weeks before randomization

A neutrophilic granulocyte absolute count <500/mm3

Autologous or allogeneic hematopoietic stem cell transplant recipient
 
 
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4. Has a history of HBV or HCV infection with any of the following: 

Cirrhosis

End-stage liver disease

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 a history of acute pancreatitis within 3 months prior to randomization or a history of 
chronic pancreatitis.
7. Has a baseline heart rate of < 50 beats per minute at rest.
8. Has hypersensitivity or other contraindication to any of the components of the study 
interventions as determined by the investigator.
9. 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 who are expected to require mechanical ventilation within 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
10.
Is taking or is anticipated to require any prohibited therapies as outlined in 
Section 6.5.
Prior/Concurrent Clinical Study Experience
11.
Is unwilling to abstain from participating in another interventional clinical trial
through Day 29 with an investigational compound or device, including those for 
COVID-19 therapeutics.
Diagnostic Assessments
Not applicable 
 
 
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Other Exclusions
12.
Is anticipated to require transfer to a non-study hospital within 72 hours.
13. 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.
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
Interven-
tion Name
Interven-
tion Type
Dose 
Formulationa
Unit Dose 
Strength(s)
Dosage 
Level(s)b
Route of 
Administra-
tion
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: Dose 
to be selected
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.
a Capsules will be administered by mouth. For participants unable to swallow study medication capsules during the treatment period, dosing of capsule contents via alternative 
routes (eg, nasogastric tube, orogastric tube, etc.) will be allowed.
b MK-4482 dose for Part 2 will be determined based on assessment of results of Part 1 and the totality of data available across the MK-4482 clinical program prior to initiating 
Part 2.
 
 
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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.
For participants unable to swallow study medication capsules during the treatment period, 
dosing of capsule contents via alternative routes (eg, nasogastric tube, orogastric tube, etc.) 
will be allowed. Preparation details will be provided in the pharmacy manual.
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.
 
 
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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.
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 (at selected dose) or 
placebo.
6.3.2
Stratification
Intervention randomization will be stratified according to the following factors:
1.
Time from symptom onset prior to the day of randomization (≤5 days, >5 days)
2.
Age (≤60 years, >60 years)
3.
Remdesivir use for treatment of the index diagnosis of COVID-19 prior to or at the
time of randomization (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 early treatment 
(≤5 days) rather than late treatment (>5 days). Older age is also associated with more severe 
outcomes, and the WHO notes that people older than 60 years are at higher risk for severe 
illness due to COVID-19. Finally, remdesivir has been demonstrated to shorten the time to 
recovery in hospitalized patients with COVID-19 and may be used concurrently in this study. 
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, enrollment of participants with severe COVID-19 (Appendix 9) will be limited to 
50% of the total planned sample size in both Parts 1 and 2.
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.
 
 
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Blinding of capsule contents for use via alternate routes (nasogastric tube, orogastric tube, 
etc.) will be performed by the unblinded site pharmacist or designee. Preparation details will 
be provided in the pharmacy manual.
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.  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 – Interim 
Analyses.
6.4
Study Intervention Compliance
When participants are dosed at the site, they will receive study intervention directly from the 
investigator or designee, under medical supervision. If local infection control restrictions do 
not allow for medical supervision, the study intervention must be administered by 
appropriately qualified institution (eg, hospital, clinic) staff. The date and time of each dose 
administered in the clinic will be recorded in the source documents and recorded in the CRF. 
The dose of study intervention and study participant ID will be confirmed at the time of 
dosing by a member of the study site staff other than the person administering the study 
intervention. If local infection control restrictions do not allow for a confirmation at the time 
of dosing by a separate study site staff member, the study intervention administration source 
documentation must be contemporaneously reviewed by a member of the study site staff 
other than the person administering study intervention.
For participants who are discharged prior to receiving all 10 doses of study intervention, a 
Study Medication Diary will be provided for documentation of doses and assessment of 
compliance (Section 8.1.14).
A record of the number of capsules dispensed to and taken by each participant must be 
maintained and reconciled with study intervention and compliance records. Intervention start 
and stop dates, including dates for intervention delays and/or dose reductions will also be 
recorded in the CRF. Deviation(s) from the prescribed dosage regimen should be recorded in 
the CRF.
6.5
Concomitant Therapy
Medications or vaccinations specifically prohibited in the exclusion criteria are not allowed
during time periods specified by this protocol for those medications or vaccinations. If there 
is a clinical indication for any medications or vaccinations specifically prohibited, 
discontinuation from study intervention may be required. The investigator should discuss any 
questions regarding this with the Sponsor Clinical Director. The final decision on any
 
 
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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. 
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 
Therapeutics

Sponsor-designated standard of care for treatment for 
COVID-19 is permitted (eg, remdesivir, corticosteroids, 
etc.) 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
Supportive therapies (including but not limited to 
anti-pyretic and anti-inflammatory agents) to manage 
COVID-19 signs/symptoms are allowed. 
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.
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. 
6.5.1
Rescue Medications and Supportive Care
Sponsor-designated standard of care for COVID-19 is permitted.
 
 
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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.
•
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. 
 
 
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•
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 confirmed (ie, verified by repeat testing) platelet count of 
<50,000/µL.
•
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).
For country-specific requirements see Appendix 7. 
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.
Survival status at Day 29 and LFU is required for all randomized participants and should still 
be reported for participants who withdraw from the study where permitted by local 
guidelines.
Specific details regarding procedures to be performed at the time of withdrawal from the 
study, are outlined in Section 8.11.3. The procedures to be performed should a participant 
repeatedly fail to return for scheduled visits and/or if the study site is unable to contact the 
participant are outlined in Section 7.3.
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.
 
 
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•
The investigator or designee must make every effort to regain contact with the 
participant at each missed visit (eg, telephone calls and/or a certified letter to the 
participant’s last known mailing address or locally equivalent methods). These 
contact attempts should be documented in the participant’s medical record.
•
Note: A participant is not considered lost to follow-up until the last scheduled visit for 
the individual participant. The missing data for the participant will be managed via 
the prespecified statistical data handling and analysis guidelines.
8
STUDY ASSESSMENTS AND PROCEDURES
•
Study procedures and their timing are summarized in the SoA.
•
Adherence to the study design requirements, including those specified in the SoA, is 
essential and required for study conduct.
•
The investigator is responsible for ensuring that procedures are conducted by 
appropriately qualified (by education, training, and experience) staff. Delegation of 
study site personnel responsibilities will be documented in the Investigator Trial File 
Binder (or equivalent).
•
All study-related medical decisions must be made by an investigator who is a 
qualified physician.
•
All screening evaluations must be completed and reviewed to confirm that potential 
participants meet all eligibility criteria. The investigator will maintain a screening log 
to record details of all participants screened and to confirm eligibility or record 
reasons for screening failure, as applicable.
•
Procedures conducted as part of the participant’s routine clinical management (eg, 
blood count) and obtained before signing of ICF may be utilized for screening or 
baseline purposes provided the procedure met the protocol-specified criteria and were 
performed within the time frame defined in the SoA.
•
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 212 mL for participants in the PBMC Cohort or 
approximately 132 mL for all other participants (Appendix 2, Table 11).
Repeat or unscheduled samples may be taken for safety reasons or due to technical issues 
with the samples.
 
 
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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. If there are changes to 
the participant’s status during the study (eg, health or age of majority requirements), the 
investigator or medically qualified designee must ensure the appropriate documented 
informed consent is in place.
8.1.1.1
General Informed Consent
Informed consent given by the participant or their legally acceptable representative must be 
documented on a consent form. The form must include the trial protocol number, trial 
protocol title, dated signature, and agreement of the participant (or his/her legally acceptable 
representative) and of the person conducting the consent discussion.
A copy of the signed and dated informed consent form should be given to the participant (or 
their legally acceptable representative) before participation in the study.
The initial ICF, any subsequent revised ICF, and any written information provided to the 
participant must receive the IRB/IEC’s approval/favorable opinion in advance of use. The 
participant or his/her legally acceptable representative should be informed in a timely manner 
if new information becomes available that may be relevant to the participant's willingness to 
continue participation in the study. The communication of this information will be provided 
and documented via a revised consent form or addendum to the original consent form that 
captures the participant’s or the participant’s legally acceptable representative’s dated 
signature.
Specifics about the study and the study population are to be included in the study informed 
consent form. 
Informed consent will adhere to IRB/IEC requirements, applicable laws and regulations, and 
Sponsor requirements.
8.1.1.2
Consent 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.
 
 
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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, mid-
turbinate swab, saliva, etc.), test method (eg, RT-PCR) and result (positive result is required). 
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
(segmented neutrophils and bands). 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 serum pregnancy test is required 
within 24 hours of the first dose of study drug per inclusion criteria.
All other inclusion/exclusion criteria determination (eg, HIV status, pancreatitis, etc.) can be 
based on participant-reported medical history, available medical records, and the most 
recently available laboratory results for the participant (eg, HIV RNA viral load or CD4 
count).
8.1.3
Participant Identification Card
All participants will be given a participant identification card identifying them as participants 
in a research study. The card will contain study site contact information (including direct 
telephone numbers) to be used in the event of an emergency. The investigator or qualified 
designee will provide the participant with a participant identification card immediately after 
the participant provides documented informed consent. At the time of intervention
randomization, site personnel will add the treatment/randomization number to the participant 
identification card.
The participant identification card also contains contact information for the emergency 
unblinding call center so that a healthcare provider can obtain information about study 
intervention in emergency situations where the investigator is not available.
8.1.4
Medical History
A medical history will be obtained by the investigator or qualified designee. 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 
 
 
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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, obesity, active cancer (excluding minor cancers not 
associated with immunosuppression or significant morbidity/mortality), congestive cardiac 
failure, coronary artery disease, cardiomyopathies, sickle cell disease, and diabetes mellitus.
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.
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.
 
 
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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. The first dose of study intervention is preferably 
administered on Day 1 (randomization), but must be 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.
While the participant is hospitalized, study intervention(s) will be administered by the 
investigator and/or study staff according to the specifications within the pharmacy manual.
If a participant is discharged prior to study intervention completion, study intervention and 
the Study Medication Diary will be dispensed to the participant according to the pharmacy 
manual. Study intervention will then be self-administered by the participant Q12H at 
approximately the same times each day. 
8.1.8.1
Timing of Dose Administration
Study staff will administer the appropriate number of capsules of study intervention per the 
pharmacy manual Q12H (±2 hours) each day for 10 doses. Study intervention can be 
administered without regard to food. Refer to Section 8.6 for details 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, the first dose of study intervention is preferably administered on Day 
1 but may be administered 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.

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 timing 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 participants who are discharged prior to EOT, if the participant takes their 
 
 
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EOT dose without observation by study staff, and prior to the pre-dose PK blood draw, then 
the timing of the dose will be reported from the Study Medication Diary to study staff by the 
participant or legally acceptable representative and recorded in the appropriate source 
documentation.
For all doses, the timing of dose administration will be recorded by study staff. If the 
participant has been discharged, doses will 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 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 resumed. The participant should 
not double the next dose to compensate for what has been missed
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 4-6 
hours prior to dialysis where possible. For country-specific requirements see Appendix 7.
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 
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.
8.1.10
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.
 
 
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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.
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
Domiciling
PBMC cohort participants who have been discharged prior to the EOT visit will undergo 
intensive blood sampling from pre-dose to 8 hours post-dose on the EOT visit. The 
investigator may make arrangements (including local accommodations outside the context of 
a clinic visit if warranted) such that all sampling at specified timepoints can be performed as 
scheduled. 
8.1.12
Calibration of Equipment
The investigator or qualified designee has the responsibility to ensure that any device or 
instrument used for a clinical evaluation/test during a clinical study that provides information 
about inclusion/exclusion criteria and/or safety or efficacy parameters shall be suitably 
calibrated and/or maintained to ensure that the data obtained are reliable and/or reproducible. 
Documentation of equipment calibration must be retained as source documentation at the 
study site.
8.1.13
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 after discharge. Contact information for secondary contacts or health care 
 
 
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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).
8.1.14
Study Medication Diary
For participants who are discharged prior to receiving all 10 doses of study intervention, a 
paper Study Medication Diary and instructions on how to take study intervention will be 
provided for documentation of doses and assessment of compliance. Participants should 
complete the Study Medication Diary for each dose taken. In the event that the participant is 
(in the judgment 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. The participant’s Study Medication Diary doses will be recorded in the eCRF for all 
doses after discharge. The Study Medication Diary should be reviewed in conjunction with 
capsule counts by study staff with the participant 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.
8.2
Efficacy Assessments
8.2.1
Nasopharyngeal and Oropharyngeal Swabs 
NP and OP 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 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.
NP and OP swab collection may be adapted to remove 1 method or timepoints throughout the 
life of the study; this will be communicated via Protocol Clarification Letters.
 
 
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8.2.2
Assessment of COVID-19 Signs, Symptoms, and Functional Status
The investigator or medically qualified designee (consistent with local requirements) will 
assess COVID-19 signs and symptoms daily while the participant is hospitalized. After 
participant discharge, signs and symptoms will only be assessed on study visit days. 
Functional status will only be assessed at Day 1, Day 3, EOT, Day 10, Day 15, and Day 29.
The participant’s ability to independently perform daily activities with minimal or no 
symptoms will be assessed and evaluated at the discretion of the investigator/designee.
8.2.3
Assessment of Level of Consciousness
Level of consciousness will be assessed using the Alert, Voice, Pain, Unresponsive scale
[Royal College of Physicians 2012]. This assessment is conducted in sequence and only 1 
outcome should be recorded as follows:

Alert: participant is fully awake

Voice: participant responds (in any manner) when spoken to

Pain: participant responds to painful stimulus

Unresponsive: participant does not respond to voice or pain 
8.2.4
Respiratory/Oxygenation Status
SpO2 will be measured once daily via pulse oximetry (SoA, Section 1.3) after the participant
has been at rest for at least 5 minutes. If applicable, FiO2 and arterial blood gas PaO2 should 
be reported. The oxygenation saturation level should be reported at a consistent time of day 
at each visit as noted in the SoA. Ensure the value is not impacted by external forces (eg,
during rotating the participant’s position).
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. 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).
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. 
8.2.5
Hospitalization Status
Hospitalization status will be assessed daily while hospitalized as outlined in the SoA
(Section 1.3). The date and time that the participant is deemed medically ready for discharge 
will be recorded in addition to the actual date and time of discharge as applicable. 
 
 
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In the event of hospital discharge, the residence to which the participant was discharged and 
whether it was the residence occupied at the time of onset of COVID-19 symptoms will be 
ascertained.
In the event of re-hospitalization after initial discharge, 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.
Information related to the re-hospitalization will be collected, including if the admission is 
related to COVID-19.
The Sponsor must be notified within 24 hours of site’s awareness of a participant’s 
hospitalization.
8.2.6
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.
8.3
Safety Assessments
Details regarding specific safety procedures/assessments to be performed in this study are 
provided. The total amount of blood to be drawn over the course of the study (from 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 examinations 
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.
 
 
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8.3.2
Vital Signs
Body temperature, heart rate, respiratory rate, and blood pressure will be assessed.
Blood pressure and heart rate measurements should be preceded by at least 5 minutes of rest 
for the participant in a quiet setting without distractions.
8.3.3
Electrocardiograms
A local 12-lead ECG will be obtained and reviewed by an investigator or medically qualified 
designee (consistent with local requirements) as outlined in the SoA (Section 1.3).
Calculation of heart rate and measurement of PR, QRS, QT, and QTc intervals may be 
manually calculated by a qualified physician or via an ECG machine that automatically 
calculates the values. Clinically significant findings must be documented in the source 
documents and captured in the appropriate eCRF.
If an ECG is performed for any medical reason while the participant is on study intervention 
or during the follow-up period, any clinically significant changes compared with the baseline 
ECG must be captured as AEs.
8.3.4
Clinical Safety Laboratory Assessments
Refer to Appendix 2 for the list of clinical laboratory tests to be performed and to the SoA for 
the timing and frequency.
•
The investigator or medically qualified designee (consistent with local requirements) 
must review the laboratory report, document this review, and record any clinically 
relevant changes occurring during the study in the AE section of the CRF. The 
laboratory reports must be filed with the source documents. Clinically significant 
abnormal laboratory findings are those which are not associated with the underlying 
disease, unless judged by the investigator to be more severe than expected for the 
participant's condition.
•
All protocol-required laboratory assessments, as defined in Appendix 2, must be 
conducted in accordance with the laboratory manual and the SoA.
•
If laboratory values from nonprotocol-specified laboratory assessments performed at 
the institution’s local laboratory require a change in study participant management or 
are considered clinically significant by the investigator (eg, SAE or AE), then the 
results must be recorded in the appropriate CRF (eg, SLAB).
•
For any laboratory tests with values considered clinically significantly abnormal 
during participation in the study or within 14 days after the last dose of study 
intervention, every attempt should be made to perform repeat assessments until the 
values return to normal or baseline or if a new baseline is established as determined 
by the investigator.
 
 
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8.3.5
Pregnancy Testing
•
Pregnancy testing:
-
Pregnancy testing requirements for study inclusion are described in Section 5.1.
-
Pregnancy testing (serum) should be conducted at screening and on Day 29, 
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).
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 
treatment, all AEs, SAEs, and other reportable safety events must be reported by the 
investigator.
 
 
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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.
Additionally, all pregnancies with a conception date occurring within 28 days after the first 
dose of study intervention for female participants or within 90 days after the last dose of 
study intervention for female partners of male participants must be reported by the 
investigator.
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.
 
 
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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 the initial 
screening is not a 
reportable event.
Report all
Previously 
reported – Follow 
to completion/
termination; 
report outcome
Within 24 hours of 
learning of event
ECI (require 
regulatory 
reporting)
Report if:
- due to intervention
- causes exclusion
Report
- Potential DILI
- Require regulatory 
reporting
Not required
Within 24 hours of 
learning of event
ECI (do not 
require regulatory 
reporting)
Report if:
- due to intervention
- causes exclusion
Report
- non-DILI ECIs and 
those not requiring 
regulatory reporting
Not required
Within 5 calendar 
days of learning of 
event
Cancer
Report if:
- due to intervention
- causes exclusion
Report all
Not required
Within 5 calendar 
days of learning of 
event
(unless serious)
Overdose
Report if:
- receiving placebo run-
in or other run-in 
medication 
Report all
Not required
Within 5 calendar 
days of learning of 
event
DILI=drug-induced liver injury; ECI=event of clinical interest; NSAE=nonserious adverse event; SAE=serious adverse 
event
 
 
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8.4.2
Method of Detecting AEs, SAEs, and Other Reportable Safety Events
Care will be taken not to introduce bias when detecting AEs and/or SAEs and other 
reportable safety events. Open-ended and nonleading verbal questioning of the participant is 
the preferred method to inquire about AE occurrence.
8.4.3
Follow-up of AE, SAE, and Other Reportable Safety Event Information
After the initial AE/SAE report, the investigator is required to proactively follow each 
participant at subsequent visits/contacts. All AEs, SAEs, and other reportable safety events,
including pregnancy and exposure during breastfeeding, ECIs, cancer, and overdose will be 
followed until resolution, stabilization, until the event is otherwise explained, or the 
participant is lost to follow-up (as defined in Section 7.3). In addition, the investigator will 
make every attempt to follow all nonserious AEs that occur in randomized participants for 
outcome. Further information on follow-up procedures is given in Appendix 3.
8.4.4
Regulatory Reporting Requirements for SAE
Prompt notification (within 24 hours) by the investigator to the Sponsor of SAE is essential 
so that legal obligations and ethical responsibilities towards the safety of participants and the 
safety of a study intervention under clinical investigation are met.
The Sponsor has a legal responsibility to notify both the local regulatory authority and other 
regulatory agencies about the safety of a study intervention under clinical investigation. The 
Sponsor will comply with country-specific regulatory requirements and global laws and 
regulations relating to safety reporting to regulatory authorities, IRB/IECs, and investigators.
Investigator safety reports must be prepared for SUSARs according to local regulatory 
requirements and Sponsor policy and forwarded to investigators as necessary.
An investigator who receives an investigator safety report describing an SAE or other 
specific safety information (eg, summary or listing of SAE) from the Sponsor will file it 
along with the IB and will notify the IRB/IEC, if appropriate according to local requirements.
8.4.5
Pregnancy and Exposure During Breastfeeding
Although pregnancy and infant exposure during breastfeeding are not considered AEs, any 
pregnancy or infant exposure during breastfeeding in a participant (spontaneously reported to 
the investigator or their designee), including the pregnancy of a male participant’s female 
partner, that occurs during the study are reportable to the Sponsor as described in Section 
8.4.1. 
All reported pregnancies must be followed to the completion/termination of the pregnancy.
Any pregnancy complication will be reported as an AE or SAE. 
 
 
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The medical reason (example: maternal health or fetal disease) for an elective termination of 
a pregnancy will be reported as an AE or SAE. Prenatal testing showing fetus will be born 
with severe abnormalities/congenital anomalies that lead to an elective termination of a 
pregnancy will be reported as an SAE for the fetus. 
Pregnancy outcomes of ectopic pregnancy, spontaneous abortion, missed abortion, benign 
hydatidiform mole, blighted ovum, fetal death, intrauterine death, miscarriage, and stillbirth 
must be reported as serious events (Important Medical Events). If the pregnancy continues to 
term, the outcome (health of infant) must also be reported.
8.4.6
Disease-related Events and/or Disease-related Outcomes Not Qualifying as 
AEs or SAEs
Certain efficacy endpoints, including hospitalizations and mortality, must be collected 
throughout the study (ie, during both treatment and follow-up). 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 confirmed (ie, verified by repeat testing) platelet value <50,000 /µL, as determined 
by protocol-specified and/or unscheduled laboratory testing. 
3. Any confirmed (ie, verified by repeat testing) amylase or lipase value >3X the upper limit 
of normal determined by protocol-specified and/or unscheduled laboratory testing.
 
 
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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.
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/home health care 
personnel. If participants discontinue study intervention prior to the morning dose of the EOT 
visit (dose 9 or 10 depending on study intervention start), samples for PK will not be 
collected.
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

1 sample pre-dosea

1 sample post-dose at each of the following timepoints:
o
1 hour (±30 min)
o
3 hours (±30 min)
o
5 hours (±1 hour)
o
8 hours (±1 hour)
Part 2

1 sample pre-dosea

1 sample post-dose, each for the following timepoints:
o
1 hour (±30 min)
o
5 hours (±1 hour)
a Pre-dose sample should be collected within 2 hours prior to dosing.
 
 
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8.6.2
Blood Collection for Measurement of NHC-TP in PBMCs
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: 

2 tubes pre-dose (within 2 hours prior to dosing)

2 tubes post-dose at each of the following timepoints:
o
1 hour (±30 min)
o
3 hours (±30 min)
o
5 hours (± 1 hour)
o
8 hours (±1 hour)
The timing of blood collection will be aligned with the timing of dose administration as 
outlined in Section 8.1.8.1. If participants discontinue study intervention prior to the morning 
dose of the EOT visit (dose 9 or 10 depending on study intervention start), samples for 
PBMCs will not be collected.
Sample collection, storage, and shipment instructions for PBMC samples will be provided in 
a separate manual.
In cases where PBMC cohort participants are discharged prior to the EOT visit but because 
of local infection control regulations are not able to return to the study site or alternate 
domiciling arrangements are not possible, or where home health services would not be able 
to obtain PBMC samples according to the laboratory manual specifications, PBMC samples 
are not required.
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.
 
 
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8.8
Biomarkers and Exploratory Research Samples
8.8.1
Biomarkers
Collection of samples for biomarker research is also part of this study, as outlined in 
Appendix 2. Samples for biomarker research are required and will be collected from all 
participants as specified in the SoA.
Sample collection, storage, and shipment instructions for the exploratory biomarker 
specimens will be in the laboratory manual.
8.8.2
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, co-
infections, 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
FBR samples will not be collected in this study.
8.10
Medical Resource Utilization and Health Economics
Sites will report hospitalization status and oxygenation and oxygen therapy data to support 
health economics assessments as per the SoA (Section 1.3) and Section 8.2.
8.11
Visit Requirements
Visit requirements are outlined in Section 1.3. Specific procedure-related details are provided 
in Section 8.
8.11.1
Infection Prevention Procedures
Each site will follow their institutional procedures and/or local requirements to protect study 
staff and other patients from infectious exposure to SARS-CoV-2. These procedures may 
include but are not limited to:

Provision of PPE to site staff, participants, and LARs

Performing at-home and/or virtual visits (as allowed per the SoA)

Designating special entry points for study participants for clinic visits
 
 
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8.11.2
Types of Study Visits
8.11.2.1
Screening/Rescreening Visits
Screening
Screening will occur ≤24 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 one 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 24 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
•
12-lead ECG
•
Urinalysis (repeat if central laboratory sample from prior screening visit was not 
within 48 hours of first dose of study drug)
•
Local laboratory assessments for inclusion/exclusion (results within 72 hours prior to 
randomization may be used for eligibility)
•
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.
8.11.2.2
Hospitalized Visits
Screening will occur during hospitalization and ≤24 hours prior to study intervention 
randomization. Eligible participants must require medical care in the hospital for ongoing 
clinical manifestations of COVID-19 (not just for public health or quarantine purposes).
Participants must be hospitalized for screening and Day 1. All other visits may occur outside 
of the hospital after discharge.
 
 
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For participants who remain hospitalized through the study duration, study visits will be 
conducted as part of the hospital stay.
8.11.2.3
Clinic or At-Home Visits
For participants discharged from the hospital before completing the study, subsequent study 
visits may be performed at an alternative location from the hospital, such as the clinic/study 
site. In lieu of a participant traveling to the study site, an at-home visit by the site personnel 
or a healthcare provider (eg, home health care company, visiting nurse, etc.) may be 
appropriate to perform study assessments and procedures per the SoA (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) 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. 
8.11.2.4
Virtual Visits
For participants discharged prior to EOT, the investigator or designee may conduct the Day 2 
and Day 4 visits with the participant virtually (eg, 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
 
 
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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.
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.
8.11.4
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). 
In addition, pregnancy status (eg, estimated date of conception and delivery date) for female 
participants of childbearing potential and female partners of male participants will be 
collected at this visit. Collection of pregnancy data for female partners of male participants is 
not required if the male participant is confirmed to be azoospermic (vasectomized or 
secondary to medical cause) as documented in medical history. Current and prior pregnancy 
data for any pregnancies with a conception date occurring within 28 days after the first dose 
of study intervention for female participants or within 90 days after the last dose of study 
intervention for female partners of male participants will be reported in relevant eCRFs. All 
reported pregnancies must be followed to the completion/termination of the pregnancy as 
described in Section 8.4.5.
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 plasma research samples) are beyond the scope of this document or will be documented 
in separate analysis plans.
 
 
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9.1
Statistical Analysis Plan Summary
Key elements of the statistical analysis plan are summarized below; the comprehensive plan 
is provided in Section 9.2 to Section 9.12.
Study Design 
Overview
A Phase 2/3, Randomized, Placebo-Controlled, Double-Blind 
Clinical Study to Evaluate the Efficacy, Safety, and 
Pharmacokinetics of MK-4482 in 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 6.3.2) to receive 1 of the 
following 4 blinded 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 1000 participants will be 
randomized in a 1:1 ratio (stratified per Section 6.3.2) to receive 
either the selected dose of MK-4482 or placebo Q12H for 5 
days.
Analysis Populations
Efficacy: MITT (Parts 1 and 2 separately)
Safety: APaT (Parts 1 and 2 combined) 
Primary 
Endpoint(s)
Efficacy: Time-to-sustained recovery from randomization 
through Day 29
Safety: Number of participants with AEs, and discontinuing 
study intervention due to AEs
Key Secondary 
Endpoints

All-cause mortality through Day 29

Odds of a more favorable response on Pulmonary score at 
Day 3, EOT, Day 10, Day 15 and Day 29

Odds of a more favorable response on Pulmonary+ score at 
Day 3, EOT, Day 10, Day 15 and Day 29

Odds of a more favorable response in the clinical risk of 
mortality category from the National Early Warning Score
at EOT

Odds of a more favorable response on the WHO 11-point 
ordinal scale on Day 3, EOT, Day 10, Day 15 and Day 29
 
 
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Statistical Methods 
for Key Efficacy 
Analyses
The primary hypothesis will be evaluated by comparing MK-4482
(with selected dose) to placebo with respect to time-to-sustained 
recovery by Day 29 using a stratified log-rank test. The sustained 
recovery rate ratio will be estimated using the stratified Cox 
Proportional Hazards regression model.
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 the adverse events; these 
analyses will be performed using the unstratified Miettinen and 
Nurminen method [Miettinen, O. 1985].
Interim Analyses
There will be 3 interim analyses during the study.
IA1 - Part 1: Dose Evaluation 
This IA will be used to review data to inform dose selection 
models and analyses.
IA2 – Part 1: Dose Selection
This IA will be used to evaluate the dose/exposure-response to
select the dose for Phase 3.
IA3 – 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
Multiplicity adjustments for interim analyses regarding type I 
error control are described in Section 9.7. Multiplicity adjustment 
strategy for sequential hypothesis testing is specified in Section 
9.8. 
Sample Size and 
Power 
The total sample size for primary efficacy assessment (Part 2)
will be ~1000 participants (~500 for the selected dose of 
MK-4482 and ~500 for the placebo group). The study has 
overall power of 90% to demonstrate that participants treated 
with MK-4482 have a higher rate of sustained recovery than 
participants treated with placebo at an overall one-sided, 2.5% 
alpha-level, if the underlying constant sustained recovery rate 
ratio between treatment groups is 1.3.
Additional details and assumptions for sample size and power 
calculation are in Section 9.9. 
 
 
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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 two 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 (i.e., 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 (i.e., 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. 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 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.
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.
 
 
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9.4.1
Efficacy/Pharmacokinetics Endpoints
9.4.1.1
Efficacy Endpoints
Primary:
•
Time-to-sustained recovery from randomization through Day 29
Sustained recovery is defined as:
1. Participant is alive and not hospitalized through Day 29 (including those re-
hospitalized and discharged again before Day 29). Includes those discharged to 
home, home with nursing care, a rehabilitation facility, a long-term care facility, 
or a non-hospital intermediate care facility.  
OR
2. Participant is alive and medically ready for discharge through Day 29 as 
determined by the investigator. Includes those hospitalized or re-hospitalized 
participants who no longer require ongoing medical care but remain hospitalized 
for infection-control reasons or due to delay in identifying living accommodation 
outside the hospital.
The time to sustained recovery is the time from randomization to the day of discharge 
or the day that the participant is medically ready for discharge for participants who 
are not re-hospitalized.  For participants who are re-hospitalized but discharged again 
before Day 29, the time to sustained recovery is the time from randomization to the 
day of the latest discharge.
The following events do not meet the definition of sustained recovery:

Died

Discharged to hospice care

Remains in facility receiving ongoing medical care

Transferred to a general hospital unit or another hospital for ongoing medical care

Re-hospitalized and not discharged or not medically ready for discharge again 
before Day 29.

Initially discharged to home, home with nursing care, a rehabilitation facility, a 
long-term care facility, or a non-hospital intermediate care facility, but 
subsequently transferred by Day 29 to hospice care or to a medical care facility 
due to worsening condition.

Discharged but lost to follow-up through Day 29.
Section 9.6.1 describes the censoring dates for these participants.
 
 
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Secondary: 
•
All-cause mortality through Day 29
•
Odds of a more favorable response on Pulmonary score at Day 3, EOT, Day 10, Day
15, and Day 29
•
Odds of a more favorable response on Pulmonary+ score at Day 3, EOT, Day 10, Day
15, and Day 29
•
Odds of a more favorable response in the clinical risk of mortality category from the
National Early Warning Score at EOT
•
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: All ordinal scores will be determined programmatically by the Sponsor based on 
relevant data collected in eCRFs. Relevant data to support determination of each ordinal 
score will be collected in eCRFs as follows:

Pulmonary and Pulmonary+ scores: supplemental oxygen use and methods, oxygen 
saturation, dialysis and vasopressor use, vital status, adverse events, and investigator 
assessment of the participant’s ability to independently perform daily activities with 
minimal or no symptoms

NEWS: vital signs (i.e., respiratory rate, pulse rate, blood pressure, temperature, 
oxygen saturation) and investigator assessment of the participant’s level of 
consciousness using the Alert, Voice, Pain, Unresponsive scale

WHO 11-point scale: 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
Exploratory:

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

Viral RNA mutation rate as assessed by comparison of baseline and post-baseline 
virus sequencing (Part 1)

Mean change from baseline in inflammatory biomarkers (eg, IL-6, hs-CRP, ESR, 
D-dimer, PCT)
 
 
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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, Cmax, tmax, t1/2, AUC0-12) (Part 1)

Pharmacokinetic concentrations (eg, C8hr) (Part 2)
9.4.2
Safety Endpoints
A description of safety measures is contained in Sections 8.3 and 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 (i.e., 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, July 2017, version 2.1. A listing of the participants who meet the criteria 
will also be provided.
9.5
Analysis Populations
9.5.1
Efficacy Analysis Populations
The MITT 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.
 
 
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A supportive analysis using the Per-Protocol population will be performed for primary and 
secondary 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 one 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 one laboratory value or vital sign obtained subsequent to at least one 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.
Efficacy results that will be deemed to be statistically significant after consideration of the 
type I error control for interim analyses are discussed in Sections 9.7 and 9.8. There are no 
additional adjustments for multiplicity. Statistical testing and inference for safety analyses 
are described in Section 9.6.2. 
 
 
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9.6.1
Statistical Methods for Efficacy Analyses
The stratified log-rank test will be used for the comparison of MK-4482 with placebo for the 
primary endpoint of the time-to-sustained recovery. Stratification factors are specified in
Section 6.3.2. The relevant treatment efficacy parameter is the “sustained recovery rate ratio” 
(for MK-4482 relative to placebo), which is akin to the hazard ratio in survival analysis but 
for the beneficial outcome of sustained recovery. Sustained recovery rate ratios will be based 
on the stratified Cox Proportional Hazards regression model with stratification by factors 
specified in Section 6.3.2. Geographic region will not be used as a covariate in the primary 
analyses, but it may be considered as an additional stratification factor for the stratified log 
rank test and as a covariate for the Cox Proportional Hazards regression model 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. The Efron 
approximation will be used for handling ties. Failure to recover will be censored at Day 29.
Death before Day 29, including death following a prior recovery, will be censored at Day 29 
to eliminate any bias that would be introduced by censoring at time of death. Lost to follow-
up before Day 29, regardless of prior recovery, will not be considered a sustained recovery
and will be censored at the day of last contact. Withdrawal (ie, discontinuation from the 
study for reasons other than death or lost to follow up) before Day 29, regardless of prior 
recovery, will not be considered a sustained recovery and will be censored at the day of 
discontinuation.
Participants who initiate Sponsor-designated standard of care for treatment for COVID-19 
48 hours or more following start of randomized study therapy will be treated as a failure to 
recover. Sustained recovery rate ratios greater than 1 indicate a benefit for MK-4482. 
Superiority will be concluded based on p-value boundaries as described in Sections 9.7 and 
9.8.
A sensitivity analyses for the primary efficacy endpoint will be performed in the MITT 
population that does not impute “failure to recover” for participants who initiate Sponsor-
designated standard of care for treatment for COVID-19 following start of randomized study 
therapy. In the case where the number of participants who require re-hospitalization but are 
then discharged again (or medically ready for discharge) before Day 29 exceeds 5% of the 
total MITT population, an additional sensitivity analysis will be performed in which all 
participants with re-hospitalizations by Day 29 are considered as not meeting the primary 
endpoint.
If superiority of MK-4482 over placebo is demonstrated as assessed by time-to-sustained 
recovery at the end of Part 2, the superiority of MK-4482 over placebo as assessed for the 
key secondary endpoint of all-cause mortality at Day 29 will be tested. Due to the relatively 
low number of deaths expected and the large number of strata levels, the unstratified 
Miettinen and Nurminen method [Miettinen, O. 1985] will be used to estimate and test the 
treatment difference for all-cause mortality. Every effort will be made to ascertain survival 
status for all participants.  Missing data for this endpoint will be treated as failure (M=F 
approach) in the MITT population.
 
 
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Ordinal outcome scales such as Pulmonary and Pulmonary+ 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 in Section 6.3.2. In addition, 
the proportion of participants in each ordinal scale category by treatment groups will also be 
presented.
The National Early Warning Score and the WHO 11-point ordinal scale score will be 
categorized to ordinal outcomes and will be further analyzed using the same approach as for 
Pulmonary and Pulmonary+ outcomes.
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 and OP 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 SAS-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 and OP swabs will be summarized 
separately by treatment group and time point. Between-treatment differences and 95% 
confidence intervals will be estimated using the stratified Miettinen and Nurminen method 
[Miettinen, O. 1985].  
A detailed analysis strategy for key efficacy endpoints is listed in Table 5. The strategy to 
address multiplicity issues with regard to multiple efficacy endpoints and interim analyses is 
described in Section 9.7, Interim Analyses and in Section 9.8, Multiplicity.
 
 
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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 and Data
Imputation Approach
Primary Endpoint
Time-to-sustained recovery from 
randomization through Day 29
P (MITT)
S (PP)
Stratified log-
rank testc
Stratified Cox 
Proportional 
Hazards 
regressiond
MITT
PP
Missing data will not be imputed. 
Participants who initiate Sponsor-designated standard of care for 
treatment for COVID-19 48 hours or more following start of 
randomized study therapy will be treated as a failure to recover.
A sensitivity analysis for the primary efficacy endpoint will be 
performed in the MITT population that does not impute “failure to 
recover” for participants who initiate Sponsor-designated standard 
of care for treatment for COVID-19.
Depending upon the number of participants who required re-
hospitalization but were discharged or medically ready for 
discharge again before Day 29, an additional sensitivity analyses 
will be performed in which all participants with re-hospitalizations 
by Day 29 are considered as not meeting the primary endpoint.
Failure to recover will be censored at Day 29. Death will also be 
censored at Day 29. Recovery followed by subsequent lost to 
follow up before Day 29 will be censored at the day of lost to 
follow up. Withdrawal (ie, discontinuation from the study for
reasons other than death or lost to follow up) before Day 29 will 
be censored at the day of discontinuation.
 
 
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Endpoint/Variable
(Description, Time Point)
Primary vs. 
Supportive 
Approacha
Statistical 
Methodb
Analysis 
Population
Missing Data and Data
Imputation Approach
Secondary Endpoints
All-cause mortality through Day 29
P (MITT)
S (PP)
Unstratified 
M & N 
methode
MITT
PP
Missing = Failure (M=F) – MITT
Data as Observed (DAO) - PP
Odds of a more favorable response on 
Pulmonary score at Day 3, EOT, Day 10, 
Day 15, and Day 29
P (MITT)
S (PP)
Proportional 
odds modelf
MITT
PP
Model-based
Odds of a more favorable response on 
Pulmonary+ score at Day 3, EOT, Day 
10, Day 15, and Day 29
P (MITT)
S (PP)
Proportional 
odds modelf
MITT
PP
Model-based
Odds of a more favorable response in the 
clinical risk of mortality category from 
the National Early Warning Score at 
EOT 
P (MITT)
S (PP)
Proportional 
odds modelf
MITT
PP
Model-based
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 modelf
MITT
PP
Model-based
EOT=End of Treatment; MITT= modified intent-to-treat; M & N= Miettinen and Nurminen; PP=Per-protocol; WHO=World Health Organization.
a P=Primary approach; S=Supportive approach.
b Statistical models are described in further detail below:
c The stratified log-rank test includes stratification factors specified in Section 6.3.2.
d Stratified Cox Proportional Hazards regression includes terms for treatment, stratification factors specified in Section 6.3.2.
e Unstratified Miettinen and Nurminen method.
f 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. Adverse events (specific terms as well as system organ class terms) 
and events that meet predefined limits of change (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 one of the treatment 
groups)
PDLCsb (incidence ≥4 participants in at least 
one 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
Note: AE=adverse event; CI=confidence interval; 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.
 
 
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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 
modifications to the protocol to protect the safety of participants 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. Membership on
this cross-functional unblinded team will be documented in an unblinding plan and the 
details of the planned analyses will be outlined in the Modeling Analysis Plan 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 3 interim analyses during the study as shown in Table 7.
 
 
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Table 7
Description of Interim Analyses
Interim Analysis
Timing
P001 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-4482-001 and 
MK-4482-002a. 
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 the 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
Futility/Early 
Efficacy
Targeted to occur during Phase 3 after 
~343 of an expected 685 sustained
recovery events, expected to be at 
approximately 50% of the full planned 
enrollment in the selected MK-4482
group and the placebo group in Part 2.
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 P002 is a companion MK-4482 dose-ranging study in non-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-4482-002 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: Futility/Early Efficacy 
This study will include one planned interim analysis when ~50% of the expected sustained 
recovery events have occurred (~343 of an expected 685 events). 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. The statistical 
criteria to inform this decision was developed as part of a group sequential design strategy 
that applies only to Part 2 (Phase 3) of the study. Given the expected rapid enrollment, there
are no plans 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. Assuming the 
information fraction of 50%, the non-binding futility boundary expressed on the sustained
recovery rate ratio scale is 1.071 (ie, an observed point estimate for the sustained recovery 
rate ration of 1.071 or lower will meet the criterion for futility). The boundary crossing 
probabilities for futility are 74% under H0 and 3.6% under H1 (sustained recovery rate 
 
 
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ratio=1.3). The p-value boundary for efficacy is 0.009, corresponding to a sustained recovery 
rate ratio of 1.289 (ie, an observed point estimate for the sustained recovery rate ratio of 
1.289 or higher will meet the criterion for early efficacy). The boundary crossing 
probabilities for efficacy are 0.9% under H0 and 53% under H1 (sustained recovery rate 
ratio=1.3).
9.8
Multiplicity
Multiplicity adjustment with regard to controlling type I error for the Futility/Early Efficacy 
(Phase 3) Interim Analysis is described in Section 9.7.
There are two hierarchical superiority hypotheses in the Phase 3 part of this study 
(Section 3). A sequential testing approach will be employed to control overall type I error at 
0.025, 1-sided across the primary efficacy endpoint (time-to-sustained recovery) and the key 
secondary efficacy endpoint (all-cause mortality). The all-cause mortality endpoint will not 
be tested at the interim analysis. At the end of Part 2, testing will be performed for the time-
to-sustained recovery endpoint at an alpha level of 0.019. If superiority is demonstrated, the 
all-cause mortality endpoint will be tested at alpha level of 0.025. This strategy provides 
strong control of type I error at the study level. All tests are 1-sided unless otherwise noted.
9.9
Sample Size and Power Calculations
9.9.1
Sample Size and Power Calculations for Efficacy Analyses (Part 2)
The primary analysis of Phase 3 study endpoints will include ~1000 participants from Part 2
of the study (~500 for the selected MK-4482 group and ~500 for the placebo group) who 
meet the criteria for inclusion in the MITT population. The primary endpoint is time-to-
sustained recovery. The study has overall power of 90% to demonstrate that participants 
treated with MK-4482 have a higher rate of sustained recovery than participants treated with 
placebo at an overall one-sided, 2.5% alpha-level, if the underlying constant sustained
recovery rate ratio between treatment groups is 1.3.
The power and sample size are based on the following assumptions: 1) the time-to-sustained 
recovery follows an exponential distribution with sustained recovery rates of 0.351 and 0.270 
for the MK-4482 and placebo groups, respectively, 2) a futility/efficacy interim analysis at 
50% information as outlined in Section 9.7, 3) an enrollment period of 10 weeks, and 4) 
dropout hazard rates of 0.02 for both the MK-4482 and placebo groups, respectively. The 
above sustained recovery rates correspond to approximately 366 (73%) and 319 (64%)
sustained recovery events for the MK-4482 and placebo groups, respectively. These are 
nearly identical to the recovery rates presented for remdesivir and placebo in the NEJM 
[Beigel, J. H., et al 2020]. The calculation was computed using both EAST and gsDesign. To 
meet the statistical criterion for success (one-sided p value≤0.019 at the final analysis), the 
observed sustained recovery rate ratio must be approximately 1.17 or larger.
 
 
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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 
titer, calculated as log10 (post) minus log10 (baseline). Approximately 80% of this cohort 
(60/group) is expected to have baseline viral load 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 8 provides power calculations for true log differences of 0.75 to 1.25 and for 
various assumptions about the true underlying standard deviation.
Table 8
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 575 for MK-4482 
selected dose group and placebo. 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 a 99.7% chance of observing at least one AE among 575 participants in 
the treatment group. If no AE of that type is observed among the 575 participants in any 
treatment group, this study will provide 97.5% confidence that the underlying percentage of 
participants with the AE is < 0.64% (1 out of every 156 participants).
Table 9 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 575 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 9
Differences in Incidence of AE Rates Between the 2 Treatment Groups That Can 
be Detected With an ~90% Probability (Assuming 2-sided 5% Alpha Level with 
575 Participants in Each Group)
Incidence of Adverse Event
Risk Difference
Placebo (%)
MK-4482 (%)
Percentage Points
1.0
4.0
3.0
5.0
10.0
5.0
10.0
16.5
6.5
20.0
28.2
8.2
30.0
39.1
9.1
40.0
49.5
9.5
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 (≤60 years, >60 years)

Sex (female, male)

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)

Baseline (Day 1) disease severity (mild, moderate, severe) per Appendix 9

Remdesivir use prior to or at the time of randomization (yes, no)

Corticosteroid use prior to or at the time of randomization (yes, no)

Geographic region (North America, Europe, Asia Pacific, Latin America)
 
 
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
Participants at increased risk for severe illness from COVID-19 (yes, no)
o
age >60 years, active cancer, chronic kidney disease, chronic obstructive 
pulmonary disease, immunocompromised state from solid organ transplant, 
obesity (BMI ≥30), serious heart conditions such as heart failure, coronary 
artery disease, or cardiomyopathies, sickle cell disease, diabetes mellitus
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 10 will be performed by the central laboratory.
•
Local laboratory test is required for initial COVID-19 RT-PCR 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 either study intervention administration 
and/or response evaluation. If a local sample is required, it is important that the 
sample for central analysis is obtained at the same time. Additionally, if the local 
laboratory results are used 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.
Table 10
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
Phosphorus
Alkaline phosphatase
Glucose (nonfasting)
Magnesium
GGT
Potassium
Amylase
LDH
Bicarbonate
Lipase
Total bilirubin (and direct bilirubin 
if total bilirubin is elevated above 
upper limit of normal
Sodium 
Total protein
CK
 
 
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Laboratory 
Assessments
Parameters
Urinalysis
•
Specific gravity
•
Color and clarity
•
pH, glucose, protein, blood, ketones, bilirubin, urobilinogen, nitrite, leukocyte 
esterase by dipstick
•
Microscopic examination (if blood or protein is abnormal)
Pregnancy 
Testing
•
Serum hCG pregnancy test (as needed for WOCBP)
Virology
•
SARS-CoV-2 RNA real time PCR OP and NP swabs (quantitative and 
qualitative)
•
SARS-CoV-2 Gene Sequencing
Inflammatory 
Biomarkers
•
Pro-inflammatory cytokine (IL-6)
•
hs-CRP

Note: hs-CRP will be tested at all visits with chemistry collection as 
the test is performed on the same blood sample
•
D-dimer
•
Erythrocyte Sedimentation Rate 
•
Procalcitonin
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
•
Co-infection with other respiratory pathogens
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; WONCBP=women of nonchildbearing 
potential.
 
 
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Table 11
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)
Urine (~10 mL)
Urine (preservative)
X
NA
Nasopharyngeal Swab
flocked or polyester-
tipped swab (3 mL 
universal transport 
medium)
X
X
X
X
X
X
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
Procalcitonin
Plasma (EDTA)
2
2
Erythrocyte Sedimentation 
Rate (ESR)
Whole Blood (NA 
Citrate)
1.2
1.2
Interleukin-6 (IL-6)
Serum (no additive)
2.5
2.5
D-Dimer
Plasma (Na Citrate)
1.8
1.8
Sub Total for all 
Participants for Central 
Laboratory 
NA
0
30.5
0
4.5
0
30.5
23
4.5
24
Pharmacokinetics
NA
Pharmacokinetic Plasma 
Sampling Part 1
Plasma (EDTA)
15
Pharmacokinetic Plasma 
Sampling Part 2
Plasma (EDTA)
9
Pharmacokinetic PBMC 
Sampling Part 1
Whole Blood (Sodium 
Heparin) processed to 
PBMCs
80
 
 
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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)
Total For Participants in 
Part 1
NA
0
30.5
0
4.5
0
45.5
23
4.5
24
132
Total For Participants in 
Part 2
0
30.5
0
4.5
0
39.5
23
4.5
24
126
Total For PBMC Cohort 
Participants in Part 1
0
30.5
0
4.5
0
125.5
23
4.5
24
212
hCG=human chorionic gonadotropin; 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 
 
 
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TO THE SPONSOR’S PRODUCT POSES ADDITIONAL POTENTIAL SIGNIFICANT 
RISK TO THE PARTICIPANT THEN THE RECHALLENGE MUST BE APPROVED IN 
ADVANCE BY THE SPONSOR CLINICAL DIRECTOR, AND IF REQUIRED, THE 
IRB/IEC.
•
Consistency with study intervention profile: Is the clinical/pathological presentation of 
the AE consistent with previous knowledge regarding the Sponsor’s product or drug class 
pharmacology or toxicology?
•
The assessment of relationship will be reported on the 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 contraceptionb
-
Oral
-
Injectable
Barrier methods to be used with 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
Not applicable. 
 
 
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10.7
Appendix 7: Country-specific Requirements
10.7.1
Country-specific Request for South Korea 
Section 7.1 Discontinuation of Study Intervention
The following discontinuation criterion applies to participants in South Korea: 
The participant’s renal function deteriorates leading to dialysis while on study intervention.
Section 8.1.8.1 Timing of Dose Administration
The following information is not applicable in South Korea: 
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 4-6 
hours prior to dialysis where possible.
 
 
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10.8
Appendix 8: Ordinal Outcome Scales
10.8.1
Pulmonary and Pulmonary+
The Pulmonary ordinal outcome focuses on the respiratory sequalae of COVID-19 and is 
defined based on oxygen requirements using the following 7 well-defined mutually exclusive 
categories:
1. Can independently undertake personal usual activities with minimal or no symptoms
2. Symptomatic and currently unable to independently undertake usual personal 
activities
3. Supplemental oxygen (<4 liters/min, or <4 liters/min above premorbid requirements)
4. Supplemental oxygen (≥4 liters/min, or ≥4 liters/min above premorbid requirements 
but not high-flow oxygen
5. Non-invasive assisted ventilation or high-flow oxygen
6. Invasive assisted ventilation, ECMO or mechanical circulatory support
7. Death 
The Pulmonary+ ordinal outcome is also a 7-category assessment that captures the range of 
severity, including coagulation-related complications and respiratory dysfunction, 
experienced by hospitalized patients with COVID 19 as follows:
1. Can independently undertake personal usual activities with minimal or no symptoms
2. Symptomatic and currently unable to independently undertake usual personal 
activities
3. Supplemental oxygen (<4 liters/min, or <4 liters/min above premorbid requirements)
4. Supplemental oxygen (≥4 liters/min, or ≥4 liters/min above premorbid requirements 
but not high-flow oxygen) or any of the following: stroke, meningitis, encephalitis, 
myelitis, myocardial ischemia, myocarditis, pericarditis, symptomatic congestive 
heart failure, or arterial or deep venous thrombosis
5. Non-invasive assisted ventilation or high-flow oxygen
6. Invasive assisted ventilation, ECMO or mechanical circulatory support or vasopressor 
therapy or renal replacement therapy
7. Death
The Pulmonary and Pulmonary+ scales are reproduced based on the NAIDS and NIH 
Therapeutics for Inpatients with COVID-19 (TICO) protocol. Of note, the Pulmonary+ scale 
was adapted to remove the use of the NIHSS in assessing stroke-related neurologic deficits 
due to challenges in implementing the NIHSS tool at all participating clinical sites.
 
 
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10.8.2
National Early Warning Score
The National Early Warning Score is as follows [Royal College of Physicians 2012]:
Physiological Parameter
Point Value
Respiration Rate (breaths per minute)
≤8
3
9-11
1
12-20
0
21-24
2
≥25
3
Oxygen Saturation (%)
≤91
3
92-93
2
94-95
1
≥96
0
Any Supplemental Oxygen 
Yes
2
No
0
Temperature (ºC)
≤35.0
3
35.1-36.0
1
36.1-38.0
0
38.1-39.0
1
≥39.1
2
Systolic BP (mmHg)
≤90
3
91-100
2
101-110
1
111-219
0
≥220
3
Heart Rate (beats per minute)
≤40
3
41-50
1
51-90
0
91-110
1
111-130
2
≥131
3
Level of Consciousness
A
0
V,P,U
3
A, V, P, U= Alert, Voice, Pain, Unresponsive
 
 
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10.8.3
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 Administration (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 but not limited to one or more of the following: fever 
>38.0ºC, chills, cough, sore throat, shortness of breath or difficulty 
breathing, fatigue, nasal congestion, runny nose, headache, muscle or body 
aches, nausea, vomiting, diarrhea, loss of taste, loss of smell
o
Of note, symptoms attributable to COVID-19 not listed above can be 
considered per the investigator as supportive for COVID-19 baseline 
severity categorization
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, moderate, or severe 
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.
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, 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

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 ≤2 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, 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

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 > 2 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 systolic blood pressure <90 mmHg, or diastolic blood pressure 
<60 mmHg or 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: 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:
o
eGFR = estimated glomerular filtration rate
o
SCr = standardized serum creatinine
o
age = years
 
 
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10.11 Appendix 11: 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 2hours
C12hr
plasma concentration value collected at 12hours
CBC
complete blood count
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
DAO
data as observed
DAIDS
Division of Acquired Immunodeficiency Syndrome 
DDI
drug-drug interaction
DILI
drug-induced liver injury
DMC
data monitoring committee
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
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
 
 
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Abbreviation
Expanded Term
ESR
erythrocyte sedimentation rate
EUA
Emergency Use Authorization
FBR
future biomedical research
FDA
Food and Drug Administration
FDAAA
Food and Drug Administration Amendments Act
FiO2
fraction of inspired oxygen
FIH
First-in-human
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
IB
investigator’s brochure 
ICF
informed consent form
ICH
International Council for Harmonisation of Technical 
Requirements for Pharmaceuticals for Human Use
IEC
Independent Ethics Committee
IA
interim analysis
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 amenorrhea method
LAR
legally acceptable representative
LAM
lactational amenorrhea method
LAM
lactational amenorrhea method
LFU
late follow-up
LSD
late stage development
mAb
monoclonal antibody
 
 
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Abbreviation
Expanded Term
MAD
multiple ascending doses
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
MSD
Merck Sharp & Dohme
NAIDS
National Institute of Allergy and Infectious Diseases
NEJM
New England Journal of Medicine
NEWS
National Early Warning score
NHC
N-hydroxycytidine
NHC-TP
N-hydroxycytidine pharmacologically-active 
triphosphate
NIH
National Institutes of Health
NIHSS
NIH Stroke Scale
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 
 
 
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Abbreviation
Expanded Term
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
t1/2
half life
US
United States
WBC
white blood cell
WHO
World Health Organization
WOCBP
woman/women of childbearing potential 
 
 
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11
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17-DEC-2020
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