A Phase 2b/3 Double-Blind, Randomized, Placebo-Controlled Study to Evaluate the Efficacy and Safety of MK-1654 in Healthy Pre-Term and Full-Term Infants
Phase: PHASE2
Conditions: Respiratory Syncytial Virus Infection
Sponsor: Merck Sharp & Dohme LLC

Official Protocol Title: 
NCT number: 
NCT04767373 
Document Date: 
02-Dec-2022
A Phase 2b/3 Double-Blind, Randomized, Placebo-
Controlled Study to Evaluate the Efficacy and Safety of 
MK-1654 in Healthy Pre-Term and Full-Term Infants

PRODUCT: MK-1654  
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PROTOCOL/AMENDMENT NO.: 004-05
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02-DEC-2022
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 2b/3 Double-Blind, Randomized, Placebo-Controlled Study to 
Evaluate the Efficacy and Safety of MK-1654 in Healthy Pre-Term and Full-Term Infants
Protocol Number: 004-05
Compound Number: MK-1654
Sponsor Name:
Merck Sharp & Dohme LLC
(hereafter referred to as the Sponsor or MSD)
Legal Registered Address:
126 East Lincoln Avenue
P.O. Box 2000
Rahway, NJ 07065 USA
Regulatory Agency Identifying Number(s):
IND
130097
EudraCT
2020-002405-26
EU CT
2022-500350-42-00
Approval Date: 02 December 2022
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Sponsor Signatory
Typed Name:
Title:
Date
Protocol-specific Sponsor contact information can be found in the Investigator Study
File Binder (or equivalent).
Investigator Signatory
I agree to conduct this clinical study in accordance with the design outlined in this protocol 
and to abide by all provisions of this protocol.
Typed Name:
Title:
Date
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DOCUMENT HISTORY
Document
Date of Issue
Overall Rationale
Amendment 5
02-DEC-2022
The key reasons for this amendment are to: 1) allow for over enrollment of participants in 
the study and 2) allow for local sourcing of placebo.
Amendment 4
01-APR-2022
The primary purpose of this amendment is to: 1) Clarify that blood collection for 
participants with an anaphylaxis or hypersensitivity AESI of Grade 3 or 4 is to assay for 
potential ADA to MK-1654, and additional ADA characterization, if indicated; 2) Add 
China-specific protocol requirements for a separate, additional swab collection for COVID-
19 testing.
Amendment 3
29-SEP-2021
The primary purpose of this amendment is to: 1) Provide additional guidance on respiratory 
infection assessment and nasopharyngeal (NP) sample collection; and 2) Add China-
specific protocol requirements.
Amendment 2
23-APR-2021
The purpose of this amendment is to address regional Health Authority feedback.
Amendment 1
08-FEB-2021
The primary purpose of this amendment is to add changes that align with the pediatric 
development plan and changes in severity grading of adverse events, which has been 
adapted from the National Cancer Institute Common Terminology Criteria for Adverse 
Events (NCI CTCAE) version 5.0.
Original Protocol
28-JUL-2020
Not applicable.
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PROTOCOL AMENDMENT SUMMARY OF CHANGES
Amendment: 05
Overall Rationale for the Amendments:
The key reasons for this amendment are to: 1) allow for over enrollment of participants in the study and 2) allow for local sourcing of 
placebo.
Summary of Changes Table:
Section # and Name
Description of Change 
Brief Rationale 
Section 1.1 Synopsis
Section 1.2 Schema
Section 4.1 Overall Design
Section 6.3.2 Stratification
Section 8.13.4 Early Withdrawal 
Visit
Section 9.1 Statistical Analysis 
Plan Summary
Section 9.7 Interim Analyses
Section 9.9.1.1 Sample Size and 
Power for Testing the Primary 
Efficacy Hypothesis

Updated content to allow for over enrollment up to 
10%. Made updates for these additional 
participants to be enrolled and followed through 
Day 365 (RSV Season 1 only).

Adjusted the early and moderate pre-term infant 
enrollment from at least 20% of participants to at 
least 600 participants.

To ensure that a sufficient number 
of participants are enrolled to 
support registration. Additional 
participants do not need to be 
followed through Day 515.

Adjusted early and moderate pre-
term infant enrollment to align 
with absolute count originally 
anticipated to be enrolled.
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Section # and Name
Description of Change 
Brief Rationale 
Section 4.1 Overall Design
Section 6.1 Study Intervention(s) 
Administered
Section 6.2.1 Dose Preparation

Removed “USP” from placebo description.

Changed dose formulation from vial to sterile 
solution.

Added local sourcing option for placebo.
Allow for local sourcing of placebo.
Title Page
Section 10.1.1 Code of Conduct 
for Clinical Trials
Throughout
Sponsor entity name and address change.
Merck Sharp & Dohme Corp. 
underwent an entity name and address 
change to Merck Sharp & Dohme 
LLC, Rahway, NJ, USA. This 
conversion resulted only in an entity 
name change and update to the 
address.
Title Page
Added EU CT study identifier.
EU CT number now available.
Section 1.1 Synopsis
Section 6.1 Study Intervention(s) 
Administered
Descriptions of Use and NIMP have been updated:

NIMP to NIMP/AxMP

For use, experimental to test product; placebo to 
comparator
The note in Table 2 describing the classification IMP 
and NIMP/AxMP was edited accordingly.
Per Regulation (EU) No 536/2014 of 
the European Parliament and of the 
Council
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Section # and Name
Description of Change 
Brief Rationale 
Section 1.3.2 Schedule of 
Activities – RSV Season 2 (First 
1650 Participants)
Removed “Start of RSV Season 2 follow-up” and 
“End of RSV Season 2 follow-up” from Visits 7 and 
8, respectively, and the notes.
The beginning and end of the RSV 
Season 2 may not align with study 
Days 365 and 515, respectively, due to 
the changing epidemiology of RSV
disease due to the COVID-19
pandemic.
Section 4.4 Beginning and End of 
Study Definition
Added text defining the local start of the study for
countries in the European Economic Area as First Site 
Ready in any Member State.
Per Regulation (EU) No 536/2014 of 
the European Parliament and of the 
Council
Section 5 Study Population
Added text regarding the Code of Conduct for Clinical 
Trials at the beginning of this section.
To clarify the collection, use, and 
confidentiality of demographic data 
provided by the participants.
Section 8.4 Adverse Events, 
Serious Adverse Events, and 
Other Reportable Safety Events
Section 10.3.1 Definitions of 
Medication Error, Misuse, and 
Abuse
Added definitions for medication error, misuse, or 
abuse and the need for investigator to report instances 
as an AE or SAE.
Per Regulation (EU) No 536/2014 of 
the European Parliament and of the 
Council
Section 8.13.3 Delay in 
Randomization and Study 
Medication Administration
Text was updated to associate Day 1 with the day
study medication is administered, not the day 
screening procedures are performed.
Clarification to define Day 1 if 
screening and dosing do not occur the 
same day.
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Section # and Name
Description of Change 
Brief Rationale 
Section 9.4.1 Efficacy/ 
Pharmacokinetics/ 
Pharmacodynamics/ 
Immunogenicity Endpoints
Tertiary efficacy endpoints were added to evaluate 
RSV-associated outpatient and inpatient ARI.
To evaluate efficacy endpoints of 
interest for the study.
Section 10.1.7 Compliance with 
Law, Audit, and Debarment
Added content to immediately report any 
serious/suspected serious breaches.
Per Regulation (EU) No 536/2014 of 
the European Parliament and of the 
Council
Section 8.1.1.1 General Informed 
Consent
Section 10.7.3 China
Added specifications for informed consent for 
participants in China.
Align with local regulatory guidelines.
Section 10.7.3 China
Updated timing of COVID-19 swab collection.
Clarification and to align with 
standard of practice.
Throughout document
Minor administrative, formatting, grammatical, and/or 
typographical changes were made throughout the 
document.
To ensure clarity and accurate 
interpretation of the intent of the 
protocol.
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Table of Contents
DOCUMENT HISTORY ........................................................................................................3
PROTOCOL AMENDMENT SUMMARY OF CHANGES...............................................4
1
PROTOCOL SUMMARY ............................................................................................16
1.1
Synopsis.................................................................................................................16
1.2
Schema ..................................................................................................................20
1.3
Schedule of Activities...........................................................................................21
1.3.1
Schedule of Activities – RSV Season 1 (All Participants) ..........................21
1.3.2
Schedule of Activities – RSV Season 2 (First 1650 Participants)...............26
2
INTRODUCTION..........................................................................................................27
2.1
Study Rationale....................................................................................................27
2.2
Background ..........................................................................................................28
2.2.1
Pharmaceutical and Therapeutic Background .............................................29
2.2.2
Preclinical and Clinical Studies ...................................................................29
2.2.3
Ongoing Clinical Studies.............................................................................30
2.2.4
Information on Other Study-related Therapy ..............................................30
2.3
Benefit/Risk Assessment......................................................................................30
3
HYPOTHESES, OBJECTIVES, AND ENDPOINTS................................................31
4
STUDY DESIGN............................................................................................................35
4.1
Overall Design......................................................................................................35
4.2
Scientific Rationale for Study Design.................................................................38
4.2.1
Rationale for Endpoints ...............................................................................38
4.2.1.1
Efficacy Endpoints.............................................................................38
4.2.1.1.1
RSV Season Definition............................................................40
4.2.1.2
Safety Endpoints................................................................................41
4.2.1.3
Pharmacokinetic Endpoints ...............................................................41
4.2.1.3.1
MK-1654 Serum Concentration...............................................41
4.2.1.4
Immunogenicity Endpoints................................................................42
4.2.1.4.1
Antidrug Antibodies (ADA) ....................................................42
4.2.1.5
Pharmacodynamic Endpoints.............................................................42
4.2.1.5.1
Serum Neutralizing Activity Against RSV..............................42
4.2.1.6
Additional Tertiary Endpoints ...........................................................42
4.2.1.6.1
RSV F Gene Sequencing and MK-1654 Sensitivity Testing...42
4.2.1.7
Future Biomedical Research..............................................................42
4.2.2
Rationale for the Use of Placebo .................................................................43
4.3
Justification for Dose...........................................................................................43
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4.4
Beginning and End of Study Definition .............................................................44
4.4.1
Clinical Criteria for Early Study Termination .............................................44
5
STUDY POPULATION ................................................................................................44
5.1
Inclusion Criteria.................................................................................................44
5.2
Exclusion Criteria................................................................................................45
5.3
Lifestyle Considerations......................................................................................46
5.4
Screen Failures.....................................................................................................46
5.5
Participant Replacement Strategy......................................................................46
6
STUDY INTERVENTION............................................................................................46
6.1
Study Intervention(s) Administered...................................................................47
6.2
Preparation/Handling/Storage/Accountability .................................................49
6.2.1
Dose Preparation..........................................................................................49
6.2.2
Handling, Storage, and Accountability........................................................49
6.3
Measures to Minimize Bias: Randomization and Blinding..............................50
6.3.1
Intervention Assignment..............................................................................50
6.3.2
Stratification.................................................................................................50
6.3.3
Blinding........................................................................................................50
6.4
Study Intervention Compliance..........................................................................51
6.5
Concomitant Therapy..........................................................................................51
6.5.1
Rescue Medications and Supportive Care ...................................................52
6.6
Dose Modification ................................................................................................52
6.7
Intervention After the End of the Study............................................................52
6.8
Clinical Supplies Disclosure................................................................................52
7
DISCONTINUATION OF STUDY INTERVENTION AND PARTICIPANT 
WITHDRAWAL............................................................................................................53
7.1
Discontinuation of Study Intervention...............................................................53
7.2
Participant Withdrawal From the Study...........................................................53
7.3
Lost to Follow-up .................................................................................................53
8
STUDY ASSESSMENTS AND PROCEDURES........................................................53
8.1
Administrative and General Procedures ...........................................................55
8.1.1
Informed Consent.........................................................................................55
8.1.1.1
General Informed Consent.................................................................55
8.1.1.2
Consent and Collection of Specimens for Future Biomedical 
Research.............................................................................................55
8.1.2
Inclusion/Exclusion Criteria ........................................................................56
8.1.3
Participant Identification Card.....................................................................56
8.1.4
Medical History ...........................................................................................56
8.1.5
Prior and Concomitant Medications Review...............................................56
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8.1.5.1
Prior Medications...............................................................................56
8.1.5.2
Concomitant Medications..................................................................56
8.1.6
Assignment of Screening Number...............................................................57
8.1.7
Assignment of Randomization Number.......................................................57
8.1.8
Study Intervention Administration ..............................................................57
8.1.8.1
Timing of Dose Administration.........................................................57
8.1.9
Discontinuation and Withdrawal .................................................................58
8.1.9.1
Withdrawal From Future Biomedical Research ................................58
8.1.10
Participant Blinding/Unblinding..................................................................59
8.1.11
Domiciling ...................................................................................................59
8.1.12
Calibration of Equipment.............................................................................59
8.2
Efficacy (Respiratory Pathogen) Assessments ..................................................60
8.2.1
Surveillance for Respiratory Infection Symptoms.......................................60
8.2.1.1
Definition of Distinct Episodes of Respiratory Infection ..................61
8.2.2
Respiratory Infection Assessment................................................................61
8.2.2.1
Requirements for Scheduling a Respiratory Infection Assessment...61
8.2.2.2
Procedures at a Respiratory Infection Assessment ............................62
8.2.3
Nasopharyngeal Sample Collection for RT-PCR Testing for Respiratory 
Pathogen Identification ................................................................................63
8.3
Safety Assessments...............................................................................................64
8.3.1
Physical Examinations Including Length and Weight.................................65
8.3.2
Vital Signs....................................................................................................65
8.3.3
Body Temperature Measurement.................................................................65
8.3.4
30-minute Postdose Safety Observation ......................................................66
8.3.5
Electronic Diary...........................................................................................66
8.3.6
Day 3 Safety Phone Call..............................................................................67
8.3.7
Clinical Laboratory Assessments.................................................................68
8.4
Adverse Events, Serious Adverse Events, and Other Reportable Safety 
Events....................................................................................................................68
8.4.1
Time Period and Frequency for Collecting AE, SAE, and Other 
Reportable Safety Event Information ..........................................................69
8.4.2
Method of Detecting AEs, SAEs, and Other Reportable Safety Events......70
8.4.3
Follow-up of AE, SAE, and Other Reportable Safety Event Information...71
8.4.4
Regulatory Reporting Requirements for SAE .............................................71
8.4.5
Pregnancy and Exposure During Breastfeeding ..........................................71
8.4.6
Disease-related Events and/or Disease-related Outcomes Not Qualifying 
as AEs or SAEs............................................................................................71
8.4.7
Events of Clinical Interest............................................................................71
8.4.8
Adverse Events of Special Interest ..............................................................71
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8.4.8.1
Anaphylaxis/Hypersensitivity Events................................................72
8.4.8.2
Rash Events........................................................................................73
8.4.8.2.1
Photography.............................................................................74
8.4.8.2.2
Dermatology Consultation.......................................................75
8.5
Treatment of Overdose........................................................................................75
8.6
Pharmacokinetics.................................................................................................75
8.7
Immunogenicity....................................................................................................76
8.7.1
Blood Collection for Antidrug Antibodies (ADA) Assay ...........................76
8.8
Pharmacodynamics..............................................................................................76
8.8.1
Blood Collection for Serum Neutralizing Antibodies Against RSV 
(SNA) Assay ................................................................................................76
8.9
Gene Sequencing and Sensitivity Testing ..........................................................76
8.9.1
Nasopharyngeal Sample Collection for RT-PCR Testing and RSV F 
Gene Sequencing for Sensitivity to MK-1654.............................................76
8.10
Biomarkers ...........................................................................................................76
8.11
Future Biomedical Research Sample Collection...............................................76
8.12
Medical Resource Utilization and Health Economics.......................................77
8.13
Visit Requirements...............................................................................................77
8.13.1
Screening (Visit 1 Predose) .........................................................................77
8.13.1.1
Predose Nasopharyngeal Sample Collection for RT-PCR Testing....77
8.13.2
Randomization/Dose Administration/Observation (Visit 1) .......................77
8.13.3
Delay in Randomization and Study Medication Administration.................78
8.13.4
Early Withdrawal Visit ................................................................................78
8.13.5
Visits at the Study Site, at Home, or at an Alternate Study Site Location...78
9
STATISTICAL ANALYSIS PLAN .............................................................................79
9.1
Statistical Analysis Plan Summary.....................................................................79
9.2
Responsibility for Analyses/In-house Blinding .................................................81
9.3
Hypotheses/Estimation ........................................................................................81
9.4
Analysis Endpoints...............................................................................................81
9.4.1
Efficacy/Pharmacokinetics/Pharmacodynamics/Immunogenicity 
Endpoints .....................................................................................................81
9.4.2
Safety Endpoints..........................................................................................83
9.5
Analysis Populations............................................................................................84
9.5.1
Efficacy Analysis Populations.....................................................................84
9.5.2
Immunogenicity and Pharmacodynamic Analysis Populations...................85
9.5.3
Pharmacokinetic Analysis Populations........................................................85
9.5.4
Safety Analysis Populations ........................................................................85
9.6
Statistical Methods...............................................................................................85
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9.6.1
Statistical Methods for Efficacy Analyses...................................................86
9.6.2
Statistical Methods for Safety Analyses ......................................................87
9.6.3
Demographic and Baseline Characteristics .................................................88
9.6.3.1
Population Pharmacokinetic Analyses...............................................89
9.7
Interim Analyses ..................................................................................................89
9.8
Multiplicity ...........................................................................................................91
9.9
Sample Size and Power Calculations .................................................................91
9.9.1
Sample Size and Power for Efficacy Analyses............................................91
9.9.1.1
Sample Size and Power for Testing the Primary Efficacy 
Hypothesis..........................................................................................91
9.9.1.2
Sample Size and Power for Testing the Secondary Efficacy 
Hypothesis..........................................................................................91
9.9.2
Sample Size and Power for Safety Analyses ...............................................92
9.10
Subgroup Analyses...............................................................................................93
9.11
Compliance (Medication Adherence).................................................................93
9.12
Extent of Exposure...............................................................................................93
10
SUPPORTING DOCUMENTATION AND OPERATIONAL 
CONSIDERATIONS.....................................................................................................94
10.1
Appendix 1: Regulatory, Ethical, and Study Oversight Considerations........94
10.1.1
Code of Conduct for Clinical Trials.............................................................94
10.1.2
Financial Disclosure.....................................................................................96
10.1.3
Data Protection.............................................................................................96
10.1.3.1
Confidentiality of Data ......................................................................97
10.1.3.2
Confidentiality of Participant Records...............................................97
10.1.3.3
Confidentiality of IRB/IEC Information............................................97
10.1.4
Committees Structure...................................................................................98
10.1.4.1
Scientific Advisory Committee (SAC)..............................................98
10.1.4.2
Executive Oversight Committee........................................................98
10.1.4.3
External Data Monitoring Committee ...............................................98
10.1.5
Publication Policy........................................................................................98
10.1.6
Compliance with Study Registration and Results Posting Requirements ...99
10.1.7
Compliance with Law, Audit, and Debarment ............................................99
10.1.8
Data Quality Assurance .............................................................................100
10.1.9
Source Documents .....................................................................................101
10.1.10
Study and Site Closure...............................................................................101
10.2
Appendix 2: Clinical Laboratory Tests............................................................102
10.3
Appendix 3: Adverse Events: Definitions and Procedures for Recording, 
Evaluating, Follow-up, and Reporting.............................................................104
10.3.1
Definitions of Medication Error, Misuse, and Abuse................................104
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10.3.2
Definition of AE ........................................................................................104
10.3.3
Definition of SAE ......................................................................................105
10.3.4
Additional Events Reported.......................................................................107
10.3.5
Recording AE and SAE .............................................................................107
10.3.6
Reporting of AEs, SAEs, and Other Reportable Safety Events to the 
Sponsor ......................................................................................................116
10.4
Appendix 4: Medical Device and Drug-device Combination Products: 
Product Quality Complaints/Malfunctions: Definitions, Recording, and 
Follow-up ............................................................................................................117
10.5
Appendix 5: Contraceptive Guidance..............................................................118
10.6
Appendix 6: Collection and Management of Specimens for Future 
Biomedical Research..........................................................................................119
10.7
Appendix 7: Country-specific Requirements..................................................124
10.7.1
Countries in the European Union Region and the United Kingdom .........124
10.7.2
South Korea ...............................................................................................124
10.7.3
China..........................................................................................................125
10.8
Appendix 8: Abbreviations ...............................................................................126
11
REFERENCES.............................................................................................................128
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LIST OF TABLES
Table 1
Respiratory Syncytial Virus (RSV)-associated Medically Attended Lower 
Respiratory Infection (MALRI) Diagnostic Criteria .......................................39
Table 2
Study Interventions..........................................................................................48
Table 3
Reporting Time Periods and Time Frames for Adverse Events and Other 
Reportable Safety Events.................................................................................70
Table 4
Terms for Anaphylaxis/Hypersensitivity Events.............................................72
Table 5
Terms for Rash Events.....................................................................................73
Table 6
Analysis Strategy for Key Efficacy Variables.................................................87
Table 7
Analysis Strategy for Safety Parameters..........................................................88
Table 8
Futility Evaluation Operating Characteristics (Interim Analysis #2) ..............90
Table 9
Differences in Incidence of Adverse Event Rates Between the 2 Groups 
That can be Detected With an ~80% Probability (Assuming 2-sided 5% 
Alpha Level With 2200 Participants in the MK-1654 Group and 
1100 Participants in the Placebo Group) .........................................................92
Table 10
Laboratory Assessments in the MK-1654-004 Study....................................102
Table 11
Blood Draw Schedule and Approximate Blood Sample Volumes Drawn 
Per Study Visit for Participants who Weigh ≥3kg.........................................103
Table 12
Maximum Blood Sample Volume Drawn Per Study Visit by Participant 
Weight............................................................................................................103
Table 13
Solicited Injection-site AE Severity Grading Scale.......................................109
Table 14
Solicited Systemic AE Severity Grading Scale .............................................109
Table 15
Elevated Temperature (Rectal) Severity Grading Scale................................110
Table 16
AESI: Anaphylaxis/Hypersensitivity Severity Grading Scale.......................111
Table 17
AESI: Rash Severity Grading Scale ..............................................................112
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LIST OF FIGURES
Figure 1
MK-1654-004 Study Design......................................................................20
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1
PROTOCOL SUMMARY
1.1
Synopsis
Protocol Title: A Phase 2b/3 Double-Blind, Randomized, Placebo-Controlled Study to 
Evaluate the Efficacy and Safety of MK-1654 in Healthy Pre-Term and Full-Term Infants
Short Title: Efficacy and Safety of MK-1654 in Healthy Pre-term and Full-Term Infants
Acronym: Not applicable
Hypotheses, Objectives, and Endpoints:
Hypotheses are aligned with objectives in the Objectives and Endpoints table.
The following objectives will be evaluated in healthy pre-term and full-term infants receiving 
a single IM dose of MK-1654 or placebo.
Primary Objectives
Primary Endpoints
- To evaluate the efficacy of MK-1654 
compared to placebo as assessed by the 
incidence of RSV-associated MALRI 
(outpatient and inpatient) from Days 1 
through 150 postdose.
Hypothesis: Administration of MK-1654 
reduces the incidence of RSV-associated 
MALRI from Days 1 through 150 postdose 
compared to placebo (The statistical 
criterion for success requires the lower limit 
of the 95% CI for efficacy to be greater than 
25%).
- RSV-associated MALRI (outpatient and 
inpatient), defined as the following seen in 
an outpatient or inpatient clinical setting: 
- Cough or difficulty breathing; AND
- 1 or more of the following: wheezing, 
chest wall in-drawing/retractions, 
rales/crackles, hypoxemia, tachypnea, 
dehydration due to respiratory symptoms; 
AND
- RSV-positive RT-PCR NP sample
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- To evaluate the safety and tolerability of 
MK-1654 compared to placebo as assessed 
by the proportion of participants 
experiencing AEs.
- Solicited injection-site AEs from Days 1 
through 5 postdose
- Solicited daily body temperature, with 
fever defined as rectal temperature 
≥102.2°F (≥39.0°C) or axillary temperature 
≥101.7°F (≥38.7°C), from Days 1 through 5 
postdose
- Solicited systemic AEs from Days 1 
through 5 postdose
- Anaphylaxis/hypersensitivity AESI from 
Days 1 through 42 postdose
- Rash AESI from Days 1 through 42 
postdose
- Nonserious AEs from Days 1 through 42 
postdose
- SAEs through the duration of study 
participation
Secondary Objectives
Secondary Endpoints
- To evaluate the efficacy of MK-1654 
compared to placebo as assessed by the 
incidence of RSV-associated hospitalization 
from Days 1 through 150 postdose.
Hypothesis: Administration of MK-1654 
reduces the incidence of RSV-associated 
hospitalization from Days 1 through 150 
postdose compared to placebo (The 
statistical criterion for success requires the 
lower limit of the 95% CI for efficacy to be 
greater than 0%).
- RSV-associated hospitalization, defined as 
the following: 
- Hospital admission for respiratory illness; 
AND 
- RSV-positive RT-PCR NP sample
- To estimate the efficacy of MK-1654 
compared to placebo as assessed by the 
incidence of RSV-associated MALRI 
(outpatient and inpatient) from Days 1 
through 180 postdose.
- RSV-associated MALRI (outpatient and 
inpatient), defined as above
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Overall Design:
Study Phase
Phase 2/Phase 3
Primary Purpose
Prevention
Indication
Respiratory syncytial virus infection
Population
Healthy pre-term and full-term infants
Study Type
Interventional
Intervention Model
Parallel
This is a multi-site study.
Type of Control
Placebo
Study Blinding
Double-blind with in-house blinding
Blinding Roles
Participants or Subjects
Investigator
Sponsor
Estimated Duration of 
Study
The Sponsor estimates that the study will require 
approximately 3.5 years from the time the first participant's 
legally acceptable representative provides documented 
informed consent until the last participant’s last study-
related contact. For purposes of analysis and reporting, the 
overall study ends when the Sponsor receives the last 
laboratory result or at the time of final contact with the last 
participant, whichever comes last.
Number of Participants:
Approximately 3300 participants will be allocated/randomized in this study as described in 
Section 9.9.
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Intervention Groups and Duration:
Intervention 
Groups
Intervention 
Group Name
Drug
Dose 
Strength
Dose 
Frequency
Route 
of 
Admin.
Regimen/ 
Treatment 
Period
Use
MK-1654
MK-1654
105 mg dose
(150 mg/mL 
dose strength)
Single dose
IM
Single dose at 
Visit 1
(Day 1)
Test 
product
Placebo
Placebo
0 mg
Single dose
IM
Single dose at 
Visit 1
(Day 1)
Placebo
Admin.=administration; IM=intramuscular.
Total 
Number of 
Intervention 
Groups/ 
Arms
2 intervention groups
Duration of 
Participation
Each participant will be screened, randomized, and receive the assigned 
study intervention on Day 1 and will be followed for either 365 days or 
515 days. The first 1650 participants (300 from the Phase 2b cohort and the 
first 1350 from the Phase 3 cohort) will participate in the study for 
approximately 515 days from the time the participant’s legally acceptable 
representative provides documented informed consent through the final 
contact. The remainder of participants in the Phase 3 cohort will participate 
in the study for 365 days from the time the participant’s legally acceptable 
representative provides documented informed consent through the final 
contact.
Study Governance Committees:
Steering Committee
No
Executive Oversight Committee
Yes
Data Monitoring Committee
Yes
Clinical Adjudication Committee
No
Study governance and SAC considerations are outlined in Appendix 1 (Section 10.1.4).
Study Accepts Healthy Volunteers: Yes
A list of abbreviations used in this document can be found in Appendix 8.
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1.2
Schema
The study design is depicted in Figure 1.
Figure 1
MK-1654-004 Study Design
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1.3
Schedule of Activities
1.3.1
Schedule of Activities – RSV Season 1 (All Participants)
Study Period
Screening, 
Randomization, and 
Intervention
Follow-up
(through 365 days postdose)
Notes
Visit Number/Title
1
TC 2
Weekly 
TC
start
3
4
5
Weekly 
TC
end
6
TC
7
UNSCH
See Section 8.13 for descriptions of study 
visits.
UNSCH for respiratory infection and 
AESI assessment, if indicated.
Scheduled Day and 
Window (Days):
Day 1
3
7
+2
14
±2a
42
+2
90
±5
150
±5
180
±2a
240
±5
300
±5
365
+14b
a Weekly TCs will start at Day 14 and 
end at Day 180; each weekly TC should 
occur within 1 week ±2 days of the prior 
TC.
b The Visit 7 window (+14 days) applies 
to participants who complete the study at 
this visit. For participants who continue 
on to RSV Season 2, see Section 1.3.2.
Pre
dose
Dose Post
dose
Administrative Procedures
Informed Consent
X
Informed Consent for FBR
X
Participation in FBR is optional and 
consent must be obtained before 
collection of buccal swab DNA samples.
Not applicable for participants in China 
(see Appendix 7).
Inclusion/Exclusion Criteria
X
Participant Identification 
Card
X
Randomization number will be added to 
the card.
Medical History
X
Prior/Concomitant 
Medication Review
X
X
X
X
X
X X
X
X
X
X
X
X
After Day 42, only record concomitant 
medications associated with an SAE.
Predose NP Sample 
Collection for RT-PCR 
Testing
X (if 
indicated)
Collect if respiratory infection symptoms 
are present within 7 days before Visit 1. 
See Section 8.13.1.1 and Section 8.2.3.
Assignment of 
Randomization Number
X
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Study Period
Screening, 
Randomization, and 
Intervention
Follow-up
(through 365 days postdose)
Notes
Visit Number/Title
1
TC 2
Weekly 
TC
start
3
4
5
Weekly 
TC
end
6
TC
7
UNSCH
See Section 8.13 for descriptions of study 
visits.
UNSCH for respiratory infection and 
AESI assessment, if indicated.
Scheduled Day and 
Window (Days):
Day 1
3
7
+2
14
±2a
42
+2
90
±5
150
±5
180
±2a
240
±5
300
±5
365
+14b
a Weekly TCs will start at Day 14 and 
end at Day 180; each weekly TC should 
occur within 1 week ±2 days of the prior 
TC.
b The Visit 7 window (+14 days) applies 
to participants who complete the study at 
this visit. For participants who continue 
on to RSV Season 2, see Section 1.3.2.
Pre
dose
Dose Post
dose
MK-1654 or Placebo 
Administration
X
Provide or Configure 
Device for eDiary Data 
Collection and Provide 
LAR Training
X
Review instructions for daily eDiary use 
with LAR (see Section 8.3.5). Instruct
LAR on how to detect AESI (see 
Section 8.4.8 and AESI guidance 
document).
Review eDiary Data with 
LAR
X
X
X
X
Collect eDiary Device from 
LAR
X
For participants using a study-provided 
device, collect after the 42-day period.
Safety Procedures
Full Physical Examination 
including Weight and 
Length
X
Brief Directed Physical 
Examination including 
Weight and Length
X
X X
X
X
X
Xc
Measure weight and length at all visits.
c Perform brief directed examination at an 
unscheduled visit if necessary.
Vital Signs
X
X
X
X X
X
X
X
X
See Section 8.3.2.
30-minute Postdose Safety 
Observation
X
Performed by blinded site staff only. 
Postdose vital signs should be repeated 
after the observation period.
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Study Period
Screening, 
Randomization, and 
Intervention
Follow-up
(through 365 days postdose)
Notes
Visit Number/Title
1
TC 2
Weekly 
TC
start
3
4
5
Weekly 
TC
end
6
TC
7
UNSCH
See Section 8.13 for descriptions of study 
visits.
UNSCH for respiratory infection and 
AESI assessment, if indicated.
Scheduled Day and 
Window (Days):
Day 1
3
7
+2
14
±2a
42
+2
90
±5
150
±5
180
±2a
240
±5
300
±5
365
+14b
a Weekly TCs will start at Day 14 and 
end at Day 180; each weekly TC should 
occur within 1 week ±2 days of the prior 
TC.
b The Visit 7 window (+14 days) applies 
to participants who complete the study at 
this visit. For participants who continue 
on to RSV Season 2, see Section 1.3.2.
Pre
dose
Dose Post
dose
AE/SAE Review
X
X
X
X
X X
X
X
X
X
X
X
Venous Blood for ADA and 
Additional ADA 
Characterization
X
(if indicated)
X
Collect if participant experiences a 
Grade 3 or 4 anaphylaxis/ 
hypersensitivity AESI on Day 2-42. See 
Section 8.4.8.1 and Appendix 2.
Respiratory Pathogen Assessments
Surveillance for 
Respiratory Infection 
Symptoms
X
X
Weekly TC
Determine if participant had respiratory
symptoms or was seen in a clinical 
setting. Weekly TC after the Day 7 visit 
through Day 180. See Section 8.2.1.
Respiratory Infection
Assessment
X (if indicated)
X
Required if respiratory infection 
symptoms require further assessment.
See Section 8.2.2.
NP Sample Collection for 
RT-PCR Testing
X (if indicated)
X
Collect if respiratory infection symptoms 
are observed. See Section 8.2.2.2 and
Section 8.2.3. See Appendix 7 for China-
specific requirements.
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Study Period
Screening, 
Randomization, and 
Intervention
Follow-up
(through 365 days postdose)
Notes
Visit Number/Title
1
TC 2
Weekly 
TC
start
3
4
5
Weekly 
TC
end
6
TC
7
UNSCH
See Section 8.13 for descriptions of study 
visits.
UNSCH for respiratory infection and 
AESI assessment, if indicated.
Scheduled Day and 
Window (Days):
Day 1
3
7
+2
14
±2a
42
+2
90
±5
150
±5
180
±2a
240
±5
300
±5
365
+14b
a Weekly TCs will start at Day 14 and 
end at Day 180; each weekly TC should 
occur within 1 week ±2 days of the prior 
TC.
b The Visit 7 window (+14 days) applies 
to participants who complete the study at 
this visit. For participants who continue 
on to RSV Season 2, see Section 1.3.2.
Pre
dose
Dose Post
dose
Pharmacokinetics/Immunogenicity/Pharmacodynamics
All participants will be randomly 
assigned by IRT to 1 of the 2 blood 
sampling groups (Group 1 or Group 2), 
then assigned to 1 of the 2 testing 
subgroups (a or b). Collect predose from 
randomized participants only. 
Group 1
Group 1a:
Group 1a Venous Blood for
MK-1654 PK
X
X
X
Group 1a Venous Blood for
ADA
X
X
See Section 4.2.1.4.1.
Group 1a Venous Blood for
SNA
X
X
X
Not applicable for participants in China 
(see Appendix 7).
Group 1b:
Group 1b Venous Blood for
MK-1654 PK
X
X
X
Group 1b Venous Blood for
ADA
X
X
See Section 4.2.1.4.1.
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Study Period
Screening, 
Randomization, and 
Intervention
Follow-up
(through 365 days postdose)
Notes
Visit Number/Title
1
TC 2
Weekly 
TC
start
3
4
5
Weekly 
TC
end
6
TC
7
UNSCH
See Section 8.13 for descriptions of study 
visits.
UNSCH for respiratory infection and 
AESI assessment, if indicated.
Scheduled Day and 
Window (Days):
Day 1
3
7
+2
14
±2a
42
+2
90
±5
150
±5
180
±2a
240
±5
300
±5
365
+14b
a Weekly TCs will start at Day 14 and 
end at Day 180; each weekly TC should 
occur within 1 week ±2 days of the prior 
TC.
b The Visit 7 window (+14 days) applies 
to participants who complete the study at 
this visit. For participants who continue 
on to RSV Season 2, see Section 1.3.2.
Pre
dose
Dose Post
dose
Group 2
Group 2a:
Group 2a Venous Blood for
MK-1654 PK
X
X
X
Group 2a Venous Blood for
ADA
X
X
X
See Section 4.2.1.4.1.
Group 2a Venous Blood for
SNA
X
X
X
Not applicable for participants in China 
(see Appendix 7).
Group 2b:
Group 2b Venous Blood for
MK-1654 PK
X
X
X
Group 2b Venous Blood for
ADA
X
X
X
See Section 4.2.1.4.1.
Future Biomedical Research
Buccal Swabs (DNA) for 
FBR
X
Should be obtained predose on 
randomized and FBR-consented 
participants only. However, it can be 
collected at any later study visit after 
randomization. Not applicable for 
participants in China (see Appendix 7).
ADA=antidrug antibodies; AE=adverse event; AESI=adverse event of special interest; DNA=deoxyribonucleic acid; eDiary=electronic diary; FBR=future biomedical research; IRT=interactive response 
technology; LAR=legally acceptable representative; NP=nasopharyngeal; PK=pharmacokinetics; RSV=respiratory syncytial virus; RT-PCR=reverse transcriptase-polymerase chain reaction; 
SAE=serious adverse event; SNA=serum neutralizing antibodies against RSV; TC=telephone call; UNSCH=unscheduled visit.
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1.3.2
Schedule of Activities – RSV Season 2 (First 1650 Participants)
Study Period:
Follow-up
(365 through 515 days postdose)
Notes
Visit Number/Title:
7
Weekly 
TC start
8
UNSCH
See Section 8.13 for descriptions of study visits.
UNSCH for respiratory infection assessment, if indicated.
Scheduled Day and Window 
(Days):
365
±5
372
±2a
515
+14
If 
indicated
RSV Season 2 Visit 7 (Day 365) is the same visit as RSV 
Season 1 Visit 7 (Day 365). Follow-up will be Days 365 through 
515 postdose.
a Weekly TCs will start at Day 372 and continue until 1 week 
before the day Visit 8 is scheduled; each weekly TC should occur
within 1 week ±2 days of the prior TC.
Administrative Procedures
Concomitant Medication Review
X
X
X
X
Only record concomitant medications associated with an SAE.
Safety Procedures
Brief Directed Physical
Examination including Weight 
and Length
X
X
Xb
Measure weight and length at all visits.
b Perform brief directed examination at an unscheduled visit if 
necessary.
Vital Signs
X
X
X
See Section 8.3.2.
SAE Review
X
X
X
X
Only record SAEs.
Respiratory Pathogen Assessments
Surveillance for Respiratory 
Infection Symptoms
Weekly TC
Determine if participant had respiratory symptoms or was seen in 
a clinical setting. Weekly TC after Visit 7 through RSV Season 2 
follow-up.
Respiratory Infection Assessment
X (if indicated)
X
Required if respiratory infection symptoms require further 
assessment. See Section 8.2.2.
NP Sample Collection for RT-
PCR Testing
X (if indicated)
Collect if respiratory infection symptoms are observed. See 
Section 8.2.2.2 and Section 8.2.3. See Appendix 7 for China-
specific requirements.
Immunogenicity/Pharmacodynamics
Venous Blood for ADA
X
X
Collected only in the first 750 participants continuing in RSV 
Season 2. These participants will be from Season 1 Group 1a and 
Group 2a. For ADA, see Section 4.2.1.4.1. 
Venous Blood for SNA
X
X
ADA=antidrug antibodies; LAR=legally acceptable representative; NP=nasopharyngeal; RSV=respiratory syncytial virus; RT-PCR=reverse transcriptase-polymerase chain 
reaction; SAE=serious adverse event; SNA=serum neutralizing antibodies against RSV; TC=telephone call; UNSCH=unscheduled visit.
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2
INTRODUCTION
MK-1654 is a fully human mAb targeting the RSV F protein, which the virus utilizes to enter 
host cells and fuse infected cells with adjacent cells, spreading by forming syncytia. The 
F protein is considered a key antigen for protective immunity, based on natural immunity 
studies and active and passive immunization approaches (eg, palivizumab) [American 
Academy of Pediatrics Committee on Infectious Diseases 2014] [Graham, B. S., et al 2015].
MK-1654 has an extended half-life, and PK modeling suggests that a single dose of MK-
1654 will sustain therapeutic levels for 5 months in the majority of infants entering their first 
RSV season.
RSV remains a major health problem in infants (see Section 2.2) as well as adults. Vaccine 
development has been a longstanding challenge. Passive immunization with a neutralizing 
mAb against the RSV F protein is a proven prophylaxis approach in infants. Palivizumab
(SynagisTM, MedImmune) is a prophylactic mAb targeting the RSV F protein approved for 
the prevention of serious lower respiratory tract disease caused by RSV in children at high 
risk for RSV disease [U.S. Prescribing Information 2009] [American Academy of Pediatrics 
Committee on Infectious Diseases 2014]. This approach provides near-immediate protection 
at birth [American Academy of Pediatrics Committee on Infectious Diseases 2014] and 
accommodates the immature immune system and high safety requisites of this infant 
population [Acosta, P. L., et al 2015] [Graham, B. S., et al 2015]. Similarly, MK-1654 is also 
a neutralizing mAb against RSV, with additional attributes to facilitate its application as an 
RSV prophylactic for infants currently not receiving palivizumab, as outlined in Section 2.1
and Section 2.2.
2.1
Study Rationale
MK-1654 is being developed to prevent RSV infection in infants. Very premature infants, 
and those with chronic heart and lung disease, are at highest risk for complications of RSV 
infection, and palivizumab is available for this narrow population. However, the vast 
majority of RSV infections occur among otherwise healthy pre-term and full-term infants. 
An efficacious prophylactic agent has the potential to make a substantial positive impact on 
infant health, caregivers, and the healthcare system. To have the greatest impact on the 
pediatric RSV disease burden, prophylaxis must be active nearly immediately after birth for 
infants born in the RSV season. MK-1654 is a fully human anti-RSV mAb being developed 
to prevent MALRI in infants with a single dose administered before the onset of the RSV 
season or, for those infants born during the RSV season, soon after birth.
The MK-1654-004 study is being conducted to assess the efficacy and safety, along with PK,
of MK-1654 for the prevention of RSV-associated MALRI in healthy pre-term and full-term
infants. The study will enroll participants with a chronological age from birth up to 1 year 
and entering their first RSV season at the time that documented informed consent is provided
(see Inclusion Criteria 3 and 4 in Section 5.1); infants 0 through 8 months (ie, up to 8 months 
and 29 days) of age at the time of consent will comprise at least 90% of the participants (see 
Section 4.2.1.1.1). 
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2.2
Background
Burden of RSV Infection in Infants
RSV is the most common cause of bronchiolitis, LRI, and hospitalization in infants. An 
estimated 74,000 to 126,000 infant hospitalizations in the US result from RSV each year, 
representing an annual rate of 25 to 40 per 1000 infants [Hall, C. B., et al 2013] [Shay, D. K., 
et al 1999] [Holman, R. C., et al 2004]. RSV infection has been associated with 43% to 74% 
of bronchiolitis and 19% to 54% of pneumonia cases in hospitalized children [Shay, D. K., et 
al 1999]. Globally, RSV is estimated to cause 22% of all acute LRI among children <5 years 
old and 3.4 million episodes of severe acute LRI [Garcia, C. G., et al 2010]. Moreover, 
mortality from RSV infection is significant, with an estimated 94,600 to 149,400 childhood 
deaths reported annually worldwide [Shi, T., et al 2015]. The overwhelming majority of 
these deaths occur in developing countries. In contrast, in the US, the death rate in infants 
due to RSV is low, likely due to quality supportive care [Nair, H., et al 2010].
Beyond hospitalization and death, RSV infection is a significant driver of outpatient 
healthcare utilization in infants, leads to the development of some chronic respiratory 
illnesses, and results in workdays missed by caregivers [Bourgeois, F. T., et al 2009]. An 
estimated 2.2% (1.7 million visits) of all United States primary care visits of children ≤5 
years old in 2000 were due to RSV infection. Pre-term infants with RSV averaged 12.4
physician office visits for any cause and 5 visits for respiratory causes during their first 
2 years of life, whereas children without RSV averaged 9.4 visits for any cause and 2.9 visits 
for respiratory causes during their first 2 years of life [Diez-Domingo, J., et al 2014]. 
Compared to influenza, children with RSV were more likely to receive intensive medical 
care, medications (including antibiotics), and radiologic studies [Bourgeois, F. T., et al 
2009]. Children previously infected with RSV also have a higher risk of developing some 
chronic conditions, including allergic rhino-conjunctivitis [Diez-Domingo, J., et al 2014], 
recurrent wheezing, and asthma [Polack F. P. 2015]. Taken together, these data highlight the 
burden of RSV for infants, caregivers, and healthcare providers and systems.
A prophylactic to prevent RSV infection in the majority of healthy infants remains an unmet 
medical need.
Pre-term infants, and those with underlying medical conditions, are at risk for severe RSV 
infection, due to comorbidities, relative immunodeficiency, paucity of maternal RSV-specific 
antibodies, and/or incomplete airway development or damage [van Drunen Littel-van den 
Hurk, S. 2012]. A prophylactic mAb targeting the RSV F protein, palivizumab (SynagisTM, 
MedImmune), is approved for the prevention of serious lower respiratory tract disease caused 
by RSV in children at high risk for RSV disease and with medical conditions that place them 
at risk of complications from this disease [U.S. Prescribing Information 2009] [American 
Academy of Pediatrics Committee on Infectious Diseases 2014]. In the published controlled 
study of the IMPact-RSV Study Group, palivizumab reduced RSV hospitalization by 
approximately 55% compared to placebo in premature and high-risk infants (≤35 weeks 
gestation and ≤6 months of age; or ≤24 months with a clinical diagnosis of CLD (also 
referred to as bronchopulmonary dysplasia) requiring ongoing medical treatment within the 
past 6 months) [Joffe, S., et al 1999] [The IMpact-RSV Study Group. 1998]. The safety and 
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efficacy of palivizumab were assessed in 2 randomized, double-blind, placebo-controlled 
studies of prophylaxis against RSV infection in children at high risk of an RSV-related 
hospitalization in participants ≤24 months of age with CLD and infants with premature birth 
(≤35 weeks gestational age who were ≤6 months of age at study entry) (Trial 1) or 
hemodynamically significant congenital heart disease (Trial 2). Fever and rash were each 
reported more frequently in participants who received palivizumab compared to placebo 
(27% vs. 25% and 12% vs. 10%, respectively). The clinical studies do not suggest that RSV 
infection was less severe among children hospitalized with RSV infection who received 
palivizumab for RSV prophylaxis compared to those who received placebo. However, the 
majority of infants hospitalized with RSV infection have no predisposing risk factors and are 
otherwise healthy (only a younger age and prematurity have been independently associated 
with RSV illness requiring hospitalization) [Hall, C. B., et al 2009]. The infant population in 
which palivizumab is recommended has narrowed considerably due to limited clinical benefit 
and high cost [American Academy of Pediatrics Committee on Infectious Diseases 2014];
monthly dosing to cover the entire RSV season also limits the wide application of 
palivizumab. Therefore, there is a need for prophylaxis to prevent RSV infection and related 
complications in infants not recommended to receive palivizumab, which represents the 
overwhelming majority of healthy pre-term and full-term infants.
Refer to the IB for detailed background information on MK-1654.
2.2.1
Pharmaceutical and Therapeutic Background
MK-1654 binds to the F protein and neutralizes RSV infection of cells in vitro and reduces
viral load in the nose and lungs of cotton rats infected with RSV A or B when administered 
prophylactically [Wyde, P. R., et al 1995]. Compared to palivizumab, MK-1654 exhibits 
greater potency both in vitro and in the preclinical cotton-rat model. Substitutions in the Fc 
region of MK-1654 result in an extended half-life such that PK modeling suggests that a 
single dose of MK-1654 will sustain therapeutic levels for 5 months in the majority of infants 
entering their first RSV season. Refer to the IB for additional details.
2.2.2
Preclinical and Clinical Studies
Refer to the IB for preclinical information on MK-1654.
In a completed Phase 1a randomized, placebo-controlled, double-blind, single-rising dose 
study evaluating MK-1654 in healthy adult participants (MK-1654-001, also known as 
PN001), MK-1654 was generally well tolerated at doses up to 300 mg IM and 3000 mg IV
and had an extended half-life as predicted.
In a completed Phase 1 randomized, placebo-controlled, double-blind study evaluating
MK-1654 in healthy Japanese male adult participants (MK-1654-003, also known as PN003),
single doses of MK-1654 (100 and 300 mg IM, and 300 and 1000 mg IV) were generally 
well tolerated. No apparent differences in PK parameters were observed between healthy 
non-Japanese (PN001) and Japanese (PN003) adult participants.
Refer to the IB for additional details on the completed clinical studies of MK-1654.
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2.2.3
Ongoing Clinical Studies
A Phase 1b/2a randomized, placebo-controlled, double-blind, single-ascending dose study to 
evaluate the safety and serum PK of MK-1654 in healthy pre-term and full-term infants
(MK-1654-002, also known as PN002) was initiated on 31-AUG-2018 and is fully enrolled. 
An important objective of PN002 is to characterize the PK and quantify the SNA titer of 
MK-1654 in this population. Information on the safety and PK of MK-1654 in pre-term and 
full-term infants will further facilitate clinical development in the target infant population.
Administration of MK-1654 has been generally well tolerated in healthy pre-term and full-
term infant participants in PN002. No deaths or drug-related SAEs have been reported, and 
no participants have discontinued from the study due to an AE. Safety-related study pause 
rules have not been triggered.
A Phase 3 randomized, partially blinded, palivizumab-controlled study (MK-1654-007, also 
known as PN007) to evaluate the safety, tolerability, and efficacy of MK-1654 versus 
palivizumab in infants and children at increased risk of severe RSV disease began enrollment 
on 30-NOV-2021. MK-1654 will be evaluated in infants who are eligible and recommended 
to receive palivizumab (in accordance with national or local guidelines or professional 
society recommendations) in their first RSV season. The PK of MK-1654 will also be 
evaluated in this study population. A secondary purpose of the study is to evaluate the safety, 
efficacy, and PK of a dose of MK-1654 administered at the start of the second RSV season 
(RSV Season 2) for eligible participants who continue to be at risk of severe RSV who are 
entering their second RSV season, regardless of RSV Season 1 treatment assignment group.
Refer to the IB for additional details on the ongoing clinical studies of MK-1654.
2.2.4
Information on Other Study-related Therapy
Not applicable.
2.3
Benefit/Risk Assessment
It cannot be guaranteed that participants in clinical studies will directly benefit from 
treatment during participation, as clinical studies are designed to provide information about 
the safety and effectiveness of an investigational medicine.
A total of 2200 healthy infants will receive MK-1654 and 1100 healthy infants will receive
placebo in this study. MK-1654 is expected to provide lower incidences of RSV-associated 
MALRI and RSV-associated hospitalization through the RSV season and a comparable 
safety profile compared to placebo in the target population (healthy early and moderate pre-
term and late pre-term and full-term infants with a chronological age from birth up to 1 year 
and entering their first RSV season at the time that documented informed consent is provided 
[see Inclusion Criteria 3 and 4 in Section 5.1]). As stated in Section 2.1 and Section 5.2, the 
population enrolled in this study is not eligible or recommended to receive palivizumab. The 
lack of an available RSV prophylaxis for this study population provides the justification for 
inclusion of the placebo control group.
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MK-1654 is a fully human, neutralizing mAb targeting the RSV F protein (see Section 2.2).
The currently approved palivizumab is a humanized mAb and also targets the RSV F protein.
A fully human mAb administered only once, like MK-1654, should display a relatively lower
risk of hypersensitivity events compared to a humanized mAb like palivizumab that must be 
dosed multiple times. As with all biologic medications, MK-1654 carries a risk of acute 
systemic events on exposure, as detailed in the IB. These events can be categorized as 
common acute systemic injection events, acute hypersensitivity events, and high cytokine 
release events. The risk of any of these acute systemic injection events after administration of
the MK-1654 antibody is considered very low because MK-1654 is a fully human mAb, with 
modifications at the YTE substitutions in the Fc domain only, and has no endogenous target 
in humans (refer to the IB for additional details). Administration of MK-1654 as a single 
injection or 2 divided-dose injections on the same day in ongoing and planned clinical studies 
further reduces the risk of hypersensitivity events, which were largely seen with re-exposure 
to palivizumab or motavizumab after multiple monthly doses. Administration of MK-1654 
has been generally well tolerated in ongoing clinical studies in healthy infant participants to 
date (PN002) and in healthy Japanese adult male participants at doses up to 300 mg IM and 
1000 mg IV (PN003), with no study pause rules triggered at any point in either study (see 
Section 2.2.3).
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.
The following objectives will be evaluated in healthy pre-term and full-term infants receiving 
a single IM dose of MK-1654 or placebo.
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Objectives
Endpoints
Primary

To evaluate the efficacy of MK-1654 
compared to placebo as assessed by the 
incidence of RSV-associated MALRI 
(outpatient and inpatient) from Days 1 
through 150 postdose.

Hypothesis: Administration of MK-1654 
reduces the incidence of RSV-associated 
MALRI from Days 1 through 150 
postdose compared to placebo (The 
statistical criterion for success requires 
the lower limit of the 95% CI for efficacy 
to be greater than 25%).

RSV-associated MALRI (outpatient 
and inpatient), defined as the following 
seen in an outpatient or inpatient 
clinical setting:

Cough or difficulty breathing; 
AND

1 or more of the following: 
wheezing, chest wall in-
drawing/retractions, rales/crackles, 
hypoxemia, tachypnea, 
dehydration due to respiratory 
symptoms; AND

RSV-positive RT-PCR NP sample

To evaluate the safety and tolerability of 
MK-1654 compared to placebo as 
assessed by the proportion of participants 
experiencing AEs.

Solicited injection-site AEs from 
Days 1 through 5 postdose

Solicited daily body temperature, with 
fever defined as rectal temperature 
≥102.2°F (≥39.0°C) or axillary 
temperature ≥101.7°F (≥38.7°C), from 
Days 1 through 5 postdose

Solicited systemic AEs from Days 1 
through 5 postdose

Anaphylaxis/hypersensitivity AESI 
from Days 1 through 42 postdose

Rash AESI from Days 1 through 42 
postdose

Nonserious AEs from Days 1 through 
42 postdose

SAEs through the duration of study 
participation
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Objectives
Endpoints
Secondary

To evaluate the efficacy of MK-1654 
compared to placebo as assessed by the 
incidence of RSV-associated 
hospitalization from Days 1 through 150 
postdose.

Hypothesis: Administration of MK-1654 
reduces the incidence of RSV-associated 
hospitalization from Days 1 through 150 
postdose compared to placebo (The 
statistical criterion for success requires 
the lower limit of the 95% CI for efficacy 
to be greater than 0%).

RSV-associated hospitalization, 
defined as the following:

Hospital admission for respiratory 
illness; AND

RSV-positive RT-PCR NP sample

To estimate the efficacy of MK-1654 
compared to placebo as assessed by the 
incidence of RSV-associated MALRI 
(outpatient and inpatient) from Days 1 
through 180 postdose.

RSV-associated MALRI (outpatient 
and inpatient), defined as above
Tertiary/Exploratory

To estimate the efficacy of MK-1654 
compared to placebo as assessed by the 
incidence of RSV-associated severe 
MALRI (outpatient and inpatient) from 
Days 1 through 150 postdose. 

RSV-associated severe MALRI, 
defined as the following seen in an 
outpatient or inpatient clinical setting:

Cough or difficulty breathing; 
AND

1 or more of the following: 
wheezing, chest wall in-drawing/ 
retractions, rales/crackles, 
tachypnea, dehydration due to 
respiratory symptoms; AND

Severe hypoxemia or the need for 
high flow nasal cannula, oxygen 
mask, or mechanical ventilatory 
support; AND

RSV-positive RT-PCR NP sample
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Objectives
Endpoints

To estimate the efficacy of MK-1654 
compared to placebo as assessed by the 
incidence of RSV-associated 
hospitalization from Days 1 through 180 
postdose.

RSV-associated hospitalization, 
defined as above

To estimate the incidence of MALRI 
(outpatient and inpatient) due to any 
cause from Days 1 through 150 postdose
for the MK-1654 and placebo groups.

MALRI (outpatient and inpatient) due 
to any cause, defined as above

To describe the incidence of RSV-
associated MALRI (outpatient and 
inpatient) from Days 365 through 515 
postdose for the MK-1654 and placebo 
groups.

RSV-associated MALRI (outpatient 
and inpatient), defined as above

To describe the incidence of RSV-
associated hospitalization from Days 365 
through 515 postdose for the MK-1654 
and placebo groups.

RSV-associated hospitalization, 
defined as above

To describe the serum PK concentration 
of MK-1654 at Days 7, 150, and 240 
postdose.

MK-1654 PK concentration

To estimate the incidence and magnitude 
of ADA to MK-1654 on Day 1 (predose) 
and Days 150, 240, 365, and 515
postdose.

Incidence and magnitude (titer) of 
ADA to MK-1654 

To estimate the level of SNA to RSV A 
on Day 1 (predose) and Days 7, 150, 240, 
365, and 515 postdose.

Level (titer) of SNA to RSV A 

To determine RSV F gene sequence in 
NP samples from infants infected with 
RSV who received MK-1654 or placebo.

RSV F gene sequence determined by 
deep sequencing in NP samples from 
infants infected with RSV
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4
STUDY DESIGN
4.1
Overall Design
This is a double-blind with in-house blinding, randomized, placebo-controlled, multi-site
study to evaluate the efficacy and safety of MK-1654 for the prevention of RSV-associated 
MALRI in healthy pre-term and full-term infants. The Sponsor estimates that the study will 
require approximately 3.5 years from the time that documented informed consent is provided 
for the first participant until the last participant’s last study-related telephone call or visit.
Approximately 3300 healthy male and female infants, from birth up to 1 year of age (see 
Inclusion Criteria 3 and 4 in Section 5.1) and entering their first RSV season at the time that
documented informed consent is provided, will be randomized in a 2:1 ratio to receive a 
single dose of MK-1654 or placebo. The sample size was selected to ensure collection of 
adequate safety information on the use of MK-1654 in this otherwise healthy population of 
pre-term and full-term infants. If sites in China have not met their participant allocation 
targets after enrollment of the global study is closed, these sites may continue to enroll 
participants until their allocation targets are met to meet local regulatory requirements (see
Appendix 7). Up to an additional 10% of participants may be enrolled to ensure an adequate
sample size for the safety evaluation for the program.
Randomization will be stratified according to the following factors:
1. Region:
•
Northern Hemisphere
•
Southern Hemisphere
2. Gestational age:
•
Early and moderate pre-term infants* (≥29 to <35 weeks gestational age)
•
Late pre-term and full-term infants (≥35 weeks gestational age)
*Note: Early and moderate pre-term infants will comprise at least 600 participants.
3. Chronological age at the time of consent**:
•
<6 months of age
•
≥6 months of age
**Note: Infants 0 through 8 months of age (ie, up to 8 months and 29 days) will 
comprise at least 90% of the participants.
IRT will be used to meet the enrollment target of at least 90% of participants having a 
chronological age of 0 through 8 months (ie, up to 8 months and 29 days) at the time of 
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consent. Infants who are eligible or recommended to receive palivizumab, per national or
local guidelines or professional society recommendations, must not be enrolled.
Enrollment will begin during the 4 weeks before the estimated onset of the RSV season and 
will end before the estimated peak of the RSV season (approximately a 17-week duration in 
temperate regions during a routine RSV season; see Section 4.2.1.1.1). Infants born before
the RSV season should be enrolled before the onset of the RSV season. Infants born during 
the RSV season should be enrolled as soon as possible after birth. Special considerations for 
RSV season determination in tropical and subtropical regions, as well as disrupted RSV
seasonality (eg, due to COVID-19), are in the regional RSV seasonality guidance document 
(or equivalent).
This study will include 2 cohorts of participants:
•
Phase 2b cohort: This is the lead-in portion of the study and will include 300 healthy 
pre-term and full-term infants. Infants enrolled in this cohort must be >2 weeks of age
and up to 1 year of age (see Inclusion Criterion 3 in Section 5.1). Data from this 
cohort will be reviewed by the eDMC (see IA#1 below).
•
Phase 3 cohort: Approximately 3000 healthy pre-term and full-term infants from 
birth to 1 year of age (see Inclusion Criterion 4 in Section 5.1) will be enrolled.
After randomization to MK-1654 or placebo, all participants will also be randomized by IRT 
to 1 of the 2 different blood sampling groups (Group 1 or Group 2) that differ in the schedule 
of serum PK, ADA, and SNA sampling (see Section 1.3.1). Participants will then be assigned
to 1 of the 2 testing subgroups (a or b) that differ in the types of tests to be performed, as 
follows:
•
Group 1a and Group 2a will have PK, ADA, and SNA in Season 1 (see Section 1.3.1) 
and ADA and SNA in RSV Season 2 (see Section 1.3.2).
•
Group 1b and Group 2b will have PK and ADA only in Season 1 (see Section 1.3.1).
In RSV Season 1, samples for SNA will be collected only in the first 1650 participants 
randomized. In RSV Season 2, samples for ADA and SNA will be collected only in the first 
750 participants (from the 1650 participants continuing to RSV Season 2; these participants 
will be from Season 1 Group 1a and Group 2a).
This approach provides sufficient safety, PK, ADA, and SNA data to meet study objectives, 
while minimizing the number of blood draws and total blood volume drawn from each 
participant during the study. Each participant will have a maximum of 3 planned blood draws 
during RSV Season 1 and the first 750 participants continuing in RSV Season 2 will have an 
additional 2 planned blood draws during RSV Season 2.
In the event a participant experiences a Grade 3 or 4 anaphylaxis/hypersensitivity AESI 
postdose, as confirmed by the investigator, an additional blood draw is required for
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evaluation for potential ADA to MK-1654, and additional ADA characterization, if indicated
(see Section 1.3.1 and Appendix 2).
The approximate maximum blood volume drawn per participant ≥3 kg at each visit is 
2.4 mL. Further requirements for the maximum blood draw volume, based on participant 
weight, are provided in Appendix 2.
All participants will receive the assigned study intervention (MK-1654 or placebo 
[0.9% sodium chloride, sterile saline]) administered via IM injection on Day 1.
All participants will be followed for 365 days after receiving study intervention (see 
Section 1.3.1). Efficacy surveillance for respiratory infection symptoms will be conducted for 
180 days postdose. All AEs will be collected for 42 days postdose, and SAEs will be 
collected for the duration of study participation.
A subset of participants (the first 1650 participants enrolled) will continue to be followed
throughout the second RSV season, from Days 365 through 515 postdose, in order to have at 
least 1500 participants complete the follow-up through Day 515 (see Section 1.3.2). No 
additional study intervention will be administered in RSV Season 2. Weekly surveillance will 
continue to monitor the incidence of RSV-associated MALRI and hospitalization.
Two IAs (IA#1 and IA#2) are planned for this study and will be conducted by an external 
unblinded statistician and reviewed by an eDMC (see Section 10.1.4.3).
IA#1: IA#1 will be conducted after the last participant randomized in the Phase 2b cohort 
completes the Day 42 visit and the safety data are available. The eDMC will review safety 
data and all available PK data as well as efficacy estimates for the endpoints of RSV-
associated MALRI and RSV-associated hospitalization to determine the benefit-risk of 
continued enrollment (see Section 9.7). During the eDMC review, participant screening and 
randomization will continue.
IA#2: If the study continues after IA#1, IA#2 for futility evaluation will be conducted when 
40 total RSV-associated MALRI cases in the combined MK-1654 and placebo groups have 
been observed in the study. If ≥21 cases are observed in the MK-1654 group (observed 
efficacy <50%), the study may stop for futility. Available safety, PK, SNA, and ADA data
will also be summarized and reviewed by the eDMC.
If the study does not stop at IA#2, the study will continue as planned. After all participants in 
the global study (see Appendix 7 regarding enrollment in China) have completed 180 days 
postdose follow-up, a database lock will be executed, and the Sponsor study team will be 
unblinded. A separate blinded study team will be appointed to continue assessments for the 
remainder of the study.
If the study stops after either IA, no further participants will be enrolled; however, 
participants already enrolled in the study will continue to be monitored for safety for 
365 days postdose.
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Specific procedures to be performed during the study, as well as their prescribed times and 
associated visit windows, are outlined in the SoA in Section 1.3. Details of each procedure 
are provided in Section 8.
4.2
Scientific Rationale for Study Design
This study will collect efficacy and safety data to evaluate the efficacy and safety of 
MK-1654 compared to placebo for the prevention of RSV-associated MALRI in the target 
population (healthy pre-term and full-term infants), in accordance with the 2017 draft FDA 
Guidance for Industry: Respiratory Syncytial Virus Infection: Developing Antiviral Drugs for 
Prophylaxis and Treatment [Food and Drug Administration 2017]. The study is designed to 
have a high level of statistical significance for the primary endpoint with >90% statistical 
power to show the efficacy of MK-1654 compared to placebo for the prevention of RSV-
associated MALRI with a lower bound of the 95% CI exceeding 25%.
This study will also assess the PK of MK-1654 for up to 240 days after administration of the 
single dose of MK-1654 to obtain PK data in this population. A subset of participants (the 
first 1650 participants randomized) will continue to be followed during RSV Season 2 from 
365 to 515 days after administration of the single dose of MK-1654 or placebo in order to 
have at least 1500 participants complete the follow-up through Day 515. The purpose of this 
additional follow-up is to monitor the incidence of RSV-associated MALRI and 
hospitalization in the absence of additional RSV prophylaxis and to collect safety data (SAEs 
only).
4.2.1
Rationale for Endpoints
4.2.1.1
Efficacy Endpoints
The primary efficacy endpoint for this study is RSV-associated outpatient and inpatient 
MALRI diagnosed as in Table 1. The diagnostic criteria are based on published literature and 
information from clinical studies, RSV expert panels, and WHO and CDC guidelines
[Manoha, C., et al 2007] [Nair, H., et al 2010] [Simoes, E. A. F., et al 2015]. Cough or 
difficulty breathing are included based on the case definition for severe and very severe LRI 
by the expert panel on RSV vaccine development convened by the WHO [Simoes, E. A. F., 
et al 2015].
RSV-associated MALRI represents most of the RSV disease burden, and is a clinically 
important and well-defined RSV disease endpoint across geographies and healthcare settings
[Nair, H., et al 2010] that has been recommended by RSV prophylaxis trial expert 
committees [Simoes, E. A. F., et al 2015]. The primary time point for evaluation of efficacy 
against RSV-associated MALRI will be from Days 1 through 150 postdose (the length of a 
typical RSV season in a temperate climate).
A secondary time point for evaluation of efficacy against RSV-associated MALRI will be 
from Days 1 through 180 postdose, as an additional month of efficacy would allow flexibility 
in healthcare practitioners’ timing of dosing MK-1654 and additional coverage for regions 
with longer RSV seasons (see Section 4.2.1.1.1). An assessment of efficacy against
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RSV-associated hospitalization from Days 1 through 150 postdose is also planned as a 
secondary efficacy endpoint as this is an outcome of clinical importance to healthcare 
practitioners and healthcare systems.
Table 1
Respiratory Syncytial Virus (RSV)-associated Medically Attended Lower 
Respiratory Infection (MALRI) Diagnostic Criteria
Signs/Symptoms
Indicators of LRI/Severity
RSV
Endpoint definition requires at least 1 from each column seen in an outpatient or inpatient clinical setting 
(outpatient clinic, clinical study visit, Emergency Department, urgent care center, or hospital) and confirmed 
or observed by the investigator.

Cough

Difficulty breathing

Wheezing

Chest wall in-drawing/Retractions

Rales/Crackles

Hypoxemia (SpO2 <95% on room air at 
sea level, <92% on room air at altitude 
≥1800 m)a

Tachypnea (RR ≥60 breaths per minute
for <2 months of age; ≥50 breaths per 
minute for 2 to 12 months of age; or 
≥40 breaths per minute for >12 to
24 months of age)

Dehydration due to respiratory symptoms

RSV-positive 
RT-PCR NP
sample (collected 
within 12 days of 
symptom onset or 
worsening)
LRI=lower respiratory infection; MALRI=medically attended lower respiratory infection; 
NP=nasopharyngeal; RR=respiratory rate; RSV=respiratory syncytial virus; RT-PCR=reverse transcriptase-
polymerase chain reaction; SpO2=oxygen saturation as measured by pulse oximetry.
a
For severe MALRI: Severe hypoxemia (SpO2 <90% on room air at sea level; <87% on room air at 
altitude ≥1800 m) or the need for high flow nasal cannula, oxygen mask, or mechanical ventilatory 
support.
In addition, RSV-associated hospitalization through 180 days postdose, RSV-associated 
severe MALRI through 150 days postdose, and RSV-associated MALRI and hospitalization 
in RSV Season 2 (Days 365 through 515 postdose) are planned as tertiary endpoints. The 
burden of RSV-associated hospitalizations is described in Section 2.2, and a decrease in 
hospitalization rate represents a benefit to public health.
An RSV expert panel convened for design of clinical endpoints for RSV prophylaxis studies
in 2014 suggested that cough or difficulty breathing be a required component of the LRI
clinical endpoint definition [Simoes, E. A. F., et al 2015]. This panel also proposed that the 
definition of LRI include the presence of lower chest wall in-drawing, or wheezing or 
crackles, or hypoxemia (SpO2 <95% on room air at sea level, <92% on room air at altitude 
≥1800 m) in a child <5 years of age with cough, tachypnea, or difficulty breathing. Typically, 
RSV infection starts with several days of mild upper respiratory tract signs, cough, and low-
grade fever, followed by lower respiratory tract involvement and a worsening cough, with the 
infant becoming tachypneic and possibly having progressively more labored breathing, with 
dyspnea and retractions of the chest wall; crackles and wheezes are the most common 
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auscultatory signs. Dehydration due to respiratory symptoms encompasses dehydration 
secondary to inability to feed.
The terms “difficulty breathing” or “labored breathing” are conventional in describing the 
signs and symptoms of pediatric RSV in the published literature; several recent active 
surveillance studies have reported a high frequency of difficult or labored breathing in infants 
and young children with RSV. Among hospitalized infants, it was reported that 81%, 75%, 
and 73% of infants age 0 to 2 months, 3 to 5 months, and 6 to 11 months had difficulty 
breathing on admission [Rha, B., et al 2018]. A CDC active surveillance study in children 
<5 years of age with RSV found that 73%, 85%, and 95% of children presenting to the 
pediatrician’s office, Emergency Department, and hospital for admission, respectively, had 
labored breathing [Hall, C. B., et al 2013]. Clinical signs of difficulty breathing or labored 
breathing may include tachypnea, grunting, nasal flaring, retractions, cyanosis, and/or apnea.
4.2.1.1.1
RSV Season Definition
RSV epidemics begin each year near the equator and then move toward temperate regions. 
Global patterns in monthly RSV activity have been observed and annual average percentage 
of RSV activity calculated for 152 sites globally in an ongoing review of RSV seasonality 
studies and online datasets by RESCEU [You, Li 2017].
In the US, RSV season onset has ranged from late October to late January and season offset 
has ranged from late January to early April in all 10 DHHS regions, except in Florida, which 
has an earlier RSV season onset and longer duration, as reported by the CDC NREVSS
[Haynes, A. K., et al 2014]. During the 2013–2014 RSV season, similarly to previous 
national patterns, RSV began circulating nationally in early November and ended in late 
March, with circulation peaking at 24% (the number of RSV-positive specimens among all 
respiratory specimens tested) in late December. The RSV season (onset, offset, peak, and 
duration) is defined nationally, by DHHS region, and by state, based on CDC analysis of 
RSV laboratory detections reported to the NREVSS. The CDC and WHO define the onset of 
the RSV season as a 10% threshold of RSV-positive specimens during 2 consecutive weeks.
In the European Union, the RSV season is typically November to April with a peak in the 
midwinter months [European Medicines Agency 2017]. The European influenza surveillance 
system captures RSV detection through the ILI or ARI surveillance system from 
21 European Union countries, as reported for the 2014-2015 RSV season by the ECDC 
[European Center For Disease Prevention And Control 2015].
In the Southern Hemisphere, the RSV season is typically April to August, peaking in July in 
temperate regions. Tropical and subtropical regions have different RSV season profiles, as 
detailed in the regional RSV seasonality guidance document (or equivalent).
Infants entering their first RSV season are typically under 9 months of age. For example:
•
An infant born in the Northern Hemisphere in January during their first RSV season 
may be enrolled during this RSV season. When the infant is 9 months old, they will 
be entering their second RSV season.
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•
An infant born in a temperate region of the Southern Hemisphere in June during their 
first RSV season may be enrolled during this RSV season. When the infant is 
9 months old, they will be entering their second RSV season.
These considerations support enrollment of at least 90% of participants who are 0 through
8 months of age (ie, up to 8 months and 29 days), with up to 10% of the remaining 
participants ≥9 months of age to allow for potential moves between hemispheres in infancy 
(ie, where an infant may be 9 to 12 months of age and still in their first RSV season).
The Sponsor will define the expected start and end of the RSV season for each region 
participating in the study, based on several prior years’ RSV seasons, as determined by 
national surveillance and/or available peer-reviewed literature. Detailed instructions will be 
provided in the regional RSV seasonality guidance document (or equivalent).
4.2.1.2
Safety Endpoints
The safety endpoints evaluated in this study were selected based on the MK-1654 safety 
profile observed in previous studies, published data from palivizumab, and guidance from 
regulatory agencies during product development. An eDiary will be used to record AEs 
during the postdose period as recommended in the 2009 FDA Guidance for Industry: Patient-
Reported Outcome Measures: Use In Medical Product Development To Support Labeling 
Claims [U.S. Food and Drug Administration 2009]. See Section 8.3.5 for details on the AEs
to be collected on the eDiary.
Certain hypersensitivity and rash AEs are of special interest (AESI) in this study. MK-1654 
is a fully human mAb; prior humanized mAbs in this class have had associated 
hypersensitivity and rash AEs. See Section 8.4.8 for details on the AESI to be collected, 
further evaluated, and reported. In the event of a Grade 3 or 4 anaphylaxis or hypersensitivity 
AESI, a blood sample for ADA and additional ADA characterization, if indicated, is also to 
be collected (see Section 1.3.1 and Section 10.2). Details on the safety endpoints evaluated in 
this study are provided in Section 8.3 and Section 9.4.2. Details on AEs, including definitions 
and reporting requirements, are provided in Appendix 3.
4.2.1.3
Pharmacokinetic Endpoints
4.2.1.3.1
MK-1654 Serum Concentration
A sparse PK collection of no more than 3 samples per participant is planned for the pediatric 
participants in this study. The PK serum collection time points have been developed based on 
known information from preclinical and clinical studies evaluating MK-1654. MK-1654 
concentrations will be measured using a validated bioanalytical assay on samples collected at 
several time points from Day 1 to Day 240 to determine the PK profile of the molecule, 
which will provide information regarding the MK-1654 PK profile in the target pediatric 
population.
Samples for PK will be collected in all participants in RSV Season 1 (see Section 1.3.1).
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4.2.1.4
Immunogenicity Endpoints
4.2.1.4.1
Antidrug Antibodies (ADA)
The presence and titer of ADA will be measured in this study. ADA to biologics like 
MK-1654 may develop and be either clinically inconsequential or change the drug PK. 
Therefore, ADA incidence and magnitude may be analyzed for association with PK and 
safety events and, as applicable, for associations with changes in RSV serum neutralizing 
activity, as described below. In RSV Season 1, samples for ADA will be collected in all 
participants (see Section 1.3.1). In RSV Season 2, samples for ADA will be collected only in 
the first 750 participants (from the first 1650 participants continuing to RSV Season 2; these 
participants will be from RSV Season 1 Group 1a and Group 2a) (see Section 1.3.2). The 
collected samples will yield a sufficient amount of serum to be used for further 
characterization of immunogenicity, if needed.
4.2.1.5
Pharmacodynamic Endpoints
4.2.1.5.1
Serum Neutralizing Activity Against RSV
This study will also evaluate the effect of a single dose of MK-1654 on RSV serum 
neutralizing activity to model the relationship between SNA and efficacy. (Note: SNA will 
not be tested in participants enrolled at sites in China; see Appendix 7.) In this assay, serial 
dilutions of the participant’s serum will be used to inhibit the entry of RSV into target cells in 
vitro. Total RSV serum neutralizing activity may be influenced by environmental exposure to 
RSV in addition to the presence of MK-1654. Moreover, the activity of MK-1654 may be 
inhibited by the presence of ADA. Therefore, unexpected changes in RSV serum neutralizing 
activity will be examined for associations with respiratory infection and ADA titer.
In RSV Season 1, samples for SNA will be collected only in the first 1650 participants 
randomized (see Section 1.3.1). In RSV Season 2, samples for SNA will be collected only in 
the first 750 participants (from the first 1650 participants continuing to RSV Season 2; these
participants will be from RSV Season 1 Group 1a and Group 2a) (see Section 1.3.2).
4.2.1.6
Additional Tertiary Endpoints
4.2.1.6.1
RSV F Gene Sequencing and MK-1654 Sensitivity Testing
This study will also evaluate RSV F gene sequence in NP samples from cases of infants 
infected with RSV who received MK-1654 or placebo. To assess for the potential emergence 
or selection of MK-1654 resistance, the entire F protein coding region will be sequenced and 
variants with substitutions in the MK-1654 binding site/highly conserved sites/unusual 
substitutions at polymorphic sites will be tested for sensitivity to MK-1654.
4.2.1.7
Future Biomedical Research
The Sponsor will conduct FBR on specimens for which consent was provided during this 
study. This research may include genetic analyses (DNA), gene expression profiling (RNA), 
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proteomics, metabolomics (serum, plasma), and/or the measurement of other analytes, 
depending on which specimens are consented for FBR.
Such research is for biomarker testing to address emergent questions not described elsewhere 
in the protocol (as part of the main study) 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 that participants receive the 
correct dose of the correct drug/vaccine at the correct time. The details of FBR research are 
presented in Appendix 6.
4.2.2
Rationale for the Use of Placebo
The primary goals of the study are to evaluate the efficacy of MK-1654 compared to placebo
(sterile 0.9% saline) in preventing RSV-associated outpatient and inpatient MALRI and to 
evaluate the safety and tolerability of MK-1654 in the target infant population. There is no 
agent currently approved for RSV prophylaxis in healthy full-term infants, and pre-term 
enrollment in this study is restricted to infants not eligible or recommended for palivizumab; 
therefore, there is no approved agent suitable for use as a comparator in this study.
A placebo-controlled study is needed to establish baseline RSV disease and will allow for an 
unbiased assessment of the efficacy, safety, and tolerability of MK-1654. Secondary and 
tertiary outcomes are also supported by the use of placebo, including the effect of MK-1654 
on RSV serum neutralizing activity, which could be influenced by environmental exposure to 
RSV, making a placebo arm a key negative control.
4.3
Justification for Dose
The dose of MK-1654 (105 mg) in this study was determined based on the results of robust 
modeling analyses, which included data from the Phase 1b/2a dose-finding study in the target 
pediatric population (PN002) (see Section 2.2.3). The dose was selected based on the totality 
of information, including preclinical data, published clinical data for anti-RSV mAbs, and 
PK/pharmacodynamic modeling based on data in adults (PN001, up to 300 mg IM and 
3000 mg IV) and the target pediatric population (PN002, up to 100 mg IM). Modeling results 
indicated that a dose of 105 mg in an infant’s first year of life has a high likelihood of 
providing high efficacy for the prevention of RSV-MALRI in the target population.
Data from the ongoing Phase 1b/2a study in the target population (PN002) has provided no 
evidence for contraindications to the administration of MK-1654 via the IM route in infants
in this study. Doses up to 100 mg have been administered to pre-term infants in PN002. No 
deaths, treatment-related SAEs, hypersensitivity AEs, discontinuations due to AEs, or dose-
dependent pattern of treatment-related AEs have been reported in PN002. PK modeling 
predicts that exposures (Cmax and AUC0-∞) after a 105-mg dose in infants in their first RSV 
season will be 8- and 5-fold lower, respectively, than the highest well-tolerated exposures 
observed in healthy adults (PN001).
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Refer to the IB for additional information.
4.4
Beginning and End of Study Definition
The overall study begins when documented informed consent is provided for the first 
participant. For the purposes of analysis and reporting, the overall study ends when the 
Sponsor receives the last laboratory result or the last participant completes the last study-
related contact, withdraws consent, or is lost to follow-up (ie, the participant’s legally 
acceptable representative is unable to be contacted by the investigator), whichever comes 
last.
If the study includes countries in the European Economic Area (EEA), the local start of the 
study in the EEA is defined as First Site Ready (FSR) in any Member State.
4.4.1
Clinical Criteria for Early Study Termination
The clinical study may be terminated early if the extent (incidence and/or severity) of 
emerging effects is such that the risk/benefit ratio to the study population as a whole is 
unacceptable. In addition, further recruitment in the study or at (a) particular study site(s) 
may be stopped as described in Appendix 1.10.
5
STUDY POPULATION
Healthy male and female infants who have a chronological age from birth up to 1 year and 
are entering their first RSV season at the time of consent will be enrolled in this study.
As stated in the Code of Conduct for Clinical Trials (Appendix 1.1) this study includes 
participants of varying age (as applicable), race, ethnicity, and sex (as applicable). The 
collection and use of these demographic data will follow all local laws and participant 
confidentiality guidelines while supporting the study of the disease, its related factors, and 
the IMP under investigation.
Prospective approval of protocol deviations to recruitment and enrollment criteria, also 
known as protocol waivers or exemptions, is not permitted.
5.1
Inclusion Criteria
A participant will be eligible for inclusion in the study if the participant:
Type of Participant and Disease Characteristics
1. Is healthy (based on medical history and physical examination results). Healthy is defined 
as the absence of medical conditions or acute illnesses (beyond mild symptoms requiring 
no more than minimal medical intervention). Any congenital or chronic medical 
conditions should be stable.
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Demographics
2. Is male or female and is an early or moderate pre-term infant (≥29 to 34 weeks and 
6 days gestational age) or a late pre-term or full-term infant (≥35 weeks gestational age).
3. For the Phase 2b cohort only: Has a chronological age >2 weeks of age up to 1 year and 
is entering their first RSV season at the time that documented informed consent is 
provided. (See Appendix 7 for age requirements specific for participants who are enrolled 
at sites in countries from the European Union or the United Kingdom.)
4. For the Phase 3 cohort only: Has a chronological age from birth up to 1 year and is 
entering their first RSV season at the time that documented informed consent is provided.
(See Appendix 7 for age requirements specific for participants who are enrolled at sites in 
countries from the European Union or the United Kingdom.)
5. For South Korea only: Participant weighs ≥2 kg. (See Appendix 7 for weight 
requirements specific for participants who are enrolled at sites in South Korea.)
Informed Consent
6. The participant’s legally acceptable representative provides documented informed 
consent for the study. The participant’s legally acceptable representative may also 
provide documented consent for future biomedical research. However, the participant 
may participate in the main study without participating in future biomedical research.
5.2
Exclusion Criteria
The participant must be excluded from the study if the participant:
1. Is eligible or recommended to receive palivizumab per national or local (eg, state or 
provincial) guidelines or professional society recommendations.
Medical Conditions
2. Has known hypersensitivity to any component of MK-1654 (refer to the IB for a list of 
components).
3. Has a bleeding disorder contraindicating intramuscular administration.
4. Has had a recent illness with rectal temperature ≥100.5°F (≥38.1°C) or axillary 
temperature ≥100.0°F (≥37.8°C) within 72 hours predose. 
Note: If the participant meets this exclusion criterion, the participant may be rescreened
when this criterion is not met.
Prior/Concomitant Therapy
5. Has received any vaccine or mAb for the prevention of RSV, including receipt of 
maternal RSV vaccination during the mother’s pregnancy.
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Prior/Concurrent Clinical Study Experience
6. Is currently participating in or has participated in an interventional clinical study with an 
investigational compound or device at any time before first dose administration or while 
participating in this current study. Participants enrolled in observational studies may be 
included and will be reviewed on a case-by-case basis for approval by the Sponsor.
7. Has enrolled previously in the current study and been discontinued.
Diagnostic Assessments
Not applicable.
Other Exclusions
8. Has a parent/legal guardian/legally acceptable representative who is unlikely to adhere to 
study procedures, keep appointments, or is planning to relocate during the study.
9. Has any other reason that in the opinion of the investigator may interfere with the 
evaluation required by the study.
10. Is or has an immediate family member (eg, spouse, parent/legal guardian, sibling, or 
child) who is investigational site or Sponsor staff directly involved with this study.
5.3
Lifestyle Considerations
No restrictions are required.
5.4
Screen Failures
Screen failures are defined as participants whose legally acceptable representative provides
consent to participate in the clinical study but are not subsequently randomized in the study. 
A minimal set of screen failure information is required to ensure transparent reporting of 
screen failure participants to meet the CONSORT publishing requirements and to respond to 
queries from regulatory authorities. Minimal information includes demography, screen 
failure details, eligibility criteria, and any AEs or SAEs meeting reporting requirements as 
outlined in the data entry guidelines.
5.5
Participant Replacement Strategy
A participant who withdraws from the study will not be replaced.
6
STUDY INTERVENTION
Study intervention is defined as any investigational intervention(s), marketed product(s), 
placebo, or medical device(s) intended to be administered to a study participant according to 
the study protocol.
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Clinical supplies provided by the Sponsor will be packaged to support enrollment. Clinical 
supplies will be affixed with a clinical label in accordance with regulatory requirements.
6.1
Study Intervention(s) Administered
The study intervention(s) to be used in this study are outlined in Table 2.
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Table 2
Study Interventions
Arm Name
Arm Type
Inter-
vention 
Name
Type
Dose 
Formu-
lation
Unit Dose 
Strength
Dosage 
Level
Route 
of 
Admini-
stration
Regimen/
Treatment 
Period/
Vaccination 
Regimen
Use
IMP or
NIMP/
AxMP
Sourcing
MK-1654
Experimental
MK-1654
Biological/
Vaccine
Vial
150 mg/mL
105 mg
IM
Single 
administration
Test 
Product
IMP
Sponsor
Placebo
Placebo 
Comparator
Placebo
Other
Sterile 
Solution
0 mg/mL
0 mg
IM
Single 
administration
Placebo
IMP
Sponsor 
or local
EEA=European Economic Area; IM=intramuscular; IMP=investigational medicinal product; NIMP/AxMP-noninvestigational/auxiliary medicinal product.
Placebo=Sterile saline 0.9% sodium chloride injection. Equivalent volumes of saline will be used to correspond with the respective dose level.
The classification of IMP and NIMP/AxMP in this table is based on guidance issued by the European Commission and applies to countries in the EEA. Country 
differences with respect to the definition/classification of IMP and NIMP/AxMP may exist. In these circumstances, local legislation is followed.
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All supplies indicated in Table 2 will be provided per the "Sourcing" column depending upon 
local country operational requirements. If local sourcing, every attempt should be made to 
source these supplies from a single lot/batch number where possible (eg, not applicable in the 
case where multiple lots or batches may be required due to the length of the study, etc.).
Refer to Section 8.1.8 for details regarding administration of the study intervention.
6.2
Preparation/Handling/Storage/Accountability
6.2.1
Dose Preparation
There are no specific calculations or evaluations required to be performed in order to 
administer the proper dose to each participant. The rationale for selection of doses to be used 
in this study is provided in Section 4.3.
MK-1654 and placebo (0.9% sodium chloride, sterile saline) will be prepared by an 
unblinded pharmacist or medically qualified study personnel (see Section 6.3.3).
Study intervention should be equilibrated to room temperature prior to dose administration,
and the syringes for IM injection should be prepared shortly before administration, per the 
instructions provided in the pharmacy manual.
6.2.2
Handling, Storage, and Accountability
The investigator or designee must confirm appropriate temperature conditions have been 
maintained during transit for all study intervention received, and any discrepancies are 
reported and resolved before use of the study intervention.
Only participants enrolled in the study may receive study intervention, and only authorized 
site staff may supply or administer study intervention. All study interventions must be stored 
in a secure, environmentally controlled, and monitored (manual or automated) area in 
accordance with the labeled storage conditions with access limited to the investigator and 
authorized site staff.
The investigator, institution, or the head of the medical institution (where applicable) is 
responsible for study intervention accountability, reconciliation, and record maintenance (ie, 
receipt, reconciliation, and final disposition records).
For all study sites, the local country Sponsor personnel or designee will provide appropriate 
documentation that must be completed for drug accountability and return, or local discard 
and destruction if appropriate. Where local discard and destruction is appropriate, the 
investigator is responsible for ensuring that a local discard/destruction procedure is 
documented.
The study site is responsible for recording the lot number, manufacturer, and expiry date for 
any locally purchased product (if applicable) as per local guidelines unless otherwise 
instructed by the Sponsor.
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The investigator shall take responsibility for and shall take all steps to maintain appropriate 
records and ensure appropriate supply, storage, handling, distribution, and usage of study 
interventions in accordance with the protocol and any applicable laws and regulations.
6.3
Measures to Minimize Bias: Randomization and Blinding
6.3.1
Intervention Assignment
Intervention randomization will occur centrally using an IRT system. There are 2 study 
intervention arms. Participants will be assigned randomly in a 2:1 ratio to MK-1654 or
placebo.
6.3.2
Stratification
Intervention randomization will be stratified according to the following factors:
1. Region:
•
Northern Hemisphere
•
Southern Hemisphere
2. Gestational age:
•
Early and moderate pre-term infants* (≥29 to <35 weeks gestational age)
•
Late pre-term and full-term infants (≥35 weeks gestational age).
*Note: Early and moderate pre-term infants will comprise at least 600 participants.
3. Chronological age at the time of consent**:
•
<6 months of age
•
≥6 months of age
**Note: Infants 0 through 8 months of age (ie, up to 8 months and 29 days) will 
comprise at least 90% of the participants.
6.3.3
Blinding
A double-blinding technique will be used. MK-1654 and placebo will be prepared and/or 
dispensed in a blinded fashion by an unblinded pharmacist or qualified study site personnel
otherwise not involved in the conduct of the study. Unblinded study personnel should not 
have contact with participants for any study-related procedures/assessments post-dose, 
including all safety follow-up procedures. The participant, the investigator, and Sponsor 
personnel or delegate(s) who are involved in the study intervention administration or clinical 
evaluation of the participants are unaware of the intervention assignments.
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6.4
Study Intervention Compliance
Participant study intervention compliance is defined in this study as a participant who 
receives the protocol-specified single dose of MK-1654 or placebo. Any changes in the 
protocol-specified study intervention plan require consultation between the investigator and 
the Sponsor and written documentation of the collaborative decision on participant 
management.
Study interventions will be prepared and administered as described in Section 6.2.1 and
Section 6.3.3 and stored, handled, and documented as described in Section 6.2.2. Study 
intervention information, such as Component Identification Number and time of 
administration, must be recorded on the appropriate eCRF as outlined in the data entry 
guidelines.
6.5
Concomitant Therapy
Medications or vaccinations specifically prohibited in the exclusion criteria are not allowed
during time periods specified by this protocol for that medication or vaccination. If there is a 
clinical indication for any medications or vaccinations specifically prohibited, 
discontinuation from the study 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 in the study requires the mutual 
agreement of the investigator, the Sponsor, and the participant’s legally acceptable 
representative.
Specifically, if a participant receives palivizumab after randomization, discontinuation from 
the study may be required after discussion with the Sponsor Clinical Director.
Participants should receive recommended childhood vaccines in alignment with 
local/national immunization guidelines. The site staff should follow their local/national 
immunization recommendations for administering multiple injectable vaccines at the same 
visit. Any licensed COVID-19 vaccine (including for emergency use) in a particular country 
is allowed to be used in the study as recommended per local and national immunization 
guidelines, as long as they are mRNA vaccines, adenoviral vaccines, or inactivated vaccines. 
Investigational vaccines (ie, those not licensed or approved for emergency use) are not 
allowed.
If any injectable vaccine(s), including recommended childhood vaccines or licensed COVID-
19 vaccines, are given at Visit 1 (when study intervention is given), they should be 
administered in the contralateral (opposite) thigh from that used for study intervention to 
avoid confounding results. If possible, multiple injection sites on the same limb should be 
separated by 1 inch or more.
On the day that study intervention is administered, any concomitant vaccinations should be
administered AFTER the 30-minute postdose observation period of the study intervention.
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Also, the participant must wait at the site for an additional 15 minutes postconcomitant 
vaccination to observe for any AEs (see Section 8.3.4).
Any concurrent medications, vaccines, or medical treatments must be recorded on the 
appropriate eCRF as described in Section 8.1.5.2.
Allowed rescue medications and supportive care are discussed in Section 6.5.1.
6.5.1
Rescue Medications and Supportive Care
As the purpose of the study is to characterize the safety and efficacy profile of MK-1654, 
prophylactic premedications to reduce the risk of injection reactions should not be given to 
participants before administration of study intervention. However, medications such as 
paracetamol and acetaminophen may be administered postadministration of study 
intervention for minor ailments without prior consultation with the Sponsor.
Participants should receive appropriate supportive care measures as deemed necessary by the 
treating physician.
As a precaution, study sites should have medications and support to treat hypersensitivity 
reactions available at the time of study intervention administration.
Any AEs will be reported according to the guidelines in Section 8.4 and Appendix 3. All 
concomitant medications and medical interventions will be reported in the appropriate 
eCRFs.
6.6
Dose Modification
No dose modification is allowed in this study.
6.7
Intervention After the End of the Study
There is no study-specified intervention after the end of the study.
6.8
Clinical Supplies Disclosure
The emergency unblinding call center will use the intervention/randomization schedule for 
the study to unblind participants and to unmask study intervention identity. The emergency 
unblinding call center should only be used in cases of emergency (see Section 8.1.10). If the 
emergency unblinding call center is not available for a given site in this study, the central 
electronic intervention randomization system (IRT) should be used to unblind participants 
and to unmask study intervention identity. The Sponsor will not provide random 
code/disclosure envelopes or lists with the clinical supplies.
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7
DISCONTINUATION OF STUDY INTERVENTION AND PARTICIPANT 
WITHDRAWAL
7.1
Discontinuation of Study Intervention
In clinical studies with a single intervention, discontinuation of study intervention can only 
occur prior to the intervention and generally represents withdrawal from the study.
Participants who receive a single-dose intervention cannot discontinue study intervention.
7.2
Participant Withdrawal From the Study
A participant must be withdrawn from the study if the participant’s legally acceptable 
representative withdraws consent from the study.
If a participant withdraws from the study, they will no longer be followed at scheduled 
protocol visits.
Specific details regarding procedures to be performed at the time of withdrawal from the 
study, as well as specific details regarding withdrawal from future biomedical research, 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’s 
legally acceptable representative 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’s legally acceptable representative, the following procedures are to 
be performed:
•
The site must attempt to contact the participant’s legally acceptable representative and 
reschedule the missed visit. If the participant’s legally acceptable representative is 
contacted, the participant’s legally acceptable representative 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’s legally acceptable representative at each missed visit (eg, telephone calls 
and/or a certified letter to the participant’s legally acceptable representative’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 
pre-specified statistical data handling and analysis guidelines.
8
STUDY ASSESSMENTS AND PROCEDURES

Study procedures and their timing are summarized in the SoA.
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
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.

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’s legally 
acceptable representative. In these cases, such evaluations/testing will be performed in 
accordance with those regulations.
Blood Collection and Maximum Blood Volumes
The maximum amount of blood collected from each participant over the duration of the 
study, including for any extra assessments that may be required, will be in accordance with 
regulatory guidelines for pediatric studies and recommended maximum blood draw volume 
[European Commission 2017]. Repeat or unscheduled samples may be taken for safety 
reasons or for technical issues with the samples.
Each participant should have a maximum of 3 planned blood draws during RSV Season 1 
and the first 750 participants continuing in RSV Season 2 should have an additional 
2 planned blood draws during RSV Season 2 (see Section 1.3.2 and Table 11).
The maximum amount of blood obtained from each participant is dependent upon the 
participant’s weight at the visit. If the participant does not meet the weight requirement of 
≥3 kg, then the maximum blood draw volume should be reduced according to criteria in 
Table 12. The approximate maximum blood volume drawn per participant ≥3 kg at each visit 
is 2.4 mL (Table 11). The approximate total maximum blood volume drawn per participant
≥3 kg in RSV Season 1 is 7.2 mL and for those participants continuing into RSV Season 2, 
the approximate total maximum blood volume drawn is 12.0 mL (combined RSV Season 1 
and RSV Season 2, Table 11). In the event a participant experiences a Grade 3 or 4 
anaphylaxis/hypersensitivity AESI postdose, an additional blood draw of 1.2 mL is required
for evaluation for potential ADA to MK-1654, and additional ADA characterization, if 
indicated (see Section 1.3.1 and Appendix 2).
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Study sites should follow infection control and prevention practices, per local guidelines, for 
encounters with legally acceptable representatives and/or participants, including practices
pertaining to control and prevention of COVID-19.
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’s legally acceptable 
representative prior to participating in this clinical study or future biomedical research. If 
there are changes to the participant’s status during the study (eg, health or age of majority 
requirements), the investigator or medically qualified designee must ensure the appropriate 
documented informed consent is in place.
8.1.1.1
General Informed Consent
Informed consent given by the participant's legally acceptable representative must be 
documented on a consent form (see Appendix 7 for China-specific requirements). The form 
must include the trial protocol number, trial protocol title, dated signature, and agreement of 
the participant's 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’s 
legally acceptable representative before the individual’s participation in the study.
The initial ICF, any subsequent revised ICF, and any written information provided to the 
participant’s legally acceptable representative must receive the IRB/IEC’s approval/favorable 
opinion in advance of use. The participant’s legally acceptable representative should be 
informed in a timely manner if new information becomes available that may be relevant to 
the willingness for the participant 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 legally acceptable representative's 
dated signature.
Specifics about the study and the study population are to be included in the study informed 
consent form.
Informed consent will adhere to IRB/IEC requirements, applicable laws and regulations, and 
Sponsor requirements.
8.1.1.2
Consent and Collection of Specimens for Future Biomedical Research
The investigator or medically qualified designee will explain the future biomedical research 
consent to the participant’s legally acceptable representative, answer all of his/her questions, 
and obtain documented informed consent before performing any procedure related to future 
biomedical research. A copy of the informed consent will be given to the participant’s legally 
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acceptable representative before performing any procedure related to future biomedical 
research.
8.1.2
Inclusion/Exclusion Criteria
Before randomization, all inclusion and exclusion criteria will be reviewed by the 
investigator, who is a qualified physician, to ensure that the participant qualifies for the 
study.
8.1.3
Participant Identification Card
The legally acceptable representative for each participant will be given a participant 
identification card identifying the individual as a participant in a research study. The card 
will contain study site contact information (including direct telephone numbers) to be utilized
in the event of an emergency. The investigator or qualified designee will provide the legally 
acceptable representative for each participant with a participant identification card
immediately after documented informed consent is provided. At the time of treatment 
randomization, site personnel will add the treatment/randomization number to the participant 
identification card.
The participant identification card also contains contact information for the emergency 
unblinding call center so that a healthcare provider can obtain information about study 
intervention in emergency situations where the investigator is not available.
8.1.4
Medical History
A medical history will be obtained by the investigator or qualified designee predose at Visit 1 
(Day 1). All medical history, including risk factors for RSV, any respiratory conditions, prior 
RSV infections, low birth weight, and any relevant history of the mother, will be obtained 
and recorded on the appropriate eCRFs. Risk factors for RSV may include, for example, 
gestational age, gender, maternal smoking status, breastfeeding status, and number and age of 
siblings.
8.1.5
Prior and Concomitant Medications Review
8.1.5.1
Prior Medications
The investigator or qualified designee will review prior medication/vaccination use and 
record prior medications/vaccinations taken by the participant to assess inclusion and 
exclusion criteria including time windows for medication/vaccination use.
8.1.5.2
Concomitant Medications
The investigator or qualified designee will record medications/vaccinations, if any, taken by 
the participant during the study. In addition, the participant’s legally acceptable 
representative will record new and/or concomitant medications/vaccinations taken after 
Visit 1 (Day 1) up to Day 42 in the eDiary. Palivizumab taken after randomization (see 
Section 6.5) at any time during the study will also be recorded on the appropriate eCRF.
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After Day 42, only concomitant medications associated with an SAE will be recorded on the 
appropriate eCRF.
8.1.6
Assignment of Screening Number
All consented participants will be given a unique screening number that will be used to 
identify the participant for all procedures that occur prior to randomization. Each participant 
will be assigned only 1 screening number. Screening numbers must not be re-used for 
different participants.
Any individual who is screened multiple times will retain the original screening number 
assigned at the initial screening visit. Specific details on the screening/rescreening visit 
requirements are provided in Section 8.13.1. Pre-trial participant screening logs may be 
collected for review by the Sponsor. If applicable, participant names or any information that 
would make the participant identifiable will be removed.
8.1.7
Assignment of Randomization Number
All eligible participants will be randomly allocated and will receive a randomization number. 
The randomization number identifies the participant for all procedures occurring after 
treatment randomization. Once a randomization number is assigned to a participant, it can 
never be re-assigned to another participant.
A single participant cannot be assigned more than 1 randomization number.
8.1.8
Study Intervention Administration
Study intervention should be prepared and administered by appropriately qualified members 
of the study personnel (eg, physician, nurse, physician’s assistant, nurse practitioner, 
pharmacist, or medical assistant) as allowed by local/state, country, and institutional 
guidance.
Study intervention is given on the day of treatment allocation/randomization or as close as 
possible to the date on which the participant is allocated/assigned.
8.1.8.1
Timing of Dose Administration
Study intervention (MK-1654 or placebo) will be administered at Visit 1 (Day 1), after the 
participant is deemed eligible for the study. MK-1654 or placebo will be administered via IM 
injection into the side of the participant’s thigh (vastus lateralis). Study staff administering 
study intervention will be unblinded and not otherwise involved in any study-related 
procedures/assessments, as described in Section 6.3.3.
See Section 8.13.3 for required procedures if study intervention cannot be administered on 
the same day as the screening procedures due to unanticipated circumstances.
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Study intervention may be administered at any time of day, and without regard to timing of 
meals. See Section 6.5 on the timing of study intervention administration with regard to 
concomitant therapy.
Rectal or axillary temperature will be taken by study staff predose and after the 30-minute 
postdose safety observation period as indicated in the SoA (see Section 1.3.1). Participants 
who have had a recent illness with rectal temperature ≥100.5°F (≥38.1°C) or axillary 
temperature ≥100.0°F (≥37.8°C) within 72 hours predose should not be administered study 
intervention and may be rescreened (see Section 8.13.1).
Participants will be observed for 30 minutes postdose for any immediate reactions; this 
observation must be performed by the blinded investigator and/or study staff, as described in 
Section 8.3.4.
8.1.9
Discontinuation and Withdrawal
Participants in this study will receive a single dose intervention and cannot discontinue study 
intervention.
Participants who withdraw from the study should be encouraged to complete all applicable 
activities scheduled for the final study visit at the time of withdrawal. Any AEs that are 
present at the time of withdrawal should be followed in accordance with the safety 
requirements outlined in Section 8.4.
8.1.9.1
Withdrawal From Future Biomedical Research
Consent for future biomedical research may be withdrawn by the participant’s legally 
acceptable representative. Consent may be withdrawn by the legally acceptable 
representative at any time by contacting the principal investigator for the main study. If 
medical records for the main 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 future biomedical research 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’s legally acceptable representative
of completion of withdrawal. Any analyses in progress at the time of request for withdrawal 
or already performed prior to 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.
In the event that the medical records for the main study are no longer available (eg, if the 
investigator is no longer required by regulatory authorities to retain the main study records) 
or the specimens have been completely anonymized, there will no longer be a link between 
the participant’s personal information and their specimens. In this situation, the request for 
specimen withdrawal cannot be processed.
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8.1.10
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. Prior to contacting the emergency 
unblinding call center to request unblinding of a participant’s intervention assignment, the 
investigator who is a qualified physician should make reasonable attempts to enter the 
severity grade of the AEs observed, the relation to study intervention, the reason thereof, etc., 
in the medical chart. If it is not possible to record this assessment in the chart prior to the 
unblinding, the unblinding should not be delayed.
In the event that 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.
Participants whose treatment assignment has been unblinded by the investigator or medically 
qualified designee and/or nonstudy treating physician should continue to be monitored in the 
study.
Additionally, the investigator or medically qualified designee must go into the IRT system 
and perform the unblind in the IRT system to update drug disposition. In the event that the 
emergency unblinding call center is not available for a given site in this study, the IRT 
system should be used for emergency unblinding in the event that this is required for 
participant safety.
8.1.11
Domiciling
Not applicable for this study.
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.
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8.2
Efficacy (Respiratory Pathogen) Assessments
See the SoA (Section 1.3) for the timing of respiratory pathogen assessments.
8.2.1
Surveillance for Respiratory Infection Symptoms
To facilitate the collection of relevant efficacy data, sites will conduct weekly active
surveillance during the time periods defined in the SoA (Section 1.3).
Weekly surveillance will be conducted via phone call. Phone calls must be performed by 
appropriately trained site staff. The Sponsor will provide each site with a guidance document 
outlining the questions to be asked at the weekly surveillance call. If the initial call is 
unsuccessful, the site staff should make a total of 3 additional attempts for each scheduled 
call. All attempts to call the participant’s legally acceptable representative will be recorded in 
the call log (or equivalent). In addition, site staff will review the eDiary data with the legally 
acceptable representative (see Section 8.3.5).
In addition to site-conducted weekly active surveillance, the legally acceptable representative 
will be instructed at Visit 1 (and reminded during the weekly phone calls) to proactively call
the site as soon as possible to report respiratory infection symptoms, symptoms of concern, 
or any outpatient or inpatient visits. If any of these are reported, the procedures in 
Section 8.2.2 and Section 8.2.3 should be followed.
The purpose of this surveillance is to:
1) Identify if the following respiratory infection symptoms have occurred or 
worsened:
•
Signs/symptoms of ARI and indicators of ARI severity (at least 2 of the following 
for at least 2 days):
-
Cough
-
Congestion (stuffy or runny nose)
-
Fever (see Section 8.3.3)
-
Trouble feeding
•
Signs/symptoms of LRI and indicators of LRI severity, as follows:
-
Cough or difficulty breathing for at least 1 day; AND
-
At least 1 of the following:
◦
Wheezing
◦
Chest wall in-drawing/Retractions
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◦
Tachypnea (rapid breathing)
If respiratory infection symptoms are reported (as defined above), the participant 
should be assessed at the site by the investigator or medically qualified designee (see 
Section 8.2.2).
2) Identify if the participant was assessed or is being assessed for respiratory 
infection symptoms in an outpatient or inpatient clinical setting (outpatient clinic, 
Emergency Department, urgent care center, or hospital), and if this is the case, the 
participant should also be assessed at the site by the investigator or medically 
qualified designee (see Section 8.2.2).
Medical records from the outpatient facility or hospital (if available) should be 
obtained and relevant information (respiratory infection symptoms, PCR results, etc.)
should be recorded on the appropriate eCRF(s).
8.2.1.1
Definition of Distinct Episodes of Respiratory Infection
Multiple respiratory infections may occur for some participants during a single RSV season
and multiple respiratory assessment visits may be needed to assess a respiratory infection 
episode. A respiratory infection episode is defined as the onset of respiratory symptoms after 
a period of at least 48 hours free of respiratory infection symptoms (except mild runny nose) 
and feeding well.
The start and stop dates of each respiratory infection episode should be documented in the 
participant’s source record and appropriate eCRF.
8.2.2
Respiratory Infection Assessment
8.2.2.1
Requirements for Scheduling a Respiratory Infection Assessment
To identify potential cases of RSV-associated LRI, participants with any respiratory infection 
symptoms should be assessed at the site by the investigator or medically qualified designee.
RSV-associated MALRI is defined in Section 4.2.1.1.
A respiratory infection assessment is required when:
•
Respiratory infection symptoms are reported (see Section 8.2.1).
•
New respiratory infection symptoms arise or symptoms worsen during an existing 
episode.
•
The participant is seen in an outpatient or inpatient clinical setting for respiratory 
infection symptoms.
The respiratory infection assessment should be performed within 3 days of symptom onset or 
worsening.* If this is not possible or the visit for the assessment is missed, it can be 
performed within 12 days of symptom onset or worsening.*
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*Note: Symptom onset or worsening may refer to the symptom onset or worsening that led to 
the outpatient visit or hospital admission.
A respiratory infection assessment may occur during an unscheduled visit or at a scheduled 
study visit (ie, Visits 2, 3, 4, or 5) if that visit occurs within the time requirements noted 
above.
Every attempt should be made to assess the participant at the study site. If this is not possible,
a home visit or visit to an alternate study site may be used, where available and when 
permitted by local regulations and IRB/IEC. In the case of a home visit or visit to an alternate 
study site, all indicated study procedures should be performed, including NP swab collection
for RT-PCR testing at the central laboratory (see Appendix 7 for specific requirements for 
sites in China).
8.2.2.2
Procedures at a Respiratory Infection Assessment
The respiratory infection assessment must be performed by the investigator or medically 
qualified designee.
The following procedures are to be performed to assess the participant for respiratory 
infection:
1. A brief directed physical examination and vital signs measurement (including heart rate, 
RR, SpO2, and body temperature) to assess the participant’s symptoms.
2. Confirm if any signs or symptoms of respiratory infection are present:
•
Cough
•
Congestion (stuffy or runny nose)
•
Fever
•
Trouble feeding
•
Difficulty breathing (clinical signs of difficulty breathing or labored breathing may 
include tachypnea, grunting, nasal flaring, retractions, cyanosis, and/or apnea)
•
Wheezing
•
Chest wall in-drawing/Retractions
•
Rales/Crackles
•
Hypoxemia (SpO2 <95% on room air at sea level, <92% on room air at altitude 
≥1800 m); severe hypoxemia is defined in Table 1.
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•
Tachypnea (RR ≥60 breaths per minute for <2 months of age, ≥50 breaths per minute 
for 2 to 12 months of age, or ≥40 breaths per minute for >12 to 24 months of age)
•
Dehydration due to respiratory symptoms
All respiratory infection signs/symptoms observed during the visit will be recorded on the 
appropriate eCRF(s).
3. If any signs or symptoms of respiratory infection are present, then an NP sample will be 
collected from the participant for RT-PCR testing (see Section 8.2.3).
Collect an NP sample:
•
If any of the signs/symptoms listed above are observed or confirmed during the initial 
assessment for a new respiratory infection episode;
OR
•
If there are new or worsening LRI signs/symptoms observed or confirmed at a 
subsequent assessment for an existing respiratory infection episode
4. Determine if further triage or clinical evaluation is needed, consistent with the standard of 
care, and in conjunction with the participant’s primary physician (if applicable).
5. Review medical records (if available) for participants assessed for respiratory infection 
symptoms in an outpatient or inpatient clinical setting and record relevant information 
(respiratory infection symptoms, PCR results, etc.) on the appropriate eCRF.
8.2.3
Nasopharyngeal Sample Collection for RT-PCR Testing for Respiratory 
Pathogen Identification
NP samples should be collected within the time requirements for the respiratory infection 
assessment in Section 8.2.2.1.
The swabs for collecting NP samples for RT-PCR testing are provided by the central 
laboratory. Sample collection, storage, and shipment instructions for the NP sample are
provided in the laboratory manual (see Appendix 7 for specific requirements for sites in 
China).
All swabs collected for NP sampling by a qualified designee will be sent to the central 
laboratory for analysis. The analysis will determine the presence or absence of RSV, 
including the strain of RSV (ie, RSV A or B) if RSV is detected, as well as other respiratory 
pathogens included in the RT-PCR assay panel and COVID-19 (see Appendix 7 for specific 
requirements for sites in China). Additional details are available in the laboratory manual.
An NP sample should be collected for RT-PCR testing for respiratory pathogen identification 
if any respiratory symptoms are observed during a respiratory infection assessment (see 
Section 8.2.2). If a participant requires collection of another sample(s) (at the same visit or 
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any subsequent visits), the subsequent sample(s) should be taken from the same nostril as the 
first sample.
The following procedures should be followed for obtaining RT-PCR results for respiratory 
pathogen identification during a nonstudy visit to an outpatient clinic, Emergency 
Department, urgent care center, or hospital visit (ie, other than during a scheduled or 
unscheduled visit to the study site), under each of the following circumstances:
1) Site staff can collect NP sample at a nonstudy visit
If a participant first visits an outpatient facility or hospital (ie, a nonstudy visit) and is 
confirmed to have respiratory symptoms, the study staff should make every effort to obtain 
an NP sample using the study-supplied swab, as permitted, and the site should send this 
sample to the central laboratory for analysis.
2) Site staff cannot collect NP sample at a nonstudy visit
If an NP sample using the study-supplied swab cannot be collected by site staff during an 
outpatient visit or hospitalization, the sample should be collected using the study-supplied 
swab as soon as possible postvisit or postdischarge. The medical records (if available) should 
also be obtained from the outpatient facility or hospital.
Note: Collection of the NP sample using the study-supplied swab during either of the above
circumstances should be within the time requirements in Section 8.2.2.1.
3) PCR results from a local laboratory
If an NP sample using the study-supplied swab cannot be collected, but nonstudy staff at an
outpatient facility or hospital collected a sample and PCR results for respiratory pathogen
identification are available from a local laboratory, medical records (if available) should be 
obtained to collect the:
•
Name of the local laboratory
•
Pathogens identified (details will be provided in the data entry guidelines)
Note: Only PCR diagnostic test results are acceptable.
8.3
Safety Assessments
Details regarding specific safety procedures/assessments to be performed in this study are 
provided in this section. Planned time points for all safety assessments are provided in the 
SoA.
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8.3.1
Physical Examinations Including Length and Weight
A complete physical examination and brief directed physical examinations will be conducted 
by an investigator or medically qualified designee and consistent with local requirements. 
Length and weight will also be measured and recorded.
The complete physical examination should include an assessment of the head, eyes, ears, 
nose and throat, skin, lymph nodes, neurological system, and musculoskeletal system as well 
as auscultation of the heart and lungs, and an examination of the abdomen.
The brief directed physical examination should include a general assessment for respiratory 
distress, auscultation of the heart and lungs, and examination of the abdomen.
Investigators should pay special attention to clinical signs related to previous serious 
illnesses.
8.3.2
Vital Signs
•
Body temperature, heart rate, RR, and SpO2 will be assessed at the specified visits (see 
Section 1.3) including predose and at the end of the 30-minute postdose safety 
observation period (see Section 8.3.4) and at any respiratory infection assessments (see 
Section 8.2.2.2) and any AESI assessments (see Section 8.4.8).
•
Body temperature and RR will be measured and recorded as single measurements. The 
same method should be used for all measurements for each individual participant and 
should be the same for all participants, where possible (see Section 8.3.3 for body 
temperature measurement procedures).
8.3.3
Body Temperature Measurement
Rectal or axillary temperature will be taken by study staff predose and after the 30-minute 
postdose safety observation period at Visit 1 and at all scheduled and unscheduled visits 
postdose, as indicated in the SoA (Section 1.3).
Rectal is the preferred method of obtaining participant’s temperature and should be 
performed unless prohibited by local authorities or local pediatric guidelines. Axillary 
(underarm) is an acceptable method. Use of oral, temporal, or tympanic thermometers to 
collect temperature for this study is not permitted.
Additionally, the participant’s legally acceptable representative will be asked to record a 
temperature reading and method of measurement (rectal* or axillary) in the eDiary on Days 1 
through 5 postdose. Temperature readings should be taken at approximately the same time 
each day with the thermometer provided by the study.
*Note: For legally acceptable representatives unfamiliar with how to take a rectal 
temperature, site staff should provide training.
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If an elevated temperature is detected using the axillary method (≥100.0F [≥37.8C]), the 
temperature should be confirmed by rectal measurement (unless prohibited by local 
authorities or local pediatric guidelines). If rectal measurement is prohibited, a repeat axillary 
temperature measurement should be obtained.
Fever is defined as any rectal temperature ≥102.2ºF (≥39.0ºC) or axillary temperature 
≥101.7ºF (≥38.7ºC). All fevers must be reported for Days 1 through 42 unless the fever is a 
symptom of another reported AE. If a temperature is recorded in the eDiary that meets this
definition of fever, the site should call the legally acceptable representative to inquire about
respiratory symptoms or any other symptoms. If no other symptoms are present, the fever 
should be reported as an AE.
8.3.4
30-minute Postdose Safety Observation
Participants will be monitored at the study site during a 30-minute postdose observation 
period for any signs/symptoms of:
•
An immediate anaphylaxis/hypersensitivity AE (see Section 8.4.8.1);
•
An immediate rash AE (see Section 8.4.8.2);
•
Injection-site AEs (including redness/erythema, swelling, and tenderness/pain); and
•
Any other AEs.
This observation period may be extended if deemed necessary.
If any AEs are observed during this period, the type of event, the time at which the event 
started, any concomitant medications that were administered, any medical intervention 
provided, and resolution of the event (if applicable), must be recorded on the appropriate 
eCRFs.
Vital signs should be repeated after the observation period (see Section 8.3.2).
If concomitant vaccinations are given at Visit 1 after administration of study intervention, the 
participant must undergo an additional 15-minute postconcomitant vaccination observation 
period at the study site for any AEs.
8.3.5
Electronic Diary
Each participant’s legally acceptable representative will be provided an eDiary device or 
have their own device configured, if compatible, to complete the eDiary. At Visit 1, the 
participant’s legally acceptable representative will be instructed by the investigator or 
delegate on how to complete the eDiary and how to identify suspected AESI.
The investigator or delegate will review the data captured in the eDiary throughout the 42-
day period, and with the participant’s legally acceptable representative at the time points 
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indicated in the SoA (see Section 1.3.1). Noncompliance with the eDiary will require 
retraining by the site as soon as possible to ensure accurate and complete data capture.
The study-provided eDiary device will be collected from the participant’s legally acceptable 
representative after the 42-day period to ensure safety data is completed for all 42 days, as 
indicated in the SoA (see Section 1.3.1).
Legally acceptable representatives will use the eDiary from Days 1 through 42 postdose to 
record the following information:
1. Solicited daily body temperature to identify fever* Days 1 through 5 postdose (see 
Section 8.3.3);
*Note: Fever is defined as rectal temperature ≥102.2°F (≥39.0°C) or axillary 
temperature ≥101.7°F (≥38.7°C).
2. Solicited injection-site AEs (redness/erythema, swelling, and tenderness/pain)**
Days 1 through 5 postdose;
**Note: Injection-site AEs of redness/erythema and swelling will be measured by the 
legally acceptable representative using a study-supplied ruler.
3. Solicited systemic AEs (irritability, drowsiness, and appetite lost) Days 1 through 5
postdose;
4. Anaphylaxis/hypersensitivity AESI Days 1 through 42 postdose (see Section 8.4.8.1);
5. Rash AESI Days 1 through 42 postdose (see Section 8.4.8.2);
6. Any other AEs Days 1 through 42 postdose; and
7. Concomitant medications and nonstudy vaccinations on Days 1 through 42 postdose.
If any respiratory infection symptoms are reported that might require further assessment, the 
site staff should call the legally acceptable representative to ascertain additional information 
and arrange a site visit if needed (see Section 8.2.1 and Section 8.2.2).
The investigator will use the information provided by the participant’s legally acceptable 
representative, both from the eDiary and verbally at the time of eDiary review, to provide an 
assessment for severity of AEs (see Section 10.3.5).
8.3.6
Day 3 Safety Phone Call
Site staff are required to call the legally acceptable representative of each participant on 
Day 3 postdose to inquire about the participant’s safety, in particular, if any AESI
(anaphylaxis/hypersensitivity events and rash events) and SAEs have occurred since Day 1,
in addition to reviewing any data entered into the eDiary, including information pertaining to 
potential injection-site AEs (redness, swelling, or tenderness). The Sponsor will provide each 
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site with a guidance document (or equivalent) outlining the questions to be asked during this
phone call.
If the first attempt on Day 3 is unsuccessful, site staff should try to call the legally acceptable 
representative an additional 2 times that same day. If the legally acceptable representative is 
unreachable on Day 3, site staff should continue to try to call at least 3 additional times 
within the following 7 days. Each attempt should be recorded on the log provided by the 
Sponsor (or equivalent).
If any respiratory infection symptoms (see Section 8.2.1) or suspected AESI (see 
Section 8.4.8) are reported, the participant should be brought to the site for further 
assessment, if applicable.
8.3.7
Clinical 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.

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 after the 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
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 need to document if an SAE was associated with a medication error, misuse, or 
abuse.
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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, severity,
and causality.
8.4.1
Time Period and Frequency for Collecting AE, SAE, and Other Reportable 
Safety Event Information
All AEs, SAEs, and other reportable safety events that occur after the participant's legally 
acceptable representative provides documented informed consent but before intervention 
randomization must be reported by the investigator if the event causes the participant to be 
excluded from the study, or is the result of a protocol-specified intervention.
From the time of intervention randomization through 42 days following cessation of study 
intervention, all AEs, SAEs, and other reportable safety events must be reported by the 
investigator.
Additionally, any SAE brought to the attention of an investigator at any time outside of the 
time period specified in the previous paragraph must be reported immediately to the Sponsor.
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, the investigator 
must promptly notify the Sponsor.
All initial and follow-up AEs, SAEs, and other reportable safety events will be recorded and 
reported to the Sponsor or designee within the time frames as indicated in Table 3.
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Table 3
Reporting Time Periods and Time Frames for Adverse Events and Other 
Reportable Safety Events
Type of Event
Reporting Time 
Period:
Consent to 
Randomization/ 
Allocation
Reporting Time 
Period:
Randomization/ 
Allocation 
through 
Protocol-
specified Follow-
up Period
Reporting Time 
Period:
After the Protocol-
specified Follow-up 
Period
Time Frame 
to Report 
Event and 
Follow-up 
Information 
to Sponsor:
Nonserious Adverse 
Event (NSAE)
Report if:
- due to protocol-
specified 
intervention
- causes 
exclusion
Report all
Not required
Per data entry 
guidelines
Serious Adverse 
Event (SAE)
Report if:
- due to protocol-
specified 
intervention
- causes 
exclusion
Report all
Report all
Within 24 
hours of 
learning of 
event
Pregnancy/
Lactation Exposure
Not applicable since participants are infants.
Event of Clinical 
Interest (require 
regulatory reporting)
There are no events of clinical interest for this study.
Event of Clinical 
Interest (do not 
require regulatory 
reporting)
There are no events of clinical interest for this study.
Adverse Event of 
Special Interest 
(AESI)
Report if:
- due to 
intervention
- causes 
exclusion
Report all
Report Serious AESI in 
the same manner as SAE
Within 5 
calendar days 
of learning of 
event (unless 
serious)
Cancer
Report if:
- due to 
intervention
- causes 
exclusion
Report all
Report Serious Cancer in 
the same manner as SAE
Within 5 
calendar days 
of learning of 
event (unless 
serious)
Overdose
Not applicable
Report all
Not required
Within 5 
calendar days 
of learning of 
event
8.4.2
Method of Detecting AEs, SAEs, and Other Reportable Safety Events
Care will be taken not to introduce bias when detecting AEs and/or SAEs and other 
reportable safety events. Open-ended and nonleading verbal questioning of the participant is 
the preferred method to inquire about AE occurrence.
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8.4.3
Follow-up of AE, SAE, and Other Reportable Safety Event Information
After the initial AE/SAE report, the investigator is required to proactively follow each 
participant at subsequent visits/contacts. All AEs, SAEs, and other reportable safety events,
including pregnancy and exposure during breastfeeding, ECIs, cancer, and overdose will be 
followed until resolution, stabilization, until the event is otherwise explained, or the 
participant is lost to follow-up (as defined in Section 7.3). In addition, the investigator will 
make every attempt to follow all nonserious AEs that occur in randomized participants for 
outcome. Further information on follow-up procedures is given in Appendix 3.
8.4.4
Regulatory Reporting Requirements for SAE
Prompt notification (within 24 hours) by the investigator to the Sponsor of SAE is essential 
so that legal obligations and ethical responsibilities towards the safety of participants and the 
safety of a study intervention under clinical investigation are met.
The Sponsor has a legal responsibility to notify both the local regulatory authority and other 
regulatory agencies about the safety of a study intervention under clinical investigation. The 
Sponsor will comply with country-specific regulatory requirements and global laws and 
regulations relating to safety reporting to regulatory authorities, IRB/IECs, and investigators.
Investigator safety reports must be prepared for SUSARs according to local regulatory 
requirements and Sponsor policy and forwarded to investigators as necessary.
An investigator who receives an investigator safety report describing an SAE or other 
specific safety information (eg, summary or listing of SAE) from the Sponsor will file it 
along with the IB and will notify the IRB/IEC, if appropriate according to local requirements.
8.4.5
Pregnancy and Exposure During Breastfeeding
Information in this section is not applicable, as participants are infants.
8.4.6
Disease-related Events and/or Disease-related Outcomes Not Qualifying as 
AEs or SAEs
Not applicable for this study.
8.4.7
Events of Clinical Interest
Not applicable; there are no ECIs defined for this study.
8.4.8
Adverse Events of Special Interest
All AESI occurring through Day 42 postdose will be reported to the Sponsor. After Day 42, 
only AESI that meet the serious AE criteria (see Section 10.3.3) should be reported to the 
Sponsor.
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The investigator will provide an assessment of severity for AESI according to the grading 
scales provided in both Section 10.3.5 and the Severity Grading for Adverse Events
document, which are based on an adaption of the NCI CTCAE, version 5.
8.4.8.1
Anaphylaxis/Hypersensitivity Events
The following anaphylaxis/hypersensitivity events (Table 4) are defined as AESI in this 
study. The Sponsor will provide each site with an AESI guidance document (or equivalent). 
Refer to the AESI guidance document for the most updated list of terms, definitions, and 
additional details.
Table 4
Terms for Anaphylaxis/Hypersensitivity Events
Term
Definition
Anaphylaxis
A disorder characterized by an acute inflammatory reaction resulting 
from the release of histamine and histamine-like substances from mast 
cells, causing a hypersensitivity immune response.
Clinically, it presents with breathing difficulty, dizziness, hypotension, 
cyanosis, and loss of consciousness and may lead to death.
Angioedema
Localized, non-pitting, and transient swelling of submucosal or 
subcutaneous region.
Bronchospasm
A disorder characterized by a sudden contraction of the smooth 
muscles of the bronchial wall.
Drug 
hypersensitivity
(drug-related 
allergic reaction)
Adverse effects of drugs that clinically resemble allergic reactions.
Immediate clinical manifestations may include urticaria, angioedema, 
rhinitis, conjunctivitis bronchospasm, and anaphylaxis. Delayed 
clinical manifestations may include urticaria, maculopapular eruptions, 
fixed drug eruptions, vasculitis, toxic epidermal necrolysis (TEN), 
Stevens-Johnson syndrome (SJS), drug reaction with eosinophilia and 
systemic symptoms (DRESS), and acute generalized exanthematous 
pustulosis (AGEP).
Dyspnea 
(difficulty 
breathing)
A disorder characterized by an uncomfortable sensation of difficulty 
breathing.
Hypersensitivity
Excessive immune response.
Clinically, manifestations may include allergic manifestations such as 
urticaria, anaphylaxis, angioedema, allergic rhinitis, Stevens-Johnson 
syndrome (SJS), toxic epidermal necrolysis (TEN), acute generalized 
exanthematous pustulosis (AGEP), drug reaction with eosinophilia and 
systemic symptoms (DRESS), serum sickness, and vasculitis.
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Term
Definition
Dysphonia
A disorder characterized by an inflammation involving the larynx.
Wheezing
A disorder characterized by a high-pitched, whistling sound during 
breathing. It results from the narrowing or obstruction of the 
respiratory airways.
Before study start, the investigator or medically qualified designee will receive support from 
the Sponsor to assist in identifying the anaphylaxis/hypersensitivity AESI terms listed above 
in addition to instructions on the process from identification to data entry. At Visit 1, the 
investigator will provide anticipatory guidance to the legally acceptable representative for a 
suspected anaphylaxis or hypersensitivity event.
If any anaphylaxis/hypersensitivity event is reported in the eDiary (through Day 42) or 
during weekly surveillance calls, further assessment by the site may be required. The site 
must call the legally acceptable representative for additional information; if it is determined 
that an onsite assessment is required, a site visit should be conducted as soon as possible after 
becoming aware of the anaphylaxis/hypersensitivity event or within 3 days.
In addition, the legally acceptable representative should call the site as soon as possible if 
they suspect an anaphylaxis/hypersensitivity event or within 3 days of event onset.
In the event a participant experiences a Grade 3 or 4 anaphylaxis/hypersensitivity AESI
postdose, as confirmed by the investigator, an additional blood draw is required for 
evaluation for potential ADA to MK-1654, and additional ADA characterization, if indicated
(see Section 1.3.1 and Appendix 2).
8.4.8.2
Rash Events
The following rash events (Table 5) are defined as AESI in this study. Refer to the AESI 
guidance document (or equivalent) for the most updated list of terms, definitions, and 
additional details.
Table 5
Terms for Rash Events
Term
Definition
Acute generalized 
exanthematous pustulosis 
(AGEP)
A disorder characterized by fever and sterile pustules, 
circumscribed and elevated skin lesions filled with pus.
Drug eruption
An adverse skin reaction to a drug, not otherwise 
included in this table of rash terms.
Drug reaction with eosinophilia 
and systemic symptoms 
(DRESS)
A disorder characterized by fever, influenza-like 
symptoms, skin rash, eosinophilia, with or without 
atypical lymphocytes, elevated transaminase 
concentration, and/or impaired renal function.
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Term
Definition
Erythema multiforme
A disorder characterized by target lesions (a pink-red 
ring around a pale center).
Generalized rash of exfoliative 
nature (including dermatitis 
exfoliative and exfoliative rash)
A disorder characterized by generalized inflammatory 
erythema and exfoliation. The inflammatory process 
involves >90% of the body surface area.
Stevens-Johnson syndrome 
(SJS)
A disorder characterized by ≤30% total body skin area 
separation of dermis. The syndrome is thought to be a 
hypersensitivity complex affecting the skin and the 
mucous membranes.
Toxic epidermal necrolysis 
(TEN)
A disorder characterized by >30% total body skin area 
separation of dermis. The syndrome is thought to be a 
hypersensitivity complex affecting the skin and the 
mucous membranes.
Urticaria
A disorder characterized by an itchy skin eruption 
characterized by wheals with pale interiors and well-
defined red margins.
The investigator or medically qualified designee will receive support from the Sponsor to 
assist in identifying the rash AESI terms listed above (eg, representative photographic 
images) in addition to detailed instructions on the process from identification to photographic 
image submission. At Visit 1, the investigator will provide anticipatory guidance to the 
legally acceptable representative for suspected rash events.
If any rash event is reported in the eDiary (through Day 42) or during weekly surveillance 
calls, further assessment for AESI by the site may be required. The site must call the legally 
acceptable representative for additional information; if it is determined that an onsite 
assessment for AESI is required, a site visit should be conducted as soon as possible after 
becoming aware of the rash event or within 3 days. Photographs (see Section 8.4.8.2.1) and a 
dermatology consultation (see Section 8.4.8.2.2) may also be required.
In addition, the legally acceptable representative should call the site as soon as possible if 
they suspect a rash AESI or within 3 days of event onset.
8.4.8.2.1
Photography
If a participant has a suspected or confirmed rash AESI on evaluation, photographs must be 
taken. For all other rashes (non-AESI), photographs are not required.
Photographs will be taken to document the visual appearance and scope of dermal 
involvement. Whenever possible, photographs of participant’s faces or any other identifying 
features should be avoided or redacted. Sites should follow local policies for maintaining 
participant confidentiality and privacy.
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Before the end of the visit, the photographs should be reviewed by site staff to ensure they 
meet the imaging vendor requirements; additional photographs should be taken if needed. All 
photographs will be uploaded to the central vendor repository.
The imaging vendor will provide the following to each site:
•
Training
•
Details and requirements for the photographs (eg, number of photos, lighting)
•
Instructions for uploading photographs to the vendor repository
•
All imaging equipment
8.4.8.2.2
Dermatology Consultation
Severe rash AESI (Grade 3 and Grade 4) are unusual in general pediatric practice and 
therefore require evaluation by dermatologic specialists.
If the investigator determines that the suspected rash is indeed a Grade 3 or 4 AESI, every 
effort should be made to schedule a consultation with a local dermatologist (pediatric 
dermatologist is preferred where possible). This consultation with the local dermatologist 
should occur as soon as possible or within 3 days from the time the site diagnoses the 
Grade 3 or Grade 4 AESI.
The purpose of the dermatology consultation is to gain confirmation of the rash diagnosis.
This consultation should be conducted per local standards of care. The dermatologist should 
be provided access to the photos taken at the site visit and copies of relevant source 
documents collected for the purpose of this study.
After the dermatology consultation, the local dermatologist’s assessment and 
recommendations should be obtained. The diagnosis from the local dermatologist as well as 
any procedures or other intervention should be recorded on the appropriate eCRFs and added 
to the source documents.
See the AESI guidance document (or equivalent) for additional details.
8.5
Treatment of Overdose
In this study, an overdose is any dose higher than the protocol-defined dose.
No specific information is available on the treatment of overdose.
8.6
Pharmacokinetics
The decision as to which serum samples collected will be tested to evaluate PK will be 
determined by the Sponsor. If indicated, these samples may also be tested and/or pooled for 
testing in an exploratory manner for metabolites and/or additional markers.
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See the Pharmacokinetics/Immunogenicity/Pharmacodynamics schedule in the SoA for the 
timing of each blood draw. Detailed instructions including blood volumes to be drawn are 
provided in the laboratory manual.
8.7
Immunogenicity
8.7.1
Blood Collection for Antidrug Antibodies (ADA) Assay
Sample collection, storage, and shipment instructions for serum samples are provided in the 
laboratory manual.
See the Pharmacokinetics/Immunogenicity/Pharmacodynamics schedule in the SoA for the 
timing of each blood draw.
8.8
Pharmacodynamics
8.8.1
Blood Collection for Serum Neutralizing Antibodies Against RSV (SNA) 
Assay
Sample collection, storage, and shipment instructions for pharmacodynamic samples are
provided in the laboratory manual.
See the Pharmacokinetics/Immunogenicity/Pharmacodynamics schedule in the SoA for the 
timing of each blood draw.
8.9
Gene Sequencing and Sensitivity Testing
8.9.1
Nasopharyngeal Sample Collection for RT-PCR Testing and RSV F Gene 
Sequencing for Sensitivity to MK-1654
See the SoA (Section 1.3) and Section 8.2.3 for the timing of collection of the NP sample for 
RT-PCR testing for respiratory pathogen identification.
RSV F gene sequencing will only be performed if the NP specimen tests positive for RSV.
Detailed instructions are provided in the laboratory manual.
8.10
Biomarkers
Biomarkers are not evaluated in this study.
8.11
Future Biomedical Research Sample Collection
If the participant’s legally acceptable representative provides documented informed consent 
for future biomedical research, the following specimens will be obtained as part of future 
biomedical research:

DNA for future research
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
Leftover serum from the PK assay will be stored for future research.

Leftover serum from the ADA, SNA, and additional ADA characterization assays
will be stored for future research.

Leftover NP swabs from RT-PCR testing will be stored for future research.
8.12
Medical Resource Utilization and Health Economics
Medical Resource Utilization and Health Economics are not evaluated in this study.
8.13
Visit Requirements
Visit requirements are outlined in Section 1.3. Specific procedure-related details are provided 
in Section 8.1 through Section 8.11. Additional specific requirements are detailed below.
8.13.1
Screening (Visit 1 Predose)
At Visit 1, potential participants will be evaluated to determine whether they meet entry 
requirements as set forth in Section 5. Potential participants will be screened at the study site.
Infants with a recent illness with fever (rectal temperature ≥100.5°F [≥38.1°C] or axillary 
temperature ≥100.0°F [≥37.8°C]) within 72 hours predose at Visit 1 before administration of 
study intervention are not eligible, but may be rescreened (see Section 5.2 Exclusion
Criterion 4).
Participants may be rescreened up to 4 times. Screening procedures listed in the SoA 
(including consent review; see Section 1.3.1) should be repeated at each rescreen visit.
8.13.1.1
Predose Nasopharyngeal Sample Collection for RT-PCR Testing
If symptoms of respiratory infection have been present within 7 days before Visit 1, an NP
sample should be collected. Collecting an NP sample at Visit 1 does not exclude an infant 
from participating in the study.
8.13.2
Randomization/Dose Administration/Observation (Visit 1)
If a participant is deemed eligible for the study, and completes all other predose procedures, 
the participant will be assigned a unique treatment/randomization number by the IRT system.
All participants will also be randomized by IRT to 1 of the 2 different blood sampling groups 
(Group 1 or Group 2) that differ in the schedule of serum PK, ADA, and SNA sampling (see 
Section 1.3.1). Participants will then be assigned by IRT to 1 of the 2 subgroups (a or b) that 
differ in the tests to be performed.
Predose samples should be collected from randomized participants only. Samples should be 
collected after randomization in the IRT system but before dose administration. If the 
predose blood sample cannot be collected after 3 attempts, the dose should be administered.
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After randomization in the IRT system, participants will receive study intervention
administered as a single IM injection at the study site as described in Section 6.1 and 
Section 8.
Participants will be observed at the study site for at least 30 minutes postdose for any 
immediate AEs (see Section 8.3.4). This observation must be performed by the blinded 
investigator and/or study staff.
Vital sign measurements should be repeated at the end of the 30-minute postdose safety 
observation period.
8.13.3
Delay in Randomization and Study Medication Administration
All efforts should be made to randomize participants and administer study medication on 
Day 1 after predose screening procedures as per protocol. However, if randomization and
study medication administration cannot be conducted on the same day as screening, they may 
be conducted within 5 days of the predose screening procedures.
Prior to randomization in the IRT system and administration of study medication (Day 1), the 
site should confirm participant’s eligibility by repeating vital signs measurements, the full 
physical examination (including weight), and review the eligibility criteria and the informed 
consent.
8.13.4
Early Withdrawal Visit
If the legally acceptable representative withdraws consent prior to the last study visit, the 
participant should be brought in for a final visit (at the study site, at home, or at an alternate 
study site location; see Section 8.13.5) as follows:
•
First 1650 participants: Complete all assessments and procedures indicated for Visit 8 in 
the SoA (Section 1.3.2).
•
Remaining participants: Complete all assessments and procedures indicated for Visit 7 in 
the SoA (Section 1.3.1).
If the participant withdraws consent while attending a scheduled visit, any additional 
assessments and procedures needed for the final study visit should be conducted in addition 
to the assessments and procedures for the scheduled visit.
8.13.5
Visits at the Study Site, at Home, or at an Alternate Study Site Location
Every attempt should be made to assess the participant at the study site for all scheduled 
study visits (see Section 1.3.1 and Section 1.3.2) and for any unscheduled visit to assess 
possible respiratory infection symptoms or a suspected AESI (see Section 8.2.2 and
Section 8.4.8). However, if this is not possible, additional efforts should be made to ensure 
the per-protocol assessments are conducted for these visits.
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A visit at the study site is required at Visit 1 (Day 1). Study site visits are preferred for 
Visits 2 through 8 to ensure the participants are seen in person by the investigator and site 
staff in the event respiratory infection symptoms or a suspected AESI are present. See 
Section 1.3.1 and Section 1.3.2 for the visit schedules.
If circumstances do not support a visit at the study site, a home visit by the site personnel or a 
healthcare service provider (eg, home healthcare vendor) or a visit to an alternate study site 
location may be appropriate to perform study assessments and procedures per the SoA, where 
available and when permitted by local regulations and IRB/IEC. All indicated study 
procedures should be completed, including blood draws. The documentation from the visit 
should be provided to the investigator or medically qualified designee (consistent with local 
requirements) for review and assessment per institutional standard. Also, this documentation 
should be provided to site staff for data entry purposes.
Refer to the home visit manual (or equivalent) for details.
9
STATISTICAL ANALYSIS PLAN
This section outlines the statistical analysis strategy and procedures for the study. If, after the 
study has begun, but prior to any unblinding/final database lock, changes are made to 
primary and/or key secondary hypotheses, or the statistical methods related to those 
hypotheses, then the protocol will be amended (consistent with ICH Guideline E-9). Changes 
to tertiary or other nonconfirmatory analyses made after the protocol has been finalized, but 
prior to unblinding/final database lock, will be documented in an sSAP and referenced in the 
CSR for the study. Post hoc tertiary analyses will be clearly identified in the CSR.
9.1
Statistical Analysis Plan Summary
Key elements of the statistical analysis plan are summarized below; the comprehensive plan 
is provided in Section 9.2 through Section 9.12.
Study Design Overview
A Phase 2b/3 Double-Blind, Randomized, Placebo-Controlled Study to 
Evaluate the Efficacy and Safety of MK-1654 in Healthy Pre-Term and 
Full-Term Infants
Treatment Assignment
Participants will be assigned randomly in a 2:1 ratio to receive a single 
dose of MK-1654 or placebo. Randomization will be stratified by region 
(Southern Hemisphere and Northern Hemisphere), gestational age (≥29
to <35 weeks; ≥35 weeks), and chronological age at the time of consent
(<6 months; ≥6 months).
Analysis Populations
Efficacy: Full Analysis Set (FAS)
Safety: All Participants as Treated (APaT)
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Primary Endpoint(s)

Efficacy: Number of participants with RSV-MALRI in the MK-
1654 and placebo groups from Days 1 through 150 postdose.

Safety: Number of participants experiencing solicited injection-site 
AEs from Days 1 through 5 postdose, solicited daily body 
temperature to identify fever from Days 1 through 5 postdose, 
solicited systemic AEs from Days 1 through 5 postdose, 
anaphylaxis/hypersensitivity AESI from Days 1 through 42
postdose, rash AESI from Days 1 through 42 postdose, nonserious
AEs from Days 1 through 42 postdose, and SAEs through the
duration of study participation.
Key Secondary Endpoints

Efficacy: Number of participants with RSV hospitalization in the 
MK-1654 and placebo groups from Days 1 through 150 postdose.

Efficacy: Number of participants with RSV-MALRI in the MK-
1654 and placebo groups from Days 1 through 180 postdose.
Statistical Methods for Key 
Efficacy Analyses
The primary efficacy hypothesis will be evaluated by calculating the 
efficacy of MK-1654 compared to placebo with respect to the RSV-
MALRI endpoint. The p-value for testing the primary hypothesis that 
efficacy>25% as well as estimation of the 95% CI of efficacy will be 
based on the modified Poisson regression with robust variance proposed
by Zou [Zou, G. 2004].
Statistical Methods for Key 
Safety Analyses
There are no a priori clinical events identified in this trial as Tier 1 
events. Tier 2 events identified in this trial include solicited injection-
site AEs; solicited daily body temperature to identify fever; solicited 
systemic AEs; drug-related AEs; any serious AEs; discontinuations due 
to AEs; anaphylaxis/hypersensitivity AESI; rash AESI; nonserious AEs; 
and AEs by system organ class observed in ≥1% of participants in at 
least one group. Estimates of 95% CIs for between-treatment differences 
in the percentage of participants with events will be calculated using the 
Miettinen and Nurminen method [Miettinen, O. and Nurminen, M. 
1985].
Interim Analyses
Two IAs are planned in this study. The first IA (IA#1) will be conducted 
after the last participant in the Phase 2b cohort completes the Day 42 visit. 
Summaries of the safety, available PK, and efficacy for the endpoints of 
RSV-associated MALRI and hospitalization will be assessed at the IA#1
to evaluate the benefit versus risk for continued enrollment. The second IA
(IA#2) will be conducted when 40 total cases of RSV-associated MALRI 
have accrued across the MK-1654 and placebo groups. Futility of the 
primary hypothesis will be assessed at IA#2. The IAs will be performed by 
an unblinded statistician and results will be reviewed by an eDMC. Details 
are provided in Section 9.7.
Multiplicity
The overall 1-sided Type 1 error in testing the efficacy hypotheses is 
controlled at 2.5% based on gatekeeping procedure. The primary efficacy 
hypothesis will be tested at an overall 1-sided Type 1 error of 2.5%, as 
discussed in Section 9.9.1.1. The secondary efficacy hypothesis regarding 
RSV hospitalization from Days 1 through 150 postdose will be tested at 
1-sided Type 1 error of 2.5% only if the primary efficacy hypothesis is 
successfully demonstrated, as discussed in Section 9.9.1.2.
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Sample Size and Power 
This study will randomize approximately 3300 healthy infants in a 2:1 
allocation ratio into the MK-1654 group and the placebo group. 
Approximately 167 total cases of RSV-MALRI in the MK-1654 and 
placebo groups are expected to accrue by the end of the study. For RSV-
MALRI, the study has >95% power to demonstrate that the efficacy of 
MK-1654 compared to placebo to prevent RSV-MALRI is >25% if the 
underlying efficacy is 70% at an overall 1-sided Type 1 error of 2.5%. A
total of approximately 33 cases of RSV hospitalization in the MK-1654 
and placebo groups are expected to accrue by the end of the study. For
RSV hospitalization, the study has 93.6% power to demonstrate that the 
efficacy of MK-1654 compared to placebo to prevent RSV
hospitalization is >0% if the underlying efficacy is 70% at an overall 
1-sided Type 1 error of 2.5%.
9.2
Responsibility for Analyses/In-house Blinding
The statistical analysis of the data obtained from this study will be the responsibility of the 
Clinical Biostatistics department of the Sponsor.
This study will be conducted as a double-blind study under in-house blinding procedures. 
The official, final database will not be unblinded until medical/scientific review has been 
performed, protocol deviations have been identified, and data have been declared final and 
complete.
The Clinical Biostatistics department will generate the randomized allocation schedule(s) for 
study treatment assignment. Randomization will be implemented using IRT.
Blinding issues related to the planned IAs are described in Section 9.7.
9.3
Hypotheses/Estimation
Objectives and hypotheses of the study are stated in Section 3.
9.4
Analysis Endpoints
The efficacy, PK, pharmacodynamics, immunogenicity, and safety endpoints that will be 
evaluated are listed below.
9.4.1
Efficacy/Pharmacokinetics/Pharmacodynamics/Immunogenicity Endpoints
Efficacy Endpoints
The primary efficacy endpoint that will be used to evaluate and test the primary efficacy 
hypothesis is the number of participants with RSV-associated outpatient and inpatient 
MALRI occurring from Days 1 through 150 postdose, as described in Section 4.2.1.1. RSV-
associated outpatient and inpatient MALRI is defined by the presence of the following seen 
in an outpatient or inpatient clinical setting: cough or difficulty breathing; AND 1 or more of 
the following: wheezing, chest wall in-drawing/retractions, rales/crackles, hypoxemia, 
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tachypnea, dehydration due to respiratory symptoms; AND RSV-positive RT-PCR NP
sample. The secondary efficacy endpoints are:
•
Number of participants with RSV-associated hospitalization from Days 1 through 150 
postdose, defined as hospital admission for respiratory illness; AND RSV-positive RT-
PCR NP sample
•
Number of participants with RSV-associated outpatient and inpatient MALRI from 
Days 1 through 180 postdose
The following are the tertiary efficacy endpoints for this study:
•
Number of participants with RSV-associated outpatient and inpatient severe MALRI
from Days 1 through 150 postdose
•
Number of participants with RSV-associated outpatient and inpatient severe MALRI 
from Days 1 through 180 postdose
•
Number of participants with RSV-associated hospitalization from Days 1 through 180 
postdose
•
Number of participants with outpatient and inpatient MALRI due to any cause from 
Days 1 through 150 postdose
•
Number of participants with RSV-associated outpatient and inpatient MALRI from 
Days 365 through 515 postdose
•
Number of participants with RSV-associated hospitalization from Days 365 through 515 
postdose
•
Number of participants hospitalized with RSV-associated LRI from Days 1 through 150 
postdose
•
Number of participants hospitalized with RSV-associated LRI from Days 1 through 180 
postdose
•
Number of participants hospitalized with LRI due to any cause from Days 1 through 150 
postdose
•
Number of participants with non-RSV-associated outpatient and inpatient MALRI from 
Days 1 through 150 postdose
•
Number of participants with RSV-associated outpatient and inpatient MALRI excluding 
cases where other pathogens are found from Days 1 through 150 postdose
•
Number of participants with RSV-associated outpatient and inpatient ARI from Days 1 
through 150 postdose
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•
Number of participants with RSV-associated outpatient and inpatient ARI from Days 1 
through 180 postdose
•
Number of participants with physician-assessed wheezing from Days 1 through 180 
postdose
•
Number of participants with physician-assessed wheezing from Days 365 through 515 
postdose
Pharmacokinetics Endpoints
The tertiary PK endpoints are the serum PK concentration of MK-1654 at Days 7, 150, and 
240 postdose.
Pharmacodynamics Endpoints
The tertiary pharmacodynamics endpoints are SNA titers against RSV A at Day 1 (predose) 
and Days 7, 150, 240, 365, and 515 postdose.
Immunogenicity Endpoints
The tertiary immunogenicity endpoints are ADA to MK-1654 at Day 1 (predose) and 
Days 150, 240, 365, and 515 postdose.
Additional Tertiary Endpoints
The additional tertiary endpoint is RSV F gene sequence determined by deep sequencing in 
NP samples from infants infected with RSV.
9.4.2
Safety Endpoints
Safety and tolerability of MK-1654 in this study will be assessed by clinical review of all 
relevant parameters including AEs and laboratory values. The endpoints that will be used to 
assess the safety and tolerability of MK-1654 include the following:
•
Number of participants experiencing solicited injection-site AEs (redness/erythema, 
swelling, and pain/tenderness) from Days 1 through 5 postdose
•
Number of participants experiencing solicited daily body temperature, with fever defined 
as rectal temperature ≥102.2°F (≥39.0°C) or axillary temperature ≥101.7°F (≥38.7°C), 
from Days 1 through 5 postdose
•
Number of participants experiencing solicited systemic AEs (irritability, drowsiness, and 
appetite lost) from Days 1 through 5 postdose
•
Number of participants with anaphylaxis/hypersensitivity AESI from Days 1 through 42
postdose
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•
Number of participants with rash AESI from Days 1 through 42 postdose
•
Number of participants experiencing nonserious AEs occurring from Days 1 through 42 
postdose
•
Number of participants experiencing SAEs through the duration of study participation
(from the time the consent form is signed through completion of the participant’s 
participation in the study; for complete details on SAE data collection, see
Section 10.3.5).
9.5
Analysis Populations
9.5.1
Efficacy Analysis Populations
Full Analysis Set (FAS) Population
The FAS population will serve as the primary population for the evaluation of efficacy and 
for the estimation of incidence of RSV-associated disease. The FAS population consists of all 
randomized participants who receive 1 dose of study treatment. Participants will be included 
in the treatment group corresponding to the study treatment they were randomized to for the 
analysis using the FAS population.
For an episode of respiratory infection to be considered for evaluation of an efficacy endpoint 
for the analysis in the FAS population, a PCR result from the study central laboratory must 
be available for an NP sample that is collected no more than 12 days after symptom onset or 
symptom worsening, or after symptom onset and no more than 7 days before symptom 
worsening. A sensitivity analysis will be conducted, which will include PCR results from NP
samples collected within the timeframe mentioned above, but not tested at the study central 
laboratory.
Per-Protocol Efficacy (PPE) Population
The PPE population will serve as a supportive analysis population for the evaluation of 
efficacy and for the estimation of incidence of RSV-associated disease. To be eligible for 
inclusion in the PPE population, study participants must satisfy the following criteria:
•
Receive 1 dose of the correct clinical material corresponding to the treatment group the 
participants were randomized into,
•
Have at least 1 follow-up visit/phone call for assessment of RSV disease, and
•
At any time during dosing or efficacy follow-up, do not experience a protocol deviation 
that may interfere with the assessment of protection against RSV infection conferred by 
MK-1654.
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The final determination on important protocol deviations, and thereby the composition of the 
PPE population, will be made prior to the final unblinding of the database and will be 
documented in a separate memo.
For an episode of respiratory infection to be considered for evaluation of an efficacy endpoint
for the analysis in the PPE population, a PCR result from the study central laboratory must be 
available for an NP sample that is collected no more than 12 days after symptom onset or 
symptom worsening, or after symptom onset and no more than 7 days before symptom 
worsening.
For both analysis populations, if a participant with symptoms of respiratory infection prior to
dosing has an NP sample collected predose on Day 1 or any subsequent NP samples
collected for this episode that are PCR positive for RSV, this episode will not be counted as a 
case toward the efficacy endpoints.
9.5.2
Immunogenicity and Pharmacodynamic Analysis Populations
The immunogenicity and pharmacodynamic analysis populations that will be used in tertiary
analyses of immunogenicity and pharmacodynamic endpoints will be described in the sSAP 
that will be written for this study.
9.5.3
Pharmacokinetic Analysis Populations
The PK analysis populations that will be used in tertiary analyses of PK will be described in 
the sSAP that will be written for this study.
9.5.4
Safety Analysis Populations
Safety Analyses will be conducted in the APaT population, which consists of all randomized 
participants who received a dose of study treatment. Participants will be included in the 
treatment group corresponding to the study treatment they actually received for the analysis 
of safety data using the APaT population.
9.6
Statistical Methods
Statistical testing and inference relating to efficacy are described in Section 9.6.1. Statistical 
methods relating to safety analyses are described in Section 9.6.2. Demographic and baseline 
characteristics are described in Section 9.6.3. Statistical methods relating to immunogenicity 
and PK analyses are described in the sSAP. Efficacy results that will be deemed to be 
statistically significant after consideration of the Type 1 error control strategy are described 
in Section 9.8. Nominal p-values may be computed for other efficacy analyses, but should be 
interpreted with caution due to potential issues of multiplicity, sample size, etc.
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9.6.1
Statistical Methods for Efficacy Analyses
To address the primary efficacy hypothesis, a 1-sided test of the null hypothesis that the 
efficacy is ≤25% versus the alternative that efficacy is >25% will be conducted. The primary 
efficacy hypothesis will be tested at 1-sided α=0.025 level (ie, 2.5% Type 1 error). Efficacy 
is defined as:
E% = 100*{1-(Rt/Rp)}
where Rt and Rp are the incidence rates of RSV-associated MALRI in the MK-1654 and
placebo groups, respectively. The incidence rate Rt is defined as Rt=Ct/Tt, where Ct=the 
count of RSV-associated MALRI cases in the MK-1654 group and Tt=total person-time of 
follow-up for efficacy in the MK-1654 group. The incidence rate Rp is defined similarly. The 
95% CI for E is denoted as (EL, EU), and the statistical criterion for success with respect to 
the primary efficacy hypothesis will be met if EL >25%.
A modified Poisson regression approach with robust variance [Zou, G. 2004] will be used for 
the efficacy analyses. The mean and 95% CI of relative risk, Rt/Rp, will be obtained from the 
model, and will be used to estimate the mean and 95% CI of E. The modified Poisson 
regression model will include treatment group, and stratification variables of region
(Southern Hemisphere and Northern Hemisphere), gestational age (early and moderate pre-
term infants [≥29 to <35 weeks gestational age] and late pre-term and full-term infants 
[≥35 weeks gestational age]), and chronological age at the time of consent (<6 months; 
≥6 months) as covariates. To allow for differences in follow-up times among the participants, 
log (follow-up time) as the offset term will be added in the modified Poisson regression.
If the number of participants in any stratum is too small and/or convergence cannot be 
achieved for either of the primary and secondary efficacy endpoints, the covariate will be 
excluded from the model for the final analysis of all primary and secondary efficacy 
endpoints. If convergence issues persist, additional covariates will be excluded from the 
model in the following order: region, chronological age, and gestational age, until the model 
converges for all primary and secondary efficacy endpoints. Therefore, the same set of 
covariates will be used in the models for all of the primary and secondary efficacy endpoints 
in the final analyses.
For the primary analyses of efficacy, cases of RSV-associated outpatient and inpatient 
MALRI will be counted starting at Day 1 postdose and through 150 days postdose. For the 
primary efficacy hypothesis, cases of both RSV A and RSV B associated MALRI will be 
counted as endpoints. The efficacy of MK-1654 against RSV A and RSV B associated 
MALRI will also be estimated separately.
For the secondary efficacy hypothesis of RSV-associated hospitalization from Days 1 
through 150 postdose, the statistical criterion for success will be met if EL >0%. For the 
secondary efficacy endpoint of RSV-associated outpatient and inpatient MALRI occurring 
from Days 1 through 180 postdose, the estimate of efficacy and corresponding 95% CI will 
be provided. The analysis strategy for key efficacy variables is summarized in Table 6.
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Table 6
Analysis Strategy for Key Efficacy Variables
Endpoint/Variable
(Description, Time Point)
Primary vs. 
Supportive 
Approach
Statistical Methoda
Analysis 
Population
Missing Data 
Approach
Primary Endpoint
Incidence of RSV-associated 
outpatient and inpatient 
MALRI from Days 1 through 
150 postdose
P/S
Modified Poisson 
regression
(estimate, 95% CI, 
P-value)
FAS/PPE
Missing data will 
not be imputed
Secondary Endpoints
Incidence of RSV-associated 
hospitalization from Days 1 
through 150 postdose
P/S
Modified Poisson 
regression
(estimate, 95% CI, 
P-value)
FAS/PPE
Missing data will 
not be imputed
Incidence of RSV-associated 
outpatient and inpatient 
MALRI from Days 1 through 
180 postdose
P/S
Modified Poisson 
regression
(estimate, 95% CI)
FAS/PPE
Missing data will 
not be imputed
CI=confidence interval; FAS=Full Analysis Set; MALRI=medically attended lower respiratory infection; 
P=primary approach; PPE=per-protocol efficacy; S=supportive approach; RSV=respiratory syncytial virus.
a
The statistical methods are described in Section 9.6.1.
9.6.2
Statistical Methods for Safety Analyses
Safety and tolerability will be assessed by clinical review of all relevant parameters including 
AEs. All safety summaries will be provided separately for the first and second RSV seasons.
The analysis of safety results will follow a tiered approach (Table 7). AEs (specific terms as 
well as system organ class terms) and events that meet predefined limits of change (PDLCs) 
in laboratory and vital signs parameters are either pre-specified as “Tier 1” endpoints or will 
be classified as belonging to “Tier 2” or “Tier 3” based on the observed proportions of 
participants with an event.
Tier 1 Events
Safety parameters or AESI that are identified a priori constitute “Tier 1” safety endpoints that 
will be subject to inferential testing for statistical significance. There are no Tier 1 events for 
this protocol as no treatment-related SAEs have been observed in the Phase 1 studies of 
MK-1654.
Tier 2 Events
Membership in Tier 2 requires that at least 1% participants in any treatment group exhibit the 
event; OR AEs listed in Table 7. All other AEs will belong to Tier 3. Maximum body 
temperature will be summarized using Brighton Collaboration cutoffs.
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The threshold of at least 1% was chosen to draw clinical meaningful inference. When less 
than 1% of participants report AEs in both groups, the 95% CI for the between-group 
difference may exclude zero. However, the clinical significance of these differences is 
unknown given the small number of participants who report AEs. Because many 95% CIs for 
Tier 2 events may be provided without adjustment for multiplicity, the CIs should be 
regarded as a helpful descriptive measure to be used in review, not a formal method for 
assessing the statistical significance of the between-group differences in AEs.
Tier 3 Events
Safety endpoints that are not Tier 1 or 2 events are considered Tier 3 events. Only point 
estimates by treatment group are provided for Tier 3 safety parameters.
Table 7
Analysis Strategy for Safety Parameters
Safety 
Tier
Safety Endpoint
95% CI for Comparison of 
MK-1654 and Placebo
Descriptive 
Statistics
Tier 2
Any AEa
X
X
Any Serious AE
X
X
Any Drug-related AE
X
X
Any Serious and Drug-related AE
X
X
Discontinuation due to AE
X
X
Solicited Injection-site AEs Days 1-5 Postdose
X
X
Solicited Daily Body Temperature Days 1-5 
Postdose
X
X
Solicited Systemic AEs Days 1-5 Postdose
X
X
Anaphylaxis/hypersensitivity AESI Days 1-42
Postdose
X
X
Rash AESI Days 1-42 Postdose
X
X
Nonserious AEs Days 1-42 Postdose
X
X
AEs by SOC (incidence ≥1% of participants in 
1 of the treatment groups)
X
X
Tier 3
AEs by SOC (incidence <1% of participants in all 
of the treatment groups)
X
AE=adverse event; AESI=adverse event(s) of special interest; SAE=serious adverse event; CI=confidence 
interval; SOC=System Organ Class; X=results will be provided.
a
Indicates broad AE category of the number of participants reporting any AE.
9.6.3
Demographic and Baseline Characteristics
The comparability of the treatment groups for each relevant demographic and baseline 
characteristic will be assessed by the use of tables and/or graphs. No statistical hypothesis 
tests will be performed on these characteristics. The number and percentage of participants 
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screened and randomized and the primary reasons for screening failure and discontinuation 
will be displayed. Demographic variables (eg, age, gender, race, and ethnicity), baseline 
characteristics (including medical history as outlined in Section 8.1.4), primary and 
secondary diagnoses, and prior and concomitant therapies will be summarized by treatment 
group either by descriptive statistics or categorical tables.
9.6.3.1
Population Pharmacokinetic Analyses
Based on PK data obtained within this study, a separate population PK analysis will be 
performed and reported separately. The prospective details of this analysis will be specified 
in a separate population PK analysis plan.
9.7
Interim Analyses
A total of 2 IAs are planned for this study. All IAs will be conducted by an external 
unblinded statistician. Enrollment will not be paused during IAs/review of results by eDMC. 
All available safety, PK, and RSV disease incidence data will be summarized for each IA. 
Ongoing PK bioanalysis and PK modeling will be conducted by a separate, unblinded 
modeling group and external bioanalysts. In addition to these planned IAs, the eDMC will 
review available safety and RSV disease incidence data from this study at least once every 
6 months while the study is still enrolling or as outlined in the eDMC charter.
Treatment-level results and/or participant-level data from the IA will be provided by the 
unblinded statistician to the eDMC. The extent to which individuals are unblinded with 
respect to results of the IAs will be documented by the unblinded statistician. The results of 
the IAs will not be shared with the investigators prior to the completion of the study. 
Participant-level unblinding will be restricted to the external unblinded statistician and 
scientific programmer performing the IA, who will have no other responsibilities associated 
with the study.
IA#1: After the last participant randomized in the Phase 2b cohort completes the Day 42 visit
and the safety data are available, the first IA will be conducted. Summaries of the safety data 
will be reviewed by the eDMC. Additionally, the eDMC will review a summary of the
available PK data, and estimates of efficacy along with the 95% CIs for the endpoints of 
RSV-associated MALRI and RSV-associated hospitalization (based on the exact binomial 
method proposed by Chan and Bohidar [Chan, I. S. F. and Bohidar, N. R. 1998]). Futility of 
the primary efficacy endpoint will not be assessed at this IA. The eDMC will assess the 
benefit versus risk for continued enrollment and a recommendation on whether the study 
should continue will be made by the eDMC. The study will not stop for success of the 
primary efficacy hypothesis at the IA. If the study stops at the IA, no further participants will 
be enrolled. However, participants that have already been enrolled in the study will continue 
to be monitored for safety for 365 days postdose.
IA#2: If the study continues, the second IA for futility evaluation will be conducted when 
40 total RSV-MALRI cases in the combined MK-1654 and placebo groups have been 
observed in the study. If ≥21 cases are observed in the MK-1654 group (observed efficacy 
<50%), the study may stop for futility. If the study stops at this IA due to futility, no further 
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participants will be enrolled. However, participants that have already been enrolled in the 
study will continue to be monitored for safety for 365 days postdose. The study will not stop 
for success of the primary efficacy hypothesis at the IA. The operating characteristics of the 
futility criterion are shown in Table 8. Summaries of the available safety and PK data will be 
summarized and reviewed at the second IA.
Table 8
Futility Evaluation Operating Characteristics (Interim Analysis #2)
Analysis 
Time 
Point
Total 
Cases to 
Accrue
Stop for 
Futility 
(MK-1654 
Cases)
Observed 
Efficacy (%) 
(95% CI)
True 
Efficacy
Probability of 
Stopping for 
Futility at IA#2 
(%)a
Probability of NOT 
Stopping for Futility 
at IA#2 
(%)a,b
IA 2
40
≥21
45 (-9, 72)
25% 
(Null)
87.0
13.0
50%
43.7
56.3
60%
19.3
80.7
70%
3.8
96.2
80%
0.1
99.9
90%
0.0
100.0
CI=confidence interval; IA=interim analysis.
a
Probability is based on the exact binomial method proposed by Chan and Bohidar [Chan, I. S. F. and 
Bohidar, N. R. 1998].
b
=100 − probability of stopping for futility at IA#2.
If the study does not stop at the second IA, the study will continue as planned. After all
participants in the global study (see Appendix 7 regarding enrollment in China) have
completed 180 days postdose follow-up, a database lock will be executed, and the Sponsor 
study team will be unblinded. All analyses to evaluate the primary, secondary, and tertiary
objectives of the study will be conducted, and a CSR will be written. A separate blinded 
Sponsor study team will be appointed to conduct the remainder of the study. All participants 
will continue in the study until all follow-up assessments per the protocol have occurred.
When all participants have completed all follow-up assessments per the protocol 365 days 
postdose, a database lock will be executed, and the supplemental CSR will be written. If the 
first 1650 participants enrolled finish the follow-up through RSV Season 2 by the time all 
participants finish the follow-up through 365 days postdose, all analyses will be written in 1
supplemental CSR; otherwise, another supplemental CSR will be written at the end of RSV 
Season 2 follow-up. Investigators, study participants, and their legally accepted 
representatives will remain blinded to individual treatment assignments throughout the 
duration of the entire study and will be unblinded upon completion of the end-of-study CSR.
The details for the reports of data reviewed by the eDMC and processes by which 
recommendations and decisions are reached and communicated by the eDMC will be 
documented in the eDMC charter for the Sponsor. The eDMC charter will be referenced in 
the CSR. Prior to final study unblinding, Sponsor individuals who have been unblinded at 
any level will not be involved in any discussions regarding modifications to the protocol, 
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statistical methods, identification of protocol deviations, or data validation efforts after the 
IAs.
9.8
Multiplicity
The overall 1-sided Type 1 error in testing the efficacy hypotheses is controlled at 2.5% 
based on a gatekeeping procedure.
The primary efficacy hypothesis will be tested at an overall 1-sided Type 1 error equal to 
2.5% (see Section 9.9.1.1). The secondary efficacy hypothesis regarding RSV hospitalization 
from Days 1 through 150 postdose will be tested at 1-sided Type 1 error of 2.5% only if the 
primary efficacy hypothesis is successfully demonstrated (see Section 9.9.1.2).
A futility analysis of the primary endpoint will be conducted when 40 total RSV-MALRI 
cases in the combined MK-1654 and placebo groups have been observed. No Type 1 error 
adjustment is needed for the futility analysis because there is no possibility to stop the study
and conclude efficacy.
9.9
Sample Size and Power Calculations
9.9.1
Sample Size and Power for Efficacy Analyses
9.9.1.1
Sample Size and Power for Testing the Primary Efficacy Hypothesis
The sample size of approximately 3300 was selected to ensure collection of adequate safety 
information on the use of MK-1654 in this otherwise healthy population of pre-term and 
full-term infants. This study will randomize approximately 2200 healthy infants into the 
MK-1654 group and approximately 1100 healthy infants into the placebo group. A total of
approximately 167 cases of RSV-associated MALRI in the MK-1654 and placebo groups are 
expected to accrue by the end of the study, under the following assumptions: 1) incidence of 
RSV-associated MALRI in the placebo group is 10% per season; 2) efficacy=70%, so that 
the incidence of RSV-associated MALRI in the MK-1654 group is 3% per season; and 3) 
attrition rate is 5%. Under these assumptions, there is >95% power to demonstrate that the 
efficacy of MK-1654 compared to placebo to prevent RSV-associated MALRI is >25% if the 
underlying efficacy is 70% at an overall 1-sided Type 1 error of 2.5%. The calculations are 
based on a simulation study for the modified Poisson regression and carried out using the 
SAS software.
9.9.1.2
Sample Size and Power for Testing the Secondary Efficacy Hypothesis
RSV-associated hospitalization is the secondary efficacy endpoint. A total of approximately 
33 cases of RSV-associated hospitalization in the MK-1654 and placebo groups are expected 
to accrue by the end of the study, under the following assumptions: 1) incidence of RSV-
associated hospitalization in the placebo group is 2% per season; 2) efficacy=70%, so that the 
incidence of RSV-associated hospitalization in the MK-1654 group is 0.6% per season; and 
3) attrition rate is 5%. Under these assumptions, there is 93.6% power to demonstrate that the 
efficacy of MK-1654 compared to placebo to prevent RSV-associated hospitalization is >0%
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if the underlying efficacy is 70% at an overall 1-sided Type 1 error of 2.5%. The calculations 
are based on a simulation study for the modified Poisson regression and carried out using the 
SAS software.
9.9.2
Sample Size and Power for Safety Analyses
The probability of observing at least 1 SAE in this study depends on the number of 
participants treated and the underlying percentage of participants with a SAE in the study 
population. Calculations below assume that 100% of the randomized participants will be 
evaluable for safety analyses. If the underlying incidence of an SAE is 0.069% (1 of every 
1456 participants receiving the MK-1654), there is an 80% chance of observing at least 
1 SAE among 2200 participants in the MK-1654 group. If the underlying incidence of an
SAE is 0.033% (1 of every 3039 participants receiving the MK-1654), there is a 50% chance 
of observing at least 1 SAE among 2200 participants in the MK-1654 group. If no SAEs are 
observed among the 2200 participants in the MK-1654 group, this study will provide 
97.5% confidence that the underlying percentage of participants with an SAE is <0.139% 
(1 in every 720 participants) in the MK-1654 group.
The percentage point differences between the 2 groups that could be detected with 80% 
probability for a variety of hypothetical underlying incidences of an AE are summarized in 
Table 9. These calculations assume 2200 participants in the MK-1654 group and
1100 participants in the placebo group and are based on a 2-sided 5% alpha level. The 
calculations are based on an asymptotic method proposed by Farrington and Manning (1990) 
[Farrington, C. P. 1990]; no multiplicity adjustments were made.
Table 9
Differences in Incidence of Adverse Event Rates Between the 2 Groups That can
be Detected With an ~80% Probability (Assuming 2-sided 5% Alpha Level With
2200 Participants in the MK-1654 Group and 1100 Participants in the Placebo Group)
Incidence of Adverse Event
Risk Difference
Placebo (%)
MK-1654 (%)
Percentage Points
0.1
0.8
0.7
2.0
3.8
1.8
5.0
7.5
2.5
10.0
13.3
3.3
15.0
18.9
3.9
20.0
24.3
4.3
30.0
34.9
4.9
Incidences presented here are hypothetical and do not represent actual adverse experiences in either group.
Based on an asymptotic method [Farrington, C. P. 1990].
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9.10
Subgroup Analyses
The consistency of the treatment effect will be assessed descriptively by category for the 
classification variables listed below. Efficacy of MK-1654 against RSV-associated MALRI 
will be estimated separately in (1) Southern Hemisphere and Northern Hemisphere regions; 
(2) the early and moderate pre-term infants (≥29 to <35 weeks gestational age) and late pre-
term and full-term infants (≥35 weeks gestational age) subgroups; (3) age groups at the time 
of consent (<6 months; ≥6 months); (4) weight groups at the time of consent. In addition to 
the 2 age groups, efficacy will also be summarized in infants ≤2 weeks of age. The incidence
of RSV-associated MALRI in each treatment group, the estimate of efficacy, and the nominal 
95% CI will be reported for each subgroup.
Subgroup analyses of safety and PK profiles will be summarized descriptively by age groups 
at randomization. The descriptive statistics will be reported for each subgroup.
9.11
Compliance (Medication Adherence)
Given that participants will receive just a single dose of MK-1654 or a single dose of 
placebo, compliance will not be calculated. However, the number and proportion of 
randomized participants receiving each treatment will be summarized (see Section 9.12).
9.12
Extent of Exposure
The extent of exposure will be summarized by the number and proportion of randomized 
participants administered MK-1654 and the number and proportion of randomized 
participants administered placebo.
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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 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. Participants must meet protocol entry criteria to be enrolled in the trial. 
2. Site Selection
MSD selects investigative sites based on medical expertise, access to appropriate participants, adequacy of 
facilities and staff, previous performance in clinical trials, as well as budgetary considerations. Prior to trial 
initiation, sites are evaluated by MSD personnel (or individuals acting on behalf of MSD) to assess the ability 
to successfully conduct the trial.
3. Site Monitoring/Scientific Integrity
Investigative trial sites are monitored to assess compliance with the trial protocol and Good Clinical Practice 
(GCP). MSD reviews clinical data for accuracy, completeness, and consistency. Data are verified versus 
source documentation according to standard operating procedures. Per MSD policies and procedures, if fraud, 
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scientific/research misconduct or serious GCP-non-compliance is suspected, the issues are investigated. 
When necessary, the clinical site will be closed, the responsible regulatory authorities and ethics review 
committees 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. Unless required by 
law, only the investigator, Sponsor (or individuals acting on behalf of MSD), ethics committee, and/or regulatory 
authorities will have access to confidential medical records that might identify the participant by name.
D. Genomic Research
Genomic research will only be conducted in accordance with a protocol and informed consent authorized by an 
ethics committee.
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IV. Financial Considerations
A. Payments to Investigators
Clinical trials are time- and labor-intensive. It is MSD’s policy to compensate investigators (or the sponsoring 
institution) in a fair manner for the work performed in support of MSD trials. MSD does not pay incentives to 
enroll participants in its trials. However, when enrollment is particularly challenging, additional payments may be 
made to compensate for the time spent in extra recruiting efforts.
MSD does not pay for participant referrals. However, MSD may compensate referring physicians for time spent 
on chart review and medical evaluation to identify potentially eligible participants.
B. Clinical Research Funding
Informed consent forms will disclose that the trial is sponsored by MSD, and that the investigator or sponsoring 
institution is being paid or provided a grant for performing the trial. However, the local ethics committee may 
wish to alter the wording of the disclosure statement to be consistent with financial practices at that institution. As 
noted above, all publications resulting from MSD trials will indicate MSD as a source of funding.
C. Funding for Travel and Other Requests
Funding of travel by investigators and support staff (e.g., to scientific meetings, investigator meetings, etc.) will be 
consistent with local guidelines and practices.
V. Investigator Commitment
Investigators will be expected to review MSD’s Code of Conduct as an appendix to the trial protocol, and in signing the 
protocol, agree to support these ethical and scientific standards.
10.1.2
Financial Disclosure
Financial Disclosure requirements are outlined in the US Food and Drug Administration 
Regulations, Financial Disclosure by Clinical Investigators (21 CFR Part 54). It is the 
Sponsor's responsibility to determine, based on these regulations, whether a request for 
Financial Disclosure information is required. It is the investigator's/subinvestigator's 
responsibility to comply with any such request.
The investigator/subinvestigator(s) agree, if requested by the Sponsor in accordance with 21 
CFR Part 54, to provide his/her financial interests in and/or arrangements with the Sponsor to 
allow for the submission of complete and accurate certification and disclosure statements. 
The investigator/subinvestigator(s) further agree to provide this information on a 
Certification/Disclosure Form, commonly known as a financial disclosure form, provided by 
the Sponsor. The investigator/subinvestigator(s) also consent to the transmission of this 
information to the Sponsor in the United States for these purposes. This may involve the 
transmission of information to countries that do not have laws protecting personal data.
10.1.3
Data Protection
The Sponsor will conduct this study in compliance with all applicable data protection 
regulations.
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Participants will be assigned a unique identifier by the Sponsor. Any participant records or 
datasets that are transferred to the Sponsor will contain the identifier only; participant names 
or any information that would make the participant identifiable will not be transferred.
The participant must be informed that his/her personal study-related data will be used by the 
Sponsor in accordance with local data protection law. The level of disclosure must also be 
explained to the participant. 
The participant must be informed that his/her medical records may be examined by Clinical 
Quality Assurance auditors or other authorized personnel appointed by the Sponsor, by 
appropriate IRB/IEC members, and by inspectors from regulatory authorities.
10.1.3.1
Confidentiality of Data
By signing this protocol, the investigator affirms to the Sponsor that information furnished to 
the investigator by the Sponsor will be maintained in confidence, and such information will 
be divulged to the IRB, IEC, or similar or expert committee; affiliated institution and 
employees, only under an appropriate understanding of confidentiality with such board or 
committee, affiliated institution and employees. Data generated by this study will be 
considered confidential by the investigator, except to the extent that it is included in a 
publication as provided in the Publications section of this protocol.
10.1.3.2
Confidentiality of Participant Records
By signing this protocol, the investigator agrees that the Sponsor (or Sponsor representative), 
IRB/IEC, or regulatory authority representatives may consult and/or copy study documents to 
verify worksheet/CRF data. By signing the consent form, the participant agrees to this 
process. If study documents will be photocopied during the process of verifying 
worksheet/CRF information, the participant will be identified by unique code only; full 
names/initials will be masked prior to transmission to the Sponsor.
By signing this protocol, the investigator agrees to treat all participant data used and 
disclosed in connection with this study in accordance with all applicable privacy laws, rules 
and regulations.
10.1.3.3
Confidentiality of IRB/IEC Information
The Sponsor is required to record the name and address of each IRB/IEC that reviews and 
approves this study. The Sponsor is also required to document that each IRB/IEC meets 
regulatory and ICH GCP requirements by requesting and maintaining records of the names 
and qualifications of the IRB/IEC members and to make these records available for 
regulatory agency review upon request by those agencies.
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10.1.4
Committees Structure
10.1.4.1
Scientific Advisory Committee (SAC)
This study was developed in collaboration with a SAC. The SAC is comprised of both 
Sponsor and non-Sponsor scientific experts who provide input with respect to study design, 
interpretation of study results, and subsequent peer-reviewed scientific publications.
10.1.4.2
Executive Oversight Committee
The EOC is comprised of members of Sponsor Senior Management. The EOC will receive 
and decide upon any recommendations made by the eDMC regarding the study.
10.1.4.3
External Data Monitoring Committee
To supplement the routine study monitoring outlined in this protocol, an external DMC will 
monitor the interim data from this study. The voting members of the committee are external 
to the Sponsor. The members of the DMC must not be involved with the study in any other 
way (eg, they cannot be study investigators) and must have no competing interests that could 
affect their roles with respect to the study.
The DMC will make recommendations to the EOC regarding steps to ensure both participant 
safety and the continued ethical integrity of the study. Also, the DMC will review interim 
study results, consider the overall risk and benefit to study participants (Section 9.7) and 
recommend to the EOC whether the study should continue in accordance with the protocol.
Specific details regarding composition, responsibilities, and governance, including the roles 
and responsibilities of the various members and the Sponsor protocol team; meeting 
facilitation; the study governance structure; and requirements for and proper documentation 
of DMC reports, minutes, and recommendations will be described in the DMC charter that is 
reviewed and approved by all the DMC members.
10.1.5
Publication Policy
The results of this study may be published or presented at scientific meetings. The Sponsor 
will comply with the requirements for publication of study results. In accordance with 
standard editorial and ethical practice, the Sponsor will generally support publication of 
multicenter studies only in their entirety and not as individual site data. In this case, a 
coordinating investigator will be designated by mutual agreement.
If publication activity is not directed by the Sponsor, the investigator agrees to submit all 
manuscripts or abstracts to the Sponsor before submission. This allows the Sponsor to protect 
proprietary information and to provide comments.
Authorship will be determined by mutual agreement and in line with International Committee 
of Medical Journal Editors authorship requirements.
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10.1.6
Compliance with Study Registration and Results Posting Requirements
Under the terms of the FDAAA of 2007 and the EMA clinical trial Directive 2001/20/EC, the 
Sponsor of the study is solely responsible for determining whether the study and its results 
are subject to the requirements for submission to http://www.clinicaltrials.gov, 
www.clinicaltrialsregister.eu or other local registries. MSD, as Sponsor of this study, will 
review this protocol and submit the information necessary to fulfill these requirements. MSD 
entries are not limited to FDAAA or the EMA clinical trial directive mandated trials. 
Information posted will allow participants to identify potentially appropriate studies for their 
disease conditions and pursue participation by calling a central contact number for further 
information on appropriate study locations and study site contact information.
By signing this protocol, the investigator acknowledges that the statutory obligations under 
FDAAA, the EMA clinical trials directive, or other locally mandated registries are that of the 
Sponsor and agrees not to submit any information about this study or its results to those 
registries.
10.1.7
Compliance with Law, Audit, and Debarment
By signing this protocol, the investigator agrees to conduct the study in an efficient and 
diligent manner and in conformance with this protocol; generally accepted standards of GCP
(eg, International Council on Harmonisation of Technical Requirements for Registration of 
Pharmaceuticals for Human Use GCP: Consolidated Guideline and other generally accepted 
standards of GCP); and all applicable federal, state and local laws, rules and regulations 
relating to the conduct of the clinical study.
The Code of Conduct, a collection of goals and considerations that govern the ethical and 
scientific conduct of clinical investigations sponsored by MSD, is provided in this appendix 
under the Code of Conduct for Clinical Trials.
The investigator agrees not to seek reimbursement from participants, their insurance 
providers, or from government programs for procedures included as part of the study 
reimbursed to the investigator by the Sponsor.
The investigator will promptly inform the Sponsor of any regulatory authority inspection 
conducted for this study.
The investigator agrees to provide the Sponsor with relevant information from inspection 
observations/findings to allow the Sponsor to assist in responding to any citations resulting 
from regulatory authority inspection and will provide the Sponsor with a copy of the 
proposed response for consultation before submission to the regulatory authority. 
Persons debarred from conducting or working on clinical studies by any court or regulatory 
authority will not be allowed to conduct or work on this Sponsor’s studies. The investigator 
will immediately disclose in writing to the Sponsor if any person who is involved in 
conducting the study is debarred or if any proceeding for debarment is pending or, to the best 
of the investigator’s knowledge, threatened.
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For investigators located in countries with serious breach reporting requirements, investigator 
will promptly report to the Sponsor any serious breach or suspected serious breach that 
occurs in compliance with those requirements. Unless more specifically defined in the 
applicable requirements, a serious breach is any breach of the applicable clinical trial 
regulation or of the clinical trial protocol which is likely to affect to a significant degree: (i) 
the safety or rights of a trial participant, or (ii) the reliability and robustness of the data 
generated in the clinical trial.
10.1.8
Data Quality Assurance
All participant data relating to the study will be recorded on printed or electronic CRF unless 
transmitted to the Sponsor or designee electronically (eg, laboratory data). The investigator 
or qualified designee is responsible for verifying that data entries are accurate and correct by 
physically or electronically signing the CRF.
Detailed information regarding Data Management procedures for this protocol will be 
provided separately.
The investigator must maintain accurate documentation (source data) that supports the 
information entered in the CRF.
The investigator must permit study-related monitoring, audits, IRB/IEC review, and 
regulatory agency inspections and provide direct access to source data documents.
Study documentation will be promptly and fully disclosed to the Sponsor by the investigator 
upon request and also shall be made available at the study site upon request for inspection, 
copying, review, and audit at reasonable times by representatives of the Sponsor or any 
regulatory authorities. The investigator agrees to promptly take any reasonable steps that are 
requested by the Sponsor or any regulatory authorities as a result of an audit or inspection to 
cure deficiencies in the study documentation and worksheets/CRFs.
The Sponsor or designee is responsible for the data management of this study including 
quality checking of the data.
Study monitors will perform ongoing source data review and verification to confirm that data 
entered into the CRF by authorized site personnel are accurate, complete, and verifiable from 
source documents; that the safety and rights of participants are being protected; and that the 
study is being conducted in accordance with the currently approved protocol and any other 
study agreements, ICH GCP, and all applicable regulatory requirements.
Records and documents, including participant's documented informed consent, pertaining to 
the conduct of this study must be retained by the investigator for 15 years after study 
completion unless local regulations or institutional policies require a longer retention period. 
No records may be destroyed during the retention period without the written approval of the 
Sponsor. No records may be transferred to another location or party without written 
notification to the Sponsor.
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10.1.9
Source Documents
Source documents provide evidence for the existence of the participant and substantiate the 
integrity of the data collected. The investigator/institution should maintain adequate and 
accurate source documents and study records that include all pertinent observations on each 
of the site’s participants. Source documents and data should be attributable, legible, 
contemporaneous, original, accurate, and complete. Changes to source data should be 
traceable, should not obscure the original entry, and should be explained if necessary (eg, via 
an audit trail). Source documents are filed at the investigator’s site.
Data reported on the CRF or entered in the eCRF that are transcribed from source documents 
must be consistent with the source documents or the discrepancies must be explained. The 
investigator/institution may need to request previous medical records or transfer records, 
depending on the study. Also, current medical records must be available.
10.1.10
Study and Site Closure
The Sponsor or its designee may stop the study or study site participation in the study for 
medical, safety, regulatory, administrative, or other reasons consistent with applicable laws, 
regulations, and GCP.
In the event the Sponsor prematurely terminates a particular study site, the Sponsor or 
designee will promptly notify that study site’s IRB/IEC as specified by applicable regulatory 
requirement(s).
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10.2
Appendix 2: Clinical Laboratory Tests
•
The tests described in Table 10 will be performed by the central laboratory.
•
The overall blood draw schedule, the approximate total blood sample volume at each 
visit, and the total blood volume for RSV Seasons 1 and 2 for participants in the study are 
provided in Table 11. The maximum amount of blood drawn from each participant is 
dependent upon weight at each study visit. For participants who weigh <3 kg at the time 
of the blood draw, the maximum blood sample volume must be adjusted according to the 
participant weight cutoffs provided in Table 12.
•
Collect a blood sample (1.2 mL) if participant has a Grade 3 or 4 
anaphylaxis/hypersensitivity AESI postdose, as confirmed by the investigator, for 
evaluation for potential ADA to MK-1654, and additional ADA characterization, if 
indicated (see Section 1.3.1, Section 8.4.8.1, and Table 10).
•
Additional tests may be performed at any time during the study as determined necessary 
by the investigator or required by local regulations.
•
The participant/participant’s legally acceptable representative, the investigator, and 
Sponsor personnel or delegate(s) who are involved in the study intervention 
administration or clinical evaluation of the participants will be blinded to the data. Only 
unblinded study team members will have access to the data.
•
Laboratory/analyte results that could unblind the study will not be reported to 
investigative sites or other blinded personnel until the study has been unblinded.
•
Unblinding may be appropriate for safety issues (see Section 8.1.10).
Table 10
Laboratory Assessments in the MK-1654-004 Study
Laboratory Assessments
Parameters
Protocol-required Laboratory Assessments
Virology

RT-PCR assay for RSV and other respiratory pathogens included in the 
RT-PCR assay panel

Assay for COVID-19

RSV F gene sequencing will only be performed if RT-PCR test is positive 
for RSV
Pharmacokinetics

Assay to measure serum PK concentration of MK-1654
Immunogenicitya

Assay for ADA to MK-1654, and additional ADA characterization, if 
indicated
Pharmacodynamics

Assay for SNA
Safety (if indicated)

Assay for ADA to MK-1654, and additional ADA characterization, if 
indicated, in the event a participant experiences a Grade 3 or 4 anaphylaxis
or hypersensitivity AESI
ADA=antidrug antibodies; PK=pharmacokinetics; RSV=respiratory syncytial virus; RT-PCR=reverse 
transcriptase-polymerase chain reactions; SNA=serum neutralizing antibodies against RSV.
a
A sufficient amount of serum will be stored for further characterization of immunogenicity, if needed.
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Table 11
Blood Draw Schedule and Approximate Blood Sample Volumes Drawn Per Study Visit for Participants who Weigh ≥3kg
RSV Season 1
RSV Season 2
Study Period
Screening, 
Randomization, and 
Intervention
Follow-up
(through 365 days 
postdose)
Total 
Blood 
Volumea
for RSV 
Season 1
Follow-up
(365 through 515 days 
postdose)
Total 
Blood 
Volumea
for RSV 
Season 2
Total 
Blood 
Volumea
for RSV 
Seasons
1 and 2
Visit Number/Title
1
2b
5
6
7
8
Scheduled Day and 
Window (Days):
Day 1
Predose
7
+2
150
±5
240
±5
365
±5
515
+14
Group 1a:
Blood Volumea
2.4 mL
1.2 mL
2.4 mL
-
6.0 mL
2.4 mL
2.4 mL
4.8 mL
10.8 mL
Group 1b:
Blood Volumea
2.4 mL
1.2 mL
2.4 mL
-
6.0 mL
-
-
-
6.0 mL
Group 2a:
Blood Volumea
2.4 mL
-
2.4 mL
2.4 mL
7.2 mL
2.4 mL
2.4 mL
4.8 mL
12.0 mL
Group 2b:
Blood Volumea
2.4 mL
-
2.4 mL
2.4 mL
7.2 mL
-
-
-
7.2 mL
RSV=respiratory syncytial virus.
a
The blood sample volume at each visit and total blood sample volume for RSV Seasons 1 and 2 are provided for participants who weigh ≥3 kg at the time 
of the visit. For participants who weigh <3 kg at a visit, the maximum blood sample volume at the visit must be adjusted according to the participant 
weight cutoffs provided in Table 12.
b
In the event a participant experiences a Grade 3 or 4 anaphylaxis/hypersensitivity AESI postdose (see Section 1.3.1 and Section 8.4.8.1), an additional
blood sample (1.2 mL) is required.
Table 12
Maximum Blood Sample Volume Drawn Per Study Visit by Participant Weight
Participant Weighta
Maximum Blood Sample Volume Per Study Visit
≥3 kg
2.4 mL
≥1.5 to <3 kg
1.2 mL
<1.5 kg
No sampling
a
Indicates participant weight at the time of the visit.
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10.3
Appendix 3: Adverse Events: Definitions and Procedures for Recording, 
Evaluating, Follow-up, and Reporting
10.3.1
Definitions of Medication Error, Misuse, and Abuse
Medication Error
This is an unintended failure in the drug treatment process that leads to or has the potential to 
lead to harm to the patient.
Misuse
This refers to situations where the medicinal product is intentionally and inappropriately used 
not in accordance with the terms of the product information.
Abuse
This corresponds to the persistent or sporadic, intentional excessive use of a medicinal 
product for a perceived psychological or physiological reward or desired non-therapeutic 
effect.
10.3.2
Definition of AE
AE definition

An AE is any untoward medical occurrence in a clinical study participant, temporally 
associated with the use of study intervention, whether or not considered related to the 
study intervention.

NOTE: An AE can therefore be any unfavorable and unintended sign (including an 
abnormal laboratory finding), symptom, or disease (new or exacerbated) temporally 
associated with the use of a study intervention.

NOTE: For purposes of AE definition, study intervention includes any pharmaceutical 
product, biological product, vaccine, diagnostic agent, medical device, combination 
product, or protocol specified procedure whether investigational or marketed (including 
placebo, active comparator product, or run-in intervention), manufactured by, licensed 
by, provided by, or distributed by the Sponsor for human use in this study.
Events meeting the AE definition

Any abnormal laboratory test results (hematology, clinical chemistry, or urinalysis) or 
other safety assessments (eg, ECG, radiological scans, vital signs measurements), 
including those that worsen from baseline, considered clinically significant in the medical 
and scientific judgment of the investigator.
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
Exacerbation of a chronic or intermittent pre-existing condition including either an 
increase in frequency and/or intensity of the condition.

New conditions detected or diagnosed after study intervention administration even 
though it may have been present before the start of the study.

Signs, symptoms, or the clinical sequelae of a suspected drug-drug interaction.

Signs, symptoms, or the clinical sequelae of a suspected overdose of either study 
intervention or a concomitant medication.

For all reports of overdose (whether accidental or intentional) with an associated AE, the 
AE term should reflect the clinical symptoms or abnormal test result. An overdose 
without any associated clinical symptoms or abnormal laboratory results is reported using 
the terminology “accidental or intentional overdose without adverse effect.”

Any new cancer or progression of existing cancer.
Events NOT meeting the AE definition

Medical or surgical procedure (eg, endoscopy, appendectomy): the condition that leads to 
the procedure is the AE.

Situations in which an untoward medical occurrence did not occur (social and/or 
convenience admission to a hospital).

Anticipated day-to-day fluctuations of pre-existing disease(s) or condition(s) present or 
detected at the start of the study that do not worsen.

Surgery planned prior to informed consent to treat a pre-existing condition that has not 
worsened.

Congenital disorder (eg, present from birth) that is detected/diagnosed in an infant 
participant.
10.3.3
Definition of SAE
If an event is not an AE per definition above, then it cannot be an SAE even if serious 
conditions are met.
An SAE is defined as any untoward medical occurrence that, following dosing:
a. Results in death
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b. Is life-threatening
•
The term “life-threatening” in the definition of “serious” refers to an event in which
the participant was at risk of death at the time of the event. It does not refer to an 
event, which hypothetically might have caused death, if it were more severe.
c. Requires inpatient hospitalization or prolongation of existing hospitalization
•
Hospitalization is defined as an inpatient admission, regardless of length of stay, even 
if the hospitalization is a precautionary measure for continued observation. (Note: 
Hospitalization for an elective procedure to treat a pre-existing condition that has not 
worsened is not an SAE.) A pre-existing condition is a clinical condition that is 
diagnosed prior to the use of an MSD product and is documented in the participant’s 
medical history.
d. Results in persistent or significant disability/incapacity
•
The term disability means a substantial disruption of a person’s ability to conduct 
normal life functions.
•
This definition is not intended to include experiences of relatively minor medical 
significance such as uncomplicated headache, nausea, vomiting, diarrhea, influenza, 
and accidental trauma (eg, sprained ankle) that may interfere with or prevent 
everyday life functions but do not constitute a substantial disruption.
e. Is a congenital anomaly/birth defect
•
In offspring of participant taking the product regardless of time to diagnosis.
f. Other important medical events
•
Medical or scientific judgment should be exercised in deciding whether SAE 
reporting is appropriate in other situations such as important medical events that may 
not be immediately life-threatening or result in death or hospitalization but may 
jeopardize the participant or may require medical or surgical intervention to prevent 1 
of the other outcomes listed in the above definition. These events should usually be 
considered serious.
•
Examples of such events include invasive or malignant cancers, intensive treatment in 
an emergency room or at home for allergic bronchospasm, blood dyscrasias or 
convulsions that do not result in hospitalization, or development of drug dependency 
or drug abuse.
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10.3.4
Additional Events Reported
Additional events that require reporting
In addition to the above criteria, AEs meeting either of the below criteria, although not 
serious per ICH definition, are reportable to the Sponsor.
1.
Is a cancer
2.
Is associated with an overdose
10.3.5
Recording AE and SAE
AE and SAE recording

When an AE/SAE occurs, it is the responsibility of the investigator to review all 
documentation (eg, hospital progress notes, laboratory, and diagnostics reports) related to 
the event.

The investigator will record all relevant AE/SAE information on the AE 
CRFs/worksheets at each examination.

It is not acceptable for the investigator to send photocopies of the participant’s medical 
records to the Sponsor in lieu of completion of the AE CRF page.

There may be instances when copies of medical records for certain cases are requested by 
the Sponsor. In this case, all participant identifiers, with the exception of the participant 
number, will be blinded on the copies of the medical records before submission to the 
Sponsor.

The investigator will attempt to establish a diagnosis of the event based on signs, 
symptoms, and/or other clinical information. In such cases, the diagnosis (not the 
individual signs/symptoms) will be documented as the AE/SAE.
Assessment of severity

An event is defined as “serious” when it meets at least 1 of the predefined outcomes as 
described in the definition of an SAE, not when it is rated as severe.

The investigator will assess the severity for each AE, SAE, and AESI (and other 
reportable safety event) reported during the study. Severity will be graded according to an 
adaption of NCI CTCAE version 5.0 as applicable for pediatric assessments. Where 
necessary, the NCI CTCAE scale has been adapted to conform to AE assessment for 
infant participants. Once the assessment has been made, the severity grade should be 
recorded in the “overall toxicity grade” section of the AE eCRF.
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
The severity of solicited injection-site AEs, solicited systemic AEs, elevated temperature, 
and AESI will be assessed according to the grading criteria (for Grade 1 through Grade 4)
provided in Table 13 through Table 17. Additional grading definitions for AEs are 
provided in the separate study document: Severity Grading for Adverse Events.

The severity for all other types of AEs that are not in the adapted NCI CTCAE will be 
determined by the investigator based upon clinical judgment and by using the following
severity grading criteria (for Grade 1 through Grade 4):
-
Grade 1: Mild; mild symptoms; clinical or diagnostic observations only; intervention 
not indicated; awareness of symptoms, but easily tolerated.
-
Grade 2: Moderate; minimal, local, or noninvasive intervention indicated. Infant is 
definitely acting like something is wrong.
-
Grade 3: Severe or medically significant but not immediately life-threatening; 
intensive intervention indicated; disabling. Infant is extremely irritable or unable to 
do usual activities.
-
Grade 4: Life-threatening consequences; urgent intervention indicated.
-
Any AE that results in death will be assigned a severity grade of Grade 5.
It is important to distinguish between seriousness criteria and severity of an AE. Severity is a 
measure of intensity whereas seriousness is defined by the criteria in Section 10.3.3. A 
Grade 3 AE is not necessarily considered an SAE. For example, a Grade 3 headache that 
persists for several hours may not meet the definition of an SAE and would be considered a 
nonserious event, whereas a Grade 2 seizure resulting in a hospital admission would be 
considered an SAE.
Grading Scales for the Assessment of Severity for Solicited Injection-Site AEs, Solicited 
Systemic AEs, Elevated Temperature, and AESI
Note: Injection-site redness/erythema and injection-site swelling reported from Days 1 
through 5 postdose will be evaluated by maximum size.
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Table 13
Solicited Injection-site AE Severity Grading Scale
Solicited Injection-
Site AEa
Severity Grade
Grade 1
Grade 2
Grade 3
Grade 4
Pain/Tenderness
Mild pain or 
tenderness with or 
without associated 
symptoms; does not 
interfere with normal 
activity
Moderate pain or 
tenderness. 
Interferes with 
normal activity
Severe pain or 
tenderness; 
prevents normal 
activity
Life-threatening 
consequences; urgent 
intervention indicated
Erythema/Redness
Size measured as 
>0 and ≤1
Size measured as 
>1 and ≤2
Size measured 
as >2
Necrosis or 
exfoliative dermatitis 
OR results in ER visit 
or hospitalization
Swelling
Size measured as 
>0 and ≤1
Size measured as 
>1 and ≤2
Size measured 
as >2
Necrosis or 
exfoliative dermatitis 
OR results in ER visit 
or hospitalization
AE=adverse event; eDiary=electronic diary; ER=emergency room.
a Based upon information provided by the legally acceptable representative in the eDiary and verbally during 
the eDiary review. Erythema/redness and swelling are specific injection-site AEs with size designations of 
numbers 1 through 8, as indicated on the study-supplied ruler. If the participant has an ER visit or is 
hospitalized for any injection-site AE, that AE is to be assigned a grade of 4, regardless of the size measured.
Table 14
Solicited Systemic AE Severity Grading Scale
Solicited 
Systemic 
AEa
Severity Grade
Grade 1
Grade 2
Grade 3
Grade 4
Irritability
Mild; mild symptoms; 
clinical or diagnostic 
observations only; 
intervention not 
indicated; awareness 
of symptoms but 
easily tolerated.
Moderate; 
minimal local or 
noninvasive 
intervention 
indicated. Infant is 
definitely acting 
like something is 
wrong.
Severe or medically 
significant but not 
immediately life-
threatening; 
hospitalization or 
prolongation of 
hospitalization indicated; 
disabling. Infant is 
extremely irritable or 
unable to do usual 
activities. 
Life-threatening 
consequences; 
urgent 
intervention 
indicated.
Drowsiness
Mild; asymptomatic or 
mild symptoms; 
clinical or diagnostic 
observations only; 
intervention not 
indicated; awareness 
of symptoms but 
easily tolerated.
Moderate; 
minimal local or 
noninvasive 
intervention 
indicated. Infant is 
definitely acting 
like something is 
wrong.
Severe or medically 
significant but not 
immediately life-
threatening; 
hospitalization or 
prolongation of 
hospitalization indicated; 
disabling. Infant is 
extremely distressed or 
unable to do usual 
activities. 
Life-threatening 
consequences; 
urgent 
intervention 
indicated.
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Solicited 
Systemic 
AEa
Severity Grade
Grade 1
Grade 2
Grade 3
Grade 4
Irritability
Mild; mild symptoms; 
clinical or diagnostic 
observations only; 
intervention not 
indicated; awareness 
of symptoms but 
easily tolerated.
Moderate; 
minimal local or 
noninvasive 
intervention 
indicated. Infant is 
definitely acting 
like something is 
wrong.
Severe or medically 
significant but not 
immediately life-
threatening; 
hospitalization or 
prolongation of 
hospitalization indicated; 
disabling. Infant is 
extremely irritable or 
unable to do usual 
activities. 
Life-threatening 
consequences; 
urgent 
intervention 
indicated.
Appetite 
lost
Mild; asymptomatic or 
mild symptoms; 
clinical or diagnostic 
observations only; 
intervention not 
indicated; awareness 
of symptoms but 
easily tolerated.
Moderate; 
minimal local or 
noninvasive 
intervention 
indicated. Infant is 
definitely acting 
like something is 
wrong.
Severe or medically 
significant but not 
immediately life-
threatening; 
hospitalization or 
prolongation of 
hospitalization indicated; 
disabling. Infant is 
extremely distressed or 
unable to do usual 
activities. 
Life-threatening 
consequences; 
urgent 
intervention 
indicated.
AE=adverse event; eDiary=electronic diary.
a Based upon information provided by the legally acceptable representative in the eDiary and verbally during 
the eDiary review.
Table 15
Elevated Temperature (Rectal) Severity Grading Scale
Severity Grade
Grade 1
Grade 2
Grade 3
Grade 4
Elevated Temperature
(°C) a
(°F) a
≥38.0 to <39.0
≥100.4 to <102.2
≥39.0 to <40.0
≥102.2 to <104.0
≥40.0
≥104.0 for ≤24 hours
≥40.0
≥104.0 for >24 hours
a Rectal temperature. Correction factors to adjust axillary temperatures for an equivalent rectal temperature are axillary 
temperature +2 degrees in Fahrenheit OR axillary temperature +1.1 degrees in Celsius.
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Table 16
AESI: Anaphylaxis/Hypersensitivity Severity Grading Scale
AESI Term
Severity Grade
Grade 1
Grade 2
Grade 3
Grade 4
Anaphylaxis
Not applicable
Not applicable
Symptomatic bronchospasm, with or 
without urticaria; parenteral intervention 
indicated; allergy-related 
edema/angioedema; hypotension
Life-threatening 
consequences; urgent 
intervention indicated
Angioedema 
Mild; asymptomatic or mild 
symptoms; clinical or diagnostic 
observations only; intervention not 
indicated; awareness of symptoms, 
but easily tolerated
Moderate; minimal, local or 
noninvasive intervention 
indicated. Infant is definitely 
acting like something is 
wrong
Severe or medically significant but not 
immediately life-threatening; intensive 
intervention indicated; disabling. Infant is 
extremely distressed or unable to do usual 
activities
Life-threatening 
consequences; urgent 
intervention indicated
Bronchospasm
Mild symptoms; intervention not 
indicated
Symptomatic; medical 
intervention indicated; 
limiting routine activities 
such as feeding
Limiting routine activities such as feeding; 
supplemental oxygen indicated
Life-threatening respiratory 
or hemodynamic 
compromise; intubation or 
urgent intervention 
indicated
Drug 
hypersensitivity
(drug-related 
allergic reaction)
Allergic reaction; systemic 
intervention not indicated
Oral intervention indicated
Bronchospasm; hospitalization indicated 
for clinical sequelae; IV intervention 
indicated
Life-threatening 
consequences; urgent 
intervention indicated
Hypersensitivity
Allergic reaction; systemic 
intervention not indicated
Oral intervention indicated
Bronchospasm; hospitalization indicated 
for clinical sequelae; IV intervention 
indicated
Life-threatening 
consequences; urgent 
intervention indicated
Dyspnea 
(difficulty 
breathing)
Shortness of breath with moderate 
exertion
Shortness of breath with 
minimal exertion; limiting 
routine activities such as 
feeding
Shortness of breath at rest; limiting routine 
activities such as feeding
Life-threatening 
consequences; urgent 
intervention indicated
Dysphonia
Mild sore throat; raspy voice
Moderate sore throat; 
analgesics indicated
Severe throat pain; endoscopic intervention 
indicated
Not applicable
Wheezing
Detectable airway noise with 
minimal symptoms
Moderate symptoms; 
medical intervention 
indicated; limiting routine 
activities such as feeding
Severe respiratory symptoms limiting 
routine activities such as feeding; oxygen 
therapy or hospitalization indicated
Life-threatening 
consequences; urgent 
intervention indicated
AESI=adverse event(s) of special interest.
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Table 17
AESI: Rash Severity Grading Scale
AESI Term
Severity Grade
Grade 1
Grade 2
Grade 3
Grade 4
Acute generalized 
exanthematous pustulosis 
(AGEP)
Not applicable
Not applicable
Severe or medically significant but not 
immediately life-threatening; 
hospitalization or prolongation of 
existing hospitalization indicated; 
limiting routine activities such as 
feeding
Life-threatening consequences; 
urgent intervention indicated
Drug eruption
Lesions covering 
<10% BSA; topical 
intervention indicated
Lesions covering 10–
30% BSA; oral 
intervention indicated
Lesions covering >30% BSA; IV 
intervention indicated
Not applicable
Drug reaction with 
eosinophilia and systemic 
symptoms (DRESS)
Not applicable
Not applicable
Severe or medically significant but not 
immediately life-threatening; 
hospitalization or prolongation of 
existing hospitalization indicated; 
limiting routine activities such as 
feeding
Life-threatening consequences; 
urgent intervention indicated
Erythema multiforme
Target lesions 
covering <10% BSA 
and not associated 
with skin tenderness
Target lesions 
covering 10-30% 
BSA and associated 
with skin tenderness
Target lesions covering >30% BSA and 
associated with oral or genital erosions
Target lesions covering >30% 
BSA; associated with fluid or 
electrolyte abnormalities; ICU care 
or burn unit indicated
Generalized rash of 
exfoliative nature 
(including dermatitis 
exfoliative and exfoliative 
rash)
Not applicable
Erythema covering 
>90% BSA without 
associated symptoms
Erythema covering >90% BSA with 
associated symptoms (eg, pruritus or 
tenderness); limiting routine activities 
such as feeding
Erythema covering >90% BSA 
with associated fluid or electrolyte 
abnormalities; ICU care or burn 
unit indicated
Stevens-Johnson syndrome
Not applicable
Not applicable
Skin sloughing covering <10% BSA 
with associated signs (eg, erythema, 
purpura, epidermal detachment, and 
mucous membrane detachment)
Skin sloughing covering 10–30% 
BSA with associated signs (ie, 
erythema, purpura, epidermal 
detachment, and mucous 
membrane detachment)
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AESI Term
Severity Grade
Grade 1
Grade 2
Grade 3
Grade 4
Toxic epidermal necrolysis
Not applicable
Not applicable
Not applicable
Skin sloughing covering ≥30% 
BSA with associated symptoms 
(eg, erythema, purpura, or 
epidermal detachment)
Urticaria (hives or welts)
Urticarial lesions 
covering <10% BSA; 
topical intervention 
indicated
Urticarial lesions 
covering 10-30% 
BSA; oral 
intervention indicated
Urticarial lesions covering >30% BSA; 
IV intervention indicated
Not applicable
AESI=adverse event(s) of special interest; BSA=body surface area; ICU=intensive care unit; IV=intravenous.
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Assessment of causality
•
Did the study intervention cause the AE?
•
The determination of the likelihood that the study intervention caused the AE will be 
provided by an investigator who is a qualified physician. The investigator’s signed/dated 
initials on the source document or worksheet that supports the causality noted on the AE 
form, ensures that a medically qualified assessment of causality was done. This initialled
document must be retained for the required regulatory time frame. The criteria below are 
intended as reference guidelines to assist the investigator in assessing the likelihood of a 
relationship between the test product and the AE based upon the available information.
•
The following components are to be used to assess the relationship between the study 
intervention and the AE; the greater the correlation with the components and their 
respective elements (in number and/or intensity), the more likely the study intervention
caused the AE:
-
Exposure: Is there evidence that the participant was actually exposed to the study 
intervention such as: reliable history, acceptable compliance assessment (diary, etc.), 
seroconversion? 
-
Time Course: Did the AE follow in a reasonable temporal sequence from 
administration of the study intervention? Is the time of onset of the AE compatible 
with a vaccine-induced effect?
-
Likely Cause: Is the AE not reasonably explained by another etiology such as 
underlying disease, other drug(s)/vaccine(s), or other host or environmental factors?
-
Rechallenge: Was the participant re-exposed to the study intervention in the study?
◦
If yes, did the AE recur or worsen? 
◦
If yes, this is a positive rechallenge.
◦
If no, this is a negative rechallenge.
(Note: This criterion is not applicable if: (1) the initial AE resulted in death or 
permanent disability, or (2) the study is a single-dose intervention study; or (3) study 
intervention(s) is/are used only 1 time.)
NOTE: IF A RECHALLENGE IS PLANNED FOR AN AE THAT WAS SERIOUS AND 
MAY HAVE BEEN CAUSED BY THE STUDY INTERVENTION, OR IF RE-
EXPOSURE TO THE STUDY INTERVENTION POSES ADDITIONAL POTENTIAL 
SIGNIFICANT RISK TO THE PARTICIPANT THEN THE RECHALLENGE MUST BE 
APPROVED IN ADVANCE BY THE SPONSOR CLINICAL DIRECTOR, AND IF 
REQUIRED, THE IRB/IEC.
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•
Consistency with study intervention profile: Is the clinical/pathological presentation of 
the AE consistent with previous knowledge regarding the study intervention or drug class 
pharmacology or toxicology?
•
The assessment of relationship will be reported on the CRFs/worksheets by an 
investigator who is a qualified physician according to his/her best clinical judgment, 
including consideration of the above elements.
•
Use the following scale of criteria as guidance (not all criteria must be present to be 
indicative of a study intervention relationship).
-
Yes, there is a reasonable possibility of study intervention relationship:
◦
There is evidence of exposure to the study intervention. The temporal sequence of 
the AE onset relative to the administration of the study intervention is reasonable. 
The AE is more likely explained by the study intervention than by another cause.
-
No, there is not a reasonable possibility of study intervention relationship:
◦
Participant did not receive the study intervention OR temporal sequence of the AE 
onset relative to administration of the study intervention is not reasonable OR the 
AE is more likely explained by another cause than the study intervention. (Also 
entered for a participant with overdose without an associated AE.)
•
For each AE/SAE, the investigator must document in the medical notes that he/she has 
reviewed the AE/SAE and has provided an assessment of causality.
•
There may be situations in which an SAE has occurred and the investigator has minimal 
information to include in the initial report to the Sponsor. However, it is very important 
that the investigator always make an assessment of causality for every event before the 
initial transmission of the SAE data to the Sponsor.
•
The investigator may change his/her opinion of causality in light of follow-up 
information and send an SAE follow-up report with the updated causality assessment.
•
The causality assessment is 1 of the criteria used when determining regulatory reporting 
requirements.
Follow-up of AE and SAE

The investigator is obligated to perform or arrange for the conduct of supplemental 
measurements and/or evaluations as medically indicated or as requested by Sponsor to 
elucidate the nature and/or causality of the AE or SAE as fully as possible. This may 
include additional laboratory tests or investigations, histopathological examinations, or 
consultation with other health care professionals.

New or updated information will be recorded in the CRF.
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
The investigator will submit any updated SAE data to the Sponsor within 24 hours of 
receipt of the information.
10.3.6
Reporting of AEs, SAEs, and Other Reportable Safety Events to the Sponsor
AE, SAE, and other reportable safety event reporting to Sponsor via electronic data 
collection tool

The primary mechanism for reporting to the Sponsor will be the EDC tool.
-
Electronic reporting procedures can be found in the EDC data entry guidelines (or 
equivalent).
-
If the electronic system is unavailable for more than 24 hours, then the site will use 
the paper AE Reporting form.
◦
Reference Section 8.4.1 for reporting time requirements.

The site will enter the SAE data into the electronic system as soon as it becomes 
available.

After the study is completed at a given site, the EDC tool will be taken off-line to prevent 
the entry of new data or changes to existing data.

If a site receives a report of a new SAE from a study participant or receives updated data 
on a previously reported SAE after the EDC tool has been taken off-line, then the site can 
report this information on a paper SAE form or by telephone (see next section).

Contacts for SAE reporting can be found in the Investigator Study File Binder (or 
equivalent).
SAE reporting to the Sponsor via paper CRF

If the EDC tool is not operational, facsimile transmission or secure 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
Not applicable for this study in infants.
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10.6
Appendix 6: Collection and Management of Specimens for Future Biomedical 
Research
1. Definitions
a. Biomarker: A biological molecule found in blood, other body fluids, or tissues that is a 
sign of a normal or abnormal process or of a condition or disease. A biomarker may be 
used to see how well the body responds to a treatment for a disease or condition.1
b Pharmacogenomics: The investigation of variations of DNA and RNA characteristics as 
related to drug/vaccine response.2
c. Pharmacogenetics: A subset of pharmacogenomics, pharmacogenetics is the influence of 
variations in DNA sequence on drug/vaccine response.2
d. DNA: Deoxyribonucleic acid.
e. RNA: Ribonucleic acid.
2. Scope of Future Biomedical Research
The specimens consented and/or collected in this study as outlined in Section 8.11 will be 
used in various experiments to understand:
◦
The biology of how drugs/vaccines work
◦
Biomarkers responsible for how a drug/vaccine enters and is removed by the body
◦
Other pathways with which drugs/vaccines may interact
◦
The biology of disease
The specimen(s) may be used for future assay development and/or drug/vaccine 
development.
It is now well recognized that information obtained from studying and testing clinical 
specimens offers unique opportunities to enhance our understanding of how individuals 
respond to drugs/vaccines, enhance our understanding of human disease and ultimately 
improve public health through development of novel treatments targeted to populations 
with the greatest need. All specimens will be used by the Sponsor or those working for or 
with the Sponsor.
3. Summary of Procedures for Future Biomedical Research
a. Participants for Enrollment
All participants enrolled in the clinical study will be considered for enrollment in future 
biomedical research.
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b. Informed Consent
Informed consent for specimens (ie, DNA, RNA, protein, etc.) will be obtained during 
screening for protocol enrollment from all participants or legally acceptable 
representatives, at a study visit by the investigator or his or her designate. Informed 
consent for future biomedical research should be presented to the participants or legally 
acceptable representatives on the visit designated in the SoA. If delayed, present consent 
at next possible Participant Visit. Consent forms signed by the participant or legally 
acceptable representative will be kept at the clinical study site under secure storage for 
regulatory reasons.
A template of each study site’s approved informed consent will be stored in the Sponsor’s 
clinical document repository.
c. eCRF Documentation for Future Biomedical Research Specimens
Documentation of participant consent for future biomedical research will be captured in 
the eCRFs. Any specimens for which such an informed consent cannot be verified will be 
destroyed.
d. Future Biomedical Research Specimen(s)
Collection of specimens for future biomedical research will be performed as outlined in 
the SoA. In general, if additional blood specimens are being collected for future 
biomedical research, these will usually be obtained at a time when the participant is 
having blood drawn for other study purposes.
4. Confidential Participant Information for Future Biomedical Research
In order to optimize the research that can be conducted with future biomedical research 
specimens, it is critical to link participant’s 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 gender, age, medical history and intervention outcomes are 
critical to understanding clinical context of analytical results.
To maintain privacy of information collected from specimens obtained for future 
biomedical research, the Sponsor has developed secure policies and procedures. All 
specimens will be single-coded per ICH E15 guidelines as described below.
At the clinical study site, unique codes will be placed on the future biomedical research 
specimens. This code is a random number which does not contain any personally 
identifying information embedded within it. The link (or key) between participant 
identifiers and this unique code will be held at the study site. No personal identifiers will 
appear on the specimen tube.
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5. Biorepository Specimen Usage
Specimens obtained for the Sponsor will be used for analyses using good scientific 
practices. Analyses utilizing the future biomedical research specimens may be performed 
by the Sponsor, or an additional third party (eg, a university investigator) designated by 
the Sponsor. The investigator conducting the analysis will follow the Sponsor’s privacy 
and confidentiality requirements. Any contracted third party analyses will conform to the 
specific scope of analysis outlined in future biomedical research protocol and consent. 
Future biomedical research specimens remaining with the third party after specific 
analysis is performed will be reported to the Sponsor.
6. Withdrawal From Future Biomedical Research
Participants or legally acceptable representatives may withdraw their consent for future 
biomedical research and ask that their biospecimens not be used for future biomedical 
research. Participants or legally acceptable representatives may withdraw consent at any 
time by contacting the investigator for the main study. If medical records for the main 
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 main study use only. If 
specimens were collected from study participants specifically for future biomedical 
research, 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 or legally 
acceptable representative 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 prior to 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.
In the event that the medical records for the main study are no longer available (eg, if the 
investigator is no longer required by regulatory authorities to retain the main study 
records) or the specimens have been completely anonymized, there will no longer be a 
link between the participant’s personal information and their specimens. In this situation, 
the request for withdrawal of consent and/or destruction cannot be processed.
7. Retention of Specimens
Future biomedical research specimens will be stored in the biorepository for potential 
analysis for up to 20 years from the end of the main 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 
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specimens will be stored under strict supervision in a limited access facility which 
operates to assure the integrity of the specimens. Specimens will be destroyed according 
to Sponsor policies and procedures and this destruction will be documented in the 
biorepository database.
8. Data Security
Databases containing specimen information and test results are accessible only to the 
authorized Sponsor representatives and the designated study administrator research 
personnel and/or collaborators. Database user authentication is highly secure, and is 
accomplished using network security policies and practices based on international 
standards to protect against unauthorized access.
9. Reporting of Future Biomedical Research Data to Participants
No information obtained from exploratory laboratory studies will be reported to the 
participant, family, or physicians. Principle reasons not to inform or return results to the 
participant include: Lack of relevance to participant health, limitations of predictive 
capability, and concerns regarding misinterpretation.
If important research findings are discovered, the Sponsor may publish results, present 
results in national meetings, and make results accessible on a public website in order to 
rapidly report this information to doctors and participants. Participants will not be 
identified by name in any published reports about this study or in any other scientific 
publication or presentation.
10. Future Biomedical Research Study Population
Every effort will be made to recruit all participants diagnosed and treated on Sponsor 
clinical studies for future biomedical research.
11. Risks Versus Benefits of Future Biomedical Research
For future biomedical research, risks to the participant have been minimized and are 
described in the future biomedical research informed consent.
The Sponsor has developed strict security, policies, and procedures to address participant 
data privacy concerns. Data privacy risks are largely limited to rare situations involving 
possible breach of confidentiality. In this highly unlikely situation, there is risk that the 
information, like all medical information, may be misused.
12. Questions
Any questions related to the future biomedical research should be emailed directly to 
clinical.specimen.management@MSD.com.
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13. References
1. National Cancer Institute [Internet]: Available from 
https://www.cancer.gov/publications/dictionaries/cancer-terms?cdrid=45618
2. International Council on Harmonisation [Internet]: E15: Definitions for Genomic 
Biomarkers, Pharmacogenomics, Pharmacogenetics, Genomic Data and Sample Coding 
Categories. Available from http://www.ich.org/products/guidelines/efficacy/efficacy-
single/article/definitions-for-genomic-biomarkers-pharmacogenomics-pharmacogenetics-
genomic-data-and-sample-cod.html 
3. Industry Pharmacogenomics Working Group [Internet]: Understanding the Intent, Scope 
and Public Health Benefits of Exploratory Biomarker Research: A Guide for IRBs/IECs 
and Investigational Site Staff. Available at http://i-pwg.org/ 
4. Industry Pharmacogenomics Working Group [Internet]: Pharmacogenomics 
Informational Brochure for IRBs/IECs and Investigational Site Staff. Available at http://i-
pwg.org/
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10.7
Appendix 7: Country-specific Requirements
10.7.1
Countries in the European Union Region and the United Kingdom
A potential participant from an investigator site located in a country in the European Union
or the United Kingdom must be assessed for eligibility for enrollment in the study according 
to the inclusion and exclusion criteria in Section 5 1 and Section 5.2, respectively, with the 
exception of the age criteria below. For age criteria, a potential participant from an 
investigator site located in a country in the European Union or the United Kingdom must 
meet the following age criteria for eligibility for enrollment in the study:
Inclusion Criteria
Demographics
•
For the Phase 2b cohort only: Has a chronological age >2 weeks of age up to 8 months 
and 29 days and is entering their first RSV season at the time that documented informed 
consent is provided.
•
For the Phase 3 cohort only: Has a chronological age from birth up to 8 months and 
29 days and is entering their first RSV season at the time that documented informed 
consent is provided.
The European Union countries participating in this study include the following:
•
Belgium
•
Denmark
•
Finland
•
France
•
Italy
•
Poland
•
Romania
•
United Kingdom (no longer in the European Union, but following these age criteria)
10.7.2
South Korea
A potential participant from an investigator site located in South Korea must be assessed for 
eligibility for enrollment in the study according to the inclusion and exclusion criteria in 
Section 5.1 and Section 5.2, respectively. As an additional inclusion criteria requirement
(included in Section 5.1), participants must weigh ≥2 kg at Visit 1.
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10.7.3
China
Enrollment of Participants in China
If sites in China have not met their participant allocation targets after enrollment of the global 
study is closed, these sites may continue to enroll participants until their allocation targets are 
met.
Future Biomedical Research (FBR)
No samples collected from participants enrolled at sites located in China will be used for 
FBR.
Informed Consent
To be consistent with local requirements, the investigator or medically qualified designee 
must obtain documented informed consent from each potential participant’s legally 
acceptable representative prior to participating in this clinical study. Informed consent given 
by at least one of the participant’s legally acceptable representatives is acceptable. A 
participant cannot be enrolled in this study under emergencies without the documented 
informed consent of the legally acceptable representative.
Serum Neutralizing Antibodies Against RSV (SNA)
SNA will not be tested in participants enrolled at sites in China.
Sample Collection for RT-PCR Testing for Respiratory Pathogen Identification and
Testing for COVID-19
Within 24 hours after the NP sample collection for RT-PCR testing for identification of 
respiratory pathogens (included in the RT-PCR assay panel), a separate, additional swab will 
be collected for COVID-19 testing for participants enrolled at sites in China. If a COVID-19 
test was performed within 24 hours before the site visit and the results are provided to the 
site, then the COVID-19 test does not need to be performed at the site visit.
Sample collection, storage, shipment, and laboratory testing for COVID-19 should follow 
local site requirements. Specimen information and local COVID-19 testing results will be 
entered into the database by site staff, as detailed in the data entry guidelines.
If 2 separate NP samples are required to be collected in the same respiratory infection 
assessment per local site requirements, the first NP sample should be collected for RT-PCR 
testing for identification of respiratory pathogens (included in the RT-PCR assay panel), and
the second NP sample should be collected for COVID-19 testing.
If a participant requires collection of another NP sample(s) for RT-PCR testing for 
identification of respiratory pathogens (included in the RT-PCR assay panel), at the same 
visit or any subsequent visits, the subsequent sample(s) should be taken from the same nostril 
as the first sample. This requirement does not apply for separate, additional sample(s) for 
COVID-19 testing.
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10.8
Appendix 8: Abbreviations
Abbreviation
Expanded Term
ADA
Antidrug antibodies
AE
Adverse event
AESI
Adverse event(s) of special interest
APaT
All Participants as Treated
ARI
Acute respiratory infection
AUC0-∞
Area under the concentration-time curve from time 0 extrapolated to infinity
BSA
Body surface area
CDC
Centers for Disease Control and Prevention
CFR
Code of Federal Regulations
CI
Confidence interval
CLD
Chronic lung disease
Cmax
Maximum concentration
CONSORT
Consolidated Standards of Reporting Trials
COVID-19
Coronavirus disease caused by severe acute respiratory syndrome coronavirus 2
Cp
The count of RSV-associated MALRI cases in the placebo group
CRF
Case Report Form
CSR
Clinical Study Report
Ct
The count of RSV-associated MALRI cases in the MK-1654 group
DHHS
Department of Health and Human Services
DMC
Data Monitoring Committee
DNA
Deoxyribonucleic acid
E
Efficacy
ECDC
European Centre for Disease Control
ECG
Electrocardiogram
ECI
Event of clinical interest
eCRF
Electronic case report form
EDC
Electronic data collection
eDiary
Electronic diary
eDMC
External Data Monitoring Committee
EEA
European Economic Area
EL
Lower bound of the confidence interval of efficacy
EMA
European Medicines Agency
EOC
Executive Oversight Committee
ER
Emergency room
EU
Upper bound of the confidence interval of efficacy
EudraCT
European Union Drug Regulating Authorities Clinical Trials database
FAS
Full Analysis Set
FBR
Future biomedical research
FDA
Food and Drug Administration
FDAAA
Food and Drug Administration Amendments Act
FSR
First Site Ready
GCP
Good Clinical Practice
hMPV
Human metapneumovirus
IA
Interim analysis
IB
Investigator’s Brochure
ICF
Informed consent form
ICH
International Council for Harmonisation of Technical Requirements for 
Pharmaceuticals for Human Use
ICU
Intensive care unit
IEC
Independent Ethics Committee
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Abbreviation
Expanded Term
ILI
Influenza-like illness
IM
Intramuscular(ly)
IND
Investigational New Drug
IRB
Institutional Review Board
IRT
Interactive response technology
IV
Intravenous(ly)
LRI
Lower respiratory infection
mAb
Monoclonal antibody
MALRI
Medically attended lower respiratory infection
NCI CTCAE
National Cancer Institute Common Terminology Criteria for Adverse Events
NP
Nasopharyngeal
NREVSS
National Respiratory and Enteric Virus Surveillance System
PCR
Polymerase chain reaction
PDLC
Predefined limit of change
PK
Pharmacokinetic(s)
PPE
Per-protocol efficacy
RESCEU
Respiratory Syncytial Virus Consortium in Europe
RNA
Ribonucleic acid
Rp
Incidence rate of RSV-associated MALRI in the placebo group
RR
Respiratory rate
RSV
Respiratory syncytial virus
Rt
Incidence rate of RSV-associated MALRI in the MK-1654 group
RT-PCR
Reverse transcriptase-polymerase chain reaction
SAC
Scientific Advisory Committee
SAE
Serious adverse event
SNA
Serum neutralizing antibodies against RSV
SoA
Schedule of Activities
SOC
System Organ Class
SpO2
Oxygen saturation as measured by pulse oximetry
sSAP
Supplemental Statistical Analysis Plan
SUSAR
Suspected unexpected serious adverse reaction
TC
Telephone call
Tp
Total person-time of follow-up for efficacy in the placebo group
Tt
Total person-time of follow-up for efficacy in the MK-1654 group
UNSCH
Unscheduled visit
US
United States
WHO
World Health Organization
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