Conditions: Influenza Infection
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 161
Healthy volunteers: yes

Brief summary:
This is a phase 2a double-blind, randomized, placebo-controlled study to evaluate the efficacy and safety of molnupiravir (MK-4482) in healthy participants inoculated with experimental influenza virus. The primary hypotheses are that MK-4482 initiated 12 hours following intranasal inoculation of the influenza challenge virus reduces the peak viral load compared to placebo and that MK-4482 initiated 2 days following intranasal inoculation of the influenza challenge virus reduces the viral load area under the curve (AUC) compared to placebo.

Detailed description:
This study has two parts. Part 1 is an open-label validation study, with a cohort of 20 untreated participants undergoing nasal inoculation with the A/France/759/21 \[H1N1\] strain on Day 0 to confirm viral infectivity and disease. Part 2 will be a randomized, double-blind placebo- and active-comparator-controlled study where participants will be inoculated on Day 0 with either the A/France/759/21 \[H1N1\] virus used in Part 1 or an alternative influenza virus. Part 2 will evaluate the antiviral efficacy, pharmacokinetics, and safety of MK-4482 in participants inoculated with the challenge virus.

Arms:
arm 1: Molnupiravir 800 mg every 12 hours Day 0 PM through Day 5 AM, placebo molnupiravir every 12 hours Day 5 PM through Day 6 PM arm 2: Placebo molnupiravir every 12 hours Day 0 PM through Day 1 PM, molnupiravir 800 mg every 12 hours Day 2 AM through Day 6 PM arm 3: Placebo oseltamivir Day 0 PM through Day 1 PM, oseltamivir 75 mg plus placebo so the total number of capsules is always 4 per dose every 12 hours Day 2 AM through Day 6 PM arm 4: Placebo molnupiravir every 12 hours Day 0 PM through Day 6 PM arm 5: Influenza A challenge virus given once by intranasal administration

Interventions: intervention 1: Molnupiravir intervention 2: Placebo molnupiravir intervention 3: Placebo oseltamivir intervention 4: Oseltamivir intervention 5: Influenza A Virus
Intervention descriptions: intervention 1: Four molnupiravir 200 mg capsules (800 mg total dose) taken twice daily by mouth. intervention 2: Four placebo capsules matched to molnupiravir taken twice daily by mouth. intervention 3: Placebo capsule matched to oseltamivir taken twice daily by mouth. intervention 4: One capsule of oseltamivir 75 mg taken twice daily by mouth. intervention 5: Influenza A challenge virus given once by intranasal administration at an inoculum concentration of between approximately 5 and 7 Log10 tissue culture infective dose 50% (TCID50/mL).

Protocol document:
Prot_SAP_000.pdf: 
Official Protocol Title:
NCT number:  
     NCT05818124
Document Date:            14-Aug-2023
A Phase 2a Double-Blind, Randomized, Placebo-
Controlled Study to Evaluate the Efficacy and Safety of 
MK-4482 in Healthy Participants Inoculated with 
Experimental Influenza Virus


PRODUCT: MK-4482
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TITLE PAGE
THIS PROTOCOL AND ALL OF THE INFORMATION RELATING TO IT ARE 
CONFIDENTIAL AND PROPRIETARY PROPERTY OF MERCK SHARP & 
DOHME LLC, RAHWAY, NJ, USA (MSD).
Protocol Title: A Phase 2a Double-Blind, Randomized, Placebo-Controlled Study to 
Evaluate the Efficacy and Safety of MK-4482 in Healthy Participants Inoculated with 
Experimental Influenza Virus
Protocol Number: 019-01
Compound Number: MK-4482
Sponsor Name: Merck Sharp & Dohme LLC (hereafter called the Sponsor or MSD)
Legal Registered Address:
126 East Lincoln Avenue
P.O. Box 2000
Rahway, NJ 07065 USA
Regulatory Agency Identifying Number(s):
NCT
Not Applicable 
EU CT
Not Applicable
EudraCT
Not Applicable
JRCT
Not Applicable
WHO
Not Applicable 
UTN
Not Applicable
IND
Not Applicable
Approval Date: 14 August 2023
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Sponsor Signatory
Typed Name:
Title:
Date
Protocol-specific Sponsor contact information can be found in the Investigator Study 
File Binder (or equivalent).
Investigator Signatory
I agree to conduct this clinical study in accordance with the design outlined in this protocol 
and to abide by all provisions of this protocol.
Typed Name:
Title:
Date
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DOCUMENT HISTORY
Document
Date of Issue
Overall Rationale
Amendment 01
14-AUG-2023
The key reason for this amendment is to revise 
inclusion criterion #6 to align with contraception 
requirements for the overall MK-4482 program. 
Clarifications the PCL were also incorporated 
into the amendment.
Original Protocol
10-FEB-2023
Not applicable
PROTOCOL AMENDMENT SUMMARY OF CHANGES
Amendment: 01
Overall Rationale for the Amendment:
The key reason for this amendment is to revise inclusion criterion #6 to align with 
contraception requirements for the overall MK-4482 program. Clarifications from a PCL 
were also incorporated into the amendment.
Summary of Changes Table
Section Number 
and Name
Description of Change
Brief Rationale
Primary Reason for Amendment
Section 5.1: 
Inclusion Criteria
Added acceptable user dependent contraception 
methods for WOCBP to inclusion criterion #6.
Text was revised to align with contraception 
requirements for the overall MK-4482 program.
Section Number 
and Name
Description of Change
Brief Rationale
Additional Changes
Throughout
Formatting and other editorial changes 
Editorial modifications were incorporated to 
address minor errors including corrections in 
formatting.
Section 1.3 
Schedule of 
Activities Parts 1 
and 2
Moved the ‘X’ for Calculation of eGFR to 
Day -2/-1 rather than Day -90 
Calculation of eGFR will occur upon admission 
for study specific eligibility.
Section 1.3 
Schedule of 
Activities Parts 1 
and 2
Moved the ‘X’ for Assignment of Study-
Specific Screening Number to Day -2/-1 rather 
than Day -90 
The study specific screening number is assigned 
after study specific consent on Day -2/-1.
Section 1.3 
Schedule of 
Activities Part 2 
only
Replaced ‘Assignment of Allocation Number’ 
with ‘Assignment of Randomization Number’
Participants in Part 2 will receive a 
randomization number prior to dosing rather 
than an allocation number (as in Part 1).
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Section Number 
and Name
Description of Change
Brief Rationale
Section 1.3 
Schedule of 
Activities Parts 1 
and 2
Removed the ‘X’ under ‘Serum for Exploratory 
Immunological Biomarkers’ for Study Days 7, 
8, and 28 
Based on newly available information, 
collections for PD assessment at these time 
points are no longer needed to support the study 
objectives.
Section 1.3 
Schedule of 
Activities Parts 1 
and 2
Added note that Serum for Exploratory 
Immunological Biomarker samples for Study 
Days 1-6 are collected in the PM
Clarification for when the sample is collected
was provided.
Section 1.3 
Schedule of 
Activities Parts 1 
and 2
Removed ‘X’ for Days 1-8 Nasal Sample for 
Mucosal Antibodies and Inflammatory 
Markers’
Based on newly available information, 
collections for respiratory samples at these time 
points are no longer needed to support the study 
objectives.
Section 1.3 
Schedule of 
Activities Parts 1 
and 2
Removed the ‘X’ for AE review at the 
timepoint for Day 0, challenge virus
AE review will not occur on Day 0, challenge 
virus.
Section 1.3 
Schedule of 
Activities Parts 1 
and 2
Added ‘and global impression questions’ to row 
for FLU-PRO Plus© Questionnaire
Text was added to clarify that data from the 
FLU-PRO Plus© will be analyzed based on 
multiple time points, in addition to 1- item 
patient global impression questions, as described 
in Section 8.4.2 of the study protocol
Synopsis 1.1
Intervention 
Groups and 
Duration
Section 6.1 
Study 
Intervention 
Administered
Replaced unit dose strength from 800 mg to 200 
mg for MK-4482
A typographical error in the unit dose column
was corrected. The dosage level is 800 mg (4 x 
200-mg capsules).
Section 6.1 Study 
Intervention 
Administered
Replaced cross references for Table 2 and Table 
3 with Table 3 and Table 4
A typographical error in the cross-referencing
was corrected.
Section 10.5.2 
Contraception 
Requirements
Revised table to include highly effective 
contraceptive methods that are user dependent.
The table was revised to align with contraception 
requirements for the overall MK-4482 program.  
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TABLE OF CONTENTS
DOCUMENT HISTORY ........................................................................................................3
PROTOCOL AMENDMENT SUMMARY OF CHANGES...............................................3
1
PROTOCOL SUMMARY ............................................................................................12
1.1
Synopsis.................................................................................................................12
1.2
Schema ..................................................................................................................19
1.3
Schedule of Actvities............................................................................................20
2
INTRODUCTION..........................................................................................................31
2.1
Study Rationale....................................................................................................31
2.1.1
Overview of Influenza Human Challenge Model........................................31
2.2
Background ..........................................................................................................33
2.2.1
Pharmaceutical and Therapeutic Background .............................................33
2.2.2
Preclinical Studies........................................................................................33
2.2.3
Completed and Ongoing Clinical Studies....................................................35
2.2.3.1
Completed Clinical Studies................................................................35
2.2.3.2
Ongoing Clinical Studies...................................................................38
2.2.4
Information on Other Study-related Therapy ..............................................39
2.3
Benefit/Risk Assessment......................................................................................39
3
HYPOTHESES, OBJECTIVES, AND ENDPOINTS................................................41
4
STUDY DESIGN............................................................................................................47
4.1
Overall Design......................................................................................................47
4.2
Scientific Rationale for Study Design.................................................................49
4.2.1
Rationale for Endpoints ...............................................................................49
4.2.1.1
Pharmacodynamic Endpoints.............................................................53
4.2.1.2
Efficacy Endpoints.............................................................................54
4.2.1.3
Safety Endpoints................................................................................54
4.2.1.4
Pharmacokinetic Endpoints ...............................................................54
4.2.1.5
Planned Exploratory Biomarker Research.........................................55
4.2.1.5.1
Planned Genetic Analysis ........................................................55
4.2.1.6
Future Biomedical Research..............................................................55
4.2.2
Rationale for the Use of Comparator/Placebo .............................................56
4.3
Justification for Dose...........................................................................................56
4.4
Beginning and End-of-Study Definition ............................................................57
4.4.1
Clinical Criteria for Early Study Termination .............................................57
5
STUDY POPULATION ................................................................................................58
5.1
Inclusion Criteria.................................................................................................58
5.2
Exclusion Criteria................................................................................................60
5.3
Lifestyle Considerations......................................................................................64
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5.3.1
Meals and Dietary Restrictions - Part 2 Only..............................................64
5.3.1.1
Diet Restrictions.................................................................................64
5.3.1.2
Fruit Juice Restrictions ......................................................................64
5.3.2
Caffeine, Alcohol, and Tobacco Restrictions – Parts 1 and 2 .....................64
5.3.2.1
Caffeine Restrictions..........................................................................64
5.3.2.2
Alcohol Restrictions...........................................................................65
5.3.2.3
Tobacco Restrictions..........................................................................65
5.3.3
Activity Restrictions ....................................................................................65
5.4
Screen Failures.....................................................................................................65
5.5
Participant Replacement Strategy......................................................................65
6
STUDY INTERVENTION............................................................................................67
6.1
Study Intervention(s) Administered...................................................................67
6.2
Preparation/Handling/Storage/Accountability .................................................71
6.2.1
Dose Preparation..........................................................................................71
6.2.2
Handling, Storage, and Accountability........................................................71
6.3
Measures to Minimize Bias: Randomization and Blinding..............................72
6.3.1
Intervention Assignment..............................................................................72
6.3.2
Stratification.................................................................................................72
6.3.3
Blinding........................................................................................................72
6.4
Study Intervention Compliance..........................................................................73
6.5
Concomitant Therapy..........................................................................................73
6.5.1
Rescue Medications and Supportive Care ...................................................74
6.6
Dose Modification ................................................................................................74
6.6.1
Stopping Rules.............................................................................................74
6.7
Intervention After the End of the Study............................................................74
6.8
Clinical Supplies Disclosure................................................................................74
6.9
Standard Policies..................................................................................................75
7
DISCONTINUATION OF STUDY INTERVENTION AND PARTICIPANT 
WITHDRAWAL............................................................................................................76
7.1
Discontinuation of Study Intervention...............................................................76
7.2
Participant Withdrawal From the Study...........................................................76
7.3
Lost to Follow-up .................................................................................................77
8
STUDY ASSESSMENTS AND PROCEDURES........................................................78
8.1
Administrative and General Procedures ...........................................................78
8.1.1
Informed Consent.........................................................................................78
8.1.1.1
General Informed Consent.................................................................79
8.1.1.2
Consent and Collection of Specimens for Future Biomedical 
Research.............................................................................................79
8.1.2
Inclusion/Exclusion Criteria ........................................................................79
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8.1.3
Participant Identification Card.....................................................................79
8.1.4
Medical History ...........................................................................................80
8.1.5
PHQ-9 and GAD-7 Questionnaire...............................................................80
8.1.6
Prior and Concomitant Medications Review...............................................80
8.1.6.1
Prior Medications...............................................................................80
8.1.6.2
Concomitant Medications..................................................................80
8.1.7
Assignment of Screening Number...............................................................80
8.1.8
Assignment of Treatment/Randomization Number.....................................80
8.1.9
Study Intervention Administration ..............................................................81
8.1.9.1
Timing of Dose Administration.........................................................81
8.1.10
Discontinuation and Withdrawal .................................................................81
8.1.10.1
Withdrawal From Future Biomedical Research ................................81
8.1.11
Participant Blinding/Unblinding..................................................................82
8.1.12
Domiciling ...................................................................................................82
8.1.13
Calibration of Equipment.............................................................................82
8.2
Serosuitability Assessment..................................................................................83
8.3
Intranasal Administration of the Challenge Virus ...........................................83
8.4
Efficacy Assessments ...........................................................................................83
8.4.1
Symptom Diary Card...................................................................................84
8.4.2
FLU-PRO Plus© Questionnaire ..................................................................85
8.4.3
Nasal Discharge Collection from Paper Tissues..........................................85
8.4.4
Nasopharyngeal Swabs ................................................................................86
8.4.5
Nasal Sample for Immunology....................................................................86
8.5
Safety Assessments...............................................................................................87
8.5.1
Physical Examinations.................................................................................87
8.5.2
Vital Signs....................................................................................................88
8.5.2.1
Resting Vital Signs ............................................................................88
8.5.3
Electrocardiograms ......................................................................................89
8.5.4
Spirometry....................................................................................................90
8.5.5
Clinical Safety Laboratory Assessments .....................................................91
8.5.6
Pregnancy Testing........................................................................................91
8.5.7
Photograph of Rash......................................................................................91
8.6
Adverse Events, Serious Adverse Events, and Other Reportable Safety 
Events....................................................................................................................91
8.6.1
Time Period and Frequency for Collecting AE, SAE, and Other 
Reportable Safety Event Information ..........................................................92
8.6.2
Method of Detecting AEs, SAEs, and Other Reportable Safety Events......94
8.6.3
Follow-up of AE, SAE, and Other Reportable Safety Event Information...94
8.6.4
Regulatory Reporting Requirements for SAE .............................................94
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8.6.5
Pregnancy and Exposure During Breastfeeding ..........................................95
8.6.6
Disease-related Events and/or Disease-related Outcomes Not Qualifying 
as AEs or SAEs............................................................................................95
8.6.7
Events of Clinical Interest............................................................................96
8.7
Treatment of Overdose........................................................................................96
8.8
Pharmacokinetics.................................................................................................96
8.8.1
Blood Collection for Plasma NHC ..............................................................97
8.8.2
Blood Collection for Plasma Oseltamivir Carboxylate ...............................97
8.9
Pharmacodynamics..............................................................................................97
8.10
Immunological Assessments................................................................................97
8.11
Biomarkers ...........................................................................................................97
8.11.1
Planned Genetic Analysis Sample Collection..............................................97
8.12
Future Biomedical Research Sample Collection...............................................98
8.13
Health Economics Medical Resource Utilization and Health Economics.......98
8.14
Visit Requirements...............................................................................................98
8.14.1
Screening......................................................................................................98
8.14.2
Intranasal IAV Inoculation Period...............................................................98
8.14.3
Study Drug Intervention Period – Part 2......................................................99
8.14.4
Participants Discontinued From Study Intervention but Continuing to be 
Monitored in the Study ................................................................................99
8.14.5
Poststudy......................................................................................................99
8.14.6
Critical Procedures Based on Study Objectives: Timing of Procedure.......99
8.14.7
Study Design/Dosing/Procedures Modifications Permitted Within 
Protocol Parameters ...................................................................................101
9
KEY STATISTICAL CONSIDERATIONS .............................................................103
9.1
Responsibility for Analyses/In-house Blinding ...............................................103
9.2
Hypotheses/Estimation ......................................................................................103
9.3
Analysis Endpoints.............................................................................................103
9.4
Analysis Populations..........................................................................................107
9.5
Statistical Methods.............................................................................................107
9.5.1
Statistical Methods for Safety Analyses ....................................................107
9.5.2
Statistical Methods for Efficacy Analyses.................................................108
9.5.3
Statistical Methods for Pharmacokinetics Analyses..................................109
9.6
Interim Analyses ................................................................................................109
9.7
Multiplicity .........................................................................................................109
9.8
Sample Size and Power Calculations ...............................................................110
10
SUPPORTING DOCUMENTATION AND OPERATIONAL 
CONSIDERATIONS...................................................................................................111
10.1
Appendix 1: Regulatory, Ethical, and Study Oversight Considerations......111
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10.1.1
Code of Conduct for Interventional Clinical Trials...................................111
10.1.2
Financial Disclosure...................................................................................114
10.1.3
Data Protection...........................................................................................115
10.1.3.1
Confidentiality of Data ....................................................................115
10.1.3.2
Confidentiality of Participant Records.............................................115
10.1.3.3
Confidentiality of IRB/IEC Information..........................................116
10.1.4
Committees Structure.................................................................................116
10.1.5
Publication Policy......................................................................................116
10.1.6
Compliance with Study Registration and Results Posting Requirements .116
10.1.7
Compliance with Law, Audit, and Debarment ..........................................117
10.1.8
Data Quality Assurance .............................................................................117
10.1.9
Source Documents .....................................................................................118
10.1.10
Study and Site Closure...............................................................................119
10.2
Appendix 2: Clinical Laboratory Tests............................................................120
10.3
Appendix 3: Adverse Events: Definitions and Procedures for Recording, 
Evaluating, Follow-up, and Reporting.............................................................122
10.3.1
Definitions of Medication Error, Misuse, and Abuse................................122
10.3.2
Definition of AE ........................................................................................122
10.3.3
Definition of SAE ......................................................................................124
10.3.4
Additional Events Reported.......................................................................125
10.3.5
Recording AE and SAE .............................................................................125
10.3.6
Reporting of AEs, SAEs, and Other Reportable Safety Events to the 
Sponsor ......................................................................................................126
10.4
Appendix 4: Medical Device and Drug–Device Combination Products: 
Product Quality Complaints/Malfunctions: Definitions, Recording, and 
Follow-up ............................................................................................................127
10.5
Appendix 5: Contraceptive Guidance..............................................................128
10.5.1
Definitions..................................................................................................128
10.5.2
Contraceptive Requirements......................................................................130
10.6
Appendix 6: Collection and Management of Specimens for Future 
Biomedical Research..........................................................................................131
10.7
Appendix 7: Country-specific Requirements..................................................135
10.8
Appendix 8: Blood Volume Table ....................................................................136
10.9
Appendix 9: 12-Lead Electrocardiogram Evaluation Criteria......................137
10.10 Appendix 10: Algorithm for Assessing Out of Range Laboratory Values ...139
10.11 Appendix 11: Alternative Challenge Viruses for Part 2 – Summary............140
10.12 Appendix 12: Abbreviations .............................................................................142
11
REFERENCES.............................................................................................................147
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LIST OF TABLES
Table 1
Study Interventions – Part 2.........................................................................19
Table 2
Definitions of Study Endpoints....................................................................50
Table 3
Study Interventions......................................................................................68
Table 4
Study Administration Schedule ...................................................................70
Table 5
Sample Allocation Schedule for Part 1........................................................72
Table 6
Sample Allocation Schedule for Part 2........................................................72
Table 7
Reporting Periods and Time Frames for Adverse Events and Other 
Reportable Safety Events.............................................................................93
Table 8
PK Collection Windows ............................................................................100
Table 9
Protocol-required Safety Laboratory Assessments....................................120
Table 10
Study Challenge Agent Details: A/Perth/16/2009 [H3N2]........................140
Table 11
Study Challenge Agent Details: A/California 2009-like [H1N1]..............141
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LIST OF FIGURES
Figure 1
Study Schematic...........................................................................................19
Figure 2
Study Schema...............................................................................................19
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1
PROTOCOL SUMMARY
1.1
Synopsis
Protocol Title: A Phase 2a Double-Blind, Randomized, Placebo-Controlled Study to 
Evaluate the Efficacy and Safety of MK-4482 in Healthy Participants Inoculated with 
Experimental Influenza Virus
Short Title: Phase 2a Influenza Human Challenge Study of MK-4482 in Healthy 
Participants
Acronym: Not applicable.
Hypotheses, Objectives, and Endpoints:
Hypotheses are aligned with objectives in the Objectives and Endpoints table.
This study will be conducted in healthy participants.
Primary Objective
Primary Endpoint
Part 1
Objective 1: To evaluate the infectivity rate 
of the influenza challenge virus in healthy 
adult participants.
Day 1 PM to planned discharge, Day 2 PM 
to planned discharge:
•
Quantitative reverse transcriptase-
polymerase chain reaction (qRT-PCR)-
confirmed influenza infection
Objective 2: To assess the safety of the 
influenza challenge virus in healthy adult 
participants
Viral challenge to Follow-up Visit:
•
Adverse events (AEs) related to viral 
challenge
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Part 2
Objective 3: To evaluate the effectiveness 
of MK-4482 (800 mg Q12H for 5 days) as a 
post-exposure intervention in reducing 
influenza viral load, as compared to 
placebo.
Hypothesis (Post-exposure prophylaxis
[PEP]): MK-4482 (800 mg Q12H for 5 
days), initiated 12 h following intranasal 
inoculation of the influenza challenge virus 
reduces the peak viral load (as determined 
by quantitative viral culture) compared to
placebo.
Hypothesis (Treatment): MK-4482 (800 mg 
Q12H for 5 days), initiated 2 days following 
intranasal inoculation of the influenza 
challenge virus reduces the viral load AUC 
(as determined by quantitative viral culture)
compared to placebo.
PEP (MK-4482) Day 1 PM to planned 
discharge:
•
Peak viral load (PVL) (by quantitative 
viral culture) 
Treatment (MK-4482) First dose of study 
drug to planned discharge:
•
Area under the viral load-time curve
(VL-AUC) (by quantitative viral 
culture)
Secondary Objectives
Secondary Endpoints
Part 1
Objective 4: To characterize the virological 
profile of the influenza challenge virus in 
healthy adult participants
Day 1 PM to planned discharge, Day 2 PM 
to planned discharge:
•
Quantitative viral culture-confirmed 
influenza infection
•
VL-AUC (qRT-PCR and quantitative 
viral culture) 
•
PVL (qRT-PCR and quantitative viral 
culture) 
•
Duration of quantifiable influenza 
(qRT-PCR and quantitative viral 
culture)
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Objective 5: To characterize the clinical 
symptom profile of the influenza challenge 
virus in healthy adult participants.
Day 1 AM to planned discharge, Day 2 
middle of day to planned discharge:
•
Area under the total symptom score-
time curve (TSS-AUC)
•
Peak total symptom score (TSS)
•
Daily maximum TSS 
•
Duration (days) of Grade ≥2 symptoms 
•
Time (days) to symptom resolution 
•
Time (days) to peak daily maximum 
TSS
Part 2
Objective 6: To estimate the effect of MK-
4482 (800 mg Q12H for 5 days) as post-
exposure prophylaxis (initiated 12 h 
following intranasal inoculation of 
influenza challenge virus) or as treatment 
(initiated 2 days following intranasal 
inoculation of influenza challenge virus) on 
the reduction of influenza viral load, as 
compared to placebo.
Objective 7: To estimate the effect of 
oseltamivir (75 mg Q12H for 5 days) as 
treatment (initiated 2 days following 
intranasal inoculation of influenza challenge 
virus) on the reduction of influenza viral 
load, as compared to placebo
PEP (MK-4482) – Virology: Day 1 PM to 
planned discharge:
Symptoms and temperature Day 1 AM to 
planned discharge:
•
VL-AUC (qRT-PCR and quantitative 
viral culture) 
•
PVL (qRT-PCR)
•
qRT-PCR-confirmed influenza infection
•
qRT-PCR-confirmed symptomatic 
influenza infection
•
qRT-PCR-confirmed moderately severe 
symptomatic influenza infection
•
qRT-PCR-confirmed febrile influenza 
infection
•
Quantitative viral culture-confirmed 
influenza infection 
•
Quantitative viral culture-confirmed 
symptomatic influenza infection
•
Duration of quantifiable influenza 
(qRT-PCR and quantitative viral 
culture)
•
Time (days) to confirmed negative test 
(qRT-PCR and quantitative viral 
culture) 
08V4GT


PRODUCT: MK-4482
15
PROTOCOL/AMENDMENT NO.: 019-01
MK-4482-019-01 FINAL PROTOCOL
14-AUG-2023
•
Time (days) to peak viral load (qRT-
PCR and quantitative viral culture)
Treatment (MK-4482 and oseltamivir) –
first dose study drug to planned discharge:
•
VL-AUC (qRT-PCR and quantitative 
viral culture) 
•
PVL (quantitative viral culture and 
qRT-PCR)
•
Duration of quantifiable influenza 
(qRT-PCR and quantitative viral 
culture)
•
Time (days) to confirmed negative test 
(qRT-PCR and quantitative viral 
culture) 
•
Time (days) to peak viral load (qRT-
PCR and quantitative viral culture) 
Objective 8: To evaluate the effect of MK-
4482 (800 mg Q12H for 5 days) as PEP
(initiated 12 h following intranasal 
inoculation of influenza challenge virus) or 
as treatment (initiated 2 days following 
intranasal inoculation of the influenza 
challenge virus) on the course of clinical 
symptoms following intranasal inoculation 
with the influenza challenge virus, 
compared to placebo
Objective 9: To evaluate the effect of 
oseltamivir (75 mg Q12H for 5 days) as 
treatment (initiated 2 days following 
intranasal inoculation of influenza challenge 
virus) on the course of clinical symptoms 
following intranasal inoculation with the 
influenza challenge virus, compared to 
placebo
PEP (MK-4482) – Day 1 AM to planned 
discharge;
Treatment (MK-4482 and oseltamivir) –
first dose study drug to planned discharge:
•
TSS-AUC
•
Peak TSS
•
Daily maximum TSS 
•
Duration (days) of Grade ≥2 symptoms 
•
Time (days) to symptom resolution 
•
Time (days) to peak daily maximum 
TSS
08V4GT


PRODUCT: MK-4482
16
PROTOCOL/AMENDMENT NO.: 019-01
MK-4482-019-01 FINAL PROTOCOL
14-AUG-2023
Objective 10: To assess the safety and 
tolerability of MK-4482 (800 mg Q12H for 
5 days)
PEP (MK-4482) and Treatment (MK-4482)
– from first dose of study drug to Follow-up 
Visit:
•
All AEs
Objective 11: To monitor the safety of the 
influenza challenge virus in healthy adult 
participants
Viral challenge to Follow-up Visit:
•
AEs related to viral challenge
•
Concomitant medication use
Objective 12: To assess the plasma PK of 
NHC following administration of MK-4482 
(800 mg Q12H for 5 days)
PEP (MK-4482) and Treatment (MK-4482):
•
NHC Cmax, Tmax, t1/2, AUC0-12hr, 
AUC0-last, Ctrough following multiple 
dose administration of MK-4482
Overall Design:
Study Phase
Phase 1
Primary Purpose
Treatment
Indication
Influenza
Population
Serosuitable healthy male and female 
participants 18 to 55 years (inclusive) of age
Study Type
Interventional
Intervention Model
This is a single site study.
Type of Control
Placebo
Study Blinding
Double-blind
Blinding Roles
Participants or Subjects
Investigator
Sponsor 
Estimated Duration of Study
The Sponsor estimates that the study will 
require approximately 3 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.
08V4GT


PRODUCT: MK-4482
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PROTOCOL/AMENDMENT NO.: 019-01
MK-4482-019-01 FINAL PROTOCOL
14-AUG-2023
Number of Participants:
Approximately 160 participants will be allocated/randomized.
Intervention Groups and Duration:
Arm Name
Intervention 
Name
Unit Dose 
Strength(s)
Dosage 
Level(s)
Route of 
Administration
Regimen/
Treatment 
Period/
Vaccination 
Regimen
Use
Active
MK-4482 
200 mg 
800 mg
Oral
MK-4482 PEP 
Q12H x 5 days
MK-4482 
Treatment: 
Q12H x 5 days
Test Product
Placebo
Placebo
N/A
N/A
Oral
Matched 
Placebo: 
Q12H x 7 days
MK-4482 
Treatment: 
Q12H Day 5 
PM and Day 6 
MK-4482 
Treatment: 
Q12H Day 0 
PM and Day 1
Placebo 
Placebo
Placebo 
N/A
N/A
Oral 
Oseltamivir 
Treatment: 
Q12H Day 0 
PM and Day 1
Placebo
Comparator 
Oseltamivir 
75 mg
75 mg
Oral
Oseltamivir 
Treatment: 
Q12H x 5 days 
Comparator
Virus 
Inoculation
Influenza A 
Virus
Approximately 
5 to 7 
TCID50*
Approximately 
5 to 7 
TCID50*
Intranasal
Single 
Administration
Challenge 
Agent
PEP = Post-exposure prophylaxis; Q12H = every 12 hours
*The Influenza A/France/759/21 [H1N1] challenge virus used in Part 1 will be prepared to have an inoculum concentration 
of between approximately 5 and 7 Log10 tissue culture infective dose 50% (TCID50/mL). The Influenza A challenge 
virus used in Part 2 will either be Influenza A/France/759/21 [H1N1] (inoculum concentration of between 
approximately 5 and 7 Log10 TCID50/mL) or an alternative virus eg, A/Perth/16/2009 [H3N2] or A/California 2009-
like [H1N1]; the inoculum concentration for an alternative virus is provided in Appendix 11, and final details of the 
virus will be outlined in the Analytical Plan.
08V4GT


PRODUCT: MK-4482
18
PROTOCOL/AMENDMENT NO.: 019-01
MK-4482-019-01 FINAL PROTOCOL
14-AUG-2023
Total Number of Intervention Groups/Arms
4
Duration of Participation
Each participant will participate in the study 
for up to approximately120 days from the 
time the participant provides documented 
informed consent through the final contact.
Participants will be screened for suitability 
for the study under a separate study site 
generic screening process. After a 
screening period of 12 weeks, each 
participant will be in the treatment period 
for approximately 8 days, including PK 
sampling and safety assessments. After the 
end of the treatment period, each participant 
will be followed for 3 weeks.
Study Governance Committees:
Executive Oversight Committee
No
Data Monitoring Committee
No
Clinical Adjudication Committee
No
Study Accepts Healthy Participants: Yes
A list of abbreviations is in Appendix 12.
08V4GT


PRODUCT: MK-4482
19
PROTOCOL/AMENDMENT NO.: 019-01
MK-4482-019-01 FINAL PROTOCOL
14-AUG-2023
1.2
Schema
The study design is depicted in Figure 1 and Figure 2.  The study interventions for Part 2 are 
shown in Table 1.
Figure 1
Study Schematic 
Figure 2
Study Schema
Table 1
Study Interventions – Part 2
Interventionᵃ
Day 0 PM – Day 1 PM 
(inclusive)
Day 2 AM-Day 5 AM 
(inclusive)
Day 5 PM -Day 6 PM 
(inclusive)
MK-4482 PEP
MK-4482 800 mgb Q12H 
MK-4482 800 mgb Q12H
Placebo (MK-4482)c Q12H
MK-4482 Tx
Placebo (MK-4482)c Q12H
MK-4482 800 mgb Q12H
MK-4482 800 mgb Q12H
OTV Tx
Placebo (OTV)d Q12H
OTV 75 mge Q12H
OTV 75 mge Q12H
Placebo
Placebo (MK-4482)c Q12H
Placebo (MK-4482)c
Q12H
Placebo (MK-4482)c Q12H
OTV = oseltamivir, PEP = post-exposure prophylaxis, Q12H = every 12 hours, Tx = treatment
a.
Participants will be randomly assigned to one of four interventions, which will be dosed in a blinded fashion. In 
order to maintain the blind, all participants will receive 4 capsules at each dose administration and will be 
blindfolded during dosing.
b.
MK-4482 will be dosed as 4 x 200 mg capsules
c.
Placebo (MK-4482) is an identical match to MK-4482, ie, 4 capsules
d.
Placebo (OTV) is a similar size and weight to OTV; 4 capsules will be administered
e.
1 capsule of OTV 75 mg plus 3 capsules of placebo (OTV) will be administered
08V4GT


PRODUCT: MK-4482
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PROTOCOL/AMENDMENT NO.: 019-01
MK-4482-019-01 FINAL PROTOCOL
14-AUG-2023
1.3
Schedule of Actvities
Part 1a
Study Period:
Screeningb
Inpatient Quarantinec
Follow 
up
Early 
WithdrawaldNotes
Scheduled Dayc
Day -90 to 
Day -2/-1 D-2e D-1e
D0
D1
D2 D3 D4 D5
D6 D7 D8
D28 (+/-
3 days)
Post-
Challenge
Pre
Challenge
Post
Administrative/Study Procedures
Informed Consent
X
X
Sec. 5.1, 8.1.1
Informed Consent for FBR
X
Sec. 5.1, 
8.1.1.2
Participant ID Card
X
Sec. 8.1.3
Inclusion/Exclusion Criteria
X
X
X
X
Sec. 5.1,
5.2, 8.1.2
Medical History
X
X
Sec. 8.1.4
Prior/Concomitant Medication 
Review
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
(X)
Sec. 5.2, 6.5,
8.1.6
Patient Health Questionnaire 
(PHQ-9)
(X)
(X)
Sec. 8.1.5
Generalized Anxiety Disorder 
Questionnaire (GAD-7)
(X)
(X)
Sec. 8.1.5
Participant Visits to Clinical 
Research Unit
X
X
X
Sec. 8.1.12,
8.14
Domiciling
X
X
X
X
X
X
X
X
X
X
X
X
X
Sec. 8.1.12
Assignment of Study-specific 
Screening Number
X
Sec. 8.1.7
Assignment of Allocation Number
X
Assigned prior
to virus 
inoculation.
Sec.8.1.8
Influenza Inoculation
X
Sec. 8.3
08V4GT


PRODUCT: MK-4482
21
PROTOCOL/AMENDMENT NO.: 019-01
MK-4482-019-01 FINAL PROTOCOL
14-AUG-2023
Part 1a
Study Period:
Screeningb
Inpatient Quarantinec
Follow 
up
Early 
WithdrawaldNotes
Scheduled Dayc
Day -90 to 
Day -2/-1 D-2e D-1e
D0
D1
D2 D3 D4 D5
D6 D7 D8
D28 (+/-
3 days)
Post-
Challenge
Pre
Challenge
Post
Safety Procedures
Full Physical Examination
X
X
X
X
(X)
Sec. 8.5.1
Directed Physical Examination 
(including nasal)
X
X
X
X
X
X
X
X
Sec. 8.5.1
Height, Weight, BMI
X
X
X
X
(X)
Height and 
BMI at 
Screening 
only. Sec. 
8.5.1
VS (HR, RR, SBP, DBP, SpO2)
X
X
X
X
X
X
X
X
X
X
X
X
X
(X)
Sec. 8.5.2
Body Temperature
X
X
3X
3X
3X
3X 3X 3X 3X
3X 3X
X
X
(X)
Sec. 8.5.2
12-lead ECG
X
X
X
X
X
(X)
Day -2 ECG 
will be 
triplicate.
All other
ECGs will be 
single 
measurements
.Sec. 8.5.3.
Spirometry
X
X
X
X
Sec. 8.5.4
Calculation of eGFR
X
Sec. 5.2
Alcohol Breath Test
X
X
App. 2
Urine Drugs of Abuse and Nicotine 
Screen
X
X
App. 2
08V4GT


PRODUCT: MK-4482
22
PROTOCOL/AMENDMENT NO.: 019-01
MK-4482-019-01 FINAL PROTOCOL
14-AUG-2023
Part 1a
Study Period:
Screeningb
Inpatient Quarantinec
Follow 
up
Early 
WithdrawaldNotes
Scheduled Dayc
Day -90 to 
Day -2/-1 D-2e D-1e
D0
D1
D2 D3 D4 D5
D6 D7 D8
D28 (+/-
3 days)
Post-
Challenge
Pre
Challenge
Post
Hematology
X
X
X
X
X
X
X
X
X
X
(X)
Sec. 8.5.5,
App. 2 & 8
Urinalysis
X
X
(X)
Sec. 8.5.5, 
App. 2
Chemistry
X
X
X
X
X
(X)
Sec. 8.5.5, 
App. 2& 8
Coagulation (PT/aPTT)
X
Sec. 4.2.1.3,
App. 2 & 8
Thyroid Function Test
X
Sec. 4.2.1.3,
App. 2 & 8
Creatine Kinase and Troponin
X
Sec. 4.2.1.3,
App. 2 & 8
Urine Pregnancy Test 
X
X
(X)
POCBP only. 
Sec. 8.5.6,
App. 2
Serum β-HCG pregnancy test
X
POCBP only. 
Sec. 8.5.6,
App. 2
& 8
Serum FSH 
X
Postmenopausa
l females only.
Sec.
5.1, App. 2 &
5
HIV, hepatitis B and C screen 
X
Sec. 8.5.5,
App. 2 & 8
08V4GT


PRODUCT: MK-4482
23
PROTOCOL/AMENDMENT NO.: 019-01
MK-4482-019-01 FINAL PROTOCOL
14-AUG-2023
Part 1a
Study Period:
Screeningb
Inpatient Quarantinec
Follow 
up
Early 
WithdrawaldNotes
Scheduled Dayc
Day -90 to 
Day -2/-1 D-2e D-1e
D0
D1
D2 D3 D4 D5
D6 D7 D8
D28 (+/-
3 days)
Post-
Challenge
Pre
Challenge
Post
AE review
X
X
X
X
X
X
X
X
X
X
X
X
X
(X)
Sec. 8.6, App.
3
Efficacy Assessments
Symptom diary card
X
3X
3X
3X
3X 3X 3X 3X
3X 3X
X
Sec. 8.4.1
FLU-PRO Plus© Questionnaire and 
global impression questions 
X
X
X
X
X
X
X
X
X
Sec. 8.4.2
24-hour tissue count & nasal 
discharge weight
X
X
X
X
X
X
X
X
X
X
(X)
Sec. 8.4.3
Respiratory Samples
NPS - Respiratory Pathogen Screen 
Including SARS-CoV-2 (eg,
Biofire)
X
Sec. 8.4.4
NPS – Viral Discharge Test
(X) (X)
Sec. 8.4.4
NPS – Virology
X
2X
2X 2X 2X 2X
2X 2X
X
Sec 8.4.4
Nasal Sample for Mucosal 
Antibodies and Inflammatory 
Markers.
X
Sec 8.4.5
Biomarkers
Blood - Serum Markers Humoral 
immunity
X
X
X
(X)
Sec. 8.2, 8.10
Blood – Serum Exploratory 
Immunological Biomarkers
X
X
X
X
X
X
X
Sec. 8.10, 
collected in the 
PM
08V4GT


PRODUCT: MK-4482
24
PROTOCOL/AMENDMENT NO.: 019-01
MK-4482-019-01 FINAL PROTOCOL
14-AUG-2023
Part 1a
Study Period:
Screeningb
Inpatient Quarantinec
Follow 
up
Early 
WithdrawaldNotes
Scheduled Dayc
Day -90 to 
Day -2/-1 D-2e D-1e
D0
D1
D2 D3 D4 D5
D6 D7 D8
D28 (+/-
3 days)
Post-
Challenge
Pre
Challenge
Post
Blood for Genetic Analysis
X
May be 
collected 
within 24 hrs 
prior to or 
post 
allocation/ran
domization. 
In 
allocated/rand
omized 
participants 
only. Sec.
8.11.1 & App.
8
08V4GT


PRODUCT: MK-4482
25
PROTOCOL/AMENDMENT NO.: 019-01
MK-4482-019-01 FINAL PROTOCOL
14-AUG-2023
Part 1a
Study Period:
Screeningb
Inpatient Quarantinec
Follow 
up
Early 
WithdrawaldNotes
Scheduled Dayc
Day -90 to 
Day -2/-1 D-2e D-1e
D0
D1
D2 D3 D4 D5
D6 D7 D8
D28 (+/-
3 days)
Post-
Challenge
Pre
Challenge
Post
AE=adverse event; App=Appendix; aPTT=activated partial thromboplastin time; β-HCG=beta human chorionic gonadotropin; BMI=body mass index; D=day; DBP=diastolic 
blood pressure; ECG=electrocardiogram; FSH=follicle stimulating hormone; GAD=generalized anxiety disorder; HIV=human immunodeficiency virus; HR=heart rate; 
hrs=hours; ID=identification; NPS=nasopharyngeal swab; PHQ=patient health questionnaire; PI=principal investigator; PT=prothrombin time; RR=respiratory rate; SARS-CoV-
2=severe acute respiratory syndrome coronavirus 2; SBP=systolic blood pressure; SpO2=oxygen saturation; VS=vital signs; POCBP=participant of childbearing potential.
a All procedures to be conducted in accordance with site’s SOPs (unless otherwise indicated).
b. Screening procedures will be performed under a generic screening process. Historical prescreening data collected through the generic screening process within 90 days (90 days
for viral serology and 56 days for other assessments including safety laboratory test) prior to inoculation may be used to determine eligibility without the need to repeat the 
assessments following study-specific consent. Study-specific consent may occur on day of admission, provided all required eligibility information has been collected through 
the Health Research Authority approved generic screening process.
c. All inpatient procedures should occur in line with inoculation day.
d Refer to Section 8.1.10 for details on discontinuation/withdrawal 
e. Participants will be admitted to quarantine on Day -2 or Day -1. If participants are admitted on Day-1 then all procedures on Day-2 may be performed on Day-1 instead, as 
applicable.
Notes:

3X: assessment conducted three times during the 24-hour period

2X: assessment conducted twice during the 24-hour period

X assessment conducted once during the 24-hour period.

(): indicate an assessment is optional and may be conducted in accordance with PI discretion
08V4GT


PRODUCT: MK-4482
26
PROTOCOL/AMENDMENT NO.: 019-01
MK-4482-019-01 FINAL PROTOCOL
14-AUG-2023
Part 2a
Study Period:
Screeningb
Inpatient Quarantinec
Follow 
up
Early 
Withdrawald Notes
Scheduled Day
Day -90 to 
Day -2/-1
D-
2e
D-
1e
D0
D1 D2 D3 D4 D5 D6 D7 D8
D28 
(+/- 3 
days)
Post-
Challenge
Pre
Challenge
Post
Administrative/Study Procedures
Informed Consent
X
X
Sec. 5.1, 8.1.1
Informed Consent for FBR
X
Sec. 5.1, 8.1.1.2
Participant ID Card
X
Sec. 8.1.3
Inclusion/Exclusion Criteria
X
X
X
X
Sec. 5.1,
5.2, 8.1.2
Medical History
X
X
Sec. 8.1.4
Prior/Concomitant 
Medication Review
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
(X)
Sec. 5.2, 6.5, 8.1.6
Patient Health Questionnaire 
(PHQ-9)
(X)
(X)
Sec. 8.1.5
Generalized Anxiety Disorder 
Questionnaire (GAD-7)
(X)
(X)
Sec. 8.1.5
Participant Visits to Clinical 
Research Unit
X
X
X
Sec. 8.1.12, 8.14
Domiciling
X
X
X
X
X
X
X
X
X
X
X
X
X
Sec. 8.1.12
Assignment of Study-specific 
Screening Number
X
Sec. 8.1.7
Assignment of 
Randomization Number
X
Assigned prior to virus 
inoculation. Sec.8.1.8
Influenza Inoculation
X
Sec. 8.3
Study Drug Administration
X
2X 2X 2X 2X 2X 2X
Intervention will be 
administered Q12H.
Sec. 8.1.9
Safety Procedures
Full Physical Examination
X
X
X
(X)
Sec. 8.5.1
08V4GT


PRODUCT: MK-4482
27
PROTOCOL/AMENDMENT NO.: 019-01
MK-4482-019-01 FINAL PROTOCOL
14-AUG-2023
Part 2a
Study Period:
Screeningb
Inpatient Quarantinec
Follow 
up
Early 
Withdrawald Notes
Scheduled Day
Day -90 to 
Day -2/-1
D-
2e
D-
1e
D0
D1 D2 D3 D4 D5 D6 D7 D8
D28 
(+/- 3 
days)
Post-
Challenge
Pre
Challenge
Post
Directed Physical 
Examination (Including 
Nasal)
X
(X) (X) (X) (X) (X) (X) (X)
(X)
Sec. 8.5.1
Height, Weight, BMI
X
X
X
X
(X)
Height and BMI at 
Screening only. Sec. 8.5.1
VS (HR, RR, SBP, DBP, 
SpO2)
X
X
X
X
X
X
X
X
X
X
X
X
X
(X)
Sec. 8.5.2
AM Predose only
Body Temperature
X
X
3X
3X
3X 3X 3X 3X 3X 3X 3X
X
X
(X)
Sec. 8.5.2
12-lead ECG
X
X
(X) (X) (X) (X) (X) (X) (X)
X
X
(X)
Day-2 ECG will be 
triplicate.
All subsequent ECGs 
will be single 
measurements Sec. 8.5.3.
Spirometry
X
(X) (X) (X) (X) (X) (X) (X) (X)
Sec. 8.5.4
Calculation of eGFR
X
Sec. 5.2
Alcohol Breath Test
X
X
App. 2
Urine Drugs of Abuse and 
Nicotine Screen
X
X
App. 2
Hematology
X
X
(X) (X) (X) (X) (X) (X)
X
X
(X)
Sec. 8.5.5, App. 2 & 8
Urinalysis
X
X
(X)
Sec. 8.5.5, App. 2
Chemistry
X
X
(X) (X) (X) (X) (X) (X)
X
X
(X)
Sec. 8.5.5, App. 2 & 8
Coagulation (PT/aPTT)
X
Sec. 4.2.1.3,
App. 2 & 8
08V4GT


PRODUCT: MK-4482
28
PROTOCOL/AMENDMENT NO.: 019-01
MK-4482-019-01 FINAL PROTOCOL
14-AUG-2023
Part 2a
Study Period:
Screeningb
Inpatient Quarantinec
Follow 
up
Early 
Withdrawald Notes
Scheduled Day
Day -90 to 
Day -2/-1
D-
2e
D-
1e
D0
D1 D2 D3 D4 D5 D6 D7 D8
D28 
(+/- 3 
days)
Post-
Challenge
Pre
Challenge
Post
Thyroid Function Test
X
Sec. 4.2.1.3,
App. 2 & 8
Creatine Kinase and Troponin
X
Sec. 4.2.1.3,
App. 2 & 8
Urine Pregnancy Test 
X
X
(X)
POCBP only. Sec. 8.5.6,
App. 2
Serum β-HCG Pregnancy 
Test
X
POCBP only. Sec. 8.5.6,
App. 2
& 8
Serum FSH 
X
Postmenopausal females
only. Sec.
5.1, App. 2 & 5
HIV, Hepatitis B and C 
Screen 
X
Sec. 8.5.5,
App. 2 & 8
AE Review
X
X
X
X
X
X
X
X
X
X
X
X
X
(X)
Sec. 8.6, App. 3
Efficacy Assessments
Symptom Diary Card
X
3X
3X
3X 3X 3X 3X 3X 3X 3X
X
Sec. 8.4.1
FLU-PRO Plus©
Questionnaire and global 
impression questions
X
X
X
X
X
X
X
X
X
Sec. 8.4.2
24-hour Tissue Count & 
Nasal Discharge Weight
X
X
X
X
X
X
X
X
X
X
(X)
8.4.3
Respiratory Samples
NPS - Respiratory Pathogen 
Screen Including SARS-
COV-2 (eg, Biofire)
X
Sec. 8.4.4
08V4GT


PRODUCT: MK-4482
29
PROTOCOL/AMENDMENT NO.: 019-01
MK-4482-019-01 FINAL PROTOCOL
14-AUG-2023
Part 2a
Study Period:
Screeningb
Inpatient Quarantinec
Follow 
up
Early 
Withdrawald Notes
Scheduled Day
Day -90 to 
Day -2/-1
D-
2e
D-
1e
D0
D1 D2 D3 D4 D5 D6 D7 D8
D28 
(+/- 3 
days)
Post-
Challenge
Pre
Challenge
Post
NPS – Viral Discharge Test
(X) (X)
Sec. 8.4.4
NPS – Virology
X
2X 2X 2X 2X 2X 2X 2X
X
Sec. 8.4.4
Nasal Sample for Mucosal 
Antibodies and Inflammatory 
Markers.
X
Sec 8.4.5
Pharmacokineticsf
Blood for Plasma MK-4482 
and/ or Metabolites Assay
X
X
X
X
X
X
X
Sampling Times  
D0, D2, D4: predose
D5: predose, 0.5, 1.5, 4, 
8, 12, 24, 48, 72 hr. Sec. 
8.8.1
Blood for Plasma Oseltamivir 
and/or Metabolites Assay
X
At 4 hr post AM dose
Sec. 8.8.2
Biomarkers
Blood - Serum Markers 
Humoral immunity
X
X
X
(X)
Sec. 8.2, 8.10
Blood – Serum Exploratory 
Immunological Biomarkers
X
X
X
X
X
X
X
Sec. 8.10, collected in the 
PM
Blood for Genetic Analysis 
X
May be collected within 
24 hrs prior to or post 
allocation/randomization. 
In allocated/randomized 
participants only.. Sec.
8.11.1 & App.
8
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Part 2a
Study Period:
Screeningb
Inpatient Quarantinec
Follow 
up
Early 
Withdrawald Notes
Scheduled Day
Day -90 to 
Day -2/-1
D-
2e
D-
1e
D0
D1 D2 D3 D4 D5 D6 D7 D8
D28 
(+/- 3 
days)
Post-
Challenge
Pre
Challenge
Post
AE=adverse event; App=Appendix; aPTT=activated partial thromboplastin time; β-HCG=beta human chorionic gonadotropin; BMI=body mass index; D=day; DBP=diastolic 
blood pressure; ECG=electrocardiogram; FSH=follicle stimulating hormone; HIV=human immunodeficiency virus; HR=heart rate; hrs=hours; ID=identification; 
NPS=nasopharyngeal swab; PI=principal investigator; PT=prothrombin time; RR=respiratory rate; SARS-COV-2=severe acute respiratory syndrome coronavirus 2; 
SBP=systolic blood pressure; SpO2=oxygen saturation; VS=vital signs; WOCBP=women of childbearing potential.
a All procedures to be conducted in accordance with site’s SOPs (unless otherwise indicated).
b Screening procedures will be performed under a generic screening process. Historical prescreening data collected through a generic screening process within 90 days (90 days
for viral serology and 56 days for other assessments including safety laboratory test) prior to inoculation may be used to determine eligibility without the need to repeat the 
assessments following study-specific consent. Study-specific consent may occur on day of admission, provided all required eligibility information has been collected through 
the Health Research Authority approved generic screening process.
c . All inpatient procedures should occur in line with inoculation day.
d. Refer to Section 8.1.10 for details on discontinuation/withdrawal
e . Participants will be admitted to quarantine on Day -2 or Day -1. If participants are admitted on Day-1 then all procedures on Day-2 may be performed on Day-1 instead, as 
applicable.
f All samples should be collected with respect to the AM dose of study drug only. All predose and 12 hr samples should be collected prior to the next scheduled dose. Windows 
for PK sampling are provided in Section 8.14.6.
Notes:

3X: assessment conducted three times during the 24-hour period

2X: assessment conducted twice during the 24-hour period

X assessment conducted once during the 24-hour period.

(): indicate an assessment is optional and may be conducted in accordance with PI discretion
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2
INTRODUCTION
IAV and IBV generally circulate annually, with several strains predominating in any given 
season and are responsible for seasonal epidemics of disease nearly every winter in temperate 
climates. Despite the availability of annual influenza vaccines and a number of approved 
antiviral treatments, there is still an unmet medical need for the treatment of influenza. 
During the 2018 to 2019 influenza season, an estimated 29 million cases occurred in the US, 
resulting in 13 million medical visits, 380,000 hospitalizations, and 28,000 deaths [Centers 
for Disease Control and Prevention 2022]. Most deaths occur in patients of advanced age, 
although young children are also at increased risk of severe disease with complications of 
hospitalizations and infrequently death. Though patterns of viral respiratory disease were 
disrupted with the COVID-19 pandemic, non-COVID-19 respiratory viruses will continue to 
present a significant health care burden. 
Influenza virus transmission is primarily through direct person-to-person respiratory spread 
via large droplets or aerosols. Longer range transmission via the airborne route as well as 
transmission through contact with fomites are also possible. The average incubation period is 
two days, with a range one to four days. Viral replication takes place predominantly in the 
respiratory tract epithelial lining. This, in combination with the host immune response, 
results in lung inflammation. Symptoms may include fever, cough, muscle pain, malaise, 
sore throat, nasal congestion, and headache. Additionally, gastrointestinal symptoms such as 
vomiting, diarrhea, nausea, and abdominal pain may occur, although these tend to be more 
common in children than in adults.
2.1
Study Rationale
MK-4482 (molnupiravir) is an orally administered prodrug of the ribonucleoside analogue 
NHC that inhibits the replication of a range of RNA viruses by viral mutagenesis. Clinical 
development is ongoing for the treatment and prevention of COVID-19 and is planned for the 
treatment and prophylaxis of other viral respiratory infections. The purpose of this study is to 
assess the antiviral activity of a regimen of MK-4482 800 mg Q12H x 5 days in treatment 
and PEP of acute IAV infection in a human challenge disease model of IAV experimental 
intranasal inoculation. Virological and clinical data from this study may be used to inform
future clinical development of MK-4482 against influenza.
Extensive nonclinical and clinical safety experience have supported the development of MK-
4482 to date; furthermore, the proposed dosing regimen for this study (800 mg Q12H x 5 
days) is the same as that currently used for the treatment of mild to moderate COVID-19. 
The current study will provide further assessments of the safety and tolerability of MK-4482,
as well as of the plasma PK of NHC and viral dynamics following inoculation with IAV. 
2.1.1
Overview of Influenza Human Challenge Model
The human viral challenge model has furthered understanding of respiratory viruses such as 
influenza, providing insight into disease pathogenesis and supporting the development of 
novel vaccines and therapeutics [Lambkin-Williams, R., et al 2018]. 
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The intent of this study is to use a human challenge model, in which a fixed inoculum of IAV 
is administered intranasally to healthy adults (whose eligibility for participation includes 
serosuitability, ie, a requirement for low pre-existing immunity to the challenge virus) in a 
controlled setting, allowing for an evaluation of MK-4482 (including assessment of nasal 
viral shedding and prospective symptom evaluation) when initiated at fixed time points 
relative to a known time of inoculation [Lambkin-Williams, R., et al 2018]. 
This study will evaluate the impact of MK-4482 on influenza viral load and on clinical 
symptoms. Previous influenza human challenge studies (using predominantly wild-type 
A/H1N1 or A/H3N2 subtypes) have reported an increase in viral shedding on the first day 
post-inoculation, peaking on day 2/3, with a duration of viral shedding of up to ~5 days, and 
a positive association between quantity of virus shed and symptom severity. Experimental 
influenza infection with these wild-type challenge viruses typically causes mild to moderate 
disease with mostly upper respiratory tract and systemic symptoms. As expected in a healthy 
younger population, the disease is similar in severity to natural community-acquired 
infection; in particular, healthy younger people very rarely exhibit more severe lower 
respiratory tract infection requiring hospitalization. Systemic symptoms (fever, myalgia, 
fatigue, and headache) tended to peak on day 2, whereas respiratory symptoms (with upper 
respiratory symptoms predominating over lower respiratory symptoms) peaked on day 3
[Carrat, F., et al 2008]. In previous human challenge studies performed by hVIVO with 
A/Perth/16/2009 [H3N2], infectivity rates of ~69%, 62%, and 48%, defined by detectable by 
PCR, quantifiable by PCR, and quantifiable by viral culture, respectively, have been 
observed in untreated/placebo-treated participants. Similarly, in studies with A/California 
2009-like [H1N1] performed by hVIVO, infectivity rates of ~50%, 47%, and 33%, defined 
by detectable by PCR, quantifiable by PCR, and quantifiable by viral culture, respectively, 
have been observed in untreated/placebo-treated participants. These are comparable to rates 
seen by other groups using the same challenge virus [Sloan, S. E., et al 2020] [Watson, J. M., 
et al 2015].
A fixed viral inoculum will be used, based on experience from previous influenza human 
challenge studies.
Typically, the majority of influenza challenge studies to date have employed IAV strains, 
with a particular focus on the H1N1 and H3N2 serotypes, reflecting that these two serotypes 
have been responsible for the majority of influenza pandemics of the 20th and 21st centuries
[Balasingam, S. 2016]. An IAV strain will be the challenge agent used in this study. The 
preferred agent is an influenza H1N1 virus from the 6B.1A.5a.1 clade
(A/France/759/21 [H1N1]), isolated from a patient with a community-acquired infection, and 
produced in a GMP-qualified Vero cell line. According to surveillance reports, the 
6B.1A.5a.1 clade is one of the predominant clades in Europe [European Centre for Disease 
Prevention and Control 2022]. Furthermore, based on surveillance, there is anticipated to be a 
lower level of immunity in the population to this more recent strain, as compared to influenza 
viral strains used in previous influenza challenge studies; therefore, higher rates of 
serosuitability and infectivity are predicted. However, this more recent strain will require 
validation in humans prior to its use as a challenge agent for the evaluation of MK-4482; this 
validation will be conducted during Part 1 of this study.
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Part 1 (Validation) will characterize the A/France/759/21 [H1N1] strain in 20 participants in 
the absence of study drug. Assuming a satisfactory outcome of Part 1 (based on safety, 
tolerability, rate of infectivity, and viral load and symptom profile), Part 2 will use the same 
challenge virus to evaluate the performance of MK-4482 in the challenge model; 
alternatively, a different viral strain that has been well-characterized in previous HCS (eg,
A/Perth/16/2009 [H3N2] or A/California 2009-like [H1N1]) will be utilized in Part 2. See 
Appendix 11 for further information on the alternative viral strains.
2.2
Background
Refer to the IB/approved labeling for detailed background information on MK-4482.
2.2.1
Pharmaceutical and Therapeutic Background
MK-4482 is the 5´-isobutyrate prodrug of the broadly active, direct-acting antiviral 
ribonucleoside analog NHC. MK-4482 is hydrolyzed by esterases either during or after 
absorption to deliver NHC into systemic circulation. NHC inhibits replication of multiple 
RNA virus families including pathogenic Coronaviruses (eg, MERS, SARS-CoV and SARS-
CoV-2), influenza viruses (seasonal, pandemic and avian subtypes), and RSV. Inside cells, 
the active nucleoside triphosphate anabolite of MK-4482 (NHC-TP) acts as a competitive, 
alternative substrate for the virally encoded RNA-dependent RNA polymerase. Upon 
incorporation into nascent chain RNA, NHC-TP induces increased mutational frequency in 
the viral genome resulting in viral error catastrophe and production of nonviable virus 
[Flavell, R. A., et al 1974] [Gordon CJ, Tchesnokov EP, Schinazi RF, Götte M. 2021] 
[Kabinger F, Stiller C, Schmitzová J, Dienemann C, Kokic G, Hillen HS, et al. 2021].
Following administration of MK-4482 in humans, NHC appears rapidly in plasma (median 
Tmax ranging from approximately 1.5 to 2 hours).  Minimal to no accumulation of NHC 
exposure, in terms of AUC0-12 and Cmax, was observed in healthy participants following 
multiple-dose administration of MK-4482.  No significant differences in NHC PK between 
healthy participants and participants infected with SARS-CoV-2 have been observed.  
Currently, four agents are approved for the treatment/prevention of influenza disease: oral 
oseltamivir, oral baloxavir, inhaled zanamivir, and IV peramivir. However, due to concerns 
around emerging resistance, there is a continued need for new therapeutic/prophylactic 
antiviral agents. 
2.2.2
Preclinical Studies
MK-4482 and NHC inhibit replication of viral pathogens from multiple RNA virus families, 
including pathogenic coronaviruses (SARS-CoV-2, MERS-CoV), alphaviruses (Venezuelan 
Equine Encephalitis virus), orthomyxoviruses (influenza) and paramyxoviruses (RSV). 
Primary pharmacology studies demonstrating the antiviral activity of MK-4482 when 
administered as NHC against SARS-CoV-2 and other RNA viruses were conducted in vitro 
and in mouse, guinea pig, hamster, and ferret models of coronavirus, RSV, and influenza
infection. 
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Published studies by Yoon et al. have demonstrated the antiviral activity of NHC with in 
vitro and in vivo preclinical models of influenza infection [Yoon, J. J., et al 2018]. NHC 
exhibits dose-dependent inhibition of viral replication against a broad panel of IAV and IBV 
laboratory strains and isolates with EC50 values in the low- to sub-micromolar range.
Studies in a ferret model of influenza virus infection demonstrated that administration of 
MK-4482 provided therapeutic benefit against IAV (H1N1). MK-4482 in doses of 0.8, 2.3, 
or 7 mg/kg (3.5 mL) by oral gavage BID was tested in a ferret model of influenza virus 
infection and disease. Animals were infected intranasally with 1 × 105 pfu (200 µL) of IAV 
H1N1 virus and MK-4482 dosing was initiated 12 hours later. Treatment with 7 mg/kg BID 
led to a reduction in shed virus load by multiple orders of magnitude, and alleviated fever 
and inflammation while improving airway epithelium histopathology. Treatment with 2.3 
mg/kg BID resulted in moderate reduction of virus titer but no significant reduction of fever. 
The 0.8 mg/kg dose BID had no significant therapeutic effect. By 48 hours post-infection, the 
disease in ferrets began to self-resolve; therefore, initiating treatment up to 36 hours post-
infection allows for detection of antiviral activity before self-resolution of disease. 
Administered in 12-hour intervals, three 7 mg/kg doses of MK-4482 were sufficient for 
maximal therapeutic benefit against a pandemic IAV and significantly shortened the time to 
resolution of clinical signs. Ferrets infected with pandemic IAV (H1N1) and treated with 
MK-4482 at a dose of 7 mg/kg demonstrated significantly less viral shedding and 
inflammatory cellular infiltrates in nasal lavages but mounted a normal humoral antiviral 
response [Toots, M., et al 2020]. A similar study using ferrets infected intranasally with 1 × 
106 pfu (200 µL) of IAV H3N2 virus demonstrated the same results for MK-4482 (0.8, 2.3, 
or 7 mg/kg by oral gavage BID) in the seasonal IAV model. When examining the effect of 
delayed dosing in a different study in the same pandemic IAV ferret model (H1N1), the study
demonstrated that treatment with 20 mg/kg of MK-4482 initiated 24 hours after challenge 
with IAV (H1N1) resulted in a rapid decrease in both shed virus and fever relative to control, 
with fever returning to baseline at 24 hours. When OTV (20 mg/kg, corresponding to 2x the 
human equivalent dose for treatment) was administered prophylactically as a positive control, 
a modest suppression of fever was observed; however, there was no reduction in shed virus 
titer [Toots, M., et al 2019].
MK-4482 was evaluated in nonclinical safety studies, including a standard battery of in vitro 
and in vivo safety pharmacology studies, genotoxicity assays (including Ames assays, in 
vitro and in vivo micronucleus assays, an in vivo Pig-a assay in rats, and an in vivo mutation 
assay in Big Blue® transgenic rats), tolerability/dose-range-finding studies in mice, rats, and 
dogs, repeat-dose toxicity studies of up to 3 months in rats and 1 month in mice and dogs, a 
6-month oral carcinogenicity study in rasH2 transgenic mice, fertility studies in male and 
female rats, embryo-fetal developmental toxicity studies in rats and rabbits, a pre- and 
postnatal developmental toxicity study in rats, and toxicity studies in juvenile rats. Additional 
nonpivotal short-term tolerability and/or TK studies were conducted in mice, rats, rabbits, 
and monkeys.
MK-4482 was devoid of effects on CNS, respiratory, or cardiovascular functions in well-
characterized safety pharmacology models. Based on the totality of genotoxicity data, MK-
4482 is not mutagenic or genotoxic in in vivo mammalian systems.
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Target organs of toxicity identified in the repeat-dose toxicity studies were limited to bone 
marrow in dogs only, and growth plate in rats only. Hematologic changes observed after 
7 days of dosing in the dog 28-day toxicity study were mild and reversible on 
discontinuation, and hematopoietic effects have not been in clinical studies to date with a 
dose of 800 mg Q12H x 5 days. The growth plate findings are not relevant to adult humans, 
because growth plates are no longer present in the mature skeleton of adult humans. MOV 
was not carcinogenic in a 6-month oral carcinogenicity study in rasH2 transgenic CByB6F1 
Tg(HRAS)2Jic hemizygous mice at any dose tested (0, 30, 100, and 300 mg/kg/day).
In fertility studies in rats there were no MK-4482-related effects on female or male fertility, 
or on early embryonic development up to the highest dose tested, 500 mg/kg/day, (2.3-/6.8-
fold [female/male] the clinical NHC exposure at 800 mg Q12H). In pregnant rats 
administered MK-4482 during the organogenesis period, developmental toxicity including 
embryolethality (post-implantation losses) and malformations/teratogenicity was observed at 
1000 mg/kg/day (8.4-fold the clinical NHC exposure at 800 mg Q12H), and reduced fetal 
growth was noted at ≥500 mg/kg/day (≥3.2-fold the clinical NHC exposure at 800 mg 
Q12H). There was no developmental toxicity at doses up to 250 mg/kg/day (0.9-fold the 
clinical NHC exposure at 800 mg Q12H). Maternal toxicity included decreased food 
consumption and body weight losses, resulting in the early sacrifice at 1000 mg/kg/day, and 
decreased body weight gain at ≥500 mg/kg/day. In pregnant rabbits, developmental toxicity 
was limited to reduced mean fetal body weights at 750 mg/kg/day (20-fold the clinical NHC 
exposure at 800 mg Q12H).
There was no developmental toxicity in rabbits up to 400 mg/kg/day (7.2-fold the clinical 
NHC exposure at 800 mg Q12H). Maternal toxicity included decreased food consumption 
and body weight gain, and abnormal fecal output at ≥400 mg/kg/day. In the pre- and
postnatal developmental study in rats, there was no F0 maternal or F1 generation toxicity up 
to the highest dose evaluated of 500 mg/kg/day (1.8-fold the clinical NHC exposure at 
800 mg Q12H).
Further details of preclinical studies are provided in the IB. Collectively, the safety 
pharmacology and toxicology results support continued clinical development of MK-4482.
2.2.3
Completed and Ongoing Clinical Studies
2.2.3.1
Completed Clinical Studies
MK-4482 has been evaluated in 11 completed or clinically completed (ie, the last participant
visit was completed but final data are pending) clinical trials, as summarized below. (Refer to 
the IB Section 5 for additional details of the study designs on each study).
Phase 1 Studies:
MK-4482-004 was a randomized, double-blind, placebo-controlled, first in human study 
designed to evaluate the safety, tolerability, and PK of MK-4482 following oral 
administration to healthy participants. Oral doses (50 to 1600 mg as a single dose, including 
200 mg with a high-fat meal, and 50 to 800 mg as multiple doses [Q12H for 5.5 days]) of 
MK-4482 or placebo administered to 130 healthy participants were generally well tolerated. 
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Out of these 130 participants, 100 received at least one dose of MK-4482. No deaths or SAEs 
were reported.
MK-4482-008 was a single and multiple dose, randomized, placebo-controlled, double-blind 
study of MK-4482 in healthy Japanese adult male participants. Single doses of MK-4482 up 
to 1600 mg, including 800 mg with a high-fat meal, and multiple doses of MK-4482 400 mg 
and 800 mg Q12H for 5.5 days were generally well tolerated in healthy Japanese male adult 
participants. Out of 65 randomized participants, 51 received at least 1 dose of MK-4482. No 
SAEs, deaths or ECIs were reported.
MK-4482-010 was a randomized, 4-treatment, 4-period crossover, single site, open-label, 
relative bioavailability study of MK-4482 oral granules and MK-4482 reference capsule 
formulations in healthy adult participants. A total of 16 participants were randomized into 
4 treatment sequences consisting of a single 800-mg dose of MK-4482 administered as oral 
granules in water, apple sauce or pudding or as the reference capsule formulation with water. 
Relative bioavailability was assessed through repeat evaluations of plasma NHC PK. No 
SAEs, deaths or ECIs were reported.
MK-4482-012 was a randomized, double-blind, placebo-controlled, multiple ascending dose 
study to evaluate the safety, tolerability, and PK of MK-4482. Doses of 400, 600, and 
800 mg MK-4482 Q12H for 10.5 days were generally well tolerated in healthy adult study 
participants. Out of 32 randomized participants, 24 received at least 1 dose of MK-4482. No 
SAEs, deaths or ECIs were reported and no study intervention-related clinically meaningful 
changes in vital sign values, ECGs, or safety laboratory values (including hematology) were 
observed as a function of dose or treatment.
MK-4482-016 is a Phase 1 non-randomized, open-label, single dose, clinical study to 
evaluate the tolerability and PK of a single 800-mg dose of MK-4482 in participants with 
moderate hepatic impairment (n=7) compared to participants with normal hepatic function
(n=7). This study is clinically completed. No SAEs, discontinuations, or serious drug-related 
AEs were reported.
Phase 1/2, 2a Studies:
MK-4482-005 is a Phase 1/2 randomized, multicenter, seamless, adaptive study to determine 
the optimal dose, safety, and efficacy of MK-4482 for the treatment of COVID-19. The 
primary efficacy objective is to determine the ability of MK-4482 to reduce serious 
complications of COVID-19 including hospitalization, reduction in SaO2 <92%, or death. As 
of 14-MAR-2022, 18 participants enrolled in Phase 1 (12 received MK-4482; 300 mg n=4; 
600 mg n=4; 800 mg n=4), and 178 participants enrolled in Phase 2. This study is clinically 
completed and final unblinded results are pending. Based on preliminary review of blinded 
safety data, 5 SAEs were reported, 1 of which (vomiting) was considered related to study 
intervention by the investigator. No deaths were reported.
MK-4482-006 was a Phase 2a, randomized, double-blind, placebo-controlled study to 
evaluate the safety, tolerability, and efficacy of MK-4482 (Q12H for 5 days) in 
nonhospitalized adults with COVID-19. The time to undetectable SARS-CoV-2 of viral RNA 
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in nasopharyngeal swabs was shorter in participants receiving 800-mg MK-4482 (median: 
14 days) compared with those administered placebo (median: 15 days). MK-4482 200 mg 
(n=23), 400 mg (n=62) or 800 mg (n=55) or placebo (n=62) was generally well tolerated 
with a comparable incidence of AEs across the intervention groups. Four SAEs were reported 
(3 participants in the MK-4482 groups combined, 1 in the placebo group); none were 
considered related to study intervention by the investigator. No participants died while 
enrolled in the study.
MK-4482-007 is a Phase 2a randomized, placebo-controlled, double-blind clinical study of 
MK-4482 in adults who have tested positive for SARS-CoV-2 infection via PCR and are 
hospitalized with a diagnosis of COVID-19 with symptoms of ≤8 days. The primary efficacy 
objective is to measure the proportion of nasopharyngeal swabs and saliva from recipients 
becoming undetectable for SARS-CoV-2 RNA at Day 5 of MK-4482 administration 
compared with placebo. A total of 71 participants were enrolled in the study and received at 
least one dose of study drug (placebo or MOV 200 mg, 400 mg, or 800 mg). This study is 
completed. SAEs were reported for 4 participants, 3 in the placebo group and 1 in the MOV 
800-mg group (2 SAEs of acute respiratory failure [fatal] and hypovolemic shock); none 
were considered related to study intervention by the investigator. The only AE leading to 
discontinuation of the study drug and withdrawal from the study was reported in the MOV 
400-mg group. This was an AE of nausea that was moderate, nonserious, and considered 
related to study drug. There were no obvious treatment- or dose-related trends in any mean 
laboratory or vital sign data. 
Phase 2/3 or 3 Studies:
MK-4482-001 is a Phase 2/3 randomized, placebo-controlled, double-blind clinical study to 
evaluate the efficacy, safety, and PK of MK-4482 in hospitalized adults with COVID-19. In 
the Phase 2 portion of the study (Part 1) a total of 218 hospitalized participants with COVID-
19 received at least 1 dose of MK-4482 (72 participants received MK-4482 800 mg) and 75 
participants received placebo. MK-4482 was generally well tolerated with a comparable 
incidence of AEs across the intervention groups. SAEs were reported for 15.4% participants 
(15.1% MK-4482 groups, 16.0% placebo), with 1 SAE deemed related to study intervention 
by the investigator (Grade 3 urticaria) for 1 participant in the MK-4482 200-mg treatment 
group. A total of 16 participants had AEs leading to death (6.4% MK-4482 groups combined, 
2.7% placebo), none of which were considered study intervention-related by investigator 
assessment. The study was stopped due to lack of clinical benefit in this population 
(participants already hospitalized prior to randomization) and did not proceed to the Phase 3 
portion of the study (Part 2).
MK-4482-002 is a Phase 2/3, randomized, placebo-controlled, double-blind, multisite study 
to evaluate the efficacy, safety, and PK of MK-4482 administered to nonhospitalized adults 
with laboratory-confirmed COVID-19 and symptom onset within 7 days (Part 1, Phase 2) or 
within 5 days (Part 2, Phase 3) prior to randomization, and all participants must have at least 
one risk factor for progressing to severe illness from COVID-19. A final total of 1433 
participants were enrolled in the study and the study is completed. Unblinded data are 
available for Part 1 and Part 2 through Day 29 as well as for the Month 7 visit in both Part 1 
and Part 2 which includes collection of survival status, current supplemental oxygen use, and 
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any hospitalizations that occurred since last contact. MK-4482 200 mg (n=74), 400 mg 
(n=77), 800 mg (n=74) or placebo (n=74) Q12H for 5 days in Part 1 and MK-4482 800 mg 
(n=710) or placebo (n=701) Q12H for 5 days in Part 2 were generally well tolerated. In both 
Parts, the proportion of participants with AEs, drug-related AEs (per investigator 
assessment), SAEs, AEs leading to study intervention discontinuation and laboratory values 
that met predefined limits of change (worsening Grade 3 or 4), were comparable for the 
intervention groups. No clinically meaningful trends in changes in liver enzymes or 
hematology parameters as a function of either dose or treatment were observed. In Part 1, one 
participant had an AE leading to death in the placebo group. In Part 2, AEs leading to death 
occurred in a higher proportion of participants who received placebo compared with MK-
4482.
MK-4482-013 is a Phase 3, multicenter, randomized, double-blind, placebo-controlled study 
to evaluate the efficacy and safety of MK-4482 for the prevention of COVID-19 (laboratory-
confirmed SARS-CoV-2 infection with symptoms) in adults residing with a person with 
COVID-19. 1539 participants were randomized out of a planned total of approximately 1376 
participants. This study is clinically completed and final unblinded results are pending. Based 
on preliminary review of blinded safety data, SAEs were reported by 5 participants during 
the treatment or follow-up period (COVID-19 pneumonia [3], acute myocardial infarction [1; 
fatal], and fractured femur [1]); none were considered related to study intervention by the 
investigator. 4 participants discontinued study drug because of an AE.
2.2.3.2
Ongoing Clinical Studies
MK-4482 is being evaluated in 2 ongoing Phase 1 studies (P003 and P011) and 1 ongoing 
Phase 2a study (P017) (Refer to the IB Section 5 for the additional details on study designs 
on each study).
Phase 1 studies:
MK-4482-003 is a Phase 1 non-randomized, open-label, single dose, clinical study to 
evaluate the tolerability and PK of a single 800-mg dose of MK-4482 in participants with 
severe renal impairment compared to participants with normal renal function (target 
enrollment of approximately N = 16-18). This study is ongoing. No SAEs, discontinuations, 
or serious drug-related AEs have been reported.
MK-4482-011 is a Phase 1 open-label, cross-over, bioequivalence study, evaluating the PK 
of a MK-4482 tablet formulation in comparison to the MK-4482 capsule formulation in 
healthy adult participants. Approximately 64 participants are to be randomized. This study is 
ongoing. 
Phase 2a Studies:
MK-4482-017 is a Phase 2a double blind randomized placebo-controlled study to evaluate 
the efficacy and safety of MK-4482 in healthy adult participants inoculated with 
experimental RSV. The study is evaluating MK-4482 as pre-exposure prophylaxis and as a 
post-exposure treatment. As of 06-FEB-2023, 52 participants have been randomized out of a 
planned total of 105 participants.
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2.2.4
Information on Other Study-related Therapy
OTV is a neuraminidase inhibitor that interferes with the release of progeny influenza virus 
from infected cells, thereby preventing new rounds of infection. It is approved for the 
treatment and prevention (pre-exposure and post-exposure) of influenza, with an adult 
recommended dose of 75 mg twice daily; the duration for treatment is 5 days, with a longer 
duration in the prophylactic setting (10 days for PEP and up to 6 weeks for prevention during 
a community outbreak). The most commonly-reported AEs in clinical trials with OTV are 
nausea and vomiting [Dutkowski, R., et al 2003].
Oseltamivir is ingested in the form of prodrug (oseltamivir phosphate) that is rapidly 
converted into the active metabolite, oseltamivir carboxylate (OC). Plasma OC 
concentrations are near maximal 3 to 4 hours after drug administration. The PK of OC is 
dose proportional after repeated doses of up to 500 mg BID. Steady state plasma 
concentrations are achieved within 3 days of 75 mg BID dosing. There is only modest 
accumulation (<2-fold) of OC prior to reaching steady state [Davies, B. E. 2010] [He, G., et 
al 1999].
Refer to the OTV SmPC for additional details.
2.3
Benefit/Risk Assessment
Participants in clinical studies will not receive direct benefit from treatment during 
participation as clinical studies are designed to provide information about the safety and 
properties of an investigational medicine.
The totality of the safety data from Phase 1 through Phase 3 clinical studies and post-
authorization surveillance for the use of MK-4482 in the treatment of COVID-19 
demonstrate an acceptable safety and tolerability profile of MK-4482.
There were no effects on cardiovascular, neurological, and respiratory function in several 
well-characterized safety pharmacology experimental models. The integrated assessment of 
the mutagenic and genotoxic potential of MK-4482 indicates that MK-4482 is not mutagenic 
or genotoxic in in vivo mammalian systems.
As described in Section 2.2.2, in a 28-day repeat dose toxicity study with MK-4482 in dogs, 
reversible hematologic toxicities were noted after Day 7 at exposures 0.4-fold those of the 
anticipated clinical exposures at the 800-mg Q12H dose. However, to date no clinically 
meaningful hematological changes have been observed in healthy participants up to 800-mg 
MK-4482 Q12H for up to 10.5 days or in participants with COVID-19 at multiple doses up 
to 800-mg Q12H for 5 days.
Histopathology results from the 3-month rat toxicity study demonstrated an increase in the
thickness of the growth plate/physis, a finding not observed in 1-month studies in rats, dogs,
or mice. These findings are not considered to represent a significant new risk to human
adults.
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In fertility studies in rats there were no MK-4482-related effects on female or male fertility, 
or on early embryonic development up to the highest dose tested, 500 mg/kg/day, (2.3-/6.8-
fold [female/male] the clinical NHC exposure at 800 mg Q12H). While embryolethality 
(postimplantation losses) and teratogenicity were limited to rats exposed to 8.4-fold the 
clinical NHC exposure at 800 mg Q12H during the organogenesis period, and these 
developmental findings were not observed in rats up to 3.2-fold the clinical NHC exposure at 
800 mg Q12H and rabbits up to 20-fold the clinical NHC exposure at 800 mg Q12H, 
WOCBP will be required to use effective contraception for the duration of treatment and for 
at least 28 days postdose.
Additional details regarding specific benefits and risks for participants participating in this
clinical study may be found in the accompanying IB (for MK-4482), SmPC (for OTV), and 
informed consent documents.
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3
HYPOTHESES, OBJECTIVES, AND ENDPOINTS
Hypotheses are aligned with objectives in the Objectives and Endpoints table.
This study will be conducted in healthy participants.
Primary Objective
Primary Endpoint
Part 1
Objective 1: To evaluate the infectivity 
rate of the influenza challenge virus in 
healthy adult participants.
Day 1 PM to planned discharge, Day 2 PM to 
planned discharge:
•
Quantitative reverse transcriptase-
polymerase chain reaction (qRT-PCR)-
confirmed influenza infection
Objective 2: To assess the safety of the 
influenza challenge virus in healthy adult 
participants
Viral challenge to Follow-up Visit:
•
Adverse events (AEs) related to viral 
challenge
Part 2
Objective 3: To evaluate the effectiveness 
of MK-4482 (800 mg Q12H for 5 days) as 
a post-exposure intervention in reducing 
influenza viral load, as compared to 
placebo.
Hypothesis (Post-exposure prophylaxis
[PEP]): MK-4482 (800 mg Q12H for 5 
days), initiated 12 h following intranasal 
inoculation of the influenza challenge virus 
reduces the peak viral load (as determined 
by quantitative viral culture) compared to 
placebo.
Hypothesis (Treatment): MK-4482 (800 
mg Q12H for 5 days), initiated 2 days 
following intranasal inoculation of the 
influenza challenge virus reduces the viral 
load AUC (as determined by quantitative 
viral culture) compared to placebo.
PEP (MK-4482) Day 1 PM to planned 
discharge:
•
Peak viral load (PVL) (by quantitative 
viral culture) 
Treatment (MK-4482) First dose of study 
drug to planned discharge:
•
Area under the viral load-time curve
(VL-AUC) (by quantitative viral culture)
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Secondary Objectives
Secondary Endpoints
Part 1
Objective 4: To characterize the virological 
profile of the influenza challenge virus in 
healthy adult participants
Day 1 PM to planned discharge, Day 2 PM 
to planned discharge:
•
Quantitative viral culture-confirmed 
influenza infection
•
VL-AUC (qRT-PCR and quantitative 
viral culture) 
•
PVL (qRT-PCR and quantitative viral 
culture) 
•
Duration of quantifiable influenza (qRT-
PCR and quantitative viral culture)
Objective 5: To characterize the clinical 
symptom profile of the influenza challenge 
virus in healthy adult participants.
Day 1 AM to planned discharge, Day 2 
middle of day to planned discharge:
•
Area under the total symptom score-time 
curve (TSS-AUC)
•
Peak total symptom score (TSS)
•
Daily maximum TSS 
•
Duration (days) of Grade ≥2 symptoms 
•
Time (days) to symptom resolution 
•
Time (days) to peak daily maximum TSS
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Part 2
Objective 6: To estimate the effect of MK-
4482 (800 mg Q12H for 5 days) as post-
exposure prophylaxis (initiated 12 h 
following intranasal inoculation of 
influenza challenge virus) or as treatment 
(initiated 2 days following intranasal 
inoculation of influenza challenge virus) 
on the reduction of influenza viral load, as 
compared to placebo.
Objective 7: To estimate the effect of 
oseltamivir (75 mg Q12H for 5 days) as 
treatment (initiated 2 days following 
intranasal inoculation of influenza 
challenge virus) on the reduction of 
influenza viral load, as compared to 
placebo
PEP (MK-4482) – Virology: Day 1 PM to 
planned discharge:
Symptoms and temperature Day 1 AM to 
planned discharge:
•
VL-AUC (qRT-PCR and quantitative 
viral culture) 
•
PVL (qRT-PCR)
•
qRT-PCR-confirmed influenza infection
•
qRT-PCR-confirmed symptomatic 
influenza infection
•
qRT-PCR-confirmed moderately severe 
symptomatic influenza infection
•
qRT-PCR-confirmed febrile influenza 
infection
•
Quantitative viral culture-confirmed 
influenza infection 
•
Quantitative viral culture-confirmed 
symptomatic influenza infection
•
Duration of quantifiable influenza (qRT-
PCR and quantitative viral culture)
•
Time (days) to confirmed negative test 
(qRT-PCR and quantitative viral culture) 
•
Time (days) to peak viral load (qRT-PCR 
and quantitative viral culture)
Treatment (MK-4482 and oseltamivir) – first 
dose study drug to planned discharge:
•
VL-AUC (qRT-PCR and quantitative 
viral culture) 
•
PVL (quantitative viral culture and qRT-
PCR)
•
Duration of quantifiable influenza (qRT-
PCR and quantitative viral culture)
•
Time (days) to confirmed negative test 
(qRT-PCR and quantitative viral culture) 
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•
Time (days) to peak viral load (qRT-PCR 
and quantitative viral culture) 
Objective 8: To evaluate the effect of MK-
4482 (800 mg Q12H for 5 days) as PEP
(initiated 12 h following intranasal 
inoculation of influenza challenge virus) or 
as treatment (initiated 2 days following 
intranasal inoculation of the influenza 
challenge virus) on the course of clinical 
symptoms following intranasal inoculation 
with the influenza challenge virus, 
compared to placebo
Objective 9: To evaluate the effect of 
oseltamivir (75 mg Q12H for 5 days) as 
treatment (initiated 2 days following 
intranasal inoculation of influenza 
challenge virus) on the course of clinical 
symptoms following intranasal inoculation 
with the influenza challenge virus, 
compared to placebo
PEP (MK-4482) – Day 1 AM to planned 
discharge;
Treatment (MK-4482 and oseltamivir) – first 
dose study drug to planned discharge:
•
TSS-AUC
•
Peak TSS
•
Daily maximum TSS 
•
Duration (days) of Grade ≥2 symptoms 
•
Time (days) to symptom resolution 
•
Time (days) to peak daily maximum TSS
Objective 10: To assess the safety and 
tolerability of MK-4482 (800 mg Q12H for 
5 days)
PEP (MK-4482) and Treatment (MK-4482) –
from first dose of study drug to Follow-up 
Visit:
•
All AEs
Objective 11: To monitor the safety of the 
influenza challenge virus in healthy adult 
participants
Viral challenge to Follow-up Visit:
•
AEs related to viral challenge
•
Concomitant medication use
Objective 12: To assess the plasma PK of 
NHC following administration of MK-
4482 (800 mg Q12H for 5 days)
PEP (MK-4482) and Treatment (MK-4482):
•
NHC Cmax, Tmax, t1/2, AUC0-12hr, 
AUC0-last, Ctrough following multiple 
dose administration of MK-4482
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Tertiary/Exploratory Objectives
Tertiary/Exploratory Endpoints
Part 2
Objective 13: To explore the effect of MK-
4482 as a post viral exposure intervention 
(PEP or treatment) on the rate of 
seroconversion to the challenge virus.
Objective 14: To explore the effect of 
oseltamivir as treatment on the rate of 
seroconversion to the challenge virus.
•
Number of seroconversions by Day 28 
post inoculation
Objective 15: To explore the effect of MK-
4482 (800 mg Q12H for 5 days), initiated 2 
days (treatment) following intranasal 
inoculation with influenza challenge virus 
in reducing incidence of influenza 
infection, symptomatic influenza infection, 
moderately severe symptomatic influenza 
infection, and febrile influenza infection, 
as compared to placebo
Objective 16: To explore the effect of 
oseltamivir (75 mg Q12H for 5 days), 
initiated 2 days following intranasal 
inoculation with the influenza challenge 
virus in reducing incidence of influenza 
infection, symptomatic influenza infection, 
moderately severe symptomatic influenza 
infection, and febrile influenza infection, 
as compared to placebo
Treatment (MK-4482 and oseltamivir) – first 
dose of study drug to planned discharge:
•
qRT-PCR-confirmed influenza infection
•
qRT-PCR-confirmed symptomatic 
influenza infection
•
qRT-PCR-confirmed moderately severe 
symptomatic influenza infection
•
qRT-PCR-confirmed febrile influenza 
infection
•
Quantitative viral culture-confirmed 
influenza infection 
•
Quantitative viral culture-confirmed 
symptomatic influenza infection
Objective 17: To estimate the effect of 
MK-4482 (800 mg Q12H for 5 days) on 
symptom severity scores (total and 
domains) assessed using a patient-reported 
outcome measure (FLU-PRO Plus©) 
following intranasal inoculation with the 
influenza challenge virus.
PEP (MK-4482) – Day 1 PM to planned 
discharge;
Treatment (MK-4482) – Day 2 PM to planned 
discharge:
•
Symptom severity score (total and 
domains) by FLU-PRO Plus©
questionnaire
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Objective 18: To estimate the effect of 
administration of MK-4482 (800 mg Q12H 
x 5 days) on mucus production after 
intranasal inoculation with influenza 
challenge virus, as compared to placebo.
PEP (MK-4482) – Day 1 AM to planned 
discharge;
Treatment (MK-4482) - Day 2 AM - Day 8 
AM:
•
Total weight of mucus produced 
•
Total number of tissues used by 
participants
Objective 19: To explore baseline 
immunology and response to infection with 
the influenza challenge virus.
•
Exploratory assays related to respiratory 
viral infection and immunology (blood 
and nasal samples)
Objective 20: To explore the effect of MK-
4482 (800 mg Q12H x 5 days) on the rate 
of low frequency nucleotide substitutions 
(LNS) after intranasal inoculation with the 
influenza challenge virus, as compared to 
placebo.
LNS quantitation by viral sequencing of 
nasal samples.
Objective 21: To explore the relationship 
between genetic variation and response to 
the treatment(s) administered, and 
mechanisms of disease. Variation across 
the human genome may be analyzed for 
association with clinical data collected in 
the study.
Germline genetic variation and association to 
clinical data collected in this study.
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4
STUDY DESIGN
4.1
Overall Design
This is a two-part study in healthy male and female participants aged 18 to 55 years 
(inclusive), who will be inoculated with either the A/France/759/21 [H1N1] strain (from the 
6B.1A.5a.1 clade) or an alternative influenza A viral strain eg, A/Perth/16/2009 [H3N2] or 
A/California 2009-like [H1N1]. This study will be conducted in conformance with GCP.
Initially participants will be screened according to generic criteria for recruitment into a 
general population of eligible participants. Participants will have serosuitability confirmed 
during the generic screening process prior to beginning study-specific screening for the 
challenge study and within 90 days prior to inoculation. Participants having passed both the 
generic screening process and meeting the study-specific inclusion/exclusion criteria of the 
study will be admitted to quarantine on Day -2/-1. Prior to viral inoculation, quarantined 
participants will undergo additional screening to exclude those with respiratory pathogens, 
and participants who are excluded at this time will not undergo dosing of study intervention.
Historical generic screening data collected through the generic screening process may be 
transferred to this study after the study-specific ICF has been signed by the participant.
Part 1
Part 1 is an open-label validation study, with a cohort of 20 untreated (ie, not receiving study 
drug) participants undergoing nasal inoculation with the A/France/759/21 [H1N1] strain on 
Day 0 to confirm viral infectivity and disease. A single inoculum titer will be used based on 
prior experience with influenza challenge viruses.
Assessment of viral load (twice-daily nasal sampling), symptoms (using a diary card three 
times per day, in addition to once-daily administration of the FLU-PRO Plus© tool), 
immunological markers, and safety will be performed during quarantine until discharge on 
Day 8. Participants will be discharged from the quarantine unit on Day 8 (or may remain 
longer at the discretion of the investigator). Suitability for discharge will be based on clinical 
judgment; nasal swab samples may be tested for the presence of virus if deemed necessary
prior to discharge. Participants will have a follow up visit at Day 28, which will be the last 
visit for the study.
Following the completion of Part 1, a review of safety, tolerability, rate of infectivity by 
plaque assay and PCR, the viral load profile, and symptoms of infection by the the 
A/France/759/21 [H1N1] strain will be performed by the Sponsor in collaboration with the 
study site. At a minimum, the review of safety, tolerability, and rate of infectivity by PCR 
will be required to confirm that Part 2 may proceed using the same challenge strain. The 
infectivity rate of the A/France/759/21 [H1N1] strain at this inoculum is expected to be 
>50%; however, in case the infectivity rate is too low to be viable or there are safety 
concerns that preclude further use of the A/France/759/21 [H1N1] challenge strain then an 
alternative plan will be to revert to another virus that has been previously well-characterized 
eg, A/Perth/16/2009 [H3N2] or A/California 2009-like [H1N1]. Further details of the 
alternative viral strains are provided in Appendix 11.
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Additionally, based on review of Part 1 data, the following modifications may be made to 
Part 2 (see Section 8.16.7):
Sample size re-estimation (this is currently estimated to be ~140 [~35 participants per 
intervention group], based on data from prior influenza HCSs using A/Perth/16/2009
[H3N2]). The revised sample size is not anticipated to vary (increase or decrease) outside the 
range of 25 to 50 per intervention group.
Extension of the quarantine period beyond Day 8; this will be at the discretion of the 
Investigator based on observed prolonged viral shedding in Part 1 and/or a need for 
prolonged safety monitoring
Removal of discretionary safety monitoring assessments in Part 2. The intent of Part 1 is to 
define an appropriate level of safety monitoring in Part 2. As such, safety assessments at 
certain time points in the SoA for Part 2 have been designated as discretionary; the retention 
vs removal of such time points in Part 2 will be determined by the observed safety profile in 
Part 1. 
Viral inoculum titer adjustment (increase or decrease)
Following the review of Part 1 data, any decisions regarding the conduct of Part 2, including 
confirmation of viral strain and any of the above-mentioned potential modifications, will be 
documented in a PCL.
Part 2
Part 2 will be a randomized, double-blind placebo- and active-comparator-controlled study 
where participants will be inoculated on Day 0 with either the A/France/759/21 [H1N1] virus 
used in Part 1 or an alternative influenza virus; the challenge agent will thus be referred to as 
“IAV”, to allow for either option.
Participants will be randomly allocated to one of four interventions; each intervention will be 
received by approximately 35 participants. Active study drug (MK-4482 or OTV) will be 
administered Q12H for 5 days in total, with dosing of all 4 groups (with active drug or 
placebo) commencing on Day 0 PM (approximately 12 hours post-inoculation) and 
completing at Day 6 PM (see Table 1). All participants will be blindfolded during dosing, 
and an unblinded dosing team will carry out dosing. At each dose administration, each 
participant will receive a total of 4 capsules. It is important for each capsule to be 
administered separately, ie, the participant will administer and swallow the first capsule 
before being given the second capsule by the unblinded dosing team staff member, and so on.
In the MK-4482 PEP group, dosing with MK-4482 (4 x 200 mg capsules) will begin on Day 
0 PM (approximately 12 hours post-inoculation) and finish on Day 5 AM. To maintain 
blinding, participants in this group will complete the dosing period by receiving placebo 
(identically matched to MK-4482, ie, 4 capsules) from Day 5 PM to Day 6 PM, inclusive.
In the MK-4482 and OTV Treatment groups, participants will receive placebo from Day 0 
PM through Day 1 PM. In the MK-4482 group, this will be a placebo identically-matched to 
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MK-4482 (ie, 4 capsules), and in the OTV group this will be 4 capsules of placebo of similar 
size and weight, but not appearance, to the OTV capsules. Dosing with MK-4482 or OTV, 
respectively, will begin on Day 2 AM (ie, 2 days post-inoculation) and finish on Day 6 PM. 
Each dose administration of MK-4482 will comprise 4 x 200 mg MK-4482 capsules. To 
maintain participant blinding, each dose administration of OTV will comprise 1 x 75 mg 
OTV capsule and 3 x placebo capsules.
Participants in the placebo group will receive 4 capsules of the placebo identically matched 
to MK-4482 from Day 0 PM through Day 6 PM
Assessment of viral load (twice-daily nasal sampling), symptoms (using a diary card three 
times per day, in addition to once-daily administration of the FLU-PRO Plus© tool), PK, 
immunological and other exploratory markers, and safety will be performed during 
quarantine until discharge on Day 8 (or may remain longer at the discretion of the 
investigator). Suitability for discharge will be based on clinical judgment; nasal swab
samples may be tested for the presence of virus if deemed necessary prior to discharge. 
Participants will have a follow up visit at Day 28, which will be the last visit for the study.
Specific procedures to be performed during the study, including prescribed times and 
associated visit windows, are outlined in Section 1.3 of the SoA. Details of each procedure 
are provided in Section 8.
4.2
Scientific Rationale for Study Design
The purpose of this influenza challenge study is to provide an assessment of the antiviral 
activity of MK-4482 against IAV in humans. An influenza human challenge model was 
selected based on the demonstration in multiple previous influenza HCSs of the ability of the 
model to generate safe and reproducible mild to moderate infection from a wild-type virus in 
healthy human participants. Part 1 (Validation study) will characterize the A/France/759/21 
[H1N1] viral strain to support its use as a challenge agent in Part 2 for the MK-4482 
evaluation. 
By assessing MK-4482 as PEP (initiation 12 hours post-inoculation) and Treatment 
(initiation 2 days post-inoculation), this study provides an opportunity to gain an 
understanding of the impact of timing of drug initiation on antiviral activity under controlled 
conditions where the timing of inoculation is known.
The OTV comparator arm will serve a positive control and includes an approved agent 
known to be clinically effective against IAV.
4.2.1
Rationale for Endpoints
Endpoints for Parts 1 and 2 of this study are described separately in Section 3. The primary 
endpoints of Part 1 (Validation Study) will be used for decision-making for Part 2 (MK-4482 
Challenge Study), and the primary endpoints of Part 2 will be used for the evaluation of MK-
4482 as a post-exposure intervention in reducing influenza viral load.
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The primary endpoints for Part 2 are virological, and further described in 4.2.1.1. Clinical 
endpoints (described in 4.2.1.2) are intended to provide support to the primary (virology-
based) endpoints.
Definitions of the endpoints listed in Section 3 are provided in Table 2 below.
Table 2
Definitions of Study Endpoints
Endpoint 
Type
Endpoint
Definition
PD 
(virological)
qRT-PCR-confirmed 
influenza infection
2 x quantifiable (≥ LLOQ) influenza 
challenge virus qRT-PCR measurements 
(reported on ≥2 independent nasopharyngeal 
samples over 2 days)
Quantitative viral culture-
confirmed influenza 
infection
1 x quantifiable (≥ LLOQ) influenza 
challenge virus measurement from 
quantitative viral culture from a 
nasopharyngeal sample
Peak viral load (PVL)
Maximum viral load of influenza challenge 
virus from nasopharyngeal samples (to be 
determined by both quantitative viral culture 
and qRT-PCR)
Area under the viral load-
time curve (VL-AUC)
Area under the viral load-time curve of 
influenza challenge virus nasopharyngeal 
samples (to be determined by both 
quantitative viral culture and qRT-PCR)
Duration of quantifiable 
influenza
Time (in days) from the first quantifiable (≥ 
LLOQ) influenza challenge virus 
measurement until the first confirmed 
unquantifiable (ie, <LLOQ detected or not 
detected) assessment after the peak measure 
(after which there are no more confirmed 
quantifiable samples). 
(Endpoint to be determined by both 
quantitative viral culture and qRT-PCR)
Time (days) to confirmed 
negative test (qRT-PCR and 
quantitative viral culture)
Time (in days) from the beginning of the 
specified time frame until the first confirmed 
unquantifiable (ie, <LLOQ detected or not 
detected) assessment after the peak measure 
(after which there are no more confirmed 
quantifiable samples).
(Endpoint to be determined by both 
quantitative viral culture and qRT-PCR)
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Endpoint 
Type
Endpoint
Definition
Time (days) to peak viral 
load 
Time (in days) from the beginning of the 
specified time frame until the peak viral load 
measurement (to be determined by both 
quantitative viral culture and qRT-PCR)
PD 
(serological)
Number of seroconversions 
by Day 28 post inoculation 
To be determined using HAI and/or 
neutralization assays.

In HAI assays, seroconversion is 
defined as one of the following:
o
an increase from a negative 
pre-inoculation titer (<10) to a 
Day 28 titer of ≥40
o
a significant increase in 
antibody titer, ie, at least a 4-
fold increase between pre-
inoculation and Day 28 titers, 
where the pre-inoculation titer 
is ≥ 10

In neutralization assays, 
seroconversion is defined as:
o
a significant increase in 
antibody titer, ie, at least a 4-
fold increase between pre-
inoculation and Day 28 titers 
Clinical
  
Area under the total 
symptom score-time curve 
(TSS-AUC)
Area under the total clinical symptom score-
time curve (TSS-AUC), as measured by 
graded symptom scoring system collected 3 
times daily; each symptom is graded on a 
scale of 0 to 3 or 4, where a higher grade 
represents a higher symptom intensity/impact 
Peak total symptom score 
(TSS)
Maximum total symptoms score (TSS), as 
measured by graded symptom scoring system 
collected 3 times daily
Daily maximum TSS
Maximum TSS on each day, measured by 
graded symptom scoring system collected 3 
times daily 
Duration (days) of Grade ≥2 
symptoms 
Duration of time (in days) from the first 
occurrence of any symptom assigned Grade 2 
or higher, to the beginning of the first 24-
hour period without any symptom assigned 
Grade 2 or higher, after the peak TSS  
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Endpoint 
Type
Endpoint
Definition
Time (days) to symptom 
resolution 
Time (in days) from the beginning of the 
specified time frame until the beginning of a 
24-hour period with no symptoms above the 
baseline maximum TSS, as measured by 
graded symptom scoring system collected 3 
times daily.
Baseline maximum is defined as the 
maximum TSS on Day -1
Time (days) to peak daily 
maximum TSS 
Time (in days) from the beginning of the 
specified time frame to the time of the peak 
daily maximum TSS
Combined: 
virological/
clinical
  
qRT-PCR-confirmed 
symptomatic influenza 
infection

qRT-PCR-confirmed influenza 
infection (2 x quantifiable [≥ LLOQ] 
influenza challenge virus qRT-PCR 
measurements [reported on ≥2 
independent nasopharyngeal samples 
over 2 days])
AND

Total symptoms score (TSS) ≥2 at ≥1 
time point following inoculation
qRT-PCR-confirmed 
moderately severe 
symptomatic influenza 
infection

qRT-PCR-confirmed influenza 
infection (2 x quantifiable [≥ LLOQ] 
influenza challenge virus qRT-PCR 
measurements [reported on ≥2 
independent nasopharyngeal samples 
over 2 days])
AND

Any symptom of Grade ≥2 at ≥1 time 
point following inoculation
qRT-PCR-confirmed febrile 
influenza infection

qRT-PCR-confirmed influenza 
infection (2 x quantifiable [≥ LLOQ] 
influenza challenge virus qRT-PCR 
measurements [reported on ≥2 
independent nasopharyngeal samples 
over 2 days])
AND

Temperature of ≥37.9°C at ≥1 time 
point following inoculation
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Endpoint 
Type
Endpoint
Definition
Quantitative viral culture-
confirmed symptomatic 
influenza infection

Quantitative viral culture-confirmed 
influenza infection (1 x quantifiable 
[≥ LLOQ] influenza challenge virus 
measurement from quantitative viral 
culture from a nasopharyngeal sample
AND

TSS ≥2 at ≥1 time point following 
inoculation
HAI=hemagglutination inhibition; LLOD=lower limit of detection; LLOQ=lower limit of 
quantification; PD=pharmacodynamic; qRT-PCR= quantitative reverse transcriptase-
polymerase chain reaction; TSS=total symptom score
4.2.1.1
Pharmacodynamic Endpoints
The primary endpoints for Part 2 of this study (MK-4482 challenge study) are virological; 
this approach was selected based on the rationale that demonstration of antiviral activity (ie, 
viral load reduction) is reflective of the mechanism of action of the drugs included in the 
study. Furthermore, viral shedding has been shown to have an association with symptoms, 
both in terms of magnitude and duration [Fry, A. M., et al 2014]. 
Reduction in PVL compared to placebo has been selected for the analysis of MK-4482 as 
PEP, and reduction in the area under the viral load-time curve (VL-AUC) has been selected 
for the analysis of MK-4482 and OTV as treatment; these selections are based on influenza 
viral dynamics and anticipated antiviral effects of MK-4482 and OTV when initiated either 
12 hours or 2 days post-inoculation (ie, prior to or following predicted PVL, respectively).
Quantitative viral culture (by plaque assay) has been selected as the means of determining 
viral load, based on the mechanism of action of MK-4482 in halting productive viral 
replication; qRT-PCR is also included within the secondary virological endpoints. Additional 
secondary virological endpoints include the duration of quantifiable virus detection; this is 
intended to complement the clinical endpoints related to time to symptom resolution. 
Combined virological/clinical secondary endpoints will also assess the impact of MK-4482 
and OTV on the incidence of symptomatic/febrile influenza infection; these are included with 
the intent of estimating the performance of study drug in a subset of participants with more 
severe disease. 
Exploratory analyses may be performed to define the antiviral activity of MK-4482 relative 
to the viral dynamics of influenza. Serum and/or nasal immunological biomarkers (Sec. 8.4.5 
and 8.10) may be explored for their ability to predict disease severity and/or response to 
treatment; this will be described separately in a supplemental SAP. Viral sequencing to 
assess rates of LNS will also be used to explore the exposure-response relationship for NHC 
in influenza, based on the known mechanism of action.
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4.2.1.2
Efficacy Endpoints
Clinical efficacy endpoints are included as secondary and exploratory in this study to provide 
support to the primary (virology-based) endpoints. Symptom scores, measured from 13 self-
reported symptoms on a diary card, will be used to derive a peak symptom score, 
corresponding to peak illness, and a total symptom score AUC, as a measure of disease 
burden over time. Additionally, time to symptom resolution will be measured, noting that
existing approved antiviral agents have demonstrated a reduction in time to alleviation of 
symptoms when tested against placebo in randomized clinical trials [Liu, J. W., et al 2021].
In addition to the standard 13-symptom diary card administered 3 times per 24 hours, the 
FLU-PRO Plus© tool will be administered once every 24 hours (in the evening), and 
endpoints assessed will be the symptom severity scores (global and by domain). Use of FLU-
PRO© (an earlier version of the tool) was assessed based on information from 200 patients 
with influenza-like illness (28% hospitalized). It has been shown to produce scores that are 
well defined, reliable, valid, and responsive to change in influenza-positive and influenza-
negative adults, demonstrating its utility in clinical trials and epidemiological studies
[Powers, J. H. 3rd., et al 2018]. In addition to its demonstration of utility in clinical trials of 
patients with influenza, the FLU-PRO© has been studied and demonstrated usefulness in a 
previous influenza HCS. Aligned with FDA PRO-development guidance, the FLU-PRO
Plus© can provide additional insight into treatment efficacy and safety in a manner that is 
more precise and less biased than non-standardized metrics in registrational trials [Coles, C., 
et al 2019].
Mucus weights will be measured as an objective exploratory endpoint in conjunction with
symptom score-based endpoints.
4.2.1.3
Safety Endpoints
Based on available clinical safety data to date, evaluation of safety will be adequately 
assessed from the following standard safety assessments: VS, 12-lead ECG, laboratory safety 
tests (blood chemistry, hematology, urinalysis) and AEs. Additional laboratory safety 
assessments in the setting of the influenza challenge model are also included (coagulation 
studies, CK, and thyroid function testing). Safety evaluations will be conducted throughout 
the study at intervals dictated by the viral challenge model and NHC PK properties.
Participants will be domiciled in quarantine conditions for at least 8 days after inoculation 
with IAV, to allow for a sufficient duration of time to clear the virus. 28 days post-
inoculation is deemed an adequate follow-up period for safety following viral inoculation as 
well as administration of either study drug in this protocol. 
4.2.1.4
Pharmacokinetic Endpoints
Plasma PK for NHC
Blood samples for the assessment of PK of NHC in plasma will be collected (as described in 
Sec. 1.3) and used to evaluate standard PK parameters (eg, Cmax, Tmax, AUC0-12, 
Ctrough) following multiple dose administration of MK-4482.  The PK analyses will be 
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based on only plasma NHC PK (ie, not PBMC NHC-TP). Plasma NHC exposures have been 
shown to be well correlated with NHC-TP exposures in PBMCs, with plasma NHC AUC 
being a consistent strong correlate of NHC-TP exposures. Additionally, the t1/2 of NHC-TP 
in PBMCs was consistent with the terminal t1/2 of NHC in plasma. Based on this, the more 
readily available NHC exposures can be considered an appropriate surrogate for NHC-TP for 
the evaluation of exposure-dependency in pharmacometric modeling analyses.
Plasma PK for Oseltamivir Carboxylate
A single blood sample for assessment of oseltamivir carboxylate in plasma will be collected 
near the Tmax (ie, at 4 hours) following the AM dose of study drug administration on Day 2
(as described in Section 8.8.2).  These samples will be stored and tested to evaluate plasma 
oseltamivir carboxylate exposures if deemed necessary by the Sponsor.  
4.2.1.5
Planned Exploratory Biomarker Research
4.2.1.5.1
Planned Genetic Analysis
Genetic variation may impact a participant’s response to therapy, susceptibility to, severity, 
and progression of disease. Variable response to therapy may be due to genetic determinants 
that impact drug ADME, mechanism of action of the drug, disease etiology, and/or molecular 
subtype of the disease being treated. Therefore, where local regulations and IRB/IEC allow, a 
sample will be collected for DNA analysis from consenting participants.
DNA samples may be used for research related to the study intervention(s), the disease under 
study, or related diseases. They may also be used to develop tests/assays including diagnostic 
tests related to the disease under study, related diseases, and study intervention(s). Genetic 
research may consist of the analysis of 1 or more candidate genes, the analysis of genetic 
markers throughout the genome, or analysis of the entire genome. Analysis may be 
conducted if it is hypothesized that this may help further understand the clinical data.
The samples may be analyzed as part of a multistudy assessment of genetic factors involved 
in the response to understand study disease or related conditions.
4.2.1.6
Future Biomedical Research
The Sponsor will conduct FBR on DNA specimens for which consent was provided during 
this clinical study.
Such research is for biomarker testing to address emergent questions not described elsewhere 
in the protocol and will only be conducted on specimens from appropriately consented 
participants. The objective of collecting/retaining specimens for FBR is to explore and 
identify biomarkers that inform the scientific understanding of diseases and/or their 
therapeutic treatments. The overarching goal is to use such information to develop safer, 
more effective drugs/vaccines, and/or to ensure participants receive the correct dose of the 
correct drug/vaccine at the correct time. The details of FBR are presented in Appendix 6.
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4.2.2
Rationale for the Use of Comparator/Placebo
OTV has been selected as a comparator for this study, with its initiation at 48 hours post-
inoculation mirroring the MK-4482 Treatment arm. This is in alignment with its approved 
usage as a treatment of influenza, where it is recommended to be initiated within 2 days of 
symptom onset; in those participants who develop symptoms in this study, symptom onset is 
anticipated to occur between 24 and 48 hours post-inoculation. The use of an approved 
antiviral treatment as a comparator will help to benchmark the performance of MK-4482 in 
this human challenge model. Additionally, placebo will be used as a direct comparator in the 
assessments of antiviral activity and symptom resolution in order to evaluate the effects of 
MK-4482.
4.3
Justification for Dose
An 800-mg dose of MK-4482 will be administered Q12H for 5 days in this study, which is 
the same as the proposed therapeutic dose for adults and was the dose assessed in the pivotal 
Phase 3 portion of the Phase 2/3 study for the treatment of adults with COVID-19 (P002 Part 
2) and in a Phase 3 study of MK-4482 for post-exposure prophylaxis of COVID-19 in adults 
(P013). This dose is similarly being evaluated in an ongoing human challenge study for the 
prevention and treatment of RSV in healthy adults (P017). 
Preclinical data place the potency of MK-4482 against influenza within the range of the 
potency against SARS-CoV-2. Comparison of effective dose amounts based on in vitro 
assays and in vivo preclinical models suggest that similar concentrations of NHC may be 
effective against both influenza and SARS-CoV-2 infection. In vitro assessments of NHC 
activity against influenza show a range of EC50 values (0.006-3.2 µM) that overlaps with the 
range of EC50 values (0.08-2.66 µM) demonstrated against SARS-CoV-2, indicating a 
similar range of potency, allowing for differences in cell and assay types.  As described in 
Section 2.2.2, in a ferret influenza model, treatment with 7 mg/kg BID MOV was sufficient 
for maximal therapeutic benefit [Toots, M., et al 2020].  A similar MOV dosing level (5 
mg/kg BID) was effective in a ferret model of SARS-CoV-2 infection (Cox 2020). Together 
these data suggest that the same MK-4482 dose used in the treatment of COVID-19 (800 mg 
Q12H) should be appropriate for influenza.
PK analyses indicate no difference in NHC exposure between healthy participants and 
participants infected with SARS-CoV-2. Therefore, the same 800-mg dose administered 
Q12H for 5 days for patients with SARS-CoV-2 has been selected for evaluation against IAV
in this study, as it is expected to achieve exposures that are believed to be efficacious based 
on the totality of preclinical data.
Of note, multiple doses up to 800 mg MK-4482 Q12H for up to 10.5 days and single doses 
up to 1600 mg, were generally well tolerated in healthy participants.
The dosing regimen of OTV to be used in this study (75 mg twice daily for 5 days) is the 
indicated regimen for the treatment of influenza in adults.
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4.4
Beginning and End-of-Study Definition
The overall study begins when the first participant (or their legally acceptable representative) 
provides documented informed consent. The overall study ends when the last participant 
completes the last study-related contact, withdraws consent, or is lost to follow-up (Section 
7.3). For purposes of analysis and reporting, the overall study ends when the Sponsor 
receives the last laboratory test result or at the time of final contact with the last participant, 
whichever comes last.
If the study includes countries in the European Economic Area (EEA), the local start of the 
study in the EEA is defined as First Site Ready (FSR) in any Member State.
A study may be paused during review of newly available preclinical/clinical safety, PK, 
pharmacodynamic, efficacy, or biologic data or other items of interest, prior to a final 
decision on continuation or termination of the study. It may be necessary to keep the study 
open for gathering/reviewing of additional supportive data to optimally complete the 
objective(s) of the study. If necessary, the appropriate amendment(s) to the protocol and/or 
appropriate communication(s) will be generated. If the decision has been made to end the 
study following this review period, the study end will be defined as the date of the Sponsor 
decision, and this end of study date supersedes the definitions outlined above. The 
Competent Authority(ies) and IRB(s)/IEC(s) will be apprised of the maximum duration of 
the study beyond the last participant out and the justification for keeping the study open.
4.4.1
Clinical Criteria for Early Study Termination
There are no prespecified criteria for terminating the study early.
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5
STUDY POPULATION
As stated in the Code of Conduct for Clinical Trials (Appendix 1.1), this study includes 
participants of varying age (as applicable), race, ethnicity, and sex (as applicable). The 
collection and use of these demographic data will follow all local laws and participant 
confidentiality guidelines while supporting the study of the disease, its related factors, and 
the IMP under investigation.
Prospective approval of protocol deviations to recruitment and enrollment criteria, also 
known as protocol waivers or exemptions, is not permitted.
5.1
Inclusion Criteria
An individual is eligible for inclusion in the study if the individual meets all of the following 
criteria:
Type of Participant and Disease Characteristics
1. The participant is in good health based on medical history, physical examination, VS 
measurements, spirometry, and ECGs performed before inoculation.
Appendix 9 provides a table of the 12-Lead Electrocardiogram Evaluation Criteria.
2. The participant is in good health based on laboratory safety tests obtained at the screening 
visit. Appendix 2 provides a table of laboratory safety tests to be performed. Appendix 10 
provides an algorithm for the assessment of out-of-range laboratory values.
The laboratory safety test parameter value(s) for hemoglobin and platelet levels must 
be ≥LLN, total white cell count must be ≥3000/µL, and absolute neutrophil count 
must be ≥1500/µL before the participant can be considered eligible for inclusion.
Appendix 10 provides an algorithm for the assessment of out-of-range laboratory values.
Demographics
3. The participant is an individual of any sex/gender, from 18 years to 55 years of age 
inclusive, at the time of providing study-specific informed consent.
4. The participant has a total body weight ≥50 kg and Body Mass Index (BMI) ≥18 kg/m2
and ≤35 kg/m2.
Male Participants
5. Contraception used by men should be consistent with local regulations regarding the 
methods of contraception for those participating in clinical trials.
Male participants must agree to the following during the intervention period and for at least 
28 days after viral challenge (in Part 1) and for at least 90 days after the last dose of study 
intervention (in Part 2):
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
Abstains from heterosexual intercourse as their preferred and usual lifestyle (abstinent 
on a long-term and persistent basis) and agrees to remain abstinent
OR

Uses contraception unless confirmed to be azoospermic (vasectomized or secondary 
to medical cause, documented from the site personnel’s review of the participant’s 
medical records, medical examination, or medical history interview) as detailed 
below
Uses a male condom plus partner use of an additional contraceptive method when having 
penile-vaginal intercourse with a POCBP 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.
Female Participants
6. A participant assigned female sex at birth is eligible to participate if not pregnant or 
breastfeeding, and at least one of the following conditions applies:
•
Is not a POCBP
OR
•
Is a POCBP and:
Uses a contraceptive method that is highly effective (a low user dependency method OR a 
user dependent hormonal method in combination with barrier method), or is abstinent from 
penile-vaginal intercourse as their preferred and usual lifestyle (abstinent on a long-term and 
persistent basis), as described in Appendix 5 for at least 28 days after viral challenge (in Part 
1) and for at least 28 days after the last dose of study intervention (in Part 2). The participant 
agrees not to donate eggs (ova, oocytes) to others or freeze/store eggs during this period for 
the purpose of reproduction.
The investigator should evaluate the potential for contraceptive method failure (ie, 
noncompliance, recently initiated) in relationship to the first dose of study intervention. 
Contraceptive use by POCBPs should be consistent with local regulations regarding the 
methods of contraception for those participating in clinical studies. If the contraception 
requirements in the local label for any of the study interventions are more stringent than the 
requirements above, the local label requirements are to be followed.
Has a negative highly sensitive pregnancy test (serum) as required by local regulations)
within 24 hours before the first dose of study intervention. In such cases, the participant must 
be excluded from participation if the serum pregnancy result is positive. Additional 
requirements for pregnancy testing during and after study intervention are in Section 8.5.6.
Abstains from breastfeeding during the study intervention period and for at least 28 days 
after viral challenge (in Part 1) and for at least 28 days after the last dose of study 
intervention (in Part 2). 
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Medical history, menstrual history, and recent sexual activity has been reviewed by the 
investigator to decrease the risk for inclusion of a POCBP with an early undetected 
pregnancy.
Informed Consent
7. The participant (or legally acceptable representative) has provided documented informed
consent/assent for the study, including for FBR.
Additional Categories
8. The participant is serosuitable* to the challenge virus within 90 days prior to study 
intervention.

A participant must be serosuitable to take part in the study, ie, he/she must have no or 
low pre-existing serum levels of antibodies specific to the challenge agent. This 
antibody titer cut-off for serosuitability will be described in the AP.

Serum levels of pre-existing IAV (A/France/759/21 [H1N1] or the alternative virus 
eg, A/Perth/16/2009 [H3N2] or A/California 2009-like [H1N1])-specific antibodies 
will be determined as described in the AP.
5.2
Exclusion Criteria
The participant must be excluded from the study if the participant meets any of the following 
criteria:
Medical Conditions
1. The participant has a history of, or has currently active, symptoms or signs suggestive of 
upper or lower respiratory tract infection within 4 weeks prior to admission to 
quarantine..
2. The participant has a history of clinically significant endocrine, GI, cardiovascular, 
hematological, hepatic, immunological, renal, respiratory, genitourinary, or major 
neurological (including stroke and chronic seizures) abnormalities or diseases. 
Participants with a remote history of uncomplicated medical events (eg, uncomplicated 
kidney stones, as defined as spontaneous passage and no recurrence in the last 5 years, or 
childhood asthma) may be enrolled in the study at the discretion of the investigator.
Additionally, participants with a physician-diagnosed mild Irritable Bowel Syndrome not 
requiring regular treatment can be included at the discretion of the investigator.
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3. The participant is mentally or legally incapacitated, has significant emotional problems at 
the time of prestudy (screening) visit, or expected during the conduct of the study, or has 
a history of clinically significant psychiatric disorder of the last 5 years. Participants who 
have had situational depression may be enrolled in the study at the discretion of the 
investigator. Participants with a history of resolved depression and/or anxiety 1 or more 
years ago may be included at the discretion of the investigator. Participants with a history 
of stress related illness, which is not ongoing or requiring current therapy, with good 
evidence of preceding stressors may also be included at the investigator’s discretion. If
required, participants will be assessed prior to enrolment with a Patient Health 
Questionnaire (PHQ-9) and/or Generalized Anxiety Disorder Questionnaire (GAD-7) 
which must score ≤4 on admission.
4. The participant has a history of cancer (malignancy).  Exceptions: (1) Adequately treated 
nonmelanomatous skin carcinoma or carcinoma in situ of the cervix or; (2) Other 
malignancies that have been successfully treated with appropriate follow up and therefore 
unlikely to recur for the duration of the study, in the opinion of the investigator and with
agreement of the Sponsor (eg, malignancies that have been successfully treated ≥10 years 
prior to admission to quarantine).
5. The participant has a history of rhinitis (including hay fever) which is clinically active, or
history of moderate to severe rhinitis, or history of seasonal allergic rhinitis likely to be 
active at the time of inclusion into the study and/or requiring regular nasal corticosteroids 
on an at least weekly basis, within 30 days prior to admission to quarantine. Participants 
with a history of currently inactive rhinitis (within the last 30 days) or mild rhinitis may 
be included at the investigator’s discretion.
6. The participant has a history of atopic dermatitis/eczema which is clinically severe and/or 
requiring moderate to large amounts of daily dermal corticosteroids. Participants with 
mild to moderate atopic dermatitis/eczema, taking small amounts of regular dermal 
corticosteroids may be included at the investigator’s discretion.
7. The participant has a diagnosis of cluster headache/migraine or is receiving prophylaxis
against migraine. A participant whose reporting physician has diagnosed migraine may
be included provided there are no associated neurological symptoms such as hemiplegia 
or visual loss. Investigator discretion may also be based on whether or a participant will 
be receiving study drug (Part 1 versus Part 2.).
8. The participant has an estimated eGFR ≤80 mL/min/1.73 m2 based on the CKD-EPI 
Equation.
At the discretion of the investigator a measured CrCl, as determined by a 24-hour urine 
collection, may be used in place of, or in conjunction with, the estimate of the eGFR.
Participants who have an eGFR or measured CrCl of up to 10% below either 80 mL/min (for 
CrCl) or 80 mL/min/1.73 m2 (for eGFR) may be enrolled in the study at the discretion of the 
investigator.
eGFR = 141 × min(Scr κ, 1
⁄
)α × max(Scr κ, 1
⁄
)−1.209 × 0.993Age × 1.018 if female
× 1.159 if black or African American
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9. The participant has a lifetime history of anaphylaxis and/or a lifetime history of severe
allergic reaction. Significant intolerance to any food or drug in the last 12 months, as
assessed by the Investigator. 
10. The participant has a positive test(s) for HBsAg, hepatitis C antibodies or HIV. 
11. The participant has had major surgery and/or donated or lost 1 unit of blood 
(approximately 550 mL) within 3 months prior to the prestudy (screening) visit.
Prior/Concomitant Therapy
12. The participant uses or anticipates the use of concomitant medications (prescription 
and/or non-prescription), including vitamins or herbal and dietary supplements from 
approximately 2 weeks (or 5 half-lives, whichever is longer) prior to the planned date of
viral challenge until the poststudy visit. There may be certain medications that are 
permitted (see Section 6.5). An exception to this criterion would be if, in the opinion of 
the study physician/Investigator, the medication will not interfere with the study
procedures or compromise participant safety. Specifically, the following are excluded:
•
Herbal supplements within 7 days prior to the planned date of viral challenge.
•
Chronically used medications, vitamins, or dietary supplements, including any 
medications known to be potent inducers or inhibitors of CYP450 enzymes, within 21
days prior to the planned date of viral challenge.
•
Medications or products (prescription or over-the-counter) for symptoms of nasal 
congestion or respiratory tract infection within 48 hours prior to the planned date of
viral challenge and during the inpatient quarantine period.
•
Systemic anti-viral administration within 4 weeks prior to the planned date of viral
challenge.
•
Chronic administration (defined as more than 14 continuous days) of an 
immunosuppressant or other immune-modifying drug within 6 months prior to the
planned date of viral challenge and through the Follow-up visit (Day 28).
Prior/Concurrent Clinical Study Experience
13. The participant has evidence of receipt of vaccine within the 4 weeks prior to the planned 
date of viral challenge.
14. The participant intends to receive any vaccine(s) before the last day of follow-up. (Note: 
no travel restrictions will apply after the Day 28 follow-up visit.)
15. The participant has received any investigational drug within 3 months (or 5 half-lives, 
whichever is greater) prior to the planned date of viral challenge.
16. The participant has received 3 or more investigational drugs within the previous 12 
months prior to the planned date of viral challenge.
17. The participant has had prior inoculation with a virus from the same virus subtype as the 
challenge virus.
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18. The participant has had prior inoculation with a virus from the same virus-family as the 
challenge virus in the last 12 months
19. The participant has had prior participation in another human viral challenge study with a 
respiratory virus in the preceding 3 months, taken from the date of viral challenge in the 
previous study to the date of expected viral challenge in this study.
Diagnostic Assessments
20. The participant has a presence of fever, defined as participant presenting with a 
temperature reading of ≥37.9°C on Day -2, Day -1, and/or pre-Challenge on Day 0.
21. The participant has any of the following: QTc interval ≥470 msec (males) or ≥480 msec 
(females), a history of risk factors for Torsades de Pointes (eg, heart
failure/cardiomyopathy or family history of long QT syndrome), uncorrected 
hypokalemia or hypomagnesemia, or is taking concomitant medications that prolong the 
QT/QTc interval.
22. The participant has a confirmed positive test for drugs of abuse and/or cotinine at the Day 
-2/-1 visit. One repeat test allowed at PI discretion.
23. The participant has a forced expiratory volume in 1 second <80%.
Other Exclusions
24. The participant is under the age of legal consent.
25. The participant has smoked ≥10 pack-years at any time (10 pack-years is equivalent to 
one pack of 20 cigarettes a day for 10 years).
26. The participant has a recent history or presence of alcohol addiction, or excessive use of 
alcohol (weekly intake in excess of 28 units alcohol; 1 unit being a half glass of beer, a 
small glass of wine or a measure of spirits).
27. The participant consumes excessive amounts, defined as more than 6 servings of 
caffeinated beverages or xanthine-containing products (1 serving is approximately 
equivalent to 120 mg of caffeine) per day.
28. The participant has venous access deemed inadequate for the phlebotomy and cannulation 
demands of the study.
29. The participant has any significant abnormality altering the anatomy of the nose in a 
substantial way or nasopharynx that may interfere with the aims of the study and, in 
particular, any of the nasal assessments or viral challenge. History of nasal polyps is 
allowed, but large nasal polyps causing current and significant symptoms and/or 
requiring regular treatments in the last month is exclusionary.
30. The participant has any clinically significant history of epistaxis (large nosebleeds) 
within the 3 months prior to the Day -2/-1 visit and/or history of being hospitalized due to 
epistaxis on any previous occasion.
31. The participant has had any nasal or sinus surgery within 3 months prior to the Day -2/-1
visit.
32. The participant is a regular user of cannabis or any illicit drugs, or has a history of drug 
(including alcohol) abuse within approximately 1 year prior to study-specific screening. 
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33. The investigator has any concern regarding safe participation in the study, or for any 
other reason the investigator considers the participant inappropriate for participation in 
the study.
34. Is or has an immediate family member (eg, spouse, parent/legal guardian, sibling, or 
child) who is investigational site or Sponsor staff directly involved with this study.
5.3
Lifestyle Considerations
5.3.1
Meals and Dietary Restrictions - Part 2 Only
5.3.1.1
Diet Restrictions
In Part 2, participants will fast from all food and drinks, except water, for at least 8 hours 
before administration of the AM dose on Day 5, after which rich PK sampling will take 
place. Water will be restricted 1 hour before and 1 hour after study intervention 
administration but will be unrestricted at all other times. 
On days with sparse PK sampling (ie, trough samples), meals and snacks will be unrestricted 
in caloric content, composition and timing.
Each study intervention administration will be taken with 250 mL water. Additional water, in 
increments of 50 mL if needed, may be provided.
5.3.1.2
Fruit Juice Restrictions
In Part 2, participants will refrain from the consumption of grapefruit juice, grapefruits, and 
grapefruit products beginning approximately 2 weeks before administration of the initial dose 
of study intervention, throughout the study and until the poststudy visit.
Participants will refrain from the consumption of all fruit juices 24 hours before the study 
intervention administration at Day 5 AM until 12 hours after drug administration at this time 
point.
On all other days during the study, the consumption of all fruit juices (except for grapefruit, 
grapefruit juices, and grapefruit products) is allowed, and consumption of all fruits (except 
for grapefruit) is not restricted throughout the study.
5.3.2
Caffeine, Alcohol, and Tobacco Restrictions – Parts 1 and 2
5.3.2.1
Caffeine Restrictions
The consumption of caffeine or xanthine-containing products (e.g., coffee, tea, cola drinks, 
and chocolate) should be limited to no more than 6 units per day (1 unit = 120 mg of 
caffeine) from 48 hours prior to quarantine admission and during quarantine and for 48 hours 
prior to each study clinic visit.
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5.3.2.2
Alcohol Restrictions
Participants will not be allowed to consume alcohol from 72 hours prior to quarantine 
admission and while in the clinic unit, and for 72 hours prior to each study clinic visit.
5.3.2.3
Tobacco Restrictions
Participants will follow the smoking restrictions (and if applicable, the use of 
nicotine/nicotine-containing products) defined by the CRU as follows:
Participants must not smoke or use tobacco or nicotine containing products for 72 hours prior 
to and during quarantine. Participants that are current smokers may be enrolled in the study 
if, in the opinion of the Investigator, cessation of smoking during quarantine will not lead to 
withdrawal symptoms which could interfere with the accurate recording on the symptom 
diary card.
5.3.3
Activity Restrictions
Participants must refrain from strenuous exercise for 48 hours prior to and during quarantine 
and for at least 48 hours prior to each clinic visit (unless it is within the usual activity of the 
participant) and participants are advised to avoid any new strenuous activities for 1 week 
prior to clinic visits such as weightlifting or running to avoid potential spurious elevation of 
clinical laboratory safety parameters.
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 
may be included, as outlined in the eCRF entry guidelines. Minimal information may include 
demography, screen failure details, eligibility criteria, and any AEs or SAEs meeting 
reporting requirements. For individuals who do not meet the criteria for participation in this 
study (screen failure), the Investigator will decide whether the participant should be 
permanently excluded from the study or invited back for repeat assessments (i.e., repeat 
clinical laboratory test) if the initial screening assessments are still within the allowed 
screening windows or rescreening for a later quarantine, as appropriate. A minimal set of 
screen failure information is required to ensure transparent reporting of screen failure 
participants to meet the Consolidated Standards of Reporting Trials (CONSORT) publishing 
requirements and to respond to queries from regulatory authorities.
5.5
Participant Replacement Strategy
If a participant discontinues from study intervention OR withdraws from the study a 
replacement participant may be enrolled if deemed appropriate by the investigator and 
Sponsor. The replacement participant will generally receive the same intervention or 
intervention sequence (as appropriate) as the participant being replaced. The replacement 
participant will be assigned a unique treatment/randomization number.
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The study site should contact the Sponsor for the replacement participant’s 
treatment/randomization number.
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6
STUDY INTERVENTION
Study intervention is defined as any investigational intervention(s), marketed product(s), 
placebo, or medical device(s) intended to be administered to a study participant according to 
the study protocol.
Clinical supplies (MK-4482 200-mg capsules and MK-4482 placebo capsules) will be 
packaged to support enrollment and replacement participants as required. When a 
replacement participant is required, the Sponsor or designee needs to be contacted before 
dosing the replacement participant. Clinical supplies will be affixed with a clinical label in 
accordance with regulatory requirements.
6.1
Study Intervention(s) Administered
The study intervention(s) to be used in this study are outlined in Table 3.  Table 4 depicts the 
study administration schedule. 
Country-specific requirements are noted in Appendix 7.
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Table 3
Study Interventions
Arm 
Name
Arm Type
Interventi
on Name
Interventi
on Type
Dose 
Formulati
on
Unit Dose 
Strength(s)
Dosage 
Level(s)
Route of 
Administrati
on
Treatment 
Period
Use
IMP or 
NIMP/Ax
MP
Sourcin
g
Active
Experiment
al
MK-4482 
Drug
Capsule
200 mg 
800 mg
Oral
MK-4482 
PEP Q12H x 
5 days
MK-4482 
Treatment: 
Q12H x 5 
days
Test 
Product
IMP
Sponsor
Placebo
Placebo 
Placebo
Drug
Capsule
N/A
N/A
Oral
Matched 
Placebo: 
Q12H x 7
days
MK-4482 
Treatment:
Q12H Day 5 
PM and Day 
6
MK-4482 
Treatment: 
Q12H Day 0 
PM and Day 
1
Placebo 
IMP
Sponsor
Placebo
Placebo 
Placebo 
Drug
Capsule 
N/A
N/A
Oral 
Oseltamivir 
Treatment: 
Q12H Day 0 
PM and Day 
1
Placebo
IMP
Sponsor
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Arm 
Name
Arm Type
Interventi
on Name
Interventi
on Type
Dose 
Formulati
on
Unit Dose 
Strength(s)
Dosage 
Level(s)
Route of 
Administrati
on
Treatment 
Period
Use
IMP or 
NIMP/Ax
MP
Sourcin
g
Comparat
or 
Active 
Comparato
r 
Oseltamivi
r 
Drug
Capsule
75 mg
75 mg
Oral
Oseltamivir
Treatment: 
Q12H x 5 
days 
Comparat
or
IMP
Sourced 
locally 
by the 
site
Virus 
Inoculatio
n
N/A
Influenza 
A Virus*
Virus 
(Challenge 
Agent)
N/A
Approximate
ly 5 to 7 
TCID50*
Approximate
ly 5 to 7 
TCID50*
Intranasal
Single 
Administrati
on
Challenge 
Agent
AxMP
Site 
EEA=European Economic Area; IMP=investigational medicinal product; NIMP/AxMP=noninvestigational/auxiliary medicinal product, PEP=post-exposure prophylaxis.
The classification of IMP and NIMP/AxMP in this table is based on guidance issued by the European Commission and applies to countries in the EEA. Country differences 
with respect to the definition/classification of IMP and NIMP/AxMP may exist. In these circumstances, local legislation is followed.
* The Influenza A/France/759/21 [H1N1] challenge virus used in Part 1 will be prepared to have an inoculum concentration of between approximately 5 and 7 Log10 tissue culture 
infective dose 50% (TCID50/mL). The Influenza A challenge virus used in Part 2 will either be Influenza A/France/759/21 [H1N1] (inoculum concentration of between 
approximately 5 and 7 Log10 TCID50/mL) or an alternative virus eg, A/Perth/16/2009 [H3N2] or A/California 2009-like [H1N1]; the inoculum concentration for an 
alternative virus is provided in Appendix 11, and final details of the virus will be outlined in the Analytical Plan.
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Table 4
Study Administration Schedule 
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All supplies indicated in Table 2 will be provided per the “Sourcing” column depending on 
local country operational requirements. If local sourcing, every attempt should be made to 
source these supplies from a single lot/batch number where possible (eg, not applicable in the 
case where multiple lots or batches may be required due to the length of the study, etc).
Refer to Section 8.1.8 for details regarding administration of the study intervention.
6.2
Preparation/Handling/Storage/Accountability
6.2.1
Dose Preparation
There are no specific calculations or evaluations required to be performed to administer the
proper dose to each participant. The rationale for selection of doses to be used in this study is
in Section 4.3.
6.2.2
Handling, Storage, and Accountability
The investigator or designee must confirm appropriate temperature conditions have been 
maintained during transit for all study intervention received, and any discrepancies are 
reported and resolved before use of the study intervention.
Only participants enrolled in the study may receive study intervention, and only authorized 
site staff may supply or administer study intervention. All study interventions must be stored 
in a secure, environmentally controlled, and monitored (manual or automated) area in 
accordance with the labeled storage conditions with access limited to the investigator and 
authorized site staff.
The investigator, institution, or the head of the medical institution (where applicable) is 
responsible for study intervention accountability, reconciliation, and record maintenance (ie, 
receipt, reconciliation, and final disposition records).
For all study sites, the local country Sponsor personnel or designee will provide appropriate 
documentation that must be completed for drug accountability and return, or local discard 
and destruction if appropriate. Where local discard and destruction is appropriate, the 
investigator is responsible for ensuring that a local discard/destruction procedure is 
documented.
The study site is responsible for recording the lot number, manufacturer, and expiry date for 
any locally purchased product (if applicable) as per local guidelines unless otherwise 
instructed by the Sponsor.
The investigator shall take responsibility for and shall take all steps to maintain appropriate 
records and ensure appropriate supply, storage, handling, distribution, and usage of study 
interventions in accordance with the protocol and any applicable laws and regulations.
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6.3
Measures to Minimize Bias: Randomization and Blinding
6.3.1
Intervention Assignment
Participants will be assigned randomly according to a computer-generated allocation 
schedule.
Sample allocation schedules are shown in Table 5 and Table 6.
Table 5
Sample Allocation Schedule for Part 1
Number of Participants
Treatment 
20
Viral inoculation on Day 0
Table 6
Sample Allocation Schedule for Part 2
Interventiona
Approximate 
Number of 
Participantsb
Treatment
MK-4482 PEP
35
800 mg MK-4482 Q12H  
MK-4482 Tx
35
800 mg MK-4482 Q12H
OTV Tx
35
75 mg OTV Q12H
Placebo
35
PBO Q12H 
OTV = oseltamivir, PEP = post-exposure prophylaxis, Q12H = every 12 hours, Tx = treatment
a Participants will be randomly assigned to one of four interventions, which will be dosed in a blinded 
fashion. In order to maintain the blind, all participants will receive 4 capsules at each dose administration and 
will be blindfolded during dosing. 
b. The number of participants to be enrolled in Part 2 will be confirmed following the review of Part 1 data.
6.3.2
Stratification
No stratification based on age, sex, or other characteristics will be used in this study.
6.3.3
Blinding
A double-blinding technique will be used. MK-4482, placebo, and OTV will be prepared 
and/or dispensed in a blinded fashion by an unblinded pharmacist or delegated unblinded 
study-site personnel. Dosing will be carried out by an unblinded dosing team and participants 
will be blindfolded during dose administration (see Section 4.1 for further details). 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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6.4
Study Intervention Compliance
Interruptions from the protocol-specified treatment plan require consultation between the 
investigator and the Sponsor and written documentation of the collaborative decision on 
participant management.
6.5
Concomitant Therapy
Medications or vaccinations specifically prohibited in the exclusion criteria are not allowed 
during the time periods specified by this protocol. If there is a clinical indication for any 
medications or vaccinations specifically prohibited, discontinuation from study intervention 
may be required. The investigator should discuss any questions regarding this with the 
Sponsor Clinical Director. The final decision on any supportive therapy or vaccination rests 
with the investigator and/or the participant’s primary physician. However, the decision to 
continue the participant on study intervention requires the mutual agreement of the 
investigator, the Sponsor, and the participant.
Listed below are specific restrictions for concomitant therapy or vaccination:
•
Receipt of blood or blood products, or loss (including blood donations) of 550 mL or 
more of blood within the 3 months prior to the planned date of viral challenge or 
planned during the 3 months after the Follow-up visit.
•
Herbal supplements within 7 days prior to the planned date of viral challenge.
•
Chronically used medications, vitamins, or dietary supplements, including any 
medications known to be potent inducers or inhibitors of CYP450 enzymes, within 21 
days prior to the planned date of viral challenge.
•
Medications or products (prescription or over-the-counter) for symptoms of nasal 
congestion or respiratory tract infection for 48 hours prior to viral challenge and 
during the inpatient quarantine period.
•
Systemic anti-viral administration within 4 weeks prior to the planned date of viral 
challenge.
•
Chronic administration (defined as more than 14 continuous days) of an 
immunosuppressant or other immune-modifying drug within 6 months prior to the 
planned date of viral challenge and through the Follow-up visit (Day 28).
Paracetamol/acetaminophen may be used for minor ailments without prior consultation with 
the Sponsor. 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 along with:
•
Reason for use
•
Dates of administration including start and end dates
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•
Dosage information including dose and frequency
The Sponsor Clinical Director should be contacted if there are any questions regarding 
concomitant or prior therapy.
6.5.1
Rescue Medications and Supportive Care
No rescue or supportive medications are specified for use in this study.
6.6
Dose Modification
The suggested doses may be adjusted downward at the discretion of the sponsor based upon 
newly available safety, tolerability, and/or PK data from this study or other studies within the 
program.
6.6.1
Stopping Rules
The following stopping rules will be used during the conduct of this study.
If any of the below stopping rules are met, the study will be paused, and no further dosing 
will occur until the Sponsor has reviewed the totality of data available. To continue the study 
(on joint agreement with the Sponsor and investigator), a substantial amendment will be 
submitted for approval.
1. An individual participant reports an SAE considered related to the study intervention by 
the investigator.
2. Any unexpected virus-related SAE or unexpected virus-related AEs of clinical concern
have been reported following Human Viral Inoculation (expectedness will be assessed by 
referring to the inoculation virus dossier). Clinical concern will be determined at the 
discretion of the investigator.
6.7
Intervention After the End of the Study
There is no study-specified intervention after the end of the study.
6.8
Clinical Supplies Disclosure
The emergency unblinding call center will use the intervention allocation/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 
8.1.11). The Sponsor will not provide random code/disclosure envelopes or lists with the 
clinical supplies.
See Section 8.1.11 for a description of the method of unblinding a participant during the 
study, should such action be warranted.
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6.9
Standard Policies
Not applicable for this study.
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7
DISCONTINUATION OF STUDY INTERVENTION AND PARTICIPANT 
WITHDRAWAL
7.1
Discontinuation of Study Intervention
Discontinuation of study intervention does not represent withdrawal from the study. As 
certain data on clinical events beyond study intervention discontinuation may be important to 
the study, they must be collected through the participant’s last scheduled follow-up, even if 
the participant has discontinued study intervention. Therefore, all participants who 
discontinue study intervention before completion of the protocol-specified treatment period 
will still continue to participate in the study as specified in Section 1.3 and Section 8.1.9, or 
if available, a PCL.
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. Specific details regarding procedures to be 
performed at study intervention discontinuation are provided in Section 8.1.9.
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’s treatment assignment has been unblinded by the investigator, MSD 
subsidiary, or through the emergency unblinding call center.
•
The participant has a medical condition or personal circumstance which, in the opinion of 
the investigator and/or Sponsor, placed the participant at unnecessary risk from continued 
administration of study intervention.
•
The participant has a confirmed positive serum pregnancy test.
•
The participant has a positive urine drug screen at any time during the course of the study
prior to the final follow up visit. The drug screen can be confirmed by a recheck at the 
discretion of the investigator after discussion with the Sponsor.
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.
Specific details regarding procedures to be performed at the time of withdrawal from the 
study, as well as specific details regarding withdrawal from FBR, are outlined in 
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Section 8.1.10. The procedures to be performed should a participant repeatedly fail to return 
for scheduled visits and/or if the study site is unable to contact the participant are outlined in
Section 7.3.
7.3
Lost to Follow-up
If a participant fails to return to the clinic for a required study visit and/or if the site is unable 
to contact the participant, the following procedures are to be performed:
•
The site must attempt to contact the participant and reschedule the missed visit. If the 
participant is contacted, the participant should be counseled on the importance of 
maintaining the protocol-specified visit schedule.
•
The investigator or designee must make every effort to regain contact with the participant 
at each missed visit (eg, telephone calls and/or a certified letter to the participant’s last 
known mailing address or locally equivalent methods). These contact attempts should be 
documented in the participant’s medical record.
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8
STUDY ASSESSMENTS AND PROCEDURES
•
Study procedures and their timing are summarized in the SoA.
•
Adherence to the study design requirements, including those specified in the SoA, is 
essential and required for study conduct.
•
The investigator is responsible for ensuring that procedures are conducted by 
appropriately qualified (by education, training, and experience) staff. Delegation of 
study-site personnel responsibilities will be documented in the Investigator Trial File 
Binder (or equivalent).
•
All study-related medical (or dental) decisions must be made by an investigator who is a 
qualified physician (or dentist when appropriate).
•
All screening evaluations must be completed and reviewed to confirm that potential 
participants meet all eligibility criteria. The investigator will maintain a screening log to 
record details of all participants screened and to confirm eligibility or record reasons for 
screening failure, as applicable.
•
Procedures conducted as part of the participant’s routine clinical management (eg, blood 
count) and obtained before signing of ICF may be used for screening or baseline purposes 
provided the procedures meet the protocol-specified criteria and were performed within 
the time frame defined in the SoA.
•
Additional evaluations/testing may be deemed necessary by the investigator and or the 
Sponsor for reasons related to participant safety. In some cases, such evaluation/testing 
may be potentially sensitive in nature (eg, HIV, hepatitis C), and thus local regulations 
may require that additional informed consent be obtained from the participant. In these 
cases, such evaluations/testing will be performed in accordance with those regulations.
•
The maximum amount of blood collected from each participant over the duration of the 
study will not exceed the volume mentioned in Appendix 8.
•
Repeat or unscheduled samples may be taken for safety reasons or for technical issues 
with the samples.
8.1
Administrative and General Procedures
8.1.1
Informed Consent
The investigator or medically qualified designee (consistent with local requirements) must 
obtain documented informed consent from each potential participant (or their legally 
acceptable representative) prior to participating in this clinical study or FBR. If there are 
changes to the participant’s status during the study (eg, health or age of majority 
requirements), the investigator or medically qualified designee must ensure the appropriate 
documented informed consent is in place.
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8.1.1.1
General Informed Consent
Informed consent given by the participant or their legally acceptable representative must be 
documented on a consent form. The form must include the study protocol number, study 
protocol title, dated signature, and agreement of the participant (or his/her legally acceptable 
representative) and of the person conducting the consent discussion.
A copy of the signed and dated informed consent form should be given to the participant (or 
their legally acceptable representative) before participation in the study.
The initial ICF, any subsequent revised ICF, and any written information provided to the 
participant must receive the IRB/IEC’s approval/favorable opinion in advance of use. The 
participant or his/her legally acceptable representative should be informed in a timely manner 
if new information becomes available that may be relevant to the participant’s willingness to 
continue participation in the study. The communication of this information will be provided 
and documented via a revised consent form or addendum to the original consent form that 
captures the participant’s or the participant’s legally acceptable representative’s dated 
signature.
If the investigator recommends continuation of study intervention beyond disease 
progression, the participant or their legally acceptable representative will be asked to provide 
documented informed consent.
Specifics about the study and the study population are to be included in the study informed 
consent form.
Informed consent will adhere to IRB/IEC requirements, applicable laws and regulations, and 
Sponsor requirements.
8.1.1.2
Consent and Collection of Specimens for Future Biomedical Research
The investigator or medically qualified designee will explain the FBR consent to the 
participant, or the participant’s legally acceptable representative, answer all of his/her 
questions, and obtain documented informed consent before performing any procedure related 
to FBR. A copy of the informed consent will be given to the participant before performing 
any procedure related to FBR.
8.1.2
Inclusion/Exclusion Criteria
All inclusion and exclusion criteria will be reviewed by the investigator, who is a qualified 
physician, to ensure that the participant qualifies for the study.
8.1.3
Participant Identification Card
All participants will be given a participant identification card identifying them as participants 
in a research study. The card will contain study-site contact information (including direct 
telephone numbers) to be used in the event of an emergency. The participants will be 
quarantined from the time the study specific informed consent is signed (Day -2/Day-1) until 
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discharge from the site (Day 8). The investigator or qualified designee will provide the 
participant with a participant identification card at the time of discharge from the inpatient 
quarantine. At the time of intervention allocation/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 health care provider can obtain information about study 
intervention in emergency situations where the investigator is not available.
8.1.4
Medical History
A medical history will be obtained by the investigator or qualified designee.
8.1.5
PHQ-9 and GAD-7 Questionnaire
PHQ-9 and GAD-7 questionnaires will be used at the discretion of the investigator to assess 
participants’ eligibility in terms of ability to tolerate isolation in the quarantine unit.
8.1.6
Prior and Concomitant Medications Review
8.1.6.1
Prior Medications
The investigator or qualified designee will review before medication use, including any 
protocol-specified washout requirement, and record prior medication taken by the participant 
within 14 days before starting the study.
8.1.6.2
Concomitant Medications
The investigator or qualified designee will record medication, if any, taken by the participant 
during the study.
8.1.7
Assignment of Screening Number
All consented participants will be given a unique screening number that will be used to 
identify the participant for all procedures that occur before randomization. Each participant 
will be assigned only 1 screening number. Screening numbers must not be reused for 
different participants.
8.1.8
Assignment of Treatment/Randomization Number
All eligible participants will be randomly allocated and will receive a randomization number. 
The randomization number identifies the participant for all procedures occurring after 
randomization. Once a randomization number is assigned to a participant, it can never be 
reassigned to another participant.
A single participant cannot be assigned more than 1 randomization number.
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8.1.9
Study Intervention Administration
In Part 2, study medication will be administered by unblinded study staff, as described in the 
pharmacy manual.
8.1.9.1
Timing of Dose Administration
In Part 2, the first dose of MK-4482 or placebo will be administered in the PM on Day 0, 
approximately 12 hours post-inoculation. All subsequent doses of MK-4482, OTV, or 
placebo will be given in the morning and evening (ie, Q12H) on Days 1 through Day 6, at 
approximately the same time each day.
8.1.10
Discontinuation and Withdrawal
The investigator or study coordinator must notify the Sponsor when a participant has been 
discontinued/withdrawn from the study. If a participant discontinues for any reason at any 
time during the course of the study and/or intervention, the participant may be asked to return 
to the clinic (or be contacted) for a poststudy visit as per the number of days described in 
Section 8.12.5 to have the applicable procedures conducted. However, the investigator may 
decide to perform the poststudy procedures at the time of discontinuation or as soon as 
possible after discontinuation. If the poststudy visit occurs prior to the safety follow-up time 
frame as specified in Section 8.5, the investigator should perform a follow-up telephone call 
at the end of the follow-up period (Section 8.5) to confirm if any AEs have occurred since the 
poststudy clinic visit. Any AEs that are present at the time of discontinuation/withdrawal 
should be followed in accordance with the safety requirements outlined in Section 8.5.
8.1.10.1
Withdrawal From Future Biomedical Research
Participants may withdraw their consent for FBR. Participants may withdraw consent at any 
time by contacting the study investigator. If medical records for the study are still available, 
the investigator will contact the Sponsor using the designated mailbox 
(clinical.specimen.management@MSD.com). Subsequently, the participant’s consent for 
FBR will be withdrawn. A letter will be sent from the Sponsor to the investigator confirming 
the withdrawal. It is the responsibility of the investigator to inform the participant of 
completion of withdrawal. Any analyses in progress at the time of request for withdrawal or 
already performed before the request being received by the Sponsor will continue to be used 
as part of the overall research study data and results. No new analyses would be generated 
after the request is received.
If the medical records for the study are no longer available (eg, if the investigator is no longer 
required by regulatory authorities to retain the study records) or the specimens have been 
completely anonymized, there will no longer be a link between the participant’s personal 
information and their specimens. In this situation, the request for specimen withdrawal 
cannot be processed.
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8.1.11
Participant Blinding/Unblinding
STUDY INTERVENTION IDENTIFICATION INFORMATION IS TO BE UNMASKED 
ONLY IF NECESSARY FOR THE WELFARE OF THE PARTICIPANT. EVERY 
EFFORT SHOULD BE MADE NOT TO UNBLIND.
For emergency situations where the investigator or medically qualified designee (consistent 
with local requirements) needs to identify the intervention used by a participant and/or the 
dosage administered, he/she will contact the emergency unblinding call center by telephone 
and make a request for emergency unblinding. As requested by the investigator or medically 
qualified designee, the emergency unblinding call center will provide the information to 
him/her promptly and report unblinding to the Sponsor. Before contacting the emergency 
unblinding call center to request unblinding of a participant’s intervention assignment, the 
investigator who is qualified physician should make reasonable attempts to enter the intensity
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 must be discontinued from study 
intervention, but should continue to be monitored in the study.
8.1.12
Domiciling
Participants will report to the CRU on Day -2/Day-1 before the scheduled day of study 
intervention administration on Day 0 and remain in the unit until Day 8. At the discretion of 
the investigator, participants may be requested to remain in the CRU longer. 
Participants may be permitted to leave the unit, for emergency situations or if this is the wish 
of the participant, during the domiciling period. Leaving the CRU early during the quarantine 
period will be strongly discouraged, due to potential risks to the participant and his/her 
contacts, in particular vulnerable people, as outlined in Section 8.14.3. The CRU will notify 
the Sponsor and the decision how to monitor the participant will be at the discretion of the 
investigator after discussion with the Sponsor.
8.1.13
Calibration of Equipment
The investigator or qualified designee has the responsibility to ensure that any device or 
instrument used for a clinical evaluation/test during a clinical study that provides information 
about inclusion/exclusion criteria and/or safety or efficacy parameters shall be suitably 
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calibrated and/or maintained to ensure that the data obtained are reliable and/or reproducible. 
Documentation of equipment calibration must be retained as source documentation at the 
study site.
8.2
Serosuitability Assessment
A participant must be serosuitable to take part in the study, ie, he/she must have no or low 
pre-existing serum levels of antibodies specific to the challenge agent. Participant 
serosuitability will be determined within 90 days prior to challenge virus inoculation (Day 0) 
to determine participant eligibility; this will be conducted under a generic screening protocol 
and serosuitability criteria. At baseline and at follow-up, a sample will be taken to check for 
seroconversion. Serum levels of pre-existing influenza-specific antibodies to the challenge 
virus will be determined using HAI for influenza.
8.3
Intranasal Administration of the Challenge Virus
The challenge agent used in Part 1 of this study is A/France/759/21 [H1N1], and in Part 2 is 
either A/France/759/21 [H1N1] or an alternative strain eg, A/Perth/16/2009 [H3N2] or 
A/California 2009-like [H1N1].
The challenge agent stock was manufactured under current GMP. The challenge agent stock 
has undergone quality testing performed during manufacturing (identity, appearance, 
sterility, infectivity, and contaminants) according to predetermined specifications, and has 
subsequently also passed an extensive panel of adventitious agent testing. The challenge 
agent is stored in a secure -80oC freezer (normal temperature range -60°C to -90°C).
Inoculum vials containing the challenge agent will be used for intranasal inoculation of each 
participant. The inoculum will be prepared and/or provided according to the AP and 
administered in accordance with site SOPs.
All administrations will be made by a member of the study staff and witnessed by a second 
study staff member. The exact time of challenge agent inoculation will be recorded in the 
administration log. Accurate records will be kept of when and how much inoculum is 
prepared and used. The oversight process will be signed off prior to administration of the 
challenge agent. Any noncompliance or problems with the inoculation will be recorded in the 
participant’s source notes and reported to the Investigator.
Following challenge agent inoculation, participants will be closely observed specifically for 
potential allergic reactions and any AEs for the following 24 hours. Post inoculation, 
participants will lie flat for 10 minutes then sit up with nose pegs on for 20 minutes. 
Participants will continue to be monitored throughout the clinical phase of the study.
8.4
Efficacy Assessments
Compliance with the efficacy and safety assessments (along with study treatment use) is 
essential, and any noncompliance noted by the investigator or designee should result in 
consultation with the participant on corrective measures needed to ensure compliance.
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8.4.1
Symptom Diary Card
Participants will report and assess the severity of any challenge agent-related signs and 
symptoms 3 times per day during quarantine, at the same time each day (±1 hour), using the 
SDC. This information will be collected using a paper form.
The following symptoms in the 13-item symptom questionnaire will be graded on a scale of 0 
to 3 (Grade 0: no symptoms; Grade 1: just noticeable; Grade 2: clearly bothersome from time 
to time but does not interfere with me doing my normal daily activities; Grade 3: quite 
bothersome most or all of the time, and it stops me participating in activities); shortness of
breath and wheeze have an additional grade, ie, Grade 4: symptoms at rest.
•
Runny nose
•
Stuffy nose
•
Sneezing
•
Sore throat
•
Earache
•
Malaise/tiredness
•
Headache
•
Muscle and/or joint ache
•
Chilliness/feverishness
•
Cough
•
Chest tightness
•
Shortness of breath
•
Wheeze
Additional to the categorical SDC, a visual analogue scale diary card using a 100 mm scale, 
with the same symptoms, will be completed by the participants.
Between 10 and 13 of the 13 items in the SDC will be used for the primary analysis; the 
selected items will be summarized in the sSAP. Those items not included in the primary 
analysis may be explored separately. 
SDC: Participant Common Cold Perception Questions
Two additional common cold-related questions will be answered by the participant within the 
SDC each morning. The responses to these questions will be analyzed in an exploratory 
manner. The first question asks the participant’s perception of whether they have a cold or 
not, the second asks the participant’s perception of improvement/worsening of the cold.
1. Do you have a cold: Yes/No
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If the participant selects Yes to having a cold, then the second 7-point Likert scale “global 
change since yesterday” question is completed by the participant, as below:
1. Compared to yesterday, I feel that my cold is:
•
Very much better
•
Somewhat better
•
A little better
•
The same
•
A little worse
•
Somewhat worse
•
Very much worse
8.4.2
FLU-PRO Plus© Questionnaire 
The FLU-PRO Plus© tool will be administered once every 24 hours, in the evening before 
bedtime, considering the prior 24-hour period. The FLU-PRO© is a patient-reported outcome 
measure developed to assess symptoms of viral respiratory illness in adults. The measure 
contains 32 items in six domains evaluating the severity of symptoms in the nose (4 items), 
throat (3 items), eyes (3 items), chest/respiratory (7 items), gastrointestinal (4 items), and 
body/systemic (11 items). A higher score indicates more severe symptoms. There is a global 
score and scoring by domain. 
An adaptation, FLU-PRO Plus©, is intended to assess a broader array of viral respiratory 
tract infections and considers an additional body system, senses (taste and smell). This 
measure can yield both FLU-PRO© scores as well as the new FLU-PRO Plus© scores. Data 
from the FLU-PRO Plus© will be analyzed based on multiple time points, in addition to 1-
item patient global impression questions, intended to serve as anchor for the psychometric 
analyses to estimate responder definitions (ie, meaningful changes) used for score 
interpretation. The FLU-PRO Plus© will be completed first, followed by the patient global 
impression questions.
8.4.3
Nasal Discharge Collection from Paper Tissues
Each participant will be given pre-weighed packets of paper tissues. Participants will be 
asked to place single tissues used for nose blowing or sneezing into a specified collection bag 
(for that participant only).
A daily 24-hour paper tissue collection will take place throughout the quarantine period. 
Distribution of paper tissues and collection bags will start on Day -1, with the first collection 
on Day 0. Thereafter, distribution and collection of tissues will occur daily at the same time 
each day (±1 hour) until discharge from quarantine.
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24-hour paper tissue collections will be analyzed to determine the following over the 
quarantine period:
•
24-hour nasal discharge weight
•
The number of paper tissues used for nose blowing or sneezing over each 24-hour period
8.4.4
Nasopharyngeal Swabs
Nasopharyngeal swabs will be performed to collect samples of epithelial lining fluid for:
•
Respiratory pathogen screen
•
Virological assessments 
•
Pre-discharge viral test (if determined by the Investigator to be needed)
On entry to quarantine, a nasopharyngeal swab will be collected and tested to detect the 
presence of a set of respiratory pathogens, including SARS-CoV-2, that could potentially 
contraindicate a person’s participation in the study. The methodology to be used to conduct 
the respiratory pathogen screen will be documented in the AP. Additional nasopharyngeal 
swabs may be collected if the results from the first test were invalid to support study 
eligibility prior to challenge agent inoculation, or if a community-acquired infection is 
suspected during quarantine.
Any additional screening tests will be conducted at the discretion of the Investigator.
Viral titer may be determined by qRT-PCR and/or a viral culture assay to investigate the 
following parameters:
•
Viral load
•
Infectivity status and rate
•
Viral dynamics (e.g., duration, peak, time to peak)
Where required, a rapid viral antigen test or PCR-based test will be used to determine the 
presence of influenza in a nasopharyngeal swab sample taken prior to discharge from the 
quarantine unit on Day 8. The rapid viral antigen test will be performed at the discretion of 
the Investigator and only if indicated for a clinical or other reason. Additional tests may be 
performed at the discretion of the Investigator.
8.4.5
Nasal Sample for Immunology
Nasal sampling using either a nasal swab or nasosorption will be performed as outlined in the 
SoA for the exploratory evaluation of mucosal antibodies and inflammatory markers. Sample 
collection, storage, and shipment instructions for nasal samples will be provided in the Study 
Operations Manual.
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8.5
Safety Assessments
Details regarding specific safety procedures/assessments to be performed in this study are 
provided. The total amount of blood to be drawn/collected over the course of the study (from 
prestudy to poststudy visits), including approximate blood volumes drawn/collected by visit 
and by sample type per participant, can be found in Appendix 8.
Planned time points for all safety assessments are provided in the SoA.
8.5.1
Physical Examinations
A complete physical examination will be conducted by an investigator or medically qualified 
designee (consistent with local requirements) per institutional standard. Height (recorded at 
screening only) and weight will also be measured and recorded. Investigators should pay 
special attention to clinical signs related to previous serious illnesses.
A brief directed physical examination, including nasal exam, will be conducted by an 
investigator or medically qualified designee (consistent with local requirements) per 
institutional standard.
Symptom-directed physical examinations will be conducted as appropriate by the 
Investigator and may include (as applicable) examination of the eyes, ears, nose, throat, and 
respiratory system/chest (via stethoscope). Based upon the presence or absence of clinical 
signs and symptoms, Investigator discretion will be used to determine the requirement to 
perform certain ongoing assessments.
Assessment and grading of any upper respiratory tract (nasal discharge, otitis, pharyngitis, 
sinus tenderness) and lower respiratory tract findings (abnormal breath sounds externally 
[e.g., stridor, wheezing] and on chest auscultation [rhonchi, crepitations, or other]) will be 
performed, as applicable. Physician reported assessments of challenge agent-related illness 
will be graded in accordance with its intensity and documented in the source data.
Following challenge agent inoculation, additional symptoms that are not available in the list 
of symptoms of the symptom diary card and are deemed to be clinically significant (in the 
opinion of the Investigator) will be captured as AEs (for more details see Section 8.6).
Following challenge agent inoculation all unexpected (in the opinion of the Investigator) 
symptom-directed physical examination findings will be captured as AEs, along with all 
other occurrences that meet the criteria for an AE. 
BMI
BMI equals a person’s weight in kilograms divided by height in meters squared 
(BMI = kg/m2). BMI will be rounded to the nearest whole number according to the standard 
convention of 0.1 to 0.4 round down and 0.5 to 0.9 round up.
Body weight and height will be obtained with the participant’s shoes off and jacket or coat 
removed.
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8.5.2
Vital Signs
Vital signs assessments will be recorded according to the study site’s SOPs:
•
Tympanic temperature, heart rate, respiratory rate, O2 saturation, and blood pressure will 
be assessed.
•
BP and HR measurements will be assessed with a completely automated device. Manual 
techniques will be used only if an automated device is not available.
•
Peripheral arterial oxygen saturation will be assessed using pulse oximetry.
•
VS are to be taken before blood collection for laboratory tests.
8.5.2.1
Resting Vital Signs
Vital Sign Measurements (Heart Rate and Blood Pressure)
Participants should be resting in a quiet setting without distractions, and in position for at 
least 10 minutes before having VS measurements obtained - during generic screening, the 
supine position will be used, and for all other time points, the semirecumbent position will be 
used. VS will include HR, systolic and diastolic BP, RR, and body temperature at time points 
indicated in the SoA. The correct size of the BP cuff and the correct positioning on the 
participant’s arm is essential to increase the accuracy of BP measurements.
Upon admission to the CRU on Day -2/-1, HR and BP will be single measurements used to 
assess for participant eligibility. These may be repeated at the discretion of the study 
investigator.
The pre-inoculation (baseline) HR and BP on Day 0 will be triplicate measurements, 
obtained at least 1 minute apart within 3 hours prior to inoculation. The median of these three
measurements will be used as the baseline to calculate change from baseline for safety 
evaluations (and for rechecks, if needed). Post-inoculation VS measurements will be single 
measurements, and in Part 2 are to be taken within 3 hours prior to the AM dose of study 
drug.
In Part 2 participants will rest semirecumbent from dosing until 4 hours following the AM 
dose on Days 2 and 5, except to stand for study-related procedures, if required, per the SoA.
Body Temperature
Body temperature (tympanic) will be measured. The same method must be used for all 
measurements for each individual participant and should be the same for all participants.
Temperature is to be monitored as outlined in the SoA, but may be monitored more 
frequently during quarantine, if appropriate.
Following challenge agent inoculation, pyrexia (temperature ≥37.9oC) will be expected and 
presumed to represent infection consequent to vial challenge and will not be additionally 
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captured as an AE unless it meets the definition of an AE and is deemed to be clinically 
significant (in the opinion of the Investigator) to be classed as an AE.
Following challenge agent inoculation, all unexpected (in the opinion of the Investigator) 
pyrexia will be captured as an AE, along with all other occurrences that meet the criteria for 
an AE.
8.5.3
Electrocardiograms
•
12-lead ECGs will be obtained and reviewed by an investigator or medically qualified 
designee (consistent with local requirements) as outlined in the SoA using an ECG 
machine that automatically calculates the HR and measures PR, QRS, QT, and QTc 
intervals. Refer to Appendix 9 for evaluation and potentially significant findings.
Special care must be taken for proper lead placement by qualified personnel. Skin should be 
clean and dry before lead placement. Participants may need to be shaved to ensure proper 
lead placement. Female participants may need to remove interfering garments.
Participants should be resting in position for at least 10 minutes before each ECG 
measurement – during generic screening, the supine position will be used, and for all other 
time points, the semirecumbent position will be used.
The correction formula to be used for QTc is Fridericia.
If repeat ECGs are required, the clinical site will decide whether to leave the electrodes in 
place or mark the position of the electrodes for subsequent ECGs. To mark the position of the 
electrodes, 12-lead electrode sites will be marked on the skin of each participant with an 
ECG skin-marker pen to ensure reproducible electrode placement.
ECGs taken on Day -2/-1 will be triplicate measurements. The median of these 
measurements will be used as the baseline to calculate change from baseline for safety 
evaluations (and for rechecks, if needed). All other ECG measurements will be single 
measurements.
During the treatment period, if a participant demonstrates an increase in QTc interval 
≥60 msec compared with median predose baseline measurement, the ECG will be repeated 
twice within 5 minutes. The median value of the QTc interval from the 3 ECGs will represent 
the value at that time point. If the median QTc interval increase from baseline for any 
postdose time point is ≥60 msec, the participant will continue to be monitored by repeat 12-
lead ECGs every 15 minutes for at least 1 hour or until the QTc interval is within 60 msec of 
baseline. If prolongation of the QTc interval ≥60 msec persists, a consultation with a study 
cardiologist may be appropriate and the Sponsor should be notified.
During the treatment period, if a participant demonstrates a QTc interval ≥500 msec on a 
postdose ECG, the ECG will be repeated twice within 5 minutes. The median value of the 
QTc interval from the 3 ECGs will represent the value at that time point. If the median QTc 
interval is ≥500 msec, the Sponsor should be notified, and the ECGs should be reviewed by a 
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cardiologist. The participant should be telemetry monitored (until the QTc interval is 
<500 msec) or should be considered for transfer to a location where closer monitoring and 
definitive care (eg, a CCU or ICU) is available.
If the participant has unstable hemodynamics, or has any clinically significant dysrhythmias 
noted on telemetry, the participant should be immediately transferred to an acute care setting 
for definitive therapy.
If prolongation of the QTc interval is noted, concomitant medications that prolong QTc 
interval should be held until the QTc interval is within 60 msec of baseline and the QTc 
interval is <500 msec.
A cardiologist will be consulted by the investigator as needed to review ECG tracings with 
significant abnormalities.
8.5.4
Spirometry
Spirometry will be performed according to the study site’s SOPs. Height at screening will be 
used as the baseline measurement for all spirometry assessments.
Spirometry should meet the American Thoracic Society/European Respiratory Society 
guidelines criteria [Graham, B. L., et al 2019]. For FEV1 and forced vital capacity (FVC), 
the highest value from a minimum of 3 technically satisfactory attempts will be considered. 
For FEV1 and FVC the highest and the second-highest value should not exceed more than 
150 mL or 5% (whichever is greater). If the difference is larger, up to 8 technically 
acceptable measurements will be made with repeatability assessed after each additional 
attempt. If after 8 technically acceptable attempts the difference remains greater than 150 mL 
or 5% (whichever is greater) the highest values will be reported, and an operator comment 
will be made to the source data. Values for FEV1 and FVC will be assessed and reported as 
the highest values regardless of curve.
Predicted values will be calculated according to the formula of the Report of the Global Lung 
Function Initiative, European Respiratory Society Task Force Lung Function Reference 
Values [Quanjer, P. H., et al 2012].
Spirometry may be repeated at any time in the event of respiratory signs or symptoms 
(repeated coughing, bradypnea, tachypnoea, rales, and rhonchi) or respiratory difficulties.
A 15% drop in a spirometry value (compared to baseline and confirmed by a repeat on the 
same day) may be judged a Grade 1 (mild) AE. However, due to variability in participants’ 
ability to perform these tests with adequate technique, the Investigator will use his/her 
clinical judgement to assess whether abnormal spirometry readings are consistent with a true 
drop and whether an AE should be raised. The Investigator will use his/her clinical 
judgement to assign severity grades above Grade 1, based on evaluation of clinical signs and 
symptoms. If a spirometry reading on repeat assessment has returned to normal an AE will 
not be raised.
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8.5.5
Clinical Safety Laboratory Assessments
Refer to Appendix 2 for the list of clinical laboratory tests to be performed and to the SoA for 
the timing and frequency.
•
The investigator or medically qualified designee (consistent with local requirements) 
must review the laboratory report, document this review, and record any clinically 
relevant changes occurring during the study in the AE section of the CRF. The laboratory 
reports must be filed with the source documents. Clinically significant abnormal 
laboratory findings are those which are not associated with the underlying disease, unless 
judged by the investigator to be more severe than expected for the participant’s condition.
•
All protocol-required laboratory assessments, as defined in Appendix 2, must be 
conducted in accordance with the laboratory manual and the SoA.
•
If laboratory values from nonprotocol-specified laboratory assessments performed at the 
institution’s local laboratory require a change in study participant management or are 
considered clinically significant by the investigator (eg, SAE or AE or dose 
modification), then the results must be recorded in the appropriate CRF (eg, SLAB).
•
For any laboratory tests with values considered clinically significantly abnormal during 
participation In the study or within 14 days after the last dose of study intervention, every 
attempt should be made to perform repeat assessments until the values return to normal or 
baseline or if a new baseline is established as determined by the investigator.
8.5.6
Pregnancy Testing
•
Pregnancy testing:
Pregnancy testing requirements for study inclusion are described in Sections 1.3 and 5.1.
Additional serum or urine pregnancy tests may be performed, as determined necessary by the 
investigator or required by local regulation, to establish the absence of pregnancy at any time 
during the participant’s participation in the study.
8.5.7
Photograph of Rash
Photographs of the rash are highly recommended to be taken immediately, along with any 
additional information that may assist the investigator to evaluate the skin reaction, skin 
eruption, or rash occurrence in determining etiology and study intervention relationship.
8.6
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.
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Adverse events, SAEs, and other reportable safety events will be reported by the participant 
(or, when appropriate, by a caregiver, surrogate, or the participant’s legally authorized 
representative).
The investigator and any designees are responsible for detecting, documenting, and reporting 
events that meet the definition of an AE or SAE as well as other reportable safety events. 
Investigators need to document if an SAE was associated with a medication error, misuse, or 
abuse.
Investigators remain responsible for following up AEs, SAEs, and other reportable safety 
events for outcome according to Section 8.5.3. 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.
8.6.1
Time Period and Frequency for Collecting AE, SAE, and Other Reportable 
Safety Event Information
AEs, SAEs, and other reportable safety events that occur after the participant provides 
documented informed consent, but before intervention allocation/randomization, must be 
reported by the investigator under any of the following circumstances:
•
if the participant is receiving placebo run-in or other run-in treatment,
•
if the event causes the participant to be excluded from the study,
•
if it is the result of a protocol-specified intervention, including, but not limited to washout 
or discontinuation of usual therapy, diet, placebo, or a procedure.
From the time of intervention allocation/randomization through 22 days after cessation of 
intervention, all AEs, SAEs, and other reportable safety events must be reported by the 
investigator.
Additionally, any SAE brought to the attention of an investigator any time outside the period 
specified in the previous paragraph also must be reported immediately to the Sponsor if the 
event is considered related to study intervention.
Investigators are not obligated to actively seek AEs or SAEs or other reportable safety events 
in former study participants. However, if the investigator learns of any SAE, including a 
death, at any time after a participant has been discharged from the study, and the investigator 
considers the event to be reasonably related to the study intervention or study participation, 
the investigator must promptly notify the Sponsor.
All initial and follow-up AEs, SAEs, and other reportable safety events will be recorded and 
reported to the Sponsor or designee within the time frames as indicated in Table 7.
Exception: A positive pregnancy test at the time of initial screening is not a reportable event 
unless the participant has received study intervention.
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Table 7
Reporting Periods and Time Frames for Adverse Events and Other Reportable 
Safety Events
Type of Event
Reporting Period:
Consent to 
Randomization/Alloca
tion
Reporting Period:
Randomization/Alloca
tion through Protocol-
specified Follow-up 
Period
Reporting Period:
After the Protocol-
specified Follow-up 
Period
Time 
Frame to 
Report 
Event and 
Follow-up 
Informati
on 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/Lactat
ion Exposure
Report if:
– participant has been 
exposed to any 
protocol-specified 
intervention (eg, 
procedure, washout,
or run-in treatment 
including placebo 
run-in)
Exception: A positive 
pregnancy test at the 
time of initial screening 
is not a reportable 
event.
Report all
Previously reported 
– Follow to 
completion/terminat
ion; report outcome
Within 
24 hours
of learning 
of event
ECI (require 
regulatory 
reporting)
Report if:
– due to intervention
– causes exclusion
Report
– potential DILI
– require regulatory 
reporting
Not required
Within 
24 hours
of learning 
of event
ECI (do not 
require 
regulatory 
reporting)
Report if:
– due to intervention
– causes exclusion
Report
– non-DILI ECIs and 
those not requiring 
regulatory reporting
Not required
Within 
5 calendar
days of 
learning of 
event
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Type of Event
Reporting Period:
Consent to 
Randomization/Alloca
tion
Reporting Period:
Randomization/Alloca
tion through Protocol-
specified Follow-up 
Period
Reporting Period:
After the Protocol-
specified Follow-up 
Period
Time 
Frame to 
Report 
Event and 
Follow-up 
Informati
on to 
Sponsor
Cancer
Report if:
– due to intervention
– causes exclusion
Report all
Not required
Within 
5 calendar
days of 
learning of 
event
(unless 
serious)
Overdose
Report if:
– receiving placebo run-
in or other run-in 
medication 
Report all
Not required
Within 
24 hours
of learning 
of event
DILI=drug-induced liver injury; ECI=event of clinical interest; NSAE=nonserious adverse event; SAE=serious 
adverse event.
8.6.2
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.
8.6.3
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.
8.6.4
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 toward 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.
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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 SAEs) from the Sponsor will file it 
along with the IB and will notify the IRB/IEC, if appropriate according to local requirements.
8.6.5
Pregnancy and Exposure During Breastfeeding
Although pregnancy and infant exposure during breastfeeding are not considered AEs, any 
pregnancy or infant exposure during breastfeeding (spontaneously reported to the 
investigator or their designee) that occurs in a participant during the study are reportable to 
the Sponsor.
All reported pregnancies must be followed to the completion/termination of the pregnancy.
Any pregnancy complication will be reported as an AE or SAE.
The medical reason (example: maternal health or fetal disease) for an elective termination of 
a pregnancy will be reported as an AE or SAE. Prenatal testing showing fetus will be born 
with severe abnormalities/congenital anomalies that leads to an elective termination of a 
pregnancy will be reported as an SAE for the fetus.
Pregnancy outcomes of ectopic pregnancy, spontaneous abortion, missed abortion, benign 
hydatidiform mole, blighted ovum, fetal death, intrauterine death, miscarriage, and stillbirth 
must be reported as serious events (Important Medical Events). If the pregnancy continues to 
term, the outcome (health of infant) must also be reported.
8.6.6
Disease-related Events and/or Disease-related Outcomes Not Qualifying as 
AEs or SAEs
The following events do not qualify as AEs for this study:
1. Typical/normal/solicited viral infection symptoms on symptom diary cards.
2. Procedure-related events may be noted during the study while conducting nasal sampling 
(collection of nasopharyngeal swabs or other nasal samples), specifically:
⦁
Nasal discomfort/irritation
⦁
Nasal abrasions
⦁
Nasal epistaxis
⦁
Sneezing
⦁
Watery eyes
When mild in nature and as expected in the opinion of the Investigator or delegated 
physician, these events will not be reported as AEs.
3. Asymptomatic bruising following venipuncture, or removal of an intravenous cannula.
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4. Dry lips and skin if solely due to the air-conditioning in the quarantine unit, with or 
without the use of emollients to maintain skin integrity.
8.6.7
Events of Clinical Interest
Selected serious and nonserious AEs are also known as ECIs and must be reported to the 
Sponsor.
Events of clinical interest for this study include:
1. An overdose of Sponsor’s product, as defined in Section 8.7.
2. Potential DILI events defined as an elevated AST or ALT laboratory value that is greater 
than or equal to 3× the ULN and an elevated total bilirubin laboratory value that is greater 
than or equal to 2× the ULN and, at the same time, an alkaline phosphatase laboratory 
value that is less than 2× the ULN, as determined by way of protocol-specified laboratory 
testing or unscheduled laboratory testing.*
*Note: These criteria are based on available regulatory guidance documents. The purpose 
of the criteria is to specify a threshold of abnormal hepatic tests that may require an 
additional evaluation for an underlying etiology. The study-site guidance for assessment 
and follow-up of these criteria can be found in the Investigator Study File Binder (or 
equivalent).
It may also be appropriate to conduct additional evaluation for an underlying etiology in the 
setting of abnormalities of liver blood tests including AST, ALT, bilirubin, and alkaline 
phosphatase that do not meet the criteria noted above. In these cases, the decision to proceed 
with additional evaluation will be made through consultation between the study investigators 
and the Sponsor Clinical Director. However, abnormalities of liver blood tests that do not 
meet the criteria noted above are not ECIs for this study.
8.7
Treatment of Overdose
For purposes of this study, an overdose will be defined as any dose of any drug administered 
as part of the study exceeding the dose prescribed by the protocol. It is up to the investigator 
or the reporting physician to decide whether a dose is to be considered an overdose, in 
consultation with the Sponsor.
The Sponsor does not recommend specific treatment for an 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.
8.8
Pharmacokinetics
The decision as to which plasma samples collected will be measured for evaluation of PK 
will be collaboratively determined by the Sponsor. If indicated, these samples may also be 
measured and/or pooled for assay in an exploratory manner for metabolites and/or additional 
pharmacodynamic markers. Blood samples collected may be stored and further analysis may 
be performed, if required.
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8.8.1
Blood Collection for Plasma NHC
Sample collection, storage, and shipment instructions for plasma samples will be provided in 
the Study Operations Manual.
8.8.2
Blood Collection for Plasma Oseltamivir Carboxylate
A single sample will be drawn at 4 hours following the AM dose of study drug on Day 2 in 
all participants. These samples will be stored and only tested if deemed necessary by the 
Sponsor.
8.9
Pharmacodynamics
The virologic endpoints (as described in Sec. 3) will be used to evaluate any 
PK/pharmacodynamics relationships for NHC. Blood samples collected may be stored and 
further analysis may be performed, if required.
8.10
Immunological Assessments
In addition to serum testing for the determination of serosuitability (Sec. 8.2), serum will be 
collected for the following analyses:
•
Assessment of seroconversion (based on HAI and/or neutralization assays) at Day 28
•
Serum immunological biomarker (cytokine/chemokine) responses may be evaluated in an 
exploratory manner.
Additionally, mucosal antibodies and inflammatory markers may be explored in nasal 
samples (Sec. 8.4.5).
Sample collection, storage, and shipment instructions for serum and nasal samples will be 
provided in the Study Operations Manual.
8.11
Biomarkers
Collection of samples for other biomarker research is also part of this study. The following 
samples for biomarker research are required and will be collected from all participants as 
specified in the SoA:
•
Blood for genetic analysis
8.11.1
Planned Genetic Analysis Sample Collection
The planned genetic analysis sample should be drawn for planned analysis of the association 
between genetic variants in DNA and drug response. This sample will not be collected at the 
site if there is either a local law or regulation prohibiting collection, or if the IRB/IEC does 
not approve the collection of the sample for these purposes. If the sample is collected, 
leftover extracted DNA will be stored for FBR if the participant provides documented 
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informed consent for FBR. If the planned genetic analysis is not approved, but future 
biomedical research is approved, this sample will be collected for the purpose of FBR.
Sample collection, storage, and shipment instructions for planned genetic analysis samples 
will be in the Operations/Laboratory Manual.
8.12
Future Biomedical Research Sample Collection
If the participant provides documented informed consent for FBR, the following specimens 
will be obtained as part of FBR:
•
Leftover DNA for future research
8.13
Health Economics Medical Resource Utilization and Health Economics
This section is not applicable. Health Economics OR Medical Resource Utilization and 
Health Economics are not evaluated in this study.
8.14
Visit Requirements
Visit requirements are outlined in Section 1.3. Specific procedure-related details are provided 
in Section 8.
8.14.1
Screening
Participants will be screened under a generic screening process. Participants who fulfill 
inclusion and exclusion criteria for this study through a generic screening process, including 
being serosuitable within 90 days prior to viral challenge and having normal or not clinically 
significant laboratory safety data within 56 days prior to viral challenge, will be invited for 
admission to the quarantine unit on Day -2/-1.
Upon admission on Day -2/-1, a protocol-specific consent form will be signed, and eligibility
will be confirmed prior to allocation/randomization on Day 0. On Day 0, after all pre-
inoculation procedures have been completed, participants will be assigned a unique 
allocation number associated with a specific treatment as defined by a computer-generated 
allocation schedule.
Participants on Day 0 who have an acute illness or fever prior to the inoculation may be 
rescheduled as long as their Day 1 visit falls within the screening window (within 90 days for 
serosuitability and 56 days for laboratory safety data prior to admission to quarantine).
8.14.2
Intranasal IAV Inoculation Period
On Day 0, participants will be inoculated with IAV according to the study site’s SOPs. 
Further details of the inoculum will be provided in the AP. The study site will be responsible 
for recording the lot number, manufacturer, and expiry date of applicable supplies related to 
IAV administration.
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To reduce the risk of passing the Challenge Virus to others, participants will be asked to 
avoid contact with vulnerable people for 2 weeks after they leave quarantine. For the 
purposes of this protocol, a vulnerable individual is as follows:
1. Elderly individuals ≥65 years old;
2. Children ≤2 years old;
3. Anyone who lives in a nursing home;
4. Anyone with a low resistance to infection or who takes drugs that lower their 
resistance;
5. Anyone who is having or is about to have drug treatment for cancer (chemotherapy);
6. Anyone who has chronic obstructive pulmonary disease (COPD), emphysema or other 
severe lung disease;
7. Anyone who has heart disease such as heart failure; has had a heart attack or heart 
surgery;
8. Anyone with cerebral palsy, epilepsy, who has seizures or who has had a stroke.
8.14.3
Study Drug Intervention Period – Part 2
Participants will be dosed with study drug commencing Day 0 PM at the study site as set 
forth in the SoA and Section 6.
8.14.4
Participants Discontinued From Study Intervention but Continuing to be 
Monitored in the Study
At any point if a participant discontinues from treatment but continues to be monitored in the 
study, all or a subset of study procedures specified in the SoA may be completed at the 
discretion of the investigator and with Sponsor agreement. The subset of study procedures 
completed will be communicated in a PCL.
8.14.5
Poststudy
Participants will be required to return to clinic approximately 28 days after the administration 
of IAV. If the poststudy visit occurs earlier than 28 days post-inoculation, a subsequent 
follow-up telephone call should be made at Day 28 to determine if any AEs have occurred 
since the poststudy clinic visit.
8.14.6
Critical Procedures Based on Study Objectives: Timing of Procedure
For this study, the nasopharyngeal swab for virology is the critical procedure.
At any postdose time point, the nasopharyngeal swab for virology needs to be collected as 
close to the exact time point as possible. All other procedures should be completed as close 
to the prescribed/scheduled time as possible. Study procedures can be performed before or 
after the prescribed/scheduled time.
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The order of priority can be changed during the study with joint agreement of the investigator 
and the Sponsor Clinical Director.
Any nonscheduled procedures required for urgent evaluation of safety concerns take 
precedence over all routine scheduled procedures.
The following variance in procedure conduct times will be permitted.
•
Nasopharyngeal swab sampling: to be conducted 2X per day at the same times each day
(+/- 1 hour)
•
Tissue collection (for mucus production analysis): to be 1X per day at the same time each 
day (+/- 1 hour) 
•
Symptom reporting (SDC): to be conducted 3X per day at the same times each day (+/- 1 
hour)
•
FLU-PRO Plus© Questionnaire: to be completed once per day (in the evening) at the 
same time each day (+/- 1 hour)
•
Dosing of study drug: first dose to be administered 12 hours (+/- 30 min) post-
inoculation. Subsequent doses to be administered every 12 hours (+/- 1 hour)
•
PK Collection as outlined in Table 8.
Table 8
PK Collection Windows
Plasma NHC or OTV PK
Collection
Collection Window
Predose (Day 0 PM)
Within 3 hr prior to first dose
Predose (all other days)
Within 30 min prior to the next dose
0 to <1 h
5 min
1 to <12 h
10 min
12 to <24 h
15 min
24 to <48 h
1 h
48 to 72 h
2 h
PK collection windows are +/- relative to the AM dose on the respective day, with the exception of the 
Predose Day 0 sampling, which occurs prior to the PM dose.
•
Pre-inoculation standard safety evaluations: VS and ECG within 3 hours prior to 
inoculation; laboratory safety tests and physical examination within 24 hours prior to 
inoculation
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•
Post-inoculation standard safety evaluations: VS, ECG, laboratory safety tests, and 
physical examination
Starting from Day 1, post-inoculation safety evaluations may be obtained within +/-a hour of 
the theoretical sampling time
Day 28 follow-up visit may be conducted within ±3 calendar days.
8.14.7
Study Design/Dosing/Procedures Modifications Permitted Within Protocol 
Parameters
This protocol is written with some flexibility to accommodate the inherent dynamic nature of 
early phase clinical studies. Modifications to the dose, dosing regimen, and/or clinical or 
laboratory procedures currently outlined may be required to achieve the scientific goals of 
the study objectives and/or to ensure appropriate safety monitoring of the study participants.
As such, some alterations from the currently outlined dose and/or dosing regimen may be 
permitted based on newly available data, but the maximum daily dose may not exceed those 
currently outlined in the protocol.
•
Switch from A/France/759/21 [H1N1] to alternative challenge virus (eg, 
A/Perth/16/2009 [H3N2] or A/California 2009-like [H1N1]) for Part 2
•
Change in A/France/759/21 [H1N1] viral inoculum titer for Part 2
•
Change in sample size for Part 2 (within an anticipated range of 25 to 50 per 
intervention group)
•
Increase in duration of quarantine period (Part 1 or 2)
•
Omission of discretionary safety assessments in Part 2
•
Decrease in the dose of the study intervention(s)
•
Decrease in the duration of study intervention administration (eg, number of days)
•
Instructions to take study intervention with or without food or drink may also be 
modified based on newly available data
•
Modification of the PK/PD sample processing and shipping details based on newly 
available data
The PK and/or PD sampling scheme currently outlined in the protocol may be modified 
during the study based on newly available data. These collected samples may also be assayed 
in an exploratory manner for metabolites and/or additional PD markers.
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The timing of procedures for assessment of safety procedures (eg, vital signs, ECG, safety
laboratory tests, etc.) currently outlined in the protocol may be modified during the study
based on newly available data. Additional laboratory safety tests may be added to blood
samples previously drawn to obtain additional safety information.
•
Additional blood samples may be taken for laboratory safety tests or other tests, such 
as measurement for PK or PD analysis. The total blood volume withdrawn from any 
single participant will not exceed the maximum allowable volume during his/her 
participation in the entire study (Appendix 8).
•
Additional noninvasive, painless procedures that are already specified in this protocol
may be performed based on newly available data.
•
An additional 24 hours residence in the CRU and up to 2 additional outpatient visits 
per period will be permitted, in the event of a technical failure, and/or if extra blood 
samples, or extra PD measurements, are needed.
It is understood that the current study may use some or none of the alterations described 
above. Any alteration made to this protocol to meet the study objectives must be detailed by 
the Sponsor in a letter to the Study File and forwarded to the investigator for retention. The 
letter may be forwarded to the IRB/IEC at the discretion of the investigator.
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9
KEY STATISTICAL CONSIDERATIONS
This section outlines the statistical analysis strategy and procedures for the study. Changes to 
analyses made after the protocol has been finalized, but prior to unblinding, will be 
documented in the SAP and referenced in the CSR for the study. Post hoc exploratory 
analyses will be clearly identified in the CSR.
9.1
Responsibility for Analyses/In-house Blinding
The statistical analysis of the data obtained from this study will be conducted by, or under the 
direct auspices of, the Early Clinical Development Statistics Department in collaboration 
with the Quantitative Pharmacology and Pharmacometrics Department and Translational 
Medicine Departments of the Sponsor. If, after the study has begun, changes are made to the 
statistical analysis plan stated below, then these deviations to the plan will be listed, along 
with an explanation as to why they occurred, in the CSR.
9.2
Hypotheses/Estimation
Objectives and hypotheses of the study are stated in Section 3.
No hypotheses in Part 1.
Part 2 
Primary Hypotheses:
Hypothesis (Post-exposure prophylaxis [PEP]): MK-4482 (800 mg Q12H for 5 days), 
initiated 12 h following intranasal inoculation of the influenza challenge virus reduces the 
peak viral load (as determined by quantitative viral culture) compared to placebo.
Hypothesis (Treatment): MK-4482 (800 mg Q12H for 5 days), initiated 2 days following 
intranasal inoculation of the influenza challenge virus reduces the viral load AUC (as 
determined by quantitative viral culture) compared to placebo.
9.3
Analysis Endpoints
Primary Endpoints:
Part 1:
• Day 1 PM to planned discharge, Day 2 PM to planned discharge:
•
Quantitative reverse transcriptase-polymerase chain reaction (qRT-PCR)-
confirmed influenza infection
Safety: Viral challenge to Follow-up Visit
•
Adverse events (AEs) related to viral challenge
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Part 2:
PEP (MK-4482) Day 1 PM to planned discharge:
•
Peak viral load (PVL) (by quantitative viral culture) 
Treatment (MK-4482) First dose of study drug to planned discharge:
•
Area under the viral load-time curve (VL-AUC) (by quantitative viral culture)
Secondary Endpoints:
Part 1:
Day 1 PM to planned discharge, Day 2 PM to planned discharge:
•
Quantitative viral culture-confirmed influenza infection
•
VL-AUC (qRT-PCR and quantitative viral culture) 
•
PVL (qRT-PCR and quantitative viral culture) 
•
Duration of quantifiable influenza (qRT-PCR and quantitative viral culture)
Day 1 AM to planned discharge, Day 2 middle of day to planned discharge:
•
Area under the total symptom score-time curve (TSS-AUC)
•
Peak total symptom score (TSS)
•
Daily maximum TSS 
•
Duration (days) of Grade ≥2 symptoms 
•
Time (days) to symptom resolution 
•
Time (days) to peak daily maximum TSS
Part 2:
PEP (MK-4482) – Virology: Day 1 PM to planned discharge:
Symptoms and temperature Day 1 AM to planned discharge:
•
VL-AUC (qRT-PCR and quantitative viral culture) 
•
PVL (qRT-PCR)
•
qRT-PCR-confirmed influenza infection
•
qRT-PCR-confirmed symptomatic influenza infection
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•
qRT-PCR-confirmed moderately severe symptomatic influenza infection
•
qRT-PCR-confirmed febrile influenza infection
•
Quantitative viral culture-confirmed influenza infection
•
Quantitative viral culture-confirmed symptomatic influenza infection
•
Duration of quantifiable influenza (qRT-PCR and quantitative viral culture)
•
Time (days) to confirmed negative test (qRT-PCR and quantitative viral culture) 
•
Time (days) to peak viral load (qRT-PCR and quantitative viral culture)
Treatment (MK-4482 and oseltamivir) – first dose study drug to planned discharge:
•
VL-AUC (qRT-PCR and quantitative viral culture) 
•
PVL (quantitative viral culture and qRT-PCR)
•
Duration of quantifiable influenza (qRT-PCR and quantitative viral culture)
•
Time (days) to confirmed negative test (qRT-PCR and quantitative viral culture) 
•
Time (days) to peak viral load (qRT-PCR and quantitative viral culture) 
PEP (MK-4482) – Day 1 AM to planned discharge:
Treatment (MK-4482 and oseltamivir) – first dose study drug to planned discharge:
•
TSS-AUC
•
Peak TSS
•
Daily maximum TSS 
•
Duration (days) of Grade ≥2 symptoms 
•
Time (days) to symptom resolution 
•
Time (days) to peak daily maximum TSS
• Safety 
PEP (MK-4482) and Treatment (MK-4482) – from first dose of study drug to Follow-up 
Visit:
•
All AEs
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Viral challenge to Follow-up Visit:
•
AEs related to viral challenge
•
Concomitant medication use
• Pharmacokinetics:
PEP (MK-4482) and Treatment (MK-4482):
•
NHC Cmax, Tmax, t1/2, AUC0-12hr, AUC0-last, Ctrough following multiple dose 
administration of MK-4482
Tertiary/Exploratory Endpoints:
Part 2:
•
Number of seroconversions by Day 28 post inoculation
Treatment (MK-4482 and oseltamivir) – first dose of study drug to planned discharge:
•
qRT-PCR-confirmed influenza infection
•
qRT-PCR-confirmed symptomatic influenza infection
•
qRT-PCR-confirmed moderately severe symptomatic influenza infection
•
qRT-PCR-confirmed febrile influenza infection
•
Occurrence viral culture-confirmed influenza infection
•
Quantitative viral culture-confirmed symptomatic influenza infection 
PEP (MK-4482) – Day 1 PM to planned discharge;
Treatment (MK-4482) – Day 2 PM to planned discharge:
•
Symptom severity score (total and domains) by FLU-PRO Plus© questionnaire
PEP (MK-4482) – Day 1 AM to planned discharge;
Treatment (MK-4482) - Day 2 AM - Day 8 AM:
•
Total weight of mucus produced 
•
Total number of tissues used by participants
•
Exploratory assays related to respiratory viral infection and immunology (blood and 
nasal samples)
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• LNS quantitation by viral sequencing of nasal samples.
• Germline genetic variation and association to clinical data collected in this study.
9.4
Analysis Populations
Full Analysis Set (FAS) Population
The FAS will serve as the primary population for the PEP portion for the evaluation of 
pharmacodynamics and efficacy. The FAS population consists of all randomized participants 
who received 1 dose of the correct clinical material corresponding to the treatment group the 
participants were randomized into and who received the viral inoculation.
Full Analysis Set – Infected (FAS-I) Population
The FAS-I will serve as the primary population for the treatment portion for the evaluation of
pharmacodynamics and efficacy. For the treatment portion, only those that are virus infected 
participants in the FAS will be included in the pharmacodynamics and efficacy analysis.
Safety Analysis Population
The following populations are defined for the analysis and reporting of data. All participants
will be reported, and their data analyzed, according to the treatment(s) they actually received.
All Participants as Treated (APaT): The All Participants as Treated Population consists of all
participants who received at least one dose of treatment. This population will be used for
assessments of safety and tolerability.
PK Analysis Population
Per-Protocol (PP): The Per-Protocol Population consists of the subset of participants who 
comply with the protocol sufficiently to ensure that generated data will be likely to exhibit 
the effects of treatment, according to the underlying scientific model. Compliance covers 
such considerations as exposure to treatment, availability of measurements and absence of 
important protocol deviations. Important protocol deviations will be identified to the extent 
possible prior to unblinding by individuals responsible for data collection/compliance, and its 
analysis and interpretation. Any participants or data values excluded from analysis will be 
identified, along with their reason for exclusion, in the CSR. At the end of the study, all 
participants who are compliant with the study procedure as aforementioned and have 
available data from at least one treatment will be included in the Per-Protocol dataset. This 
population will be used for the PK analyses.
9.5
Statistical Methods
9.5.1
Statistical Methods for Safety Analyses
Safety and tolerability will be assessed by clinical review of AEs and other relevant 
parameters, including laboratory test results, vital signs, and ECG measurements.
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9.5.2
Statistical Methods for Efficacy Analyses
Methods:
Part 1
Primary
The peak viral load (on the log10 scale) from Part 1 determined by viral quantitative culture 
(plaque assay) will be summarized. Geometric means with corresponding 95% confidence 
intervals (CI) will be reported. 
VL-AUC (on the log10 scale) from Part 1 determined by viral quantitative culture (plaque 
assay) will be summarized. Geometric means with corresponding 95% confidence intervals 
(CI) will be reported. The infectivity rate will be calculated.
The infectivity rate will be calculated.
Part 2
Primary
PEP
Only placebo and PEP (MK-4482) will be included in the model.
Peak viral load (on the log10 scale) from Part 2 determined by viral quantitative culture 
(plaque assay) will be analyzed using a linear model with treatment group as a fixed 
categorical effect.  The model will estimate the variance of each treatment group separately. 
The mean difference in peak viral load between MK-4482 (PEP; ‘early’ administration) and 
placebo and the corresponding 2-sided 95% CI will be computed based on the model.  
Treatment
Only placebo and Tx (MK-4482) will be included in the model. For both panels, only the 
participants with virus infection will be included.
VL-AUC (on the log10 scale) from Part 2 determined by viral quantitative culture (plaque 
assay) will be analyzed using a linear model with treatment group as a fixed categorical 
effect.  The model will estimate the variance of each treatment group separately. 
The mean difference in VL-AUC between MK-4482 (Treatment; ‘late’ administration) and 
placebo and the corresponding 2-sided 95% CI will be computed based on the model. 
The primary hypothesis for PEP and treatment will be tested separately. The primary 
hypothesis will be supported if the upper limit of the two-sided 95% CI for the difference in 
mean peak viral load (PEP) or VL-AUC (Treatment) between MK-4482 and placebo is <0 
(indicating a reduction).
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For both the PEP and treatment arm, if the assumption of normality of log10 peak viral 
load/VL-AUC is not met, an alternative method, such as Wilcoxon-Rank-Sum test will be 
applied.
Secondary
OTV 
Only placebo and OTV Tx will be included in the model.
VL-AUC (on the log10 scale) from Part 2 determined by viral quantitative culture (plaque 
assay) will be analyzed using a linear model with treatment group as a fixed categorical 
effect.  The model will estimate the variance of each treatment group separately. 
The mean difference in VL-AUC between OTV (Treatment; ‘late’ administration) and 
placebo and the corresponding 2-sided 95% CI will be computed based on the model. 
If the assumption of normality of log10 peak viral load/VL-AUC is not met, an alternative 
method, such as Wilcoxon-Rank-Sum test will be applied.
Details for analyses of the numerous secondary and exploratory endpoints will be included in
a supplemental statistical analysis plan (sSAP).
9.5.3
Statistical Methods for Pharmacokinetics Analyses
The following (non-model-based) descriptive statistics will be provided for all PK 
parameters: N (number of participants with non-missing data), arithmetic mean, standard 
deviation, arithmetic percent CV (calculated as 100 x standard deviation/arithmetic mean), 
median, minimum, maximum, geometric mean, and geometric percent CV (calculated as 100 
x sqrt( exp(s2) - 1), where s2 is the observed variance on the natural log-scale).
9.6
Interim Analyses
Prior to the start of Part 2, an analysis for Part 1 will be performed to characterize the viral 
load/time profile of the H1N1 influenza challenge virus and to evaluate the infectivity rate of 
the H1N1 influenza challenge virus in healthy adult participants. If the infectivity rate is 
smaller than expected or variability in PVL or AUC is larger than expected, the sample size 
and power calculations may be re-estimated for Part 2.
9.7
Multiplicity
The study has only 1 primary hypothesis for PEP and Treatment arm respectively which will 
each be addressed separately and at the alpha level at 0.05 2-sided level; therefore, there is no 
multiplicity adjustment being applied.
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9.8
Sample Size and Power Calculations
The sample size for Part 1 was determined based on the Moore et al 2011 paper and prior 
work on the SARS-CoV-2 study. 20 participants are deemed adequate to evaluate the 
performance of the H1N1 challenge virus.
The assumed CV in PVL and VL-AUC from viral quantitative culture were obtained from 
previous published and unpublished influenza challenge studies using the influenza 
A/Perth/16/2009 [H3N2] (as an estimate for what will be observed with the new H1N1 virus) 
conducted by hVIVO. Following the completion of Part 1 of the study (sentinel cohort), the 
required sample size will be re-estimated; depending on the outcome of this re-estimate, Part 
2 may be conducted without changes, or a change may be implemented (update the sample 
size or the A/Perth/16/2009 [H3N2] virus substituted for the new H1N1). The current design 
proposes a sample size of 35 per arm which allows for a potential evaluable dropout rate of 5 
(~14% of 35), which is adequate to demonstrate the treatment effect sizes described below.
For PEP: A sample size of 30 per group would give ~81% power to detect a decrease in PVL 
of 60% (on the log10 scale) in the MK-4482 group vs. the placebo group assuming a CV in 
PVL of 0.806 with a 2-sided alpha=0.05 test.
For Treatment: With a sample size of 18 that test positive per group, there is ~82.7% power 
to detect a decrease in VL-AUC of 55% (on the log10 scale) in the MK-4482 group vs. the 
placebo group assuming a CV in VL-AUC of 0.552 with a 2-sided alpha=0.05 test. 
Considering the infection rate of 61.6%, a sample size of 30 per group will maintain 80% 
power.
For viral load, the estimates of CV for PEP and Treatment incorporate the following 
imputation approach: a value of 0.5 x log10 LLOQ is imputed for detected but not 
quantifiable values, and a value of 0.25 x log10 LLOQ is imputed for undetectable values; 
this approach avoids the impact of several zero values on the AUC in particular. 
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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 Interventional Clinical Trials
Merck Sharp & Dohme LLC, Rahway, NJ, USA (MSD)
I.
Introduction
A. Purpose
Merck Sharp & Dohme LLC, Rahway, NJ, USA (MSD), through its subsidiaries, 
conducts clinical trials worldwide to evaluate the safety and effectiveness of our 
products. As such, we are committed to designing, planning, 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 MSD’s global standards, local and/or national 
regulations (including all applicable data protection laws and regulations), and 
International Council for Harmonisation Good Clinical Practice (ICH GCP) E6 and 
ICH General Considerations for Clinical Studies E8, and 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. Input may be considered from a broad range of stakeholders, including 
patient advocacy groups/patients representing the trial population, caregivers, and 
healthcare providers to ensure operational feasibility. Trial design also includes 
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proactive identification of critical to quality factors utilizing a risk-based 
approach. Plans are then developed to assess and mitigate risks to those factors as 
appropriate during the trial. All trial protocols are and will be assessed for the 
need and capability to enroll underrepresented groups. Participants must meet 
protocol entry criteria to be enrolled in the trial.
2. Site Selection
MSD’s clinical trials are conducted globally in many different countries and in 
diverse populations, including people of varying age, race, ethnicity, gender, and 
accounting for other potential disease related factors. MSD selects investigative 
sites based on medical expertise, access to appropriate participants, adequacy of 
facilities and staff, previous performance in clinical trials, as well as budgetary 
considerations. Prior to trial initiation, sites are evaluated by MSD personnel (or 
individuals acting on behalf of MSD) to assess the ability to successfully conduct 
the trial. Individuals involved in trial conduct receive training commensurate with 
their role prior to their becoming involved in the trial.
Where appropriate, and in accordance with regulatory authority guidance, MSD 
will make concerted efforts to raise awareness of clinical trial opportunities in 
various communities. MSD will seek to engage underrepresented groups and 
those disproportionately impacted by the disease under study. MSD will support 
clinical trial investigators to enroll underrepresented groups and expand access to 
those who will ultimately use the products under investigation.
3. Site Monitoring/Scientific Integrity
Investigative trial sites are monitored to assess compliance with the trial protocol 
and Good Clinical Practice (GCP). MSD reviews clinical data for accuracy, 
completeness, and consistency. Data are verified versus source documentation 
according to standard operating procedures. Per MSD policies and procedures, if 
potential fraud, scientific/research misconduct, privacy incidents/breaches or 
Clinical Trial-related Significant Quality Issues are reported, such matters are 
investigated. When necessary, appropriate corrective and/or preventative actions 
are defined and regulatory authorities and/or ethics review committees are 
notified.
B. Publication and Authorship
Regardless of trial outcome, MSD commits to publish the primary and secondary 
results of its registered trials of marketed products in which treatment is assigned, 
according to the pre-specified plans for data analysis. To the extent scientifically 
appropriate, MSD seeks to publish the results of other analyses it conducts that are 
important to patients, physicians, and payers. Some early phase or pilot trials are 
intended to be hypothesis generating rather than hypothesis testing; in such cases, 
publication of results may not be appropriate since the trial may be underpowered and 
the analyses complicated by statistical issues such as multiplicity.
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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 and ICH Guidelines. 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. Trial designs include procedures and systems for 
the identification, monitoring, and reporting of safety concerns. 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.
During trial planning, the need for an independent Data Monitoring Committee 
(DMC) is assessed. DMC review of data accumulated during the conduct of the trial 
is integral to the well-being of trial participants.
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.
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D. Genomic Research
Genomic research will only be conducted in accordance with a protocol and informed 
consent authorized by an ethics committee.
E. Trial Results
At the time of providing informed consent and in accordance with local laws and 
regulations, participants should be informed about the plans for availability of trial 
results.
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 medical record 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 
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financial disclosure information is required. It is the investigator’s/subinvestigator’s 
responsibility to comply with any such request.
The investigator/subinvestigator(s) agree, if requested by the Sponsor in accordance with 21 
CFR Part 54, to provide his/her financial interests in and/or arrangements with the Sponsor to 
allow for the submission of complete and accurate certification and disclosure statements. 
The investigator/subinvestigator(s) further agree to provide this information on a 
Certification/Disclosure Form, frequently known as a financial disclosure form, provided by 
the Sponsor. The investigator/subinvestigator(s) also consent to the transmission of this 
information to the Sponsor in the United States for these purposes. This may involve the 
transmission of information to countries that do not have laws protecting personal data.
10.1.3
Data Protection
The Sponsor will conduct this study in compliance with all applicable data protection 
regulations.
Participants will be assigned a unique identifier by the Sponsor. Any participant records or 
datasets that are transferred to the Sponsor will contain the identifier only; participant names 
or any information that would make the participant identifiable will not be transferred.
The participant must be informed that his/her personal study-related data will be used by the 
Sponsor in accordance with local data protection law. The level of disclosure must also be 
explained to the participant.
The participant must be informed that his/her medical records may be examined by Clinical 
Quality Assurance auditors or other authorized personnel appointed by the Sponsor, by 
appropriate IRB/IEC members, and by inspectors from regulatory authorities.
10.1.3.1
Confidentiality of Data
By signing this protocol, the investigator affirms to the Sponsor that information furnished to 
the investigator by the Sponsor will be maintained in confidence, and such information will 
be divulged to the IRB, IEC, or similar or expert committee, affiliated institution, and 
employees, only under an appropriate understanding of confidentiality with such board or 
committee, affiliated institution, and employees. Data generated by this study will be 
considered confidential by the investigator, except to the extent that it is included in a 
publication as provided in the Publications section of this protocol.
10.1.3.2
Confidentiality of Participant Records
By signing this protocol, the investigator agrees that the Sponsor (or Sponsor representative), 
IRB/IEC, or regulatory authority representatives may consult and/or copy study documents to 
verify worksheet/CRF data. By signing the consent form, the participant agrees to this 
process. If study documents will be photocopied during the process of verifying 
worksheet/CRF information, the participant will be identified by unique code only; full 
names/initials will be masked before transmission to the Sponsor.
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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.
10.1.4
Committees Structure
This section is not applicable.
10.1.5
Publication Policy
The results of this study may be published or presented at scientific meetings. The Sponsor 
will comply with the requirements for publication of study results. In accordance with 
standard editorial and ethical practice, the Sponsor will generally support publication of 
multicenter studies only in their entirety and not as individual site data. In this case, a 
coordinating investigator will be designated by mutual agreement.
If publication activity is not directed by the Sponsor, the investigator agrees to submit all 
manuscripts or abstracts to the Sponsor before submission. This allows the Sponsor to protect 
proprietary information and to provide comments.
Authorship will be determined by mutual agreement and in line with ICMJE authorship 
requirements.
10.1.6
Compliance with Study Registration and Results Posting Requirements
Under the terms of the FDAAA of 2007 and the EMA clinical trial Directive 2001/20/EC, the 
Sponsor of the study is solely responsible for determining whether the study and its results 
are subject to the requirements for submission to http://www.clinicaltrials.gov, 
www.clinicaltrialsregister.eu, or other local registries. MSD, as Sponsor of this study, will 
review this protocol and submit the information necessary to fulfill these requirements. MSD 
entries are not limited to FDAAA or the EMA clinical trials directive mandated trials. 
Information posted will allow participants to identify potentially appropriate studies for their 
disease conditions and pursue participation by calling a central contact number for further 
information on appropriate study locations and study-site contact information.
By signing this protocol, the investigator acknowledges that the statutory obligations under 
FDAAA, the EMA clinical trials directive, or other locally mandated registries are that of the 
Sponsor and agrees not to submit any information about this study or its results to those 
registries.
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10.1.7
Compliance with Law, Audit, and Debarment
By signing this protocol, the investigator agrees to conduct the study in an efficient and 
diligent manner and in conformance with this protocol, generally accepted standards of GCP 
(eg, ICH GCP: Consolidated Guideline and other generally accepted standards of GCP), and 
all applicable federal, state, and local laws, rules, and regulations relating to the conduct of 
the clinical study.
The Code of Conduct, a collection of goals and considerations that govern the ethical and 
scientific conduct of clinical investigations sponsored by MSD, is provided in this appendix 
under the Code of Conduct for Clinical Trials.
The investigator agrees not to seek reimbursement from participants, their insurance 
providers, or from government programs for procedures included as part of the study 
reimbursed to the investigator by the Sponsor.
The investigator will promptly inform the Sponsor of any regulatory authority inspection 
conducted for this study.
The investigator agrees to provide the Sponsor with relevant information from inspection 
observations/findings to allow the Sponsor to assist in responding to any citations resulting 
from regulatory authority inspection and will provide the Sponsor with a copy of the 
proposed response for consultation before submission to the regulatory authority.
Persons debarred from conducting or working on clinical studies by any court or regulatory 
authority will not be allowed to conduct or work on this Sponsor’s studies. The investigator 
will immediately disclose in writing to the Sponsor if any person who is involved in 
conducting the study is debarred or if any proceeding for debarment is pending or, to the best 
of the investigator’s knowledge, threatened.
For investigators located in countries with serious breach reporting requirements, investigator 
will promptly report to the Sponsor any serious breach or suspected serious breach that 
occurs in compliance with those requirements. Unless more specifically defined in the 
applicable requirements, a serious breach is any breach of the applicable clinical trial 
regulation or of the clinical trial protocol which is likely to affect to a significant degree: (i) 
the safety or rights of a trial participant, or (ii) the reliability and robustness of the data 
generated in the clinical trial.
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.
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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.
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.
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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 9 will be performed by the local laboratory.
•
Protocol-specific requirements for inclusion or exclusion of participants are detailed in 
Section 5 of the protocol.
•
Additional tests may be performed at any time during the study as determined necessary 
by the investigator or required by local regulations.
Table 9
Protocol-required Safety Laboratory Assessments
Laboratory 
Assessments
Parameters
Hematology
Platelet Count
RBC Indices:
MCV
MCH
Reticulocytes
WBC count with 
Differential:
Neutrophils
Lymphocytes
Monocytes
Eosinophils
Basophils
RBC Count
Hemoglobin
Hematocrit
Chemistry
BUN
Potassium
AST/SGOT
Total bilirubin (and 
direct bilirubin, if total 
bilirubin is above the 
ULN)
Albumin
Bicarbonate
Chloride
Phosphorous
Creatinine
Sodium
ALT/SGPT
Total Protein
Glucose (fasted –
except at screening, 
admission, and follow-
up)
Calcium
Alkaline 
phosphatase
C-reactive protein
Routine Urinalysis
Specific gravity
pH, glucose, protein, blood, ketones, bilirubin, urobilinogen, nitrite, leukocyte 
esterase by dipstick
Microscopic examination (if blood or protein is abnormal)
Pregnancy Testing
Highly sensitive serum or urine hCG pregnancy test (as needed for WOCBP)
Other Screening 
Tests
FSH (as needed in WONCBP only)
Urine drug screen (to include at minimum: amphetamines, barbiturates, cocaine, 
opiates, cannabinoids, and benzodiazepines)
Serology (HIV antibody, HBsAg, and hepatitis C virus antibody)
Breath alcohol test
Coagulation (PT/aPTT)
Cardiac Enzymes (CK and Troponin)
Thyroid Function Test
ALT=alanine aminotransferase; aPTT=activated partial thromboplastin time; AST=aspartate aminotransferase; 
BUN=blood urea nitrogen; CK=creatine kinase; FSH=follicle-stimulating hormone; HBsAg=hepatitis B surface 
antigen; hCG=human chorionic gonadotropin; HIV=human immunodeficiency virus; MCH=mean corpuscular 
hemoglobin; MCV=mean corpuscular volume; PT=prothrombin time; RBC=red blood cell; SGOT=serum glutamic-
oxaloacetic transaminase; SGPT=serum glutamic-pyruvic transaminase; ULN=upper limit of normal; WBC=white 
blood cell; WOCBP=women of childbearing potential; WONCBP=women of nonchildbearing potential
Notes: Laboratory safety tests (hematology and chemistry) will be performed after approximately an 8-hour fast, except 
on the day of admission and follow up. Screening safety tests and any repeat hematology tests to confirm out of 
range values do not need to be fasted.
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The investigator (or medically qualified designee) must document their review of each 
laboratory safety report.
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10.3
Appendix 3: Adverse Events: Definitions and Procedures for Recording, 
Evaluating, Follow-up, and Reporting
10.3.1
Definitions of Medication Error, Misuse, and Abuse
Medication Error
This is an unintended failure in the drug treatment process that leads to or has the potential to 
lead to harm to the patient.
Misuse
This refers to situations where the medicinal product is intentionally and inappropriately used 
not in accordance with the terms of the product information.
Abuse
This corresponds to the persistent or sporadic intentional, excessive use of a medicinal 
product for a perceived psychological or physiological reward or desired nontherapeutic 
effect.
10.3.2
Definition of AE
AE definition
•
An AE is any untoward medical occurrence in a clinical study participant, temporally 
associated with the use of study intervention, whether or not considered related to the 
study intervention.
•
Note: An AE can therefore be any unfavorable and unintended sign (including an 
abnormal laboratory finding), symptom, or disease (new or exacerbated) temporally 
associated with the use of a study intervention.
•
Note: For purposes of AE definition, study intervention includes any pharmaceutical 
product, biological product, vaccine, diagnostic agent, medical device, combination 
product, or protocol-specified procedure whether investigational or marketed (including 
placebo, active comparator product, or run-in intervention), manufactured by, licensed 
by, provided by, or distributed by the Sponsor for human use in this study.
Events meeting the AE definition
•
Any abnormal laboratory test results (hematology, clinical chemistry, or urinalysis) or 
other safety assessments (eg, ECG, radiological scans, vital signs measurements), 
including those that worsen from baseline, considered clinically significant in the medical 
and scientific judgment of the investigator.
•
Exacerbation of a chronic or intermittent preexisting condition including either an 
increase in frequency and/or intensity of the condition.
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•
New conditions detected or diagnosed after study intervention administration even 
though it may have been present before the start of the study.
•
Signs, symptoms, or the clinical sequelae of a suspected drug-drug interaction.
•
Signs, symptoms, or the clinical sequelae of a suspected overdose of either study 
intervention or a concomitant medication.
•
For all reports of overdose (whether accidental or intentional) with an associated AE, the 
AE term should reflect the clinical symptoms or abnormal test result. An overdose 
without any associated clinical symptoms or abnormal laboratory results is reported using 
the terminology “accidental or intentional overdose without adverse effect.”
•
Signs or symptoms following challenge agent inoculation that are unexpected (in the 
opinion of the Investigator) post-inoculation (ie, they are not included on the SDC) will 
be captured as AEs. Additionally, challenge agent-related signs or symptoms that are 
considered by the investigator to be clinically significant will be captured as AEs.
Events NOT meeting the AE definition
•
Medical or surgical procedure (eg, endoscopy, appendectomy): the condition that leads to 
the procedure is the AE.
•
Situations in which an untoward medical occurrence did not occur (social and/or 
convenience admission to a hospital).
•
Anticipated day-to-day fluctuations of preexisting disease(s) or condition(s) present or 
detected at the start of the study that do not worsen.
•
Surgical procedure(s) planned prior to informed consent to treat a preexisting condition 
that has not worsened.
•
Refer to Section 8.6.6 for protocol-specific exceptions.
•
Signs or symptoms following challenge agent inoculation that are expected (ie, are 
included on the list on the SDC) will be presumed to represent infection consequent to 
challenge agent inoculation, and will not be additionally captured as AEs unless they 
meet the definition of an AE and are deemed to be clinically significant (in the opinion of 
the investigator).
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10.3.3
Definition of SAE
If an event is not an AE per definition above, then it cannot be an SAE even if serious 
conditions are met.
An SAE is defined as any untoward medical occurrence that, at any dose:
a.
Results in death
b. Is life-threatening
The term “life-threatening” in the definition of “serious” refers to an event in which the 
participant was at risk of death at the time of the event. It does not refer to an event, which 
hypothetically might have caused death, if it were more severe.
c.
Requires inpatient hospitalization or prolongation of existing hospitalization
Hospitalization is defined as an inpatient admission, regardless of length of stay, even if the 
hospitalization is a precautionary measure for continued observation. (Note: Hospitalization 
for an elective procedure to treat a preexisting condition that has not worsened is not an 
SAE.) A preexisting condition is a clinical condition that is diagnosed prior to the use of an 
MSD product and is documented in the participant’s medical history.
d. Results in persistent or significant disability/incapacity
The term disability means a substantial disruption of a person’s ability to conduct normal life 
functions.
This definition is not intended to include experiences of relatively minor medical significance 
such as uncomplicated headache, nausea, vomiting, diarrhea, influenza, and accidental 
trauma (eg, sprained ankle) that may interfere with or prevent everyday life functions but do 
not constitute a substantial disruption.
e.
Is a congenital anomaly/birth defect
In offspring of participant taking the product regardless of time to diagnosis.
f.
Other important medical events
Medical or scientific judgment should be exercised in deciding whether SAE reporting is 
appropriate in other situations such as important medical events that may not be immediately 
life-threatening or result in death or hospitalization but may jeopardize the participant or may 
require medical or surgical intervention to prevent 1 of the other outcomes listed in the above 
definition. These events should usually be considered serious.
Examples of such events include invasive or malignant cancers, intensive treatment in an 
emergency room or at home for allergic bronchospasm, blood dyscrasias, or convulsions that 
do not result in hospitalization, or development of drug dependency or drug abuse.
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10.3.4
Additional Events Reported
Additional events that require reporting
In addition to the above criteria, AEs meeting either of the below criteria, although not 
serious per ICH definition, are reportable to the Sponsor.
•
Is a cancer.
•
Is associated with an overdose.
10.3.5
Recording AE and SAE
AE and SAE recording
•
When an AE/SAE occurs, it is the responsibility of the investigator to review all 
documentation (eg, hospital progress notes, laboratory, and diagnostics reports) related to 
the event.
•
The investigator will record all relevant AE/SAE information on the AE 
CRFs/worksheets at each examination.
•
It is not acceptable for the investigator to send photocopies of the participant’s medical 
records to the Sponsor in lieu of completion of the AE CRF page.
•
There may be instances when copies of medical records for certain cases are requested by 
the Sponsor. In this case, all participant identifiers, with the exception of the participant 
number, will be blinded on the copies of the medical records before submission to the 
Sponsor.
•
The investigator will attempt to establish a diagnosis of the event based on signs, 
symptoms, and/or other clinical information. In such cases, the diagnosis (not the 
individual signs/symptoms) will be documented as the AE/SAE.
Assessment of intensity/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.
Assessment of causality
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.
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•
The investigator will submit any updated SAE data to the Sponsor within 24 hours of 
receipt of the information.
10.3.6
Reporting of AEs, SAEs, and Other Reportable Safety Events to the Sponsor
AE, SAE, and other reportable safety event reporting to Sponsor via electronic data 
collection tool
•
The primary mechanism for reporting to the Sponsor will be the EDC tool.
Electronic reporting procedures can be found in the EDC data entry guidelines (or 
equivalent).
If the electronic system is unavailable for more than 24 hours, then the site will use the paper 
AE Reporting form.
Reference Section 8.4.1 for reporting time requirements.
•
The site will enter the SAE data into the electronic system as soon as it becomes 
available.
•
After the study is completed at a given site, the EDC tool will be taken off-line to prevent 
the entry of new data or changes to existing data.
•
If a site receives a report of a new SAE from a study participant or receives updated data 
on a previously reported SAE after the EDC tool has been taken off-line, then the site can 
report this information on a paper SAE form or by telephone (see next section).
•
Contacts for SAE reporting can be found in the Investigator Study File Binder (or 
equivalent).
SAE reporting to the Sponsor via paper CRF
•
If the EDC tool is not operational, facsimile transmission or secure email 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
Participants of Childbearing Potential (POCBP)
A participant assigned female sex at birth is considered fertile following menarche and 
capable of becoming pregnant 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.
Participants assigned female sex at birth who are in the following categories are not capable 
of becoming pregnant and, therefore, not considered POCBP:
•
Premenarchal
•
Premenopausal 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, Müllerian 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
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 participants assigned female sex at birth who are not 
using hormonal contraception or HRT. However, in the absence of 12 months of 
amenorrhea, confirmation with 2 FSH measurements in the postmenopausal range 
is required.
Participants assigned female sex at birth who are 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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Participants of Nonchildbearing Potential (PONCBP)
Participants assigned female sex at birth who are in the following categories are not capable 
of becoming pregnant and, therefore, are considered PONCBP:
•
Premenopausal 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, Müllerian 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
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 participants assigned female sex at birth not using 
hormonal contraception or HRT. However, in the absence of 12 months of 
amenorrhea, confirmation with 2 FSH measurements in the postmenopausal range 
is required.
Participants assigned female sex at birth on HRT and whose menopausal status is in doubt 
must discontinue HRT to allow confirmation of postmenopausal status before study 
enrollment.
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10.5.2
Contraceptive Requirements
Contraceptives allowed during the study include:
Highly Effective Contraceptive Methods That Have Low User Dependencya
Failure rate of <1% per year when used consistently and correctly.
Progestogen-only contraceptive implant b,c
IUS b,d
Nonhormonal IUD
Bilateral tubal occlusion (Tubal occlusion includes tubal ligation)
Azoospermic partner (vasectomized or secondary to medical cause, confirmed by medical history) –
All sexual partner(s) of the POCBP must be azoospermic. The participant must provide verbal 
confirmation of partner azoospermia during Medical History. If not, an additional highly effective method 
of contraception should be used. A spermatogenesis cycle is approximately 90 days.
Highly Effective Contraceptive Methods That Are User Dependenta
Failure rate of <1% per year when used consistently and correctly.
Combined (estrogen- and progestogen-containing) hormonal contraception b,c
- Oral
- Intravaginal
- Transdermal
- Injectable
Progestogen-only hormonal contraception b,c
- Oral
- Injectable
Sexual Abstinence
Sexual abstinence is considered a highly effective method only if defined as refraining from penile-
vaginal intercourse with a partner capable of producing sperm, during the entire period of risk associated 
with the study intervention. The reliability of sexual abstinence needs to be evaluated in relation to the 
duration of the study and the preferred and usual lifestyle of the participant.
a
Typical use failure rates are higher than perfect-use failure rates (ie, when used consistently and correctly)
b
Penile/external condoms must be used in addition to the POCBP’s hormonal contraception
c
If locally required, in accordance with CTFG guidelines, acceptable contraceptives are limited to those which inhibit 
ovulation
d
IUS is a progestin releasing IUD
Note: Tubal occlusion includes tubal ligation
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10.6
Appendix 6: Collection and Management of Specimens for Future Biomedical 
Research
1. Definitions
a.
Biomarker: A biological molecule found in blood, other body fluids, or tissues that is 
a sign of a normal or abnormal process or of a condition or disease. A biomarker may 
be used to see how well the body responds to a treatment for a disease or condition.1
b. Pharmacogenomics: The investigation of variations of DNA and RNA characteristics 
as related to drug/vaccine response.2
c.
Pharmacogenetics: A subset of pharmacogenomics, pharmacogenetics is the influence 
of variations in DNA sequence on drug/vaccine response.2
d. DNA: Deoxyribonucleic acid.
e.
RNA: Ribonucleic acid.
2. Scope of Future Biomedical Research3, 4
The specimens consented and/or collected in this study as outlined in Section 8.11 will be 
used in various experiments to understand:
The biology of how drugs/vaccines work
Biomarkers responsible for how a drug/vaccine enters and is removed by the body
Other pathways with which drugs/vaccines may interact
The biology of disease
The specimen(s) may be used for future assay development and/or drug/vaccine 
development.
It is now well recognized that information obtained from studying and testing clinical 
specimens offers unique opportunities to enhance our understanding of how individuals 
respond to drugs/vaccines, enhance our understanding of human disease, and ultimately 
improve public health through development of novel treatments targeted to populations 
with the greatest need. All specimens will be used by the Sponsor or those working for or 
with the Sponsor.
3. Summary of Procedures for Future Biomedical Research3, 4
a.
Participants for Enrollment
All participants enrolled in the clinical study will be considered for enrollment in 
future biomedical research.
b. Informed Consent
Informed consent for specimens (ie, DNA, RNA, protein, etc) will be obtained during 
screening for protocol enrollment from all participants or legal guardians, at a study 
visit by the investigator or his or her designate. Informed consent for future 
biomedical research should be presented to the participants on the visit designated in 
the SoA. If delayed, present consent at next possible Participant Visit. Consent forms 
signed by the participant will be kept at the clinical study site under secure storage for 
regulatory reasons.
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A template of each study site’s approved informed consent will be stored in the 
Sponsor’s clinical document repository.
c.
eCRF Documentation for Future Biomedical Research Specimens
Documentation of participant consent for future biomedical research will be captured 
in the eCRFs. Any specimens for which such an informed consent cannot be verified 
will be destroyed.
d. Future Biomedical Research Specimen(s)
Collection of specimens for future biomedical research will be performed as outlined 
in the SoA. In general, if additional blood specimens are being collected for future 
biomedical research, these will usually be obtained at a time when the participant is 
having blood drawn for other study purposes.
4. Confidential Participant Information for Future Biomedical Research3, 4
In order to optimize the research that can be conducted with future biomedical research 
specimens, it is critical to link participants’ clinical information with future test results. In 
fact, little or no research can be conducted without connecting the clinical study data to 
the specimen. The clinical data allow specific analyses to be conducted. Knowing 
participant characteristics like sex, age, medical history, and intervention outcomes is
critical to understanding clinical context of analytical results.
To maintain privacy of information collected from specimens obtained for future 
biomedical research, the Sponsor has developed secure policies and procedures. All 
specimens will be single coded per ICH E15 guidelines as described below.
At the clinical study site, unique codes will be placed on the future biomedical research 
specimens. This code is a random number that does not contain any personally 
identifying information embedded within it. The link (or key) between participant 
identifiers and this unique code will be held at the study site. No personal identifiers will 
appear on the specimen tube.
5. Biorepository Specimen Usage3, 4
Specimens obtained for the Sponsor will be used for analyses using good scientific 
practices. Analyses using the future biomedical research specimens may be performed by 
the Sponsor, or an additional third party (eg, a university investigator) designated by the 
Sponsor. The investigator conducting the analysis will follow the Sponsor’s privacy and 
confidentiality requirements. Any contracted third-party analyses will conform to the 
specific scope of analysis outlined in future biomedical research protocol and consent. 
Future biomedical research specimens remaining with the third party after specific 
analysis is performed will be reported to the Sponsor.
6. Withdrawal From Future Biomedical Research3, 4
Participants may withdraw their consent for FBR and ask that their biospecimens not be 
used for FBR. Participants may withdraw consent at any time by contacting the study 
investigator. If medical records for the study are still available, the investigator will 
contact the Sponsor using the designated mailbox 
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(clinical.specimen.management@MSD.com). Subsequently, the participant's specimens 
will be flagged in the biorepository and restricted to study use only. If specimens were 
collected from study participants specifically for FBR, these specimens will be removed 
from the biorepository and destroyed. Documentation will be sent to the investigator 
confirming withdrawal and/or destruction, if applicable. It is the responsibility of the 
investigator to inform the participant of completion of the withdrawal and/or destruction, 
if applicable. Any analyses in progress at the time of request for withdrawal/destruction 
or already performed before the request being received by the Sponsor will continue to be 
used as part of the overall research study data and results. No new analyses would be 
generated after the request is received.
If the medical records for the study are no longer available (eg, if the investigator is no 
longer required by regulatory authorities to retain the study records) or the specimens 
have been completely anonymized, there will no longer be a link between the 
participant’s personal information and their specimens. In this situation, the request for 
withdrawal of consent and/or destruction cannot be processed.
7. Retention of Specimens3, 4
Future biomedical research specimens will be stored in the biorepository for potential 
analysis for up to 20 years from the end of the study. Specimens may be stored for longer 
if a regulatory or governmental authority has active questions that are being answered. In 
this special circumstance, specimens will be stored until these questions have been 
adequately addressed.
Specimens from the study site will be shipped to a central laboratory and then shipped to 
the Sponsor-designated biorepository. If a central laboratory is not used in a particular 
study, the study site will ship directly to the Sponsor-designated biorepository. The 
specimens will be stored under strict supervision in a limited access facility, which 
operates to assure the integrity of the specimens. Specimens will be destroyed according 
to Sponsor policies and procedures and this destruction will be documented in the 
biorepository database.
8. Data Security3, 4
Databases containing specimen information and test results are accessible only to the 
authorized Sponsor representatives and the designated study administrator research 
personnel and/or collaborators. Database user authentication is highly secure, and is 
accomplished using network security policies and practices based on international 
standards to protect against unauthorized access.
9. Reporting of Future Biomedical Research Data to Participants3, 4
No information obtained from exploratory laboratory studies will be reported to the 
participant, family, or physicians. Principle reasons not to inform or return results to the 
participant include lack of relevance to participant health, limitations of predictive 
capability, and concerns regarding misinterpretation.
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If important research findings are discovered, the Sponsor may publish results, present 
results in national meetings, and make results accessible on a public website in order to 
rapidly report this information to doctors and participants. Participants will not be 
identified by name in any published reports about this study or in any other scientific 
publication or presentation.
10. Future Biomedical Research Study Population3, 4
Every effort will be made to recruit all participants diagnosed and treated on Sponsor 
clinical studies for future biomedical research.
11. Risks Versus Benefits of Future Biomedical Research3, 4
For future biomedical research, risks to the participant have been minimized and are 
described in the future biomedical research informed consent.
The Sponsor has developed strict security, policies, and procedures to address participant 
data privacy concerns. Data privacy risks are largely limited to rare situations involving 
possible breach of confidentiality. In this highly unlikely situation, there is risk that the 
information, like all medical information, may be misused.
12. Questions
Any questions related to the future biomedical research should be emailed directly to 
clinical.specimen.management@MSD.com.
13. References
1. National Cancer Institute [Internet]: Available from 
https://www.cancer.gov/publications/dictionaries/cancer-terms?cdrid=45618
2. International Council on Harmonisation [Internet]: E15: Definitions for Genomic 
Biomarkers, Pharmacogenomics, Pharmacogenetics, Genomic Data and Sample 
Coding Categories. Available from 
http://www.ich.org/products/guidelines/efficacy/efficacy-single/article/definitions-
for-genomic-biomarkers-pharmacogenomics-pharmacogenetics-genomic-data-and-
sample-cod.html
3. Industry Pharmacogenomics Working Group [Internet]: Understanding the Intent, 
Scope and Public Health Benefits of Exploratory Biomarker Research: A Guide for 
IRBs/IECs and Investigational Site Staff. Available at http://i-pwg.org/
4. Industry Pharmacogenomics Working Group [Internet]: Pharmacogenomics 
Informational Brochure for IRBs/IECs and Investigational Site Staff. Available at 
http://i-pwg.org/
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10.7
Appendix 7: Country-specific Requirements
Not applicable.
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10.8
Appendix 8: Blood Volume Table
Parts 1 and 2
Screening
Treatment 
and Inoculation
Period
Poststudy
Total 
Collections
mL Per 
Collection
Total mL/ 
Test
Screening & Admission 
Laboratory Safety Test 
(chemistry and hematology)
1
-
-
1
7.0
7.0
Coagulation Testing 
(PT/aPTT)
1
-
-
1
2.7
2.7
Routine Safety Laboratory 
Test
-
7
1
8
5.5
44
FSH (for WONCBP only, if 
applicable) (blood from 
chemistry sample)
1
-
-
1
-
-
Serum β-hCG for WOCBP 
only, if applicable) (blood 
from chemistry sample)
1
-
-
1
-
-
HIV/Hepatitis Screen (at the 
discretion of the 
investigator) (blood from 
chemistry sample)
1
-
-
1
-
-
Blood - Serum Markers 
Humoral Immunity
1
-
1
2
5
10
Blood - Serum Exploratory 
Immunological Biomarkers
-
9
1
10
5
50
Blood for Plasma NHC 
Assayb
-
12
-
12
3
36
Blood for Plasma OTV 
Assayb
1
1
3
3
Blood for Planned Genetic 
Analysis
-
1
-
1
8.5
8.5
Total Blood Volume per Participant in Part 1a
122.2 mL
Total Blood Volume per Participant in Part 2a
161.2 mL
aPTT=activated partial thromboplastin time; β-hCG=beta human chorionic gonadotropin; FSH=follicle stimulating hormone;
HIV-human immunodeficiency virus; NHC=N-hydroxycytidine; PT=prothrombin time; WOCBP=women of childbearing potential;
WONCBP=women of nonchildbearing potential;
a If additional pharmacokinetic/pharmacodynamic analysis is necessary, additional blood (up to 50 mL) may be 
obtained. If additional safety analysis is required, additional blood may be obtained, but not to exceed a total blood 
volume of 550 mL for the study (including blood collected for PK/PD).
b Part 2 only 
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10.9
Appendix 9: 12-Lead Electrocardiogram Evaluation Criteria
Screen Failure Criteria
Potentially Significant 
Postrandomization Findings
RHYTHM
Sinus Tachycardia
>110 bpm
HR >110 bpm and HR increase of 
≥25 bpm from baseline
Sinus Bradycardia
<40 bpm
HR <40 bpm and HR decrease of 
≥5 bpm from baseline
Sinus Pause/Arrest
>2.0 seconds
>2.0 seconds
Atrial Premature Complex
>1 beat
≥3 beats
Ventricular Premature Complex
All
≥3 beats
Ectopic Atrial Rhythm
None
None
Junctional Rhythm
Junctional Rhythm with HR 
<40 bpm
Junctional Rhythm with HR <40 bpm
Idioventricular Rhythm
All
All
Atrial Fibrillation
All
All
Atrial Flutter
All
All
Supraventricular Tachycardia
All
All
Ventricular Tachycardia
All
All
AXIS
Left Axis Deviation
RBBB With LAHB
New Onset LAHB
Right Axis Deviation
RBBB With LPHB
New Onset LPHB
CONDUCTION
1st Degree AV Block
PR ≥230 ms
PR ≥230 ms + Increase of >15 ms; or 
PR Increase of >25%
2nd Degree AV Block
Mobitz Type II
Mobitz Type II
3rd Degree AV Block
All
All
LBBB
All
All
RBBB
RBBB With LAHB/LPHB as 
Defined Above
New Onset RBBB (Not Including 
Rate-related)
ICRBBB (QRS <120 ms)
No Exclusion
Nothing
Short PR/Preexcitation Syndrome
Delta Wave + PR <120 ms
Delta Wave + PR <120 ms
Other Intraventricular Conduction 
Delay
QRS ≥130 ms
QRS ≥130 ms + Increase of ≥10 ms
QTc (B or F)
Male
QTc ≥470 ms
QTc ≥500 ms or Increase of ≥60 ms 
From Baseline
Female
QTc ≥480 ms
QTc ≥500 ms or Increase of ≥60 ms 
From Baseline
HYPERTROPHY
Atrial Abnormalities
Definite Evidence of P 
Mitrale or P Pulmonale
Definite Evidence of P. Mitrale or 
P. Pulmonale
Ventricular Abnormalities
Voltage Criteria for LVH 
Plus Strain Pattern
Voltage Criteria for LVH Plus Strain 
Pattern
MYOCARDIAL INFARCTION
Acute or Recent
All
All
Old
All
All
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Screen Failure Criteria
Potentially Significant 
Postrandomization Findings
ST/T MORPHOLOGY
ST Elevation Suggestive of 
Myocardial Injury
In 2 or more contiguous 
leads
In 2 or more contiguous leads
ST Depression Suggestive of
Myocardial Ischemia
In 2 or more contiguous 
leads
In 2 or more contiguous leads
T-wave Inversions Suggestive of 
Myocardial Ischemia
In 2 or more contiguous 
leads
In 2 or more contiguous leads
Nonspecific ST-T Changes (In 
2 or More Leads)
No exclusion
In 2 or more contiguous leads
PACEMAKER
All
All
AV=atrioventricular; bpm=beats per minute; HR=heart rate: ICRBBB=incomplete right bundle branch block; 
LAHB=left anterior hemiblock; LPHB=left posterior hemiblock; LVH=left ventricular hypertrophy; 
mm=millimeter; ms=milliseconds, PR=pulse rate; QTcB=QT correction using Bazett’s formula; QTcF=QT 
correction using Fredericia formula; RBBB=right bundle branch block; ST/T=ST-segment/T wave.
Baseline is defined as Predose Day 1.
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10.10 Appendix 10: Algorithm for Assessing Out of Range Laboratory Values
For all laboratory values obtained at screening:
A. If all protocol-specified laboratory values are normal, the participant may enter the study.
B. If a protocol-specified laboratory value is outside the parameter(s) outlined in the 
inclusion/exclusion criteria (including a repeat if performed), the participant will be 
excluded from the study.
C. If ≥1 protocol-specified laboratory value not specified in the inclusion/exclusion criteria 
is outside the normal range, the following choices are available:
a.
The participant may be excluded from the study.
b. The participant may be included in the study if the abnormal value(s) is NCS (the 
investigator must annotate the laboratory value “NCS” on the laboratory safety test 
source document).
c.
The participant may be included in the study if the abnormality is consistent with a 
pre-existing medical condition which is not excluded per protocol (eg, elevated 
eosinophil count in a participant with asthma or seasonal allergies), the medical 
condition should be annotated on the laboratory report.
OR
d. The abnormal test may be repeated (refer items a. and b. below for continuation of 
algorithm for repeated values).
i.
If the repeat test value is within the normal range, the participant may enter the 
study.
ii. If the repeat test value is still abnormal, the study investigator will evaluate the 
potential participant with a complete history and physical examination, looking 
especially for diseases that could result in the abnormal laboratory value in 
question. If such diseases can be ruled out, and if the abnormal laboratory value is 
not clinically relevant, then the participant may enter the study.
D. If there is any clinical uncertainty regarding the significance of an abnormal value, the 
participant will be excluded from the study.
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10.11 Appendix 11: Alternative Challenge Viruses for Part 2 – Summary
In the event that the challenge virus used in Part 1 (Influenza A/France/759/21 [H1N1]) is 
not deemed suitable to be studied in Part 2, an alternative challenge virus will be selected, eg, 
A/Perth/16/2009 [H3N2] or A/California 2009-like [H1N1]. An overview of these two 
alternative options is provided below. Final details of the challenge virus will be outlined in 
the Analytical Plan.
A/Perth/16/2009 [H3N2]
The influenza A/Perth/16/2009 [H3N2] challenge virus strain used in the majority of studies 
to date has been given to over 400 healthy participants by hVIVO. The virus has been well 
tolerated with no virus-related SAEs occurring in any of the participants inoculated to date. 
Furthermore, the challenge virus has been shown to induce measurable disease profiles with 
clear distinction from non-infected participants, and study participants have approximately 
60% to 75% chance of becoming infected following the administration of the virus. Typical 
influenza illness is characterized by an abrupt onset of rhinitis, nasal stuffiness, fever, 
malaise, myalgia (muscle aches), and sore throat. In healthy adults, the illness usually 
resolves without any treatment, with relief of symptoms occurring naturally within 3 to 
5 days. The disease profiles of the challenge agent are consistent with the mild to moderate 
disease profiles expected with wild-type challenge viruses in healthy adult participants 
[Fragaszy, E. B., et al 2017]. In summary, the influenza A/Perth/16/2009 [H3N2] challenge 
virus is considered safe, well tolerated, and induces appropriate disease pathogenesis to be an 
effective viral challenge agent in the human viral challenge studies.
Table 10
Study Challenge Agent Details: A/Perth/16/2009 [H3N2]
Challenge Agent Name
Influenza A/Perth/16/2009 [H3N2] Virus
Type
Virus
Dose Formulation
Ampoule, liquid
Unit Dose Strength(s)
~105.5 tissue culture infective dose (50%) (TCID50)
Dosage Level(s)
A single dose of virus will be administered on Day 0.
Dose volume and delivery method will be provided in 
the analytical plan (AP)
Route of Administration
Intranasal
Use
Infectious challenge agent
Investigational Medicinal 
Product
Auxiliary Medicinal Product (AxMP) 
Sourcing
Provided centrally by hVIVO
Packaging and Labelling
The details of the challenge agent provision will be 
provided in the AP
Current/Former Name(s) or 
Alias(es)
Not applicable
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A/California 2009-like [H1N1]
The influenza A/California/2009-like [H1N1] challenge virus has been used by several 
groups globally over the last 7 years and has helped assess influenza disease and therapies 
[Watson, J. M., et al 2015] [Sloan, S. E., et al 2020] hVIVO has safely inoculated 62 
participants with the Influenza A/California/2009-like [H1N1] challenge virus. The virus has 
been well tolerated with no virus-related SAEs occurring in any of the participants inoculated 
to date. Furthermore, the challenge virus has been shown to induce measurable disease 
profiles with clear distinction from non-infected participants, and study participants have 
approximately 40% to 60% chance of becoming infected following the administration of the 
virus. Typical influenza illness is characterized by an abrupt onset of rhinitis, nasal stuffiness, 
fever, malaise, myalgia (muscle aches), and sore throat. In healthy adults, the illness usually 
resolves without any treatment, with relief of symptoms occurring naturally within 3 to 
5 days. The disease profiles of the challenge agent are consistent with the mild to moderate 
disease profiles expected with wild-type challenge viruses in healthy adult participants 
[Fragaszy, E. B., et al 2017]. In summary, the influenza A/California/2009-like [H1N1)]
challenge virus is considered safe, well tolerated, and induces appropriate disease 
pathogenesis to be an effective viral challenge agent in the human viral challenge studies.
Table 11
Study Challenge Agent Details: A/California 2009-like [H1N1]
Challenge Agent Name
Influenza A/California/2009-like [H1N1] Virus
Type
Virus
Dose Formulation
Ampoule, liquid
Unit Dose Strength(s)
~3.5x106 tissue culture infective dose (50%) (TCID50)
Dosage Level(s)
A single dose of virus will be administered on Day 0.
Dose volume and delivery method will be provided in the 
analytical plan (AP)
Route of Administration
Intranasal
Use
Infectious challenge agent
Investigational Medicinal 
Product
AxMP
Sourcing
Provided centrally by hVIVO
Packaging and Labelling
The details of the challenge agent provision will be provided 
in the AP
Current/Former Name(s) or 
Alias(es)
Not applicable
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10.12 Appendix 12: Abbreviations
Abbreviation
Expanded Term
ADME
absorption, distribution, metabolism, and excretion
AE
adverse event
ALP
alkaline phosphatase
ALT
alanine aminotransferase
AP
analytical plan
APaT
All-Participants-as-Treated
AR
adverse reaction
ART
antiretroviral therapy
AST
aspartate aminotransferase
AUC
area under the curve
bid
twice daily
BMI
body mass index
BP
blood pressure
CHS
cough hypersensitivity syndrome
CI
confidence interval
Cmax
maximum plasma concentration
CKD-EPI
Chronic Kidney Disease Epidemiology Collaboration
CL
clearance
CrCl
creatinine clearance
CR
complete response
CRF
Case Report Form
CRU
clinical research unit
C-SSRS
Columbia-Suicide Severity Rating Scale
CSR
Clinical Study Report
CT
computed tomography
CTMS
Clinical Trial Management System
DDI
drug-drug interaction
DILI
drug-induced liver injury
DNA
deoxyribonucleic acid
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Abbreviation
Expanded Term
ECG
electrocardiogram
ECI
event of clinical interest
eCRF
electronic Case Report Form
eCTA
exploratory Clinical Trial Application
EDC
electronic data collection
eGFR
estimated glomerular filtration rate
ELISA
enzyme-linked immunosorbent assay
EMA
European Medicines Agency
ePROs
electronic patient-reported outcomes
FDA
Food and Drug Administration
FDAAA
Food and Drug Administration Amendments Act
FIH
first in human
FSH
follicle-stimulating hormone 
GAD-7
Generalized Anxiety Disorder 7 Questionnaire
GCP
Good Clinical Practice
GMP
Good Manufacturing Practice
GI
gastrointestinal
HAI
haemagglutination inhibition
HBcAb
hepatitis B core antibody
HBsAg
hepatitis B surface antigen
HBV
hepatitis B virus
hCG
human chorionic gonadotropin
HCS
human challenge study
HCV
hepatitis C virus
HIV
human immunodeficiency virus
HR
heart rate
HRT
hormone replacement therapy
IAV
influenza A virus
IB
Investigator’s Brochure
IBV
influenza B virus
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Abbreviation
Expanded Term
ICF
Informed Consent Form
ICH
International Council for Harmonisation of Technical Requirements for 
Pharmaceuticals for Human Use
ICMJE
International Committee of Medical Journal Editors
ICU
intensive care unit
IEC
Independent Ethics Committee
Ig
immunoglobulin
IND
Investigational New Drug
IRB
Institutional Review Board
IUD
intrauterine device
IUS
intrauterine hormone-releasing system
IV
intravenous
IVD
in vitro diagnostic
LAM
lactational amenorrhea method
LLN
lower limit of normal
LLOQ
lower limit of quantitation
mAb
monoclonal antibody
MAD
maximum administered dose
MedDRA
Medical Dictionary for Regulatory Activities
MERS-CoV
Middle East respiratory syndrome coronavirus
MRI
magnetic resonance imaging
mRNA
messenger RNA
NCS
not clinically significant
NDA
New Drug Application
NHC
N-hydroxycytidine
NHC-TP
N-hydroxycytidine triphosphate
NOAEL
no observed adverse effect level
OTC
over the counter
OTV
oseltamivir 
PCL
Protocol Clarification Letter
PCR
polymerase chain reaction
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Abbreviation
Expanded Term
PD
Pharmacodynamics 
PEP
post-exposure prophylaxis
PHQ-9
Patient Health Questionnaire 9
PK
pharmacokinetic
po
orally
POCBP
person of childbearing potential 
PP
per-protocol
PRO
patient-reported outcome
PVL
Peak viral load
QP2
Department of Quantitative Pharmacology and Pharmacometrics
qRT-PCR
quantitative reverse transcription polymerase chain reaction
RNA
ribonucleic acid
RR
respiratory rate
RSV
respiratory syncytial virus
SAC
Scientific Advisory Committee
SAE
serious adverse event
SAP
Statistical Analysis Plan
SARS-CoV
severe acute respiratory syndrome coronavirus
SARS-CoV-2
SARS-associated coronavirus-2
SD
standard deviation
SDC
symptom diary card
SGOT
serum glutamic oxaloacetic transaminase
SGPT
Serum glutamic pyruvic transaminase
SLAB
Supplemental laboratory test(s)
SmPC
summary of product characteristics
SoA
schedule of activities
SOC
standard of care
SOP
Standard Operating Procedures
sSAP
supplemental Statistical Analysis Plan
SUSAR
suspected unexpected serious adverse reaction
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Abbreviation
Expanded Term
SVR12
sustained viral response
TCID50
tissue culture infective dose (50%)
Tmax
time to maximum plasma concentration
Tx
treatment
t½
half life
UDS
urine drug screen
ULN
upper limit of normal
VL
viral load
VL-AUC
area under the viral load-time curve
VS
vital signs
WBC
white blood cell
WPAI
Work Productivity and Activity Impairment
WOCBP
woman/women of childbearing potential
WONCBP
woman/women of nonchildbearing potential
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11
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