Clinical trial NCT05559905
Conditions: Respiratory Syncytial Virus
Sponsor: Merck Sharp & Dohme LLC
Start date: 2022-11-02; Completion date: 2023-06-08
Enrollment: 116 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This is a study of molnupiravir (MK-4482) in healthy participants who have been inoculated with an experimental Respiratory Syncytial Virus (RSV) \[RSV-A Memphis 37b\]. It is hypothesized that treatment with the drug MK-4482 (molnupiravir) will reduce the peak viral load (PVL) in the participant compared to placebo when given either before or after RSV-A Memphis 37b inoculation.

Detailed description:
Participants arrive at the study center for check-in between Day -3 and Day -1. Participants receive the assigned treatment beginning on Day -1. On Day 0, all participants receive viral inoculation with RSV-A Memphis 37b. All participants depart on Day 12 and follow-up is continued until Day 28.

The study is designed with the following arms:

* Panel A: Molupiravir Prophylaxis - in this arm, participants receive molupiravir beginning on Day -1, are incoluated with RSV-A Memphis 37b on Day 0, and continue receiving molnupiravir for a total of 5 days before switching to placebo through Day 10.
* Panel B: Molupiravir Triggered Treatment - in this arm, participants receive placebo beginning on Day -1 until testing positive for RSV. Participants are inoculated with RSV-A Memphis 37b on Day 0. When participants test positive for RSV, they switch to molnupiravir for a total of 5 consecutive days before switching back to placebo through Day 10. If participants in this arm do not test positive for RSV by Day 5, they automatically switch to molnupiravir through Day 10.
* Panel C: Placebo - in this arm, all participants receive placebo beginning on Day -1, are inoculated with RSV-A Memphis 37b on Day 0, and continue receiving placebo through Day 10.

Arms: arm 1: Participants received molnupiravir 800 mg every 12 hours for 5 days beginning on Day -1, and are inoculated with RSV-A Memphis 37b on Day 0. Participants switch to placebo beginning on the evening of Day 4 to the morning of Day 10. arm 2: Participants received placebo on Day -1, are inoculated with RSV-A Memphis 37b on Day 0, and continue to receive placebo until testing positive for RSV. Participants then received 800 mg of molnupiravir every 12 hours for 5 days. arm 3: Participants received placebo beginning on Day -1, are inoculated with RSV-A Memphis 37b on Day 0, and continue receiving placebo until the morning of Day 10.
Interventions: intervention 1: Molnupiravir intervention 2: Placebo intervention 3: RSV A Memphis 37b
Intervention descriptions: intervention 1: Four molnupiravir 200 mg capsules (800 mg total dose) taken twice daily by mouth. intervention 2: Placebo capsule matched to molnupiravir taken twice daily by mouth. intervention 3: RSV A Memphis 37b viral challenge given once by intranasal administration at a dosage of \~4 Log10 plaque forming units (PFUs).

Protocol documents:
Prot_SAP_000.pdf: 
Official Protocol Title: 
NCT number: 
NCT05559905 
Document Date: 
15-Mar-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 Respiratory Syncytial 
Virus


PRODUCT: MK-4482  
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Title Page
THIS PROTOCOL AMENDMENT AND ALL OF THE INFORMATION RELATING 
TO IT ARE CONFIDENTIAL AND PROPRIETARY PROPERTY OF MERCK 
SHARP & DOHME LLC, RAHWAY, NJ, USA (MSD).
Protocol Title: A Phase 2a Double-Blind, Randomized, Placebo-Controlled Study to 
Evaluate the Efficacy and Safety of MK-4482 in Healthy Participants Inoculated with 
Experimental Respiratory Syncytial Virus
Protocol Number: 017-01
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):
Not Applicable
Approval Date: 15 March 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
15-MAR-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 from the prior 4 PCLs were also incorporated into the 
amendment.
Original Protocol
15-JUL-2022
Not applicable
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PROTOCOL AMENDMENT SUMMARY OF CHANGES
Amendment: 01
Overall Rationale for the Amendments:
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 the prior 4 PCLs were also incorporated into the amendment. 
Summary of Changes Table:
Section # and Name
Description of Change 
Brief Rationale 
1.3 Schedule of Activities
10.2 Appendix 2: Clinical 
Laboratory Tests
10.8 Appendix 8: Blood 
Volume Table
aPTT as opposed to PTT will be measured
at Screening.
The clinical safety laboratory is measuring aPTT as 
opposed to PTT. There is no impact to participant safety 
as aPTT measures the same function but with a more 
narrow reference range (as documented in PCL #3 dated 
20-DEC-2022).
5.1: Inclusion Criteria
Added acceptable user dependent 
contraception methods for WOCBP to 
inclusion criterion #6.
Corrected to align with contraception requirements for 
the overall MK-4482 program.
8.1.3 Participant 
Identification Card 
Section updated to reflect that participants 
will be provided with a participant 
identification (ID) card upon discharge 
from quarantine on Day 12 as opposed to 
providing immediately following 
informed consent signature. 
As participants will remain in quarantine until Day 12, 
the ID card will be provided upon discharge to ensure 
participants do not misplace. 
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Section # and Name
Description of Change 
Brief Rationale 
10.2 Appendix 2: Clinical 
Laboratory Tests
The table note in Table 8 indicates 
“laboratory safety tests (hematology and 
chemistry) will be performed after 
approximately 8-hour fast”. Modified text 
to indicate that the Day -3/-2 laboratory 
safety tests do not require an 8-hour fast. 
However, all other fasting requirements 
within the protocol remain as stated.
Fasting laboratory tests prior to admission are
logistically challenging, and fasting before these tests 
does not provide additional safety information 
compared to laboratory tests conducted in the fed state. 
Therefore, the fasting requirement has been removed (as 
documented in PCL #1 dated 11-OCT-2022).
10.5.2 Contraception 
Requirements
Table has been revised to include highly 
effective contraceptive methods that are 
user dependent.
Corrected 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...............................................4
1
PROTOCOL SUMMARY ............................................................................................13
1.1
Synopsis.................................................................................................................13
1.2
Schema ..................................................................................................................21
1.3
Schedule of Activities...........................................................................................23
2
INTRODUCTION..........................................................................................................30
2.1
RSV Clinical Manifestations and Epidemiology...............................................30
2.1.1
RSV Pathogenesis and Immune Mechanisms..............................................30
2.1.2
Summary of RSV Inoculation Model ..........................................................31
2.2
Study Rationale....................................................................................................31
2.3
Background ..........................................................................................................32
2.3.1
Pharmaceutical and Therapeutic Background .............................................32
2.3.2
Preclinical and Clinical Studies ...................................................................32
2.3.3
Completed and Ongoing Clinical Studies....................................................34
2.3.3.1
Completed Clinical Studies................................................................34
2.3.3.2
Ongoing Clinical Studies...................................................................36
2.4
Benefit/Risk Assessment......................................................................................36
3
HYPOTHESES, OBJECTIVES, AND ENDPOINTS................................................37
4
STUDY DESIGN............................................................................................................46
4.1
Overall Design......................................................................................................46
4.2
Scientific Rationale for Study Design.................................................................47
4.2.1
Rationale for Endpoints ...............................................................................48
4.2.1.1
Efficacy Endpoints.............................................................................48
4.2.1.2
Safety Endpoints................................................................................49
4.2.1.3
Pharmacokinetic Endpoints ...............................................................49
4.2.1.4
Pharmacodynamic Endpoints.............................................................49
4.2.1.5
Planned Exploratory Biomarker Research.........................................50
4.2.1.5.1
Planned Genetic Analysis ........................................................50
4.2.1.6
Future Biomedical Research..............................................................50
4.2.2
Rationale for the Use of Comparator/Placebo .............................................51
4.3
Justification for Dose...........................................................................................51
4.4
Beginning and End-of-Study Definition ............................................................51
4.4.1
Clinical Criteria for Early Study Termination .............................................52
5
STUDY POPULATION ................................................................................................52
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5.1
Inclusion Criteria.................................................................................................52
5.2
Exclusion Criteria................................................................................................54
5.3
Lifestyle Considerations......................................................................................58
5.3.1
Meals and Dietary Restrictions....................................................................58
5.3.1.1
Diet Restrictions.................................................................................58
5.3.1.2
Fruit Juice Restrictions ......................................................................58
5.3.2
Caffeine, Alcohol, and Tobacco Restrictions ..............................................59
5.3.2.1
Caffeine Restrictions..........................................................................59
5.3.2.2
Alcohol Restrictions...........................................................................59
5.3.2.3
Tobacco Restrictions..........................................................................59
5.3.3
Activity Restrictions ....................................................................................59
5.4
Screen Failures.....................................................................................................59
5.5
Participant Replacement Strategy......................................................................60
6
STUDY INTERVENTION............................................................................................60
6.1
Study Intervention(s) Administered...................................................................60
6.2
Preparation/Handling/Storage/Accountability .................................................63
6.2.1
Dose Preparation..........................................................................................63
6.2.2
Handling, Storage, and Accountability........................................................63
6.3
Measures to Minimize Bias: Randomization and Blinding..............................64
6.3.1
Intervention Assignment..............................................................................64
6.3.2
Stratification.................................................................................................64
6.3.3
Blinding........................................................................................................64
6.4
Study Intervention Compliance..........................................................................64
6.5
Concomitant Therapy..........................................................................................65
6.5.1
Rescue Medications and Supportive Care ...................................................65
6.6
Dose Modification (Escalation/Titration/Other)...............................................66
6.6.1
Stopping Rules.............................................................................................66
6.7
Intervention After the End of the Study............................................................66
6.8
Clinical Supplies Disclosure................................................................................66
6.9
Standard Policies..................................................................................................66
7
DISCONTINUATION OF STUDY INTERVENTION AND PARTICIPANT 
WITHDRAWAL............................................................................................................66
7.1
Discontinuation of Study Intervention...............................................................66
7.2
Participant Withdrawal From the Study...........................................................68
7.3
Lost to Follow-up .................................................................................................68
8
STUDY ASSESSMENTS AND PROCEDURES........................................................69
8.1
Administrative and General Procedures ...........................................................69
8.1.1
Informed Consent.........................................................................................69
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8.1.1.1
General Informed Consent.................................................................70
8.1.1.2
Consent and Collection of Specimens for Future Biomedical 
Research.............................................................................................70
8.1.2
Inclusion/Exclusion Criteria ........................................................................70
8.1.3
Participant Identification Card.....................................................................71
8.1.4
Medical History ...........................................................................................71
8.1.5
Prior and Concomitant Medications Review...............................................71
8.1.5.1
Prior Medications...............................................................................71
8.1.5.2
Concomitant Medications..................................................................71
8.1.6
Assignment of Screening Number...............................................................71
8.1.7
Assignment of Treatment/Randomization Number.....................................71
8.1.8
Study Intervention Administration ..............................................................72
8.1.8.1
Timing of Dose Administration.........................................................72
8.1.9
Discontinuation and Withdrawal .................................................................72
8.1.9.1
Withdrawal From Future Biomedical Research ................................72
8.1.10
Participant Blinding/Unblinding..................................................................73
8.1.11
Domiciling ...................................................................................................73
8.1.12
Calibration of Equipment.............................................................................74
8.2
Intranasal Administration of the Challenge Virus ...........................................74
8.3
Efficacy Assessments ...........................................................................................74
8.3.1
RSV Symptom Diary Card ..........................................................................74
8.3.2
Nasal Wash for RSV Virology ....................................................................76
8.3.3
Nasopharyngeal Swab..................................................................................76
8.4
Safety Assessments...............................................................................................76
8.4.1
Physical Examinations.................................................................................76
8.4.2
Vital Signs....................................................................................................77
8.4.2.1
Resting Vital Signs ............................................................................77
8.4.3
Electrocardiograms ......................................................................................78
8.4.4
Clinical Safety Laboratory Assessments .....................................................79
8.4.5
Pregnancy Testing........................................................................................79
8.4.6
Photograph of Rash......................................................................................80
8.5
Adverse Events, Serious Adverse Events, and Other Reportable Safety 
Events....................................................................................................................80
8.5.1
Time Period and Frequency for Collecting AE, SAE, and Other 
Reportable Safety Event Information ..........................................................80
8.5.2
Method of Detecting AEs, SAEs, and Other Reportable Safety Events......83
8.5.3
Follow-up of AE, SAE, and Other Reportable Safety Event Information...83
8.5.4
Regulatory Reporting Requirements for SAE .............................................83
8.5.5
Pregnancy and Exposure During Breastfeeding ..........................................83
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8.5.6
Disease-related Events and/or Disease-related Outcomes Not Qualifying 
as AEs or SAEs............................................................................................84
8.5.7
Events of Clinical Interest............................................................................84
8.6
Treatment of Overdose........................................................................................84
8.7
Pharmacokinetics.................................................................................................85
8.7.1
Blood Collection for Plasma NHC and/or Metabolites Assay.....................85
8.7.2
Blood Collection for PBMC NHC-TP and/or Metabolites Assay...............85
8.8
Pharmacodynamics..............................................................................................85
8.9
Biomarkers ...........................................................................................................85
8.9.1
Planned Genetic Analysis Sample Collection..............................................85
8.10
Future Biomedical Research Sample Collection...............................................86
8.11
Health Economics Medical Resource Utilization and Health Economics.......86
8.12
Visit Requirements...............................................................................................86
8.12.1
Screening......................................................................................................86
8.12.2
Treatment Period..........................................................................................86
8.12.3
Intranasal RSV Inoculation Period ..............................................................86
8.12.4
Participants Discontinued From Study Intervention but Continuing to be 
Monitored in the Study ................................................................................87
8.12.5
Poststudy......................................................................................................87
8.12.6
Critical Procedures Based on Study Objectives: Timing of Procedure.......88
8.12.7
Study Design/Dosing/Procedures Modifications Permitted Within 
Protocol Parameters .....................................................................................89
9
STATISTICAL ANALYSIS PLAN .............................................................................90
9.1
Statistical Analysis Plan Summary.....................................................................90
9.2
Responsibility for Analyses.................................................................................92
9.3
Hypotheses/Estimation ........................................................................................92
9.4
Analysis Endpoints...............................................................................................92
9.5
Analysis Populations............................................................................................96
9.6
Statistical Methods...............................................................................................97
9.7
Interim Analyses ..................................................................................................98
9.8
Multiplicity ...........................................................................................................99
9.9
Sample Size and Power Calculations .................................................................99
10
SUPPORTING DOCUMENTATION AND OPERATIONAL 
CONSIDERATIONS...................................................................................................100
10.1
Appendix 1: Regulatory, Ethical, and Study Oversight Considerations......100
10.1.1
Code of Conduct for Clinical Trials...........................................................100
10.1.2
Financial Disclosure...................................................................................102
10.1.3
Data Protection...........................................................................................103
10.1.3.1
Confidentiality of Data ....................................................................103
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10.1.3.2
Confidentiality of Participant Records.............................................103
10.1.3.3
Confidentiality of IRB/IEC Information..........................................103
10.1.4
Committees Structure.................................................................................104
10.1.5
Publication Policy......................................................................................104
10.1.6
Compliance with Study Registration and Results Posting Requirements .104
10.1.7
Compliance with Law, Audit, and Debarment ..........................................104
10.1.8
Data Quality Assurance .............................................................................105
10.1.9
Source Documents .....................................................................................106
10.1.10
Study and Site Closure...............................................................................106
10.2
Appendix 2: Clinical Laboratory Tests............................................................107
10.3
Appendix 3: Adverse Events: Definitions and Procedures for Recording, 
Evaluating, Follow-up, and Reporting.............................................................109
10.3.1
Definition of AE ........................................................................................109
10.3.2
Definition of SAE ......................................................................................110
10.3.3
Additional Events Reported.......................................................................111
10.3.4
Recording AE and SAE .............................................................................111
10.3.5
Reporting of AEs, SAEs, and Other Reportable Safety Events to the 
Sponsor ......................................................................................................112
10.4
Appendix 4: Medical Device and Drug-device Combination Products: 
Product Quality Complaints/Malfunctions: Definitions, Recording, and 
Follow-up ............................................................................................................114
10.5
Appendix 5: Contraceptive Guidance..............................................................115
10.5.1
Definitions..................................................................................................115
10.5.2
Contraception Requirements......................................................................117
10.6
Appendix 6: Collection and Management of Specimens for Future 
Biomedical Research..........................................................................................118
10.7
Appendix 7: Country-specific Requirements..................................................123
10.8
Appendix 8: Blood Volume Table ....................................................................124
10.9
Appendix 9: 12-Lead Electrocardiogram Abnormality Criteria ..................125
10.10 Appendix 10: Algorithm for Assessing Out of Range Laboratory Values ...127
10.11 Appendix 11: Abbreviations .............................................................................128
11
REFERENCES.............................................................................................................132
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LIST OF TABLES
Table 1
Study Schema.............................................................................................21
Table 2
Study Interventions....................................................................................61
Table 3
Study Administration Schedule .................................................................62
Table 4
Sample Allocation Schedule of Participants to Treatment ........................64
Table 5
Reporting Time Periods and Time Frames for Adverse Events and 
Other Reportable Safety Events.................................................................81
Table 6
Pharmacokinetic (Blood for Plasma NHC and/or Metabolites Assay) 
Collection Windows...................................................................................88
Table 7
Pharmacokinetic (Blood for PBMC NHC-TP and/or Metabolites 
Assay) Collection Windows ......................................................................89
Table 8
Protocol-required Safety Laboratory Assessments..................................107
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LIST OF FIGURES
Figure 1
Study Design Diagram...............................................................................22
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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 Respiratory Syncytial Virus
Short Title: Phase 2a RSV 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 is to be conducted in healthy adult male and female participants. 
Objectives
Endpoints
Primary
To determine if MK-4482 (800 mg Q12 x 5 
days) results in a reduction in viral load 
after intranasal inoculation (with RSV A
Memphis 37b) compared to placebo.
Hypothesis (Prophylaxis): MK-4482 (800 
mg Q12 x 5 days), when administered to 
begin prior to intranasal inoculation with 
respiratory syncytial virus (RSV-A 
Memphis 37b), reduces the Peak Viral Load 
(PVL) after viral inoculation compared to 
placebo. 
Hypothesis (Treatment): MK-4482 (800 mg 
Q12 x 5 days), when administered 
following infection with respiratory 
syncytial virus (RSV-A Memphis 37b), 
reduces the Area Under the Viral-Load-time 
(VL-AUC) after MK-4482 administration 
compared to placebo.
Prophylaxis:

Peak Viral Load (PVL) as defined by 
the maximum viral load determined by 
viral quantitative culture (plaque assay) 
starting from Day 2 up to planned 
discharge from quarantine (Day 12 am) 
Treatment:

Area Under the Viral Load-time Curve 
(VL-AUC) determined by viral 
quantitative culture (plaque assay) 
starting at initial administration of MK-
4482/placebo up to planned discharge 
from quarantine (Day12 am)
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Objectives
Endpoints
Secondary
To estimate the effect of MK-4482 (800 mg 
Q12H x 5 days) on the reduction in viral 
load after intranasal inoculation (with RSV 
A Memphis 37b) compared to placebo.
Prophylaxis:

Area Under the Viral Load-time Curve 
(VL-AUC) determined by viral 
quantitative culture (plaque assay) 
starting from Day 2 up to planned 
discharge from quarantine (Day 12 am) 

Area Under the Viral Load-time Curve 
(VL-AUC) determined by qRT-PCR 
starting from Day 2 up to planned 
discharge from quarantine (Day 12 am) 

Peak Viral Load (PVL) defined by the 
maximum viral load determined by 
qRT-PCR starting from Day 2 up to 
planned discharge from quarantine 
(Day 12am)
Treatment:

Peak Viral Load (PVL) as defined by 
the maximum viral load determined by 
viral quantitative culture (plaque assay) 
starting at initial administration of MK-
4482/placebo up to planned discharge 
from quarantine (Day 12 am) 

Time (days) to confirmed negative test 
by viral quantitative culture (plaque 
assay) measurements starting at initial 
administration of MK-4482/placebo to 
first confirmed undetectable (<LLOQ) 
assessment after peak measure.

Area Under the Viral Load-time Curve 
(VL-AUC) determined by qRT-PCR 
starting at initial administration of MK-
4482/placebo up to planned discharge 
from quarantine (Day 12 am) 
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Objectives
Endpoints

Peak Viral Load (PVL) defined by the 
maximum viral load determined by 
qRT-PCR starting at initial 
administration of MK-4482/placebo up 
to planned discharge from quarantine 
(Day 12 am).

Time (days) to confirmed negative test 
by qRT-PCR starting at initial 
administration of MK-4482/placebo to 
first confirmed undetectable (<LLOQ) 
assessment after peak measure.
To estimate the effect of MK-4482 (800 mg 
Q12 x 5 days) on course of clinical 
symptoms after intranasal inoculation (with 
RSV A Memphis 37b) compared to placebo
Prophylaxis:

Area under the curve over time of total 
clinical symptoms (TSS-AUC) as 
measured from 10 symptoms within the 
graded symptom scoring starting from 
Day 2 up to planned discharge from 
quarantine (Day 12 am).

Area under the curve over time of total 
clinical symptoms change from baseline 
(TSS-AUC-CFB) as measured from 10 
symptoms within the graded symptom 
scoring system starting from Day 2 up to 
planned discharge from quarantine 
(Day 12 am).

Peak symptoms diary card score: peak 
total clinical symptoms (TSS) as 
measured from 10 symptoms within the 
graded symptom scoring system starting 
from Day 2 up to planned discharge 
from quarantine (Day 12 am).

Peak daily symptom score: individual 
maximum daily sum of symptom score 
starting from Day 2 up to planned 
discharge from quarantine (Day 12 am).
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Objectives
Endpoints
Treatment:

Area under the curve over time of total 
clinical symptoms (TSS-AUC) as 
measured from 10 symptoms within the 
graded symptom scoring system starting 
at initial administration of MK-
4482/placebo up to planned discharge 
from quarantine (Day 12 am).

Area under the curve over time of total 
clinical symptoms change from baseline 
(TSS-AUC-CFB) as measured from 10 
symptoms within the graded symptom 
scoring system starting at initial 
administration of MK-4482/placebo up 
to planned discharge from quarantine 
(Day 12 am).

Peak symptoms diary card score: peak 
total clinical symptoms (TSS) as 
measured from 10 symptoms within the 
graded symptom scoring system starting 
from initial administration of MK-
4482/placebo up to planned discharge 
from quarantine (Day 12 am).

Peak daily symptom score: individual 
maximum daily sum of symptom score 
from initial administration of MK-
4482/placebo up to planned discharge 
from quarantine (Day 12 am).

Time (days) to symptom resolution as 
measured from 10 symptoms within the 
graded daily symptom scoring system 
starting at initial administration of MK-
4482/placebo to time of returning to 
baseline score.
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Objectives
Endpoints
To estimate the effect of MK-4482 (800 mg 
Q12 x 5 days) on the incidence of RSV 
infection and symptomatic RSV infection 
after intranasal inoculation (with RSV A 
Memphis 37b) compared to placebo.
Prophylaxis:

RT-PCR-confirmed RSV infection, 
defined as 2 quantifiable (≥ lower limit 
of quantification [LLOQ]) qRT-PCR 
measurements (reported on 2 or more 
independent samples over 2 days), from 
Day 2 up to Day 12.

Occurrence of at least 1 positive 
quantitative (≥LLOQ) cell culture 
measurement in nasal samples, from 
Day 2 up to Day 12.

RT-PCR-confirmed symptomatic RSV 
infection, defined as:
o
RT-PCR-confirmed RSV 
infection (2 quantifiable 
[≥LLOQ] qRT-PCR 
measurements [reported on 2 or 
more independent samples over 
2 days]), from Day 2 up to 
Day 12, AND
o
Symptoms score ≥2 at a single 
time point.

RT-PCR-confirmed moderately severe 
symptomatic RSV infection, defined as:
o
RT-PCR-confirmed RSV 
infection (2 quantifiable 
[≥LLOQ] qRT-PCR 
measurements [reported on 2 or 
more independent samples over 
2 days]), from Day 2 up to 
Day 12, AND
o
Any symptoms of Grade ≥2 at a 
single time point.
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Objectives
Endpoints

Culture lab-confirmed symptomatic RSV 
infection, defined as:
o
Lab-confirmed culturable 
RSV infection 
(1 quantifiable [≥LLOQ] 
cell culture measurement), 
from Day 2 up to Day 12, 
AND
o
Symptoms score ≥2 at a 
single time point.
To evaluate the safety and tolerability of 
MK-4482 (800 mg Q12 x 5 days) compared 
to placebo

Safety data including, but not limited 
to, occurrence of adverse events (AEs) 
from initial administration of MK-
4482/placebo up to the Day 28 follow-
up.

Occurrence of serious AEs (SAEs) 
from initial administration of MK-
4482/placebo up to the Day 28 follow-
up.
To monitor the safety of the challenge virus

Occurrence of AEs related to the viral 
challenge from viral challenge (Day 0) 
up to the Day 28 follow-up.

Occurrence of SAEs related to the viral 
challenge from viral challenge (Day 0) 
up to the Day 28 follow-up.

Use of concomitant medications from 
viral challenge (Day 0) up to the 
Day 28 follow-up.
To evaluate plasma NHC concentrations 
after administration of MK-4482 (800 mg 
Q12 x 5 days)
Plasma NHC concentrations at specified 
timepoints
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Overall Design:
Study Phase
Phase 2
Primary Purpose
Treatment and Prevention
Indication
Respiratory Syncytial Virus
Population
Serosuitable healthy male and female participants 18 to 55 
years (inclusive) of age
Study Type
Interventional
Intervention Model
Parallel
This is a single-site study.
Type of Control
Placebo-controlled
Study Blinding
Double-blind
Blinding Roles
Investigator
Participants or Subjects
Sponsor
Estimated Duration of Study
The Sponsor estimates that the study will require 
approximately 5 months from the time the first participant 
(or their legally acceptable representative) provides 
documented informed consent until the last participant’s 
last study-related contact.
Number of Participants:
Approximately 105 participants will be allocated/randomized.
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Intervention Groups and Duration:
Inter-
vention 
Groups
Panel
Intervention 
Group Name
Drug
Dose 
Strength
Dose 
Frequency
Route of 
Administr
ation
Use
A
Prophylactic 
Dosing
MK-4482
800 mg 
Q12H x 5 
days (from 
Day -1pm to 
Day 4am 
inclusive)
Oral 
Experimental 
Matched 
Placebo
Placebo
0 mg 
Q12H x 6
days (from 
Day 4pm to 
Day 10am 
inclusive)
Oral 
Experimental
B
Triggered 
Dosing
MK-4482
800 mg 
Q12H x 5 
days after 
triggering for 
a total of 
10doses
Oral 
Experimental 
Matched 
Placebo
Placebo
0 mg 
Q12H x 6
days (when 
not receiving 
MK-4482)
Oral 
Experimental
C
Matched 
Placebo
Placebo
0 mg 
Q12H x 11
days (from 
Day -1pm to 
Day 10am 
inclusive)
Oral 
Experimental
Q12H=every12 hours
Total 
Number of 
Inter-
vention 
Groups/
Arms
3
Duration of 
Participa-
tion
Each participant will participate in the study for approximately 9 weeks 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. Following signing the study 
specific Informed Consent Form (ICF) eligibility will be confirmed and then 
each participant will be randomized to receive the assigned intervention on 
Day -1. Up to 3 days prior to RSV A Memphis 37b inoculation the 
participants will be admitted to quarantine where they will stay until 12 days 
post inoculation. After the end of the quarantine period, each participant will 
be followed through Day 28. 
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Study Governance Committees:
Executive Oversight Committee
No
Data Monitoring Committee
No
Clinical Adjudication Committee
No
Insert Other Oversight Committee
No
There are no governance committees in this study. Regulatory, ethical, and study oversight 
considerations are outlined in Appendix 1.
Study Accepts Healthy Volunteers: Yes
A list of abbreviations is in Appendix 11.
1.2
Schema
The study design is depicted in Table 1 and Figure 1.
Table 1
Study Schema 
Panel 
Treatment Arm 
Number of
Participants
Treatment Day
Inoculation 
Day
Poststudy 
Visit (+/- 3 
days)
A
MK-4482 
(Prophylactic 
Administration)
35
Day -1 pm through 
Day 4 am inclusive)a
Day 0
Day 28
B
MK-4482
(Triggered Dose 
Treatment)
35
Day 2/5 through 
Day 6/10 amb
Day 0
Day 28
C
Matched Placebo
35
Day -1 through
Day 10 am
Day 0
Day 28 
qicPCR=qualitative integrative cycler PCR
All participants will be treated with either active or placebo from Day -1 of the study through Day 10 am of 
the study. 
aParticipants will receive MK-4482 on Day -1 pm through Day 4 am and placebo from Day 4 pm through 
Day 10 am.
bParticipants will receive placebo until they test positive by qicPCR at which point MK-4482 dosing will be 
triggered.
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Figure 1
Study Design Diagram
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1.3
Schedule of Activities
Study Phase:
Scree
n-inga
Inpatient Quarantineb
Follo
w-up
Early 
With-
draw
al
Scheduled Dayc
D-90 
to D-2
D-3/
D-2
D-
1
D0
D1
D2
D3
D4
D5
D6
D7
D8
D9
D1
0
D1
1
D1
2
D28
(+/-
3d)
Post-
Chal-
lenge
Notes
Predose
Viral 
Challeng
Postdose
Administrative 
/Study Procedures
Informed Consenta
X
X
Sec. 5.1, 8.1.1.1
Informed Consent for 
FBR
X
Sec. 5.1, 8.1.1
Participant ID Card
X
Sec. 8.1.3
Inclusion/Exclusion 
Criteria
X
X
X
Review of IC/EC 
criteria will occur at 
Screening & specific 
criteria from Day -3 
to predose & after 
predose procedures 
(if applicable) on 
Day 1 only. 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
X
X
X
X
Sec 5.2, 6.5, 8.1.5
Domiciling
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Sec. 8.1.11
RSV A Memphis 37b 
Inoculation
X
Sec. 8.12.3
MK-4482/Placebo 
Administration
X
X
X
2X
2X
2X
2X
2X
2X
2X
2X
2X
X
Intervention will be 
administered Q12H. 
Sec. 8.1.8, Sec. 5.3.1
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Study Phase:
Scree
n-inga
Inpatient Quarantineb
Follo
w-up
Early 
With-
draw
al
Scheduled Dayc
D-90 
to D-2
D-3/
D-2
D-
1
D0
D1
D2
D3
D4
D5
D6
D7
D8
D9
D1
0
D1
1
D1
2
D28
(+/-
3d)
Post-
Chal-
lenge
Notes
Predose
Viral 
Challeng
Postdose
Participant Visits to 
Clinical Research 
Unit
X
X
X
Sec. 8.1.11, 8.12.5
Assignment of 
Screening Number
X
Sec. 8.1.6
Assignment of 
Treatment/
Randomization
Number
X
Assigned prior to 
study drug 
administration. Sec. 
5.5, 8.1.7
Safety Procedures
Full Physical 
Examination
X
X
X
X
X
Physical exam may 
be conducted up to 
24 hrs prior to 
randomization. Sec. 
8.4.1
Directed Physical 
Examination 
(including nasal)
(X)
(X) (X)
(X) (X) (X) (X) (X) (X) (X) (X) (X) (X) (X) (X)
Sec. 8.4.1
Vital signs (HR, RR, 
SBP, DBP, SpO2)
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Sec. 8.4.2
AM Predose only 
Temperature
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Sec. 8.4.2
RSV Symptom Diary 
Card 
X
3X
3X
3X
3X
3X
3X
3X
3X
3X
3X
3X
3X
3X
X
Sec. 8.3.1
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Study Phase:
Scree
n-inga
Inpatient Quarantineb
Follo
w-up
Early 
With-
draw
al
Scheduled Dayc
D-90 
to D-2
D-3/
D-2
D-
1
D0
D1
D2
D3
D4
D5
D6
D7
D8
D9
D1
0
D1
1
D1
2
D28
(+/-
3d)
Post-
Chal-
lenge
Notes
Predose
Viral 
Challeng
Postdose
24-Hour Tissue Count 
& Nasal Discharge 
Weight
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Distribution of paper 
tissues and bags will 
start on Day -1, with 
first collection on 
Day 0. Thereafter, 
collection of paper 
tissues will occur at 
the same time each 
day (±1 hour) with 
tissues distributed 24 
hours ahead. Sec. 
8.3.4, 8.4
Spirometry
X
Sec. 5.1
12-Lead ECG
X
X
X
X
X
X
X
Predose ECG should 
be obtained on Day -
1 within 3 hours of 
dosing. All 
subsequent ECGs 
will be single 
measurements and 
performed in the AM 
within 3 hours of 
dosing. Sec. 8.4.3.
Height, Weight, BMI 
X
X
X
X
X
Height is only 
required at 
Screening. Sec. 8.4.1
Alcohol Breath Test
X
X
X
App. 2
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Study Phase:
Scree
n-inga
Inpatient Quarantineb
Follo
w-up
Early 
With-
draw
al
Scheduled Dayc
D-90 
to D-2
D-3/
D-2
D-
1
D0
D1
D2
D3
D4
D5
D6
D7
D8
D9
D1
0
D1
1
D1
2
D28
(+/-
3d)
Post-
Chal-
lenge
Notes
Predose
Viral 
Challeng
Postdose
Urine Drugs of Abuse 
and Nicotine Screen
X
X
X
UDS will be 
conducted per 
hVIVO standard 
operating procedures. 
Sec. 8.4.4, App. 2
Urine Pregnancy Test
X
X
X
X
Sec. 8.4.5, App. 2
Laboratory 
Procedures/
Assessments
Hematology
X
X
X
X
X
X
Sec. 8.4.4, App. 2 & 
8 (Hematology)
Urinalysis
X
X
X
X
X
X
Chemistry
X
X
X
X
X
X
Coagulation
(PT/aPTT)
X
Sec. 4.2.1.2, 
App. 2 & 8
Cardiac Enzymes (CK 
and Troponin)
X
X
X
X
Sec. 4.2.1.2, 
App. 2 & 8
Thyroid Function Test
X
Sec. 4.2.1.2, 
App. 2 & 8
Serum FSH 
X
Postmenopausal 
females only. Sec. 
5.1, App. 2 & 5
Serum β-HCG 
Pregnancy Test 
X
WOCBP only. Sec. 
8.4.5, App. 2 & 8
HIV/Hepatitis B & C 
Serology
X
Sec. 8.4.4, 
App. 2 & 8
AE/SAE Review
X------------------------------------------------------------------------------------------------------------X
X
Sec. 8.5, App. 3
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Study Phase:
Scree
n-inga
Inpatient Quarantineb
Follo
w-up
Early 
With-
draw
al
Scheduled Dayc
D-90 
to D-2
D-3/
D-2
D-
1
D0
D1
D2
D3
D4
D5
D6
D7
D8
D9
D1
0
D1
1
D1
2
D28
(+/-
3d)
Post-
Chal-
lenge
Notes
Predose
Viral 
Challeng
Postdose
Biomarkers 
Blood - Serum 
Markers Humoral 
Immunity
X
X
X
X
X
Blood for Genetic 
Analysis
X
May be collected any 
time up to 24 hrs 
postdose for enrolled 
participants only. 
Sec. 8.9.1 & App. 8
Pharmacokinetics 
and 
Pharmacodynamic 
Assessments 
Blood for Plasma 
NHC and/or 
Metabolites Assay
X
X
X
X
X
X
Sampling Timesd
D-1: predose, 12 hr
D2, D5, D6: 12 hr
D4, D7: predose, 0.5, 
1.5, 4, 8, 12 hr. Sec. 
8.7.1 & App. 8
Blood for PBMC 
NHC-TP and/or 
Metabolites Assay
X
X
X
X
Sampling Timesd
D-1: predose, 12 hr
D4, D6, D7: 12 hr. 
Sec. 8.7.2 & App. 8
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Study Phase:
Scree
n-inga
Inpatient Quarantineb
Follo
w-up
Early 
With-
draw
al
Scheduled Dayc
D-90 
to D-2
D-3/
D-2
D-
1
D0
D1
D2
D3
D4
D5
D6
D7
D8
D9
D1
0
D1
1
D1
2
D28
(+/-
3d)
Post-
Chal-
lenge
Notes
Predose
Viral 
Challeng
Postdose
Collection of 
Respiratory Samples
Nasal Swab – BioFire 
Respiratory Pathogen 
Screen including 
SARS-COV-2
X
Sec. 8.3.3, 8.12.3
Nasopharyngeal Swab 
– RSV Discharge Test
(X) (X)
Sec. 8.3.3
Nasal Wash –
Virology and Viral 
Genomicse
2X
2X
2X
2X
2X
2X
2X
2X
2X
2X
X
qicPCR/PCR/viral 
assay
2X
2X
2X
X
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Study Phase:
Scree
n-inga
Inpatient Quarantineb
Follo
w-up
Early 
With-
draw
al
Scheduled Dayc
D-90 
to D-2
D-3/
D-2
D-
1
D0
D1
D2
D3
D4
D5
D6
D7
D8
D9
D1
0
D1
1
D1
2
D28
(+/-
3d)
Post-
Chal-
lenge
Notes
Predose
Viral 
Challeng
Postdose
a All screening procedures will be performed under the hVIVO generic screening process. Historical prescreening data collected through the hVIVO generic screening process 
within 90 days (90 days for viral serology and 56 days for other assessments including safety laboratory test) of randomization 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 hVIVO generic screening process.
b Day 0 predose procedures may be performed within 3 hours of, but prior to, IMP dosing. All inpatient visits should occur in line with inoculation day.
c Participants may report to the CRU for quarantine on either Day -3 or Day -2. All eligibility/baselines assessment may occur on either Day -3 or Day -2 depending upon 
admission day. 
d All samples should be collected with respect to the AM dose only, with the exception of D-1 samples, which should be collected with respect to the first dose received. All 
predose and 12 hr samples should be collected prior to the next scheduled dose. Windows for PK sampling are provided in Section 8.12.6.
e Nasal Wash for RSV Virology samples will be taken for RSV quantification (qRT-PCR and plaque assay). Samples may be used for related viral genomics and RSV virus 
sequencing. Samples collected between the morning of Day 2 and the morning of Day 5 will also be used for assessment of participant RSV infectivity status qic-PCR prior to 
discharge (Day 12) until a positive result is received to support triggered dosing.
Note: 
Parenthesis indicate the assessment may be optional, or at the PI’s discretion.
The investigator may perform additional safety assessments as required.
Where any nasal sampling timepoints occur together, the order of sampling will typically be: (1) nasopharyngeal swab followed by; (2) nasal wash.
AM=ante meridiem (before midday); AE=adverse event; β-HCG=beta human chorionic gonadotropin; BDS=blood drug screen; BMI=body mass index; CK=creatine kinase; 
CRU=clinical research unit; D=day; DBP=diastolic blood pressure; DNA=deoxyribonucleic acid; EC=exclusion criteria; ECG=electrocardiogram; FBR=future biomedical 
research; FSH=follicle stimulating hormone; hCG=human chorionic gonadotropin; HIV=human immunodeficiency virus; HR=heart rate; IC=inclusion criteria; 
ID=identification; NHC=N-hydroxycytidine; NHC-TP=N-hydroxycytidine triphosphate; PI=primary investigator; PK=pharmacokinetics; PT=prothrombin time; PTT=partial 
thromboplastin time; qicPCR=qualitative integrative cycler PCR; qRT-PCR=real-time quantitative reverse transcription PCR; RR=respiratory rate; RSV=respiratory syncytial 
virus; SAE=serious adverse event; SARS-COV-2=severe acute respiratory syndrome coronavirus 2; SBP=systolic blood pressure; SpO2=oxygen saturation; SOP=standard 
operating procedure; UDS=urine drug screen; VS=vital signs; WOCBP=women of childbearing potential.
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2
INTRODUCTION
2.1
RSV Clinical Manifestations and Epidemiology
RSV causes upper and lower respiratory tract illness worldwide. Globally, RSV is estimated 
to infect 64 million adults and children and cause 160,000 deaths each year [National 
Institutes of Health 2008]. Before the COVID-19 pandemic, endemic RSV disease occurred
yearly during late fall, winter, and early spring (lasting about 5 months) in temperate 
climates, and throughout the year with a less predominant cyclical pattern in the tropics 
[Haynes, A. K., et al 2013] [Stensballe, L. G., et al 2003] [Bloom-Feshbach, K., et al 2013]. 
Patterns of viral respiratory disease were disrupted with the COVID-19 pandemic, when 
social distancing reduced transmission, although seasonal RSV infection is re-emerging. 
RSV is transmitted primarily via droplets from the sneeze, cough, or breathing of an infected 
person, or via contamination of environmental surfaces with infectious secretions [Hall, C. B. 
1981]. There is a single RSV serotype with 2 major antigenic subgroups, A and B strains
[Borchers, A. T., et al 2013]. Both strains often cocirculate during epidemics, though one 
may predominate [Mufson, M. A., et al 1988] [Akerlind, B. 1986] [Gilca, R., et al 2006] 
[Borchers, A. T., et al 2013]. By the end of the first year of life, approximately 70% of 
children will have been infected with RSV; 30% to 75% will have been infected twice by the 
second year of life [Glezen, W. P., et al 1986] [Hall, C. B., et al 2009] [Ohuma, E. O., et al 
2012]. Reinfection with RSV occurs throughout life and is generally associated with mild 
upper respiratory tract infection in healthy older children and immunocompetent adults [Hall, 
C. B. 2001] [Borchers, A. T., et al 2013]. The clinical manifestations of RSV reinfection in 
older adults are variable, with symptoms ranging from a mild cold to severe respiratory 
distress [Falsey, A. R. 2000] [Walsh, E. E. 2012].
The clinical manifestations of RSV reinfection in older adults are variable, with symptoms 
ranging from a mild cold to severe respiratory distress [Falsey, A. R. 2000] [Walsh, E. E. 
2012].
Elderly individuals (age >65 years), especially those with cardiopulmonary comorbidities
(eg, asthma, COPD, CHF), as well as immunocompromised adults (HSCT recipients, 
hematologic malignancies, lung transplant recipients) are at risk of more severe RSV 
infection with development of pneumonia and increased rates of hospitalization and death. 
The global number of hospital admissions for RSV related acute respiratory infection in older 
adults was estimated at 336,000 with about 14,000 in-hospital deaths in 2015 [Shi, T., et al 
2020]. Annual reinfection is common, and individuals may be contagious for days to weeks 
following infection. As the population ages and with the increase in long-term care 
institutions over time, the potential for an increasing burden of more severe RSV disease will 
continue to grow. 
2.1.1
RSV Pathogenesis and Immune Mechanisms
The incubation period after RSV exposure ranges from 2 to 8 days after the virus enters the 
body through the upper respiratory tract. In susceptible individuals (eg, infants, older adults), 
the virus may spread to the lower respiratory tract where it can cause symptoms of bronchitis, 
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bronchiolitis, pneumonia and respiratory distress (collectively called LRI). Primary infection 
and subsequent reinfections result in immune responses to RSV. These immune responses 
include: (1) the generation of SNA, through antibodies predominantly targeted to the RSV 
fusion protein; (2) RSV specific mucosal IgA and IgG; and (3) CD4 T-helper and CD8 
cytotoxic T cell responses to RSV peptide antigens. Despite these immune responses, 
reinfection occurs throughout life. Each of these mechanisms may contribute to restrict RSV 
to the upper respiratory tract in healthy children and younger adults, resulting in milder 
disease in these individuals.
2.1.2
Summary of RSV Inoculation Model
The RSV human challenge model was developed to not only aid understanding of RSV 
disease, but to also assess the efficacy of RSV antivirals, immunomodulators and vaccines. 
The RSV A Memphis 37b challenge strain has been used for over 15 years by both hVIVO 
and others and has helped assess the efficacy of numerous RSV therapies [Lambkin-
Williams, R., et al 2018] [DeVincenzo, J., et al 2020] [Stevens, M., et al 2018] and vaccines 
[Sadoff, J., et al 2021] [Schmoele-Thoma, B., et al 2022]. Specifically, hVIVO have safely 
and successfully used the RSV challenge strain in over 1400 healthy participants (18 to 
60 years of age) including the inoculation of 24 participants between 60 and 75 years of age. 
Additionally, another clone of the same strain of live RSV (Memphis 37c) has been used as 
an inoculation agent and was shown to be safe in over 77 healthy young adults across 3 
studies. Healthy RSV challenge study participants have approximately 65% to 85% chance 
of becoming infected with RSV following the administration of the virus [DeVincenzo, J. P., 
et al 2010]. Typical RSV illness is characterised by an abrupt onset of rhinitis, nasal 
stuffiness, malaise, myalgia (muscle aches), and sore throat. In healthy adults, the illness 
usually resolves without any treatment, with relief of symptoms occurring naturally within 7 
to 10 days. Respiratory syncytial virus, like many viruses, can cause more substantial health 
issues such as myocarditis (inflammation or damage to the heart muscle). Adults and children 
present with RSV-related myocarditis rarely, with symptomless occurrences likely going 
undiagnosed in the community.
2.2
Study Rationale
MK-4482 (MOV) 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 dose of MK-4482 (MOV) 800 mg Q12H x 5 days in the treatment of 
acute RSV infection or in prophylaxis against RSV infection in a human challenge disease 
model of RSV experimental intranasal inoculation. Data from this study inform as to whether
MK-4482 has sufficient antiviral activity to support investigating its efficacy in future field 
studies. 
Extensive preclinical and clinical safety experience have supported the development of MOV 
as well as the use of a dose of 800 mg Q12H x 5 days for the treatment of mild to moderate 
COVID-19 as discussed below. The current study will provide further assessments of the 
safety and tolerability of MK-4482 as well as of the PK of NHC and viral dynamics
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following inoculation with RSV. Using a human challenge model, in which a fixed inoculum 
of RSV A Memphis 37b is administered to healthy adults in a controlled setting, allows a 
preliminary evaluation of MK-4482 before subsequent, larger studies of safety and efficacy.
2.3
Background
Refer to the IB/approved labeling for detailed background information on MK-4482.
2.3.1
Pharmaceutical and Therapeutic Background
MK-4482 (MOV) is the 5´-isobutyrate prodrug of the broadly active, direct-acting antiviral 
ribonucleoside analog NHC. MOV is hydrolyzed by esterases either during or after 
absorption to deliver NHC into systemic circulation. NHC inhibits replication of multiple 
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 MOV (NHC-TP) acts as a competitive, 
alternative substrate for the virally encoded RNA-dependent RNA polymerase that upon 
incorporation into nascent chain RNA, induces increased mutational frequency in the viral 
genome resulting in induction of viral error catastrophe 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]. 
Currently, the lack of safe, broadly effective, and generally utilized vaccines or direct acting 
antiviral agents to prevent or treat RSV infection represents an unmet need. The standard of 
care for RSV-infected adults consists solely of palliative measures, including administration 
of fluids and oxygen. Antiviral agents with rapid onset and a high barrier to resistance may 
provide an effective approach for the treatment and prophylaxis of RSV infection in adults.
2.3.2
Preclinical and Clinical Studies
Primary pharmacology studies demonstrating the antiviral activity of MOV 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 viral infection. In vitro, NHC shows 
broad-spectrum activity against multiple viruses including coronaviruses SARS-CoV-2, 
SARS-CoV, and MERS-CoV, as well as RSV and influenza virus.
Published studies by Yoon et al. have demonstrated the antiviral activity of NHC with in 
vitro and in vivo preclinical models [Yoon, J. J., et al 2018]. NHC exhibits dose-dependent 
inhibition of viral replication against 2 clinical isolates of human RSV in both Hep-2 cell and 
primary human bronchial tracheal epithelial cell culture systems with EC50 values in the 
micromolar to submicromolar range. Furthermore, oral administration of NHC at 100 mg/kg 
twice daily was effective in significantly reducing viral load as well as markers of respiratory 
distress in a mouse model of RSV infection. A 100-mg/kg dose in mice corresponds to a 
human-equivalent dose of approximately 8 mg/kg, in line with the 800-mg Q12H dose for 
this study (~ 13 mg/kg for a 60-kg adult).  Comparison of effective dose amounts in in vitro 
assay an in vivo preclinical models suggest that similar levels of NHC may be effective 
against both RSV and SARS-CoV2 infection. In vitro assessments of NHC activity against 
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RSV show EC50 values within a 2-fold range those demonstrated against SARS-CoV2, 
indicating a similar range of potency, allowing for differences in cell and assay types. 
MOV was evaluated in nonclinical safety studies, including a standard battery of in vitro and 
in vivo safety pharmacology studies, genotoxicity assays (including Ames assays, in vitro 
and in vivo micronucleus assays, an in vivo Pig-a assay in rats, and an in vivo mutation assay 
in Big Blue® transgenic rats), tolerability/dose-range-finding studies in mice, rats, and dogs, 
repeat-dose toxicity studies of up to 3 months in rats and 1 month in mice and dogs, fertility 
studies in male and female rats, embryo-fetal developmental toxicity studies in rats and 
rabbits, a pre- and 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.
MOV was devoid of effects on CNS, respiratory, or cardiovascular functions in well-
characterized safety pharmacology models. Based on the totality of genotoxicity data, MOV 
is not mutagenic or genotoxic in in vivo mammalian systems. 
Target organs of toxicity identified in the repeat-dose toxicity studies were limited to bone 
marrow in dogs only, and growth plate in rats only. 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.
In fertility studies in rats there were no MOV-related effects on female or male fertility, or on 
early embryonic development up to the highest dose tested, 500 mg/kg/day, (2.1-/6.1-fold 
[female/male] the clinical NHC exposure at 800 mg Q12H). In pregnant rats administered 
MOV during the organogenesis period, developmental toxicity including embryolethality 
(post-implantation losses) and malformations/teratogenicity was observed at 1000 mg/kg/day 
(7.5-fold the clinical NHC exposure at 800 mg Q12H), and reduced fetal growth was noted at 
≥500 mg/kg/day (≥2.9-fold the clinical NHC exposure at 800 mg Q12H). There was no 
developmental toxicity at doses up to 250 mg/kg/day (0.8-fold the clinical NHC exposure at 
800 mg Q12H). Maternal toxicity included decreased food consumption and body weight 
losses, resulting in the early sacrifice at 1000 mg/kg/day, and decreased body weight gain at 
≥500 mg/kg/day. In pregnant rabbits, developmental toxicity was limited to reduced mean 
fetal body weights at 750 mg/kg/day (18-fold the clinical NHC exposure at 800 mg Q12H). 
There was no developmental toxicity in rabbits up to 400 mg/kg/day (6.5-fold the clinical 
NHC exposure at 800 mg Q12H). Maternal toxicity included decreased food consumption 
and body weight gain, and abnormal fecal output at ≥400 mg/kg/day. In the pre- and 
postnatal developmental study in rats, there was no F0 maternal or F1 generation toxicity up 
to the highest dose evaluated of 500 mg/kg/day (1.6-fold the clinical NHC exposure at 
800 mg Q12H). 
Further details of preclinical studies are provided in the IB. Collectively, the safety 
pharmacology and toxicology results support continued clinical development of MOV.
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2.3.3
Completed and Ongoing Clinical Studies
2.3.3.1
Completed Clinical Studies
MOV has been evaluated 9 completed or clinically completed (i.e. the last subject 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 MOV following oral administration to 
healthy participants. Oral doses (50 to 1600 mg as a single dose, including 200 mg with a 
high-fat meal, and 50 to 800 mg as multiple doses [Q12H for 5.5 days]) of MOV or placebo 
administered to 130 healthy participants were generally well tolerated. Out of these 
130 participants, 100 received at least one dose of MOV. No deaths or SAEs were reported.
MK-4482-008 was a single and multiple dose, randomized, placebo-controlled, double-blind 
study of MOV in healthy Japanese adult male participants. Single doses of MOV up to 
1600 mg, including 800 mg with a high-fat meal, and multiple doses of MOV 400 mg and 
800 mg Q12H for 5.5 days were generally well tolerated in healthy Japanese male adult 
participants. Out of 65 randomized participants, 51 received at least 1 dose of MOV. 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 MOV oral granules and MOV reference capsule formulations 
in healthy adult participants. A total of 16 participants were randomized into 4 treatment 
sequences consisting of a single 800-mg dose of MOV administered as oral granules in 
water, apple sauce or pudding or as the reference capsule formulation with water. Relative 
bioavailability was assessed through repeat evaluations of plasma NHC PK. No SAEs, deaths 
or ECIs were reported. 
MK-4482-012 was a randomized, double-blind, placebo-controlled, multiple ascending dose
study to evaluate the safety, tolerability, and PK of MOV. Doses of 400, 600, and 800 mg 
MOV Q12H for 10.5 days were generally well tolerated in healthy adult study participants. 
Out of 32 randomized participants, 24 received at least 1 dose of MOV. No SAEs, deaths or 
ECIs were reported and no study intervention-related clinically meaningful changes in vital 
sign values, ECGs, or safety laboratory values (including hematology) were observed as a 
function of dose or treatment.
Phase 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 MOV for the treatment of COVID-19. The primary 
efficacy objective is to determine the ability of MOV to reduce serious complications of 
COVID-19 including hospitalization, reduction in SaO2 <92%, or death. As of 
14-MAR-2022, 18 participants enrolled in Phase 1 (12 received MOV; 300 mg n=4; 600 mg 
n=4; 800 mg n=4), and 178 participants enrolled in Phase 2. This study is clinically 
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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 MOV (Q12H for 5 days) in nonhospitalized 
adults with COVID-19. The time to undetectable SARS-CoV-2 of viral RNA in 
nasopharyngeal swabs was shorter in participants receiving 800-mg MOV (median: 14 days) 
compared with those administered placebo (median: 15 days). MOV 200 mg (n=23), 400 mg 
(n=62) or 800 mg (n=55) or placebo (n=62) was generally well tolerated with a comparable 
incidence of AEs across the intervention groups. Four SAEs were reported (3 participants in 
the MOV groups combined, 1 in the placebo group); none were considered related to study 
intervention by the investigator. No participants died while enrolled in the study.
MK-4482-007 is a Phase 2a randomized, placebo-controlled, double-blind clinical study of 
MOV in adults who have tested positive for SARS-CoV-2 infection via PCR and are 
hospitalized with a diagnosis of COVID-19 with symptoms of ≤8 days. The primary efficacy 
objective is to measure the proportion of nasopharyngeal swabs and saliva from recipients 
becoming undetectable for SARS-CoV-2 RNA at Day 5 of MOV administration compared 
with placebo. As of 14-MAR-2022, 71 participants were enrolled in the study and enrollment 
is closed as of 15-FEB-2022. This study is clinically completed and final unblinded results 
are pending. Based on preliminary review of blinded safety data, SAEs were reported for 4 
participants, none were considered related to study intervention by the investigator. Of the 4 
participants who had SAE, one had SAE of hypovolemic shock on Day 12 and died of 
respiratory failure on Day 28, and one had SAE of worsening bradycardia and hypotension 
that required discontinuation of study intervention. No other deaths or other AEs requiring 
discontinuation of study intervention have been reported.
Phase 2/3 or 3 Studies:
MK-4482-001 is a Phase 2/3 randomized, placebo-controlled, double-blind clinical study to 
evaluate the efficacy, safety, and PK of MOV in hospitalized adults with COVID-19. In the 
Phase 2 portion of the study (Part 1) a total of 218 hospitalized participants with COVID-19 
received at least 1 dose of MOV (72 participants received MOV 800 mg) and 75 participants 
received placebo. MOV was generally well tolerated with a comparable incidence of AEs 
across the intervention groups. SAEs were reported for 15.4% participants (15.1% MOV 
groups, 16.0% placebo), with 1 SAE deemed related to study intervention by the investigator 
(Grade 3 urticaria) for 1 participant in the MOV 200-mg treatment group. A total of 16 
participants had AEs leading to death (6.4% MOV groups combined, 2.7% placebo), none of 
which were considered study intervention-related by investigator assessment. The study was 
stopped due to lack of clinical benefit in this population (participants already hospitalized 
prior to randomization) and did not proceed to the Phase 3 portion of the study (Part 2). 
MK-4482-002 is a Phase 2/3, randomized, placebo-controlled, double-blind, multisite study 
to evaluate the efficacy, safety, and PK of MOV administered to 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 
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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 
any hospitalizations that occurred since last contact. MOV 200 mg (n=74), 400 mg (n=77), 
800 mg (n=74) or placebo (n=74) Q12H for 5 days in Part 1 and MOV 800 mg (n=710) or 
placebo (n=701) Q12H for 5 days in Part 2 were generally well tolerated. In 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 MOV.
2.3.3.2
Ongoing Clinical Studies
MOV is being evaluated in 2 ongoing Phase 1 studies (P003, P016) and 1 ongoing Phase 3 
study (P013) (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 MOV in participants with severe 
renal impairment compared to participants with normal renal function (target enrollment of 
approximately N = 16-18). This study is ongoing. 
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 MOV in participants with 
moderate hepatic impairment compared to participants with normal hepatic function (target 
enrollment of approximately N = 14-17). This study is ongoing.
Phase 2/3 or 3 Studies:
MK-4482-013 is a Phase 3, multicenter, randomized, double-blind, placebo-controlled study 
to evaluate the efficacy and safety of MOV for the prevention of COVID-19 (laboratory-
confirmed SARS-CoV-2 infection with symptoms) in adults residing with a person with 
COVID-19. As of 14-MAR-2022, 798 household participants were randomized out of a 
planned total of 1500 participants.
2.4
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. 
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The totality of the safety data from Phase 1 through Phase 3 clinical studies and post-
authorization surveillance for the use of MOV in the treatment of COVID-19 demonstrate an 
acceptable safety and tolerability profile of MOV.
There were no effects on cardiovascular, neurological, and respiratory function in several 
well-characterized safety pharmacology experimental models. The integrated assessment of 
the mutagenic and genotoxic potential of MOV indicates that MOV is not mutagenic or 
genotoxic in in vivo mammalian systems.
As described in Section 2.2.2, in a 28-day repeat dose toxicity study with MOV in dogs, 
reversible hematologic toxicities were noted after Day 7 at exposures 0.4-fold those of the 
anticipated clinical exposures at the 800-mg Q12H dose. However, to date no clinically 
meaningful hematological changes have been observed in healthy participants up to 800-mg 
MOV Q12H for up to 10.5 days or in participants with COVID-19 at multiple doses up to 
800-mg Q12H for 5 days.
Histopathology results from the 3-month rat toxicity study demonstrated an increase in the 
thickness of the growth plate/physis, a finding not observed in 1-month studies in rats, dogs, 
or mice. These findings are not considered to represent a significant new risk to human 
adults. 
In fertility studies in rats there were no MOV-related effects on female or male fertility, or on 
early embryonic development up to the highest dose tested, 500 mg/kg/day, (2.1-/6.1-fold 
[female/male] the clinical NHC exposure at 800 mg Q12H). While embryolethality (post-
implantation losses) and teratogenicity were limited to rats exposed to 7.5-fold the clinical 
NHC exposure at 800 mg Q12H during the organogenesis period, and these developmental 
findings were not observed in rats up to 2.9-fold the clinical NHC exposure at 800 mg Q12H 
and rabbits up to 18-fold the clinical NHC exposure at 800 mg Q12H, WOCBP will be 
required to use effective contraception for the duration of treatment and for at least 4 days 
postdose.
Additional details regarding specific benefits and risks for participants participating in this 
clinical study may be found in the accompanying IB and informed consent documents.
3
HYPOTHESES, OBJECTIVES, AND ENDPOINTS
Hypotheses are aligned with objectives in the Objectives and Endpoints table.
This study is to be conducted in healthy adult male and female participants. 
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Objectives
Endpoints
Primary
To determine if MK-4482 (800 mg Q12 x 5 
days) results in a reduction in viral load after 
intranasal inoculation (with RSV A
Memphis 37b) compared to placebo.
Hypothesis (Prophylaxis): MK-4482 (800 
mg Q12 x 5 days), when administered to 
begin prior to intranasal inoculation with 
respiratory syncytial virus (RSV-A 
Memphis 37b), reduces the Peak Viral Load 
(PVL) after viral inoculation compared to 
placebo. 
Hypothesis (Treatment): MK-4482 (800 mg 
Q12 x 5 days), when administered following 
infection with respiratory syncytial virus 
(RSV-A Memphis 37b), reduces the Area 
Under the Viral-Load-time (VL-AUC) after 
MK-4482 administration compared to 
placebo.
Prophylaxis:

Peak Viral Load (PVL) as defined by 
the maximum viral load determined by 
viral quantitative culture (plaque assay) 
starting from Day 2 up to planned 
discharge from quarantine (Day 12 am) 
Treatment:

Area Under the Viral Load-time Curve 
(VL-AUC) determined by viral 
quantitative culture (plaque assay) 
starting at initial administration of MK-
4482/placebo up to planned discharge 
from quarantine (Day12 am)
Secondary
To estimate the effect of MK-4482 (800 mg 
Q12H x 5 days) on the reduction in viral 
load after intranasal inoculation (with RSV 
A Memphis 37b) compared to placebo.
Prophylaxis:

Area Under the Viral Load-time Curve 
(VL-AUC) determined by viral 
quantitative culture (plaque assay) 
starting from Day 2 up to planned 
discharge from quarantine (Day 12 am) 

Area Under the Viral Load-time Curve 
(VL-AUC) determined by qRT-PCR 
starting from Day 2 up to planned 
discharge from quarantine (Day 12 am) 

Peak Viral Load (PVL) defined by the 
maximum viral load determined by 
qRT-PCR starting from Day 2 up to 
planned discharge from quarantine 
(Day 12am)
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Objectives
Endpoints
Treatment:

Peak Viral Load (PVL) as defined by 
the maximum viral load determined by 
viral quantitative culture (plaque assay) 
starting at initial administration of MK-
4482/placebo up to planned discharge 
from quarantine (Day 12 am) 

Time (days) to confirmed negative test 
by viral quantitative culture (plaque 
assay) measurements starting at initial 
administration of MK-4482/placebo to 
first confirmed undetectable (<LLOQ) 
assessment after peak measure.

Area Under the Viral Load-time Curve 
(VL-AUC) determined by qRT-PCR 
starting at initial administration of MK-
4482/placebo up to planned discharge 
from quarantine (Day 12 am) 

Peak Viral Load (PVL) defined by the 
maximum viral load determined by 
qRT-PCR starting at initial 
administration of MK-4482/placebo up 
to planned discharge from quarantine 
(Day 12 am).

Time (days) to confirmed negative test 
by qRT-PCR starting at initial 
administration of MK-4482/placebo to 
first confirmed undetectable (<LLOQ) 
assessment after peak measure.
To estimate the effect of MK-4482 (800 mg 
Q12 x 5 days) on course of clinical 
symptoms after intranasal inoculation (with 
RSV A Memphis 37b) compared to placebo
Prophylaxis:

Area under the curve over time of total 
clinical symptoms (TSS-AUC) as 
measured from 10 symptoms within the 
graded symptom scoring starting from 
Day 2 up to planned discharge from 
quarantine (Day 12 am).
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Objectives
Endpoints

Area under the curve over time of total 
clinical symptoms change from baseline 
(TSS-AUC-CFB) as measured from 10 
symptoms within the graded symptom 
scoring system starting from Day 2 up 
to planned discharge from quarantine 
(Day 12 am).

Peak symptoms diary card score: peak 
total clinical symptoms (TSS) as 
measured from 10 symptoms within the 
graded symptom scoring system starting 
from Day 2 up to planned discharge 
from quarantine (Day 12 am).

Peak daily symptom score: individual 
maximum daily sum of symptom score 
starting from Day 2 up to planned 
discharge from quarantine (Day 12 am).
Treatment:

Area under the curve over time of total 
clinical symptoms (TSS-AUC) as 
measured from 10 symptoms within the 
graded symptom scoring system starting 
at initial administration of MK-
4482/placebo up to planned discharge 
from quarantine (Day 12 am).

Area under the curve over time of total 
clinical symptoms change from baseline 
(TSS-AUC-CFB) as measured from 10 
symptoms within the graded symptom 
scoring system starting at initial 
administration of MK-4482/placebo up 
to planned discharge from quarantine 
(Day 12 am).

Peak symptoms diary card score: peak 
total clinical symptoms (TSS) as 
measured from 10 symptoms within the 
graded symptom scoring system starting 
from initial administration of MK-
4482/placebo up to planned discharge 
from quarantine (Day 12 am).
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Objectives
Endpoints

Peak daily symptom score: individual 
maximum daily sum of symptom score 
from initial administration of MK-
4482/placebo up to planned discharge 
from quarantine (Day 12 am).

Time (days) to symptom resolution as 
measured from 10 symptoms within the 
graded daily symptom scoring system 
starting at initial administration of MK-
4482/placebo to time of returning to 
baseline score.
To estimate the effect of MK-4482 (800 mg 
Q12 x 5 days) on the incidence of RSV 
infection and symptomatic RSV infection 
after intranasal inoculation (with RSV A 
Memphis 37b) compared to placebo.
Prophylaxis:

RT-PCR-confirmed RSV infection, 
defined as 2 quantifiable (≥ lower limit 
of quantification [LLOQ]) qRT-PCR 
measurements (reported on 2 or more 
independent samples over 2 days), 
from Day 2 up to Day 12.

Occurrence of at least 1 positive 
quantitative (≥LLOQ) cell culture 
measurement in nasal samples, from 
Day 2 up to Day 12.

RT-PCR-confirmed symptomatic RSV 
infection, defined as:
o
RT-PCR-confirmed RSV 
infection (2 quantifiable 
[≥LLOQ] qRT-PCR 
measurements [reported on 2 or 
more independent samples over 
2 days]), from Day 2 up to 
Day 12, AND
o
Symptoms score ≥2 at a single 
time point.
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Objectives
Endpoints

RT-PCR-confirmed moderately severe 
symptomatic RSV infection, defined 
as:
o
RT-PCR-confirmed RSV 
infection (2 quantifiable 
[≥LLOQ] qRT-PCR 
measurements [reported on 2 or 
more independent samples over 
2 days]), from Day 2 up to 
Day 12, AND
o
Any symptoms of Grade ≥2 at a 
single time point.

Culture lab-confirmed symptomatic 
RSV infection, defined as:
o
Lab-confirmed culturable RSV 
infection (1 quantifiable 
[≥LLOQ] cell culture 
measurement), from Day 2 up 
to Day 12, AND
o
Symptoms score ≥2 at a single 
time point.
To evaluate the safety and tolerability of 
MK-4482 (800 mg Q12 x 5 days) compared 
to placebo

Safety data including, but not limited 
to, occurrence of adverse events (AEs) 
from initial administration of MK-
4482/placebo up to the Day 28 follow-
up.

Occurrence of serious AEs (SAEs) 
from initial administration of MK-
4482/placebo up to the Day 28 follow-
up.
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Objectives
Endpoints
To monitor the safety of the challenge virus

Occurrence of AEs related to the viral 
challenge from viral challenge (Day 0) 
up to the Day 28 follow-up.

Occurrence of SAEs related to the viral 
challenge from viral challenge (Day 0) 
up to the Day 28 follow-up.

Use of concomitant medications from 
viral challenge (Day 0) up to the 
Day 28 follow-up.
To evaluate plasma NHC concentrations 
after administration of MK-4482 (800 mg 
Q12 x 5 days)
Plasma NHC concentrations at specified 
timepoints
Tertiary/Exploratory
To further explore the effect of MK-4482 
(800 mg Q12H x 5 days) on the reduction in 
viral load after intranasal inoculation (with 
RSV A Memphis 37b) compared to placebo.
Prophylaxis:

Duration of quantifiable RSV qRT-PCR 
measurements starting from Day 2 up to 
Day 12 am. Duration is defined as the 
time (days) from first quantifiable 
detection until first confirmed
undetectable (<LLOQ) assessment after 
peak measure (after which no further 
virus is detected)

Duration of quantifiable RSV viral 
quantitative culture (plaque assay) 
measurements starting from Day 2 up to 
Day 12 am. Duration is defined as the 
time (days) from first quantifiable
detection until first confirmed
undetectable (<LLOQ) assessment after 
peak measure (after which no further 
virus is detected)
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Objectives
Endpoints
To further explore the effect of MK-4482 
(800 mg Q12H x 5 days) on course of 
clinical symptoms after intranasal 
inoculation (with RSV A Memphis 37b) 
compared to placebo

Clinical symptom-related endpoints 
may be further explored, as measured 
with either the full 13 or a subset of the 
13 symptoms within the graded 
symptom scoring system. 
Prophylaxis:

Duration (days) of Grade 2 symptoms 
measured from 10 symptoms within 
the graded daily symptom scoring 
system starting from Day 2 to planned 
discharge from quarantine (Day 12 
am), as measured by time from first 
occurrence of Grade 2 or higher 
symptoms to first 24 hours period 
without Grade 2 or more symptoms 
after the peak total symptom score.

Time (days) to peak as measured from 
10 symptoms within the graded daily 
symptom scoring system starting from 
Day 2 to the time of peak daily 
symptom score.
Treatment:

Time (days) to peak as measured from 
10 symptoms within the graded daily
symptom scoring system starting from 
initial administration of MK-
4482/placebo to the time of peak daily 
symptom score.
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Objectives
Endpoints
To further explore the effect of MK-4482 
(800 mg Q12H x 5 days) on the incidence of 
RSV infection and symptomatic RSV 
infection after intranasal inoculation (with 
RSV A Memphis 37b) compared to placebo.

RT-PCR-confirmed RSV infection, 
defined as 2 detectable (≥ lower limit of 
detection [LLOD]) qRT-PCR 
measurements (reported on 2 or more 
independent samples over 2 days), from 
Day 2 up to Day 12. 

RT-PCR-confirmed symptomatic RSV 
infection, defined as: 
o
RT-PCR-confirmed RSV 
infection (2 detectable 
[≥LLOD] qRT-PCR 
measurements [reported on 2 or 
more independent samples over 
2 days]), from Day 2 up to 
Day 12, AND 
o
Symptoms score ≥2 at a single 
time point
To estimate the effect of administration of 
MK-4482 (800 mg Q12H x 5 days) on 
mucus production after intranasal 
inoculation (with RSV A Memphis 37b) 
compared to placebo
Prophylaxis:

Total weight of mucus produced 
starting from Day 2 up to planned 
discharge from quarantine (Day 12 
am).

Total number of tissues used by 
participants starting from Day 2 up to 
planned discharge from quarantine 
(Day 12 am).
Treatment:

Total weight of mucus produced 
starting from initial administration of 
MK-4482/placebo up to planned 
discharge from quarantine (Day 12 
am).

Total number of tissues used by 
participants starting from initial 
administration of MK-4482/placebo up 
to planned discharge from quarantine 
(Day 12 am).
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Objectives
Endpoints
To explore baseline immunology and 
response to infection with RSV and 
response to MK-4482.
Blood and nasal samples may be used for 
exploratory assays related to respiratory 
viral infection and immunology.
To explore NHC-TP concentrations after 
administration of MK-4482 (800 mg Q12H 
x 5 days).
NHC-TP concentrations in PBMCs at 
specified timepoints.
To explore the relationship between drug 
exposure and virological endpoints.
Exposure/response relationship
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 RSV A 
Memphis 37b) compared to placebo.
Quantitation by viral sequencing of nasal 
samples.
To explore genetics and response to 
infection with RSV and response to MK-
4482. 
Blood samples may be used for exploratory 
assays related to respiratory viral infection, 
response to MK-4482, and genetics.
*Note that tertiary objectives and endpoints are optional and might be assessed only if 
needed; therefore, not all testing might be performed and reported.
4
STUDY DESIGN
4.1
Overall Design
This is a randomized, placebo-controlled, single site, double-blind study of MK-4482 in 
healthy male and female participants 18 to 55 years (inclusive) of age, screened to be in the 
bottom quartile of participants for immunogenicity to the RSV A Memphis 37b (inoculation 
strain) as determined by a serum microneutralization assay. This study will be conducted in 
conformance with GCP. 
Participants will be prescreened under a generic screening process for SNA (PRNT assay) 
activity against the inoculation strain. Participants in the lower quartile will be screened for 
eligibility for this study. 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.
As outlined in Section 1.2 (Table 1, Figure 1), the study will include 3 arms consisting of 
prophylactic administration, triggered dosed treatment (hereafter also referred to as 
treatment), and matched placebo. Approximately 105 participants who meet eligibility 
criteria will be randomized to receive 800 mg Q12H x 5 days of MK-4482 dosed prior to 
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viral challenge (prophylaxis); 800 mg Q12h x 5 days of MK-4482 dosed following viral 
challenge on Day 0 (treatment) or placebo in a 1:1:1 ratio according to the Sponsor’s 
computer-generated allocation schedule. Participants who drop out may be replaced as per 
Section 5.5 to achieve up to 105 participants inoculated. To maintain the blind across 
treatment and prophylaxis groups for the duration of the study, all participants will receive 
MK-4482 or placebo beginning on Day -1 through Day 10. Participants in the prophylaxis 
cohort will receive active study drug beginning on Day -1 and switch to placebo following 
completion of 5 days of MK-4482 800 mg Q12H. Participants in the treatment cohort will 
receive placebo until treatment is triggered based on positive PCR testing for RSV infection 
or by Day 5 if no infection is detected; if 5 days of MK-4482 800 mg Q12H is completed 
prior to Day 10, participants will resume placebo through Day 10. Switching of the 
administered treatment from placebo to MK-4482 (and back to placebo) will be managed by 
unblinded study staff in a manner that maintains the blind for the participants and other 
clinical study personnel.
Before 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. On Day 0 of the study, up to 105 participants will 
be inoculated with RSV A Memphis 37b in order to have the required number of evaluable 
participants for the analysis (see Section 9.9). Participants will remain domiciled for 12 days 
post inoculation. Participants will be queried daily while domiciled for symptoms of RSV 
infection using a standardized questionnaire starting on Day -1. Nasal wash samples will be 
collected and tested for RSV viral load by qRT-PCR twice daily from Day 2 through Day 11. 
A single nasal wash sample for RSV viral load by qRT-PCR will be collected on Day 12. 
Blood samples to measure concentrations of NHC in the plasma and NHC-TP in PBMCs will 
be collected throughout the study as outlined in the SoA. All participants inoculated with 
RSV A Memphis 37b will be followed for safety monitoring for approximately 28 days after 
RSV A Memphis 37b inoculation. Nasal wash samples may be tested for the presence of 
virus prior to discharge. Participants will be discharged from the quarantine unit on Day 12 
(or may remain longer at the discretion of the PI/investigator).
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
MK-4482 is a prodrug ribonucleoside analogue with a high barrier to resistance and activity 
against a range of RNA viruses, including RSV. The purpose of this RSV challenge study is 
to provide an assessment of the antiviral activity of MK-4482 against RSV A in humans.
Viral challenge with RSV A Memphis 37b was selected based on its ability to generate safe 
and reproducible mild to moderate infection from a wild-type virus in multiple human 
challenge studies (discussed in Section 2.1.2). The protocol follows a double blind, placebo-
controlled design. Participants will be inoculated with RSV A Memphis 37b (Day 0) 
following administration of MK-4482 or placebo (Day -1). A regimen of MK-4482 800 mg 
Q12H x 5 days will begin on Day -1 (Panel A, prophylaxis) or upon evidence of RSV 
infection (based on positive PCR testing of nasal wash samples), and no later than Day 5 
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(Panel B, treatment). A reduction in nasal viral load has been chosen as the primary efficacy-
related measure as a sensitive and predictable indicator of viral replication. The primary 
efficacy-related endpoints are reductions in Peak VL or VL-AUC, in the prophylaxis or 
triggered dosing Panels, respectively. Additional virologic assessments are included as 
secondary endpoints to support the primary endpoints. The incidence of symptomatic RSV 
infection, as well as indicators of symptom timing, intensity and duration are additional 
secondary measures that provide preliminary assessment of whether MK-4482 800 mg Q12H
could be effective in treating or preventing RSV disease. Participants will be domiciled for at 
least 12 days and followed for 28 days after inoculation with RSV A Memphis 37b, which is 
a sufficient amount of time for participants to clear the RSV A Memphis 37b virus and detect 
any potential complications of the inoculation, respectively. To understand the relationship 
between MK-4482 and changes in the viral dynamics of RSV A Memphis 37b, serum will be 
collected throughout to evaluate exposure-response with plasma NHC, the primary 
pharmacokinetic measure for MK-4482. PBMCs will also be collected to understand in 
exploratory analyses how NHC-TP exposures affect RSV A Memphis 37b viral dynamics. 
As an objective measure of clinical symptoms, total mucus weights are included as an 
exploratory endpoint, and viral sequencing will provide an additional exploratory endpoint to 
assess for any relationship between exposure and viral mutation frequency, based on the 
mechanism of action of MOV. Taken together, the design will provide a robust evaluation of 
the antiviral activity of MK-4482 in healthy adults inoculated with RSV in a highly 
controlled setting.
4.2.1
Rationale for Endpoints
4.2.1.1
Efficacy Endpoints
The study will evaluate the antiviral activity of MK-4482 as both a prophylactic and a 
triggered treatment in healthy adult participants inoculated with RSV A Memphis 37b. This 
will be assessed by comparing the level of nasal viral load and the rate of symptomatic RSV 
infection in the MK-4482 dose groups with placebo. Within this human challenge study 
model, demonstration of antiviral activity is an approximate surrogate for efficacy and will 
be assessed based on the primary endpoints as outlined below. Additional measures of 
changes in viral load will also be considered as supportive, as noted in the secondary 
endpoints. Assessment of symptomatic RSV infection is also considered as supportive, and 
secondary endpoints regarding incidence of infection and course of clinical symptoms will 
form the basis of this evaluation. 
The rationale for choice of primary endpoints is based on the relevant viral dynamic 
assessment for the intervention as well as the mechanism of action of MK-4482 in halting 
productive viral replication. Reduction in peak VL compared to placebo will establish the 
antiviral activity of a prophylaxis regimen. For demonstration of prophylactic antiviral 
activity, a reduction of 65% in PVL will allow benchmarking against performance of other 
antiviral and vaccine therapies for RSV prophylaxis. Similarly, reduction in VL-AUC 
compared to placebo will establish the antiviral activity of a triggered dosing regimen for 
treatment of RSV infection. Demonstration of a 70% reduction in VL-AUC with triggered 
dosing is viewed as comparable, to the performance of other antivirals that have progressed 
to Phase 2 field efficacy studies.
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Evaluation of endpoints relevant to clinical symptoms will be assessed through the secondary 
and exploratory endpoints. Both symptom scores and mucus weights are key endpoints in 
later stage clinical trials and their evaluation within the human challenge model may afford 
an opportunity to improve translation to later field studies. Secondary endpoints relating to 
symptom scoring will utilize a symptom diary card administered at Day -3 and Day -2 to 
establish a baseline and 3 times a day following viral inoculation. In conjunction with 
symptom scoring, the exploratory endpoint of mucus weights provides an objective measure 
relevant to symptom scores. Analysis of these secondary and exploratory endpoints are more 
fully described in a SAP. 
4.2.1.2
Safety Endpoints
Based on available clinical safety data to date, evaluation of safety will be adequately
assessed from the following standard safety assessments: VS, 12-lead ECG, laboratory safety
tests (blood chemistry, hematology, urinalysis) and AEs. Additional laboratory safety 
assessments in the setting of the RSV challenge model are also included (coagulation studies, 
CK, thyroid function testing). Safety evaluations will be conducted throughout the study at 
intervals dictated by the viral challenge model and NHC PK properties.
4.2.1.3
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. Prior analyses from clinical 
studies have shown that NHC concentrations in the plasma correlate well with NHC-TP 
concentrations in PBMCs. NHC concentrations will be measured using a validated 
bioanalytical assay. Exploratory analyses may be conducted to evaluate the relationship 
between efficacy-related endpoints with exposures of NHC in the plasma, as appropriate. 
These findings support modeling efforts and will inform dose selection and study design of
later trials.
NHC-TP PK in PBMCs
Blood samples for the assessment of intracellular NHC-TP (the pharmacologically active 
moiety of MK-4482) in PBMCs will also be collected from participants (see Sec. 1.3) to 
characterize Ctrough of NHC-TP. NHC-TP concentrations will also be measured using a 
validated bioanalytical assay. Exploratory analyses may be conducted to evaluate the 
relationship between efficacy-related endpoints with exposures of NHC-TP in PBMCs, as 
appropriate. These findings support modeling efforts and will inform dose selection and 
study design of later trials.
4.2.1.4
Pharmacodynamic Endpoints
This study will evaluate the antiviral activity of MK-4482 800 mg Q12H x 5 days against 
RSV A infection, either in prophylaxis or in triggered dosing. Assessments of antiviral 
activity as outlined in the primary and secondary objectives will assist in characterizing the 
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pharmacodynamic effects of MK-4482 in RSV infection. Exploratory analysis of the rate of 
LNS in nasal samples will also allow further evaluation of the pharmacodynamic effects of 
MOV against RSV.
Exploratory analyses may be performed to define the antiviral activity of MOV and NHC 
relative to viral dynamics of RSV. Viral sequencing to assess rates of LNS will also be used 
to explore the exposure-response relationship for MK-4482 in RSV based on the known 
mechanism of action. To better characterize the pharmacodynamic effects of MK-4482 on 
the response to RSV Memphis 37b inoculation, other exploratory assays may be performed 
with excess serum or nasal samples from PK or excess PBMCs, and with whole blood 
mRNA, as applicable, at the discretion of 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
This study is being conducted to assess the antiviral activity of MK-4482 administered to 
study population in an RSV experimental challenge model. To this end, a placebo 
comparator is required to document the influence of MK-4482 on RSV viral load, 
symptomatic infection rate and symptoms scores after inoculation with the challenge strain. 
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). This dose is similarly being evaluated in an ongoing clinical study for postexposure 
prophylaxis of COVID-19 in adults (P013). Preclinical data place the potency of MK-4482 
against RSV within the range of the potency against SARS-CoV-2 (see Sec. 2.2.2). 
Therefore, the same 800-mg dose administered Q12H for 5 days has been selected for 
evaluation against RSV.
Preclinical data place the potency of MK-4482 against RSV 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 RSV and SARS-CoV2 infection. In vitro assessments of NHC activity against RSV 
show EC50 values within a 2-fold range those demonstrated against SARS-CoV-2, indicating 
a similar range of potency, allowing for differences in cell and assay types. Pharmacokinetic 
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 
RSV in this study, as it is expected to produce exposures that are believed to be efficacious 
based on the totality of preclinical data.
Of note, multiple doses up to 800-mg MOV Q12H for up to 10.5 days and single doses up to 
1600-mg, were generally well tolerated in healthy participants.
As this is a Phase 2a assessment of MK-4482 for RSV infection in humans, the PK, 
pharmacodynamic and safety profiles of the compound are still being evaluated.
Modifications to the dose or dosing regimen may be required to achieve the scientific goals 
of the study objectives and/or to ensure appropriate safety monitoring of the study 
participants.
4.4
Beginning and End-of-Study Definition
The overall study begins when the first participant (or their legally acceptable representative) 
provides documented informed consent. The overall study ends when the last participant 
completes the last study-related contact, withdraws consent, or is lost to follow-up (ie, the 
participant is unable to be contacted by the investigator).
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 
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decision on continuation or termination of the study. It may be necessary to keep the study 
open for gathering/reviewing of additional supportive data to optimally complete the 
objective(s) of the study. If necessary, the appropriate amendment(s) to the protocol and/or 
appropriate communication(s) will be generated. If the decision has been made to end the 
study following this review period, the study end will be defined as the date of the Sponsor 
decision, and this end of study date supersedes the definitions outlined above. The 
Competent Authority(ies) and IRB(s)/IEC(s) will be apprised of the maximum duration of 
the study beyond the last participant out and the justification for keeping the study open.
4.4.1
Clinical Criteria for Early Study Termination
There are no prespecified criteria for terminating the study early. 
5
STUDY POPULATION
Prospective approval of protocol deviations to recruitment and enrollment criteria, also 
known as protocol waivers or exemptions, is not permitted.
5.1
Inclusion Criteria
A participant will be eligible for inclusion in the study if the participant 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 randomization.
Appendix 9 provides a table of the 12-Lead Electrocardiogram Abnormality 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 has a total body weight ≥50 kg and Body Mass Index (BMI) ≥18 kg/m2
and ≤35 kg/m2.
4. The participant is male or female, from 18 years to 55 years of age inclusive, at the time 
of providing informed consent.
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Male Participants
Contraception used by men should be consistent with local regulations regarding the methods 
of contraception for those participating in clinical trials.
5. Male participants must agree to the following during the intervention period and for at 
least 90 days after the last dose of study intervention:
•
Abstains from heterosexual intercourse as their preferred and usual lifestyle (abstinent on 
a long-term and persistent basis) and agrees to remain abstinent
OR
•
Uses contraception unless confirmed to be azoospermic (vasectomized or secondary to 
medical cause, documented from the site personnel’s review of the participant’s medical 
records, medical examination, or medical history interview) as detailed below:
-
Uses a male condom plus partner use of an additional contraceptive method when 
having penile-vaginal intercourse with a WOCBP who is not currently pregnant. 
Note: Men with a pregnant or breastfeeding partner must agree to remain abstinent 
from penile-vaginal intercourse or use a male condom during each episode of penile-
vaginal penetration.
Contraceptive use by men should be consistent with local regulations regarding the 
methods of contraception for those participating in clinical studies.
Female Participants
6.
A female participant is eligible to participate if she is not pregnant or breastfeeding, 
and at least one of the following conditions applies: 
•
Not a WOCBP
OR
•
A WOCBP and:
-
Uses a contraceptive method that is highly effective (a low user dependency method 
OR a user dependent hormonal method in combination with barrier method), or be 
abstinent from heterosexual intercourse as their preferred and usual lifestyle 
(abstinent on a long-term and persistent basis), as described in Appendix 5 during the 
intervention period and for at least 28 days after the last dose of study intervention. 
The investigator should evaluate the potential for contraceptive method failure (ie, 
noncompliance, recently initiated) in relationship to the first dose of study 
intervention. Contraceptive use by women should be consistent with local regulations 
regarding the methods of contraception for those participating in clinical studies.
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-
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 8.3.5.
-
Medical history, menstrual history, and recent sexual activity has been reviewed by 
the investigator to decrease the risk for inclusion of a woman with an early undetected 
pregnancy.
Informed Consent
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 of study 
intervention.

A participant must be sero-suitable to take part in the study, i.e., he/she must have 
no or low pre-existing serum levels of antibodies specific to the challenge agent. 
This antibody titre cut-off for serosuitability will be described in the applicable 
hVIVO policy and/or generic screening AP.

Serum levels of pre-existing RSV A Memphis 37b-specific antibodies will be 
determined using RSV challenge virus neutralization assay, 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 currently active, symptoms or signs suggestive of 
upper or lower respiratory tract infection within 4 weeks prior to the first study visit.
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.
3. The participant has a history of resolved depression and/or anxiety 1 or more years ago 
may be included at the discretion of the PI. Participants with a history of stress related 
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illness, which is not ongoing or requiring current therapy, with good evidence of 
preceding stressors may also be included at the PI’s discretion. As 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 less than or 
equal to 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 the prestudy (screening) visit).
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 of admission to quarantine. Participants with a 
history of currently inactive rhinitis (within the last 30 days) or mild rhinitis may be 
included at the PI’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 will be excluded. 
Participants with mild to moderate atopic dermatitis/eczema, taking small amounts of 
regular dermal corticosteroids may be included at the PI’s discretion.
7. The participant whose reporting physician has diagnosed migraine can be included 
provided there are no associated neurological symptoms such as hemiplegia or visual 
loss. Cluster headache/migraine or prophylactic treatment for migraine is an exclusion. PI 
discretion may also be based on for example IMP vs. non IMP study. 
8. The participant has a physician diagnosed mild Irritable Bowel Syndrome not requiring 
regular treatment can be included at the discretion of the PI.
9. The participant has an estimated CrCl ≤60 mL/min based on the MDRD Equation. 
MDRD Equation:
eGFR (mL/min/1.73 m2) = 
175 x (serum creatinine)-1.154 x (age)-0.203 x (0.742 [if female]) x (1.212 [if black or African 
American])
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 of either 80 mL/min 
(for CrCl) or 80 mL/min/1.73m2 (for eGFR) may be enrolled in the study at the discretion of 
the investigator.
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Prior/Concomitant Therapy
10. The participant uses or anticipated use during the conduct of the study of concomitant 
medications (prescription and/or non-prescription), including vitamins or herbal and 
dietary supplements within the specified windows, unless in the opinion of the study 
physician/PI, the medication will not interfere with the study procedures or compromise 
participant safety. Specifically, the following are excluded: 
a) Herbal supplements within 7 days prior to the planned date of Viral Challenge/first 
dosing with IMP (whichever occurs first). 
b) 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/first dosing with IMP (whichever 
occurs first). 
c) Over the counter medications (eg, paracetamol or ibuprofen) where the dose taken 
over the preceding 7 days prior to the planned date of Viral Challenge/first dosing 
with IMP (whichever occurs first) has exceeded the maximum permissible 24-hour 
dose (eg, ≥4 g paracetamol over the preceding week) 
d) Systemic anti-viral administration within 4 weeks of Viral Challenge/first dosing 
with IMP (whichever occurs first). 
11. The participant is unable to refrain from or anticipates the use of any medication, 
including prescription and nonprescription drugs or herbal remedies beginning 
approximately 2 weeks (or 5 half-lives) prior to administration of the initial dose of study 
intervention, throughout the study (including washout intervals between treatment 
periods), until the poststudy visit. There may be certain medications that are permitted 
(see Section 6.5).
Prior/Concurrent Clinical Study Experience
12. The participant has evidence of receipt of vaccine within the 4 weeks prior to the planned 
date of viral challenge/first dosing with IMP (whichever occurs first). 
13. 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.)
14. The participant has received of any investigational drug within 3 months (or 5 half-lives, 
whichever is greater) prior to the planned date of viral challenge/first dosing with IMP 
(whichever occurs first). 
15. The participant has received 3 or more investigational drugs within the previous 12 
months prior to the planned date of viral challenge/first dosing with IMP (whichever 
occurs first). 
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16. The participant has had a prior inoculation with a virus from the same virus family as the 
challenge virus. 
17. The participant has a 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
18. The participant has a presence of fever, defined as participant presenting with a 
temperature reading of ≥37.9°C on Day -3/Day -2, Day -1, and/or pre-Challenge on Day 
0. 
19. The participant has any of the following: QTc interval >450 msec, 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.
Other Exclusions
20. The participant is under the age of legal consent.
21. 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).
22. 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), or excessive consumption of xanthine 
containing substances (eg, daily intake in excess of 5 cups of caffeinated drinks, eg,
coffee, tea, cola). 
23. The participant consumes excessive amounts, defined as greater than 6 servings 
(1 serving is approximately equivalent to 120 mg of caffeine) of coffee, tea, cola, energy 
drinks, or other caffeinated beverages per day.
24. The participant has a confirmed positive test for drugs of abuse and cotinine on first study 
visit. One repeat test allowed at PI discretion 
25. 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 PI.
26. The participant has venous access deemed inadequate for the phlebotomy and 
cannulation demands of the study.
27. 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 
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allowed, but large nasal polyps causing current and significant symptoms and/or 
requiring regular treatments in the last month is exclusionary).
28. The participant has any clinically significant history of epistaxis (large nosebleeds) 
within the last 3 months of the first study visit and/or history of being hospitalized due to 
epistaxis on any previous occasion. 
29. The participant has had any nasal or sinus surgery within 3 months of the first study visit. 
30. The participant has a forced expiratory volume in 1 second  <80%.
31. 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.
32. The participant is or has an immediate family member (eg, spouse, parent/legal guardian, 
sibling, or child) who is investigational site or Sponsor staff directly involved with this 
study.
5.3
Lifestyle Considerations
5.3.1
Meals and Dietary Restrictions
5.3.1.1
Diet Restrictions
Participants will fast from all food and drinks, except water, for at least 8 hours before 
administration of the AM dose on study Day 4 and Day 7, after which rich PK sampling will 
take place. Water will be restricted 1 hour before and 1 hour after study intervention 
administration but will otherwise be provided ad libitum. Participants will fast from all food 
and drinks, except water, between administration of the AM dose on study Day 4 and Day 7
and the first scheduled meal. 
On days with sparse PK sampling (ie, trough samples), while domiciled in the clinic or at 
home, 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, if 
needed, is allowed.
5.3.1.2
Fruit Juice Restrictions
Participants will refrain from the consumption of grapefruit juice, grapefruits, and grapefruit 
products beginning approximately 2 weeks before administration of the initial dose of study 
intervention, throughout the study and until the poststudy visit.
On Day 4 and Day 7, participants will refrain from the consumption of all fruit juices 
24 hours before the AM study intervention administration until after drug administration.
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On all other days during the study, the consumption of all fruits and fruit juices (except for 
grapefruit, grapefruit juices, and grapefruit products) is allowed.
5.3.2
Caffeine, Alcohol, and Tobacco Restrictions
5.3.2.1
Caffeine Restrictions
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. 
5.3.2.2
Alcohol Restrictions
Participants will not be allowed to consume alcohol from 72 hours prior to study intervention
and 72 hours prior to quarantine admission, and while in the clinic unit. 
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 PI/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 
PI/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.
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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.
The study site should contact the Sponsor for the replacement participant’s 
treatment/randomization number.
6
STUDY INTERVENTION
Study intervention is defined as any investigational intervention(s), marketed product(s), 
placebo, or medical device(s) intended to be administered to a study participant according to 
the study protocol.
Clinical supplies (MOV 200-mg capsules and matched 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 2. Table 3 depicts the 
study administration schedule. 
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Table 2
Study Interventions
Arm 
Name
Arm Type
Inter-
vention 
Name
Inter-
vention 
Type
Dose 
Formulation
Unit Dose 
Strength(s)
Dosage 
Level(s)
Route of 
Admin-
istration
Regimen/
Treatment Period
Use
IMP or
NIMP/
AxMP
Sourcing
Active
Experimental
MK-4482
Drug
Capsule
200 mg
800 mg
Oral
Prophylaxis: MK-
4482 800 mg Q12H x 
5 days (10 doses) D-
1 to D4
Triggered dosing: 
800 mg Q12H x 5 
days (10 doses) 
D2/D5 to D6/D10
Experimental
IMP
Sponsor
Placebo
Placebo 
Comparator
Placebo
Drug
Capsule
Not applicable
Not applicable
Oral
Matched Placebo 
Arm: PBO Q12H x 
11 days
Prophylaxis: PBO 
Q12H D4 to D10 
Triggered Dosing: 
PBO Q12H x 6 days 
total, before and after 
active MK-4482
Placebo
IMP
Sponsor
Virus 
Inocula-
tion
Not applicable
RSV A 
Memphis 
37b virus
Virus 
(Challeng
e Agent)
N/A
Approximately 
4 Log10 PFU*
Approximately 
4 Log10 PFU*
Intranasal
Single 
Administration
Challenge 
Agent
N/A
Site (hVIVO)
AM=ante meridiem (before midday); D=day; EEA =European Economic Area; IMP=investigational medicinal product; N/A=not applicable; NIMP=noninvestigational medicinal product; PBO=placebo; 
PCR=polymerase chain reaction; PFU=plaque-forming unit; PM=post meridiem (after midday); Q12H=every 12 hours; RSV=respiratory syncytial virus.
The classification of IMP and NIMP in this table is based on guidance issued by the European Commission and applies to countries in the EEA. Country differences with respect to the 
definition/classification of IMP/NIMP may exist. In these circumstances, local legislation is followed.
Prophylaxis dose Active MK-4482 begins on PM of D -1 and continues for a total of 10 doses over a 5-day period. Dosing with PBO is provided on the remaining days following Active MK-4482. 
Triggered dose Active MK-4482 begins 12 hours following detection of RSV infection on nasal wash PCR, as early as D2 PM, and continues for a total of 10 doses over a 5-day period. If RSV infection 
is not detected by D5 AM, the participant is assigned to begin dosing Active MK-4482 on D5 PM for a total of 10 doses over a 5-day period. Dosing with PBO is provided on the remaining days before 
and after Active MK-4482 to span D-1 to D10.
The challenge virus will be prepared to have an inoculum concentration of between 3.5 Log10 PFU/mL and 5 Log10 PFU/mL. The details will be outlined in the Analytical Plan). 
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Table 3
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.
A sample allocation schedule is shown in Table 4.
Table 4
Sample Allocation Schedule of Participants to Treatment
Panel
Panel 
Description
Number of 
Participants
Treatment
A
Prophylactic 
Dosing
35
800-mg MOV Q12H for 5 days (10 doses) 
starting on Day -1 then matching PBO 
Q12H for 6 days from Day 4 through Day 
10 am
B
Triggered
Dosing
35
Matching PBO starting on Day -1 Q12H 
until seropositive then 800-mg MOV 
Q12H for 5 days (10 doses).a,b Then,
matching PBO Q12H through Day 10 am
(if needed)
C
Matched Placebo
35
Matching PBO Q12H for 11 days
am=ante meridiem (before midday); MOV=molnupiravir; PBO=placebo; Q12H=every 12 hours
a If participant’s serostatus does not convert by Day 5, MOV dosing will automatically commence. 
b PBO administered on alternate days to maintain participant blinding.
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 and placebo will be prepared and/or 
dispensed in a blinded fashion by an unblinded pharmacist or qualified study-site personnel. 
The participant, the investigator, and Sponsor personnel or delegate(s) who are involved in 
the study intervention administration or clinical evaluation of the participants are unaware of 
the intervention assignments.
6.4
Study Intervention Compliance
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.
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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/first 
dosing with IMP (whichever occurs first) or planned during the 3 months after the 
final visit.
−
Chronic administration (defined as more than 14 continuous days) of an 
immunosuppressant or other immune-modifying drug within 6 months prior to dose 
administration and through poststudy visit (Day 28). 
−
Medication or product (prescription or over-the-counter) for symptoms of nasal 
congestion or respiratory tract infection during the impatient quarantine visit. 
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
•
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.
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6.6
Dose Modification (Escalation/Titration/Other)
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 
concerns have been reported following Human Viral Inoculation (expectedness will 
be assessed by referring to the inoculation virus dossier). 
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 
8.1.10). The Sponsor will not provide random code/disclosure envelopes or lists with the 
clinical supplies.
See Section 8.1.10 for a description of the method of unblinding a participant during the 
study, should such action be warranted. 
6.9
Standard Policies
Not applicable for this study. 
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 
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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 UDS at any time during the course of the study prior to the 
final follow up study visit. The drug screen can be confirmed by a recheck at the 
discretion of the investigator after discussion with the Sponsor.
A participant must be discontinued prior to inoculation but continue to be monitored in the 
study for any of the following reasons:
•
Positive human immunodeficiency virus (HIV), B (HBV), or C (HCV) test within 
60 days of inoculation.
•
Any clinically significant epistaxis (large nosebleeds) from signing the study-specific 
consent to admission to quarantine. 
•
Any nasal or sinus surgery from signing the study-specific to admission to quarantine.
•
Presence of fever (≥37.9C) following admission to the quarantine unit and prior to 
inoculation. 
•
History or currently active symptoms suggestive of upper or lower respiratory tract 
infection within 4 weeks prior quarantine admission. 
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•
Use of herbal supplements within 7 days prior to inoculation unless in the opinion of the 
PI, the supplements will not interfere with the study procedures or compromise 
participant safety.
•
Use of over the counter medications (eg, paracetamol or ibuprofen) where the dose taken 
over the preceding 7 days prior to the planned date of Viral Inoculation has exceeded the 
maximum permissible 24-hour dose (eg ≥4 g paracetamol over the preceding week), 
unless in the opinion of the PI, the medication will not interfere with the study procedures 
or compromise participant safety. 
•
In the opinion of the investigator, the participant is no longer able to comply with the 
protocol and requirements of the inpatient stay.
7.2
Participant Withdrawal From the Study
Participants may withdraw from the study at any time for any reason. If a participant 
withdraws from the study, they will no longer receive study intervention or be followed at 
scheduled protocol visits.
A participant must be withdrawn from the study if:
•
The participant or participant’s legally acceptable representative withdraws consent from 
the study.
Specific details regarding procedures to be performed at the time of withdrawal from the 
study, as well as specific details regarding withdrawal from FBR, are outlined in Section 
8.1.9. The procedures to be performed should a participant repeatedly fail to return for 
scheduled visits and/or if the study site is unable to contact the participant are outlined in
Section 7.3.
7.3
Lost to Follow-up
If a participant fails to return to the clinic for a required study visit and/or if the site is unable 
to contact the participant, the following procedures are to be performed:
•
The site must attempt to contact the participant and reschedule the missed visit. If the 
participant is contacted, the participant should be counseled on the importance of 
maintaining the protocol-specified visit schedule.
•
The investigator or designee must make every effort to regain contact with the participant 
at each missed visit (eg, telephone calls and/or a certified letter to the participant’s last 
known mailing address or locally equivalent methods). These contact attempts should be 
documented in the participant’s medical record.
•
Note: A participant is not considered lost to follow-up until the last scheduled visit for the 
individual participant. The missing data for the participant will be managed via the 
prespecified statistical data handling and analysis guidelines.
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8
STUDY ASSESSMENTS AND PROCEDURES
•
Study procedures and their timing are summarized in the SoA.
•
Adherence to the study design requirements, including those specified in the SoA, is 
essential and required for study conduct.
•
The investigator is responsible for ensuring that procedures are conducted by 
appropriately qualified (by education, training, and experience) staff. Delegation of 
study-site personnel responsibilities will be documented in the Investigator Trial File 
Binder (or equivalent).
•
All study-related medical decisions must be made by an investigator who is a qualified 
physician.
•
All screening evaluations must be completed and reviewed to confirm that potential 
participants meet all eligibility criteria. The investigator will maintain a screening log to 
record details of all participants screened and to confirm eligibility or record reasons for 
screening failure, as applicable.
•
Procedures conducted as part of the participant’s routine clinical management (eg, blood 
count) and obtained before signing of ICF may be used for screening or baseline purposes 
provided the procedure met the protocol-specified criteria and were performed within the 
time frame defined in the SoA.
•
Additional evaluations/testing may be deemed necessary by the investigator and or the 
Sponsor for reasons related to participant safety. In some cases, such evaluation/testing 
may be potentially sensitive in nature (eg, HIV, hepatitis C), and thus local regulations 
may require that additional informed consent be obtained from the participant. In these 
cases, such evaluations/testing will be performed in accordance with those regulations.
•
The maximum volume of blood collected from each participant over the duration of the 
study (ie, from screening through final follow-up visit) will not exceed ~ 189.2 mL. 
Repeat or unscheduled samples may be taken for safety reasons or for technical issues 
with the samples. If additional samples are required in excess of this amount, eg, to 
monitor laboratory abnormalities, these will be taken at the discretion of the 
PI/investigator
Repeat or unscheduled samples may be taken for safety reasons or for technical issues with 
the samples.
8.1
Administrative and General Procedures
8.1.1
Informed Consent
The investigator or medically qualified designee (consistent with local requirements) must 
obtain documented informed consent from each potential participant (or their legally 
acceptable representative) prior to participating in this clinical study or FBR. If there are 
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changes to the participant’s status during the study (eg, health or age of majority 
requirements), the investigator or medically qualified designee must ensure the appropriate 
documented informed consent is in place.
8.1.1.1
General Informed Consent
Informed consent given by the participant or their legally acceptable representative must be 
documented on a consent form. The form must include the study protocol number, study 
protocol title, dated signature, and agreement of the participant (or his/her legally acceptable 
representative) and of the person conducting the consent discussion.
A copy of the signed and dated informed consent form should be given to the participant (or 
their legally acceptable representative) before participation in the study.
The initial ICF, any subsequent revised ICF, and any written information provided to the 
participant must receive the IRB/IEC’s approval/favorable opinion in advance of use. The 
participant or his/her legally acceptable representative should be informed in a timely manner 
if new information becomes available that may be relevant to the participant’s willingness to 
continue participation in the study. The communication of this information will be provided 
and documented via a revised consent form or addendum to the original consent form that 
captures the participant’s or the participant’s legally acceptable representative’s dated 
signature.
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.
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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-2) until 
discharge from the site (Day 12). The investigator or qualified designee will provide the 
participant with a participant identification card at the time of discharge form 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
Prior and Concomitant Medications Review
8.1.5.1
Prior Medications
The investigator or qualified designee will review prior medication use, including any 
protocol-specified washout requirement, and record prior medication taken by the participant 
within 14 days before starting the study.
8.1.5.2
Concomitant Medications
The investigator or qualified designee will record medication, if any, taken by the participant 
during the study.
8.1.6
Assignment of Screening Number
All consented participants will be given a unique screening number that will be used to 
identify the participant for all procedures that occur before randomization. Each participant 
will be assigned only 1 screening number. Screening numbers must not be reused for 
different participants.
8.1.7
Assignment of Treatment/Randomization Number
All eligible participants will be randomly allocated and will receive a 
treatment/randomization number. The treatment/randomization number identifies the 
participant for all procedures occurring after treatment allocation/randomization. Once a 
treatment/randomization number is assigned to a participant, it can never be reassigned to 
another participant.
A single participant cannot be assigned more than 1 treatment/randomization number.
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In a situation where rerandomization of the participants is planned (eg, study extension 
periods), the rerandomization will be based on a new randomization schedule; however, each 
participant will retain his/her original treatment/randomization number. Only the study 
intervention regimen associated with the rerandomization period or phase may change.
8.1.8
Study Intervention Administration
Study intervention(s) will be administered by the investigator and/or study staff according to 
the specifications within the pharmacy manual.
Study medication will be administered by unblinded study staff, as described in the pharmacy 
manual.
8.1.8.1
Timing of Dose Administration
Day -1 dose of MOV or placebo will be administered in the PM. All subsequent doses of 
MOV or placebo will be given in the morning and evening (ie, Q12H) on Days 0 through 
Day 10 am, at approximately the same time each day.
8.1.9
Discontinuation and Withdrawal
The investigator or study coordinator must notify the Sponsor when a participant has been 
discontinued/withdrawn from the study . If a participant discontinues for any reason at any 
time during the course of the study 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 8.5.1, the investigator should perform a follow-up telephone 
call at the end of the follow-up period ( Section 8.5.1) to confirm if any AEs have occurred 
since the poststudy clinic visit. Any AEs that are present at the time of 
discontinuation/withdrawal should be followed in accordance with the safety requirements 
outlined in Section 8.4.
8.1.9.1
Withdrawal From Future Biomedical Research
Participants may withdraw their consent for FBR. Participants may withdraw consent at any 
time by contacting the study investigator. If medical records for the study are still available, 
the investigator will contact the Sponsor using the designated mailbox 
(clinical.specimen.management@MSD.com). Subsequently, the participant’s consent for 
FBR will be withdrawn. A letter will be sent from the Sponsor to the investigator confirming 
the withdrawal. It is the responsibility of the investigator to inform the participant of 
completion of withdrawal. Any analyses in progress at the time of request for withdrawal or 
already performed before the request being received by the Sponsor will continue to be used 
as part of the overall research study data and results. No new analyses would be generated 
after the request is received.
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If the medical records for the study are no longer available (eg, if the investigator is no longer 
required by regulatory authorities to retain the study records) or the specimens have been 
completely anonymized, there will no longer be a link between the participant’s personal 
information and their specimens. In this situation, the request for specimen withdrawal 
cannot be processed.
8.1.10
Participant Blinding/Unblinding
STUDY INTERVENTION IDENTIFICATION INFORMATION IS TO BE UNMASKED 
ONLY IF NECESSARY FOR THE WELFARE OF THE PARTICIPANT. EVERY 
EFFORT SHOULD BE MADE NOT TO UNBLIND.
For emergency situations where the investigator or medically qualified designee (consistent 
with local requirements) needs to identify the intervention used by a participant and/or the 
dosage administered, he/she will contact the emergency unblinding call center by telephone 
and make a request for emergency unblinding. As requested by the investigator or medically 
qualified designee, the emergency unblinding call center will provide the information to 
him/her promptly and report unblinding to the Sponsor. Before contacting the emergency 
unblinding call center to request unblinding of a participant’s intervention assignment, the 
investigator who is 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.
8.1.11
Domiciling
Participants will report to the CRU on either Day -3 or Day -2 before the scheduled day of 
study intervention administration on Day -1 and remain in the unit until Day 12. At the 
discretion of the investigator, participants may be requested to remain in the CRU longer. 
Participants may leave the unit, for emergency situations or if this is the wish of the 
participant, during the domiciling period. The CRU will notify the Sponsor and the decision 
on how to monitor the participant will be at the discretion of the investigator after discussion 
with the Sponsor.
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8.1.12
Calibration of Equipment
The investigator or qualified designee has the responsibility to ensure that any device or 
instrument used for a clinical evaluation/test during a clinical study that provides information 
about inclusion/exclusion criteria and/or safety or efficacy parameters shall be suitably 
calibrated and/or maintained to ensure that the data obtained are reliable and/or reproducible. 
Documentation of equipment calibration must be retained as source documentation at the 
study site.
8.2
Intranasal Administration of the Challenge Virus
The challenge agent used in this study is RSV A Memphis 37b.
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 hVIVO AP and 
administered in accordance with hVIVO 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 PI/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.
8.3
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.
8.3.1
RSV 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 
hVIVO SDC. This information will be collected using a paper form.
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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.
Previous studies with RSV A Memphis 37b have used a 10-item symptom questionnaire. The 
10 symptoms out of the 13 listed above will be used for the primary analysis, and excludes 
the following 3 symptoms that may be additionally explored separately:

Chilliness/feverishness

Chest tightness

Wheeze
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8.3.2
Nasal Wash for RSV Virology
During the quarantine period, experienced site staff will collect nasal wash samples from
each participant following inoculation with RSV, as specified in the SoA (Section 1.3). 
Instructions for receipt, storage, and handling/shipment of nasal wash specimen and testing 
for RSV by PCR and plaque assay are provided in the AP.
Nasal wash samples will be collected twice daily from Day 2 through Day 11. From Study 
Day 2 to Study Day 11, nasal wash sample collections will occur 12 hours apart ± 1 hour. A 
single nasal wash sample will be collected on Day 12.
8.3.3
Nasopharyngeal Swab
Nasopharyngeal swabs will be performed to collect samples of epithelial lining fluid for: 
−
Respiratory pathogen screen
Where required, a rapid viral antigen test will be used to determine the presence of RSV in a 
nasopharyngeal swab sample taken prior to discharge from the quarantine unit on Day 12. A 
PCR test may be used as an alternative test for this purpose, details of which will be 
documented in the AP. 
A rapid viral antigen test/PCR test will be performed at the discretion of the PI/investigator 
and only if indicated for a clinical or other reason
8.4
Safety Assessments
Details regarding specific safety procedures/assessments to be performed in this study are 
provided. The total amount of blood/tissue to be drawn/collected over the course of the study 
(from prestudy to poststudy visits), including approximate blood/tissue 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.
8.4.1
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.
A brief directed physical examination, including nasal exam, will be conducted at the 
discretion of the investigator by an investigator or medically qualified designee (consistent 
with local requirements) per institutional standard.
Investigators should pay special attention to clinical signs related to previous serious 
illnesses.
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BMI
BMI equals a person's weight in kilograms divided by height in meters squared 
(BMI=kg/m2). BMI will be rounded to the nearest whole number according to the standard 
convention of 0.1 to 0.4 round down and 0.5 to 0.9 round up.
Body weight and height will be obtained with the participant’s shoes off and jacket or coat 
removed.
8.4.2
Vital Signs
•
Tympanic temperature, pulse rate, respiratory rate, O2 saturation, and BP will be 
assessed.
•
BP and pulse measurements will be assessed with a completely automated device. 
Manual techniques will be used only if an automated device is not available.
•
VS are to be taken before blood collection for laboratory tests.
8.4.2.1
Resting Vital Signs
Vital Sign Measurements (Heart Rate and Blood Pressure)
Participants should be resting in a quiet setting without distractions in a semirecumbent 
position for at least 5 minutes before having VS measurements obtained. Semirecumbent VS 
will include HR, systolic and diastolic BP, RR, and body temperature at timepoints indicated 
in the SoA. The correct size of the BP cuff and the correct positioning on the participants' 
arm is essential to increase the accuracy of BP measurements. Note that Screening vital signs 
only may be conducted in a supine as per site SOP. 
Upon admission to the CRU, on Day -1 and Day 28, HR and BP will be triplicate 
measurements obtained within a 10-minute period and the median of the three measurements 
will be used to assess for participant eligibility. This may be repeated at the discretion of the 
study investigator.
The predose (baseline) HR and BP will be triplicate measurements prior to the first dose of 
MK-4482/placebo only, obtained at least 1 to 2 minutes apart within 3 hours of dosing MK-
4482/placebo. The median of these measurements will be used as the baseline to calculate 
change from baseline for safety evaluations (and for rechecks, if needed). Postdose VS 
measurements will be single measurements except for the Day 28 Poststudy measurement 
which will be in triplicate.
Participants will continue to rest semirecumbent following the am dose until 4 hours post the 
am dose on full PK sampling days only except to stand for other study related procedures, if 
required, per the SoA.
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Body Temperature
Body temperature will be measured. The same method must be used for all measurements for 
each individual participant and should be the same for all participants.
8.4.3
Electrocardiograms
•
12-lead ECG will be obtained and reviewed by an investigator or medically qualified 
designee (consistent with local requirements) as outlined in the SoA 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 the semirecumbent for at least 10 minutes before each ECG 
measurement.
The correction formula to be used for QTc is Fridericia.
If repeat ECGs are required, the clinical site will decide whether to leave the electrodes in 
place or mark the position of the electrodes for subsequent ECGs. To mark the position of the 
electrodes, 12-lead electrode sites will be marked on the skin of each participant with an 
ECG skin-marker pen to ensure reproducible electrode placement.
Predose ECGs will be single measurements obtained within 3 hours before dosing MK-
4482/placebo. The median of these measurements will be used as the baseline to calculate 
change from baseline for safety evaluations (and for rechecks, if needed).
During the treatment period, if a participant demonstrates an increase in QTc interval 
≥60 msec compared with median predose baseline measurement, the ECG will be repeated 
twice within 5 minutes. The median value of the QTc interval from the 3 ECGs will represent 
the value at that time point. If the median QTc interval increase from baseline for any 
postdose time point is ≥60 msec, the participant will continue to be monitored by repeat 12-
lead ECGs every 15 minutes for at least 1 hour or until the QTc is within 60 msec of 
baseline. If prolongation of the QTc interval ≥60 msec persists, a consultation with a study 
cardiologist may be appropriate and the Sponsor should be notified.
During the treatment period, if a participant demonstrates a QTc interval ≥500 msec on a 
postdose ECG, the ECG will be repeated twice within 5 minutes. The median value of the 
QTc interval from the 3 ECGs will represent the value at that time point. If the median QTc 
interval is ≥500 msec, the Sponsor should be notified and the ECGs should be reviewed by a 
cardiologist. The participant should be considered for transfer to a location where closer
monitoring and definitive care (eg, a CCU or ICU) is available.
Postdose ECG measurements will be single measurements.
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If the participant has unstable hemodynamics, or has any clinically significant dysrhythmias 
noted on telemetry, the participant should be immediately transferred to an acute care setting 
for definitive therapy.
If prolongation of the QTc is noted, concomitant medications that prolong QTc should be 
held until the QTc is within 60 msec of baseline and the QTc is <500 msec.
A cardiologist will be consulted by the investigator as needed to review ECG tracings with 
significant abnormalities.
8.4.4
Clinical Safety Laboratory Assessments
Refer to Appendix 2 for the list of clinical laboratory tests to be performed and to the SoA for 
the timing and frequency.
•
The investigator or medically qualified designee (consistent with local requirements) 
must review the laboratory report, document this review, and record any clinically 
relevant changes occurring during the study in the AE section of the CRF. The laboratory 
reports must be filed with the source documents. Clinically significant abnormal 
laboratory findings are those which are not associated with the underlying disease, unless 
judged by the investigator to be more severe than expected for the participant’s condition.
•
All protocol-required laboratory assessments, as defined in Appendix 2, must be 
conducted in accordance with the laboratory manual and the SoA.
•
If laboratory values from nonprotocol-specified laboratory assessments performed at the 
institution’s local laboratory require a change in study participant management or are 
considered clinically significant by the investigator (eg, SAE or AE or dose 
modification), then the results must be recorded in the appropriate CRF (eg, SLAB).
•
For any laboratory tests with values considered clinically significantly abnormal during 
participation in the study or within 14 days after the last dose of study intervention, every 
attempt should be made to perform repeat assessments until the values return to normal or 
baseline or if a new baseline is established as determined by the investigator.
8.4.5
Pregnancy Testing
•
Pregnancy testing:
-
Pregnancy testing requirements for study inclusion are described in Section 5.1.
-
Pregnancy testing (urine), as required by local regulation, should be conducted at the 
poststudy visit. 
Additional serum or urine pregnancy tests may be performed, as determined 
necessary by the investigator or required by local regulation, to establish the absence 
of pregnancy at any time during the subject's participation in the study.
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8.4.6
Photograph of Rash
Where possible, photographs of the rash are highly recommended to be taken immediately, 
along with any additional information that may assist the investigator to evaluate the skin 
reaction, skin eruption or rash occurrence in determining etiology and drug relationship.
8.5
Adverse Events, Serious Adverse Events, and Other Reportable Safety Events
The definitions of an AE or SAE, as well as the method of recording, evaluating, and 
assessing causality of AE and SAE and the procedures for completing and transmitting AE, 
SAE, and other reportable safety event reports can be found in Appendix 3.
Adverse events, SAEs, and other reportable safety events will be reported by the participant 
(or, when appropriate, by a caregiver, surrogate, or the participant's legally authorized 
representative).
The investigator and any designees are responsible for detecting, documenting, and reporting 
events that meet the definition of an AE or SAE as well as other reportable safety events. 
Investigators remain responsible for following up AEs, SAEs, and other reportable safety 
events for outcome according to Section 8.4.3.
The investigator, who is a qualified physician, will assess events that meet the definition of 
an AE or SAE as well as other reportable safety events with respect to seriousness, 
intensity/toxicity and causality.
8.5.1
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 14 days after cessation of 
intervention, all AEs, SAEs and other reportable safety events must be reported by the 
investigator.
Additionally, any SAE brought to the attention of an investigator any time outside the period 
specified in the previous paragraph also must be reported immediately to the Sponsor if the 
event is considered related to study intervention.
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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 5.
Exception: A positive pregnancy test at the time of initial screening is not a reportable event 
unless the participant has received study intervention.
Table 5
Reporting Time Periods and Time Frames for Adverse Events and Other 
Reportable Safety Events
Type of Event
Reporting Time 
Period:
Consent to 
Randomization/ 
Allocation
Reporting Time 
Period:
Randomization/ 
Allocation 
through 
Protocol-
specified 
Follow-up 
Period
Reporting Time 
Period:
After the Protocol-
specified Follow-up 
Period
Time Frame to 
Report Event and 
Follow-up 
Information to 
Sponsor:
NSAE
Report if:
- due to protocol-
specified 
intervention
- causes 
exclusion
- participant is 
receiving placebo 
run-in or other 
run-in treatment
Report all
Not required
Per data entry 
guidelines
SAE
Report if:
- due to protocol-
specified 
intervention
- causes 
exclusion
- participant is 
receiving placebo 
run-in or other 
run-in treatment
Report all
Report if:
- drug/vaccine related.
(Follow ongoing to 
outcome)
Within 24 hours of 
learning of event
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Type of Event
Reporting Time 
Period:
Consent to 
Randomization/ 
Allocation
Reporting Time 
Period:
Randomization/ 
Allocation 
through 
Protocol-
specified 
Follow-up 
Period
Reporting Time 
Period:
After the Protocol-
specified Follow-up 
Period
Time Frame to 
Report Event and 
Follow-up 
Information to 
Sponsor:
Pregnancy/
Lactation 
Exposure
Report if:
- participant has 
been exposed to 
any protocol-
specified 
intervention (eg, 
procedure, 
washout or run-
in treatment 
including 
placebo run-in)
Exception: A 
positive 
pregnancy test at 
the time of initial 
screening is not a 
reportable event.
Report all
Previously reported –
Follow to completion/
termination; report 
outcome
Within 24 hours of 
learning of event
ECI (require 
regulatory 
reporting)
Report if:
- due to 
intervention
- causes 
exclusion
Report
- potential DILI
- require 
regulatory 
reporting
Not required
Within 24 hours of 
learning of event
ECI (do not 
require regulatory 
reporting)
Report if:
- due to 
intervention
- causes 
exclusion
Report
- non-DILI ECIs 
and those not 
requiring 
regulatory 
reporting
Not required
Within 5 calendar 
days of learning of 
event
Cancer
Report if:
- due to 
intervention
- causes 
exclusion
Report all
Not required
Within 5 calendar 
days of learning of 
event
(unless serious)
Overdose
Report if:
- receiving 
placebo run-in or 
other run-in 
medication 
Report all
Not required
Within 24 hours of 
learning of event
DILI=drug-induced liver injury; ECI=event of clinical interest; NSAE=nonserious adverse event; SAE=serious adverse 
event.
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8.5.2
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.
8.5.3
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.
8.5.4
Regulatory Reporting Requirements for SAE
Prompt notification (within 24 hours) by the investigator to the Sponsor of SAE is essential 
so that legal obligations and ethical responsibilities towards the safety of participants and the 
safety of a study intervention under clinical investigation are met.
The Sponsor has a legal responsibility to notify both the local regulatory authority and other 
regulatory agencies about the safety of a study intervention under clinical investigation. The 
Sponsor will comply with country-specific regulatory requirements and global laws and 
regulations relating to safety reporting to regulatory authorities, IRB/IECs, and investigators.
Investigator safety reports must be prepared for SUSARs according to local regulatory 
requirements and Sponsor policy and forwarded to investigators as necessary.
An investigator who receives an investigator safety report describing an SAE or other 
specific safety information (eg, summary or listing of SAE) from the Sponsor will file it 
along with the IB and will notify the IRB/IEC, if appropriate according to local requirements.
8.5.5
Pregnancy and Exposure During Breastfeeding
Although pregnancy and infant exposure during breastfeeding are not considered AEs, any 
pregnancy or infant exposure during breastfeeding in a participant (spontaneously reported to 
the investigator or their designee) that occurs during the study are reportable to the Sponsor.
All reported pregnancies must be followed to the completion/termination of the pregnancy.
Any pregnancy complication will be reported as an AE or SAE.
The medical reason (example: maternal health or fetal disease) for an elective termination of 
a pregnancy will be reported as an AE or SAE. Prenatal testing showing fetus will be born 
with severe abnormalities/congenital anomalies that leads to an elective termination of a 
pregnancy will be reported as an SAE for the fetus.
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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.
8.5.6
Disease-related Events and/or Disease-related Outcomes Not Qualifying as 
AEs or SAEs
Not applicable for this study. 
8.5.7
Events of Clinical Interest
Selected serious and nonserious AEs are also known as ECIs and must be reported to the 
Sponsor.
Events of clinical interest for this study include:
1. An overdose of Sponsor's product, as defined in Section 8.5.
2. An elevated AST or ALT laboratory value that is greater than or equal to 3X the ULN 
and an elevated total bilirubin laboratory value that is greater than or equal to 2X the 
ULN and, at the same time, an alkaline phosphatase laboratory value that is less than 2X 
the ULN, as determined by way of protocol-specified laboratory testing or unscheduled
laboratory testing.*
*Note: These criteria are based on available regulatory guidance documents. The purpose 
of the criteria is to specify a threshold of abnormal hepatic tests that may require an 
additional evaluation for an underlying etiology. The study-site guidance for assessment 
and follow up of these criteria can be found in the Investigator Study File Binder (or 
equivalent).
It may also be appropriate to conduct additional evaluation for an underlying etiology in the 
setting of abnormalities of liver blood tests including AST, ALT, bilirubin, and alkaline 
phosphatase that do not meet the criteria noted above. In these cases, the decision to proceed 
with additional evaluation will be made through consultation between the study investigators 
and the Sponsor Clinical Director. However, abnormalities of liver blood tests that do not 
meet the criteria noted above are not ECIs for this study.
8.6
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.
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.
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8.7
Pharmacokinetics
The decision as to which plasma and/or PBMC 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. 
8.7.1
Blood Collection for Plasma NHC and/or Metabolites Assay
Sample collection, storage, and shipment instructions for plasma samples will be provided in 
the Study Operations Manual. 
8.7.2
Blood Collection for PBMC NHC-TP and/or Metabolites Assay
Sample collection, storage, and shipment instructions for plasma samples will be provided in 
the Study Operations Manual and/or AP. 
8.8
Pharmacodynamics
The virologic endpoints (as described in Sec. 3) will be used to evaluate any 
pharmacokinetic/ pharmacodynamic relationships for NHC and/or NHC-TP.
8.9
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
8.9.1
Planned Genetic Analysis Sample Collection
The planned genetic analysis sample should be drawn for planned analysis of the association 
between genetic variants in DNA and drug response. This sample will not be collected at the 
site if there is either a local law or regulation prohibiting collection, or if the IRB/IEC does 
not approve the collection of the sample for these purposes. If the sample is collected, 
leftover extracted DNA will be stored for FBR if the participant provides documented 
informed consent for FBR. If the planned genetic analysis is not approved, but FBR is 
approved and consent is given, 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.
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8.10
Future Biomedical Research Sample Collection
If the participant provides documented informed consent for FBR, the following specimens 
will be obtained as part of FBR:

Leftover DNA for future research
8.11
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.
8.12
Visit Requirements
Visit requirements are outlined in Section 1.3. Specific procedure-related details are provided 
in Section 8.
8.12.1
Screening
Participants will be screened under the hVIVO generic screening process. Participants who 
fulfill inclusion and exclusion criteria for this study through the hVIVO generic screening 
process, including being serosuitable within 90 days and having normal or not clinically 
significant laboratory safety data within 56 days, will be invited for admission to the 
quarantine unit on Day -3/-2. 
Upon admission, inclusion/exclusion will be confirmed prior to randomization. A protocol 
specific consent form will be signed prior to randomization on Day 1. 
8.12.2
Treatment Period
Participants will be randomized and dosed at the study site on Day -1 as set forth in the SoA 
and Section 6. 
On Day -1, after all predose procedures have been completed, participants will be assigned a 
unique randomization number associated with a specific treatment as defined by a computer-
generated allocation schedule. 
Participants will be administered study drug as indicated in Section 6. Participants on Day -1 
who have an acute illness or fever prior to the administration of study drug 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 of the first screening). 
8.12.3
Intranasal RSV Inoculation Period
On Day -1, participants will be administered either MK-4482 or placebo. On Day 0, 
participants will be inoculated with RSV A Memphis 37b strain. Participants will undergo a 
nasal wash procedure every 12 hours for RSV viral load testing. Approximately 12 hours 
following a positive PCR test for RSV on the wash sample, participants will begin dosing 
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with 800-mg MK-4482 every 12 hours for 5 days. A detailed description of the preparation 
and administration of RSV is provided in the Procedures Manual and/or the AP. The trial site 
will be responsible for recording the lot number, manufacturer, and expiry date of applicable 
supplies related to RSV administration.
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-year-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;
9. Anyone who has had a bone marrow or solid organ transplant;
10. Women who are pregnant or trying to become pregnant
8.12.4
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.
8.12.5
Poststudy
Participants will be required to return to clinic approximately 28 days after the last dose of 
study intervention for the poststudy visit. If the poststudy visit occurs less than 28 days after 
the last dose of study intervention, a subsequent follow-up telephone call should be made at 
28 days post the last dose of study intervention to determine if any AEs have occurred since 
the poststudy clinic visit.
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8.12.6
Critical Procedures Based on Study Objectives: Timing of Procedure
For this study, the blood sample for plasma NHC and/or metabolites assay is the critical 
procedure.
At any postdose time point, the blood sample for NHC and/or metabolites assay needs to be 
collected as close to the exact time point as possible. All other procedures should be 
completed as close to the prescribed/scheduled time as possible. Study procedures can be 
performed before or after the prescribed/scheduled time.
The order of priority can be changed during the study with joint agreement of the investigator 
and the Sponsor Clinical Director.
Any nonscheduled procedures required for urgent evaluation of safety concerns take 
precedence over all routine scheduled procedures.
The following variance in procedure collection times will be permitted.
•
Screening 2 procedures: up to additional 4 hours of scheduled time
•
Plasma NHC and/or metabolites PK samples collection windows are outlined in Table 6.
PBMC NHC-TP and/or metabolites PK sample collection windows are as outlined in Table 7
Table 6
Pharmacokinetic (Blood for Plasma NHC and/or Metabolites Assay) Collection 
Windows
Plasma NHC PK Collection
Collection Window
Predose (Day -1)
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 h
15 min
PK collection windows are +/- relative to the AM dose on the respective day, with the exception of the 
Day -1 sampling, which occurs following the PM dose.
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Table 7
Pharmacokinetic (Blood for PBMC NHC-TP and/or Metabolites Assay) 
Collection Windows 
PBMC NHC-TP PK Collection
Collection Window
Predose (Day -1)
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
10 min
12 h
15 min
PK collection windows are +/- relative to the AM dose on the respective day, with the exception of the 
Day -1 sampling, which occurs following the PM dose.
•
Predose standard safety evaluations: VS and ECG at 3 hours; laboratory safety tests and 
physical exam at 24 hours
•
Postdose standard safety evaluations: VS, ECG, laboratory safety tests, and physical 
exam
-
Starting Day 1, postdose evaluations may be obtained within +/- 1 hour of the 
theoretical sampling time
•
Study intervention administration (multiple dose studies only): at 30 minutes.
8.12.7
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.
•
Decrease in the dose of the study intervention 
•
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/pharmacodynamic sample processing and shipping details based 
on newly available data
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The PK/pharmacodynamic 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 pharmacodynamic 
markers.
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 or urine samples may be taken for laboratory safety tests or other tests, 
such as measurement for PK analysis. Any additional urine collections may include 
continuous, total collections, if necessary. Up to an additional 50 mL of blood may be 
drawn for safety, PK, and/or pharmacodynamic analyses. The total blood volume 
withdrawn from any single participant will not exceed the maximum allowable volume 
during his/her participation in the entire study (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 or urine 
samples, or extra pharmacodynamic 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.
9
STATISTICAL ANALYSIS PLAN
9.1
Statistical Analysis Plan Summary
This section contains a brief summary of the statistical analyses for this study. Full detail is 
in the SAP (Section 9.2 to 9.9). The additional statistical analysis details/data derivations,
including exploratory analyses and subgroup analyses may be documented in a sSAP, if 
applicable.
Method:
Safety
AEs will be tabulated and descriptively summarized. Summary statistics and plots will be 
generated for raw laboratory safety tests, ECGs, and/or VS as well as for change from 
baseline, as deemed clinically appropriate. Depending on the safety parameter, the difference 
from baseline will either be computed on the original scale (raw change from baseline) or on 
the log scale and back-transformed for reporting (percent change from baseline).
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Efficacy
Prophylaxis:
Only Panel A (prophylaxis) and Panel C (placebo) will be included in the model.
PVL (on the log10 scale) of RSV A Memphis 37b determined by viral quantitative culture 
(plaque assay) between Day 2 and Day 12 am after intranasal inoculation (Day 0) will be 
analyzed using a linear model with treatment group as a fixed categorical effect. The mean 
PVL in each group and the differences in mean PVL between MK-4482 and placebo and the 
corresponding 2-sided 95% CI will be computed based on the model. 
Treatment:
Only Panel B (treatment) and Panel C (placebo) will be included in the model. For both 
panels, only the participants with RSV infection will be included.
VL-AUC (on the log10 scale) determined by viral quantitative culture (plaque assay) from 
initial triggered administration of MK-4482/placebo, through Day 12 am (inclusive) after 
viral inoculation (Day 0) will be analyzed using a linear model with treatment group as a 
fixed categorical effect. The mean VL-AUC in each group and the differences in mean VL-
AUC between MK-4482 and placebo and the corresponding 2-sided 95% CI will be 
computed based on the model. 
For both prophylaxis and treatment arm, if the assumptions of a linear model are not met, an 
alternative method, such as Wilcoxon-Rank-Sum test will be applied. 
Power:
105 participants will be randomized and dosed with MK-4482 or placebo. 35 per panel will 
be administered the intranasal RSV A Memphis 37b inoculation, complete the follow up and 
sample collection through Day 12 am post inoculation.
The primary hypothesis:
The assumed CV in VL-AUC or PVL as well as infection rate of 61% (based on a single 
quantitative plaque assay positive from Day 2 to Day 12) were obtained from previous 
published and unpublished RSV challenge studies conducted by hVIVO (Vendor contracted 
to perform the study) and all based on log10 pfu /mL. The evaluable sample size is assumed 
to be 35 per group with expected dropout rate of 2 (~ 5% out of 33).
For prophylaxis, with a sample size of 33 per group, there is ~ 80.9% power to detect a 
decrease in PVL of 65% (on the log10 scale) in MK-4482 group vs the placebo group 
assuming a CV in PVL of 0.917 with a 2-sided alpha=0.05 test. 
For treatment, with a sample size of 19 that test positive per group, there is ~ 80.5% power to
detect a decrease in VL-AUC of 70% (on the log10 scale) in MK-4482 group vs the placebo 
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group assuming a CV in VL-AUC of 0.767 with a 2-sided alpha=0.05 test. Considering the 
infection rate of 61%, a sample size of 31 per group will maintain 80% power.
9.2
Responsibility for Analyses
The statistical analysis of the data obtained from this study will be conducted by, or under the 
direct auspices of, the Early Clinical Development Statistics Department in collaboration 
with the Quantitative Pharmacology and Pharmacometrics Department and Translational 
Medicine 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.
9.3
Hypotheses/Estimation
To determine if MK-4482 (800 mg Q12 x 5 days) results in a reduction in viral load after 
intranasal inoculation (with RSV A Memphis 37b) compared to placebo.
Hypothesis (Prophylaxis): MK-4482 (800 mg Q12 x 5 days), when administered to begin 
prior to intranasal inoculation with respiratory syncytial virus (RSV-A Memphis 37b), 
reduces the Peak Viral Load (PVL) after viral inoculation compared to placebo. 
Hypothesis (Treatment): MK-4482 (800 mg Q12 x 5 days), when administered following 
infection with respiratory syncytial virus (RSV-A Memphis 37b), reduces the Area Under the 
Viral-Load-time (VL-AUC) after MK-4482 administration compared to placebo.
9.4
Analysis Endpoints
Primary Endpoints:
Prophylaxis: PVL as defined by the maximum viral load determined by viral quantitative 
culture (plaque assay) starting from Day 2 up to planned discharge from quarantine (Day 12
am) 
Treatment: VL-AUC determined by viral quantitative culture (plaque assay) starting at initial 
administration of MK-4482/placebo up to planned discharge from quarantine (Day 12 am)
Secondary Endpoints:
Safety:

Safety data including, but not limited to, occurrence of AEs from initial administration 
of MK-4482/placebo up to the Day 28 follow-up.

Occurrence of SAEs from initial administration of MK-4482/placebo up to the Day 28 
follow-up.

Occurrence of serious AEs (SAEs) from initial administration of MK-4482/placebo up to 
the Day 28 follow-up.
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
Occurrence of AEs related to the viral challenge from viral challenge (Day 0) up to the 
Day 28 follow-up.

Occurrence of SAEs related to the viral challenge from viral challenge (Day 0) up to the 
Day 28 follow-up.

Use of concomitant medications from viral challenge (Day 0) up to the Day 28 follow-
up.
Prophylaxis:

VL-AUC determined by viral quantitative culture (plaque assay) starting from Day 2 up 
to planned discharge from quarantine (Day 12 am) 

VL-AUC determined by qRT-PCR starting from Day 2 up to planned discharge from 
quarantine (Day 12 am) 

PVL defined by the maximum viral load determined by qRT-PCR starting from Day 2 
up to planned discharge from quarantine (Day 12 am)

Area under the curve over time of total clinical symptoms (TSS-AUC) as measured from 
10 symptoms within the graded symptom scoring starting from Day 2 up to planned 
discharge from quarantine (Day 12am).

Area under the curve over time of total clinical symptoms change from baseline (TSS-
AUC-CFB) as measured from 10 symptoms within the graded symptom scoring system 
starting from Day 2 up to planned discharge from quarantine (Day 12am).

Peak symptoms diary card score: peak total clinical symptoms (TSS) as measured from 
10 symptoms within the graded symptom scoring system starting from Day 2 up to 
planned discharge from quarantine (Day 12am).

Peak daily symptom score: individual maximum daily sum of symptom score starting 
from Day 2 up to planned discharge from quarantine (Day 12am).

RT-PCR-confirmed RSV infection, defined as 2 quantifiable (≥ lower limit of 
quantification [LLOQ]) qRT-PCR measurements (reported on 2 or more independent 
samples over 2 days), from Day 2 up to Day 12.

Occurrence of at least 1 positive quantitative (≥LLOQ) cell culture measurement in nasal 
samples, from Day 2 up to Day 12.
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
RT-PCR-confirmed symptomatic RSV infection, defined as:
o
RT-PCR-confirmed RSV infection (2 quantifiable [≥LLOQ] qRT-PCR 
measurements [reported on 2 or more independent samples over 2 days]), from 
Day 2 up to Day 12, AND
o
Symptoms ≥2 at a single time point.

RT-PCR-confirmed moderately severe symptomatic RSV infection, defined as:
o
RT-PCR-confirmed RSV infection (2 quantifiable [≥LLOQ] qRT-PCR 
measurements [reported on 2 or more independent samples over 2 days]), 
from Day 2 up to Day 12, AND
o
Any symptoms of grade ≥2 at a single time point.

Culture lab-confirmed symptomatic RSV infection, defined as:
o
Lab-confirmed culturable RSV infection (1 quantifiable [≥LLOQ] cell culture 
measurement), from Day 2 up to Day 12, AND
o
Symptoms ≥2 at a single time point.
Treatment:

PVL as defined by the maximum viral load determined by viral quantitative culture 
(plaque assay) starting at initial administration of MK-4482/placebo up to planned 
discharge from quarantine (Day 12 am) 

Time (days) to confirmed negative test by viral quantitative culture (plaque assay) 
measurements starting at initial administration of MK-4482/placebo to first confirmed 
undetectable (<LLOQ) assessment after peak measure.

VL-AUC determined by qRT-PCR starting at initial administration of MK-4482/placebo 
up to planned discharge from quarantine (Day 12 am) 

PVL defined by the maximum viral load determined by qRT-PCR starting at initial 
administration of MK-4482/placebo up to planned discharge from quarantine 
(Day 12 am).

Time (days) to confirmed negative test by qRT-PCR starting at initial administration of 
MK-4482/placebo to first confirmed undetectable (<LLOQ) assessment after peak 
measure.

Area under the curve over time of total clinical symptoms (TSS-AUC) as measured from 
10 symptoms within the graded symptom scoring system starting at initial administration 
of MK-4482/placebo up to planned discharge from quarantine (Day 12am).
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
Area under the curve over time of total clinical symptoms change from baseline (TSS-
AUC-CFB) as measured from 10 symptoms within the graded symptom scoring system 
starting at initial administration of MK-4482/placebo up to planned discharge from 
quarantine (Day 12am).

Peak symptoms diary card score: peak total clinical symptoms (TSS) as measured from 
10 symptoms within the graded symptom scoring system starting from initial 
administration of MK-4482/placebo up to planned discharge from quarantine 
(Day 12am).

Peak daily symptom score: individual maximum daily sum of symptom score from initial 
administration of MK-4482/placebo up to planned discharge from quarantine 
(Day 12am).

Time (days) to symptom resolution as measured from 10 symptoms within the graded 
daily symptom scoring system starting at initial administration of MK-4482/placebo to 
time of returning to baseline score.
Pharmacokinetics:

NHC concentrations in plasma at sampling times. The following plasma NHC 
pharmacokinetic parameters may also be evaluated: Cmax, Tmax, AUC0-12, and 
Ctrough.
Exploratory Endpoints:
Note that tertiary objectives and endpoints are optional and might be assessed only if needed; 
therefore, not all testing might be performed and reported.
Prophylaxis:

Duration of quantifiable RSV qRT-PCR measurements starting from Day 2 up to Day 
12am. Duration is defined as the time (days) from first quantifiable detection until first 
confirmed undetectable (<LLOQ) assessment after peak measure (after which no further 
virus is detected)

Duration of quantifiable RSV viral quantitative culture (plaque assay) measurements 
starting from Day 2 up to Day 12am. Duration is defined as the time (days) from first 
quantifiable detection until first confirmed undetectable (<LLOQ) assessment after peak 
measure (after which no further virus is detected)

Duration (days) of grade 2 symptoms measured from 10 symptoms within the graded 
daily symptom scoring system starting from Day 2 to planned discharge from quarantine 
(Day 12am), as measured by time from first occurrence of grade 2 or higher symptoms, 
to first 24 hours period without grade 2 or more symptoms after the peak total symptom 
score.
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
Time (days) to peak as measured from 10 symptoms within the graded daily symptom 
scoring system starting from Day 2 to the time of peak daily symptom score.

Total weight of mucus produced starting from Day 2 up to planned discharge from 
quarantine (Day 12am).

Total number of tissues used by participants starting from Day 2 up to planned discharge 
from quarantine (Day 12am).
Treatment:

Time (days) to peak as measured from 10 symptoms within the graded daily symptom 
scoring system starting from initial administration of MK-4482/placebo to the time of 
peak daily symptom score.

Total weight of mucus produced starting from initial administration of MK-4482/placebo
up to planned discharge from quarantine (Day 12am).

Total number of tissues used by participants starting from initial administration of MK-
4482/placebo up to planned discharge from quarantine (Day 12am).
Note for all endpoint analysis: 

Further sensitivity analysis may be performed on the above viral qRT-PCR-related 
incidence endpoints where detection by qRT-PCR is reported above the levels of 
detection in the assay instead of the LLOQ. Details will be provided in the statistical 
analysis plan (sSAP).

All clinical symptom-related endpoints may be further explored, as measured with 
either the full 13 or a subset of the 13 symptoms within the graded symptom scoring 
system.
Pharmacokinetics: 

NHC-TP concentrations in PBMCs at sampling times.
Pharmacokinetics/Pharmacodynamics: 

Exposure-response relationship: the relationship between plasma NHC parameters (e.g., 
AUC, Ctrough) or PBMC NHC-TP concentrations and virological endpoints for 
treatment and prophylaxis.
9.5
Analysis Populations
Full Analysis Set (FAS) Population
The FAS will serve as the primary population for the evaluation of efficacy. The FAS 
population consists of all randomized participants who received 1 dose of the correct clinical 
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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 
efficacy. For the treatment portion, only those that are RSV infected participants in the FAS 
will be included in the 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.
9.6
Statistical Methods
Safety
AEs will be tabulated and descriptively summarized.  Summary statistics and plots will be 
generated for raw laboratory safety tests, ECGs, and/or VS as well as for change from 
baseline, as deemed clinically appropriate. Depending on the safety parameter, the difference 
from baseline will either be computed on the original scale (raw change from baseline) or on 
the log scale and back-transformed for reporting (percent change from baseline).
Efficacy
Prophylaxis
Only panel A (prophylaxis) and panel C (placebo) will be included in the model. PVL (on the
log10 scale) of RSV A Memphis 37b determined by viral quantitative culture (plaque assay)
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between Day 2 and Day 12 am after intranasal inoculation (Day 0) will be analyzed using a 
linear model with treatment group as a fixed categorical effect. The mean PVL in each group 
and the differences in mean PVL between MK-4482 and placebo and the corresponding 2-
sided 95% CI will be computed based on the model. 
Treatment:
Only Panel B (treatment) and Panel C (placebo) will be included in the model. For both 
panels, only the participants with RSV infection will be included.
VL-AUC (on the log10 scale) determined by viral quantitative culture (plaque assay) from 
initial triggered administration of MK-4482/placebo, through Day 12 am (inclusive) after 
viral inoculation (Day 0) will be analyzed using a linear model with treatment group as a 
fixed categorical effect. The mean VL-AUC in each group and the differences in mean VL-
AUC between MK-4482 and placebo and the corresponding 2-sided 95% CI will be 
computed based on the model. 
The primary hypothesis for treatment and prophylaxis 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 PVL/VL-AUC between MK-4482 and placebo is <0 (indicating a reduction).
The proportion of participants with symptomatic RSV infection between Day 2 and Day 12 
am after intranasal inoculation (Day 0) will be computed along with exact 95% CIs for each 
treatment group. Exact 95% CIs will be computed for the difference in proportions between 
each MK-4482 dose and placebo [Chan, I. S. F. and Zhang, Z. 1999]. Additionally, the 
presence of symptomatic RSV infection will be modeled using a 3-parameter sigmoidal 
(logistic) function with treatment group as a fixed effect. Other discrete efficacy endpoints 
will be analyzed in a similar manner.
For both prophylaxis and treatment arm, if the assumptions of a linear model are 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).
Pharmacokinetics
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).
9.7
Interim Analyses
No interim analyses are planned.
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9.8
Multiplicity
The study has only 1 primary hypothesis for treatment and prophylaxis arm respectively 
which will be addressed and preserve the alpha level at 0.05 2-sided; therefore, there is no 
need for a multiplicity adjustment.
9.9
Sample Size and Power Calculations
105 participants will be randomized and dosed with MK-4482 or placebo. 35 per panel will 
be administered the intranasal RSV A Memphis 37b inoculation, complete the follow-up and 
sample collection through Day 12 am post inoculation.
The primary hypothesis:
The assumed CV in VL-AUC or PVL as well as infection rate of 61% (based on a single 
quantitative plaque assay positive from Day 2 to Day 12) were obtained from previous 
published and unpublished RSV challenge studies conducted by hVIVO (Vendor contracted 
to perform the study) and all based on log10 pfu/mL. The evaluable sample size is assumed 
to be 35 per group with expected dropout rate of 2 (~ 5% out of 33).
For prophylaxis, with a sample size of 33 per group, there is ~80.9% power to detect a 
decrease in PVL of 65% (on the log10 scale) in MK-4482 group vs. the placebo group 
assuming a CV in PVL of 0.917 with a 2-sided alpha=0.05 test. 
For treatment, with a sample size of 19 that test positive per group, there is ~ 80.5% power to
detect a decrease in VL-AUC of 70% (on the log10 scale) in MK-4482 group vs. the placebo 
group assuming a CV in VL-AUC of 0.767 with a 2-sided alpha=0.05 test. Considering the 
infection rate of 61%, a sample size of 31 per group will maintain 80% power. 
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10
SUPPORTING DOCUMENTATION AND OPERATIONAL 
CONSIDERATIONS
10.1
Appendix 1: Regulatory, Ethical, and Study Oversight Considerations
10.1.1
Code of Conduct for Clinical Trials
Merck Sharp & Dohme LLC, Rahway, NJ, USA (MSD)
Code of Conduct for Interventional Clinical Trials
I. Introduction
A. Purpose
MSD, through its subsidiaries, conducts clinical trials worldwide to evaluate the safety and effectiveness of our 
products. As such, we are committed to designing, implementing, conducting, analyzing, and reporting these trials 
in compliance with the highest ethical and scientific standards. Protection of participants in clinical trials is the 
overriding concern in the design and conduct of clinical trials. In all cases, MSD clinical trials will be conducted 
in compliance with local and/or national regulations (including all applicable data protection laws and
regulations), and International Council for Harmonisation Good Clinical Practice (ICH-GCP), and also in 
accordance with the ethical principles that have their origin in the Declaration of Helsinki.
B. Scope
Highest ethical and scientific standards shall be endorsed for all clinical interventional investigations sponsored by 
MSD irrespective of the party (parties) employed for their execution (e.g., contract research organizations, 
collaborative research efforts). This Code is not intended to apply to trials that are observational in nature, or 
which are retrospective. Further, this Code does not apply to investigator-initiated trials, which are not under the 
full control of MSD.
II. Scientific Issues
A. Trial Conduct
1. Trial Design
Except for pilot or estimation trials, clinical trial protocols will be hypothesis-driven to assess safety, efficacy 
and/or pharmacokinetic or pharmacodynamic indices of MSD or comparator products. Alternatively, MSD 
may conduct outcomes research trials, trials to assess or validate various endpoint measures, or trials to 
determine patient preferences, etc.
The design (i.e., participant population, duration, statistical power) must be adequate to address the specific 
purpose of the trial and shall respect the data protection rights of all participants, trial site staff and, where 
applicable, third parties. All trial protocols are and will be assessed for the need and capability to enroll 
underrepresented groups. Participants must meet protocol entry criteria to be enrolled in the trial. 
2. Site Selection
MSD’s clinical trials are conducted globally in many different countries and in diverse populations, including 
people of varying age, race, ethnicity, gender, and accounting for other potential disease related factors. MSD 
selects investigative sites based on medical expertise, access to appropriate participants, adequacy of facilities 
and staff, previous performance in clinical trials, as well as budgetary considerations. Prior to trial initiation, 
sites are evaluated by MSD personnel (or individuals acting on behalf of MSD) to assess the ability to 
successfully conduct the trial.
Where appropriate, and in accordance with regulatory authority guidance, MSD will make concerted efforts 
to raise awareness of clinical trial opportunities in various communities. MSD will seek to engage 
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underrepresented groups and those disproportionately impacted by the disease under study. MSD will support 
clinical trial investigators to enroll underrepresented groups and expand access to those who will ultimately 
use the products under investigation.
3. Site Monitoring/Scientific Integrity
Investigative trial sites are monitored to assess compliance with the trial protocol and Good Clinical Practice 
(GCP). MSD reviews clinical data for accuracy, completeness, and consistency. Data are verified versus 
source documentation according to standard operating procedures. Per MSD policies and procedures, if
potential fraud, scientific/research misconduct, privacy incidents/breaches or Clinical Trial-related 
Significant Quality Issues are reported, such matters are investigated. When necessary, appropriate corrective 
and/or preventative actions are defined and regulatory authorities and/or ethics review committees are 
notified.
B. Publication and Authorship
Regardless of trial outcome, MSD commits to publish the primary and secondary results of its registered trials of 
marketed products in which treatment is assigned, according to the pre-specified plans for data analysis. To the 
extent scientifically appropriate, MSD seeks to publish the results of other analyses it conducts that are important 
to patients, physicians, and payers. Some early phase or pilot trials are intended to be hypothesis-generating rather 
than hypothesis testing; in such cases, publication of results may not be appropriate since the trial may be 
underpowered and the analyses complicated by statistical issues such as multiplicity.
MSD’s policy on authorship is consistent with the recommendations published by the International Committee of 
Medical Journal Editors (ICMJE). In summary, authorship should reflect significant contribution to the design and 
conduct of the trial, performance or interpretation of the analysis, and/or writing of the manuscript. All named 
authors must be able to defend the trial results and conclusions. MSD funding of a trial will be acknowledged in 
publications.
III. Participant Protection
A. Regulatory Authority and Ethics Committee Review (Institutional Review Board [IRB]/Independent Ethics 
Committee [IEC])
All protocols and protocol amendments will be submitted by MSD for regulatory authority 
acceptance/authorization prior to implementation of the trial or amendment, in compliance with local and/or 
national regulations.
The protocol, protocol amendment(s), informed consent form, investigator’s brochure, and other relevant trial 
documents must be reviewed and approved by an IRB/IEC before being implemented at each site, in compliance 
with local and/or national regulations. Changes to the protocol that are required urgently to eliminate an 
immediate hazard and to protect participant safety may be enacted in anticipation of ethics committee approval. 
MSD will inform regulatory authorities of such new measures to protect participant safety, in compliance with 
local and/or national regulations.
B. Safety
The guiding principle in decision-making in clinical trials is that participant welfare is of primary importance. 
Potential participants will be informed of the risks and benefits of, as well as alternatives to, trial participation. At 
a minimum, trial designs will take into account the local standard of care.
All participation in MSD clinical trials is voluntary. Participants enter the trial only after informed consent is 
obtained. Participants may withdraw from an MSD trial at any time, without any influence on their access to, or 
receipt of, medical care that may otherwise be available to them.
C. Confidentiality
MSD is committed to safeguarding participant confidentiality, to the greatest extent possible, as well as all 
applicable data protection rights. Unless required by law, only the investigator, Sponsor (or individuals acting on 
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behalf of MSD), ethics committee, and/or regulatory authorities will have access to confidential medical records 
that might identify the participant by name.
D. Genomic Research
Genomic research will only be conducted in accordance with a protocol and informed consent authorized by an 
ethics committee.
IV. Financial Considerations
A. Payments to Investigators
Clinical trials are time- and labor-intensive. It is MSD’s policy to compensate investigators (or the sponsoring 
institution) in a fair manner for the work performed in support of MSD trials. MSD does not pay incentives to 
enroll participants in its trials. However, when enrollment is particularly challenging, additional payments may be 
made to compensate for the time spent in extra recruiting efforts.
MSD does not pay for participant referrals. However, MSD may compensate referring physicians for time spent 
on chart review and medical evaluation to identify potentially eligible participants.
B. Clinical Research Funding
Informed consent forms will disclose that the trial is sponsored by MSD, and that the investigator or sponsoring 
institution is being paid or provided a grant for performing the trial. However, the local ethics committee may 
wish to alter the wording of the disclosure statement to be consistent with financial practices at that institution. As 
noted above, all publications resulting from MSD trials will indicate MSD as a source of funding.
C. Funding for Travel and Other Requests
Funding of travel by investigators and support staff (e.g., to scientific meetings, investigator meetings, etc.) will be 
consistent with local guidelines and practices.
V. Investigator Commitment
Investigators will be expected to review MSD’s Code of Conduct as an appendix to the trial protocol, and in signing the 
protocol, agree to support these ethical and scientific standards.
10.1.2
Financial Disclosure
Financial disclosure requirements are outlined in the US Food and Drug Administration 
Regulations, Financial Disclosure by Clinical Investigators (21 CFR Part 54). It is the 
Sponsor’s responsibility to determine, based on these regulations, whether a request for 
financial disclosure information is required. It is the investigator’s/subinvestigator’s 
responsibility to comply with any such request.
The investigator/subinvestigator(s) agree, if requested by the Sponsor in accordance with 21 
CFR Part 54, to provide his/her financial interests in and/or arrangements with the Sponsor to 
allow for the submission of complete and accurate certification and disclosure statements. 
The investigator/subinvestigator(s) further agree to provide this information on a 
Certification/Disclosure Form, frequently known as a financial disclosure form, provided by 
the Sponsor. The investigator/subinvestigator(s) also consent to the transmission of this 
information to the Sponsor in the United States for these purposes. This may involve the
transmission of information to countries that do not have laws protecting personal data.
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10.1.3
Data Protection
The Sponsor will conduct this study in compliance with all applicable data protection 
regulations.
Participants will be assigned a unique identifier by the Sponsor. Any participant records or 
datasets that are transferred to the Sponsor will contain the identifier only; participant names 
or any information that would make the participant identifiable will not be transferred.
The participant must be informed that his/her personal study-related data will be used by the 
Sponsor in accordance with local data protection law. The level of disclosure must also be 
explained to the participant. 
The participant must be informed that his/her medical records may be examined by Clinical 
Quality Assurance auditors or other authorized personnel appointed by the Sponsor, by 
appropriate IRB/IEC members, and by inspectors from regulatory authorities.
10.1.3.1
Confidentiality of Data
By signing this protocol, the investigator affirms to the Sponsor that information furnished to 
the investigator by the Sponsor will be maintained in confidence, and such information will 
be divulged to the IRB, IEC, or similar or expert committee; affiliated institution and 
employees, only under an appropriate understanding of confidentiality with such board or 
committee, affiliated institution and employees. Data generated by this study will be 
considered confidential by the investigator, except to the extent that it is included in a 
publication as provided in the Publications section of this protocol.
10.1.3.2
Confidentiality of Participant Records
By signing this protocol, the investigator agrees that the Sponsor (or Sponsor representative), 
IRB/IEC, or regulatory authority representatives may consult and/or copy study documents to 
verify worksheet/CRF data. By signing the consent form, the participant agrees to this 
process. If study documents will be photocopied during the process of verifying 
worksheet/CRF information, the participant will be identified by unique code only; full 
names/initials will be masked before transmission to the Sponsor.
By signing this protocol, the investigator agrees to treat all participant data used and 
disclosed in connection with this study in accordance with all applicable privacy laws, rules 
and regulations.
10.1.3.3
Confidentiality of IRB/IEC Information
The Sponsor is required to record the name and address of each IRB/IEC that reviews and 
approves this study. The Sponsor is also required to document that each IRB/IEC meets 
regulatory and ICH GCP requirements by requesting and maintaining records of the names 
and qualifications of the IRB/IEC members and to make these records available for 
regulatory agency review upon request by those agencies.
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10.1.4
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.
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.
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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.
10.1.8
Data Quality Assurance
All participant data relating to the study will be recorded on printed or electronic CRF unless 
transmitted to the Sponsor or designee electronically (eg, laboratory data). The investigator 
or qualified designee is responsible for verifying that data entries are accurate and correct by 
physically or electronically signing the CRF.
Detailed information regarding Data Management procedures for this protocol will be 
provided separately.
The investigator must maintain accurate documentation (source data) that supports the 
information entered in the CRF.
The investigator must permit study-related monitoring, audits, IRB/IEC review, and 
regulatory agency inspections and provide direct access to source data documents.
Study documentation will be promptly and fully disclosed to the Sponsor by the investigator 
upon request and also shall be made available at the study site upon request for inspection, 
copying, review, and audit at reasonable times by representatives of the Sponsor or any 
regulatory authorities. The investigator agrees to promptly take any reasonable steps that are 
requested by the Sponsor or any regulatory authorities as a result of an audit or inspection to 
cure deficiencies in the study documentation and worksheets/CRFs.
The Sponsor or designee is responsible for the data management of this study including 
quality checking of the data.
Study monitors will perform ongoing source data review and verification to confirm that data 
entered into the CRF by authorized site personnel are accurate, complete, and verifiable from 
source documents; that the safety and rights of participants are being protected; and that the 
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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.
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 8 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 8
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)
Calcium
Alkaline 
phosphatase
Cardiac 
Enzymes (CK 
and Troponin)
Routine 
Urinalysis
•
Specific gravity
•
pH, glucose, protein, blood, ketones, bilirubin, urobilinogen, nitrite, 
leukocyte esterase by dipstick
•
Microscopic examination (if blood or protein is abnormal)
Pregnancy 
Testing
•
Highly sensitive serum hCG or urine pregnancy test (as needed for 
WOCBP)
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Laboratory 
Assessments
Parameters
Other 
Screening 
Tests
•
FSH (as needed in WONCBP only)
•
Serum or 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; FSH=follicle-stimulating hormone; HBsAg=hepatitis B surface 
antigen; hCG=human chorionic gonadotropin; HIV=human immunodeficiency virus; MCH=mean 
corpuscular hemoglobin; MCV=mean corpuscular volume; RBC=red blood cell; SGOT=serum glutamic-
oxaloacetic transaminase; SGPT=serum glutamic-pyruvic transaminase; ULN=upper limit of normal; 
WBC=white blood cell; WOCBP=women of childbearing potential; WONCBP=women of nonchildbearing 
potential
Notes:  Laboratory safety tests (hematology and chemistry) will be performed after approximately 8-hour 
fast. Screening safety tests, Day -3/-2, and any repeat hematology tests to confirm out of range values do not 
need to be fasted.
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
Definition of AE
AE definition
•
An AE is any untoward medical occurrence in a clinical study participant, temporally 
associated with the use of study intervention, whether or not considered related to the 
study intervention.
•
Note: An AE can therefore be any unfavorable and unintended sign (including an 
abnormal laboratory finding), symptom, or disease (new or exacerbated) temporally 
associated with the use of a study intervention.
•
Note: For purposes of AE definition, study intervention (also referred to as Sponsor’s 
product) includes any pharmaceutical product, biological product, vaccine, diagnostic 
agent, medical device, combination product, or protocol specified procedure whether 
investigational or marketed (including placebo, active comparator product, or run-in 
intervention), manufactured by, licensed by, provided by, or distributed by the Sponsor 
for human use in this study.
Events meeting the AE definition
•
Any abnormal laboratory test results (hematology, clinical chemistry, or urinalysis) or 
other safety assessments (eg, ECG, radiological scans, vital signs measurements), 
including those that worsen from baseline, considered clinically significant in the medical 
and scientific judgment of the investigator.
•
Exacerbation of a chronic or intermittent preexisting condition including either an 
increase in frequency and/or intensity of the condition.
•
New conditions detected or diagnosed after study intervention administration even 
though it may have been present before the start of the study.
•
Signs, symptoms, or the clinical sequelae of a suspected drug-drug interaction.
•
Signs, symptoms, or the clinical sequelae of a suspected overdose of either study 
intervention or a concomitant medication.
•
For all reports of overdose (whether accidental or intentional) with an associated AE, the 
AE term should reflect the clinical symptoms or abnormal test result. An overdose 
without any associated clinical symptoms or abnormal laboratory results is reported using 
the terminology “accidental or intentional overdose without adverse effect.”
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Events NOT meeting the AE definition
•
Medical or surgical procedure (eg, endoscopy, appendectomy): the condition that leads to 
the procedure is the AE.
•
Situations in which an untoward medical occurrence did not occur (social and/or 
convenience admission to a hospital).
•
Anticipated day-to-day fluctuations of preexisting disease(s) or condition(s) present or 
detected at the start of the study that do not worsen.
•
Surgical procedure(s) planned prior to informed consent to treat a preexisting condition 
that has not worsened.
•
Refer to Section 8.4.6 for protocol-specific exceptions.
10.3.2
Definition of SAE
If an event is not an AE per definition above, then it cannot be an SAE even if serious 
conditions are met.
An SAE is defined as any untoward medical occurrence that, at any dose:

Results in death

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.

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.

Results in persistent or significant disability/incapacity
•
The term disability means a substantial disruption of a person’s ability to conduct 
normal life functions.
•
This definition is not intended to include experiences of relatively minor medical 
significance such as uncomplicated headache, nausea, vomiting, diarrhea, influenza, 
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and accidental trauma (eg, sprained ankle) that may interfere with or prevent 
everyday life functions but do not constitute a substantial disruption.

Is a congenital anomaly/birth defect
•
In offspring of participant taking the product regardless of time to diagnosis.

Other important medical events
•
Medical or scientific judgment should be exercised in deciding whether SAE 
reporting is appropriate in other situations such as important medical events that may 
not be immediately life-threatening or result in death or hospitalization but may 
jeopardize the participant or may require medical or surgical intervention to prevent 1 
of the other outcomes listed in the above definition. These events should usually be 
considered serious.
•
Examples of such events include invasive or malignant cancers, intensive treatment in 
an emergency room or at home for allergic bronchospasm, blood dyscrasias or 
convulsions that do not result in hospitalization, or development of drug dependency 
or drug abuse.
10.3.3
Additional Events Reported
Additional events that require reporting
In addition to the above criteria, AEs meeting either of the below criteria, although not 
serious per ICH definition, are reportable to the Sponsor.
•
Is a cancer
•
Is associated with an overdose
10.3.4
Recording AE and SAE
AE and SAE recording
•
When an AE/SAE occurs, it is the responsibility of the investigator to review all 
documentation (eg, hospital progress notes, laboratory, and diagnostics reports) related to 
the event.
•
The investigator will record all relevant AE/SAE information on the AE 
CRFs/worksheets at each examination.
•
It is not acceptable for the investigator to send photocopies of the participant’s medical 
records to the Sponsor in lieu of completion of the AE CRF page.
•
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 
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number, will be blinded on the copies of the medical records before submission to the 
Sponsor.
•
The investigator will attempt to establish a diagnosis of the event based on signs, 
symptoms, and/or other clinical information. In such cases, the diagnosis (not the 
individual signs/symptoms) will be documented as the AE/SAE.
Assessment of intensity
•
An event is defined as “serious” when it meets at least 1 of the predefined outcomes as 
described in the definition of an SAE, not when it is rated as severe.
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.
•
The investigator will submit any updated SAE data to the Sponsor within 24 hours of 
receipt of the information.
10.3.5
Reporting of AEs, SAEs, and Other Reportable Safety Events to the Sponsor
AE, SAE, and other reportable safety event reporting to Sponsor via electronic data 
collection tool
•
The primary mechanism for reporting to the Sponsor will be the EDC tool.
-
Electronic reporting procedures can be found in the EDC data entry guidelines (or 
equivalent).

If the electronic system is unavailable for more than 24 hours, then the site will use the 
paper AE Reporting form.
◦
Reference Section 8.4.1 for reporting time requirements.
•
The site will enter the SAE data into the electronic system as soon as it becomes 
available.
•
After the study is completed at a given site, the EDC tool will be taken off-line to prevent 
the entry of new data or changes to existing data.
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•
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 e-mail of the SAE 
paper CRF is the preferred method to transmit this information to the Sponsor.
•
In rare circumstances and in the absence of facsimile equipment, notification by 
telephone is acceptable with a copy of the SAE data collection tool sent by overnight 
mail or courier service.
•
Initial notification via telephone does not replace the need for the investigator to 
complete and sign the SAE CRF pages within the designated reporting time frames.
•
Contacts and instructions for SAE reporting and paper reporting procedures can be found 
in the Investigator Study File Binder (or equivalent).
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10.4
Appendix 4: Medical Device and Drug-device Combination Products: Product 
Quality Complaints/Malfunctions: Definitions, Recording, and Follow-up
Not applicable.
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10.5
Appendix 5: Contraceptive Guidance
10.5.1
Definitions
Women of Childbearing Potential (WOCBP)
A woman is considered fertile following menarche and until becoming postmenopausal 
unless permanently sterile (see below):
If fertility is unclear (eg, amenorrhea in adolescents or athletes) and a menstrual cycle cannot 
be confirmed before first dose of study intervention, additional evaluation should be 
considered.
Women in the following categories are not considered WOCBP:
•
Premenarchal
•
Premenopausal female with 1 of the following:
- Documented hysterectomy
- Documented bilateral salpingectomy
- Documented bilateral oophorectomy
For individuals with permanent infertility due to an alternate medical cause other than the 
above (eg, Mullerian agenesis, androgen insensitivity), investigator discretion should be 
applied to determining study entry.
Note: Documentation can come from the site personnel’s review of the participant’s medical 
records, medical examination, or medical history interview.
•
Postmenopausal female
- A postmenopausal state is defined as no menses for 12 months without an alternative 
medical cause.
◦
A high FSH level in the postmenopausal range may be used to confirm a 
postmenopausal state in women not using hormonal contraception or HRT. 
However, in the absence of 12 months of amenorrhea, confirmation with two 
FSH measurements in the postmenopausal range is required.
- Females on HRT and whose menopausal status is in doubt will be required to use one 
of the non-hormonal highly effective contraception methods if they wish to 
continue their HRT during the study. Otherwise, they must discontinue HRT to 
allow confirmation of postmenopausal status before study enrollment.
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Women of Nonchildbearing Potential (WONCBP)
Women in the following categories are considered WONCBP:
•
Premenopausal female with 1 of the following:
- Documented hysterectomy
- Documented bilateral salpingectomy
- Documented bilateral oophorectomy
For individuals with permanent infertility due to an alternate medical cause other than 
the above (eg, Mullerian agenesis, androgen insensitivity), investigator discretion 
should be applied to determining study entry.
Note: Documentation can come from the site personnel’s review of the participant’s 
medical records, medical examination, or medical history interview.
•
Postmenopausal female
- A postmenopausal state is defined as no menses for 12 months without an alternative 
medical cause. 
◦
A high FSH level in the postmenopausal range may be used to confirm a 
postmenopausal state in women not using hormonal contraception or HRT. 
However, in the absence of 12 months of amenorrhea, confirmation with two 
FSH measurements in the postmenopausal range is required. 
- Females on HRT and whose menopausal status is in doubt must discontinue HRT to 
allow confirmation of postmenopausal status before study enrollment.
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10.5.2
Contraception 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 subdermal contraceptive implantb,c
IUSb,d
Nonhormonal IUD
Bilateral tubal occlusion
Azoospermic partner (vasectomized or secondary to medical cause) –
All sexual partner(s) of the WOCBP 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 Dependentb
Failure rate of <1% per year when used consistently and correctly.
Combined (estrogen- and progestogen-containing) hormonal contraceptionb,c
- Oral
- Intravaginal
- Transdermal
- Injectable
Progestogen-only hormonal contraceptionb,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 WOCBP’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 8.9 will be 
used in various experiments to understand:

The biology of how drugs/vaccines work

Biomarkers responsible for how a drug/vaccine enters and is removed by the body

Other pathways with which drugs/vaccines may interact

The biology of disease
The specimen(s) may be used for future assay development and/or drug/vaccine 
development.
It is now well recognized that information obtained from studying and testing clinical 
specimens offers unique opportunities to enhance our understanding of how individuals 
respond to drugs/vaccines, enhance our understanding of human disease and ultimately 
improve public health through development of novel treatments targeted to populations 
with the greatest need. All specimens will be used by the Sponsor or those working for or 
with the Sponsor.
3. Summary of Procedures for Future Biomedical Research3, 4
a. Participants for Enrollment
All participants enrolled in the clinical study will be considered for enrollment in 
future biomedical research.
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b. Informed Consent
Informed consent for specimens (ie, DNA, RNA, protein, etc) will be obtained during 
screening for protocol enrollment from all participants or legal guardians, at a study 
visit by the investigator or his or her designate. Informed consent for future 
biomedical research should be presented to the participants on the visit designated in 
the SoA. If delayed, present consent at next possible Participant Visit. Consent forms 
signed by the participant will be kept at the clinical study site under secure storage for 
regulatory reasons.
A template of each study site’s approved informed consent will be stored in the 
Sponsor’s clinical document repository.
c. eCRF Documentation for Future Biomedical Research Specimens
Documentation of participant consent for future biomedical research will be captured 
in the eCRFs. Any specimens for which such an informed consent cannot be verified 
will be destroyed.
d. Future Biomedical Research Specimen(s)
Collection of specimens for future biomedical research will be performed as outlined 
in the SoA. In general, if additional blood specimens are being collected for future 
biomedical research, these will usually be obtained at a time when the participant is 
having blood drawn for other study purposes.
4. Confidential Participant Information for Future Biomedical Research3, 4
In order to optimize the research that can be conducted with future biomedical research
specimens, it is critical to link participants' clinical information with future test results. In 
fact, little or no research can be conducted without connecting the clinical study data to 
the specimen. The clinical data allow specific analyses to be conducted. Knowing 
participant characteristics like sex, age, medical history and intervention outcomes are 
critical to understanding clinical context of analytical results.
To maintain privacy of information collected from specimens obtained for future 
biomedical research, the Sponsor has developed secure policies and procedures. All 
specimens will be single-coded per ICH E15 guidelines as described below.
At the clinical study site, unique codes will be placed on the future biomedical research
specimens. This code is a random number which does not contain any personally 
identifying information embedded within it. The link (or key) between participant 
identifiers and this unique code will be held at the study site. No personal identifiers will 
appear on the specimen tube.
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5. Biorepository Specimen Usage3, 4
Specimens obtained for the Sponsor will be used for analyses using good scientific 
practices. Analyses using the future biomedical research specimens may be performed by 
the Sponsor, or an additional third party (eg, a university investigator) designated by the 
Sponsor. The investigator conducting the analysis will follow the Sponsor’s privacy and 
confidentiality requirements. Any contracted third party analyses will conform to the 
specific scope of analysis outlined in future biomedical research protocol and consent. 
Future biomedical research specimens remaining with the third party after specific 
analysis is performed will be reported to the Sponsor.
6. Withdrawal From Future Biomedical Research3, 4
Participants may withdraw their consent for FBR and ask that their biospecimens not be 
used for FBR. Participants may withdraw consent at any time by contacting the study 
investigator. If medical records for the study are still available, the investigator will 
contact the Sponsor using the designated mailbox 
(clinical.specimen.management@MSD.com). Subsequently, the participant's specimens 
will be flagged in the biorepository and restricted to study use only. If specimens were 
collected from study participants specifically for FBR, these specimens will be removed 
from the biorepository and destroyed. Documentation will be sent to the investigator 
confirming withdrawal and/or destruction, if applicable. It is the responsibility of the 
investigator to inform the participant of completion of the withdrawal and/or destruction, 
if applicable. Any analyses in progress at the time of request for withdrawal/destruction 
or already performed before the request being received by the Sponsor will continue to be 
used as part of the overall research study data and results. No new analyses would be 
generated after the request is received.
If the medical records for the study are no longer available (eg, if the investigator is no 
longer required by regulatory authorities to retain the study records) or the specimens 
have been completely anonymized, there will no longer be a link between the 
participant’s personal information and their specimens. In this situation, the request for 
withdrawal of consent and/or destruction cannot be processed.
7. Retention of Specimens3, 4
Future biomedical research specimens will be stored in the biorepository for potential 
analysis for up to 20 years from the end of the study. Specimens may be stored for longer 
if a regulatory or governmental authority has active questions that are being answered. In 
this special circumstance, specimens will be stored until these questions have been 
adequately addressed.
Specimens from the study site will be shipped to a central laboratory and then shipped to 
the Sponsor-designated biorepository. If a central laboratory is not utilized in a particular 
study, the study site will ship directly to the Sponsor-designated biorepository. The 
specimens will be stored under strict supervision in a limited access facility which 
operates to assure the integrity of the specimens. Specimens will be destroyed according 
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to Sponsor policies and procedures and this destruction will be documented in the 
biorepository database.
8. Data Security3, 4
Databases containing specimen information and test results are accessible only to the 
authorized Sponsor representatives and the designated study administrator research 
personnel and/or collaborators. Database user authentication is highly secure, and is 
accomplished using network security policies and practices based on international 
standards to protect against unauthorized access.
9. Reporting of Future Biomedical Research Data to Participants3, 4
No information obtained from exploratory laboratory studies will be reported to the 
participant, family, or physicians. Principle reasons not to inform or return results to the 
participant include: lack of relevance to participant health, limitations of predictive 
capability, and concerns regarding misinterpretation.
If important research findings are discovered, the Sponsor may publish results, present 
results in national meetings, and make results accessible on a public website in order to
rapidly report this information to doctors and participants. Participants will not be 
identified by name in any published reports about this study or in any other scientific 
publication or presentation.
10. Future Biomedical Research Study Population3, 4
Every effort will be made to recruit all participants diagnosed and treated on Sponsor 
clinical studies for future biomedical research.
11. Risks Versus Benefits of Future Biomedical Research3, 4
For future biomedical research, risks to the participant have been minimized and are 
described in the future biomedical research informed consent.
The Sponsor has developed strict security, policies, and procedures to address participant 
data privacy concerns. Data privacy risks are largely limited to rare situations involving 
possible breach of confidentiality. In this highly unlikely situation, there is risk that the 
information, like all medical information, may be misused.
12. Questions
Any questions related to the future biomedical research should be emailed directly to 
clinical.specimen.management@MSD.com.
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13. References
1. National Cancer Institute [Internet]: Available from 
https://www.cancer.gov/publications/dictionaries/cancer-terms?cdrid=45618
2. International Council on Harmonisation [Internet]: E15: Definitions for Genomic 
Biomarkers, Pharmacogenomics, Pharmacogenetics, Genomic Data and Sample 
Coding Categories. Available from 
http://www.ich.org/products/guidelines/efficacy/efficacy-single/article/definitions-
for-genomic-biomarkers-pharmacogenomics-pharmacogenetics-genomic-data-and-
sample-cod.html 
3. Industry Pharmacogenomics Working Group [Internet]: Understanding the Intent, 
Scope and Public Health Benefits of Exploratory Biomarker Research: A Guide for 
IRBs/IECs and Investigational Site Staff. Available at http://i-pwg.org/ 
4. Industry Pharmacogenomics Working Group [Internet]: Pharmacogenomics 
Informational Brochure for IRBs/IECs and Investigational Site Staff. Available at 
http://i-pwg.org/
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10.7
Appendix 7: Country-specific Requirements
Not applicable. 
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10.8
Appendix 8: Blood Volume Table
Panels A, B and C
Screenin
g
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 
-
3
1
4
5.5
20
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
2
1
4
5
20
Blood for Plasma NHC Assay
-
17
-
17
3
51
Blood for PBMC NHC-TP 
Assay
-
5
-
5
16
80
Blood for Planned Genetic 
Analysis 
-
1
-
1
8.5
8.5
Total Blood Volume per Participanta
189.2 mL
aPTT=activated partial thromboplastin time; β-hCG=beta human chorionic gonadotropin; FSH=follicle stimulating hormone; 
HIV-human immunodeficiency virus; NHC=N-hydroxycytidine; NHC-TP=N-hydroxycytidine-triphosphate; PT=prothrombin time; 
WOCBP=women of childbearing potential; WONCBP=women of nonchildbearing potential; 
a If additional pharmacokinetic/pharmacodynamic and/or safety analysis is necessary, additional blood (up to 50 mL) 
may be obtained. Note: never to exceed 50 mL.
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10.9
Appendix 9: 12-Lead Electrocardiogram Abnormality Criteria
Screen Failure Criteria
Potentially Significant 
Postrandomization Findings 
(clarification on action to take)
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 Intra-Ventricular 
Conduction Delay
QRS 130 ms
QRS 130 ms + Increase of 10 
ms
QTc (B or F)
Male
QTc 470 ms
QTc 500 ms or Increase of 60 
ms From Baseline
Female
QTc 480 ms
QTc 500 ms or Increase of 60 
ms From Baseline
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Screen Failure Criteria
Potentially Significant 
Postrandomization Findings 
(clarification on action to take)
HYPERTROPHY
Atrial Abnormalities
Definite Evidence of P 
Mitrale or P Pulmonale
Definite Evidence of P Mitrale 
or P Pulmonale
Ventricular Abnormalities
Voltage Criteria for LVH 
Plus Strain Pattern
Voltage Criteria for LVH Plus 
Strain Pattern
MYOCARDIAL INFARCTION
Acute or Recent
All
All
Old
All
All
ST/T MORPHOLOGY
ST Elevation Suggestive of 
Myocardial Injury 
In 2 or more contiguous 
leads
In 2 or more contiguous leads
ST Depression Suggestive of
Myocardial Ischaemia 
In 2 or more contiguous 
leads
In 2 or more contiguous leads
T-wave Inversions Suggestive 
of Myocardial Ischaemia 
In 2 or more contiguous 
leads
In 2 or more contiguous leads
Non-specific ST-T Changes 
(In 2 or More Leads)
No exclusion
In 2 or more contiguous leads
PACEMAKER
All
All
AV=atrioventricular; bpm=beats per minute; HR=heart rate: ICRBBB=incomplete right bundle 
branch block; LAHB=left anterior hemiblock; LPHB=left posterior hemiblock; LVH=left 
ventricular hypertrophy; mm=millimeter; ms=milliseconds, PR=pulse rate; QTcB=QT correction 
using Bazett’s formula; QTcF=QT correction using 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 prestudy (screening) visit and/or predose evaluation:
A. If all protocol-specified laboratory values are normal, the participant may enter the study.
B. If a protocol specified laboratory value is outside of the parameter(s) outlined in the 
inclusion/exclusion criteria (including a repeat if performed), the participant will be 
excluded from the study.
C. If ≥1 protocol-specified laboratory value not specified in the inclusion/exclusion criteria 
is outside the normal range, the following choices are available:
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).
a.
If the repeat test value is within the normal range, the participant may 
enter the study.
b. If the repeat test value is still abnormal, the study investigator will 
evaluate the potential participant with a complete history and physical 
examination, looking especially for diseases that could result in the 
abnormal laboratory value in question. If such diseases can be ruled out, 
and if the abnormal laboratory value is not clinically relevant, then the 
participant may enter the study.
D. If there is any clinical uncertainty regarding the significance of an abnormal value, the 
participant will be excluded from the study.
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10.11 Appendix 11: Abbreviations
Abbreviation
Expanded Term
ADME
absorption, distribution, metabolism, and excretion
AE
adverse event 
ALT
alanine aminotransferase
am
ante meridiem (before midday)
AP
Analytical Plan
APaT
All-Participants-as-Treated
aPTT
activated partial thromboplastin time
AR
adverse reaction
AST
aspartate aminotransferase
AUC
area under the curve
AUC0-12
area under the curve from time 0 to 12 hours
BMI
body mass index
BP
blood pressure
CAC
Clinical Adjudication Committee
CCU
cardiac care unit
CFB
Change from baseline
CG
Cockcroft-Gault
CHF
congestive heart failure
CI
confidence interval
CK
creatine kinase
CKD-EPI
Chronic Kidney Disease Epidemiology Collaboration
Cmax
maximum plasma concentration
CNS
central nervous system 
CONSORT
Consolidated Standards of Reporting Trials
CL
clearance
COPD
chronic obstructive pulmonary disease 
COVID-19
coronavirus disease 2019
CrCl
creatinine clearance
CRF
Case Report Form 
CRU
clinical research unit
CSR
Clinical Study Report
CT
computed tomography
CTFG
Clinical Trial Facilitation Group 
Ctrough
trough concentration
CV
coefficient of variation 
CYP
cytochrome P450
DDI
drug-drug interaction
DILI
drug-induced liver injury
DNA
deoxyribonucleic acid 
EC50
half-maximal effective concentration
ECG
electrocardiogram s
ECI
event of clinical interest
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Abbreviation
Expanded Term
eCRF
electronic Case Report Form
eCTA
exploratory Clinical Trial Application
EDC
electronic data collection 
eGFR
estimated glomerular filtration rate
EMA
European Medicines Agency
FAS
Full Analysis Set
FAS-I
Full Analysis Set -Infected
FDA
Food and Drug Administration
FDAAA
Food and Drug Administration Amendments Act
FIH
first in human
FSH
follicle-stimulating hormone 
GCP
Good Clinical Practice 
GMP
Good Manufacturing Practice
GI
gastrointestinal
HBsAg
hepatitis B surface antigen
HBV
hepatitis B virus
hCG
human chorionic gonadotropin
HCV
hepatitis C virus
HIV
human immunodeficiency virus
HR
heart rate
HRT
hormone replacement therapy
HSCT
hematopoietic stem cell transplantation
IA(s)
interim analysis(ses)
IB
Investigator’s Brochure 
ICF
Informed Consent Form
ICH
International Council for Harmonisation of Technical Requirements 
for Pharmaceuticals for Human Use
ICU
intensive care unit
IEC
Independent Ethics Committee
IgA
immunoglobulin A
IgB
immunoglobulin B
IMP
investigational medicinal product
IND
Investigational New Drug 
IRB
Institutional Review Board
IUD
intrauterine device
IUS
intrauterine hormone-releasing system
IV
intravenous
LLN
lower limit of normal
LLOQ
lower limit of quantitation
LNS
low frequency nucleotide substitutions
LRI
lower respiratory tract illness
MAD
maximum administered dose
MDRD
Modification of Diet in Renal Disease
MERS
Middle East respiratory syndrome
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Abbreviation
Expanded Term
MERS-CoV
MERS-associated coronavirus
MOV
Molnupiravir 
mRNA
messenger RNA
NCS
not clinically significant
NHC
N-hydroxycytidine
NHC-TP
NHC 5'-triphosphate
NDA
New Drug Application 
P
protocol (number)
PBMC
peripheral blood mononuclear cell
PCL
Protocol Clarification Letter
PCR
polymerase chain reaction
PI
primary investigator
PK
pharmacokinetic
po
orally
PP
per-protocol
PRNT
Plaque Reduction Neutralization Tests
PTT
partial thromboplastin time
PVL
peak viral load
Q12H
every 12 hours
qicPCR
qualitative integrative cycler PCR
qRT-PCR
real-time quantitative reverse transcription PCR
RNA
ribonucleic acid
RR
respiratory rate
RSV 
respiratory syncytial virus
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)
SNA
serum neutralizing antibody
SoA
schedule of activities
SOC
standard of care
SOP
Standard Operating Procedures
sSAP
supplemental Statistical Analysis Plan
SUSAR
suspected unexpected serious adverse reaction
TK
toxicokinetic(s)
Tmax
time to maximum plasma concentration
TSS
total clinical symptoms
t1/2
half life
UDS
urine drug screen
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Abbreviation
Expanded Term
ULN
upper limit of normal
VL
viral load
VL-AUC
area under the viral load-time curve
VS
vital signs
WBC
white blood cell
WOCBP
woman/women of childbearing potential
WONCBP
woman/women of nonchildbearing potential
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11
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