Conditions: Respiratory Tract Infections
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 28
Healthy volunteers: no

Brief summary:
The purpose of the study is to evaluate the efficacy of rilematovir compared to placebo treatment with respect to the clinical outcome on the RSV Recovery Scale (RRS).

Detailed description:
Respiratory syncytial virus (RSV), a negative-stranded ribonucleic acid (RNA) virus belonging to the Pneumoviridae family, is considered the most important cause of acute lower respiratory tract infection (LRTI) in infants and young children. In most patients, RSV results in upper respiratory tract infection (URTI) eliciting "common cold"-like symptoms, which might last up to 2 weeks, and are usually self-limiting. RSV-related LRTI is a major cause of hospital admissions and death in young children worldwide. Rilematovir is an investigational, small molecule, RSV fusion inhibitor. This study aims to evaluate the efficacy and safety of rilematovir in hospitalized infants and children (greater than or equal to \[\>=\] 28 days to less than or equal to \[\<=\] 5 years) and, subsequent to completion of the neonatal substudy, in hospitalized neonates (born at term, less than \[\<\] 28 days of age) with RSV infection. The study will include a Screening Period, a Treatment Period, and a Follow-up Period. The total study duration for each participant will be approximately 36 days (Screening included). The efficacy assessments include evaluation under the RRS and the safety assessments include evaluations of physical examinations, vital signs, electrocardiograms, clinical laboratory tests, and adverse events.

Arms:
arm 1: Participants will receive rilematovir orally based on body weight and age group. arm 2: Participants will receive matching placebo of rilematovir based on body weight and age group.

Interventions: intervention 1: Rilematovir intervention 2: Rilematovir X mg/kg intervention 3: Placebo
Intervention descriptions: intervention 1: Participants of age group greater than or equal to (\>=) 28 days to less than (\<) 3 months (age group 1) or \>= 3 months to \< 6 months (age group 2) or \>= 6 months to less than or equal to (\<=) 5 years (age group 3) will receive rilematovir orally twice a day (BID) from Days 1 to Day 7 or Day 8. intervention 2: Participants of age group birth at term (after at least 37 weeks of gestation) to \< 28 days (age group 4) will receive rilematovir orally BID from Days 1 to Day 7 or Day 8. The dose is dependent on outcome of the substudy in neonates and following independent data monitoring (IDMC) review and recommendation. intervention 3: Participant of age group 1, 2, 3 and 4 will receive matching placebo of rilematovir BID from Days 1 to Day 7 or Day 8 as per assigned age group.

Protocol document:
Prot_000.pdf: 
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
1
Status: Approved,  Date: 04 May 2021
Janssen Research & Development *
Clinical Protocol
A Phase 3, Randomized, Double-blind, Placebo-controlled Study to Evaluate the Efficacy
and Safety of Rilematovir in Infants and Children (≥28 Days to ≤5Years of Age) and
Subsequently in Neonates (<28 Days of Age), Hospitalized With Acute Respiratory Tract
Infection Due to Respiratory Syncytial Virus (RSV)
Protocol 53718678RSV3001; Phase 3
AMENDMENT 1
JNJ-53718678  (rilematovir)
*Janssen Research & Development is a global organization that operates through different legal entities in
various countries. Therefore, the legal entity acting as the sponsor for Janssen Research & Development
studies may vary, such as, but not limited to Janssen Biotech, Inc.; Janssen Products, LP; Janssen
Biologics, BV; Janssen-Cilag International NV; Janssen, Inc; Janssen Pharmaceutica NV; Janssen
Sciences Ireland UC; Janssen Biopharma Inc.; or Janssen Research & Development, LLC. The term
“sponsor” is used throughout the protocol to represent these various legal entities; the sponsor is
identified on the Contact Information page that accompanies the protocol.
United States (US)sites of this study will be conducted under US Food & Drug Administration
Investigational New Drug (IND) regulations (21 CFR Part 312).
EudraCT NUMBER: 2020-002023-11
Status: 
Approved
Date: 
04 May 2021
Prepared by: Janssen Research & Development, a division of Janssen Pharmaceutica NV
EDMS number: 
EDMS-RIM-110384, 3.0
GCP Compliance: This study will be conducted in compliance with Good Clinical Practice, and applicable regulatory
requirements.
Confidentiality Statement
The information provided herein contains Company trade secrets, commercial or financial information that the Company
customarily holds close and treats as confidential.  The information is being provided under the assurance that the recipient
will maintain the confidentiality of the information under applicable statutes, regulations, rules, protective orders or
otherwise.
NCT04583280


JNJ-53718678 (rilematovir) 
Clinical Protocol 53718678RSV3001 Amendment 1
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Status: Approved,  Date: 04 May 2021
PROTOCOL AMENDMENT SUMMARY OF CHANGES TABLE
DOCUMENT HISTORY
Document 
Date
Amendment 1 
This document
Original Protocol 
17 August 2020
Amendment 1 (This document)
Overall Rationale for the Amendment: To add estimand language for the primary endpoint and to revise
the assessments for follow-up of participants who prematurely discontinued the study intervention/the
study. Additional modifications and clarifications have been added.
Section Number 
and Name
Description of Change 
Brief Rationale
1.3.1 During Hospitalization  
1.3.2 After Discharge 
Specifics were added on the 
monitoring of ObsRO
Signs/Symptoms and ObsRO GHQ
completion
Clarification
1.3.1 During Hospitalization  
Additional blood pressure assessment 
on Day 1 was removed in the Schedule 
of Activities During Hospitalization  
Blood pressure assessment on
Day 1 was corrected while
maintaining the bid
assessment on that day
1.3.1 During Hospitalization  
Reference to footnote d was removed 
for Day 14 in the Schedule of 
Activities During Hospitalization 
No sample for clinical
laboratory assessments is
collected on Day 14
1.3.2 After Discharge 
The concomitant medication review on 
Day 35 was updated from optional to 
mandatory assessment in the Schedule 
of Activities After Discharge
Review of the concomitant
medication is mandatory until
the end of the study
5.1 Inclusion Criteria 
Inclusion Criterion 1 was made more 
specific 
To clarify that correction for
gestational age will only be
applied for participants who
were born preterm
1.1 Synopsis 
4.1 Overall Design  
5.1 Inclusion Criteria 
Inclusion Criterion 5 was updated 
To ensure enrollment of
participants with at least
moderate RSV disease
severity who are more likely
to potentially benefit from
RSV treatment
1.1 Synopsis 
6.1 Study Intervention(s) 
Administered 
The dilution step for the preparation of 
the suspension for dosing in neonates 
was removed 
Dosing accuracy studies
confirmed the neonate starting
dose can be administered with
the 1 mL oral syringe using
the 20 mg/mL strength of the
suspension
6.8 Concomitant Therapy  
The use of mucolytics was 
recommended to be limited 
To be limited to use in line
with the clinical practice
guidelines and package inserts
6.8 Concomitant Therapy  
10.19Appendix 19: Guidance on 
Study Conduct during the COVID-19 
Pandemic 
Specifics were added on the 
administration of a locally approved 
(including emergency use-authorized) 
COVID-19 vaccine
Additions were made per
recent Health Authority
guidance
1.3 Schedule of Activities 
6.3 Measures to Minimize Bias: 
Randomization and Blinding 
Continuation of the study assessments 
and visits, including the Day 35 
Follow-up visit, as per the Schedule of 
Additions were made to allow
completion of all study visit
assessments also for


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Section Number 
and Name
Description of Change 
Brief Rationale
7.1 Discontinuation of Study 
Intervention  
7.3 Lost to Follow-up 
Activities, till the end of study was 
added as preferred option for all 
participants who early discontinue
study intervention
participants who prematurely
discontinue study intervention
1.3 Schedule of Activities 
7.2 Participant 
Discontinuation/Withdrawal From the 
Study
A safety follow-up visit in case of 
withdrawal of consent for study
participation was added
To maximize safety follow-up
8.1.1.1 RSV Recovery Scale 
Assessments 
The protocol-defined RRS categories 
were further specified
Clarifications
4.1 Overall Design  
8.1.1.3 ClinRO and ObsRO Clinical 
Outcome Assessments and Caregiver 
Impact Questions 
 Timing for completion of the 
PRESORS assessments in bid
schedule was specified
 Additional instructions for
clinicians and parents/caregivers
were added with regards to the
rating of each RSV sign/symptom
in the PRESORS ClinRO and
ObsRO assessments
 Wording was added to emphasize
the value of the Caregiver Impact
Questions
Clarifications
8.3.5.1 Hepatobiliary Effects 
“ALT elevation” was replaced by 
"Hepatobiliary effects" as safety topic 
of special interest
Alignment with the
Investigator’s Brochure
1.1 Synopsis 
8.3.5.1 Hepatobiliary Effects 
9.4.3 Safety Analyses 
10.2 Appendix 2: Clinical Laboratory 
Tests
10.4.3 Severity Criteria
10.6 Appendix 6: Division of AIDS
(DAIDS) Table for Grading the
Severity of Adult and Pediatric
Adverse Events (Corrected Version
2.1; July 2017)
Additional laboratory assessments 
were included as reflex testing 
For further evaluation of the
origin of the elevation of
potential hepatobiliary
enzymes
8.3 Adverse Events, Serious Adverse 
Events, and Other Safety Reporting 
8.3.5.2 RSV-related Complications 
Information on RSV-related 
complications was moved to Section 
8.3 Adverse Events, Serious Adverse 
Events, and Other Safety Reporting 
RSV complications are not
considered a safety topic of
special interest per the
Investigator’s Brochure
1.1 Synopsis 
9.4.2.1 Primary Endpoint 
“At a minimum” was removed and 
"RRS category at baseline" was added 
when defining the variables to be 
included for the proportional odds
model
Based on Health Authority
request to specify the primary
analysis unambiguously
9.4.2.1.1 Estimand 
Estimand attributes for the primary 
endpoint were added 
Addition as requested by
Health Authority
10.5 Appendix 5: Division of 
Microbiology and Infectious Diseases 
(DMID) Pediatric Toxicity Tables 
(November 2007, draft)
Laboratory toxicity range for Grade 2 
hypernatremia and Grade 2 hematuria
were revised
Correction
10.7 Appendix 7: Cardiovascular 
Safety –Abnormalities 
Appendix 7: values for vital signs 
abnormalities for age group 3 to 
≤5 years were updated
To implement values for this
age group per recent literature


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Section Number 
and Name
Description of Change 
Brief Rationale
10.10 Appendix 10: Parent/Caregiver 
Information v9(04 May 2021) 
10.11 Appendix 11: Pediatric RSV 
Electronic Severity and Outcome 
Rating System (PRESORS) v9 
Caregiver Diary (ObsRO PRESORS, 
04 May 2021)
 Appendix 10 was split in 2 
appendices (ie, Appendix 10 and
Appendix 11) affecting the
numbering of all subsequent
appendices
 Minor changes were made
Clarification
10.12 Appendix 12: Caregiver Impact 
Questions v9(04 May 2021) 
Minor changes were made, including 
renumbering of the questions 
Per requirements from the
eCOA smartphone and web
diary applications that will be
used in this study; correction
of typographical errors,
clarification of instructions
10.13 Appendix 13: Clinician 
PRESORS v9(04 May 2021) 
 Question 15 was removed 
 Minor changes were made 
Readiness for
discharge/medical need for
hospitalization will be
captured in the eCRF
10.14 Appendix 14: Definitions of 
Resolved/Not Resolved Based on the 
ObsRO Signs/Symptoms 
10.15 Appendix 15: Definitions of
Resolved/Not Resolved Based on the
ClinRO Signs/Symptoms
Wording adjustments were made 
To align with the wording in
the PRESORS version used in
the current study
10.19Appendix 19: Guidance on 
Study Conduct during the COVID-19 
Pandemic 
 Wording was added to specify the 
clinical management of laboratory
confirmed SARS-CoV-2 infection
in study participants, ie, per local
standard-of-care
 Section for “Study conduct related
to COVID-19 vaccine deployment
for non-COVID-19 clinical trials”
was added
Clarification
1.1 Synopsis 
2.2 Background 
3 OBJECTIVES AND ENDPOINTS
8.1.1.2 Other Clinical Course and
Clinical Severity Assessments
“medical need for” ICU was changed 
to “requiring” ICU  
For consistency with wording
in the RRS definitions
Throughout the protocol 
Minor grammatical, formatting, or 
spelling changes were made
Minor errors were noted


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TABLE OF CONTENTS
PROTOCOL AMENDMENT SUMMARY OF CHANGES TABLE ............................................................... 2
TABLE OF CONTENTS ............................................................................................................................... 5
LIST OF IN-TEXT TABLES AND FIGURES................................................................................................ 8
1. 
PROTOCOL SUMMARY..................................................................................................................... 9
1.1. 
Synopsis........................................................................................................................................... 9
1.2. 
Schema.......................................................................................................................................... 23
1.3. 
Schedule of Activities..................................................................................................................... 24
1.3.1. 
During Hospitalization................................................................................................................. 24
1.3.2. 
After Discharge ........................................................................................................................... 30
1.3.3. 
Pharmacokinetic Assessments Sampling Schedule .................................................................. 33
2. 
INTRODUCTION................................................................................................................................ 34
2.1. 
Study Rationale.............................................................................................................................. 35
2.2. 
Background .................................................................................................................................... 35
2.3. 
Benefit-Risk Assessment............................................................................................................... 48
2.3.1. 
Risks for Study Participation....................................................................................................... 48
2.3.1.1. 
Known Risks............................................................................................................................ 48
2.3.1.2. 
Potential Risks......................................................................................................................... 48
2.3.2. 
Benefits for Study Participation .................................................................................................. 49
2.3.2.1. 
Known Benefits........................................................................................................................ 49
2.3.2.2. 
Potential Benefits..................................................................................................................... 50
2.3.3. 
Benefit-Risk Assessment for Study Participation ....................................................................... 50
3. 
OBJECTIVES AND ENDPOINTS ..................................................................................................... 53
4. 
STUDY DESIGN ................................................................................................................................ 56
4.1. 
Overall Design................................................................................................................................ 56
4.2. 
Scientific Rationale for Study Design............................................................................................. 60
4.2.1. 
Study-specific Ethical Design Considerations ............................................................................ 63
4.3. 
Justification for Dose...................................................................................................................... 64
4.4. 
End of Study Definition................................................................................................................... 65
5. 
STUDY POPULATION ...................................................................................................................... 65
5.1. 
Inclusion Criteria............................................................................................................................ 66
5.2. 
Exclusion Criteria........................................................................................................................... 68
5.3. 
Lifestyle Considerations................................................................................................................. 70
5.4. 
Screen Failures.............................................................................................................................. 70
6. 
STUDY INTERVENTION................................................................................................................... 70
6.1. 
Study Intervention(s) Administered................................................................................................ 70
6.2. 
Preparation/Handling/Storage/Accountability ................................................................................ 73
6.3. 
Measures to Minimize Bias: Randomization and Blinding............................................................. 74
6.4. 
Study Intervention Compliance...................................................................................................... 75
6.5. 
Dose Modification........................................................................................................................... 75
6.6. 
Continued Access to Study Intervention After the End of the Study ............................................. 75
6.7. 
Treatment of Overdose .................................................................................................................. 75
6.8. 
Concomitant Therapy..................................................................................................................... 75
7. 
DISCONTINUATION OF STUDY INTERVENTION AND PARTICIPANT
DISCONTINUATION/WITHDRAWAL............................................................................................... 78
7.1. 
Discontinuation of Study Intervention ............................................................................................ 78
7.2. 
Participant Discontinuation/Withdrawal From the Study................................................................ 79
7.2.1. 
Withdrawal From the Use of Samples in Future Research ........................................................ 79


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7.3. 
Lost to Follow-up............................................................................................................................ 79
8. 
STUDY ASSESSMENTS AND PROCEDURES ............................................................................... 80
8.1. 
Efficacy Assessments .................................................................................................................... 83
8.1.1. 
Clinical Severity and Clinical Course of RSV Infection............................................................... 83
8.1.1.1. 
RSV Recovery Scale Assessments ........................................................................................ 83
8.1.1.2. 
Other Clinical Course and Clinical Severity Assessments ...................................................... 86
8.1.1.3. 
ClinRO and ObsRO Clinical Outcome Assessments and Caregiver Impact Questions ......... 88
8.1.2. 
Antiviral Activity........................................................................................................................... 90
8.1.3. 
Viral Sequencing......................................................................................................................... 91
8.2. 
Safety Assessments....................................................................................................................... 91
8.2.1. 
Physical Examinations................................................................................................................ 92
8.2.2. 
Vital Signs................................................................................................................................... 92
8.2.3. 
Electrocardiograms..................................................................................................................... 92
8.2.4. 
Clinical Safety Laboratory Assessments .................................................................................... 93
8.3. 
Adverse Events, Serious Adverse Events, and Other Safety Reporting ....................................... 93
8.3.1. 
Time Period and Frequency for Collecting Adverse Event and Serious Adverse Event
Information.................................................................................................................................. 94
8.3.2. 
Method of Detecting Adverse Events and Serious Adverse Events .......................................... 94
8.3.3. 
Follow-up of Adverse Events and Serious Adverse Events ....................................................... 95
8.3.4. 
Regulatory Reporting Requirements for Serious Adverse Events and Anticipated
Events......................................................................................................................................... 95
8.3.5. 
Adverse Events / Safety Topics of Special Interest.................................................................... 96
8.3.5.1. 
Hepatobiliary Effects................................................................................................................ 96
8.3.5.2. 
Cardiac Events Potentially Related to QT Prolongation.......................................................... 96
8.4. 
Pharmacokinetics........................................................................................................................... 97
8.4.1. 
Evaluations ................................................................................................................................. 97
8.4.2. 
Analytical Procedures................................................................................................................. 97
8.4.3. 
Pharmacokinetic Parameters and Evaluations........................................................................... 98
8.5. 
Pharmacokinetic/Pharmacodynamic Evaluations.......................................................................... 98
8.6. 
Medical Encounters........................................................................................................................ 98
8.7. 
Acceptability and Palatability ......................................................................................................... 98
8.8. 
Biomarkers..................................................................................................................................... 98
8.9. 
Detection of Baseline Presence of Other Respiratory Viruses and Bacteria................................. 99
9. 
STATISTICAL CONSIDERATIONS.................................................................................................. 99
9.1. 
Statistical Hypotheses.................................................................................................................... 99
9.2. 
Sample Size Determination ........................................................................................................... 99
9.3. 
Populations for Analyses.............................................................................................................. 100
9.4. 
Statistical Analyses ...................................................................................................................... 100
9.4.1. 
General Considerations............................................................................................................ 100
9.4.2. 
Efficacy Analyses...................................................................................................................... 101
9.4.2.1. 
Primary Endpoint................................................................................................................... 101
9.4.2.1.1. 
Estimand ............................................................................................................................ 102
9.4.2.2. 
Key Secondary Endpoint(s)................................................................................................... 104
9.4.2.3. 
Clinical Course of RSV Infection ........................................................................................... 104
9.4.2.4. 
Antiviral Activity ..................................................................................................................... 104
9.4.2.5. 
Viral Sequencing ................................................................................................................... 104
9.4.3. 
Safety Analyses........................................................................................................................ 105
9.4.4. 
Other Analyses ......................................................................................................................... 106
9.4.4.1. 
Pharmacokinetic Analyses .................................................................................................... 106
9.4.4.2. 
Pharmacokinetic/Pharmacodynamic Analyses ..................................................................... 106
9.4.4.3. 
Biomarkers Analyses............................................................................................................. 107
9.4.4.4. 
Medical Encounters ............................................................................................................... 107
9.4.4.5. 
Acceptability and Palatability................................................................................................. 107
9.5. 
Interim Analyses........................................................................................................................... 107
9.6. 
Independent Data Monitoring Committee .................................................................................... 107


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10. SUPPORTING DOCUMENTATION AND OPERATIONAL CONSIDERATIONS .......................... 109
10.1. 
Appendix 1: Abbreviations ........................................................................................................... 109
10.2. 
Appendix 2: Clinical Laboratory Tests ......................................................................................... 112
10.3. 
Appendix 3: Regulatory, Ethical, and Study Oversight Considerations....................................... 113
10.3.1. 
Regulatory and Ethical Considerations .................................................................................... 113
10.3.2. 
Financial Disclosure.................................................................................................................. 116
10.3.3. 
Informed Consent Process ....................................................................................................... 116
10.3.4. 
Data Protection......................................................................................................................... 117
10.3.5. 
Long-Term Retention of Samples for Additional Future Research .......................................... 118
10.3.6. 
Committees Structure............................................................................................................... 118
10.3.7. 
Publication Policy/Dissemination of Clinical Study Data.......................................................... 119
10.3.8. 
Data Quality Assurance............................................................................................................ 120
10.3.9. 
Case Report Form Completion................................................................................................. 121
10.3.10. Source Documents ................................................................................................................... 121
10.3.11. Monitoring ................................................................................................................................. 122
10.3.12. On-site Audits ........................................................................................................................... 122
10.3.13. Record Retention...................................................................................................................... 123
10.3.14. Study and Site Start and Closure ............................................................................................. 123
10.4. 
Appendix 4: Adverse Events, Serious Adverse Events, Product Quality Complaints, and
Other Safety Reporting: Definitions and Procedures for Recording, Evaluating, Follow-up,
and Reporting............................................................................................................................... 125
10.4.1. 
Adverse Event Definitions and Classifications ......................................................................... 125
10.4.2. 
Attribution Definitions................................................................................................................ 126
10.4.3. 
Severity Criteria........................................................................................................................ 126
10.4.4. 
Special Reporting Situations .................................................................................................... 126
10.4.5. 
Procedures ............................................................................................................................... 127
10.4.6. 
Product Quality Complaint Handling......................................................................................... 128
10.4.7. 
Contacting Sponsor Regarding Safety, Including Product Quality........................................... 128
10.5. 
Appendix 5: Division of Microbiology and Infectious Diseases (DMID) Pediatric Toxicity
Tables (November 2007, draft).................................................................................................... 129
10.6. 
Appendix 6: Division of AIDS (DAIDS) Table for Grading the Severity of Adult and
Pediatric Adverse Events (Corrected Version 2.1; July 2017)..................................................... 139
10.7. 
Appendix 7: Cardiovascular Safety –Abnormalities.................................................................... 140
10.8. 
Appendix 8: Liver Safety Plan: Suggested Actions and Follow-up Assessments ....................... 141
10.9. 
Appendix 9: General Guidelines for Measuring Vital Signs and SpO2 ........................................ 142
10.10. Appendix 10: 
.................................................... 145
10.11. Appendix 11: 
......................................... 146
10.12. Appendix 12: 
..................................................... 151
10.13. Appendix 13: 
.................................................................. 152
10.14. Appendix 14: 
.......................................................................................................................... 155
10.15. Appendix 15: 
156
10.16. Appendix 16: Study Medication Acceptability and Palatability Assessment................................ 157
10.17. Appendix 17: RSV Symptom Onset to Randomization Calculator .............................................. 158
10.18. Appendix 18: List and Definition/Diagnostic Criteria of Assessed RSV-related
Complications............................................................................................................................... 159
10.19. Appendix 19: Guidance on Study Conduct during the COVID-19 Pandemic.............................. 162
10.20. Appendix 20: Protocol Amendment History................................................................................. 165
11. REFERENCES................................................................................................................................. 166
INVESTIGATOR AGREEMENT............................................................................................................... 169
CCI
CCI
CCI
CCI
CCI
CCI


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LIST OF IN-TEXT TABLES AND FIGURES
TABLES
Table 1: 
RSV Disease Signs/Symptoms for Eligibility............................................................................ 57
Table 2: 
Risk Factors for Severe RSV Disease...................................................................................... 58
Table 3: 
Age Groups and Dosing Regimen............................................................................................ 59
Table 4: 
Predicted Geometric Mean AUC24h, Cmax, Ctrough  and QTcI Per Age Group After Day
1 and Day 7............................................................................................................................... 65
Table 5: 
Treatment Overview.................................................................................................................. 71
FIGURES
Figure 1: Schematic Overview of the Study............................................................................................. 23
Figure 2: Timeline from RSV Sign/Symptom Onset to First Dose........................................................... 58
Figure 3: Schedule for Collection of Nasal Mid-Turbinate Swab Samples.............................................. 91


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1. 
PROTOCOL SUMMARY
1.1. 
Synopsis
A Phase 3, Randomized, Double-blind, Placebo-controlled Study to Evaluate the Efficacy and Safety of
Rilematovir in Infants and Children (≥28 Days to ≤5 Years of Age) and Subsequently in Neonates
(<28 Days of Age), Hospitalized With Acute Respiratory Tract Infection Due to Respiratory Syncytial
Virus (RSV).
Note: The substudy at specific sites will be initiated only after positive recommendation by the Independent
Data Monitoring Committee (IDMC) upon review of interim analysis 1 results of the main study.
“Subsequently in neonates” refers to the main study being opened for enrollment of neonates at all sites
following completion of a prior substudy in neonates, IDMC review of the substudy data, and positive
recommendation. This protocol only describes the main study. The specifics to the substudy will be
described in a separate substudy protocol.
Rilematovir is an investigational, potent small-molecule RSV-specific fusion inhibitor belonging to the
indole chemical class. Rilematovir targets the RSV F protein and prevents the conformational changes of
the F  protein required for fusion of the viral envelope with the host cell membrane and for cell-to-cell
fusion, thereby inhibiting viral replication and syncytia formation.
OBJECTIVES AND ENDPOINTS
Objectives 
Endpoints
Primary
 
To evaluate the superiority of 
rilematovir compared to placebo 
treatment with respect to the clinical 
outcome on the RSV Recovery Scale 
(RRS). 
 
RRSa as assessed on the first study day when at least
50% of the participants across treatment arms are
discharged from the hospital (the study day for the
RRS evaluation will be determined based on blinded
data at the first interim analysis by an  independent
statistician).
Secondary
 
To evaluate the superiority of 
rilematovir compared to placebo 
treatment with respect to clinical 
resolution of RSV disease. 
 
Proportion of participants clinically resolved from
RSV disease based on Clinician Reported Outcome
(ClinRO) Signs/Symptomsc,e as assessed on the same
study day as the primary endpoint.
 
To evaluate the superiority of 
rilematovir compared to placebo 
treatment with respect to the time 
from first dosing to resolution of Key  
RSV  Signs/Symptomsb 
including 
supplementation free.
 
Time from first study dose to resolution of Key RSV
Signs/Symptoms (absent or mild)d,e based on
parent’s/caregiver’s Observer Reported Outcome
(ObsRO) Signs/Symptoms and supplementation free
(oxygen and feeding/hydration) for at least 24 hours.
 
To evaluate the superiority of 
rilematovir compared to placebo 
treatment with  respect to the time 
from discharge to resolution of Key  
RSV Signs/Symptoms.
 
Time from discharge to resolution of Key RSV
Signs/Symptomsd,e based on ObsRO Signs/Symptoms
(only including participants who did not reach
resolution before first discharge).
 
To evaluate the superiority of 
rilematovir compared to placebo 
treatment with respect to the time 
 
Time from first dosing to end of oxygen
supplementation  (only including participants who
were receiving oxygen supplementation at the time of
first dosing).


JNJ-53718678 (rilematovir) 
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Status: Approved,  Date: 04 May 2021
Objectives 
Endpoints
from first dosing to end of oxygen
supplementation.
 
To evaluate the superiority of 
rilematovir compared to placebo 
treatment 
with 
respect 
to 
the
incidence of post-baseline RSV-
related complications.
 
Incidence 
in 
post-baseline 
RSV-related
complications.
 
To evaluate the safety and tolerability 
of rilematovir. 
 
Safety and tolerability, as assessed by adverse events
(AEs), clinical laboratory testing, electrocardiograms
(ECGs), vital signs throughout the study.
 
To evaluate the effect of rilematovir 
on the clinical course of RSV disease 
as assessed electronically by ObsRO
Signs/Symptoms and ObsRO General
Health Questions (GHQ).
 
The following endpoints will be based on the ObsRO
Signs/Symptoms:
 time to resolution  of signs/symptoms (absent or
mild)e of RSV disease;
 actual values and changes from baseline in scores.
 
The following endpoint will be based on the ObsRO
GHQ:
 time to improvement.
 
To evaluate the effect of rilematovir 
on the clinical course of RSV disease 
as assessed electronically by ClinRO
Signs/Symptoms and ClinRO GHQ.
 
The following endpoints will be based on the ClinRO
Signs/Symptoms:
 time to resolution of signs/symptoms (absent or
mild)e of RSV disease;
 actual values and changes from baseline in scores;
 proportion of participants clinically resolved from
RSV disease based on ClinRO Signs/Symptomsc,e as
assessed each day from Day 2 to 8.
 
The following endpoint will be based on the ClinRO
GHQ:
 general impression of change.
 
To evaluate the effect of rilematovir 
on the clinical course of RSV disease 
(other than ClinRO and ObsRO
assessments).
 
RRSa as assessed each day separately from Days 2
to 8.
 
Time to hospital discharge from start of dosing.
 
Time to readiness for hospital discharge.
 
Proportion of participants requiring intensive care unit
(ICU) stay.
 
Duration of requiring ICU stay.
 
Proportion of participants requiring rehospitalization
for respiratory/other reasons.
 
Proportion 
of 
participants 
requiring oxygen
supplementation.


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Status: Approved,  Date: 04 May 2021
Objectives 
Endpoints
 
Duration of oxygen supplementation.
 
Time to end of supplemental feeding/hydration.
 
Proportion of participants requiring hydration and/or
feeding by intravenous (IV) administration or
nasogastric tube.
 
Duration of supplemental feeding/hydration.
 
Time to end of supplementation (oxygen and/or
feeding/hydration).
 
Number and type of medical encounters.
 
Incidence of antibiotic treatment episodes.
 
Incidence of systemic or inhaled corticosteroids and
bronchodilators use.
 
To evaluate the antiviral effect of
rilematovir as measured by RSV viral
load in nasal mid-turbinate (MT)
swab samples by quantitative reverse
transcription 
polymerase 
chain
reaction (qRT-PCR) assay.
 
RSV viral load (area under the RSV viral load-time
curve [AUC]) from immediately prior to first dose of
study intervention (baseline) through Day 3, Day 5,
and Day 8.
 
RSV viral load and change from baseline over time.
 
Proportion of participants with undetectable RSV
viral load at each time point of assessment throughout
the study.
 
To evaluate the emergence of
mutations in the viral genome
potentially associated with resistance
to rilematovir.
 
Sequence changes (post-baseline) in the RSV F gene
compared to baseline.
 
To evaluate the pharmacokinetics
(PK) of rilematovir.
 
PK parameters of rilematovir.
 
To explore the PK/pharmacodynamic
(PD) relationships of rilematovir for
efficacy and safety.
 
PK/PD analysis of PK  of rilematovir and selected
primary and secondary efficacy and safety
parameters.
 
To evaluate the acceptability and
palatability 
of 
the 
rilematovir
formulation.
 
Acceptability and palatability of the rilematovir
formulation as assessed through a questionnaire.
Exploratory
 
To explore other effects of rilematovir
on the clinical course of RSV disease.
 
Time from first dosing to peripheral capillary oxygen
saturation (SpO2) ≥92% on room air among
participants who were not on oxygen supplementation
prior to the onset of respiratory signs/symptoms.
 
Respiratory rate, heart/pulse rate, body temperature,
and SpO2 over time as measured by the investigator
(during scheduled visits).


JNJ-53718678 (rilematovir) 
Clinical Protocol 53718678RSV3001 Amendment 1
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
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Status: Approved,  Date: 04 May 2021
Objectives 
Endpoints
 
Proportion of participants with signs/symptoms of
RSV disease at discharge according to last ClinRO
Signs/Symptoms evaluation prior to discharge.
 
The ClinRO  Signs/Symptoms score for each
sign/symptom according to last evaluation prior to
discharge in those participants not resolved at
discharge.
 
To explore the effect of rilematovir on
the impact of the child’s RSV disease
on the parent(s)/caregiver(s) and
family  based on the PRESORS
Caregiver Impact Questions.
 
Extent of the parent’s/caregiver’s worry about the
child’s health.
 
Time missed from usual activities by the
parent/caregiver.
 
Time missed from work by anyone in child’s
household due to the child’s illness.
 
To explore the relationship between
antiviral activity and the primary and
key secondary clinical outcomes.
 
RSV viral load based endpoints and primary and key
secondary clinical course endpoints.
 
To 
explore 
the evaluation 
of
biomarkers associated with RSV or
treatment effects (optional).
 
Specific biomarkers in leftover blood samples and
nasal MT swabs (optional).
a. 
For details on the RRS see Section 8.1.1.1.
b. 
Signs are defined as objective evidence of the disease, which are apparent to the physician during
examination (such as tachycardia, tachypnea, chest wall retractions, grunting, and nasal flaring). Symptoms
are defined as subjective manifestations of the diseases, reported by the participant or by the
parent(s)/caregiver(s), but not necessarily apparent to the physician during examination (such as rhinorrhea,
cough, feeding difficulties, disturbed sleep, and disturbed activity level). Throughout this protocol, the
notation “signs/symptoms” is used.
c. 
Clinical resolution is defined by: free of oxygen supplementation, AND free of supplemental feeding, AND
not requiring ICU, AND Key RSV Signs/Symptoms resolved to absent or mild as per the ClinRO
Signs/Symptoms (see also Section 8.1.1.2).e
d. 
Key RSV Signs/Symptoms are: Breathing problems, retractions, tachypnea, cough, wheezing (ClinRO
Signs/Symptoms only), breathing sounds (ObsRO Signs/Symptoms only), and tachycardia (see also
Section 8.1.1.3).
e. 
See Section 10.14, Appendix 14 and Section 10.15, Appendix 15 for definitions of resolved/not resolved.
f. 
See Section 8.1.1.2 for the list of complications assessed.
Hypothesis
The primary hypothesis of this study is that treatment with rilematovir improves clinical outcome of RSV
infection as compared to placebo in hospitalized pediatric participants as assessed with the RRS on the first
study day when at least 50% of the participants across treatment arms are discharged from the hospital.


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Status: Approved,  Date: 04 May 2021
OVERALL DESIGN
This is a Phase 3, randomized, double-blind, placebo-controlled, multicenter, interventional study in infants
and children (≥28 days to ≤5 years of age) and subsequently in neonates (<28 days of age), hospitalized
(refers to having planned at least 24 hours with an overnight stay in the hospital) with RSV infection. The
substudy at specific sites will be initiated only after positive recommendation by the IDMC upon review of
interim analysis 1 results of the main study. “Subsequently in neonates” refers to the main study being
opened for enrollment of neonates at all sites following completion of a prior substudy in neonates, IDMC
review of the substudy data, and positive recommendation. This protocol only describes the main study.
The specifics to the substudy will be described in a separate substudy protocol.
Study participants with signs/symptoms of an acute respiratory illness supporting a diagnosis of RSV
infection (see Table: RSV Disease Signs/Symptoms for Eligibility) will be identified and tested for RSV
infection when they are hospitalized or present to the ER/clinic and are expected to be hospitalized.
Participants should only be screened if they are expected to be randomized within ≤3 days of RSV
sign/symptom onset.
Participants with RSV disease (ie, at least 1 sign/symptom of upper respiratory tract infection [URTI], at
least 1 sign/symptom of lower respiratory tract infection  [LRTI], and at least 1 systemic/general
sign/symptom [see Table: RSV Disease Signs/Symptoms for Eligibility]) will be enrolled. Cough or
wheezing cannot be the only LRTI sign/symptom present, ie, at least one other LRTI sign/symptom needs
to be present for eligibility. Eligible participants can be otherwise healthy or have (a) risk factor(s) for
severe RSV disease (as defined in the Table: Risk Factors for Severe RSV Disease). Those who are
immunocompromised and those with neuromuscular diseases that affect swallowing or the thoracic muscles
are excluded from participation.
Table: RSV Disease Signs/Symptoms for Eligibility
Upper Respiratory Tract Infection (URTI) Signs/Symptoms:
Nasal congestion
Rhinorrhea
Lower Respiratory Tract Infection (LRTI) Signs/Symptoms:
Increased respiratory efforts, evidenced by:
 
subcostal, intercostal, or tracheosternal retractions
 
grunting
 
head bobbing
 
nasal flaring
 
tachypnea
Wheezinga
Cyanosis
Cougha
Apnea
Systemic / General Signs/Symptoms:
Feeding difficulties (defined as <75% intake of normal food amounts)
Dehydration
Fever
Disturbed sleep
Disturbed activity level (irritable, restless, agitated, or less responsive)
aCough or wheezing cannot be the only LRTI sign/symptom present, ie, at least one other LRTI sign/symptom
needs to be present for eligibility.


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Status: Approved,  Date: 04 May 2021
Table: Risk Factors for Severe RSV Disease
Prematurity at birtha
Bronchopulmonary dysplasia
Congenital heart disease
Down syndrome
Neuromuscular impairmentb
Cystic fibrosis
Recurrent wheezingc
Asthma
Other congenital disease
aNote: Prematurely born participants are only eligible for this study iftheir age corrected for gestational age at
birth is ≥28 days at the time of consent.1 After this main study opens to neonate enrollment: prematurity is not
allowed for neonates (ie, neonate participants should have been born at term, after at least 37 weeks of gestation).
b Excluding neuromuscular diseases that affect swallowing or the thoracic muscles.
c Recurrent wheezing is defined as ≥1 episode of wheezing without a cold in the past year.22
Participants will be randomized in a 2:1 ratio to receive either rilematovir or placebo bid. Randomization
should occur within a maximum of 24 hours after start of screening or within 48 hours after collection of
the standard-of-care (SOC)sample used for local RSV diagnosis, whichever comes first, and no later than
3 days after RSV sign/symptom onset (see Figure: Timeline from RSV Sign/SymptomOnset to First Dose).
Randomization will be stratified by presence of risk factors for severe RSV disease (presence of [a] risk
factor[s] for severe RSV disease vs otherwise healthy, see Table: Risk Factors for Severe RSV Disease)
and by region (Asia-Oceania, EMEA, Northern America, and Latin America-The Caribbean).
Figure: Timeline from RSV Sign/Symptom Onset to First Dose
ICF = informed consent form; RSV = respiratory syncytial virus; SOC = standard-of-care.
Study intervention administration should start as soon as possible, but no later than 4 hours after
randomization. Dosing will be based on a mg/kg basis per age group and 4 age groups are defined based
on the participant’s age at the time of consent:
 
Age group 1: ≥28 days to <3 months of age (ie, 28 to 91 days of age, extremes included);
 
Age group 2: ≥3 months to <6 months of age (ie, 92 to 182 days of age, extremes included);
 
Age group 3: ≥6 months to ≤5 years of age (ie, 183 to 1,826 days, extremes included);
 
Age group 4*: at term birth (ie, after at least 37 weeks of gestation) to <28 days of age (ie, 1 day to
27 days, extremes included).
*After opening of recruitment in neonates in the main study dependent on positive IDMC recommendation
after completion of a substudy in neonates.
An IDMC will be commissioned for this study.
The end of study is considered as the last visit (phone visit or on-site visit) for the last participant in the
study.


JNJ-53718678 (rilematovir) 
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Status: Approved,  Date: 04 May 2021
NUMBER OF PARTICIPANTS
A sample size of approximately 737 hospitalized RSV-infected participants is targeted.
INTERVENTION GROUPS AND DURATION
The study will include a Screening Period (Day -1 to Day 1), a Treatment Period (Day 1 to Day 8), and a
Follow-up Period (Day 9 to Day 35 [±3]). The total study duration for each participant will be
approximately 36 days (Screening included).
Eligible participants will be randomized 2:1 (active:placebo) to receive either rilematovir or placebo bid for
7 days (14 consecutive doses). For participants who receive only 1 dose of rilematovir or placebo PM of
Day 1, dosing should continue through the morning (ie, AM) of Day 8 so that all participants receive
14 consecutive doses in total.
Treatment Overview
Treatment Age Group  
Age Range 
Dosing Regimena 
Volume Oral
Suspensionb
Rilematovir 
1 
≥28 days to <3 months 2.5 mg/kg bid on Days 1 to 7(/8) 
A mL
2 
≥3 to <6 months 
3 mg/kg bid on Days 1 to 7(/8) 
B mL
3 
≥6 months to ≤5 years 4.5 mg/kg bid on Days 1 to 7(/8) 
C mL
4*
birth at term to 
<28 days
Xc mg/kg bid on Days 1 to 7(/8) 
Dc mL
Placebo 
1,2,3, or 4*
see above 
Matching placebo bid on  
Days 1 to 7(/8) 
A, B, C, or Dc*
(respectively) mL placebo
bid = twice daily; IDMC = Independent Data Monitoring Committee; IWRS = interactive web response system.
* After opening of recruitment in neonates in the main study dependent on positive IDMC recommendation after
completion of a substudy in neonates.
a. Doses are provided for JNJ-53718678-AAA.
b. A to D represents the volume of oral rilematovir suspension to obtain the required dose of JNJ-53718678-AAA
or the volume of the matching placebo suspension. After reconstitution, rilematovir is dosed as an equivalent
20 mg/mL JNJ-53718678-AAA oral suspension (containing 23 mg/mL JNJ-53718678-ZCL, the hemi-tartrate of
JNJ-53718678-AAA), to be used depending on the bodyweight of the participant. The required volume to be
administered per intake will be calculated by the IWRS and provided to the sites.
c. Dose dependent on outcome of the substudy in neonates and following IDMC review and recommendation. The
dosing regimen will not exceed the exposures simulated for the bid regimen in pediatric subjects ≥28 days to
≤5 years of age and observed for the 250 mg bid regimen in adults.
Description of Interventions
Study supplies will be delivered as a powder and solvent for oral suspension, to be reconstituted by
appropriately trained study site personnel prior to administration/dispensing to the participant’s
parent(s)/caregiver(s). The study intervention is administered orally using a dosing syringe and is
administered regardless of food intake. During hospitalization the study intervention may also be
administered through nasogastric tube, if already in place.
EFFICACY EVALUATIONS
RSV Recovery Scale Assessments
The RRS is an ordinal scale assessing a participant’s clinical status as defined per protocol. The study day
on which the RRS will be assessed as the primary endpoint is the first study day when at least 50% of the
participants across treatment arms are discharged from the hospital (with or without signs/symptoms). This
study day will be determined in a blinded manner based on all available data irrespective of the treatment


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Status: Approved,  Date: 04 May 2021
group at the time of the first interim analysis and by an independent statistician in order to protect data
integrity. This study day will be used for any further interim analysis as well as for the final analysis. The
RRS will also be assessed on Days 2 to 8 (excluding the primary time point) as secondary endpoints.
The RRS  provides 7 mutually exclusive conditions ordered from best to worst, and the analysis score
reflects the participant’s worst situation on the study day of assessment:
1. Not Hospitalized Without Signs/Symptoms*
2. Not Hospitalized With Signs/Symptoms*
3. Non-ICU Hospitalization, Not Requiring Supplemental Oxygen NOR Supplemental Feeding/Hydration
4. Non-ICU Hospitalization, Requiring Supplemental Oxygen AND/OR Supplemental Feeding/Hydration
5. Admitted to the ICU, Not Requiring Mechanical Ventilation**
6. Requiring Mechanical Ventilation**
7. Death
*With  or without signs/symptoms is defined by the Key RSV Signs/Symptoms based on ObsRO
Signs/Symptoms assessment as being not resolved or resolved (absent or mild), respectively (see
Section 10.14, Appendix 14).
**Mechanical ventilation includes both invasive and non-invasive mechanical ventilation.
Other Clinical Course and Clinical Severity Assessments
The study will include the following additional evaluations of the clinical course of RSV disease:
 
Clinical resolution from RSV disease as assessed daily from Day 2 to Day 8, and defined by:
o Free of oxygen supplementation, AND
o Free of supplemental feeding, AND
o Not requiring ICU, AND
o Key RSV Signs/Symptoms resolved to absent or mild as per the ClinRO Signs/Symptoms.
 
Evolution and severity of signs/symptoms of RSV disease as assessed by the parent(s)/caregiver(s)
(ObsRO Signs/Symptoms) and by the investigator (ClinRO Signs/Symptoms)on an electronic device.
 
Evolution of the RSV disease based on ObsRO GHQ and ClinRO GHQ as assessed by the
parent(s)/caregiver(s) and by the investigator, respectively, on an electronic device.
 
Oxygen supplementation requirement type (invasive mechanical, non-invasive mechanical, and non-
invasive non-mechanical), and duration.
 
Hydration and feeding by IV line/nasogastric tube and duration.
 
The occurrence of the following RSV-disease related complications, with onset after treatment
initiation, as reported by the investigator as AE based on the available clinical information:
o Respiratory complications: respiratory failure, apnoeic attacks, bronchiolitis/bronchial
obstruction, pneumonia, asthmatic crisis;
o Infectious complications: otitis media, bacterial respiratory tract infections, sepsis;


JNJ-53718678 (rilematovir) 
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Status: Approved,  Date: 04 May 2021
o Cardiovascular complications: arrhythmia, cardiogenic shock, hemodynamic instability,
congestive cardiac failure;
o Acid-base or electrolyte complications, based on laboratory values if considered clinically
relevant:
 
metabolic acidosis (serum HCO3 - <16),
 
metabolic alkalosis (serum HCO3 - >30);
 
hyponatremia (Na+ <130 mEq/L),
 
hypokalemia (K+ <2.9 mEq/L),
 
hyperkalemia (K+ >6.0 mEq/L),
 
hypocalcemia (Ca2+ <7.7 mg/dL or equivalent to Grade 2 in children ≤3 months),
 
hypercalcemia (Ca2+  >11.9 mg/dL or equivalent to Grade 2 in children ≤3 months),
 
hypoglycemia (glucose <54 mg/dL)
 
hyperglycemia (glucose >160 mg/dL).
 
Clinical parameters: respiratory rate, heart/pulse rate, SpO2, and body temperature as measured by the
investigator during scheduled visits.
 
Time to first hospital discharge (from start of dosing).
 
Time to readiness for hospital discharge.
 
Reason for hospital discharge or for no discharge despite being clinically ready for discharge.
 
The requirement for transition to ICU and duration of ICU stay.
 
Proportion of participants requiring rehospitalization for respiratory/other reasons.
 
Number and type of medical encounters.
 
Incidence of antibiotic treatment episodes.
 
Incidence of systemic or inhaled corticosteroids and bronchodilators use.
 
Impact of child’s RSV disease on the parent(s)/caregiver(s) and family as assessed by the Caregiver
Impact Questions.
Antiviral Activity
The RSV viral load in nasal MT swab samples will be measured at the central laboratory using a qRT-PCR
assay. The qRT-PCR used to determine RSV viral load will also provide information on the RSV subtype.
Nasal MT swab specimens for the determination of RSV viral load will be collected at several timepoints
during the study as indicated in the Schedule of Activities. The RSV viral load data from the baseline
predose nasal MT swab will also be used for central confirmation of the local RSV diagnosis. Date and
time of sampling will be collected. Nasal MT swabs should be collected from the same nostril throughout
the study (unless precluded due to bleeding). The nostril that was sampled will be documented by the study
site personnel.
Viral Sequencing
Viral resistance will be monitored by sequencing of the RSV F gene in all baseline (predose or screening)
nasal MT swab samples and in subsequent samples upon request of the sponsor’s virologist. Other regions


JNJ-53718678 (rilematovir) 
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CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
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Status: Approved,  Date: 04 May 2021
of the RSV genome may also be sequenced at discretion of the sponsor’s virologist. Sequencing results will
be presented in a separate report. Sequencing data will not be reported to the investigators.
Changes in viral sequence will be evaluated but will not be reported as AEs.
PHARMACOKINETIC EVALUATIONS
PK assessments during the study will be based on sparse sampling to limit the number of samples
(2 samples, see Section  1.3.3, Pharmacokinetic Assessments Sampling Schedule) and will be analyzed
using a population (pop)PK model.
OTHERS
Pharmacokinetics/Pharmacodynamics
Obtained PK and PD data (selected antiviral activity parameters, clinical outcomes, and safety parameters)
will be used to explore the relationship between the PK and PD.
Medical Encounters
Medical encounters will be collected in the electronic case report form (eCRF) for all participants from
time of presentation at the hospital/clinic throughout the study. Protocol-mandated procedures, tests, and
encounters are excluded. The data collected may be used to conduct exploratory economic analyses.
Acceptability and Palatability
Acceptability and palatability of the rilematovir formulation will be assessed using a questionnaire
completed by parent(s)/caregiver(s) on an electronic device after last dosing.
Biomarkers
No specific samples will be collected for biomarker research. Leftover blood samples and leftover nasal
MT swab samples collected during the study may be used for exploratory biomarker analyses (eg, proteins,
ribonucleic acid [RNA], immune cells, microbiome) at the sponsor’s discretion and results may be reported
separately from this study.
Detection of Baseline Presence of other Respiratory Viruses or Bacteria
The presence of other respiratory viruses (other than RSV) or bacteria will be assessed in the nasal MT
swab sample collected at baseline by PCR assay at the central laboratory. Central testing for other
respiratory viruses will also include testing for the presence of SARS-CoV-2 in the nasal MT swab sample.
Nasal MT swabs from other time points may also be assessed for detection of other respiratory viruses or
bacteria at the central laboratory, if deemed necessary.
SAFETY EVALUATIONS
The study will include the following evaluations of safety and tolerability:
 
AEs, serious (S)AEs, and deaths;
 
Clinical laboratory tests (central);
 
ECG 12-lead (central);
 
Vital signs (resting, in supine position):


JNJ-53718678 (rilematovir) 
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Status: Approved,  Date: 04 May 2021
o 
vital signs assessments performed as part of the clinical course of RSV infection-related
assessments (body temperature, heart/pulse rate, respiratory rate, and SpO2),
o 
additional vital signs assessments: systolic blood pressure (SBP), diastolic blood pressure
(DBP);
 
Complete physical examination of all body systems performed at Screening (including height or
length, head circumference, and body weight measurements), and directed physical examinations
performed, inclusive of the examination needed for ClinRO Signs/Symptoms completion, as per
the Schedule of Activities (on Day 21, including height or length, head circumference, and body
weight measurements). Clinically relevant findings resulting from the physical examination post-
baseline will be reported as AEs, except those in the ClinRO Signs/Symptoms assessment that
are treated as efficacy outcomes.
In the event that an invasive procedure such as a blood draw or nasal swab and an ECG are required at
approximately the same time, the ECG should be collected first.
Safety and tolerability will be evaluated throughout the study from signing of the main informed consent
form (ICF) until the last study-related activity. For participants with only a signed pre-screening
(diagnostic) ICF (ie, for whom consent was not given to enroll in the main study), only study procedure
(nasal swabbing) related AEs will be reported.
STATISTICAL METHODS
Sample Size Calculation
The study will aim to enroll 737 participants. The sample size calculation is based on the primary endpoint,
ie, the RRS  and results from Study 53718678RSV2002. Based on the proportional odds model and
assuming a benefit of approximately 45% reduction of the common odds ratio, a total sample size of
700 participants (randomized 2:1) would provide a power of at least 95%, using an overall Type 1 error
rate of 5% (2-sided) and accounting for the group-sequential design. A reduction of 35%, which is still
considered clinically relevant, would provide a power of 80%. Assuming 5% of participants will be
excluded from the primary analysis set (intent to treat –infected [ITT-i] set), the total sample size for this
study is 737.
In the sample size calculation, it is assumed that the distribution of participants treated with placebo between
the categories of the RRS will be as follows on the selected study day:
 Not hospitalized without signs/symptoms: 20%
 Not hospitalized with signs/symptoms: 20%
 Non-ICU hospitalization, not requiring supplemental oxygen nor supplemental feeding/hydration: 15%
 Non-ICU hospitalization, requiring supplemental oxygen and/or supplemental feeding/hydration: 30%
 Admitted to the ICU, not requiring mechanical ventilation: 7%
 
Requiring mechanical ventilation: 7%
 
Death: 1%


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Status: Approved,  Date: 04 May 2021
Efficacy Analysis
As a confirmatory strategy, to account for multiplicity in the statistical evaluation of the most important
efficacy endpoints, a hierarchical testing procedure will be applied to control for the overall Type I error
rate at the 5% level (2-sided). The following endpoints are included in the confirmatory testing strategy:
1. 
RRS, ie, the primary endpoint.
2. 
Proportion of participants clinically resolved from RSV disease (based on ClinRO
Signs/Symptoms as assessed at the same study day as the primary endpoint).
3. 
Time from first dosing to resolution of Key RSV Signs/Symptoms based on ObsRO
Signs/Symptoms and supplementation-free for at least 24 hours.
4. 
Time from discharge to resolution of Key  RSV Signs/Symptoms based on ObsRO
Signs/Symptoms (for participants who did not reach resolution before first discharge).
5. 
Time from first dosing to end of oxygen supplementation (for participants who were receiving
oxygen supplementation at the time offirst dosing).
6. 
Incidence in post-baseline RSV-related complications.
Primary Endpoint
The primary efficacy analysis will be based on the ITT-i analysis set and consists of the analysis of the
RRS.
A proportional odds model will be used to analyze the RRS, including treatment, RRS category at baseline,
and the two stratification factors (stratification by presence of [a] risk factor[s] for severe RSV disease
versus otherwise healthy and by region).
Key Secondary Endpoints
For the hypothesis testing, the following methods will be used:
 
Time from first dosing to resolution of Key RSV Signs/Symptoms (based on ObsRO Signs/Symptoms),
time from discharge to resolution of Key RSV Signs/Symptoms (based on ObsRO Signs/Symptoms),
and time from first dosing to end of oxygen supplementation will be analyzed using a stratified Gehan-
Wilcoxon test (using the randomization stratification factors).
 
To compare the proportion of participants clinically resolved from RSV  (based on ClinRO
Signs/Symptoms), a logistic regression model will be used. Randomization stratification factors will be
added to the model. A similar model will be applied to analyze the incidence of treatment-emergent
RSV-related complications.
Clinical Course of RSV Infection
Endpoints related to evaluation of the clinical course of RSV infection will be analyzed graphically and
descriptively  as described in the statistical analysis plan (SAP). For continuous variables, descriptive
statistics (n, mean, standard deviation [SD], median, minimum, and maximum) will be calculated. For
categorical variables, frequency tables will be presented. Time to-variables will be analyzed using Kaplan-
Meier (KM) plots and will be modeled using an accelerated failure time model, adjusted for the
randomization stratification factors, to estimate differences between intervention groups.


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Antiviral Activity
Antiviral activity will be determined based on measurements of RSV viral load in nasal MT swab samples
by a qRT-PCR assay. These data will be analyzed graphically and descriptively as described in the SAP.
For continuous variables, descriptive statistics (n, mean, SD, median, minimum, and maximum) will be
calculated. For categorical variables, frequency tables will be presented.
Mean log10 viral load values over time will be analyzed using a restricted maximum likelihood-based
repeated measures approach. Differences between intervention groups in viral load, and the difference in
the RSV viral load AUC through Days 3, 5, and 8 between intervention groups will be derived using
appropriate contrasts deriving least square mean differences, including the 95% 2-sided confidence
intervals.
Viral Sequencing
The results of viral sequencing will be evaluated by the sponsor virologist. Pre-treatment genetic variations
and relevant post-baseline changes in the RSV F gene (and other regions of the RSV genome, if applicable
and on request of the sponsor virologist) will be tabulated and described. The effect of pre-treatment RSV
F protein genetic variations and relevant post-baseline RSV F  protein amino acid changes on antiviral
response and/or clinical outcomes will be explored.
Safety Analysis
Adverse Events
The verbatim terms used in the eCRF by investigators to identify AEs will be coded using the Medical
Dictionary for Regulatory Activities (MedDRA). Any AE or any worsening of a pre-existing condition
occurring at or after the initial administration of study intervention through the end of the study  is
considered to be treatment-emergent (TEAE). All reported TEAEs will be included in the analysis. For
each TEAE, the percentage of participants who experience at least 1 occurrence of the given event will be
summarized by intervention group.
Clinical Laboratory Tests
Laboratory data will be summarized by type of laboratory test. Reference ranges and markedly abnormal
results will be used in the summary of laboratory data. Descriptive statistics will be calculated for each
laboratory analyte at baseline and for observed values and changes from baseline at each scheduled time
point. Changes from baseline results will be presented in pre- versus post-intervention cross-tabulations
(with classes for below, within, and above normal ranges). A listing of participants with any laboratory
results outside the reference ranges or with any markedly abnormal laboratory results will be provided.
The laboratory abnormalities will be graded per the criteria specified in the Division of Microbiology and
Infectious Diseases (DMID) pediatric toxicity tables and in accordance with the normal ranges of the
clinical laboratory if no DMID gradings were available. Alkaline phosphatase (ALP)will be graded per the
criteria specified in the Division of Acquired Immunodeficiency Syndrome (DAIDS) adult and pediatric
toxicity table. For breast feeding neonates, total bilirubin will also be graded per the DAIDS adult and
pediatric toxicity table.
Electrocardiogram
The effects on cardiovascular variables will be evaluated by means of descriptive statistics and frequency
tabulations and pre- versus post-intervention cross-tabulations. These tables will include observed values
and changes from baseline values (the predose ECG will be used as baseline).


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Vital Signs
Descriptive statistics of actual values and changes from baseline will be summarized at each scheduled time
point. The percentage of participants with values beyond clinically important limits will be summarized.
Interim Analyses
Two interim analyses are planned. Each interim analysis will preferably be conducted at the end of a
Northern or Southern hemisphere RSV season. The first interim analysis will be performed at the end of
the first season where the cumulative enrollment reaches approximately 35% of the total sample size and
will include an assessment of futility. The second interim analysis will be performed at the end of the first
season where the cumulative enrollment reaches approximately 75% of the total sample size and will
include an assessment of futility and stopping for early superiority. At the second interim analysis, proper
alpha correction will be applied using the O’Brien Fleming alpha spending function to correct for
multiplicity. An additional interim analysis with assessment of stopping for early superiority might be
performed at the end of an  RSV season after the second pre-planned interim analysis, provided that
approximately 85% of the total sample size is enrolled. In case an additional interim analysis is performed,
proper alpha correction will be applied using the O’Brien Fleming alpha spending function.


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1.2. 
Schema
Figure 1: 
Schematic Overview of the Study
bid = twice daily; RMV = rilematovir; RSV = respiratory syncytial virus; SOC = standard-of-care.
a) Randomization should occur within a maximum of 24 hours after start of screening or within 48 hours
after collection of the SOC or pre-screening samples for RSV diagnosis, whichever comes first. A
study participant should be randomized ≤3 days after RSV sign/symptom onset.
b) Randomization will be stratified by the presence of risk factors for severe RSV disease and by region.
c) Study intervention administration should start as soon as possible, but no later than 4 hours after
randomization. Participants will receive either rilematovir or matching placebo bid for 7 days
(14 consecutive doses).










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i. 
Study site personnel will diagnose RSV locally for eligibility, using a study-specific nasal MT swab and a PCR or other molecular-based diagnostic assay. They
should ship the leftover specimen for any patient that is subsequently randomized. This does not apply if an SOC diagnostic sample is collected within 24 hours of
screening start and yields a positive RSV result using a molecular-based diagnostic assay.
j. 
Randomization should occur within 24 hours after start of screening or within 48 hours after collection of the SOC or pre-screening sample used for local RSV
diagnosis, whichever comes first AND within ≤3 days of RSV sign/symptom onset (see Figure 2).
k. 
First study intervention intake signifies Day 1 and should occur as soon as possible, but no later than 4 hours after randomization. Dosing should occur approximately
every 12 hours, but the second dose may be delayed or brought forward (by maximum 4 hours) if the nominal timing for this dose falls in the middle of the night.
Thereafter, dosing follows a regular AM/PM schedule. The participant will receive study intervention orally using a dosing syringe, or a nasogastric tube if one is
already in place, and with or without food.
l. 
Depending on the time of randomization/enrollment, participants receive 1 dose (PM) or 2 doses (AM and PM) of study intervention on Day 1. For participants who
receive only 1 dose of study intervention PM ofDay 1, dosing continues through the morning (ie, AM) of Day 8 so that all participants receive 14 doses in total.
m. Study site personnel will instruct the participants’ parents/caregivers on how to store and administer the study intervention at home. They will provide the study
intervention bottle(s) at discharge, from which the parent/caregiver should withdraw each dose remaining in the treatment period.
n. 
Clinical evaluation includes vital signs assessments: respiratory rate, heart/pulse rate, body temperature, and SpO2. Study site personnel should measure body
temperature immediately before or >4 hours after a participant receives an antipyretic. Study site personnel should interrupt supplemental oxygen until the SpO2
drops below 92% and remains stable at that level for 1 minute, or up to 15 minutes, whichever comes first before measuring SpO2, unless the participant is on invasive
or non-invasive mechanical ventilation. Refer to Section 10.9, Appendix 9for guidelines for measuring vital signs and SpO2.
o. 
Supplemental oxygen requirement (type and duration), supplemental feeding (type and duration), level of and duration of hospital care, and duration of hospitalization
are recorded throughout the study. Duration requires start and end dates/times.
p. 
The investigator will complete the ClinRO Signs/Symptoms and ClinRO GHQ on an electronic device. In case of a missing assessment, the reason should be
documented in the eCRF.
q. 
Participant’s parent(s)/caregiver(s) will complete the assessments on an electronic device. The study site personnel will explain to participant’s parent(s)/caregiver(s)
how to use the electronic device and when to complete assessments.
r. 
The clinical evaluation, ClinRO Signs/Symptoms, ClinRO GHQ, ObsRO Signs/Symptoms, ObsRO GHQ, and Caregiver Impact Questions assessments on Day 1
need to be completed after the PM administration of the study intervention.
s. 
The participant’s parent(s)/caregiver(s) should complete the final ObsRO Signs/Symptoms, ObsRO GHQ, and Caregiver Impact Questions before attending or as
the first activity of the Day 21 visit. The last assessment should be completed on calendar day 21 in case the Day 21 visit takes place after calendar day 21.
t. 
In case of a missing assessment, the reason should be documented in the eCRF.
u. 
Study site personnel should collect the pre-dose nasal MT swab as close as possible and prior to first study intervention intake. Leftover study-specific (pre-)screening
nasal MT swab specimen can serve as baseline IF this screening sample: was collected within 8 hours prior to first dose, is appropriately stored AND is available in
sufficient volume (volume is considered sufficient if no more than 600 µL from the original sample has been used for local RSV testing and the whole remainder of
the original sample is available).
v. 
Study site personnel should collect each nasal MT swab from the same nostril (unless precluded due to bleeding) and most preferably at approximately the same
time as on Day 1. Figure 3 summarizes the nasal MT swab collection schedule.
w. The sponsor may utilize leftover nasal MT swab samples for exploratory biomarker analyses.
x. 
Only performed if the screening assessment occurred >8 hours before anticipated first dosing.
y. 
Only applicable if clinically indicated to evaluate a participant’s ongoing AE(s) or any clinically significant laboratory or ECG abnormality identified on Day 21.
z. 
Refer to Section 10.9, Appendix 9 for guidelines for measuring vital signs. Efficacy assessments require other vital signs (footnote n).
aa. Complete physical examination of all body systems includes measurement of height or length, head circumference, and body weight.
bb. Directed physical examination includes respiratory system, nose, ear, throat, facial and neck lymph nodes.


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cc. On Day 21, also includes measurement of height or length, head circumference, and body weight.
dd. Study  site personnel should perform each 12-lead ECG prior to other scheduled assessments. The participant should be supine (infants can be lying on their
parent’s/caregiver’s arm) and rested for at least 5 minutes and preferably sleeping or calm (ie, not crying). The investigator should repeat an ECG in the presence of
an abnormal QTcF interval (see Sections 5.2, 7.1, and 8.3.5.2), or for other ECG abnormalities at his/her discretion. A central cardiologist will also evaluate all
ECGs, but not in real time (within 72 hours).
ee. Study site personnel should take the Day 1 and Day 3 ECGs approximately one hour (45-90 minutes) after administration of study intervention.
ff. 
A central laboratory analyzes the hematology and biochemistry samples. Participants may begin study intervention before the central laboratory delivers screening
results.
gg. Levels of potassium and magnesium will be determined by the central laboratory. In case of hypokalemia and/or hypomagnesemia at screening or at Day 8, the levels
of potassium and/or magnesium should be checked as soon as possible at the local laboratory and corrected to prevent cardiac disturbances. Appropriate clinical
management per local SOC (including but not limited to checking the corrected values at local laboratory) may be required.
hh. The central laboratory provides urine dipsticks for local assessment. Study site personnel should ship any specimen with an abnormality to the central laboratory for
flow cytometric and/or microscopic evaluation(s).
ii. 
Refer to Section 1.3.3 Pharmacokinetic Assessments Sampling Schedule for collection timepoints.
Notes:
1. Unscheduled visits may be performed based on the investigator’s clinical judgment and may include further evaluations, as needed.
2. See Section 10.19, Appendix 19for guidance on study conduct during the COVID-19 pandemic.
3. In case of supply issues for nasal MT swabs because of increased demand due to the COVID-19 pandemic, alternative nasal swabs instead of nasal MT swabs
may be provided for nasal sample collection for the study assessments.






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h. 
Clinical evaluation includes vital signs assessments: respiratory rate, heart/pulse rate, body temperature, and SpO2. Study site personnel should measure body
temperature immediately before or >4 hours after a participant receives an antipyretic. Study site personnel should interrupt supplemental oxygen until the SpO2
drops below 92% and remains stable at that level for 1 minute, or up to 15 minutes, whichever comes first before measuring SpO2. Refer to Section 10.9, Appendix 9
for guidelines for measuring vital signs and SpO2.
i. 
Only applicable in case of on-site visit and if clinically relevant.
j. 
The investigator will complete the ClinRO Signs/Symptoms and ClinRO GHQ on an electronic device. In case of a missing assessment, the reason should be
documented in the eCRF.
k. 
A parent/caregiver should complete the morning ObsRO Signs/Symptoms and ObsRO GHQ prior to discharge.
l. 
Parent(s)/caregiver(s) will complete the ObsRO Signs/Symptoms, ObsRO GHQ, and Caregiver Impact Questions at home after discharge.
m. The participant’s parent(s)/caregiver(s) should complete the final ObsRO Signs/Symptoms, ObsRO GHQ, and Caregiver Impact Questions before attending or as
the first activity of the Day 21 visit. The last assessment should be completed on calendar day 21 in case the Day 21 visit takes place after calendar day 21.
n. 
At least the responses to the ObsRO GHQ should be reviewed by the study site personnel. In case of significant deterioration of the child’s health, the study site
personnel should contact the parent(s)/caregiver(s) by phone (or other means of contact as agreed upon).
o. 
In case of a missing assessment, the reason should be documented in the eCRF.
p. 
Study site personnel should collect each nasal MT swab from the same nostril (unless precluded due to bleeding) and most preferably at approximately the same
time as on Day 1. Figure 3 summarizes the nasal MT swab collection schedule.
q. 
The sponsor may utilize leftover nasal MT swab samples for exploratory biomarker analyses.
r. 
Refer to Section 10.9, Appendix 9 for guidelines for measuring vital signs. Efficacy assessments require other vital signs (footnote h).
s. 
Directed physical examination includes respiratory system, nose, ear, throat, facial and neck lymph nodes.
t. 
On Day 21, also includes measurement ofheight or length, head circumference, and body weight.
u. 
Study  site personnel should perform each 12-lead ECG prior to other scheduled assessments. The participant should be supine (infants can be lying on their
parent’s/caregiver’s arm) and rested for at least 5 minutes and preferably sleeping or calm (ie, not crying). The investigator should repeat an ECG in the presence of
an abnormal QTcF interval (see Sections 7.1, and 8.3.5.2), or for other ECG abnormalities at his/her discretion. A central cardiologist will also evaluate all ECGs,
but not in real time (within 72 hours).
v. 
Study site personnel should take the Day 3 ECG approximately one hour (45-90 minutes) after administration of study intervention.
w. A central laboratory analyzes the hematology and biochemistry samples.
x. 
Levels of potassium and magnesium will be determined by the central laboratory. In case of hypokalemia and/or hypomagnesemia at Day 8, the levels of potassium
and/or magnesium should be checked as soon as possible at the local laboratory and corrected to prevent cardiac disturbances. Appropriate clinical management per
local SOC (including but not limited to checking the corrected values at local laboratory) may be required.
y. 
The central laboratory provides urine dipsticks for local assessment. Study site personnel should ship any specimen with an abnormality to the central laboratory for
flow cytometric and/or microscopic evaluation(s).
Notes:
1. Unscheduled visits may be performed based on the investigator’s clinical judgment and may include further evaluations, as needed.
2. See Section 10.19, Appendix 19for guidance on study conduct during the COVID-19 pandemic.
3. In case of supply issues for nasal MT swabs because of increased demand due to the COVID-19 pandemic, alternative nasal swabs instead of nasal MT swabs
may be provided for nasal sample collection for the study assessments.


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1.3.3. 
Pharmacokinetic Assessments Sampling Schedule
Day 1 
Day 2
Post-dose AM  
Pre-dose PM  
Post-dose PM  
Pre-dose AM  
Post-dose AM  
Pre-dose PM  
Post-dose PM
First Dose AM  Option 1 
X 
Y
Option 2* 
X 
Y
First Dose PM  Option 1 
X 
Y
Option 2* 
X 
Y
X: The Cmax PK sample will be taken after the first dose intake, after the ECG measurement (see Schedule 1.3.1) and approximately 1 hour (45-120 minutes) after dosing.
Y: The Ctrough  PK sample will be taken between 4 hours post-dose and 30 minutes pre-dose. To allow for flexibility with taking this sample, 2 different time points are
given as options.
*Option 2 should be considered only if the Day 2 sample can be collected prior to discharge.
Blood samples for determination of rilematovir concentrations will be collected through finger prick or heel stick. Leftover blood samples collected for PK
assessments may be used for exploratory biomarker analyses, at discretion of the sponsor. The following times need to be recorded: date and time of last
study intervention intake, date and time of PK blood sampling, and time of any meal consumed within 30 minutes before or after the previous study
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2. 
INTRODUCTION
Respiratory syncytial virus (RSV), a negative-stranded ribonucleic acid (RNA) virus belonging to
the Pneumoviridae family, is considered the most important cause ofacute lower respiratory tract
infection (LRTI)in infants and young children.20,37 Two subtypes of RSV have been identified, ie,
subtypes A and B that generally co-circulate simultaneously.16 The RSV season occurs during
winter months in regions with temperate climates in the Northern and Southern Hemispheres and
throughout the year or with peaks semi-annually in tropical regions.2,4,44
In most patients, RSV results in upper respiratory tract infection (URTI)eliciting “common cold”-
like symptoms, which might last up to 2 weeks, and are usually self-limiting. However,
hospitalizations occur, with hospitalizations in the United States for RSV estimated at
55.3/100,000 person-years between 1993 and 2008 for all ages.45 RSV infection can result in
LRTI/lower respiratory tract complications (LRTC) with severe respiratory compromise, causing
considerable morbidity and mortality in certain patient populations, such as infants.37
RSV-related LRTI is a major cause of hospital admissions and death in young children
worldwide.36,37 Infants born prematurely or close to the RSV season and/or suffering from
bronchopulmonary dysplasia or congenital heart disease have the highest risk of developing severe
RSV-related acute LRTI.17 In 33-35 week gestational age infants, the incidence rate of
hospitalization for RSV ranged from 3.25% to 3.63%, with hospitalization rates peaking from
December-March in the northern hemisphere.3 In 2015, there were approximately 33.1 million
RSV-LRTI episodes in children up to 4 years of age globally, which resulted in approximately
3.2 million hospitalizations and 59,600 deaths for this age group. Approximately 45% of these
hospital admissions and in-hospital deaths occurred in children younger than 6 months of age.37
Among children <5 years of age with RSV infection, 97.7% present for medical care as outpatients
in emergency departments (EDs) and in pediatric practices, while 2.7% require hospitalization.19
In children ≤3 years of age, the clinical presentation of RSV disease is linked to the anatomy of
their maturing respiratory tract. RSV infection causes inflammation and necrosis of the bronchiolar
epithelial cells. The lumina of the bronchioles become obstructed from edema of the airway wall,
increased mucus secretion, sloughed epithelium, and cellular debris. The small-diameter airways
in infants are particularly vulnerable to obstruction. Such obstruction of bronchioli may lead to
bronchiolitis and can cause respiratory distress.30,31 Between 61.3% and 77.5% of acute
bronchiolitis episodes in children <2 years have been reported as being RSV-related.12 Hence, this
population is considered at risk for severe RSV-related disease.
The duration and level of distress and anxiety of the parent/caregiver due to severe RSV infection
are underestimated.29 Bronchiolitis symptoms usually peak around Day 3 to Day 5 and in case of
early presentation (Day 2), the clinical course may deteriorate before improving.
In immunocompetent children and adults, a 3-day window between the onset of clinical symptoms
after RSV infection and peak viral load has been reported, which provides an effective window of
opportunity to initiate treatment.10,11,14 Additionally, some studies in the adult and pediatric
population have demonstrated that RSV viral load and severity of disease symptoms are closely


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correlated.10,11,14 Together, these data suggest that early initiation of treatment after RSV infection
is possible, and could result in a decrease of the viral load, syncytia formation, and in inflammatory
reactions,14 and hence may improve disease outcomes and shorten the duration and/or severity of
the disease.
Despite the large medical and economic burden, no vaccines and only 2 antiviral agents have been
approved for the prevention or treatment of RSV infection in pediatric populations, while no
vaccine or antiviral has been approved for adults.2,6,35 Palivizumab, a monoclonal antibody, is only
approved for prophylaxis of RSV infection with restricted indication for infants at risk of severe
RSV disease. However, its prophylactic effectiveness is limited (55% reduction in hospitalization
rate), and it has not proven to be an effective treatment option.38 Ribavirin (aerosol), a nucleoside
analogue, is approved in selected countries for the treatment of hospitalized infants and children
with severe LRTI, but is not recommended for use per guidelines28 and its use is minimal due to
limited efficacy, potential genotoxic effects, and complexity of administration.2,5,39 In hospitalized
patients, the current treatment of RSV infection is generally limited to supportive care, consisting
of supplemental oxygen therapy, nutrition, fluids, and, in some cases, mechanical ventilation.15,40
Overall, the unmet medical need (prophylactically and therapeutically) is substantial in both
children and adults with RSV infection, whether hospitalized or outpatients.
For the most comprehensive nonclinical and clinical information regarding rilematovir, refer to
the latest version of the Investigator's Brochure (IB).26 The term “study intervention” throughout
the protocol refers to the administration ofrilematovir or placebo.
The term "sponsor" used throughout this document refers to the entities listed in the Contact
Information page(s), which will be provided as a separate document.
2.1. 
Study Rationale
RSV is considered one of the most important viruses causing acute LRTI and a major cause of
hospital admissions and death in young children worldwide.36,37 Infants born prematurely or at the
beginning of the RSV season and/or suffering from bronchopulmonary dysplasia or congenital
heart disease have the highest risk of developing severe RSV-related acute LRTI.17
Besides ribavirin and palivizumab with their respective associated limitations as described above,
there is no direct-acting antiviral agent approved for the prevention or treatment of RSV infection
in the pediatric population. Also, no vaccines have been approved to prevent RSV infection.
Therefore, a substantial medical need for the treatment of RSV infection exists.
This study aims to evaluate the efficacy and safety  of rilematovir in hospitalized infants and
children (≥28 days to ≤5 years) and, subsequent to the completion of the substudy, in hospitalized
neonates (born at term, <28 days of age) with RSV infection.
2.2. 
Background
For the most comprehensive nonclinical and clinical information regarding rilematovir, refer to
the latest version of the IB for rilematovir.26


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Enveloped viruses like RSV have a complex membrane-fusion machinery that includes a fusion
protein that enables the deposition of the viral nucleic acid genome into the host cells and initiates
their replication.8,27 Rilematovir is an investigational RSV specific fusion inhibitor belonging to
the indole chemical class and is in development for the treatment of RSV infection. Rilematovir
has demonstrated in vitro activity against a panel of RSV-A and RSV-B strains. In addition, trends
for antiviral activity and clinical benefit of rilematovir were demonstrated during clinical studies
in healthy adults inoculated with RSV (Study  53718678RSV2001), in non-hospitalized adult
participants infected with RSV (interim analysis Study 53718678RSV2004), and in RSV-infected
hospitalized pediatric participants (Study 53718678RSV1005 and interim analysis
Study 53718678RSV2002).
Nonclinical Studies
Rilematovir has been extensively evaluated and characterized in both in vitro and in vivo
pharmacological and toxicological studies. Detailed results of nonclinical studies are described in
the IB for rilematovir.26
Rilematovir is a small molecule inhibitor of the RSV fusion protein with demonstrated activity
against RSV in in vitro and in vivo models of RSV infection. No in vitro antiviral activity was
observed for the rilematovir metabolites M12 (JNJ-53541683), M19 (JNJ-64564071), and M37
(JNJ-69101045); the effective concentration for 50% inhibition  (EC50) value for M5
(JNJ-54172794) was 7.7 nM.
In vitro, rilematovir is a moderate to strong inhibitor of cytochrome P450 (CYP)3A4/5, an inducer
of CYP3A4 and, to a lesser extent, of CYP2B6. Rilematovir is a substrate, but not an inhibitor, of
P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP), and an inhibitor of organic-
anion-transporting polypeptide (OATP)1A2, OATP1B1, OAT3, organic cation transport (OCT)1,
and OCT2.
In the in vitro human-ether-a-gogo-related (hERG)assay, rilematovir induced changes but this did
not translate to QT interval corrected for heart rate (QTc)interval prolongation in animals. In dogs,
an increase in heart rate and decrease in blood pressure were observed. Minimally and transiently
decreased neuromuscular function, with minimal effects related to gastrointestinal function were
observed in rats. Decreased general activity and tremors (minipig only) were reported in adult dogs
and minipigs given high doses of rilematovir and were considered secondary to the poor general
condition of the animals.
Repeated-dose toxicity studies up to 4 weeks of dosing in adult rats, dogs, and minipigs identified
the liver and gastrointestinal system as target systems. Administration of rilematovir in juvenile
rats up to the maximum feasible dose of 400 mg/kg/day was generally well tolerated and no target
organs of toxicity were identified. In juvenile minipigs, dose levels of 25 mg/kg/day and above
resulted in gastric ulceration and inflammation, decreases in red blood cells with increases in
bilirubin, and adaptive changes in hematopoietic organs (extramedullary hematopoiesis in liver
and spleen). There were no toxicologically relevant effects on embryo-fetal development in
pregnant rats and rabbits, while maternal toxicity was evident.


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No genotoxic or phototoxic effects have been identified for rilematovir. Rilematovir is not
irritating to the eye or skin sensitizing. The compound was classified as moderately cytotoxic in a
high content screen assay, it did not induce mitochondrial toxicity.
In conclusion, the results of the safety pharmacology, genetic toxicology, and general toxicity
studies in adult and juvenile animals and embryo-fetal development studies support the
administration of rilematovir to humans (adult and pediatric population).
Clinical Studies
Human Pharmacokinetics and Product Metabolism
Single Dose
In the single-dose escalation part of Study  53718678RSV1001 in healthy adults, the mean
maximum plasma concentration  (Cmax) of rilematovir increased proportionally with dose after
administration of rilematovir doses between 25 mg and 1,000 mg under fasted conditions. Mean
area under the plasma concentration-time curve (AUC) from time of administration extrapolated
to infinity (AUC0 ∞) of rilematovir increased slightly more than dose-proportionally with
increasing rilematovir dose from 25 mg to 1,000 mg. Median time to reach Cmax  (tmax) was
1.00 hour, except for the 1,000-mg dose group, in which it was 2.50 hours. Similar mean apparent
terminal elimination half-lives (t1/2term) for the different dose groups were observed.
Based upon data from Study  53718678RSV1004 in healthy Japanese adult men and
Study 53718678RSV1001, Cmax  and AUC0 ∞ for rilematovir are similar between Caucasian and
Japanese participants.
In Study 53718678RSV1009, the effect of rilematovir on the cardiac repolarization interval in
healthy adult participants was evaluated with dosing up to 4,500 mg. Part 1 of the study was the
dose escalation part; based on the PK and safety results of Part 1, the supratherapeutic dose of
4,500 mg was selected for Part 2 of the study, the thorough QT (TQT) part. Exposure-response
analysis was performed to determine the relationship between the concentrations of rilematovir
and QT/QTc interval changes extracted from Holter monitor ECG data. Based on this analysis, an
important potential risk of QT interval prolongation was identified for rilematovir. The model-
predicted mean ΔΔQTcI (90% CI) at the observed geometric mean of the Cmax  of the effect
compartment concentration following a single dose of 500 mg (2,165 ng/mL) and 4,500 mg
(10,153 ng/mL) rilematovir was 4.8 msec (4.2; 5.3 msec) and 20.3 msec (18.2; 22.3 msec),
respectively. The highest Cmax  at the effect compartment following a single dose associated with
an upper limit of the 90% CI for ΔΔQTcI <10 msec was 4,350 ng/mL, which corresponds with
approximately a single dose of 1,000 mg. For more details on the analysis, refer to the IB.26 A
change to a twice daily (bid) dosing regimen (see Section 4.3) and several other mitigation
measures to safeguard the participants (see Section 2.3.3) have been implemented.


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Multiple Dose
Adult Population
In the multiple-dose escalation part of Study 53718678RSV1001 in adult participants under fed
conditions, predose plasma concentrations (Ctrough) reached steady state after 1 day of treatment
with rilematovir. On Day 8, rilematovir exposure expressed as mean Ctrough, minimum plasma
concentration (Cmin), Cmax  and AUC from time of administration up to 24 hours post dosing
(AUC0 24h) demonstrated a dose-proportional increase with increasing rilematovir dose from
250 mg every 24 hours (q24h) to 500 mg q24h. Fluctuation was lower for the 250 mg bid regimen
compared with the 500 mg once daily (qd)regimen. For the 500 mg q24h dose group, mean plasma
concentration 24 h after time of administration (C24h) values of rilematovir were similar between
Day 1 and Day 8, while Cmax  and AUC0 24h  were 1.15- and 1.16-fold higher at Day 8. For the
250 mg q12h dose group, mean C12h, Cmax  and AUC0 12h of rilematovir were increased
1.53-, 1.42-, and 1.53-fold, respectively, on Day 8 compared with Day 1. The mean total amount
of rilematovir excreted in urine over the dosing interval at steady state was low; mean renal
clearance was very low, and similar between dose regimens.
In Study 53718678RSV2001 in adult participants, the pharmacokinetic (PK) profile of rilematovir
at multiple doses of 75 mg, 200 mg, and 500 mg qd for 7 days was evaluated in healthy adult
participants inoculated with RSV-A Memphis 37b virus. The PK results from this study were
consistent with those from corresponding regimens in Study 53718678RSV1001, indicating that
viral infection did not affect the PK of rilematovir.
Interim analysis results from Study 53718678RSV2004 in RSV-infected adult patients (data
cut-off 23 September 2019) demonstrate that the population (pop)PK model provides an adequate
description of most of the data, however moderate variability existed with exposures greater
(~25%) than expected based on healthy volunteer data. The mean (standard deviation [SD]) Day 7
AUC24h  and Ctrough  following administration of 500 mg rilematovir in this study (N 16) were
38,800 
(16,600) 
ng.hr/mL 
and 
698 
ng/mL 
(546), 
respectively, 
compared 
to
26,520 (7,520)ng.hr/mL 
and 
334 
(197) 
ng/mL, 
respectively, 
observed 
in
Study 53718678RSV2001 (N 17).
Pediatric Population
An initial popPK model for rilematovir has been developed using data from
Study 53718678RSV1001 in healthy adults and data from Study 53718678RSV1005 in
RSV-infected pediatric patients. The popPK model has a combination of maturation functions as
well as allometric scaling, taking into account the abundancy of specific enzymes (and their
maturation) involved in the metabolism of rilematovir in the different age groups. Using this
popPK model, the rilematovir PK parameters AUC0 24h, Cmin, and Cmax  were simulated for the
pediatric population for Days 1 and 7 in Study 53718678RSV1005. At the highest doses of 5, 6,
and 9mg/kg qd for the respective age groups, the predicted AUC0 24h, Cmin, and Cmax  values were
similar or slightly higher than the corresponding PK parameters observed for 500 mg rilematovir
qd in healthy adults.


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The popPK model for rilematovir was updated based on additional adult data (from selected
Phase 1 Studies 53718678RSV1007, 53718678RSV1009, and 53718678RSV1008 as well as
Phase 2 Study 53718678RSV2004) and pediatric data of Phase 2 Study 53718678RSV2002.
Interim analysis results from the ongoing Study 53718678RSV2002 in RSV-infected pediatric
patients (data cut-off 02 January 2020) demonstrate that the updated popPK model provides an
adequate description of the majority of the data. The observed medians, 5th  and 95th  percentiles,
are in agreement with the simulated prediction intervals. The observed exposures at steady state
AUC24h Day 7 across the age groups is in agreement with the 500 mg once daily data in adults and
slightly lower than the PK results from Study 53718678RSV1005.
Food Interaction
In Study 53718678RSV1001, mean Cmax of rilematovir was approximately 35% lower and median
tmax  increased from 1 hour to 3.5 hours when rilematovir was administered under fed conditions
compared with fasted conditions. Mean AUC0  of rilematovir was slightly lower (93%) when
rilematovir was administered under fed conditions compared with fasted conditions. The PK
results from the study part evaluating a single dose (500 mg) of the oral suspension in Study
53718678RSV1007 demonstrated that AUC0 ∞ and Cmax  of rilematovir were 5% and 35%,
respectively, lower when the oral suspension was administered under fed conditions compared to
fasted conditions. The mean fed/fasted ratio was 95% for AUC0 . Therefore, rilematovir can be
taken with or without food.
Bioavailability of the Rilematovir Oral Suspension
The interim PK results from Study 53718678RSV1007 Part 6, which is at the final analysis stage,
demonstrated similar bioavailability of the oral suspension reconstituted from powder and solvent
(formulation to be used for this study) compared to the oral solution formulation, with a relative
bioavailability of ~110% (Cmax) and ~99% (AUC) under fasted conditions and a relative
bioavailability of ~57% (Cmax) and ~100% (AUC) under fed conditions.
Metabolite Profile
Results from the mass-balance Study 53718678RSV1008 demonstrated that rilematovir was the
major circulating entity in plasma (44% to 47%), with M12 and M37 being the most abundant
metabolites at 17-22% and 9.73% of AUC0 96h of total radioactivity (TR), respectively; M19, M5,
and glucuronide metabolites (M8 and M9) represented 5%, 4%, and 1% (each), respectively. Most
of TR was recovered in feces (71%) and urine (20%), with unchanged drug representing 10% to
16% and 1%, respectively. The most important fecal metabolites were primary oxidative
metabolites, and in urine, a multitude of minor metabolites were present. The overall comparison
of duodenal fluid and feces profiles demonstrated almost complete conversion of the glucuronides
to their aglycon; there was overall a good qualitative and quantitative correlation between both
profiles.
When the abundance of rilematovir and its metabolites was determined in plasma of healthy
volunteers in Study 53718678RSV1001, similar results were obtained: Rilematovir was the main


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circulating entity; M12 represented more than 10% of total drug related material (TDRM), and
M37 represented 9.79%.
Drug-Drug Interaction
In clinical Study 53718678RSV1002, coadministration of rilematovir and a drug cocktail
consisting of CYP enzyme probe drugs (for CYP3A4, CYP1A2, and CYP2C9) and a non-selective
P-gp substrate (fexofenadine) suggested that, after single- and multiple-dose administration,
rilematovir is a weak inhibitor and a weak inducer of CYP3A4. Rilematovir had no clinically
significant effect on CYP2C9 and CYP1A2. Single and multiple doses of rilematovir reduced the
plasma exposure of fexofenadine. The observed decrease in exposure of fexofenadine after
coadministration of a single dose of rilematovir is due to the inhibition of OATP1A2, an uptake
transporter located in the gut; further reduction of the fexofenadine exposure after repeated dosing
of rilematovir, was likely due to induction of P-gp.
In clinical Study 53718678RSV1006, rilematovir was coadministered with itraconazole (a strong
CYP3A4 and P-gp inhibitor) and with rifampicin (an inducer of CYP3A4, glucuronyl transferase
[UGT], and P-gp, and an inhibitor of OATP). AUC0  of rilematovir increased approximately
3-fold upon coadministration with itraconazole 200 mg qd. After coadministration of rilematovir
with a single dose of rifampicin, no significant change in the total exposure of rilematovir was
observed, suggesting the OATP transporter is not involved in the disposition of rilematovir.
However, repeated administration of rifampicin 600 mg qd decreased the exposure of rilematovir,
primarily due to induction of CYP3A4.
Efficacy
Adult Population
In the challenge Study 53718678RSV2001 in healthy adult participants inoculated with RSV-A
Memphis 37b virus, mean and median RSV viral load AUC from baseline until discharge were
lower for all rilematovir dosing groups (75 mg qd, 200 mg qd, or 500 mg qd rilematovir for 7 days)
as compared to the placebo group, with a large variability observed in each of the rilematovir
dosing groups as well as in the placebo group. No clear dose-response relationship was observed.
This was paralleled with lower clinical symptom scores and mucus production for the rilematovir
dosing groups as compared to the placebo group. Hence, antiviral proof-of-concept for rilematovir
has been established.
In the interim analysis (data cut-off 23 September 2019, N 67) of pilot Phase 2a
Study 53718678RSV2004 in adult non-hospitalized RSV-infected participants, no clear effect of
rilematovir 80 mg and 500 mg versus placebo was observed on RSV viral load over time in both
mean nasal RSV RNA viral load AUC and change from baseline analyses. From Day 2 through
Day 8, however, the proportion of participants with undetectable RSV RNA viral load was higher
in the rilematovir 500 mg group compared to the rilematovir 80 mg group and placebo. At Day 8
(end of treatment phase), 81.3% of participants in the rilematovir 500 mg group had undetectable
RSV RNA by quantitative reverse transcription polymerase chain reaction (qRT-PCR), compared


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to 42.1% and 47.4% in the rilematovir 80 mg and placebo groups, respectively. The time to first
confirmed undetectable nasal RSV RNA was favorable for the rilematovir 500 mg group; the
median Kaplan-Meier (KM) estimate was 6 days in the rilematovir 500 mg group, 8 days in the
rilematovir 80 mg group, and 8 days in the placebo group. A similar trend was observed in the
subgroup of participants with ≤3 days from symptom onset. Data from this study showed a
favorable trend on the time to resolution of Key RSV Signs/Symptoms in the rilematovir treatment
groups as compared to placebo, especially in the subgroup of participants with ≤3 days since
symptom onset.
Pediatric Population
Study 53718678RSV1005
In Study 53718678RSV1005 in pediatric participants hospitalized due to RSV infection, a trend
towards an early antiviral effect of rilematovir was observed, despite a limited data set particularly
in the placebo arm. An effect on viral load change from baseline on Days 2 and 3, of 1 to 2 logs
difference compared to placebo was observed, as well as an effect on viral load AUC from baseline
through Days 3 and 7 (20 to 25% reduction compared to placebo). The exploration of the effects
on the clinical course of RSV infection did not reveal a difference between participants who had
received rilematovir and those who had received placebo in this limited dataset. No dose-response
relationship was observed across the rilematovir dose levels.
Study 53718678RSV2002
In the interim analysis (data cut-off 02 January 2020) of the ongoing Study 53718678RSV2002 in
pediatric participants hospitalized (Cohort 1) and non-hospitalized (Cohort 2) with RSV infection,
149 participants were evaluable for efficacy analysis (111 participants in Cohort 1 and
38 participants in Cohort 2). In Cohorts 1 and 2 combined, in Cohort 1, and in the subgroup of
participants with ≤3 days since symptom onset, a trend towards a favorable antiviral effect of
rilematovir was observed for both the rilematovir low dose and the high dose groups compared to
placebo.
In Cohort 1 (hospitalized participants), the mean nasal RSV viral load AUC through Day 5 was
lower for the rilematovir low dose and high dose groups than for placebo, with a difference
(95% CI) versus placebo of -1.46 (-3.360; 0.449) and -1.60 (-3.494; 0.288) log10 copies.day/mL,
respectively. For the subgroup of participants with ≤3 days since symptom onset, the difference in
mean viral load AUC through Day 5 for the rilematovir low dose and high dose groups versus
placebo was -3.22 (-6.106; -0.327) and -1.82 (-4.758; 1.109) log10 copies.day/mL, respectively.
In Cohort 1 and in the subgroup of participants with ≤3 days since symptom onset, a greater mean
change from baseline in nasal RSV viral load was observed for the rilematovir low dose and high
dose groups than for placebo.
In Cohort 1, the median (95% CI) time to first confirmed undetectable nasal RSV viral load based
on KM analysis was 10.9 (7.05; 12.90) days and 7.8 (6.00; 9.83) days in the rilematovir low dose


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and high dose groups, respectively, compared to 13.8 (8.99; 17.73) days in the placebo group. In
the subgroup of participants with ≤3 days since symptom onset, the median time to first confirmed
undetectable nasal RSV viral load was 12.7 (8.50; 13.88) days and 9.4 (6.65; 18.97) days in the
rilematovir low dose and high dose groups, respectively, compared to 13.4 (7.74; 13.95) days in
the placebo group.
Conclusions on the clinical course endpoints are given for Cohort 1 and for the subgroup of
participants with ≤3 days since symptom onset. In Cohort 1, a clinically relevant benefit was
observed for several clinical course endpoints and this benefit was greater in the subgroup of
participants with ≤3 days since symptom onset, supporting further study of that subgroup in the
Phase 3 studies.
- Mean (SD) decreases in Overall RSV severity score based on Pediatric RSV Electronic
Severity and Outcome Rating Systems (PRESORS)Observer Reported Outcome (ObsRO)
Signs/Symptoms were greater in the rilematovir high dose group as of Day 3 through
Day 21 compared to the rilematovir low dose and the placebo groups. A similar pattern
was present in the ≤3 days since symptom onset subgroup. The same was observed for the
Key RSV Signs/Symptoms score.
- The median (95% CI) KM time to resolution of all RSV signs/symptoms based on ObsRO
Signs/Symptoms was shorter in the rilematovir low and high dose groups compared to
placebo (6.00 [4.29; 9.18], 6.85 [5.29; 10.79] and 8.32 [6.74; 10.85] days, respectively).
Similarly, this was observed for the Key RSV Signs/Symptoms (4.63 [3.94; 6.86] and
6.31 [3.92; 8.37] days in the rilematovir low and high dose treatment groups and
7.91 [5.15; 9.92] days in the placebo group) and in the ≤3 days since symptom onset
subgroup (6.63 [2.12; 9.70 and 4.93 [3.80; 9.81] versus 9.29[6.93; 12.18]).
- No relevant differences in time to hospital discharge between treatment groups were
observed in Cohort 1. In the subgroup with symptom onset ≤3 days, KM median (95% CI)
time to hospital discharge was approximately 3 days and 1 day shorter in the rilematovir
high dose and low dose groups (3.77 [2.00; 7.67] and 5.69 [2.95; 6.03] days, respectively)
compared to the placebo group (6.79 [1.97; 7.11] days).
- No relevant differences in time to investigator-defined clinical stability between treatment
groups were observed in Cohort 1, whereas for the subgroup with symptom onset ≤3 days,
there was approximately 1 day difference between the rilematovir high dose group and the
placebo group (4.46 [2.97; 6.75] days, 3.96 [1.83; 7.86] days for the rilematovir low and
high dose groups versus 5.09 [2.95; 7.81] for the placebo group).
- The median (95% CI) time to end of supplemental oxygen based on KM analysis in
Cohort 1 was 2.49 (1.47; 4.91)days and 2.65 (1.54; 3.95)days in the rilematovir low dose
and high dose groups, respectively, compared to 2.57 (0.90; 3.16) days in the placebo
group. In the subgroup with symptom onset ≤3 days, that time was approximately 1 day
shorter in the rilematovir high dose group as compared to placebo (3.61 [1.69; 5.63] days


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and 2.80 [1.21; 5.65] days in the rilematovir low dose and high dose groups, respectively,
versus 3.79[1.40; 7.62] days in the placebo group).
- The median time to peripheral capillary oxygen saturation (SpO2)≥92% or ≥95% on room
air was similar across treatment groups in Cohort 1 as well as in the subgroup with
symptom onset ≤3 days. However, SpO2 was not measured at room air during oxygen
supplementation.
- In Cohort 1, the median (95% CI) time to protocol-defined clinical stability considering
SpO2 ≥92% or ≥95% based on KM analysis was longer in the rilematovir low dose and
high dose groups compared to the placebo group (5.09 [2.17; 6.89] days and
6.69[3.00; 10.31] days in the rilematovir low dose and high dose groups, respectively,
compared to 3.54 [2.32; 6.43] days in the placebo group). However, in the subgroup with
symptom onset ≤3 days, that time to clinical stability was approximately 1.5 days shorter
in the active treatment groups than in the placebo group (5.26 [1.92; 8.20] days and
5.32 [1.83; 10.78] days in the rilematovir low dose and high dose groups versus 6.84 [3.92;
28.90] days in the placebo group).
- Few participants in Cohort 1 were admitted to the ICU post-baseline (2, 1, versus 1 in the
low and high rilematovir dose groups and placebo, respectively). The 1 participant in the
high dose group was in the subgroup with symptom onset ≤3 days.
- Investigator-determined RSV-related complications, derived from the adverse event (AE)
reports, were reported for 8/36 of participants in the rilematovir low dose group, 12/37 of
participants in the rilematovir high dose group, and 11/38 of participants in the placebo
group. Most complications were of respiratory nature. Complications of Grade 3 to 4 were
reported in 3, 1, and 4 participants in the rilematovir low and high dose and in the placebo
group, respectively. In the subgroup with symptom onset ≤3 days, complications were
reported for 2/17 participants in the rilematovir low dose group, 5/16 participants in the
rilematovir high dose group, and 5/18 participants in the placebo group. Complications of
Grade 3 to 4 were reported in 0, 1, and 3 participants in the rilematovir low and high dose
and in the placebo groups, respectively. No Grade 4 RSV-related complications were
reported.
- The ordinal RSV Recovery Scale (RRS)provides 7 mutually exclusive conditions ordered
from best (home without symptoms based on the ObsRO  Signs/Symptoms) to worst
(death), and the score reflects the participant’s worst status on the day of assessment. The
first day on which 50% of participants was in either of the 2 home categories was on Day 6,
considering all participants in the rilematovir high dose and the placebo groups. The
observed common odds ratio was 0.38 (0.11; 1.33) including all participants, and 0.58
(0.16; 2.11) excluding participants in the ICU at Day 1 before first dosing. The odds for a
better clinical outcome are 62% to 42% lower under placebo than under rilematovir.
- The proportion of participants resolved defined as not needing either oxygen  or
feeding/hydration supplementation, not requiring ICU, and Key RSV Signs/Symptoms


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(based on ClinRO Signs/Symptoms) resolved (absent or mild) was analyzed over time. As
of Day 4, the proportion of participants resolved was greater in both the low and high
rilematovir dose groups than in the placebo group and greatest in the rilematovir high dose
group. At Day 6 (the same day at which the RRS was evaluated), the proportion of
participants resolved was 47.1% (8/17)and 62.5% (10/16)in the rilematovir low dose and
high dose groups, respectively, compared to 33.3% (6/18)in the placebo group. Using the
modified imputation rule, the proportion of participants resolved at Day 6 was 35.3% (6/17)
and 56.3% (9/16)in the rilematovir low dose and high dose groups, respectively, compared
to 33.3% (6/18)in the placebo group.
- For the time to resolution taking into account resolution of Key RSV Signs/Symptoms
(based on ObsRO  Signs/Symptoms) (using an alternative definition of “resolved” in
combination with 24 hours supplementation-free), the KM medians demonstrated a
reduction of 40% for the rilematovir high dose versus placebo group (6.48 [4.00; 11.84]
days compared to 10.83 [7.12; 13.93] days, respectively).
- The time to resolution of Key RSV Signs/Symptoms (based on ObsRO Signs/Symptoms)
after discharge was 3 days shorter for the rilematovir high dose group compared to the
placebo group (0.92 [0.51; 2.72] days compared to 4.16 [0.91; 6.78] days, respectively).
- The time to resolution of Key RSV Signs/Symptoms including supplementation-free for
12 hours based on ClinRO Signs/Symptoms was similar for the rilematovir high dose and
placebo groups (6.60 [2.67; -] days and 6.85 [3.79; 12.86] days, respectively).
- No difference was observed in the time to end of oxygen supplementation up to 72 hours
from first discharge (2.80 [1.21; 5.65] days in the rilematovir high dose group compared to
3.10 [0.98; 5.62] days in the placebo group).
- The time to end of supplementation (oxygen and feeding/hydration) up to 72 hours from
first discharge was 1 day shorter for the rilematovir high dose group compared to the
placebo group (2.80 [1.21; 6.00] days compared to 4.04 [2.32; 6.02] days, respectively).
Safety and Tolerability
Adult Population
Phase 1 Safety Pooling
For the purpose of reviewing the available clinical safety data from adult healthy volunteers, data
from Phase 1 studies 64417184RSV1003, 53718678RSV1001, 53718678RSV1002,
53718678RSV1004, 
53718678RSV1006, 
53718678RSV1007, 
53718678RSV1008, 
and
53718678RSV1009 were pooled at the time of the cut-off for the IB Ed 7.26 Overall, during these
clinical studies, single doses up to 1,000 mg rilematovir and multiple doses up to 500 mg
rilematovir qd and 250 mg rilematovir bid were generally safe and well tolerated. These studies
did not identify any safety signal for rilematovir. No deaths or other serious adverse events (SAEs)
were reported.


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Among participants who received multiple doses of rilematovir alone, 52.9% experienced a TEAE
as compared to 66.7% of all participants who received placebo. All the treatment-emergent AEs
(TEAEs) reported during these studies were either Grade 1 or Grade 2 in severity. Treatment-
emergent AEs reported more frequently (difference in incidence of ≥10% in the all rilematovir
alone + with interacting drug group) in participants who had received at least 1 dose of rilematovir
compared to participants who received placebo included fatigue, headache, and hot flush.
Based on exposure-response analysis in Study 53718678RSV1009, an important potential risk of
QT interval prolongation was identified for rilematovir. For more details on the analysis, refer to
the IB.26 A change to a bid dosing regimen (see Section 4.3) and several other mitigation measures
to safeguard the participants (see Section 2.3.3) have been implemented.
Study 53718678RSV2001
Study 53718678RSV2001 evaluated the antiviral activity, safety, and PK of rilematovir against
RSV infection in the RSV challenge model in healthy adult participants. Overall, the oral solution
formulation was generally safe and well tolerated. No SAEs or deaths were reported during the
study. No TEAEs with severity Grade 3 or higher were observed during the treatment phase.
During follow-up, 1 participant in the placebo group was reported with a Grade 3 increased lipase,
which was reported as an AE. Three participants permanently discontinued the study due to a
TEAE: 2 participants were reported with an ECG change (one Grade 2 AE [abnormally high QRS
duration, QRS 126 msec] in the 75 mg rilematovir group and one Grade 1 AE [no specific
change] in the 200 mg rilematovir group) and 1 participant (placebo group) was reported with a
Grade 2 AE urticaria.
Eight (53.3%) participants in the 75 mg rilematovir group, 13 (76.5%) participants in the 200 mg
rilematovir group, 13 (72.2%) participants in the 500 mg rilematovir group, and 9(56.3%)
participants in the placebo group were reported with at least one TEAE during the treatment phase,
which were all either Grade 1 or Grade 2 in severity. The most frequently reported TEAEs
(>2 participants in any treatment group) during the treatment phase were diarrhea, increased blood
cholesterol, increased low-density lipoprotein, and epistaxis. For diarrhea there was a trend for
dose-relationship. However, it was also observed in the placebo-treated group and was considered
related to the amount of 2-hydroxypropyl-beta-cyclodextrin (HP-β-CD) (the rilematovir and
placebo oral solution contains 30% HP-β-CD as excipient) administered, which is a known
emollient and has been correlated with increased incidences of diarrhea as main AE.
ECG abnormalities were infrequently reported, and results were generally consistent with those
observed in the pooled Phase 1 studies. Graded and non-graded laboratory abnormalities were
generally consistent with those observed in the pooled Phase 1 dataset.
Altogether, rilematovir was generally safe and well tolerated. No relation was noted between the
incidence of AEs and the dose level and/or the dose regimen of rilematovir. No safety signal was
identified.


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Study 53718678RSV2004
Interim analysis results (data cut-off 23 September 2019, N 67) from Study 53718678RSV2004
demonstrated that rilematovir was generally safe and well tolerated in RSV-infected non-
hospitalized adults. No new safety signal was identified.
There were no deaths, no treatment-emergent SAEs, and no AEs of severity Grade 3 or 4 in the
study. Overall, 55.6% of participants experienced at least 1 TEAE, of which diarrhea was the most
frequently reported TEAE. The overall incidence of TEAEs was smaller in the rilematovir 500 mg
group (36.4%) than in the placebo group (59.1%). The highest incidence rate of TEAEs was
observed in rilematovir 80 mg group (73.9%). The incidence of TEAEs leading to study
medication discontinuation was higher in rilematovir 500 mg group (13.6%) than in rilematovir
80 mg group (8.7%), or the placebo group (4.5%). There were 2 participants (in rilematovir
500 mg group) with AE (diarrhoea) leading to permanent study discontinuation. ECG
abnormalities were infrequently reported. No cardiac safety signal was identified. Graded and non-
graded laboratory abnormalities and vital signs observations were generally consistent with those
observed in the pooled Phase 1 dataset.
Pediatric Population
Overall, treatment with rilematovir was generally safe and well tolerated in pediatric participants
and no safety signals arose in pediatric participants compared to the previously established safety
profile in adults.
Study 53718678RSV1005
In Study 53718678RSV1005 in hospitalized pediatric participants receiving the oral solution
formulation, no deaths, Grade 4 AEs, or AEs leading to study discontinuation or permanent
discontinuation of study intervention were reported. Four SAEs were reported, 2 in the rilematovir
(combined) treatment group (rhinitis and bronchiolitis) and 2 in the placebo group (pneumonia and
bronchiolitis). These were reported as serious because of rehospitalization and were considered by
the investigator to be not related to the study intervention. The majority of participants were
reported with at least 1 AE, at similar incidence rates in both treatment arms (28/37 participants
[75.7%] in the rilematovir [combined) treatment group vs 6/7 participants [85.7%] in the placebo
group, respectively). Most of the reported AEs were Grade 1 or Grade 2 in severity. Two Grade 3
(severe) AEs were reported (both bronchiolitis; 1 each in the rilematovir [combined] and placebo
group, both were also reported as SAEs). By dictionary-derived term, most frequently reported
AEs in participants treated with rilematovir (reported in ≥10% of participants) were vomiting,
URTI, and feces soft.
Treatment-emergent laboratory abnormalities were infrequently reported and of low severity
(maximal Grade 2). None were observed more frequently (difference in incidence of ≥5%) in the
rilematovir (combined) group compared to the placebo group.


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No clinically relevant differences in incidence rates of vital signs abnormalities were observed
between rilematovir and placebo. ECG abnormalities were scarce and generally not considered
clinically relevant. No dose-relationship was observed for the AEs, or abnormalities in laboratory
or ECG parameters or in vital signs.
Overall, treatment with rilematovir was generally safe and well tolerated and no new safety signals
arose compared to the overall safety profile in adults.
Study 53718678RSV2002
In the interim analysis (data cut-off 02 January 2020) of the ongoing Study 53718678RSV2002 in
pediatric participants hospitalized (Cohort 1) and non-hospitalized (Cohort 2) with RSV infection,
no deaths, Grade 4 AEs, or AEs leading to premature termination of study medication or study
participation were reported. Emergent SAEs were reported in 9.6% (5/52) of participants in the
rilematovir low dose group, 3.8% (2/52) in the rilematovir high dose group, and 9.8% (5/51) in the
placebo group, of which most were Grade 3 in severity. None of these SAEs were considered
related to study treatment by the investigator and all participants recovered from their SAE within
the study period. The majority of participants (approximately 65%) in all treatment groups were
reported with at least 1 emergent AE (EAE). Most of the EAEs (>55%) were reported as Grade 1
or 2 (mild to moderate in severity) in all treatment groups. Grade 3 (severe) EAEs were reported
for 11.5% (6/52) of participants in the rilematovir low dose group, 3.8% (2/52) in the rilematovir
high dose group, and 7.8% (4/51) in the placebo group. None of these Grade 3 EAEs were
considered at least possibly related to study treatment by the investigator.
By system organ class, the most frequently (>10% in any treatment group) reported EAEs were
infections and infestations; respiratory, thoracic and mediastinal disorders; skin and subcutaneous
disorders; gastrointestinal disorders; and blood and lymphatic system disorders. By preferred term,
the most frequently reported EAEs (>5.0% in any treatment group) were nasopharyngitis, URTI,
dermatitis diaper, rash, diarrhea, vomiting, faeces soft, thrombocytosis, and pyrexia.
Emergent AEs that were considered to be at least possibly related to the study medication by the
investigator were reported for 5.8% (3/52) of participants in the rilematovir low dose group
(diarrhea, vomiting, and gastroenteritis in one participant each), 3.8% (2/52) of participants in the
rilematovir high dose group (diarrhea and urticaria in one participant each), and 11.8% (6/51)
ofparticipants in the placebo group (diarrhea and feces soft in one participant; diarrhea in
2 participants; feces soft, rash, and transaminases increased in one participant each). All these
EAEs were Grade 1, except for one EAE which was Grade 2 diarrhea in one placebo participant.
Treatment-emergent laboratory abnormalities were infrequently reported of which most were
Grade 1 or 2. No relevant differences were seen between the rilematovir treatment groups and the
placebo group. The incidences of graded abnormalities for alanine transaminase (ALT), aspartate
aminotransferase (AST), and bilirubin as well as for activated partial thromboplastin time (aPTT)
and prothrombin time (PT) were low (ie, reported for at most 1 participant in any rilematovir
treatment group).
No clinically relevant differences in incidence rates of vital signs abnormalities were observed
between rilematovir and placebo. ECG abnormalities were scarce and generally not considered


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clinically relevant. No changes from baseline in QTcF or QT interval corrected for heart rate
according to Bazett’s formula (QTcB) of >60 msec were reported. No relevant differences between
the rilematovir treatment groups and the placebo group were seen for the changes from baseline in
QTcF or QTcB intervals.
Overall, treatment with rilematovir was generally safe and well tolerated. Overall, no dose-
relationship was observed for the AEs, or abnormalities in laboratory or ECG parameters or in
vital signs. No new safety signals arose compared to the previously established safety profile.
2.3. 
Benefit-Risk Assessment
More detailed information about the known and expected benefits and risks of rilematovir may be
found in the IB.26
2.3.1. 
Risks for Study Participation
2.3.1.1. 
Known Risks
No formal adverse drug reaction analysis has yet been conducted for rilematovir. No adverse drug
reactions or known risks associated with rilematovir have been identified.
2.3.1.2. 
Potential Risks
All therapies have the potential to cause adverse drug reactions.
At the time of protocol writing, a total of 345 adult and 192 pediatric participants received at least
1 dose of rilematovir. Of the 345 adult participants, 251 received at least 1 dose of rilematovir
500 mg. In total, approximately 92 pediatric participants received multiple 500 mg adult dose
equivalents.
Please refer to Section 2.2 for details on the reported AEs and laboratory/ECG abnormalities in
the studies conducted to date.
Based upon the available clinical data, no risk related to the hepatobiliary system was identified.
However, given the hepatobiliary-related nonclinical findings and because the amount of clinical
data is limited, the sponsor considers hepatobiliary effects to be a safety topic of special interest
and hepatobiliary function will be monitored by routine hepatobiliary function tests during clinical
studies.
Review of data of the TQT Study 53718678RSV1009, has identified a new important potential
risk of QT prolongation for rilematovir (see Section 2.2 and the IB26 for more information).
Therefore, a change in dose regimen (see Section 4.3) and several other measures to safeguard the
participants (see Section 2.3.3) have been implemented.
Overall, the oral suspension formulation used in Part 1 and 2 of the TQT study was generally safe
and well tolerated in these healthy adult participants. Most AEs were mild, with diarrhea being the
most frequently reported AE. No Grade 3 or 4 AEs were reported during this study. From a clinical
safety perspective, no clinically relevant ECG abnormalities (related to QTcF or other) or


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cardiovascular AEs were observed in this study. However, exposure-response analysis based on
time-matched QTc Holter data demonstrated that, following a single dose of 500 mg, the effect of
rilematovir on cardiac repolarization is not of regulatory concern,25 but at doses 1,000 mg an
increase of placebo-corrected change from baseline for the individual-corrected QT interval
(ΔΔQTcI) above the threshold of 10 msec can be expected (Section 2.2).
Available clinical safety data do not indicate any safety signal or concern with regards to the
cardiovascular system (Section 2.2).
Study procedures such as blood sampling carry a potential risk (eg, pain, discomfort, hematoma)
to the participant. Therefore, minimal volumes of blood (by venipuncture or by finger or heel prick
with capillary blood collection) for both safety and PK assessments will be sampled only at
carefully selected timepoints. Investigators may use local anesthetics prior to sampling.
The evaluation of rilematovir antiviral activity and sequencing requires nasal MT swabbing.
However, this is a minimally invasive assessment that at most results in  some short-term
discomfort for the participant and is usually well tolerated, though occasionally nose bleeding can
occur. Examples of other AEs that may occur, but are not considered serious, are: coughing,
gagging, nausea, and vomiting.
Investigational staff should take the customary measures to ensure that study-specific assessments
such as blood sampling or nasal swabbing are performed with as little additional stress as possible
for the participant. Investigators may use local anesthetics prior to blood sampling.
2.3.2. 
Benefits for Study Participation
2.3.2.1. 
Known Benefits
Proof-of-concept antiviral effect was established in adult healthy volunteers challenged with a
laboratory strain of RSV (Study 53718678RSV2001)(Section 2.2).
Despite a limited data set, particularly in the placebo arm, a trend towards an early antiviral effect
of rilematovir was observed in the pediatric population based on data from
Study 53718678RSV1005 (Section 2.2).
In the ongoing pediatric Study 53718678RSV2002, the interim analysis (data cut-off
02 January 2020) data demonstrated a trend towards an antiviral effect of rilematovir in children
≥28 days and ≤3 years of age with RSV disease compared to placebo, with more pronounced
effects in the subgroup with symptom onset ≤3 days compared to the subgroup with symptom
onset >3-5 days.
In the adult Study 53718678RSV2004, the interim analysis (data cut-off 23 September 2019) data
demonstrated positive trends for time to first confirmed RSV undetectability  for rilematovir
compared to placebo. Effects appeared greater in the subgroup of participants with symptom onset
≤3 days compared to the subgroup with symptom onset >3-5 days.


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However, the clinical benefit of this compound remains to be established.
2.3.2.2. 
Potential Benefits
Participants participating in this study may benefit through improvement of the clinical course of
their RSV infection. Treatment with rilematovir could reduce the severity and duration of RSV
signs/symptoms, and their impact on functioning, reduce the effect of RSV infection on
physiologic parameters, prevent progression to more severe disease status, reduce the need for and
duration of supportive care (eg, oxygen supplementation, intravenous (IV) fluids/feeding, days of
hospitalization), and accelerate the participant’s return to pre-RSV health status.
Study intervention will be provided in addition to, not in replacement of, standard-of-care (SOC)
supportive and symptomatic therapy.
In the ongoing pediatric Study 53718678RSV2002, the interim analysis data demonstrated a trend
towards an improvement in the clinical course of RSV disease in children ≥28 days and ≤3 years
of age with RSV disease of rilematovir compared to placebo, with more pronounced effects in the
subgroup with symptom onset ≤3 days compared to the subgroup with symptom onset >3-5 days.
In the adult Study 53718678RSV2004, the interim analysis data demonstrated a positive trend for
time to symptom resolution of Key RSV Signs/Symptoms for rilematovir compared to placebo.
Effects appeared greater in the subgroup ofparticipants with symptom onset ≤3 days compared to
the subgroup with symptom onset >3-5 days.
The unequal randomization (2:1 active: placebo in each age group) affords the majority of
participants the potential benefit of rilematovir treatment.
2.3.3. 
Benefit-Risk Assessment for Study Participation
Currently only limited options are available for the treatment of RSV infection (see Section 2.1).
Based on the available data and proposed safety measures, the overall benefit-risk balance for
participation in this study is considered favorable because:
 
Antiviral effect proof-of-concept was established in adult healthy volunteers challenged with
a laboratory strain of RSV (Study 53718678RSV2001), in non-hospitalized adult participants
infected with RSV (interim analysis of Study 53718678RSV2004), as well as in RSV-infected
pediatric participants (Study 53718678RSV1005) (Section 2.2).
 
Data from an interim analysis of Study 53718678RSV2002 in RSV-infected pediatric
participants showed benefits for clinical course outcomes and antiviral effects, particularly in
the subgroup of participants with symptom onset ≤3 days, as planned for enrollment in this
study (Section 2.2).
 
No safety concerns were identified in completed studies in adult healthy volunteers to date
and most observed AEs and laboratory abnormalities were mild to moderate in severity and
considered not related to rilematovir by the investigator (Section 2.2);
 
No safety concerns were identified in the interim analysis of Study 53718678RSV2004 in
non-hospitalized adult participants infected with RSV (Section 2.2);


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 
No safety concerns were identified in  studies in RSV-infected pediatric participants
(Study 53718678RSV1005 in children >1 month to ≤24 months of age and from an interim
analysis of Study 53718678RSV2002 in children ≥28 days and ≤3 years of age)(Section 2.2);
 
Several safety measures have been proposed to minimize potential risk to participants,
including:
 
Only participants who meet all of the inclusion criteria and none of the exclusion criteria
(as specified in the protocol, Sections 5.1 and 5.2) will be allowed to participate in the
study. The selection criteria include adequate provisions to minimize the risk and protect
the well-being of the participants in the study.
 
Neonates will only be enrolled in the main study after recommendation from the
independent data monitoring committee (IDMC) based on results from a substudy in
neonates.
 
Utilization of study intervention discontinuation criteria and study stopping criteria
(see Sections 7.1 and 7.2).
 
Participants are to be hospitalized before treatment initiation, allowing for intensive
monitoring of participants at the beginning of the study until discharge. After discharge
from the hospital and for the remainder of the study period, a close follow-up (see
Schedule of Activities) is planned with on-site visits on Day 3, Day 5, Day 8, Day 14,
Day 21, and a phone follow-up/conditional on-site visit on Day 35, when the participant
completes the study.
 
Safety surveillance in this study will monitor standard safety parameters associated with
investigational drug development (see Section 8.2) and safety topics of special interest of
rilematovir (see Section 8.3.5) as part of the study assessments.
 
Safety surveillance will be performed in a manner that minimizes the total number of
required invasive procedures (eg, blood draws) to minimize discomfort to study
participants.
 
Utilization of results from diagnostic testing (swab) performed as part ofSOC.
 
The establishment of an IDMC (see Section 9.6) to monitor data on a regular basis to
ensure continuing safety of the participants enrolled in the study.
 
Customary measures taken by investigational staff to ensure that study-specific
assessments such as blood sampling and nasal swabbing are performed with as little
additional stress as possible for the participant and allowance of the use of local
anesthetics prior to blood sampling.
 
In view of the identified important potential risk of QT interval prolongation (see Section 2.2,
TQT Study 53718678RSV1009), the following measures have been implemented to minimize
the potential risk to participants:
 
The selection of the bid dose regimens which, relative to the respective qd dose regimens
for which no safety concern was identified, will minimize Cmax  while still maintaining
AUC and increasing Ctrough  (see Section 4.3).
 
Specific cardiovascular and ECG-based criteria were established for eligibility
assessment (see Section 5.1 and 5.2).


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Close monitoring of the use of concomitant medications will be conducted regularly.
Drugs that are moderate or strong CYP3A4 inhibitors and/or BCRP inhibitors will be
disallowed (see Section 6.8).
 
Regular ECG monitoring will be performed at screening and several timepoints during
the study, including an ECG around tmax on Day 1 and Day 3 (steady state).
 
Evaluation of clinical status, AEs, vital signs, physical examination as well as laboratory
parameters will be conducted as per the Schedule of Activities. Additional unscheduled
visits may be performed based on the overall clinical picture as per the investigator’s
clinical discretion.
 
Utilization of study intervention discontinuation and withdrawal criteria specific to QT
interval changes (see Section 7.1).
 
Rapid correction of any hypokalemia and/or hypomagnesemia during treatment period,
and check  by the investigator of the use of concomitant QT prolonging drugs (see
Section 8.3.5.2).
 
Specific toxicity management for cardiac and ECG related events was established (see
Section 8.3.5.2).
Considering the measures taken to minimize risk to participants of this study, the potential risks
identified in association with  participation in this study and rilematovir are justified by the
anticipated benefits that may be afforded to participants infected with RSV.


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3. 
OBJECTIVES AND ENDPOINTS
Objectives 
Endpoints
Primary
 
To evaluate the superiority of 
rilematovir compared to placebo 
treatment with respect to the clinical 
outcome on the RRS. 
 
RRSa as assessed on the first study day when at least
50% of the participants across treatment arms are
discharged from the hospital (the study day for the
RRS evaluation will be determined based on blinded
data at the first interim analysis by an independent
statistician).
Secondary
 
To evaluate the superiority of
rilematovir compared to placebo
treatment with respect to clinical
resolution of RSV disease.
 
Proportion of participants clinically resolved from
RSV disease based on ClinRO Signs/Symptomsc,e as
assessed on the same study day as the primary
endpoint.
 
To evaluate the superiority of
rilematovir compared to placebo
treatment with  respect to the time
from first dosing to resolution of Key
RSV 
Signs/Symptomsb 
including
supplementation free.
 
Time from first study dose to resolution of Key RSV
Signs/Symptoms (absent or mild)d,e based on
parent’s/caregiver’s ObsRO  Signs/Symptoms and
supplementation free (oxygen and feeding/hydration)
for at least 24 hours.
 
To evaluate the superiority of
rilematovir compared to placebo
treatment with respect to the time
from discharge to resolution of Key
RSV Signs/Symptoms.
 
Time from discharge to resolution of Key RSV
Signs/Symptomsd,e based on ObsRO Signs/Symptoms
(only including participants who did not reach
resolution before first discharge).
 
To evaluate the superiority of
rilematovir compared to placebo
treatment with respect to the time
from first dosing to end of oxygen
supplementation.
 
Time from first dosing to end of oxygen
supplementation (only including participants who
were receiving oxygen supplementation at the time of
first dosing).
 
To evaluate the superiority of
rilematovir compared to placebo
treatment 
with 
respect 
to 
the
incidence of post-baseline RSV-
related complications.
 
Incidence 
in 
post-baseline 
RSV-related
complications.
 
To evaluate the safety and tolerability
of rilematovir.
 
Safety and tolerability, as assessed by AEs, clinical
laboratory testing, ECGs, vital signs throughout the
study.
 
To evaluate the effect of rilematovir
on the clinical course of RSV disease
as assessed electronically by ObsRO
Signs/Symptoms and ObsRO General
Health Questions (GHQ).
 
The following endpoints will be based on the ObsRO
Signs/Symptoms:
 time to resolution of signs/symptoms (absent or
mild)e of RSV disease;
 actual values and changes from baseline in scores.


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Objectives 
Endpoints
 
The following endpoint will be based on the ObsRO
GHQ:
 time to improvement.
 
To evaluate the effect of rilematovir 
on the clinical course of RSV disease 
as assessed electronically by ClinRO
Signs/Symptoms and ClinRO GHQ.
 
The following endpoints will be based on the ClinRO
Signs/Symptoms:
 time to resolution  of signs/symptoms (absent or
mild)e of RSV disease;
 actual values and changes from baseline in scores;
 proportion of participants clinically resolved from
RSV diseases based on ClinRO Signs/Symptomsc,e
as assessed each day from Day 2 to 8.
 
The following endpoint will be based on the ClinRO
GHQ:
 general impression of change.
 
To evaluate the effect of rilematovir 
on the clinical course of RSV disease 
(other than ClinRO and ObsRO
assessments).
 
RRSa as assessed each day separately from Days 2
to 8.
 
Time to hospital discharge from start of dosing.
 
Time to readiness for hospital discharge.
 
Proportion of participants requiring intensive care unit
(ICU) stay.
 
Duration of requiring ICU stay.
 
Proportion of participants requiring rehospitalization
for respiratory/other reasons.
 
Proportion 
of 
participants 
requiring 
oxygen
supplementation.
 
Duration of oxygen supplementation.
 
Time to end of supplemental feeding/hydration.
 
Proportion of participants requiring hydration and/or
feeding by intravenous (IV) administration or
nasogastric tube.
 
Duration of supplemental feeding/hydration.
 
Time to end of supplementation (oxygen and/or
feeding/hydration).
 
Number and type of medical encounters.
 
Incidence of antibiotic treatment episodes.
 
Incidence of systemic or inhaled corticosteroids and
bronchodilators use.
 
To evaluate the antiviral effect of 
rilematovir as measured by RSV viral 
 
RSV viral load (area under the RSV viral load-time
curve [AUC]) from immediately prior to first dose of


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Objectives 
Endpoints
load in nasal mid-turbinate (MT) 
swab samples by qRT-PCR assay. 
study intervention (baseline) through Day 3, Day 5,
and Day 8.
 
RSV viral load and change from baseline over time.
 
Proportion of participants with undetectable RSV
viral load at each time point of assessment throughout
the study.
 
To evaluate the emergence of 
mutations in the viral genome 
potentially associated with resistance
to rilematovir.
 
Sequence changes (post-baseline) in the RSV F gene
compared to baseline.
 
To evaluate the PK of rilematovir. 
 
PK parameters of rilematovir.
 
To explore the PK/pharmacodynamic 
(PD) relationships of rilematovir for 
efficacy and safety. 
 
PK/PD analysis of PK  of rilematovir and selected
primary and secondary efficacy and safety
parameters.
 
To evaluate the acceptability and 
palatability 
of 
the 
rilematovir 
formulation.
 
Acceptability and palatability of the rilematovir
formulation as assessed through a questionnaire.
Exploratory
 
To explore other effects of rilematovir 
on the clinical course of RSV disease. 
 
Time from first dosing to SpO2 ≥92% on room air
among participants who were not on  oxygen
supplementation  prior to the onset of respiratory
signs/symptoms.
 
Respiratory rate, heart/pulse rate, body temperature,
and SpO2 over time as measured by the investigator
(during scheduled visits).
 
Proportion of participants with signs/symptoms of
RSV disease at discharge according to last ClinRO
Signs/Symptoms evaluation prior to discharge.
 
The ClinRO Signs/Symptoms score for each
sign/symptom according to last evaluation prior to
discharge in those participants not resolved at
discharge.
 
To explore the effect of rilematovir on 
the impact of the child’s RSV disease 
on the parent(s)/caregiver(s) and
family  based on the PRESORS
Caregiver Impact Questions.
 
Extent of the parent’s/caregiver’s worry about the
child’s health.
 
Time missed from usual activities by the
parent/caregiver.
 
Time missed from work by anyone in child’s
household due to the child’s illness.
 
To explore the relationship between 
antiviral activity and the primary and 
key secondary clinical outcomes.
 
RSV viral load based endpoints and primary and key
secondary clinical course endpoints.


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Objectives 
Endpoints
 
To 
explore 
the evaluation 
of
biomarkers associated with RSV or
treatment effects (optional).
 
Specific biomarkers in leftover blood samples and
nasal MT swabs (optional).
a. 
For details on the RRS see Section 8.1.1.1.
b. 
Signs are defined as objective evidence of the disease, which are apparent to the physician during
examination (such as tachycardia, tachypnea, chest wall retractions, grunting, and nasal flaring). Symptoms
are defined as subjective manifestations of the diseases, reported by the participant or by the
parent(s)/caregiver(s), but not necessarily apparent to the physician during examination (such as rhinorrhea,
cough, feeding difficulties, disturbed sleep, and disturbed activity level). Throughout this protocol, the
notation “signs/symptoms” is used.
c. 
Clinical resolution is defined by: free of oxygen supplementation, AND free of supplemental feeding, AND
not requiring ICU, AND Key RSV Signs/Symptoms resolved to absent or mild as per the ClinRO
Signs/Symptoms (see also Section 8.1.1.2).e
d. 
Key RSV Signs/Symptoms are: Breathing problems, retractions, tachypnea, cough, wheezing (ClinRO
Signs/Symptoms only), breathing sounds (ObsRO Signs/Symptoms only), and tachycardia (see also
Section 8.1.1.3).
e. 
See Section 10.14, Appendix 14 and Section 10.15, Appendix 15 for definitions of resolved/not resolved.
f. 
See Section 8.1.1.2 for the list of complications assessed.
Refer to Section 8 for evaluations related to endpoints.
HYPOTHESIS
The primary hypothesis of this study is that treatment with rilematovir improves clinical outcome
of RSV infection as compared to placebo in hospitalized pediatric participants as assessed with the
RRS on the first study day when at least 50% of the participants across treatment arms are
discharged from the hospital.
4. 
STUDY DESIGN
4.1. 
Overall Design
This is a Phase 3, randomized, double-blind, placebo-controlled, multicenter, interventional study
in infants and children (≥28 days to ≤5 years of age) and subsequently in neonates (<28 days of
age), hospitalized (refers to having planned at least 24 hours with an overnight stay in the hospital)
with RSV infection. The substudy at specific sites will be initiated only after positive
recommendation by the IDMC upon review of interim analysis 1 results of the main study (see
also Sections 9.5 and 9.6). “Subsequently in neonates” refers to the main study being opened for
enrollment of neonates at all sites following completion of a prior substudy in neonates, IDMC
review of the substudy data, and positive recommendation. This protocol only describes the main
study. The specifics to the substudy will be described in a separate substudy protocol. Investigators
and relevant health authorities, ethics committees, and institutional review boards (IRBs) will be
informed in writing of the decision and the selected dosing regimen for neonates.
A target of 737 hospitalized RSV-infected participants will be randomized in a 2:1 ratio to receive
either rilematovir or placebo bid.
Study participants with signs/symptoms of an acute respiratory illness supporting a diagnosis of
RSV infection (see Table 1) will be identified and tested for RSV infection when they are


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hospitalized or present to the ER/clinic and are expected to be hospitalized. Participants should
only be screened if they are expected to be randomized within ≤3 days of RSV sign/symptom onset
(see RSV Symptom Onset to Randomization Calculator in Section 10.17, Appendix 17). During
screening, a nasal MT  swab will be collected for local diagnosis of RSV infection using a
molecular-based assay (PCR or other) and for additional post-hoc analysis at a central laboratory
to determine the RSV viral load (and subtype), and viral sequencing. A SOC sample that is
collected within 24 hours prior to screening start and results in an RSV positive diagnosis may
also be used to determine study eligibility. In such case, the collection of the study-specific nasal
MT swab at screening is not required (see also Figure 3).
Participants with RSV disease (ie, at least 1 sign/symptom of URTI, at least 1 sign/symptom of
LRTI, and at least 1 systemic/general sign/symptom [see Table 1 and Section 5.1, Inclusion
Criteria])will be enrolled. Cough or wheezing cannot be the only LRTI sign/symptom present, ie,
at least one other LRTI sign/symptom needs to be present for eligibility. Eligible participants can
be otherwise healthy or have (a) risk factor(s) for severe RSV disease (as defined in Table 2).
Those who are immunocompromised and those with neuromuscular diseases that affect
swallowing or the thoracic muscles are excluded from participation.
Table 1: 
RSV Disease Signs/Symptoms for Eligibility
Upper Respiratory Tract Infection (URTI) Signs/Symptoms:
Nasal congestion
Rhinorrhea
Lower Respiratory Tract Infection (LRTI) Signs/Symptoms:
Increased respiratory efforts, evidenced by:
 
subcostal, intercostal, or tracheosternal retractions
 
grunting
 
head bobbing
 
nasal flaring
 
tachypnea
Wheezinga
Cyanosis
Cougha
Apnea
Systemic / General Signs/Symptoms:
Feeding difficulties (defined as <75% intake of normal food amounts)
Dehydration
Fever
Disturbed sleep
Disturbed activity level (irritable, restless, agitated, or less responsive)
aCough or wheezing cannot be the only LRTI sign/symptom present, ie, at least one other LRTI sign/symptom
needs to be present for eligibility.


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Table 2: 
Risk Factors for Severe RSV Disease
Prematurity at birtha
Bronchopulmonary dysplasia
Congenital heart disease
Down syndrome
Neuromuscular impairmentb
Cystic fibrosis
Recurrent wheezingc
Asthma
Other congenital disease
aNote: Prematurely born participants are only eligible for this study if their age corrected for gestational age at
birth is ≥28 days at the time of consent.1 After this main study opens to neonate enrollment: prematurity is not
allowed for neonates (ie, neonate participants should have been born at term, after at least 37 weeks of gestation).
b Excluding neuromuscular diseases that affect swallowing or the thoracic muscles.
c Recurrent wheezing is defined as ≥1 episode of wheezing without a cold in the past year.22
Randomization should occur within a maximum of 24 hours after start of screening or within
48 hours after collection of the SOC sample used for local RSV diagnosis, whichever comes first,
and no later than 3 days after RSV sign/symptom onset (see Figure 2). Randomization will be
stratified by presence of risk factors for severe RSV disease (otherwise healthy vs presence of [a]
risk factor[s] for severe RSV disease, see Table 2)and by region (Asia-Oceania, EMEA, Northern
America, and Latin America-The Caribbean).
Figure 2: 
Timeline from RSV Sign/Symptom Onset to First Dose
ICF = informed consent form; RSV = respiratory syncytial virus; SOC = standard-of-care.
Study intervention administration should start as soon as possible, but no later than 4 hours after
randomization (see Figure 2). Dosing will be based on a mg/kg basis per age group and 4 age
groups are defined based on the participant’s age at the time of consent (see Table 3). Study
intervention (oral suspension) will be administered orally, bid, with a treatment duration of 7 days
(14 consecutive doses) (see also Section 6).


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Table 3: 
Age Groups and Dosing Regimen
Age Group  
Age Range 
Dosing Regimen
Age group 1 
≥28 days to <3 months of age 
(ie, 28 to 91 days of age, extremes included)
2.5 mg rilematovir/kg bodyweight bid
Age group 2 
≥3 months to <6 months of age 
(ie, 92 to 182 days of age, extremes included)
3 mg rilematovir/kg bodyweight bid
Age group 3 
≥6 months to ≤5 years of age 
(ie, 183 to 1,826 days, extremes included)
4.5 mg rilematovir/kg bodyweight bid
Age group 4a 
at term birth (ie, after at least 37 weeks of gestation) 
to <28 days of age 
(ie, 1 day to 27 days, extremes included) 
XX mgb, rilematovir/kg bodyweight bid,
dependent on outcome of substudy and
following IDMC recommendation
bid = twice daily; IDMC = Independent Data Monitoring Committee.
Note: The above-mentioned doses refer to the amount of JNJ-53718678-AAA (free form); 20 mg
JNJ-53718678-AAA corresponds to 23 of mg JNJ-53718678-ZCL (hemi-tartrate of JNJ-53718678-AAA).
a After opening of recruitment in neonates in the main study dependent on positive IDMC recommendation after
completion of a substudy in neonates (see Section 9.6).
b The dosing regimen will not exceed the exposures simulated for the bid regimen in pediatric subjects ≥28 days to
≤5 years of age and observed for the 250 mg bid regimen in adults.
All participants will receive standard supportive care for RSV infection as per local SOC but
considering the restrictions provided in Section 6.8. All SOC intervention should be recorded as
concomitant medication/treatment on designated electronic case report form (eCRF)pages.
The study will include a Screening Period (Day -1 to Day 1), a Treatment Period (Day 1 to Day 8),
and a Follow-up Period (Day 9 to Day 35 [±3]). The total study duration for each participant will
be approximately 36 days (Screening included).
Participants can be discharged as of Day 2, if deemed appropriate by the investigator and after
completion of the required investigator-performed assessments for that day, with exception of the
PM bid assessments. Parent(s)/caregiver(s) of discharged participants are required to follow the
Schedule of Activities as outlined in Section 1.3.2.
The clinical severity and clinical course of RSV infection will be assessed through different
measures (see Section 8.1.1).
The PRESORS developed by the sponsor include several assessments that the clinicians treating
the study participants and the parents/caregivers of participants need to complete on an electronic
device at the timepoints specified in the Schedule of Activities. The PRESORS for the clinicians
consists of the ClinRO Signs/Symptoms, the ClinRO GHQ, and an additional question regarding
apnea (see Section 10.13, Appendix 13). The PRESORS for the parents/caregivers (PRESORS
ObsRO) consist of ObsRO Signs/Symptoms, ObsRO GHQ, and Caregiver Information (only
assessed during set up of the electronic device) (see Section 10.10, Appendix 10, Section 10.11,
Appendix 11, and Section10.12, Appendix 12). The sponsor developed the ClinRO and ObsRO
Signs/Symptoms assessments to monitor signs/symptoms of RSV disease severity observed and
rated by the clinicians treating the pediatric participants as well as by the participant's
parent(s)/caregiver(s) 
from 
baseline 
through 
end 
of 
follow-up. 
Clinicians 
and
parent(s)/caregiver(s) are instructed to rate each RSV sign/symptom at its worst during the recall


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period. The ClinRO and ObsRO GHQs provide assessments by the clinicians and the
parent(s)/caregiver(s), respectively, of the overall impression of the participant’s RSV disease
severity, change in the participant’s RSV disease, and overall health status. In addition to the
ObsRO Signs/Symptoms and ObsRO GHQ, parents/caregivers will also be asked to complete
Caregiver Impact Questions and an assessment of acceptability and palatability at the timepoints
specified in the Schedule of Activities on the same electronic device. Refer to Section 8.1.1.3 for
more information on ClinRO and ObsRO Clinical Outcome Assessments and Caregiver Impact
Questions.
Antiviral activity and viral sequencing will be evaluated as described in Sections 8.1.2 and 8.1.3,
respectively.
Safety and tolerability, including AEs, laboratory assessments, ECGs, vital signs, and (directed)
physical examinations will be assessed throughout the study from signing of the main informed
consent form (ICF)until the participant’s last study-related activity (see Sections 8.2 and 8.3).
Pharmacokinetic assessments during the study will be based on sparse sampling to limit the
number of pricks (2 samples, see Section 1.3.3, Pharmacokinetic Assessments Sampling Schedule)
and will be analyzed using a popPK model as described in Section 8.4.
Medical encounters and acceptability and palatability of the study intervention will be assessed as
described in Sections 8.6 and 8.7.
Residuals of blood and nasal MT  swab samples collected during the study may be used for
exploratory biomarker analyses as described in Section 8.8.
The presence of other respiratory viruses or bacteria will be assessed as described in Section 8.9.
See Section 10.19, Appendix 19for guidance on study conduct during the COVID-19 pandemic.
An IDMC will be commissioned for this study. Refer to Committees Structure in Section 10.3,
Appendix 3 for details.
A diagram of the study design is provided in Section 1.2.
4.2. 
Scientific Rationale for Study Design
This is a Phase 3, randomized, double-blind, placebo-controlled study to investigate the efficacy
and safety of rilematovir in infants and children (≥28 days to ≤5 years of age) and subsequently
including neonates (born at term, <28 days of age) after completion of the substudy (see
Section 9.6), hospitalized with acute respiratory tract infection due to RSV. The results of this
study aim to obtain efficacy and safety data to support the registration of rilematovir for treatment
of RSV infection in pediatric patients.


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Blinding, Control, Study Phase/Periods, Intervention Groups
There is currently no approved antiviral treatment routinely used for the treatment of RSV
infection. A placebo control will be used to establish the frequency and magnitude of changes in
clinical and virologic endpoints that may occur in the absence of active intervention. The use of a
placebo control will allow for any AEs or laboratory abnormalities observed during the course of
the study to be evaluated properly, ie, to differentiate between events potentially related to the use
of rilematovir versus those related to the underlying disease. Randomization will be used to
minimize bias in the assignment of participants to intervention groups, to increase the likelihood
that known and unknown participant attributes (eg, demographic and baseline characteristics) are
evenly balanced across intervention groups, and to enhance the validity of statistical comparisons
across intervention groups. Blinded intervention will be used to reduce potential bias during data
collection and evaluation of clinical endpoints.
Eligible participants will be randomized 2:1 to receive either rilematovir or placebo (see
Section 4.1). The unequal randomization (2:1 active: placebo in each age group) affords the
majority of participants the potential benefit of rilematovir treatment. For dosing purposes, 4 age
groups (at term birth to <28 days of age, ≥28 days and <3 months; ≥3 months and <6 months;
≥6 months and ≤5 years of age) are defined depending on the participant’s age at the time of
consent, taking into account the abundance of specific enzymes (and their maturation) involved in
the metabolism of rilematovir in these different age groups.
Stratification Factors
Randomization will be stratified by presence of risk factors for severe RSV disease (otherwise
healthy versus presence of [a] risk factor[s] for severe RSV disease as defined above, see Table 2)
and by region to ensure even balance across intervention groups.
Presence or absence of (a) risk factor(s) for severe RSV disease is included as stratification factor
due to potentially different (more severe) disease course of RSV infections in patients with these
conditions.
Region is included as stratification factor due to regional differences in health care systems and
standard-of-care practices.
Study Population
Hospitalized patients in the age group 1 day to ≤5 years are targeted, as they are most affected by
severe RSV disease. Hospitalized patients are targeted as RSV-related LRTI is a major cause of
hospital admissions and they are at the highest risk of developing RSV-related complications. See
Section 2.1 for more information. Patients with risk for severe RSV disease are enrolled, as they
have a high medical need for an effective treatment.
Study and Dosing Duration
The total study duration for each participant will be approximately 36 days (Screening included).
Dosing will last for 7 days (14 consecutive doses) as it has been shown that the duration of viral


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shedding upon RSV infection is at least that long. Seven days was also the duration of dosing in
the healthy volunteer challenge study in adults (Study 53718678RSV2001), in
Study 53718678RSV2004 (non-hospitalized RSV-infected adults) and in the completed
Study 53718678RSV1005 in pediatric participants, and was generally safe and well tolerated. In
addition, the same dosing duration is being evaluated in the ongoing Study 53718678RSV2002
(hospitalized and non-hospitalized RSV-infected pediatric participants ≥28 days and ≤3 years of
age). The interim analysis results of this study showed that the dosing duration was generally safe
and well tolerated.
Clinical Outcomes of RSV Treatment
Treatment with rilematovir may reduce the severity and duration of RSV signs/symptoms, and
their impact on functioning, the effect of RSV infection on physiologic parameters, prevent
progression to more severe disease status, reduce the need for and duration of supportive care
(eg, oxygen supplementation, IV fluids/feeding, days of hospitalization), and accelerate the
participants’ return to pre-RSV health status.
The interim analysis of Study 53718678RSV2002 demonstrated a trend towards an improvement
of the clinical course of RSV disease in children ≥28 days and ≤3 years of age with RSV disease,
with more pronounced effects in the subgroup with symptom onset ≤3 days.
This study will evaluate the impact of treatment with rilematovir on the clinical course of RSV
disease and on clinically relevant changes in patient status over meaningful defined levels of
improvement/resolution using a multipoint scale at a clinically relevant timepoint as defined at the
first interim analysis based on blinded data across treatment arms (ie, the study day when at least
50% of participants across treatment arms are discharged from the hospital).
RSV Disease Presentation in the Study Population
In a retrospective study, a total of 5,483 pediatric patients (≤14 years old) hospitalized with acute
respiratory tract infection, 710 of the 729 (97.4%) RSV-positive patients were children under
5 years old.32 The clinical manifestations ranged from mild URTI or otitis media to severe and
potentially life-threatening LRTI. The most common form of LRTI in RSV-infected infants was
bronchiolitis, but pneumonia and croup were also seen. Involvement of the lower airways occurred
in ∼15 50% of infants and young children with primary RSV infection and required
hospitalization in 1 3 % of the annual birth cohort, with infants between 2 and 6 months of age
being at the highest risk. However, in some regions, the highest incidence of LRTI was reported
in infants aged 6 11 months or even children between 1 and 2 years of age.
Assessed Key RSV Signs/Symptoms
For the primary and key secondary endpoints of this study, a “resolved/not resolved” scoring of
Key RSV Signs/Symptoms as assessed by the ClinRO Signs/Symptoms and ObsRO
Signs/Symptoms is used. These Key RSV Signs/Symptoms are: Breathing problems, retractions,
tachypnea, cough, wheezing/breathing sounds, and tachycardia. These Key RSV Signs/Symptoms


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were selected as the most relevant and important indicators of LRTI associated with clinically
important RSV disease that can be observed by a child’s parent/caregiver without the need for
medical technology or training. They were selected based on qualitative research  and content
validity work, including clinical expert review, caregiver interviews, review of published studies,
literature research, and results from previous studies.
The same Key RSV Signs/Symptoms will be assessed across all age groups. While some of the
signs/symptoms are recognized to be more prevalent in certain age groups compared to other age
groups, and there are age-specific criteria for defining abnormal ranges for some signs/symptoms,
the same Key RSV Signs/Symptoms adequately represent the RSV disease presentation in all age
groups included in this study.
Medical Encounters
Treatment of RSV disease with rilematovir versus placebo may result in lower need for medical
encounters; therefore, comparison will be done between intervention groups.
4.2.1. 
Study-specific Ethical Design Considerations
Potential participants’ parent(s)/legally acceptable representative(s) will be fully informed of the
risks and requirements of the study and, during the study, they will be given any new information
that may affect their decision to continue participation. They will be told that their consent to
participate in the study is voluntary and may be withdrawn at any time with no reason given and
without penalty or loss of benefits to which the participant would otherwise be entitled. Only
participants whose parent(s)/legally acceptable representative(s) is/are fully able to understand the
risks, benefits, and potential AEs of the study, and provide their consent voluntarily will be enrolled.
Prior to signing the main consent form for the study, participant’s parent(s) (preferably both if
available or as per local requirements) or their legally acceptable representative(s) may specifically
allow for the collection and testing of a nasal MT swab by signing the pre-screening (diagnostic)
ICF. This is not required if a positive RSV diagnostic result based on a local SOC sample collected
within 48 hours prior to anticipated randomization is available and used for determining study
eligibility.
When referring to the signing of the ICF, the terms legal guardian(s) and legally acceptable
representative(s)refer to the legally appointed guardian of the participant with authority to authorize
participation in research. For each participant, his or her parent(s) (preferably both parents, if
available) or legally acceptable representative(s), as required by local regulations, must give written
consent (permission) according to local requirements after the nature of the study has been fully
explained and before the performance of any study-related assessments.
The total blood volume to be collected is considered to be an acceptable amount of blood to be
collected over this time period from the population in this study (see Section 8) based upon the World
Health Organization (WHO)recommendations for this age group.23


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Investigational staff should take the customary measures to ensure that study-specific assessments
such as blood sampling or nasal swabbing are performed with as little additional stress as possible
for the participant. Investigators may use local anesthetics prior to blood sampling.
4.3. 
Justification for Dose
The pediatric exposure was targeted to be similar as the one observed in adults treated with 500 mg
rilematovir qd and was based on the results of the human challenge Study 53718678RSV2001, in
which target engagement for rilematovir was demonstrated in immunocompetent adults inoculated
with RSV-A Memphis 37b.
In the currently ongoing pediatric Study 53718678RSV2002, in which 2 dose levels were
evaluated (5, 6, and 9 mg/kg as the high dose and 1/3rd of these doses as the low dose, qd), popPK
analysis demonstrated that these high doses resulted in observed Cmin  and Cmax  values within the
range of the target concentrations (ie, the exposure observed in adults treated with 500 mg
rilematovir qd) for the different age groups (28 days to <3 months, 3 to <6 months, and 6 to
<36 months of age). Furthermore, based on review of the safety and efficacy data from
Studies 53718678RSV1005 and interim analysis of 53718678RSV2002, these proposed doses
were generally safe and well tolerated and ensure the highest potential antiviral effect (see also
Section 2.2). In addition, the efficacy data of Study 53718678RSV2002 indicate a more
pronounced clinical effect at the high dose level of rilematovir compared to the low dose level
whereas no dose-response was observed for safety outcomes.
Data from the mass-balance study (Study 53718678RSV1008) demonstrated that 8% of the parent
was excreted in the feces, 1.2% of the parent was excreted in the urine, and 8% was excreted in
the feces as the M8 metabolite (UGT pathway). Therefore, the popPK model has a combination of
maturation functions that describe the increase in CYP3A4 and UGT1A3/1A4 with age, as
fractions of their adult abundance and applied to total clearance. The popPK model has the same
combination  of maturation functions as well as allometric scaling applied to the other PK
parameters.
Based on the exposure-response analysis conducted in the TQT Study 53718678RSV1009 in
healthy adult participants, an exposure (Cmax) related important potential risk  of QT  interval
prolongation was identified. While no safety signal was observed regarding QT prolongation, other
ECG abnormalities, or cardiovascular side effects, additional modeling to evaluate alternative dose
and dosing regimens, which would allow to maintain the exposures (Ctrough) at effective levels
while reducing the Cmax, to mitigate this potential risk was performed.
Based on final PK and QTc modeling, a 7-day bid dosing regimen of 2.5, 3, and 4.5 mg/kg for the
3 different age groups (≥28 days to <3 months, ≥3 to <6 months, and ≥6 to ≤5 years of age,
respectively) was selected with disallowance of comedication with moderate or strong CYP3A4
inhibitors. Based on Table 4, the upper limit of the 90% confidence interval for QTcI for the
bid regimen for each of the age groups remains below 10 msec. It is anticipated that the proposed
bid dosing will be in the therapeutic range of rilematovir for the pediatric population (Ctrough  at
least 7 times paEC90), ensuring the highest potential antiviral effect while minimizing the risk of


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development of resistance, as well as mitigating the important potential risk of QT interval
prolongation.
Table 4: 
Predicted Geometric Mean AUC24h, Cmax, Ctrough and QTcI Per Age Group After Day 1 and
Day 7
Age Group  
(Dose mg/kg bid) 
1 - <3 Months 
(2.5 mg/kg bid) 
3 - <6 Months 
(3 mg/kg bid) 
6 Months –5 Years
(4.5 mg/kg bid)
AUC24h  Day 1 (ng.hr/mL) 
16,500 
17,200 
17,200
AUC24h  Day 7 (ng.hr/mL) 
32,900 
28,800 
21,300
Cmax  Day 1 (ng/ml) 
1,220 
1,350 
1,680
Cmax  Day 7 (ng/ml) 
1,870 
1,800 
1,830
Ctrough Day 1 (ng/mL) 
566 
509 
287
Ctrough Day 7 (ng/mL) 
998 
773 
343
QTcI Day 1 (msec) (90%CI) 
1.95 (0.97-3.66) 
2.09 (1.08-3.98) 
2.35 (1.18-4.61)
QTcI Day 7 (msec) (90%CI) 
3.17 (1.34-6.81) 
2.92 (1.31-6.23) 
2.61 (1.25-5.45)
ΔΔ  = placebo-adjusted change from baseline; AUC = area under the plasma concentration-time curve;
AUC24h  = AUC from administration to 24 hours; bid = twice daily; Cmax = maximum plasma concentration;
Ctrough  = predose plasma concentration; QTcI = individual-corrected QT interval.
The dose for neonates (Age group 4) will be determined based on the results of the substudy and
depend on IDMC recommendation, but will not exceed the exposures simulated for the bid
regimen in pediatric subjects ≥28 days to ≤5 years of age and observed for the 250 mg bid regimen
in adults. Investigators and relevant health authorities, ethics committees, and institutional review
boards (IRBs) will be informed in writing of the decision and the selected dosing regimen for
neonates.
4.4. 
End of Study Definition
End of Study Definition
The end of study is considered as the last visit (phone visit or site visit) for the last participant in
the study. The final data from the study site will be sent to the sponsor (or designee) after
completion of the final participant visit at that study site, in the time frame specified in the Clinical
Trial Agreement.
Study Completion Definition
A participant will be considered to have completed the study if (s)he has completed dosing and
has completed assessments at Day 35 (±3 days) of the follow-up phase.
5. 
STUDY POPULATION
Screening for eligible participants will be performed within 3 days of first RSV sign/symptom
onset, such that participants are randomized within ≤3 days of RSV sign/symptom onset, and
within 4 hours before administration of the study intervention. Refer to Section 5.4 for conditions
under which the repeat of any screening procedures are allowed.


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The inclusion and exclusion criteria for enrolling participants in this study are described below. If
there is a question about these criteria, the investigator must consult with the appropriate sponsor
representative and resolve any issues before enrolling a participant in the study. Waivers are not
allowed.
For a discussion of the statistical considerations of participant selection, refer to Section 9.2.
5.1. 
Inclusion Criteria
Each potential participant must satisfy all of the following criteria to be enrolled in the study:
1. 
Criterion modified per Amendment 1
1.1 
The participant is a boy or girl either:
 Born at term (ie, after ≥37 weeks of gestation) and ≥28 days old to ≤5 years old at
the time of consent.
 Born preterm (ie, at <37 weeks of gestation) and ≥28 days old corrected for
gestational age and up to ≤5 years old at the time of consent.
Note: After this main study opens to neonate enrollment: in addition, a neonate (boy or
girl) from birth at term (ie, after at least 37 weeks of gestation) to <28 days at the time of
consent.
2. 
The participant weighs within ≥2.4 kg and ≤24.6 kg.
3. 
Each participant’s parent(s) (preferably both if available or as per local requirements) or
their legally acceptable representative(s) has/have signed an ICF indicating that (s)he:
 understands the purpose of, and procedures required for, the study,
 is willing for their child to participate in the study,
 is willing for their child to remain in the hospital until at least Day 2,
 is willing and able to adhere to the prohibitions and restrictions with regards to
o the concomitant medication (see Section 6.8),
o the lifestyle consideration (see Section 5.3),
o study procedures and assessments to be performed by the
parent(s)/caregiver(s) as well as those by the investigator/study site
personnel.
Note: Prior to signing the main consent form for the study, participant’s parent(s)
(preferably both if available or as per local requirements) or their legally acceptable
representative(s) may specifically allow for the collection and testing of nasal MT swab
by signing the pre-screening (diagnostic) ICF.


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4. 
The participant has been diagnosed with RSV infection using a polymerase chain reaction
(PCR)- or other molecular-based diagnostic assay.
Note: If a participant had a positive RSV test result using a molecular-based diagnostic
assay from another study  for which (s)he was otherwise ineligible or from a SOC
molecular-based diagnostic test within 24 hours prior to start of screening and meets all
eligibility criteria for inclusion in this study, this diagnostic test result can be used for
determination of eligibility.
5. 
Criterion modified per Amendment 1
5.1 
The participant has an acute respiratory illness with at least 1 of the signs/symptoms listed
in each of the following categories within 24 hours prior to start of screening and at
screening, as evaluated by the investigator:
 
Upper respiratory tract infection: nasal congestion or rhinorrhea; AND
 
Lower respiratory tract infection: increased respiratory effort (as evidenced by
subcostal, intercostal or tracheosternal retractions, grunting, head bobbing, nasal
flaring, or tachypnea), wheezinga, cougha, cyanosis, or apnea; AND
 
Systemic/general: feeding difficulties (defined as <75% intake of normal food
amounts); dehydration; fever; disturbed sleep, or disturbed activity level
(irritable/restless/agitated/less responsive).
a Cough or wheezing cannot be the only LRTI sign/symptom present, ie, at least one other
LRTI sign/symptom needs to be present for eligibility.
6. 
The time of onset ofRSV signs/symptoms to the anticipated time of randomization must
be ≤3 days. Onset of signs/symptoms is defined as the time of the day (or part of the day
if time of the day cannot be specified) the parent(s)/caregiver(s) became aware of the first
sign and/or symptom consistent with respiratory or systemic/general manifestation of
signs/symptoms of RSV infection. The time of sign/symptom onset has to be assessed as
accurately as possible.
7. 
The participant is hospitalized or presented to the ER/clinic and expected to be
hospitalized.
Note: Hospitalized refers to having at least 24 hours with an overnight stay in the hospital.
8. 
Participants are otherwise healthy or have (a) risk factor(s) for severe RSV disease (as
listed in Table 2). Participants who are immunocompromised are excluded.


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9. 
Except for the RSV-related illness, the participant must be medically stable based on
physical examination, medical history, and vital signs performed at screening. If there are
abnormalities, they must be consistent with the underlying condition (RSV disease and/or
present risk factor[s] for severe RSV disease [refer to inclusion criterion #8] in the study
population as evaluated by the investigator. This determination must be recorded in the
participant’s source documents and initialed by the investigator.
10. 
The participant must have been assessed per local public health practice and considered
not to have SARS-CoV-2 infection during this respiratory infection.
5.2. 
Exclusion Criteria
Any potential participant who meets any of the following criteria will be excluded from
participating in the study:
1. 
The participant had major surgery within the 28 days prior to randomization or
planned major surgery through  the course of the study  (eg, bidirectional Glenn
procedure).
2. 
The participant has a neuromuscular disease that affects swallowing or the thoracic
muscles, an evolving developmental disorder, major congenital anomalies or known
cytogenetic or metabolic disorders other than the ones allowed above (see inclusion
criterion #8).
Note: Isolated open ductus arteriosus and open foramen ovale are not exclusionary
as these are not considered major anomalies.
3. 
The participant is considered by the investigator to be immunocompromised,
whether due to underlying medical condition (eg, known human immunodeficiency
virus [HIV] infection, malignancy or genetic disorder other than immunoglobulin A
deficiency) or medical therapy (eg, immunomodulators other than corticosteroids for
the treatment of comorbidities, chemotherapy, radiation, stem cell or solid organ
transplant).
4. 
The participant has a known or clinically suspected acute or chronically active
hepatitis B or C infection (based on participant’s medical history or on participant’s
examination) or history of active maternal hepatitis B or C infection around birth,
unless the participant has tested negative for hepatitis B and C infection.
5. 
The participant has had either:
a) Confirmed SARS-CoV-2 infection (test positive) during the four weeks prior to
randomization, OR
b) Close contact with a person with COVID-19 (test confirmed or suspected
SARS-CoV-2 infection) within 14 days prior to randomization.


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6. 
The participant is being treated with extracorporeal membrane oxygenation.
7. 
The participant is receiving chronic (home) oxygen  therapy (ie, is dependent on
oxygen) at the time of screening.
8. 
The participant is using any disallowed medication as listed in Section 6.8.
9. 
Participant whose mother received an investigational RSV vaccination during the
pregnancy for this child and whose age is <3 months at time of screening.
10. 
The participant has known allergies, hypersensitivity, or intolerance to rilematovir or
to any of the excipients of the rilematovir or placebo formulation (refer to the IB).26
11. 
The participant is currently participating or planned to participate in another clinical
interventional study, during their participation in this study.
12. 
The participant has any physical abnormality which limits the ability to collect
regular nasal specimens.
13. 
The participant is unable to take medications orally or has a known gastrointestinal-
related condition that is considered by the sponsor or investigator to be likely to
interfere with study intervention ingestion or absorption.
14. 
Confirmed QTcF interval >450 msec per the machine read parameter result at
screening. Presence of an abnormal QTcF interval should be confirmed by repeat
ECG recording during screening.
15. 
Known personal or family history of Long QT Syndrome or sudden cardiac death.
16. 
Presence of repetitive ventricular premature contractions (>10/min), second or third
degree heart block, or complete or incomplete left bundle branch block, or complete
right bundle branch block per the machine read ECG result at screening. Presence of
any of the above abnormalities should be confirmed by repeat ECG recording during
screening.
17. 
Other clinically significant abnormal ECG findings not consistent with the present
risk factor for severe RSV disease (if applicable) in the study population, as judged
by the investigator based on the machine read ECG results at screening.
NOTE: Investigators should ensure that all study enrollment criteria have been met before the start
of treatment. If a participant's clinical status changes (including any available laboratory results or
receipt of additional medical records) after diagnosis/randomization but before the first dose of
study intervention  is given such that (s)he no longer meets all eligibility criteria, then the
participant should be excluded from participation in the study.


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The required source documentation to support meeting the enrollment criteria are noted in
Section 10.3, Appendix 3.
5.3. 
Lifestyle Considerations
The parent(s)/caregiver(s) should complete the ObsRO Signs/Symptoms and ObsRO GHQ twice
dailyon an electronic device until Day 14, and once daily from Day 15 to Day 21 and the Caregiver
Impact Questions daily until Day 21, which takes approximately 5-10 minutes per assessment,
depending on the signs/symptoms. The parent(s)/caregiver(s) is/are required to perform all site
visits per the Schedule of Activities.
Participant’s parent(s)/caregiver(s) must be willing and able to adhere to the prohibitions and
restrictions with regards to the concomitant therapy  during the course of the study for the
participant to be eligible for participation. Refer to Section 6.8 for details regarding prohibited and
restricted therapy during the study.
5.4. 
Screen Failures
Participant Identification, Enrollment, and Screening Logs
The investigator agrees to complete a participant identification and enrollment log to permit easy
identification of each participant during and after the study. This document will be reviewed by
the sponsor study site contact for completeness.
The participant identification and enrollment log will be treated as confidential and will be filed
by the investigator in the study file. To ensure participant confidentiality, no copy will be made.
All reports and communications relating to the study will identify participants by participant
identification and age at initial informed consent. In cases where the participant is not randomized
into the study, the date seen and age at initial informed consent will be used.
Individuals who do not meet the criteria for participation in this study (screen failure) may be
rescreened, but not in the same acute respiratory infection (ARI)episode in case RSV(-)diagnosis
was the reason for screen failure.
6. 
STUDY INTERVENTION
6.1. 
Study Intervention(s) Administered
Eligible participants will be randomized 2:1 (active:placebo) to receive either rilematovir or
placebo bid for 7 days (14 consecutive doses). Study intervention administration should start as
soon as possible, but within 4 hours after randomization.


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Description of Interventions
Arm Name 
Arm 1 
Arm 2
Intervention Name 
Rilematovir 
Placebo
Type 
Drug 
Drug
Dose Formulation 
Powder and solvent for oral 
suspension 
Powder and solvent for oral
suspension
Unit Dose Strength(s) 
eq. 20 mg/mLa 
Matching placebo
Dosage Level(s) 
Doses are based on body weight and age group, see Table 5
Route of Administration 
Orally using a dosing syringe, during hospitalization may also be
administered through nasogastric tube, if already in place.
Use 
Experimental 
Placebo
Investigational Medicinal Product 
(IMP) and Non-Investigational
Medicinal Product (NIMP)
IMP  
IMP
Sourcing 
Provided centrally by the sponsor
Packaging and Labeling 
Each unit will be labeled with unique medication ID number
The powder and solvent for oral suspension are packaged in amber glass
bottles with child resistant closure.
Labels will contain information to meet the applicable regulatory
requirements.
Food/Fasting requirement 
Regardless of food intake
Other requirements 
Dosing should preferably occur approximately at the same time each day
for both intakes (AM and PM).
a After reconstitution, rilematovir is dosed as an equivalent 20 mg/mL JNJ-53718678-AAA oral suspension
(containing 23 mg/mL JNJ-53718678-ZCL, the hemi-tartrate of JNJ-53718678-AAA).
Table 5: 
Treatment Overview
Treatment Age Group  
Age Range 
Dosing Regimena 
Volume Oral
Suspensionb
Rilematovir 
1 
≥28 days to <3 months 2.5 mg/kg bid on Days 1 to 7(/8) 
A mL
2 
≥3 to <6 months 
3 mg/kg bid on Days 1 to 7(/8) 
B mL
3 
≥6 months to ≤5 years 4.5 mg/kg bid on Days 1 to 7(/8) 
C mL
4* 
birth at term to 
<28 days
Xc mg/kg bid on Days 1 to 7(/8) 
Dc mL
Placebo
1,2,3, or 4* 
see above 
Matching placebo bid on 
Days 1 to 7(/8) 
A, B, C, or Dc*
(respectively) mL placebo
bid = twice daily; IDMC = Independent Data Monitoring Committee; IWRS = interactive web response system.
* After opening of recruitment in neonates in the main study dependent on positive IDMC recommendation after
completion of a substudy in neonates (see Section 9.6).
a. Doses are provided for JNJ-53718678-AAA.
b. A to D represents the volume of oral rilematovir suspension to obtain the required dose of JNJ-53718678-AAA
or the volume of the matching placebo suspension. After reconstitution, rilematovir is dosed as an equivalent
20 mg/mL JNJ-53718678-AAA oral suspension (containing 23 mg/mL JNJ-53718678-ZCL, the hemi-tartrate of
JNJ-53718678-AAA), to be used depending on the bodyweight of the participant. The required volume to be
administered per intake will be calculated by the IWRS and provided to the sites.
c. Dose dependent on outcome of the substudy in neonates and following IDMC review and recommendation. The
dosing regimen will not exceed the exposures simulated for the bid regimen in pediatric subjects ≥28 days to
≤5 years ofage and observed for the 250 mg bid regimen in adults.


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Depending on the time of randomization/enrollment, participants will receive 1 dose (PM) or
2 doses (AM and PM) of study intervention on Day 1. Dosing should occur approximately every
12 hours. Administration of the second dose may be delayed or brought forward (by maximum
4 hours) only if the nominal timing for this second dose falls in the middle of the night; thereafter,
further dosing will follow a regular AM/PM dosing schedule. For participants who receive only
1 dose of rilematovir or placebo PM of Day 1, dosing should continue through the morning (ie,
AM) of Day 8 so that all participants receive 14 consecutive doses in total.
During hospitalization: the study intervention will be administered by the study site personnel or
by the parent(s)/caregiver(s) under supervision of the study site personnel.
After discharge: the study intervention  will continue to be administered at home by the
parent(s)/caregiver(s) through Day 7 (or Day 8 AM if first dose is given PM on Day 1). Study site
personnel will instruct each participants’ parent(s)/caregiver(s) on how to administer and store
study intervention for at-home use as indicated for this protocol.
Study site personnel will record the bid study intervention administration in the source documents
(during hospitalization)and in the eCRF (all doses).
If the participant vomited, regurgitated, or did not completely swallow the study intervention, the
participant should not be redosed for that administration timepoint.
In case a dose was missed, the dose should be given as soon as possible but within 6 hours after
the scheduled time. If more than 6 hours has elapsed, the dose should be skipped and the next dose
should be given at the next scheduled time point per the initial dosing schedule.
If a participant is rehospitalized after discharge due to worsening of RSV disease during the
treatment period, administration of study intervention in the bid regimen should continue.
If a participant’s level of care during hospitalization changes during the treatment period,
administration of study intervention in the bid regimen should continue.
The drug product is supplied as an eq. 217.4 mg/g JNJ-53718678-AAA powder (containing
250 mg/g JNJ-53718678-ZCL, the hemi-tartrate of JNJ-53718678-AAA) or placebo and solvent
for oral suspension. The powder needs to be reconstituted with an appropriate volume ofsolvent
for oral suspension to obtain an  eq. 20 mg/mL JNJ-53718678-AAA (containing 23-mg/mL
JNJ-53718678-ZCL, the hemi-tartrate of JNJ-53718678-AAA) or placebo oral suspension  by
appropriately trained study site personnel prior to administration/dispensing to the participant’s
parent/caregiver.
Depending on the body weight and age of the participant, the IWRS will assign the appropriate
number of bottles to be prepared and dispensed to the parent/caregiver.
Study intervention will be manufactured and provided under the responsibility of the sponsor.
Refer to the IB for a list of excipients.26


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For a definition of study intervention overdose, refer to Section 6.7.
6.2. 
Preparation/Handling/Storage/Accountability
Preparation/Handling/Storage
All study intervention must be stored as specified on the label.
Refer to the pharmacy manual/study site investigational product and procedures manual for
additional guidance on study intervention preparation, handling, and storage.
Accountability
The investigator is responsible for ensuring that all study intervention received at the site is
inventoried and accounted for throughout the study.
During hospitalization, the study intervention administered to the participant must be documented
on the intervention accountability form. All study intervention will be stored and disposed of
according to the sponsor's instructions. Study site personnel must not combine contents of the
study intervention containers. After discharge, the dispensing of study intervention to the
participants’ parent(s)/caregiver(s), and the return of study intervention from the participants’
parent(s)/caregiver(s) (if applicable), must be documented on the intervention accountability form.
Participants’ parent(s)/caregiver(s) must be instructed to return the original container, whether
empty or containing study intervention.
Study intervention must be handled in strict accordance with the protocol and the container label,
and must be stored at the study site in a limited-access area or in a locked cabinet under appropriate
environmental conditions. Unused study intervention, and study intervention returned by the
participants’ parent(s)/caregiver(s), must be available for verification by the sponsor's study site
monitor during on-site monitoring visits. The return to the sponsor of unused study intervention,
or used returned study intervention for destruction, will be documented on the intervention return
form. When the study site is an authorized destruction unit and study intervention supplies are
destroyed on-site, this must also be documented on the intervention return form.
Potentially hazardous materials containing hazardous liquids, ie, oral dosing syringes, should be
disposed of immediately in a safe manner and therefore will not be retained for intervention
accountability purposes.
Study intervention should be dispensed under the supervision of the investigator or a qualified
member of the study site personnel, or by a hospital/clinic pharmacist. Study intervention will be
supplied only to parent(s)/caregiver(s) of participants participating in the study. Returned study
intervention must not be dispensed again, even to the same participant. Study intervention may not
be relabeled or reassigned for use by other participants. The investigator agrees neither to dispense
the study intervention from, nor store it at, any site other than the study sites agreed upon with the
sponsor. Further guidance and information for the final disposition of unused study interventions
will be provided.


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6.3. 
Measures to Minimize Bias: Randomization and Blinding
Intervention Allocation
Procedures for Randomization and Stratification
Central randomization will be implemented in this study. Participants will be randomly assigned
to 1 of the 2 treatment groups (rilematovir or placebo) based on a computer-generated
randomization schedule prepared before the study by or under the supervision of the sponsor. The
randomization will be balanced by using randomly permuted blocks and will be stratified by
presence of risk factors for severe RSV disease (otherwise healthy vs presence of [a] risk factor[s]
for severe RSV disease) and by region. The interactive web response system (IWRS) will assign
a unique intervention code, which will dictate the intervention assignment and matching study
intervention kit(s) for the participant. The requestor must use his or her own user identification
and personal identification number when contacting the IWRS, and will then give the relevant
participant details to uniquely identify the participant.
Blinding
The investigator will not be provided with randomization codes. The codes will be maintained
within the IWRS, which has the functionality to allow the investigator to break the blind for an
individual participant.
Data that may potentially unblind the intervention  assignment (ie, rilematovir plasma
concentrations) will be handled with special care to ensure that the integrity of the blind is
maintained and the potential for bias is minimized. This can include making special provisions,
such as segregating the data in question from view by the investigators, clinical team, or others as
appropriate until the time of database lock and unblinding.
Under normal circumstances, the blind should not be broken until all participants have completed
the study and the database is finalized. The investigator may in an emergency determine the
identity of the treatmentby contacting the IWRS. While the responsibility to break the intervention
code in emergency situations resides solely with the investigator, it is recommended that the
investigator contact the sponsor or its designee if possible to discuss the particular situation, before
breaking the blind. Telephone contact with the sponsor or its designee will be available 24 hours
per day, 7 days per week. In the event the blind is broken, the sponsor must be informed as soon
as possible. The date, time, and reason for the unblinding must be documented by the IWRS and
in the source document. The documentation received from the IWRS indicating the code break
must be retained with the participant's source documents in a secure manner.
For participants who have had their intervention assignment unblinded, study intervention must be
discontinued (see Section 7.1).
In general, randomization codes will be disclosed fully only if the study is completed and the
clinical database is closed. However, if an interim analysis is specified, the randomization codes
and, if required, the translation of randomization codes into intervention and control groups will
be disclosed to those authorized and only for those participants included in the interim analysis.


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6.4. 
Study Intervention Compliance
Dosing should occur approximately every 12 hours, while hospitalized, by the studysite personnel
or by the parent(s)/caregiver(s) under supervision of the study site personnel and after discharge
by the parent(s)/caregiver(s).
At the screening visit, the participant’s parent(s)/caregiver(s) will receive instructions on
compliance with and documentation ofstudy intervention administration, and this instruction will
be repeated at the time of discharge, if applicable. During the course of the study, the investigator
or designated study  site personnel will be responsible for providing additional instruction to
re-educate any participant’s parent(s)/caregiver(s) who is (are) not compliant with administering
the study intervention and recording date, time, and any issues encountered during dosing.
6.5. 
Dose Modification
Dose modification is not allowed within this study.
6.6. 
Continued Access to Study Intervention After the End of the Study
Participants’ parent(s)/caregiver(s) will be instructed that study intervention will not be made
available to them after they have completed/discontinued study intervention and that they should
return to their primary physician to determine SOC.
6.7. 
Treatment of Overdose
For this study, any dose of the study intervention greater than the total daily calculated volume for
the respective age and body weight-based dose within a 24-hour time period will be considered an
overdose.
The sponsor does not recommend specific intervention for an overdose.
In the event of an overdose, the investigator or treating physician should:
 
Contact the Medical Monitor immediately.
 
Closely monitor the participant for AE/SAE, ECG and laboratory abnormalities for at least
3 days.
 
Document the quantity of the excess dose as well as the duration of the overdosing in the
eCRF.
Decisions regarding dose interruptions will be made by the investigator in consultation with the
Medical Monitor based on the clinical evaluation of the participant.
6.8. 
Concomitant Therapy
Concomitant medications, except those listed below, are allowed during this study. All
concomitant medications and supportive therapy (including but not limited to prescription or over-
the-counter 
medications, 
including 
vaccines, 
vitamins, 
herbal 
supplements, 
and
non-pharmacologic therapies such as electrical stimulation, acupuncture, special diets,
physiotherapy) different from the study intervention must be recorded in the eCRF, from the date


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the ICF for the study is signed through the end-of-study visit. Recorded information will include
a description of the type of the drug/therapy, treatment duration (dates oftreatment start and stop),
dose regimen, route of administration, and its indication. Modification of an effective pre-existing
chronic therapy should not be made for the explicit purpose of entering a participant into the study;
however, if a participant has received acute doses of a prohibited drug, switching to an alternative
drug chosen at the discretion of the investigator will be allowed.
All hospitalized participants will receive supportive care per local institution standards and
applicable guidelines. While treatment guidelines and standards vary based on local practice and
are guiding the management of participants, within the parameters of this study, it is recommended
that supplemental oxygen can be administered or withdrawn, as appropriate, to maintain an SpO2
≥92% as long as it is medically indicated (for participants whose SpO2 is ≥92% when clinically
stable). It is further recommended that re-initiation of oral hydration and feeding occur as soon as
possible. Refer to Section 10.9, Appendix 9for guidelines on performing SpO2 measurements.
In addition, it is recommended to limit the use of antitussives and mucolytics, following their
package insert and clinical practice guidelines, in particular in the younger age group.
Allowed Medications
Participants can receive medications such as acetaminophen/paracetamol, non-steroidal
anti-inflammatory drugs, leukotriene antagonists, or antihistamines, considering their respective
package insert, at the investigator’s discretion prior to and during the study.
In case antipyretics are used, body temperature should be measured immediately before or
>4 hours after giving antipyretics.
Fexofenadine is allowed, taking into account its package insert and dosing instructions for use in
children, but rilematovir may reduce the fexofenadine exposure by 65% and reduce its efficacy if
administered simultaneously. To limit the reduction in efficacy it is recommended to administer
fexofenadine at least 1 to 2 hours before taking study intervention and/or at least 4 hours after
taking study intervention, taking into account the local prescribing information for fexofenadine.
Prescription medications intended to treat the symptoms/sequelae of the RSV infection are
permitted, including:
 
inhaled β-agonists or anticholinergics
 
oral/IV/intramuscular antibiotics such as β-lactams (see below for antibiotics which are
CYP3A4 inhibitors)
Note: The temporary use of over-the-counter medications in the 14 days prior to randomization
and during the study is permitted. The use of vitamins and mineral supplements is also permitted.
Routine vaccinations are permitted during the study but their package inserts and/or local clinical
practice guidelines have to be followed. In case COVID-19 vaccines are locally approved


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(including emergency use authorized) in the pediatric population, please refer to Section 10.19,
Appendix 19for guidance.
Disallowed Medications
The following medications are not permitted during the study and for the time period prior to study
participation as noted:
 
Prescription medication eltrombopag, a known BCRP inhibitor, within 2 days prior to
randomization and during the study.
 
Herbal supplements with active metabolic enzyme inducing components (eg, St-John’s Wort)
within 21 days or BCRP (a transporter protein) inhibiting components (eg, curcumin) within
2 days prior to screening and during the study except for topically administered products.
 
Systemic corticosteroids if used for >7 consecutive days immediately prior to screening at
doses higher than 2 mg/kg/day of prednisone or equivalent. Participants meeting the eligibility
criteria at screening but requiring initiation or increased doses of systemic corticosteroids
(>2 mg/kg/day of prednisone or equivalent) for a prolonged period (>7 consecutive days)
during the study are allowed to continue participation in the study.
 
Medications with a known risk to prolong the QT interval24 and not belonging to the class of
moderate or strong CYP3A4 inhibitors (eg, azithromycin, a mild CYP3A4 inhibitor with
known QT prolonging risk) can be continued if the participant is already on a stable therapy
prior to screening and if the QT interval meets the eligibility criteria, however, the use of these
medications cannot be initiated at screening and/or during the study intervention treatment
period.
 
The following prescription medications within14 days prior to screening and during the study:
 Prescription medications which are known to be a moderate or strong inhibitor of CYP3A4
enzymes, such as, but not limited to, macrolide antibiotics.
 Prescription medications that are known to be strong inducers of CYP3A4 such as, but not
limited to, rifampin.
 Prescription medications intended to prevent or treat the RSV infection itself (eg, ribavirin,
IV immunoglobulin). Prescription medications intended to treat the symptoms/sequelae
of the RSV infection are permitted.
 
Palivizumab, within 5 half-lives prior to screening and during the study.
 
Any other investigational study intervention within 30 days or 5-fold half-lives of that drug
(whichever is longer) prior to screening and during the study.
 
Prior exposure to rilematovir at the time of screening.
 
Any investigational medical device prior to screening.
 
Any investigational RSV vaccine at any time prior to and during the study. Routine
vaccinations are permitted during the study but their package inserts and local clinical practice
guidelines have to be followed.


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 
Maternal vaccination with an investigational RSV vaccine during the pregnancy for this child
and whose age is <3 months at time of screening (Section 5.2, Exclusion Criteria).
The sponsor must be notified in advance (or as soon as possible thereafter) of any instances in
which prohibited therapies are administered.
7. 
DISCONTINUATION OF STUDY INTERVENTION AND PARTICIPANT
DISCONTINUATION/WITHDRAWAL
7.1. 
Discontinuation of Study Intervention
A participant's study intervention must be discontinued if:
 
The participant’s parent(s)/caregiver(s) withdraw(s)consent to receive study intervention.
 
The investigator considers that for safety reasons or tolerability reasons (eg, AE) it is in the
best interest of the participant to discontinue study intervention.
 
The participant experiences a Grade 3 rash or higher.
 
The participant is reported with a laboratory abnormality of ALT increase ≥3 × upper limit of
normal (ULN) in the screening sample and met the liver chemistry stopping criteria, refer to
Sections 8.3.5.1 and 10.8, Appendix 8.
 
The participant has a confirmed QTcF interval ≥500 msec based on a machine read ECG result
(see also Section 8.3.5.2). Confirmation needs to be obtained during the same visit day by
repeat ECG recording.
 
The participant is reported with any other laboratory abnormality of Grade 3 or 4 at screening,
confirmed in a repeat test (centrally), to be performed within 48 hours of the result being
available at the site.
 
The participant’s parent(s)/caregiver(s) is/are poorly compliant with completing ObsRO
Signs/Symptoms and ObsRO GHQ questionnaires, preferably after evaluation and discussion
between the investigator and the sponsor.
 
The participant’s parent(s)/caregiver(s) is/are poorly compliant with other study procedures,
visits, and assessments, preferably after evaluation and discussion between the investigator
and the sponsor.
 
The randomization code is broken by the investigator or the study site personnel.
 
Lost to follow-up.
 
Sponsor’s decision to terminate the study.
In case a participant prematurely discontinues study intervention for any reason, refer to the
Schedule of Activities for the required visits and assessments to be performed.
Study intervention assigned to the participant who discontinued study intervention may not be
assigned to another participant.


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7.2. 
Participant Discontinuation/Withdrawal From the Study
A participant will be withdrawn from the study for any of the following reasons:
 
Lost to follow-up
 
Withdrawal of consent
 
Death
 
The participant’s parent(s)/caregiver(s) is poorly compliant with study procedures, visits, and
assessments, preferably after evaluation and discussion between the investigator and the
sponsor
 
Decision by the sponsor to stop or cancel the study
 
Decision by the investigator to withdraw the participant from the study
 
Decision by local regulatory authorities and Independent Ethics Committee (IEC)/IRB to stop
or cancel the study.
In case the participant prematurely discontinues study participation, refer to the Schedule of
Activities for the required visits and assessments to be performed.
If a participant is lost to follow-up, every reasonable effort must be made by the study  site
personnel to contact the participant’s parent(s)/caregiver(s) and determine the reason for
discontinuation/withdrawal. The measures taken to follow-up must be documented.
Withdrawal of Consent
When a participant’s parent(s)/caregiver(s) withdraw(s) the participant before study completion,
the reason for withdrawal is to be documented in the eCRF and in the source document. If the
reason is withdrawal of consent for further study participation, then no additional assessments are
allowed. However, an optional Follow-up Visit will be offered to safeguard the participant in such
case the participant’s legally acceptable representative(s) withdraw(s) consent from the study.
A participant’s parent(s)/caregiver(s) declining to return for scheduled visits does not necessarily
constitute withdrawal of consent. Alternate follow-up mechanisms that the participant’s
parent(s)/caregiver(s)agreed to when signing the consent form apply as local regulations permit.
7.2.1. 
Withdrawal From the Use of Samples in Future Research
The participant’s parent(s)/caregiver(s) may withdraw consent for use of samples for research
(refer to Long-Term Retention of Samples for Additional Future Research  in Section 10.3,
Appendix 3). In such a case, samples will be destroyed after they are no longer needed for the
clinical study. Details of the sample retention for research are presented in the main ICF.
7.3. 
Lost to Follow-up
A participant will be considered lost to follow-up if the participant’s parent(s)/caregiver(s)
repeatedly fail(s) to return with the participant for scheduled visits and is (are) unable to be
contacted by the study site. A participant cannot be deemed lost to follow-up until all reasonable


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efforts made by the study site personnel to contact the participant’s parent(s)/caregiver(s) are
deemed futile. The following actions must be taken if a participant’s parent(s)/caregiver(s)fails to
return with the participant to the study site for a required study visit:
 
The study site personnel must attempt to contact the participant’s parent(s)/caregiver(s) to
reschedule the missed visit as soon as possible, to counsel the participant’s
parent(s)/caregiver(s)on the importance of continuing regular visits and assessments until the
end of the study (ie, visit Day 35), to ascertain whether the participant’s parent(s)/caregiver(s)
wish(es)to or should continue to have the participant in the study.
 
Before a participant is deemed lost to follow-up, the investigator or designee must make every
reasonable effort to regain contact with the participant’s parent(s)/caregiver(s) (where
possible, 3 telephone calls, e-mails, fax, and, if necessary, a certified letter to the participant’s
parent(s)/caregiver(s)’s last known mailing address, or local equivalent methods. These
contact attempts should be documented in the participant’s medical records.
 
Should the participant’s parent(s)/caregiver(s) continue to be unreachable, they will be
considered to have withdrawn from the study.
Should a study site close, eg, for operational, financial, or other reasons, and the investigator cannot
reach the participant’s parent(s)/caregiver(s) to inform them, their contact information will be
transferred to another study site.
8. 
STUDY ASSESSMENTS AND PROCEDURES
Overview
The Schedule of Activities summarizes the frequency and timing of all measurements applicable
to this study. Unscheduled visits may be performed based on the investigator’s clinical judgment
and may include further evaluations, as needed. In addition, the study site personnel may contact
the parent(s)/caregiver(s) by phone (or other means of contact as agreed upon) after the daily
review of the ObsRO GHQ up to Day 21.
If multiple assessments are scheduled for the same timepoint, it is recommended that procedures
be performed in the following sequence: non-invasive procedures should be collected first before
invasive procedures (ECG, then vital signs/SpO2, then nasal MT  swab, and blood draw last).
Repeat or unscheduled samples may be taken for safety reasons or for technical issues with the
samples.
ObsRO Signs/Symptoms, ObsRO GHQ, and Caregiver Impact Questions assessments should
preferentially be conducted/completed before any tests, procedures, or other consultations to
prevent influencing participant’s parent(s)/caregiver(s) responses, with the exception of the
screening assessment, which can take place after clinician assessment of eligibility.
Clinical course and severity of RSV infection will be assessed through different measures (see
Section 8.1.1).


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The need for supplemental oxygen and supplemental feeding/hydration  will be assessed
throughout the study. Refer to Section 8.1.1.1 for the definition of need for supplemental
oxygen/feeding/hydration.
ClinRO and ObsRO Signs/Symptoms will be used to monitor signs/symptoms of RSV disease,
ClinRO and ObsRO GHQs will be used to monitor its evolution over time, and Caregiver Impact
Questions will be used to monitor parent(s)/caregiver(s) quality of life as described in
Section 8.1.1.3.
All parental study-related assessments will ideally be performed by the same parent (or caregiver)
throughout the study, if feasible.
Assessment of antiviral activity and viral sequencing will be performed as described in
Sections 8.1.2 and 8.1.3, respectively.
Safety and tolerability, including AEs, laboratory assessments, ECGs, vital signs, and physical
examination will be assessed throughout the study from signing of the ICF until the participant’s
last study-related activity (see Sections 8.2 and 8.3). Refer to Section 10.9, Appendix 9 for
guidelines on performing vital signs and SpO2 measurements.
Pharmacokinetic assessments during the study will be based on sparse sampling and will be
performed using a popPK model (see Section 8.4).
Medical encounter data will be collected. Refer to Section 8.6 for details.
Acceptability and palatability will be assessed (see Section 8.7).
Residual blood samples and leftover nasal MT swab samples from samples collected during the
study may be used for exploratory biomarker analyses (see Section 8.8).
The presence of other respiratory viruses or bacteria will be assessed as described in Section 8.9.
Sample Collection and Handling
The actual dates and times of sample collection must be recorded in the laboratory requisition
form.
Refer to the Schedule of Activities for the timing and frequency of all sample collections.


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Instructions for the collection, handling, storage, and shipment of samples are found in the
laboratory manual that will be provided. Collection, handling, storage, and shipment of samples
must be under the specified, and where applicable, controlled temperature conditions as indicated
in the laboratory manual.
Blood Sample Collection and Handling
The maximum amount of blood drawn from each participant in this study per the Schedule of
Activities will not exceed 9.2 mL plus 80 µL for PK samples over the duration of the study and is
in line with recommendations collated by the WHO.23 Repeat tests (see Section 8.2.4) could
increase the total blood volume.
Repeat or unscheduled samples may be taken for safety reasons or for technical issues with the
samples.
Nasal Sample Collection and Handling
For the evaluation of antiviral activity, the RSV viral load in nasal MT swabs will be measured at
the central laboratory  using a qRT-PCR assay (see Section  8.1.2, Antiviral Activity). Viral
sequencing will also be performed on the nasal MT swabs (see Section 8.1.3). Only nasal MT
swabs provided for this study may be used. Other swabs are not acceptable for specimen collection
as they may inhibit recovery of the pathogens. Note that in case of supply issues for nasal MT
swabs because of increased demand due to the COVID-19 pandemic, alternative nasal swabs
instead of nasal MT swabs may be provided for nasal sample collection for the study assessments.
The presence of viral (other than RSV) or bacterial co-pathogens will be assessed in the nasal MT
swab sample by using PCR at the central laboratory (see Section 8.9).
Refer to the Schedule of Activities for the timing and frequency of all sample collections.
Study-Specific Materials
The investigator will be provided with the following supplies:
 
Rilematovir IB and any addenda
 
Pharmacy manual/study site investigational product and procedures manual, and oral dosing
syringes
 
Laboratory manual and specimen collection materials
 
IWRS Manual
 
eCRF completion guidelines
 
Sample ICF
 
eDevice and instructions for use
 
Contact information page(s)
 
ECG machine and manual


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 
Additional auxiliary materials, as needed
The participant’s parent(s)/caregiver(s) will be provided with tools to facilitate/support
participation, such as:
 
eDevice and instructions for use
 
Study information and instruction sheets for parent(s)/caregivers(s) regarding study visits and
procedures, eg, dosing, ObsRO Signs/Symptoms, ObsRO GHQ, Caregiver Impact Questions,
and Acceptability and Tolerability Assessment
 
Oral dosing syringes
8.1. 
Efficacy Assessments
8.1.1. 
Clinical Severity and Clinical Course of RSV Infection
8.1.1.1. 
RSV Recovery Scale Assessments
The RRS is an ordinal scale assessing a participant’s clinical status as defined per protocol. The
study day on which the RRS will be assessed as the primary endpoint is the first study day when
at least 50% of the participants across treatment arms are discharged from the hospital (with or
without signs/symptoms). This study day will be determined in a blinded manner based on all
available data irrespective of the treatment group at the time of the first interim analysis and by an
independent statistician in order to protect data integrity. This study day will be used for any further
interim analysis as well as for the final analysis. The RRS will also be assessed on Days 2 to 8
(excluding the primary time point) as secondary endpoints.
The RRS provides 7 mutually exclusive conditions ordered from best to worst, and the analysis
score reflects the participant’s worst situation on the study day of assessment:
1. Not Hospitalized Without Signs/Symptoms*
2. Not Hospitalized With Signs/Symptoms*
3. Non-ICU Hospitalization, Not Requiring Supplemental Oxygen NOR Supplemental
Feeding/Hydration
4. Non-ICU Hospitalization, Requiring Supplemental Oxygen AND/OR Supplemental
Feeding/Hydration
5. Admitted to the ICU, Not Requiring Mechanical Ventilation**
6. Requiring Mechanical Ventilation**
7. Death
*With or without signs/symptoms is defined by the Key RSV Signs/Symptoms of ObsRO Signs/Symptoms
as being not resolved or resolved (absent or mild), respectively (see Section 10.14, Appendix 14).
**Mechanical ventilation includes both invasive and non-invasive mechanical ventilation.


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The RRS categories are defined below and are referred to as protocol-defined categories, ie, the
categories to which the participant should be assigned based on the data reported in the eCRF and
eCOA, rather than the category where (s)he may actually be. This might result in a categorization
of the participant in a worse or better category than where (s)he actually is.
RSV Recovery Scale: Definitions
Note: For purposes of this protocol, discharge readiness refers to a participant having:
 
improved respiratory effort (eg, improved retractions, stable respiratory rate)
 
improved O2 saturation to ≥ 92% without need for supplemental oxygen
 
fever control
 
adequate hydration/feeding without supplementation
 
stable and/or baseline mental status
1. Not hospitalized without signs/symptoms
Participant met either of the 2 following criteria:
 
Discharged from the hospital before the day of assessment.
 
Hospitalized at the day of assessment but ready for discharge on both the day of
assessment and the day prior, as judged by the investigator.
Without signs/symptoms is defined by:
 
Key RSV Signs/Symptoms based on ObsRO Signs/Symptoms (see Section 10.11,
Appendix 11) resolved (absent or mild) on the day of assessment (see Section 10.14,
Appendix 14).
2. Not hospitalized with signs/symptoms
Participant met either of the 2 following criteria:
 
Discharged from the hospital before the day of assessment.
 
Hospitalized at the day of assessment but ready for discharge on both the day of
assessment and the day prior, as judged by the investigator.
With signs/symptoms is defined by:
 
Key RSV Signs/Symptoms based on  ObsRO  Signs/Symptoms (see Section 10.11,
Appendix 11) not resolved on the day of assessment (see Section 10.14, Appendix 14).
3. Non-ICU hospitalization, not requiring supplemental oxygen  NOR supplemental
feeding/hydration
Participant met either of the 2 following criteria:
 
Non-ICU hospitalized on the day of assessment (including readmittance) and neither
supplemental oxygen nor supplemental feeding/hydration is required by the participant
and not ready for discharge during the whole day of assessment, as judged by the
investigator.


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In the ICU but there is no medical reason to be in the ICU during the day of assessment
and neither supplemental oxygen nor supplemental feeding/hydration is required by the
participant and not ready for discharge during the whole day of assessment, as judged by
the investigator.
4. Non-ICU hospitalization, requiring supplemental oxygen  AND/OR supplemental
feeding/hydration
Participant met either of the 2 following criteria:
 
Non-ICU hospitalized on the day of assessment (including readmittance) and either
supplemental oxygen or supplemental feeding/hydration or both is/are required by the
participant.
 
In the ICU but there is no medical reason to be in the ICU during the day of assessment,
and either supplemental oxygen or supplemental feeding/hydration or both is/are required
by the participant.
Requiring oxygen supplementation is defined by:
 
Having an SpO2 <90% while receiving supplemental oxygen.
 
Receiving supplemental oxygen (and having an SpO2 ≥90%) through a face mask or nasal
cannula and not being able to sustain an SpO2 of ≥92% when breathing room air for
10-15 minutes at any time on the day of assessment (Refer to Section 10.9, Appendix 9
for guidelines on performing the measurement).
 
Not receiving supplemental oxygen and either:
o 
Having an SpO2 of <92% at any measurement on the day of assessment, or
o 
In case of known pre-RSV SpO2 <92% (eg, due to pulmonary dysplasia), the current
SpO2 on room air is lower than pre-RSV infection levels by at least 3%.
Requiring supplemental feeding/hydration by IV administration and/or nasogastric tube on
the day of assessment is defined by:
 
Oral intake is <50% of normal.
5. Admitted to the ICU, not requiring mechanical ventilation
Participant met either of the 2 following criteria:
 
In the ICU (and ICU level of care is required at any time during the day of assessment).
 
On the hospital ward, but deemed to require ICU level of care at any time during the day
of assessment (eg, not transferred to ICU due to bed availability), irrespective of
supplemental oxygen/feeding.
Requiring ICU level of care is defined by:
 
Some specific conditions:
o 
Treatment of acute unstable arrhythmias
o 
Treatment of complicated acid-base or electrolyte imbalances


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o 
Utilization of IV vasoactive medications
o 
Status post cardiac arrest
o 
Cardiogenic Shock
o 
Acute congestive heart failure
o 
Acute or imminent respiratory failure
o 
Hemodynamic instability
o 
High supplemental oxygen requirement (fraction of inspired oxygen
[FiO2] ≥50%)
o 
Requirement for more frequent or continuous inhaled or nebulized medications
than cannot be administered safely on general pediatric ward.
 
Other conditions requiring specialized equipment and/or staff competencies only
available in the ICU and not due solely to pre-existing conditions or prematurity
unless due to worsening of that condition.
6. Requiring mechanical ventilation
 
Any oxygen support requiring intubation or extracorporeal oxygenation.
 
Mechanical ventilation (invasive [oxygen supplementation requiring intubation or
extracorporeal oxygenation] or non-invasive [a) Positive-pressure ventilation such as
continuous positive airway pressure (CPAP), positive end-expiratory pressure (PEEP)
ventilation, b) Negative-pressure ventilation such as continuous negative extra-thoracic
pressure (CNEP), continuous negative pressure (CNP)])is used at any time on the day of
assessment.
7. Death
 
Participant died at any time on the day of assessment or earlier (all-cause mortality).
8.1.1.2. 
Other Clinical Course and Clinical Severity Assessments
The study will include the following additional evaluations of the clinical course of RSV disease:
 
Clinical resolution from RSV disease as assessed daily from Day 2 to Day 8, and defined by:
o Free of oxygen supplementation, AND
o Free of supplemental feeding, AND
o Not requiring ICU (as defined in Section 8.1.1.1), AND
o Key RSV Signs/Symptoms resolved to absent or mild as per the ClinRO
Signs/Symptoms (see Section 8.1.1.3).
 
Evolution and severity of signs/symptoms of RSV disease as assessed by the
parent(s)/caregiver(s) (ObsRO  Signs/Symptoms) and by the investigator (ClinRO
Signs/Symptoms) on an electronic device (see Section 8.1.1.3).
 
Evolution of the RSV disease based on ObsRO GHQ and ClinRO GHQ as assessed by the
parent(s)/caregiver(s) and by the investigator, respectively, on an electronic device.


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 
Oxygen supplementation requirement type (invasive mechanical, non-invasive mechanical,
and non-invasive non-mechanical), and duration.
 
Hydration and feeding by IV line/nasogastric tube and duration.
 
The occurrence of the following RSV-disease relatedcomplications, with onset after treatment
initiation (see Section 10.18, Appendix 18 for definitions), as reported by the investigator as
AE based on the available clinical information (see also Section 8.3):
o Respiratory complications: respiratory failure, apnoeic attacks, bronchiolitis/bronchial
obstruction, pneumonia, asthmatic crisis;
o Infectious complications: otitis media, bacterial respiratory tract infections, sepsis;
o Cardiovascular complications: arrhythmia, cardiogenic shock, hemodynamic instability,
congestive cardiac failure;
o Acid-base or electrolyte complications, based on laboratory values if considered
clinically relevant:
 metabolic acidosis (serum HCO3 <16),
 metabolic alkalosis (serum HCO3 >30),
 hyponatremia (Na+ <130 mEq/L),
 hypokalemia (K+ <2.9 mEq/L),
 hyperkalemia (K+ >6.0 mEq/L),
 hypocalcemia (Ca2+ <7.7 mg/dL or equivalent to Grade 2 in children ≤3 months
of age),
 hypercalcemia (Ca2+ >11.9 mg/dL or equivalent to Grade 2 in children
≤3 months of age),
 hypoglycemia (glucose <54 mg/dL),
 hyperglycemia (glucose >160 mg/dL).
 
Clinical parameters: respiratory rate, heart/pulse rate, SpO2, and body temperature as
measured by the investigator during scheduled visits. Refer to Section 10.9, Appendix 9for
guidelines on performing these assessments.
 
Time to first hospital discharge (from start of dosing).
 
Time to readiness for hospital discharge.
 
Reason for hospital discharge or for no discharge despite being clinically ready for discharge
(as defined in Section 8.1.1.1).
 
The requirement for transition to ICU and duration of ICU stay.
 
Proportion of participants requiring rehospitalization for respiratory/other reasons.
 
Number and type of medical encounters (see also Section 8.6).
 
Incidence of antibiotic treatment episodes.
 
Incidence of systemic or inhaled corticosteroids and bronchodilators use.


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 
Impact of child’s RSV disease on the parent(s)/caregiver(s) and family as assessed by the
Caregiver Impact Questions (see Section 8.1.1.3).
The pre-enrollment status of the participant will be captured based on the clinical assessments
performed at presentation to the hospital (based on source documents)or prior to enrollment.
8.1.1.3. 
ClinRO and ObsRO Clinical Outcome Assessments and Caregiver
Impact Questions
The PRESORS developed by the sponsor to monitor RSV severity and its impact in pediatric
patients include several assessments that the clinicians treating the study participants and the
parents/caregivers of participants need to complete on an electronic device at the timepoints
specified in the Schedule of Activities. In case of a bid schedule for the PRESORS, assessments
are expected to be performed approximately every 12 hours. Every effort should be made to have
at least 8 hours between assessments. The PRESORS for the clinicians consists of the ClinRO
Signs/Symptoms, the ClinRO GHQ, and an additional question regarding apnea (see
Section 10.13, Appendix 13). The PRESORS for the parents/caregivers (PRESORS ObsRO)
consist of ObsRO Signs/Symptoms, ObsRO GHQ, and Caregiver Information (only assessed
during set up of the electronic device) (see Section 10.10, Appendix 10, Section 10.11,
Appendix 11, and Section 10.12, Appendix 12). The sponsor developed the ClinRO and ObsRO
Signs/Symptoms assessments to monitor signs/symptoms of RSV disease severity observed and
rated by clinicians treating pediatric participants as well as by the participant's
parent(s)/caregiver(s) 
from 
baseline 
through 
end 
of 
follow-up. 
Clinicians 
and
parent(s)/caregiver(s) are instructed to rate each sign/symptom at its worst during the recall period.
The ClinRO and ObsRO GHQs provide assessments by the clinicians and the
parent(s)/caregiver(s), respectively, of the overall impression of the participant’s RSV disease
severity, change in the participant’s RSV disease, and overall health status. In addition to the
ObsRO Signs/Symptoms and ObsRO GHQ, parents/caregivers will also be asked to complete
Caregiver Impact Questions (see Section 10.12, Appendix 12) and an assessment of acceptability
and palatability (see Section 8.7 and Section 10.16, Appendix 16) at the timepoints specified in
the Schedule of Activities on the same electronic device.
“Resolution of Key RSV Signs/Symptoms” used in several endpoints refers to the Key RSV
Signs/Symptoms assessed by the ClinRO Signs/Symptoms or ObsRO  Signs/Symptoms, as
specified, as being resolved (absent or mild) or not resolved (see Section 10.14, Appendix 14, and
Section 10.15, Appendix 15 for definitions of resolved/not resolved). The Key RSV
Signs/Symptoms are:
 Breathing Problems
 Retractions
 Tachypnea
 Cough
 Wheezing (ClinRO) / Breathing Sounds (ObsRO)
 Tachycardia


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Additional general illness and upper respiratory tract signs/symptoms of RSV disease assessed by
the ClinRO Signs/Symptoms and/or ObsRO Signs/Symptoms are listed below. Refer to
Section 10.14, Appendix 14, and Section 10.15, Appendix 15 for definitions of resolved/not
resolved.
 Activity Level (ClinRO) / General Illness Behavior (ObsRO)
 Sleep Disturbance
 Crying (ObsRO only)
 Feeding Problems
 Dehydration
 Nasal Secretions (ClinRO)/ Nasal Signs (ObsRO)
Signs/symptoms reported in these assessments will not be reported as AEs but constitute a part of
the efficacy evaluations.
For completion of the ClinRO Signs/Symptoms, chest, nose, and head examination (including
visual inspection and auscultation) needs to be performed.
The Caregiver Impact Questions assess how worried parent(s)/caregiver(s) was/were about
his/her/their child’s health and how much time impact the child’s disease meant, including hours
missed from work. The Caregiver Impact Questions are asked to be completed by
parent(s)/caregiver(s) on an electronic device at the timepoints specified in the Schedule of
Activities (see Section 10.12, Appendix 12). Responses to these questions are not mandatory, but
provide valuable information about the impact of the child's illness and recovery on the child's
family.
ObsRO Signs/Symptoms, ObsRO GHQ, and Caregiver Impact Questions will ideally be
performed by the same parent/caregiver throughout the study, if feasible. If these assessments are
performed during hospitalization or an on-site visit, they should preferentially be
conducted/completed before any tests, procedures, or other consultations to prevent influencing
participant’s parent(s)/caregiver(s) perceptions, with the exception of the screening assessment,
which can take place after clinician assessment of eligibility.
The investigator/study staff will provide sufficient information (included in the study manual and
caregiver study information packet) to enable the parent(s)/caregiver(s) to complete the
assessments on the electronic device correctly and on schedule to avoid missing or incorrect data.
Prior to completing the screening assessment, the parent(s)/caregiver(s) must complete a training
module (included on the electronic device) on how to enter responses to questions on the electronic
device. The parent(s)/caregiver(s) may also choose to complete the Caregiver Information, ObsRO
Signs/Symptoms, ObsRO GHQ, and Caregiver Impact Questions on a personal device (web diary).
The Caregiver Information, ObsRO Signs/Symptoms, ObsRO GHQ, and Caregiver Impact
Questions will be provided in the local language in accordance with local guidelines.


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8.1.2. 
Antiviral Activity
As an evaluation of antiviral activity, the RSV viral load in nasal MT  swab samples will be
measured at the central laboratory using a qRT-PCR assay. The qRT-PCR used to determine RSV
viral load will also provide information on the RSV subtype. Nasal MT swab specimens for the
determination of RSV viral load will be collected at several timepoints during the study as
indicated in the Schedule of Activities and Figure 3. Date and time of sampling will be collected.
Nasal MT swabs should be collected from the same nostril throughout the study (unless precluded
due to bleeding). The nostril that was sampled will be documented by the study site personnel.
During screening, a study-specific screening sample (nasal MT swab) will be collected for the
local diagnosis of RSV infection using a PCR or other molecular-based diagnostic assay. If the
participant is subsequently randomized, the remaining sample content should be shipped for
central testing of RSV viral load and viral sequencing. However, if an RSV positive diagnostic
test result from a sample collected per local SOC testing within 24 hours prior to start of screening
is available this may also be used to determine study eligibility. In such case, the collection of the
study-specific screening nasal MT swab is not applicable.
The predose nasal MT swab on Day 1 should be collected as close as possible prior to the first
administration of study intervention. If a study-specific screening nasal MT swab was collected
within 8 hours prior to dosing, the leftover of that sample can serve as the baseline predose sample,
provided that the study-specific screening nasal MT swab sample was stored appropriately and has
sufficient sample volume available (volume is considered sufficient if no more than 600 µL from
the original sample has been used for local RSV testing and the whole remainder of the original
sample is available). Only in such case, no additional sample needs to be collected at Day 1
predose. The next nasal swabs should be collected preferably at approximately the same time as
the predose swab taken on Day 1 and preferably prior to dose administration of the next days.
The baseline predose nasal MT  swab will be used for central confirmation of RSV diagnosis,
determination of RSV viral load, viral sequencing and determination of the presence of other
respiratory viruses or bacteria. These assessments will be performed on the leftover from the
screening nasal MT  swab sample in case that sample can be used as the predose sample (if
collected within 8 hours prior to dosing and provided appropriate storage and sufficient volume
available).
Throughout the treatment phase and follow-up phase the investigational staff will collect nasal MT
swabs for determination of RSV viral load and viral sequencing (see Figure 3):
 
During hospitalization: Swabs will continue to be collected each day during hospitalization
through Day 8 and on Days 14 and 21 or until discharge (whichever comes first).
 
Discharged participants: Swabs will be collected at each scheduled on-site (or home) visit
through Day 21.


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Figure 3: 
Schedule for Collection of Nasal Mid-Turbinate Swab Samples
D: Day, hrs: hours, MT: mid-turbinate, RSV: respiratory syncytial virus, SOC: standard-of-care.
The collection of these nasal MT swabs and date and time of sampling should be recorded for all
participants in the eCRF.
8.1.3. 
Viral Sequencing
Viral resistance will be monitored by sequencing of the RSV F gene in all baseline (predose or
screening) nasal swab samples and in subsequent samples upon request of the sponsor’s virologist.
Other regions of the RSV genome may also be sequenced at discretion of the sponsor’s virologist.
Sequencing results will be presented in a separate report. Sequencing data will not be reported to
the investigators.
Changes in viral sequence will be evaluated but will not be reported as AEs.
8.2. 
Safety Assessments
Details regarding the IDMC are provided in Committees Structure in Section 10.3, Appendix 3.
Adverse events will be reported and followed up by the investigator as specified in Section 8.3 and
Section 10.4, Appendix 4.
Any clinically relevant changes occurring during the study must be recorded on the AE section of
the eCRF. Any clinically significant abnormalities persisting at the end of the study/early
withdrawal will be followed by the investigator until resolution or until a clinically stable condition
is reached.
The study will include the following evaluations of safety and tolerability according to the time
points provided in the Schedule of Activities.


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8.2.1. 
Physical Examinations
To evaluate the participant’s eligibility, a complete physical examination of all body systems,
including length or height, head circumference, and body weight measurements will be performed
at screening.
A directed physical examination will be performed at several time points throughout the study.
The directed physical examination  is inclusive of the examination needed for the ClinRO
Signs/Symptoms completion (see Section 8.1.1.3): respiratory system, nose and ear, as well as the
throat and facial and neck lymph nodes. On Day 21, also length or height, head circumference,
and body weight measurements will be included (see Schedule of Activities).
To obtain the actual body weight, participants are advised to be weighed unclothed with a dry
diaper only or lightly clothed, with consistency for all visits. Length may be assessed in the supine
position and the same position should be used for the subsequent assessments of that participant.
Any clinically relevant changes occurring during the study must be recorded in the AE Section of
the eCRF. Clinically relevant findings present at screening will be reported as medical history, any
worsening of these findings during the study must be reported as AE.
8.2.2. 
Vital Signs
Temperature, pulse/heart rate, respiratory rate, and SpO2 will be assessed as part of the clinical
parameters (Section 8.1.1.2).
Additional vital signs assessments include systolic blood pressure and diastolic blood pressure.
Refer to Section 10.9, Appendix 9for guidelines on performing vital signs assessments.
For the duration of hospitalization, vital signs will be assessed for each participant twice daily
preferably at approximately the same time on each scheduled day. After discharge, vital signs will
be assessed once during the on-site visits. See Schedule of Activities.
Any clinically relevant abnormalities occurring during the study should be recorded in the AE
Section of the eCRF.
8.2.3. 
Electrocardiograms
Screening and on-treatment ECGs will be collected at the time points indicated in the Schedule of
Activities. Day 1 and Day 3 ECGs should be taken approximately one hour (45-90 minutes) after
administration of study intervention.
The participant should be supine (infants can be lying on their parent’s/caregiver’s arm) and rested
for at least 5 minutes and preferably sleeping or calm (ie, not crying).
Electrocardiograms (12-lead ECG) should be performed using procedures commensurate with the
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For eligibility determination, the machine read ECG results, printed on the ECG device print-out
of the ECG tracing, will be taken into account. Central ECG readings will be performed by a
central ECG laboratory. Instructions for ECG acquisition and ECG transmission will be described
in the manual provided by the ECG laboratory. There will be 2 ECG reports generated by the
central ECG laboratory: a preliminary report and a final report. Both ECG reports will need to be
interpreted for clinical significance, signed and dated by the investigator, and filed in the
participant’s medical record. Clinically relevant abnormalities occurring during the study should
be recorded by the investigator in the AE Section of the eCRF.
In the event that an invasive procedure such as a blood draw or nasal swab and an ECG are required
at approximately the same time, the ECG should be collected first. Electrocardiograms may be
repeated at the investigator discretion.
The investigator will be responsible for evaluating the results and determining if any findings are
of clinical significance. If a participant has a QTcF interval ≥500 msec based on the machine read
ECG results, confirmation needs to be obtained during the same visit day by repeat ECG recording.
If confirmed, the participant needs to be withdrawn from study intervention (see also Section 7.1).
In case clinically relevant abnormalities are observed post-baseline, a confirmatory ECG must be
performed preferably within 48 hours, but no later than 72 hours, after the results have become
available. Evaluation of clinical relevance should be done on confirmed results.
8.2.4. 
Clinical Safety Laboratory Assessments
Blood samples for serum chemistry and hematology and a random urine sample for urinalysis will
be collected as noted in Section 10.2, Appendix 2. The investigator must review the laboratory
results, document this review, and record any clinically relevant changes occurring during the
study in the adverse event section of the eCRF. The laboratory reports must be filed with the source
documents. If a participant has a laboratory abnormality of ALT increase ≥3 × ULN in the
screening sample and met the liver chemistry stopping criteria (see Section 10.8, Appendix 8), the
participant should be permanently discontinued from the study intervention and the study.
If a participant has any other laboratory abnormality of Grade 3 or 4, confirmation needs to be
obtained by a repeat test (centrally), to be performed within 48 hours of the result being available
at the site. If confirmed, the participant should be permanently discontinued from the study
intervention (see Section 7.1).
8.3. 
Adverse Events, Serious Adverse Events, and Other Safety Reporting
Timely, accurate, and complete reporting and analysis of safety information, including AEs, SAEs,
and Product Quality Complaint (PQC), from clinical studies are crucial for the protection of
participants, investigators, and the sponsor, and are mandated by regulatory agencies worldwide.
The sponsor has established Standard Operating Procedures in conformity with regulatory
requirements worldwide to ensure appropriate reporting of safety information; all clinical studies
conducted by the sponsor or its affiliates will be conducted in accordance with those procedures.


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Adverse events will be reported by the participant’s parent(s)/caregiver(s) (or, when appropriate,
by a caregiver, surrogate, or the participant's legally acceptable representative) for the duration of
the study.
For complications related to RSV disease as listed in Section 8.1.1.2 (see also Section 10.18,
Appendix 18 for definitions and diagnostic criteria), additional data related to these events are
collected when available and will be captured separately in the eCRF. Management of these events
will be at the discretion of the investigator and should follow generally accepted medical standards.
Anticipated events for this study are defined in Section 8.3.4 and will be recorded and reported as
described in Section 8.3.4, Regulatory Reporting Requirements for Serious Adverse Events.
Further details on AEs, SAEs, and PQC can be found in Section 10.4, Appendix 4.
8.3.1. 
Time Period and Frequency for Collecting Adverse Event and Serious
Adverse Event Information
All Adverse Events
All AEs and special reporting situations, whether serious or non-serious, will be reported from the
time a signed and dated main ICF is obtained until completion of the participant's last study-related
procedure, which may include contact for follow-up of safety.
For participants with only a signed pre-screening (diagnostic) ICF (ie, for whom consent was not
given to enroll in the main study by the parent[s]/caregiver[s] by signing the main ICF), only study
procedure relatedAEs will be reported.
Serious Adverse Events
All SAEs, as well as PQC, occurring during the study must be reported to the appropriate sponsor
contact person by study site personnel within 24 hours of their knowledge of the event.
Serious adverse events, including those spontaneously reported to the investigator within 30 days
after the last dose of study intervention, must be reported. The sponsor will evaluate any safety
information that is spontaneously reported by an investigator beyond the time frame specified in
the protocol.
Information regarding SAEs will be transmitted to the sponsor using the Serious Adverse Event
Form and Safety Report Form of the eCRF, which must be completed and reviewed by a physician
from the study site, and transmitted to the sponsor within 24 hours. The initial and follow-up
reports of an SAE event should be transmitted electronically.
8.3.2. 
Method of Detecting Adverse Events and Serious Adverse Events
Care will be taken not to introduce bias when detecting AEs or SAEs. Open-ended and nonleading
verbal questioning of the participant’s parent(s)/caregiver(s) is the preferred method to inquire
about AE occurrence.


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8.3.3. 
Follow-up of Adverse Events and Serious Adverse Events
The investigator is obligated to perform or arrange for the conduct of supplemental measurements
and evaluations as medically indicated to elucidate the nature and causality of the AE, SAE, or
PQC as fully as possible. This may include additional laboratory tests or investigations,
histopathological examinations, or consultation with other health care professionals.
AEs will be followed by the investigator as specified in Section 10.4, Appendix 4.
8.3.4. 
Regulatory Reporting Requirements for Serious Adverse Events and
Anticipated Events
The sponsor assumes responsibility for appropriate reporting of AEs to the regulatory authorities.
The sponsor will also report to the investigator (and the head of the investigational institute where
required) all suspected unexpected serious adverse reactions (SUSARs). The investigator (or
sponsor where required) must report SUSARs to the appropriate IEC/IRB that approved the
protocol unless otherwise required and documented by the IEC/IRB. A SUSAR will be reported to
regulatory authorities unblinded. Participating investigators and IEC/IRB will receive a blinded
SUSAR summary, unless otherwise specified.
An anticipated event is an AE (serious or non-serious) that commonly occurs in the study
population independent of exposure to the drug under investigation. For the purposes of this study
the following SAEs will be considered anticipated events:
 
Cyanosis
 
Pneumonia
 
Bronchiolitis
 
Respiratory failure
 
Rhinitis
 
Apnea
 
Co-infections (bacterial or viral)
These anticipated events will be periodically analyzed in aggregate by the sponsor during study
conduct. The sponsor will prepare a safety report in narrative format if the aggregate analysis
indicates that the anticipated event occurs more frequently in the treatment group than in the
control group and the sponsor concludes there is a reasonable possibility that the drug under
investigation caused the anticipated event.
The plan for monitoring and analyzing the anticipated events is specified in a separate Anticipated
Events Safety Monitoring Plan. The assessment of causality will be made by the sponsor’s
unblinded Safety Assessment Committee.
The sponsor assumes responsibility for appropriate reporting of the listed anticipated events
according to the requirements of the countries in which the studies are conducted.


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8.3.5. 
Adverse Events / Safety Topics of Special Interest
The following only applies to AEs starting after initiation of study intervention.
8.3.5.1. 
Hepatobiliary Effects
Given the hepatobiliary-related nonclinical findings and because the amount of clinical data is
limited, the sponsor considers hepatobiliary effects to be a safety topic of special interest.
Hepatobiliary function will be evaluated by routine hepatobiliary function tests during the study.
In addition, a liver safety management plan is implemented based on ALT elevation. This liver
safety management plan applies to screening results after the laboratory results become available
to the site (refer to Section 10.8, Appendix 8).
Grading of ALT elevation will be based on the Division for Microbiology and Infectious Diseases
(DMID) Pediatric Toxicity Table (see Section 10.5, Appendix 5).
In case ≥ Grade 2 alkaline phosphatase (ALP) increase, additional laboratory assessments (such as
γ-glutamyltransferase [GGT] and/or 5'-nucleotidase [5’NT]) may be performed as reflex testing
for further evaluation of origins of elevation of potential hepatobiliary enzymes (see Section 10.2,
Appendix 2 and Section 10.6, Appendix 6).
For any Grade 3 or 4 laboratory abnormalities that occurred at Day 8, Day 21 and Day 35 visits,
participants should have a confirmatory  measurement, preferably within 48 hours after the
laboratory results become available to the site. For confirmed Grade 3 or 4 laboratory
abnormalities, participants should be followed until resolution (return to baseline) or stabilization
of ALT elevation. During the study, these assessments will be captured as unscheduled
assessments/visits.
8.3.5.2. 
Cardiac Events Potentially Related to QT Prolongation
Regular cardiac safety monitoring will be done in this study via assessments of AEs, laboratory
abnormalities, and regular ECGs.
A participant's study intervention must be discontinued if the participant has a confirmed QTcF
value ≥500 msec at any scheduled visit based on the machine read QTcF  value. Confirmation
needs to be obtained during the same visit day by repeat ECG recording locally at the site (see
Section 7.1). For participants with a confirmed QTcF  interval value ≥500 msec during the
treatment period, the following measures should be taken:
 The cardiac event must be reported to the sponsor within 24 hours.
 The investigator should request urgent cardiology referral.
 Clinical evaluation including safety biochemistry (such as electrolytes), assessment of the use
of concomitant QT prolonging drugs, and evaluation for the presence of any structural heart
disease must be conducted. Levels of potassium and magnesium to be determined by the


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central laboratory. In case of hypokalemia and/or hypomagnesemia at screening or Day 8, the
levels of potassium and/or magnesium should be checked as soon as possible at the local
laboratory and corrected to prevent cardiac disturbances. Appropriate clinical management per
local SOC (including but not limited to checking the corrected values at local laboratory) may
be required.
 Appropriate clinical monitoring per local SOC, including ECG, should be installed. An ECG
should be repeated every 24 hours until resolution of QTcF interval prolongation is confirmed.
The participants condition should be followed until resolution (return to baseline) or
stabilization. During the study, these assessments will be captured as unscheduled
assessments/visits.
8.4. 
Pharmacokinetics
A blood sample for determination of rilematovir concentrations will be collected through finger
prick or heel stick at 2 timepoints (see Section  1.3.3, Pharmacokinetic Assessments Sampling
Schedule).
The following times need to be recorded: date and time of last study intervention intake, date and
time of PK blood sampling, and time of any meal consumed within 30 minutes before or after the
previous study intervention intake.
Additional information about the collection, handling, and shipment ofbiological samples can be
found in the laboratory manual.
Residual samples after PK analysis can also be used for the analysis of metabolites of rilematovir,
protein binding, or endogenous markers for enzymes or transporters involved in the metabolism
and distribution of rilematovir or RSV-related biomarkers, at the discretion of the sponsor.
Residual blood samples collected for PK may also additionally be used to evaluate safety or
efficacy aspects that address concerns arising during or after the study period. Genetic analyses
will not be performed on these samples. Participant confidentiality will be maintained.
8.4.1. 
Evaluations
Samples will be used for determination of rilematovir concentrations. Samples can also be used
for the analysis of metabolites of rilematovir, protein binding, or endogenous markers for enzymes
or transporters involved in the metabolism and distribution of rilematovir or RSV-related
biomarkers, at the discretion of the sponsor.
8.4.2. 
Analytical Procedures
Pharmacokinetics
Samples will be analyzed (applicable treatment group only [not the placebo group]) to determine
concentrations of rilematovir and/or metabolites as applicable using a validated, specific, and
sensitive method by or under the supervision of the sponsor.


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8.4.3. 
Pharmacokinetic Parameters and Evaluations
Population PK analysis of plasma concentration-time data of rilematovir will be performed using
nonlinear mixed-effects modeling. Data may be combined with those of other selected studies (ie,
Phase 1 and Phase 2 studies) to support a relevant structural model. Available baseline participant
characteristics (eg, demographics, body weight, laboratory variables, genotypes, race, etc.) will be
tested as potential covariates affecting PK parameters. The results of the population PK analysis
will be reported in a separate report.
Data will be listed for all participants with available plasma concentrations per treatment arm.
Participants will be excluded from the PK analysis if their data do not allow for accurate
assessment of the PK (eg, incomplete administration of the study intervention; missing information
of dosing and sampling times; concentration data not sufficient for PK parameter calculation).
All concentrations below the lowest quantifiable concentration or missing data will be labeled as
such in the concentration database. All participants and samples excluded from the analysis will
be clearly documented in a separate PK report.
8.5. 
Pharmacokinetic/Pharmacodynamic Evaluations
Obtained PK and PD data (selected antiviral activity parameters, clinical outcomes, and safety
parameters)will be used to explore the relationship between the PK and PD.
8.6. 
Medical Encounters
Medical encounters will be collected in the eCRF for all participants from time for presentation at
the hospital/clinic throughout the study. Protocol-mandated procedures, tests, and encounters are
excluded. The data collected may be used to conduct exploratory economic analyses and will
include:
Number and duration of medical care encounters and treatments (including physician or
emergency room visits, tests and procedures, and medications, surgeries and other selected
procedures; inpatient and outpatient).
8.7. 
Acceptability and Palatability
Acceptability and palatability of the rilematovir formulation will be assessed through a
questionnaire completed by parent(s)/caregiver(s) on an electronic device after last dosing (see
Section 10.16, Appendix 16).
8.8. 
Biomarkers
No specific samples will be collected for biomarker research. Leftover blood samples and leftover
nasal MT  swab samples from samples collected during the study may be used for exploratory
biomarker analyses (eg, proteins, RNA, immune cells, microbiome)at the sponsor’s discretion and
results may be reported separately from this study.


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8.9. 
Detection of Baseline Presence of Other Respiratory Viruses and Bacteria
The presence of other respiratory viruses (other than RSV) or bacteria will be assessed in the nasal
MT swab sample collected at baseline by PCR assay at the central laboratory. Central testing for
other respiratory viruses will also include testing for the presence of SARS-CoV-2 in the nasal MT
swab sample. Nasal MT swabs from other time points may also be assessed for detection of other
respiratory viruses or bacteria at the central laboratory, if deemed necessary.
9. 
STATISTICAL CONSIDERATIONS
Statistical analysis will be done by the sponsor or under the authority of the sponsor. A general
description of the statistical methods to be used to analyze the efficacy and safety data is outlined
below. Specific details will be provided in the Statistical Analysis Plan (SAP).
The primary analysis will be performed when all randomized participants have completed the final
study visit or discontinued earlier.
9.1. 
Statistical Hypotheses
The primary hypothesis is that treatment with rilematovir improves clinical outcome of RSV
infection as compared to placebo in hospitalized pediatrics as assessed on the RRS on the first
study day when at least 50% of the participants across treatment arms are discharged from the
hospital.
9.2. 
Sample Size Determination
The study will aim to enroll 737 participants. Participants will be randomized 2:1 (active:placebo)
to receive either rilematovir or placebo.
The sample size calculation is based on the primary endpoint, ie, the RRS and results from Study
53718678RSV2002. The study day on which the RRS will be assessed as the primary endpoint is
the first study day when at least 50% of the participants across treatment arms are discharged from
the hospital (with or without signs/symptoms). This study day will be determined in a blinded
manner based on all available data irrespective of the treatment group at the time of the first interim
analysis and by an independent statistician in order to protect data integrity. This study day will be
used for any further interim analysis as well as for the final analysis.
Based on the proportional odds model and assuming a benefit of approximately 45% reduction of
the common odds ratio, a total sample size of 700 participants (randomized 2:1) would provide a
power of at least 95%, using an overall Type 1 error rate of 5% (2-sided) and accounting for the
group-sequential design.42 A reduction of 35%, which is still considered clinically relevant, would
provide a power of 80%. Assuming 5% of participants will be excluded from the primary analysis
set (intent to treat - infected [ITT-i] set), the total sample size for this study is 737.
In the sample size calculation, it is assumed that the distribution of participants treated with placebo
between the categories of the RRS will be as follows on the selected study day:


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 Not hospitalized without signs/symptoms: 20%
 Not hospitalized with signs/symptoms: 20%
 Non-ICU hospitalization, not requiring supplemental oxygen  nor supplemental
feeding/hydration: 15%
 Non-ICU 
hospitalization, 
requiring 
supplemental 
oxygen  and/or 
supplemental
feeding/hydration: 30%
 Admitted to the ICU, not requiring mechanical ventilation: 7%
 Requiring mechanical ventilation: 7%
 Death: 1%
The sample size is robust to mild to moderate changes to this distribution.
9.3. 
Populations for Analyses
For purposes of analysis, the following populations are defined:
Population 
Description
Enrolled 
All participants who signed the main ICF.
Randomized 
All participants who were randomized in the study.
ITT-i 
All participants who were randomized and treated (at least one dose) and had an RSV
infection confirmed by central laboratory analysis. Participants with confirmed SARS-CoV-2
infection (positive test by central laboratory analysis) are excluded. This population will be
used for the analysis of efficacy endpoints, as randomized.
Safety  
All participants who took at least 1 dose of study intervention. This population will be used
for the analysis of safety endpoints, as treated.
Pharmacokinetic 
All participants in the ITT-i set. Participants will be excluded from the population PK
analysis if their data do not allow for accurate assessment of the PK parameters (eg,
incomplete administration of the study intervention; missing information of dosing and
sampling times).
9.4. 
Statistical Analyses
9.4.1. 
General Considerations
Further details will be provided in the SAP.
Participant Information
For all participants who received at least 1 dose of study intervention, descriptive statistics will be
provided (safety population).
All demographic (eg, age, length, weight, race, gender) and other initial participant characteristics
(physical examination [length, body weight, head circumference], medical and surgical history,
family history, concomitant diseases, RSV disease characteristics) will be tabulated and analyzed
descriptively by treatment group.


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9.4.2. 
Efficacy Analyses
As a confirmatory strategy, to account for multiplicity in the statistical evaluation of the most
important efficacy endpoints, a hierarchical testing procedure will be applied to control for the
overall Type I error rate at the 5% level (2-sided). The following endpoints are included in the
confirmatory testing strategy:
1. 
RRS, ie, the primary endpoint.
2. 
Proportion of participants clinically resolved from RSV disease (based on ClinRO
Signs/Symptoms as assessed at the same study day as the primary endpoint).
3. 
Time from first dosing to resolution of Key RSV Signs/Symptoms based on ObsRO
Signs/Symptoms and supplementation-free for at least 24 hours.
4. 
Time from discharge to resolution of Key RSV Signs/Symptoms based on ObsRO
Signs/Symptoms (for participants who did not reach resolution before first discharge).
5. 
Time from first dosing to end of oxygen supplementation (for participants who were
receiving supplemental oxygen at the time offirst dosing).
6. 
Incidence in post-baseline RSV-related complications.
First, the primary endpoint will be tested for superiority of rilematovir over placebo at the 2-sided
5% significance level. If superiority is shown on the primary endpoint, then the first secondary
endpoint indicated by “2.” in the sequence above will be tested for superiority at the 2-sided 5%
significance level. If superiority is shown for this secondary endpoint, further secondary endpoints
will be tested for superiority in the sequence as indicated above, and at the same significance level.
In case superiority is not shown for an endpoint, no further endpoints in the sequence will be tested
for superiority.
9.4.2.1. 
Primary Endpoint
The study day on which the RRS will be assessed as the primary endpoint is the first study day
when at least 50% of the participants across treatment arms are discharged from the hospital (with
or without signs/symptoms). This study day will be determined in a blinded manner based on all
available data irrespective of the treatment group at the time of the first interim analysis and by an
independent statistician in order to protect data integrity. This study day will be used for any further
interim analysis as well as for the final analysis.
A proportional odds model will be used to analyze the RRS, including treatment, RRS category at
baseline, and the two stratification factors (stratification by presence of [a] risk factor[s] for severe
RSV disease versus otherwise healthy and by region).
In addition, each of 6 dichotomizations of the RRS, ie:


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 Not hospitalized without signs/symptoms, vs worse
 Not hospitalized with signs/symptoms (or better), vs worse
 Non-ICU hospitalized not requiring supplemental oxygen nor supplemental feeding/hydration
(or better), vs worse
 Non-ICU hospitalized requiring supplemental oxygen and/or feeding/hydration (or better), vs
worse
 Admitted to the ICU not requiring mechanical ventilation (or better), vs worse
 Requiring mechanical ventilation (or better), vs worse (ie, died)
will be analyzed using a logistic regression model, including treatment, RRS category at baseline,
and stratification factors.
9.4.2.1.1. 
Estimand
The primary estimand attributes are as follows:
A. Study intervention:
 
Rilematovir + standard-of-care (SOC)
 
Placebo + SOC
B. Population:
Hospitalized children ≤5 years of age, diagnosed with moderate to severe, central laboratory
confirmed RSV infection, randomized within onset of first RSV signs/symptoms ≤3 days and
without SARS-CoV-2 infection as confirmed by central laboratory analysis.
C. Variable:
RRS at Study Day X based on protocol-defined categories, ie, the categories to which the
participant should be assigned based on the data reported in the eCRF and eCOA, rather than the
category where (s)he may actually be. The Study Day X is the first study day when at least 50%
of the participants across intervention groups are discharged from the hospital and will be
determined in a blinded manner at the time of the first interim analysis.
D. Summary measure (Population-level summary):
The common odds ratio will be estimated by a proportional odds model.




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9.4.2.2. 
Key Secondary Endpoint(s)
For the hypothesis testing, the following methods will be used:
 Time from first dosing to resolution of Key RSV Signs/Symptoms (based on ObsRO
Signs/Symptoms), time from discharge to resolution of Key RSV Signs/Symptoms (based on
ObsRO Signs/Symptoms) and time from first dosing to end of oxygen supplementation will be
analyzed using a stratified Gehan-Wilcoxon test (using the randomization stratification
factors).
 To compare the proportion of participants clinically resolved from RSV (based on ClinRO
Signs/Symptoms), a logistic regression model will be used. Randomization stratification
factors will be added to the model. A similar model will be applied to analyze the incidence of
treatment-emergent RSV-related complications.
9.4.2.3. 
Clinical Course of RSV Infection
Endpoints related to evaluation of the clinical course of RSV infection will be analyzed graphically
and descriptively  as described in the statistical analysis plan SAP. For continuous variables,
descriptive statistics (including: n, mean, SD, median, minimum, and maximum) will be
calculated. For categorical variables, frequency tables will be presented. Time to-variables will be
analyzed using KM plots and will be modeled using an accelerated failure time model, adjusted
for the randomization stratification factors, to estimate differences between intervention groups.
More details regarding the analysis, including subgroup analyses, of these data will be described
in the SAP.
9.4.2.4. 
Antiviral Activity
Antiviral activity will be determined based on measurements of RSV viral load in nasal MT swab
samples by a qRT-PCR assay. These data will be analyzed graphically and descriptively as
described in the SAP. For continuous variables, descriptive statistics (including: n, mean, SD,
median, minimum, and maximum) will be calculated. For categorical variables, frequency tables
will be presented.
Mean log10 viral load values over time will be analyzed using a restricted maximum likelihood-
based repeated measures approach. Differences between intervention groups in viral load, and the
difference in the RSV viral load AUC through Days 3, 5, and 8 between intervention groups will
be derived using appropriate contrasts deriving least square mean differences, including the 95%
2-sided confidence intervals.
The relationship between antiviral activity and baseline characteristics, including but not limited
to RSV viral subtype, genotype and baseline neutrophils will be explored.
9.4.2.5. 
Viral Sequencing
The results of viral sequencing will be evaluated by the sponsor virologist. Pre-treatment genetic
variations and relevant post-baseline changes in the RSV F gene (and other regions of the RSV
genome, if applicable and on request of the sponsor virologist) will be tabulated and described.


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The effect of pre-treatment RSV F protein  genetic variations and relevant post-baseline RSV
F protein amino acid changes on antiviral response and/or clinical outcomes will be explored.
9.4.3. 
Safety Analyses
All safety analyses will be performed on the Safety Population.
Adverse Events
The verbatim terms used in the eCRF by investigators to identify AEs will be coded using the
Medical Dictionary for Regulatory Activities (MedDRA). Any AE or any worsening of an
pre-existing condition occurring at or after the initial administration of study intervention through
the end of the study is considered to be treatment-emergent AE (TEAE). All reported TEAEs will
be included in the analysis. For each TEAE, the percentage of participants who experience at least
1 occurrence of the given event will be summarized by intervention group.
Summaries, listings, datasets, or participant narratives may be provided, as appropriate, for those
participants who die, who discontinue intervention due to an AE, or who experience a severe AE
or an SAE, or who experience anticipated events.
Clinical Laboratory Tests
Laboratory data will be summarized by type of laboratory test. Reference ranges and markedly
abnormal results will be used in the summary of laboratory data. Descriptive statistics will be
calculated for each  laboratory analyte at baseline and for observed values and changes from
baseline at each scheduled time point. Changes from baseline results will be presented in
pre- versus post-intervention cross-tabulations (with classes for below, within, and above normal
ranges). A listing of participants with any laboratory results outside the reference ranges or with
any markedly abnormal laboratory results will be provided.
The laboratory abnormalities will be graded per the criteria specified in the DMID  (see
Section 10.5, Appendix 5) pediatric toxicity tables and in accordance with the normal ranges of
the clinical laboratory if no DMID gradings were available. ALP will be graded per the criteria
specified in the Division of Acquired Immunodeficiency Syndrome (DAIDS) adult and pediatric
toxicity table (see Section 10.6, Appendix 6). For breast feeding neonates, total bilirubin will also
be graded per the DAIDS adult and pediatric toxicity tables (see Section 10.6, Appendix 6).
Electrocardiogram
The effects on cardiovascular variables will be evaluated by means of descriptive statistics and
frequency tabulations and pre- vs post-intervention cross-tabulations. These tables will include
observed values and changes from baseline values (the predose ECG will be used as baseline).
The ECG variables that will be analyzed are heart/pulse rate, PR interval, QRS interval, QT
interval, and QTc interval using the following correction methods: QTcB and QTcF.25
Descriptive statistics of QTc intervals and changes from baseline will be summarized at each
scheduled time point. The percentage of participants with QTc interval >450 msec, >480 msec, or


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>500 msec will be summarized, as will the percentage of participants with QTc interval increases
from baseline >30 and ≤60 msec or >60 msec.
All clinically relevant abnormalities in ECG waveform that are changes from the baseline readings
will be reported (eg, changes in T-wave morphology or the occurrence of U-waves).
Vital Signs
Descriptive statistics of actual values and changes from baseline will be summarized at each
scheduled time point. The percentage of participants with values beyond clinically important limits
will be summarized.
9.4.4. 
Other Analyses
9.4.4.1. 
Pharmacokinetic Analyses
Population PK analysis of concentration-time data of rilematovir will be performed using
nonlinear mixed-effects modeling. Data may be combined with those of other selected studies to
support a relevant structural model. Available baseline participant characteristics (demographics,
laboratory variables, genotypes, race, etc.) will be tested as potential covariates affecting PK
parameters. Details will be given in a population PK analysis plan and the results of the population
PK analysis will be presented in a separate report.
A snapshot date for PK samples to be analyzed will be defined, if required. Samples collected
before this date will be analyzed for rilematovir and included in the population PK analysis.
Samples collected after the snapshot date will be analyzed at a later date, and may be included in
a population PK re-analysis when they become available after database lock.
Data will be listed for all participants with available whole blood concentrations per intervention
group. Participants will be excluded from the PK analysis if their data do not allow for accurate
assessment of the PK (eg, incomplete administration of the study intervention; missing information
of dosing and sampling times; concentration data not sufficient for PK parameter calculation).
All concentrations below the lowest quantifiable concentration or missing data will be labeled as
such in the concentration database. All participants and samples excluded from the analysis will
be clearly documented in the study report.
For each intervention group, descriptive statistics, including arithmetic mean, SD, coefficient of
variation, median, minimum, and maximum will be calculated for all individual derived PK
parameters including exposure information of rilematovir, and, if applicable, of metabolites and/or
endogenous markers.
9.4.4.2. 
Pharmacokinetic/Pharmacodynamic Analyses
Relationships of rilematovir population-derived exposure parameters with selected antiviral
activity parameters, clinical outcomes, and safety endpoints will be explored. These relationships
will be presented in a tabular and/or graphical display.


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PK/PD analyses may be conducted at the sponsor’s discretion and reported in a separate report.
9.4.4.3. 
Biomarkers Analyses
Statistical approaches to explore correlations between clinical outcome, viral load, and biomarkers
in blood (and potentially in nasal MT swab samples) vary and depend on the different data types
of the applied technology platforms, as well as on the extent of observed differences among study
participants. Analyses may be conducted at the sponsor’s discretion and reported separately from
this study.
9.4.4.4. 
Medical Encounters
Medical encounters will be descriptively summarized by intervention group.
9.4.4.5. 
Acceptability and Palatability
Data on acceptability and palatability of the rilematovir formulation will be presented
descriptively.
9.5. 
Interim Analyses
Two interim analyses are planned. Each interim analysis will preferably be conducted at the end
of a Northern or Southern hemisphere RSV season. The first interim analysis will be performed at
the end of the first season where the cumulative enrollment reaches approximately 35% of the total
sample size and will include an assessment of futility. The second interim analysis will be
performed at the end of the first season where the cumulative enrollment reaches approximately
75% of the total sample size and will include an assessment of futility and stopping for early
superiority. An additional interim analysis with assessment of stopping for early superiority might
be performed at the end of an RSV season after the second pre-planned interim analysis, provided
that approximately 85% of the total sample size is enrolled.
To account for the evaluation of early superiority at the second and at the optional additional
interim analyses, a group-sequential approach using the O’Brien Fleming type alpha spending
function will be used to calculate the significance level for each analysis, based on the total sample
size and the actual number of participants included in the interim analysis.
The interim analyses will be implemented through an IDMC providing recommendations to a
Sponsor Committee. Only the IDMC and the independent Statistical Support Group will be
unblinded to the data.
Details on the planned interim analyses and the statistical decision rules will be provided in the
IDMC Charter and SAP.
9.6. 
Independent Data Monitoring Committee
An IDMC will be established as noted in Committees Structure in Section 10.3.6 in Appendix 3.
An IDMC will be established to monitor and review data for the study in an unblinded manner on
a regular basis to ensure the continuing safety of the participants enrolled in this study. The IDMC
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completed the Day 14 assessments (or discontinued earlier). The committee will meet periodically
to review safety data and results from the interim analyses. After each review, the IDMC will
provide recommendations regarding the continuation of the study to the Sponsor Committee.
After the first interim analysis, the IDMC will also provide a recommendation regarding the
initiation of the neonatal substudy.
Once the last participant of the last cohort of the substudy in neonates has completed Day 14
assessments (or discontinued earlier), the IDMC will review the data and recommend whether
enrollment of neonates into this main study can be opened and which dosing regimen is to be used
for neonates. Investigators and relevant health authorities, ethics committees, and IRBs will be
informed in writing of the decision and the selected dosing regimen for neonates.


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10. 
SUPPORTING DOCUMENTATION AND OPERATIONAL CONSIDERATIONS
10.1. Appendix 1: Abbreviations
5’NT  
5'-nucleotidase
ADL 
activities of daily living
AE 
adverse event
ALP  
alkaline phosphatase
ALT  
alanine transaminase
aPTT  
activated partial thromboplastin time
ARI 
acute respiratory infection
AST  
aspartate aminotransferase
AUC  
area under the plasma concentration-time curve / area under the RSV viral load-time curve
AUC0-xh  
AUC from time of administration up to time x,
AUC0-∞ 
AUC from time of administration extrapolated to infinity
BCRP  
breast cancer resistance protein
bid 
twice daily
BUN  
blood urea nitrogen
CI 
confidence interval
ClinRO  
Clinician Reported Outcome
Cmax  
maximum plasma concentration
Cmin  
minimum plasma concentration
CNEP  
continuous negative extra-thoracic pressure
CNP  
continuous negative pressure
CNS  
central nervous system
COA  
clinical outcome assessment
CPAP  
continuous positive airway pressure
CPK  
creatine phosphokinase
CTC  
Common Toxicity Criteria
Ctrough  
predose plasma concentration
Cxh  
plasma concentration x hours after time of administration
CYP  
Cytochrome P450
DAIDS  
Division of Acquired Immunodeficiency Syndrome
DBP  
diastolic blood pressure
DMID  
Division of Microbiology and Infectious Diseases
DNA  
deoxyribonucleic acid
EAE 
emergent AE
EC50 
effective concentration for 50% inhibition
ECG  
electrocardiogram
eCRF  
electronic case report form
ED  
emergency department
eDC  
electronic data capture
FiO2 
fraction of inspired oxygen
GCP  
Good Clinical Practice
GGT  
γ-glutamyltransferase
GHQ  
General Health Questions
hERG  
human-ether-a-gogo-related
HIV  
human immunodeficiency virus
HP-β-CD  
2-Hydroxypropyl-beta-cyclodextrin
IB  
Investigator's Brochure
ICE 
Intercurrent Event
ICF  
informed consent form
ICH  
International Council for Harmonisation of Technical Requirements for Pharmaceuticals for
Human Use
ICMJE 
International Committee of Medical Journal Editors
ICU  
intensive care unit
IDMC  
Independent Data Monitoring Committee
IEC  
Independent Ethics Committee


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IMP  
Investigational Medicinal Product
IND  
Investigational New Drug
IRB  
Institutional Review Board
ITT-i 
intent to treat –infected
IV  
intravenous/intravenously
IWRS  
interactive web response system
KM  
Kaplan-Meier
LLN  
lower limit of normal
LRTC  
lower respiratory tract complications
LRTI 
lower respiratory tract infection
MAR  
Missing-at-Random
MCH  
mean cell hemoglobin
MCV  
mean cell volume
MedDRA  
Medical Dictionary for Regulatory Activities
MNAR  
Missing-Not-at-Random
MRU  
medical resource utilization
MT  
mid-turbinate
NCI 
National Cancer Institute
NIMP  
Non-Investigational Medicinal Product
OATP  
organic-anion-transporting polypeptide
OCT  
organic cation transporter
ObsRO  
Observer Reported Outcome
PBPK  
physiologically based PK
PCR  
polymerase chain reaction
PD 
pharmacodynamic(s)
PEEP  
positive end-expiratory pressure
P-gp 
P-glycoprotein
PK 
pharmacokinetic(s)
popPK  
population pharmacokinetic(s)
PQC  
Product Quality Complaint
PRESORS  
Pediatric RSV Electronic Severity and Outcome Rating Systems
PT  
prothrombin time
q24h  
every 24 hours
qd 
once daily
qRT-PCR  
quantitative reverse transcription polymerase chain reaction
QTc 
QT interval corrected for heart rate
QTcB  
QT interval corrected for heart rate according to Bazett’s formula
QTcF  
QT interval corrected for heart rate according to Fridericia’s formula
QTcI 
individual-corrected QT
RBC  
red blood cell
RNA  
ribonucleic acid
RRS  
RSV Recovery Scale
RSV  
respiratory syncytial virus
SAE 
serious adverse event
SAP  
statistical analysis plan
SARS-CoV-2 
severe acute respiratory syndrome coronavirus 2
SBP 
systolic blood pressure
SD 
standard deviation
SOA  
Schedule of Activities
SOC  
standard-of-care
SpO2 
peripheral capillary oxygen saturation
SUSAR  
suspected unexpected serious adverse reaction
t1/2term  
terminal elimination half-life
TDRM  
total drug related material
TEAE 
treatment-emergent adverse event
tmax  
time to reach maximum plasma concentration
TQT  
thorough QT
TR 
total radioactivity


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UGT  
glucuronyl transferase
ULN  
upper limit of normal
URTI 
upper respiratory tract infection
US  
United States
WBC  
white blood cell
WHO  
World Health Organization




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10.3. Appendix 3: Regulatory, Ethical, and Study Oversight Considerations
10.3.1. 
Regulatory and Ethical Considerations
Investigator Responsibilities
The investigator is responsible for ensuring that the study is performed in accordance with the
protocol, current ICH guidelines on Good Clinical Practice (GCP), and applicable regulatory and
country-specific requirements.
Good Clinical Practice is an international ethical and scientific quality standard for designing,
conducting, recording, and reporting studies that involve the participation of human participants.
Compliance with this standard provides public assurance that the rights, safety, and well-being of
study participants are protected, consistent with the principles that originated in the Declaration of
Helsinki, and that the study data are credible.
Protocol Amendments
Neither the investigator nor the sponsor will modify this protocol without a formal amendment by
the sponsor. All protocol amendments must be issued by the sponsor, and signed and dated by the
investigator. Protocol amendments must not be implemented without prior IEC/IRB approval, or
when the relevant competent authority has raised any grounds for non-acceptance, except when
necessary to eliminate immediate hazards to the participants, in which case the amendment must
be promptly submitted to the IEC/IRB and relevant competent authority. Documentation of
amendment approval by the investigator and IEC/IRB must be provided to the sponsor. When the
change(s) involve only logistic or administrative aspects of the study, the IEC/IRB (where
required) only needs to be notified.
During the course of the study, in situations where a departure from the protocol is unavoidable,
the investigator or other physician in attendance will contact the appropriate sponsor representative
listed in the Contact Information page(s), which will be provided as a separate document. Except
in emergency situations, this contact should be made before implementing any departure from the
protocol. In all cases, contact with the sponsor must be made as soon as possible to discuss the
situation and agree on an appropriate course of action. The data recorded in the CRF and source
documents will reflect any departure from the protocol, and the source documents will describe
this departure and the circumstances requiring it.
Regulatory Approval/Notification
This protocol and any amendment(s) must be submitted to the appropriate regulatory authorities
in each respective country, if applicable. A study may not be initiated until all local regulatory
requirements are met.
Required Prestudy Documentation
The following documents must be provided to the sponsor before shipment of study intervention
to the study site:


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 
Protocol and amendment(s), if any, signed and dated by the principal investigator.
 
A copy of the dated and signed (or sealed, where appropriate per local regulations), written
IEC/IRB approval of the protocol, amendments, ICF, any recruiting materials, and if
applicable, participant compensation programs. This approval must clearly identify the
specific protocol by title and number and must be signed (or sealed, where appropriate per
local regulations) by the chairman or authorized designee.
 
Name and address of the IEC/IRB, including a current list of the IEC/IRB members and their
function, with a statement that it is organized and operates according to GCP and the
applicable laws and regulations. If accompanied by a letter of explanation, or equivalent, from
the IEC/IRB, a general statement may be substituted for this list. If an investigator or a
member of the study site personnel is a member of the IEC/IRB, documentation must be
obtained to state that this person did not participate in the deliberations or in the vote/opinion
of the study.
 
Regulatory authority approval or notification, if applicable.
 
Signed and dated statement of investigator (eg, Form FDA 1572), if applicable.
 
Documentation of investigator qualifications (eg, curriculum vitae).
 
Completed investigator financial disclosure form from the principal investigator, where
required.
 
Signed and dated Clinical Trial Agreement, which includes the financial agreement.
 
Any other documentation required by local regulations.
The following documents must be provided to the sponsor before enrollment of the first
participant:
 
Completed investigator financial disclosure forms from all subinvestigators
 
Documentation of subinvestigator qualifications (eg, curriculum vitae)
 
Name and address of any local laboratory conducting tests for the study, and a dated copy of
current laboratory normal ranges for these tests, if applicable
 
Local laboratory documentation demonstrating competence and test reliability
(eg, accreditation/license), if applicable
Independent Ethics Committee or Institutional Review Board
Before the start of the study, the investigator (or sponsor where required) will provide the IEC/IRB
with current and complete copies of the following documents (as required by local regulations):
 
Final protocol and, if applicable, amendments
 
Sponsor-approved ICF (and any other written materials to be provided to the participants)
 
IB (or equivalent information) and amendments/addenda
 
Sponsor-approved participant recruiting materials


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 
Information on compensation for study-related injuries or payment to participants for
participation in the study, if applicable
 
Investigator's curriculum vitae or equivalent information (unless not required, as documented
by the IEC/IRB)
 
Information regarding funding, name of the sponsor, institutional affiliations, other potential
conflicts of interest, and incentives for participants
 
Any other documents that the IEC/IRB requests to fulfill its obligation
This study will be undertaken only after the IEC/IRB has given full approval of the final protocol,
amendments (if any, excluding the ones that are purely administrative, with no consequences for
participants, data or study conduct, unless required locally), the ICF, applicable recruiting
materials, and participant compensation programs, and the sponsor has received a copy of this
approval. This approval letter must be dated and must clearly identify the IEC/IRB and the
documents being approved.
During the study the investigator (or sponsor where required) will send the following documents
and updates to the IEC/IRB for their review and approval, where appropriate:
 
Protocol amendments (excluding the ones that are purely administrative, with no
consequences for participants, data or study conduct)
 
Revision(s) to ICF and any other written materials to be provided to participants
 
If applicable, new or revised participant recruiting materials approved by the sponsor
 
Revisions to compensation for study-related injuries or payment to participants for
participation in the study, if applicable
 
New edition(s) of the IB and amendments/addenda
 
Summaries of the status of the study at intervals stipulated in guidelines of the IEC/IRB (at
least annually)
 
Reports of AEs that are serious, unlisted/unexpected, and associated with the study
intervention
 
New information that may adversely affect the safety of the participants or the conduct of the
study
 
Deviations from or changes to the protocol to eliminate immediate hazards to the participants
 
Report of deaths of participants under the investigator's care
 
Notification if a new investigator is responsible for the study at the site
 
Development Safety Update Report and Line Listings, where applicable
 
Any other requirements of the IEC/IRB
For all protocol amendments (excluding the ones that are purely administrative, with no
consequences for participants, data or study conduct), the amendment and applicable ICF revisions
must be submitted promptly to the IEC/IRB for review and approval before implementation of the
change(s).


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At least once a year, the IEC/IRB will be asked to review and reapprove this study, where required.
At the end of the study, the investigator (or sponsor where required) will notify the IEC/IRB about
the study completion.
Country Selection
This study will only be conducted in those countries where the intent is to launch or otherwise help
ensure access to the developed product if the need for the product persists, unless explicitly
addressed as a specific ethical consideration in Section 4.2.1.
Other Ethical Considerations
For study-specific ethical design considerations, refer to Section 4.2.1.
10.3.2. 
Financial Disclosure
Investigators and subinvestigators will provide the sponsor with sufficient, accurate financial
information in accordance with local regulations to allow the sponsor to submit complete and
accurate financial certification or disclosure statements to the appropriate regulatory authorities.
Investigators are responsible for providing information on financial interests during the course of
the study and for one year after completion of the study.
Refer to Required Prestudy Documentation (above) and contracts for details on financial
disclosure.
10.3.3. 
Informed Consent Process
Each participant’s parent(s)/legally acceptable representative(s) must give written consent
according to local requirements after the nature of the study has been fully explained. The ICF(s)
must be signed before performance of any study-related activity. The ICF(s) that is/are used must
be approved by both the sponsor and by the reviewing IEC/IRB and be in a language that the
participant’s parent(s)/legally acceptable representative(s)can read and understand. The informed
consent should be in accordance with principles that originated in the Declaration of Helsinki,
current ICH and GCP guidelines, applicable regulatory requirements, and sponsor policy.
Before enrollment in the study, the investigator or an authorized member of the studysite personnel
must explain to potential participant’s parent(s)/legally acceptable representative(s) the aims,
methods, reasonably anticipated benefits, and potential hazards of the study, and any discomfort
participation in the study may entail. Participants’ parent(s)/legally acceptable representative(s)
will be informed that the infant’s/child’s/neonate’s participation in the study is voluntary and that
they may withdraw consent to participate at any time. They will be informed that choosing not to
participate will not affect the care the participantwill receive for the treatment of his or her disease.
Finally, they will be told that the investigator will maintain a participant identification register for
the purposes of long-term follow-up if needed and that their records may be accessed by health
authorities and authorized sponsor personnel without violating the confidentiality of the
participant, to the extent permitted by the applicable law(s) or regulations. By signing the ICF the
participant’s parent(s)/legally acceptable representative(s)is/are authorizing such access.


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Prior to signing the main ICF for the study, participant’s parent(s)/legally acceptable
representative(s) may specifically allow for the collection and testing of nasal MT swab by signing
the pre-screening (diagnostic) ICF. This is not required if a positive RSV diagnostic result based
on a study-specific local SOC sample collected within 48 hours prior to anticipated randomization
is available and used for determining study eligibility.
The participant’s parent(s)/legally acceptable representative(s)will be given sufficient time to read
the ICF and the opportunity to ask questions. After this explanation and before entry into the study,
consent should be appropriately recorded by means of the participant’s parent(s)/legally acceptable
representative(s) personally dated signature. After having obtained the consent, a copy of the ICF
must be given to the participant’s parent(s)/legally acceptable representative(s).
A participant who is rescreened is not required to sign another ICF if the rescreening occurs within
30 days from the previous ICF signature date.
If the participant’s parent(s)/legally acceptable representative(s) is/are unable to read or write, an
impartial witness should be present for the entire informed consent process (which includes
reading and explaining all written information) and should personally date and sign the ICF after
the oral consent of the participant’s parent(s)/legally acceptable representative(s)is obtained.
10.3.4. 
Data Protection
Privacy of Personal Data
The collection and processing of personal data from participants enrolled in this study will be
limited to those data that are necessary to fulfill the objectives of the study.
These data must be collected and processed with adequate precautions to ensure confidentiality
and compliance with applicable data privacy protection laws and regulations. Appropriate
technical and organizational measures to protect the personal data against unauthorized disclosures
or access, accidental or unlawful destruction, or accidental loss or alteration must be put in place.
Sponsor personnel whose responsibilities require access to personal data agree to keep the identity
of participants confidential.
The informed consent obtained from the participant’s parent(s) (or his or her legally acceptable
representative) includes explicit consent for the processing of personal data and for the
investigator/institution to allow direct access to his or her original medical records (source
data/documents) for study-related monitoring, audit, IEC/IRB review, and regulatory inspection.
This consent also addresses the transfer of the data to other entities and to other countries.
The participant’s parent(s) (or his or her legally acceptable representative) has/have the right to
request through the investigator access to the participant’s personal data and the right to request
rectification of any data that are not correct or complete. Reasonable steps will be taken to respond
to such a request, taking into consideration the nature of the request, the conditions of the study,
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Exploratory biomarker research is not conducted under standards appropriate for the return of data
to participants. In addition, the sponsor cannot make decisions as to the significance of any findings
resulting from exploratory research. Therefore, exploratory research data will not be returned to
participants or investigators, unless required by law or local regulations. Privacy and
confidentiality of data generated in the future on stored samples will be protected by the same
standards applicable to all other clinical data.
10.3.5. 
Long-Term Retention of Samples for Additional Future Research
Samples left-over after study-specific testing may be stored for up to 15 years (or according to
local regulations) for scientific and biomarker research if the participant’s parent(s)/legally
acceptable representative(s) consent. Samples will only be used to understand RSV disease, to
understand rilematovir, to understand differential drug responders, and to develop tests/assays
related to rilematovir and RSV infection. The research may begin at any time during the study or
the post-study storage period.
Stored samples will be coded throughout the sample storage and analysis process and will not be
labeled with personal identifiers. Participants may withdraw their consent for their samples to be
stored for research (refer to Section 7.2.1).
10.3.6. 
Committees Structure
Independent Data Monitoring Committee
An IDMC will be established to monitor and review data for the study in an unblinded manner on
a regular basis to ensure the continuing safety of the participants enrolled in this study. The IDMC
will perform the first unblinded safety review when approximately 10% of the participants have
completed the Day 14 assessments (or discontinued earlier). The committee will meet periodically
to review safety data and results from the interim analysis. After each review, the IDMC will
provide recommendations regarding the continuation of the study to the Sponsor Committee. At
any point during the study, the IDMC has the authority to recommend modifications to the study
conduct and/or to the safety assessments to the Sponsor Committee to ensure the safety of enrolled
participants.
The IDMC will consist of at least 3 members, including one medical expert in respiratory
infectious diseases, one cardiovascular expert knowledgeable about pediatric ECG readings, and
at least one statistician knowledgeable about statistical methods for clinical studies and sequential
analysis of study data. One of these individuals will chair the Committee. The IDMC
responsibilities, authorities, and procedures will be documented in the IDMC Charter.
After the first interim analysis, the IDMC will provide a recommendation regarding the initiation
of the neonatal substudy.
Once the last participant of the last cohort of the substudy in neonates has completed Day 14
assessments (or discontinued earlier), the IDMC will review the data and recommend whether
enrollment of neonates into this main study can be opened and which dosing regimen is to be used
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Sponsor Committee
A Sponsor Committee, consisting of senior sponsor personnel not involved in the conduct of the
study, will be established and will be responsible for decision making, considering the IDMC
recommendations, and will communicate these decisions to the study team. Details are provided
in the IDMC Charter.
Investigators and relevant health authorities, ethics committees, and institutional review boards
(IRBs) will be informed in writing of the decision and the selected dosing regimen for neonates.
10.3.7. 
Publication Policy/Dissemination of Clinical Study Data
All information, including but not limited to information regarding rilematovir or the sponsor's
operations (eg, patent application, formulas, manufacturing processes, basic scientific data, prior
clinical data, formulation information) supplied by the sponsor to the investigator and not
previously published, and any data, including exploratory biomarker research data, generated as a
result of this study, are considered confidential and remain the sole property of the sponsor. The
investigator agrees to maintain this information in confidence and use this information only to
accomplish this study and will not use it for other purposes without the sponsor's prior written
consent.
The investigator understands that the information developed in the study will be used by the
sponsor in connection with the continued development ofrilematovir, and thus may be disclosed
as required to other clinical investigators or regulatory agencies. To permit the information derived
from the clinical studies to be used, the investigator is obligated to provide the sponsor with all
data obtained in the study.
The results of the study will be reported in a Clinical Study Report generated by the sponsor and
will contain data from all study sites that participated in the study as per protocol. Recruitment
performance or specific expertise related to the nature and the key assessment parameters of the
study will be used to determine a coordinating investigator for the study. Results of exploratory
biomarker analyses performed after the Clinical Study Report has been issued will be reported in
a separate report and will not require a revision of the Clinical Study Report.
Study participant identifiers will not be used in publication of results. Any work created in
connection with performance of the study and contained in the data that can benefit from copyright
protection (except any publication by the investigator as provided for below) shall be the property
of the sponsor as author and owner of copyright in such work.
Consistent with Good Publication Practices and International Committee of Medical Journal
Editors (ICMJE) guidelines, the sponsor shall have the right to publish such primary (multicenter)
data and information without approval from the investigator. The investigator has the right to
publish study site-specific data after the primary data are published. If an investigator wishes to
publish information from the study, a copy of the manuscript must be provided to the sponsor for
review at least 60 days before submission for publication or presentation. Expedited reviews will
be arranged for abstracts, poster presentations, or other materials. If requested by the sponsor in


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writing, the investigator will withhold such publication for up to an additional 60 days to allow for
filing of a patent application. In the event that issues arise regarding scientific integrity or
regulatory compliance, the sponsor will review these issues with the investigator. The sponsor will
not mandate modifications to scientific content and does not have the right to suppress information.
For multicenter study designs and substudy approaches, secondary results generally should not be
published before the primary endpoints of a study have been published. Similarly, investigators
will recognize the integrity of a multicenter study by not submitting for publication data derived
from the individual study site until the combined results from the completed study have been
submitted for publication, within 18 months after the study end date, or the sponsor confirms there
will be no multicenter study publication. Authorship of publications resulting from this study will
be based on the guidelines on authorship, such as those described in the ICMJE Recommendations
for the Conduct, Reporting, Editing and Publication of Scholarly Work in Medical Journals, which
state that the named authors must have made a significant contribution to the conception or design
of the work; or the acquisition, analysis, or interpretation of the data for the work; and drafted the
work or revised it critically for important intellectual content; and given final approval of the
version to be published; and agreed to be accountable for all aspects of the work in ensuring that
questions related to the accuracy or integrity of any part of the work are appropriately investigated
and resolved.
Registration of Clinical Studies and Disclosure of Results
The sponsor will register and disclose the existence of and the results of clinical studies as required
by law. The disclosure of the final study results will be performed after the end of study in order
to ensure the statistical analyses are relevant.
10.3.8. 
Data Quality Assurance
Data Quality Assurance/Quality Control
Steps to be taken to ensure the accuracy and reliability of data include the selection of qualified
investigators and appropriate study sites, review of protocol procedures with the investigator and
study  site personnel before the study, periodic monitoring visits by the sponsor, and direct
transmission of clinical laboratory data from a central laboratory (if applicable) into the sponsor's
database and direct transmission of clinician PRESORS and parent(s)/caregiver(s) PRESORS,
Caregiver Impact Questions, and Acceptability and Palatability Assessment data to the electronic
device vendor database and then to the sponsor’s database. Written instructions will be provided
for collection, handling, storage, and shipment of samples.
Guidelines for eCRF completion will be provided and reviewed with study site personnel before
the start of the study.
The sponsor will review the eCRF for accuracy and completeness during on-site monitoring visits
and after transmission to the sponsor; any discrepancies will be resolved with the investigator or
designee, as appropriate. After upload of the data into the study database they will be verified for
accuracy and consistency with the data sources.


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10.3.9. 
Case Report Form Completion
Case report forms are prepared and provided by the sponsor for each participant in electronic
format. All data relating to the study must be recorded in the eCRF. All eCRF entries, corrections,
and alterations must be made by the investigator or authorized study  site personnel. The
investigator must verify that all data entries in the eCRF are accurate and correct.
The study data will be transcribed by study site personnel from the source documents onto an
eCRF, if applicable. Study-specific data will be transmitted in a secure manner to the sponsor.
Worksheets may be used for the capture of some data to facilitate completion of the eCRF. Any
such worksheets will become part of the participant's source documents. Data must be entered into
eCRF in English. The eCRF must be completed as soon as possible after a participant visit and the
forms should be available for review at the next scheduled monitoring visit.
All participative measurements (eg, pain scale information or other questionnaires) will be
completed by the same individual who made the initial baseline determinations whenever possible.
If necessary, queries will be generated in the eDC tool. If corrections to a eCRF are needed after
the initial entry into the eCRF, this can be done in either of the following ways:
 Investigator and study  site personnel can make corrections in the eDC tool at their own
initiative or as a response to an auto query (generated by the eDC tool).
 Sponsor or sponsor delegate can generate a query for resolution by the investigator and study
site personnel.
10.3.10. 
Source Documents
At a minimum, source documents consistent in the type and level of detail with that commonly
recorded at the study site as a basis for standard medical care must be available for the following:
participant identification, eligibility, and study identification; study discussion and date of signed
informed consent; dates of visits; results of safety and efficacy parameters as required by the
protocol; record of all AEs and follow-up of AEs; concomitant medication; intervention
receipt/dispensing/return records; study intervention administration information; and date of study
completion and reason for early discontinuation of study intervention  or withdrawal from the
study, if applicable.
The author of an entry in the source documents should be identifiable.
Specific details required as source data for the study and source data collection methods will be
reviewed with the investigator before the study and will be described in the monitoring guidelines
(or other equivalent document).
An electronic source system may be utilized, which contains data traditionally maintained in a
hospital or clinic record to document medical care (eg, electronic source documents) as well as the
clinical study-specific data fields as determined by the protocol. This data is electronically
extracted for use by the sponsor. If the electronic source system is utilized, references made to the


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eCRF in the protocol include the electronic source system but information collected through
electronic source may not be limited to that found in the eCRF. Data in this system may be
considered source documentation. The following data will be recorded directly on the electronic
device and will be considered source data: clinician PRESORS and parent(s)/caregiver(s)
PRESORS, Caregiver Impact Questions, and Acceptability and Palatability Assessment.
10.3.11. 
Monitoring
The sponsor will use a combination of monitoring techniques (central, remote, or on-site
monitoring)to monitor this study.
The sponsor will perform on-site monitoring visits as frequently as necessary. The monitor will
record dates of the visits in a study site visit log that will be kept at the study site. The first post-
initiation visit will be made as soon as possible after enrollment has begun. At these visits, the
monitor will compare data entered into the eCRF with the source documents (eg,
hospital/clinic/physician’s office medical records); a sample may be reviewed. The nature and
location of all source documents will be identified to ensure that all sources of original data
required to complete the eCRF are known to the sponsor and studysite personnel and are accessible
for verification by the sponsor study site contact. If electronic records are maintained at the study
site, the method of verification must be discussed with the study site personnel.
Direct access to source documents (medical records) must be allowed for the purpose of verifying
that the recorded data are consistent with the original source data. Findings from this review will
be discussed with the study site personnel. The sponsor expects that, during monitoring visits, the
relevant study site personnel will be available, the source documents will be accessible, and a
suitable environment will be provided for review of study-related documents. The monitor will
meet with the investigator on a regular basis during the study to provide feedback on the study
conduct.
In addition to on-site monitoring visits, remote contacts can occur. It is expected that during these
remote contacts, study site personnel will be available to provide an update on the progress of the
study at the site.
Central monitoring will take place for data identified by the sponsor as requiring central review.
10.3.12. 
On-site Audits
Representatives of the sponsor's clinical quality assurance department may visit the study site at
any time during or after completion of the study to conduct an audit of the study in compliance
with regulatory guidelines and company policy. These audits will require access to all study
records, including source documents, for inspection. Participant privacy must, however, be
respected. The investigator and studysite personnel are responsible for being present and available
for consultation during routinely scheduled study site audit visits conducted by the sponsor or its
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Similar auditing procedures may also be conducted by agents of any regulatory body, either as part
of a national GCP compliance program or to review the results of this study in support of a
regulatory submission. The investigator should immediately notify the sponsor if (s)he has been
contacted by a regulatory agency concerning an upcoming inspection.
10.3.13. 
Record Retention
In compliance with the ICH/GCP guidelines, the investigator/institution will maintain all eCRF
and all source documents that support the data collected from each participant, as well as all study
documents as specified in ICH/GCP Section 8, Essential Documents for the Conduct of a Clinical
Trial, and all study documents as specified by the applicable regulatory requirement(s). The
investigator/institution will take measures to prevent accidental or premature destruction of these
documents.
Essential documents must be retained until at least 2 years after the last approval of a marketing
application in an ICH region and until there are no pending or contemplated marketing applications
in an ICH region or until at least 2 years have elapsed since the formal discontinuation of clinical
development of the investigational product. These documents will be retained for a longer period
if required by the applicable regulatory requirements or by an agreement with the sponsor. It is the
responsibility of the sponsor to inform the investigator/institution as to when these documents no
longer need to be retained.
If the responsible investigator retires, relocates, or for other reasons withdraws from the
responsibility of keeping the study records, custody must be transferred to a person who will accept
the responsibility. The sponsor must be notified in writing of the name and address of the new
custodian. Under no circumstance shall the investigator relocate or dispose of any study documents
before having obtained written approval from the sponsor.
If it becomes necessary for the sponsor or the appropriate regulatory authority to review any
documentation relating to this study, the investigator/institution must permit access to such reports.
10.3.14. 
Study and Site Start and Closure
First Act of Recruitment
The first site open is considered the first act of recruitment and it becomes the study start date.
Study Termination
The sponsor reserves the right to close the study site or terminate the study at any time for any
reason at the sole discretion of the sponsor. Study sites will be closed upon study completion. A
study site is considered closed when all required documents and study supplies have been collected
and a study site closure visit has been performed.
The investigator may initiate study site closure at any time, provided there is reasonable cause and
sufficient notice is given in advance of the intended termination.


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Reasons for the early closure of a study site by the sponsor or investigator may include but are not
limited to:
 Failure of the investigator to comply with the protocol, the requirements of the IEC/IRB or
local health authorities, the sponsor's procedures, or GCP guidelines
 Inadequate recruitment of participants by the investigator
 Discontinuation of further study intervention development


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10.4. Appendix 4: Adverse Events, Serious Adverse Events, Product Quality
Complaints, and Other Safety Reporting: Definitions and Procedures for
Recording, Evaluating, Follow-up, and Reporting
10.4.1. 
Adverse Event Definitions and Classifications
Adverse Event
An AE is any untoward medical occurrence in a clinical study participant administered a medicinal
(investigational or non-investigational) product. An AE does not necessarily have a causal
relationship with the intervention. An AE can therefore be any unfavorable and unintended sign
(including an abnormal finding), symptom, or disease temporally associated with the use of a
medicinal (investigational or non-investigational) product, whether or not related to that medicinal
(investigational or non-investigational) product. (Definition per International Conference on
Harmonisation [ICH]).
This includes any occurrence that is new in onset or aggravated in severity or frequency from the
baseline condition, or abnormal results of diagnostic procedures, including laboratory test
abnormalities.
Note: The sponsor collects AEs starting with the signing of the main ICF (refer to All Adverse
Events under Section 8.3.1 for time of last AE recording). For participants with only a signed
pre-screening (diagnostic)ICF (ie, for whom consent was not given to enroll in the main study by
the parent[s]/caregiver[s] by signing the main ICF), only study procedure related AEs will be
reported.
Serious Adverse Event
An  SAE based on ICH and EU Guidelines on Pharmacovigilance for Medicinal Products for
Human Use is any untoward medical occurrence that at any dose:
 
Results in death
 
Is life-threatening
(The participant was at risk of death at the time of the event. It does not refer to an event that
hypothetically might have caused death if it were more severe.)
 
Requires inpatient hospitalization or prolongation of existing hospitalization
 
Results in persistent or significant disability/incapacity
 
Is a congenital anomaly/birth defect
 
Is a suspected transmission of any infectious agent via a medicinal product
 
Is Medically Important*
*Medical and scientific judgment should be exercised in deciding whether expedited reporting is
also 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


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require intervention to prevent one of the other outcomes listed in the definition above. These
should usually be considered serious.
Unlisted (Unexpected) Adverse Event/Reference Safety Information
An AE is considered unlisted if the nature or severity is not consistent with the applicable product
reference safety information. For rilematovir, the expectedness of an AE will be determined by
whether or not it is listed in the IB.
10.4.2. 
Attribution Definitions
Assessment of Causality
The causal relationship to study treatment is determined by the investigator. The following
selection should be used to assess all AEs.
Related
There is a reasonable causal relationship between study treatment administration and the AE.
Not Related
There is not a reasonable causal relationship between study treatment administration and the AE.
The term "reasonable causal relationship" means there is evidence to support a causal relationship.
10.4.3. 
Severity Criteria
An assessment of severity grade, as per DMID (see Section 10.5, Appendix 5) or per DAIDS for
bilirubin for breast feeding neonates and for ALP (see Section 10.6, Appendix 6), will be made.
The investigator should use clinical judgment in assessing the severity of events not directly
experienced by the participant (eg, laboratory abnormalities).
10.4.4. 
Special Reporting Situations
Safety events of interest on a sponsor study intervention in an interventional study that may require
expedited reporting or safety evaluation include, but are not limited to:
 
Overdose of a sponsor study intervention
 
Suspected abuse/misuse of a sponsor study intervention
 
Accidental or occupational exposure to a sponsor study intervention
 
Medication error, intercepted medication error, or potential medication error involving a
Johnson & Johnson medicinal product (with or without patient exposure to the Johnson &
Johnson medicinal product, eg, product name confusion, product label confusion, intercepted
prescribing or dispensing errors)
Special reporting situations should be recorded in the eCRF. Any special reporting situation that
meets the criteria of an SAE should be recorded on the SAE page of the eCRF.


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10.4.5. 
Procedures
AEs will be reported by the participant’s parent(s)/legally acceptable representative(s) (or, when
appropriate, by a caregiver, surrogate, or the participant's legally acceptable representative) for the
duration of the study (see Section 8.3.1).
All Adverse Events
All AEs, regardless of seriousness, severity, or presumed relationship to study intervention, must
be recorded using medical terminology in the source document and the eCRF. Whenever possible,
diagnoses should be given when signs and symptoms are due to a common etiology (eg, cough,
runny nose, sneezing, sore throat, and head congestion should be reported as "upper respiratory
infection"). Investigators must record in the eCRF their opinion concerning the relationship of the
AE to study therapy. All measures required for AE management must be recorded in the source
document and reported according to sponsor instructions.
For all studies with an outpatient phase, including open-label studies, the participant’s
parent(s)/legally acceptable representative(s) must be provided with a "wallet (study) card" and
instructed to keep this card with the participant for the duration of the study indicating the
following:
 
Study number
 
Statement, in the local language(s), that the participant is participating in a clinical study
 
Investigator's name and 24-hour contact telephone number
 
Local sponsor's name and 24-hour contact telephone number (for medical personnel only)
 
Site number
 
Participant number
 
Any other information that is required to perform an emergency breaking of the blind
Serious Adverse Events
All SAEs that have not resolved by the end of the study, or that have not resolved upon
discontinuation of the participant's participation in the study, must be followed until any of the
following occurs:
 
The event resolves
 
The event stabilizes
 
The event returns to baseline, if a baseline value/status is available
 
The event can be attributed to agents other than the study intervention or to factors unrelated
to study conduct
 
It becomes unlikely that any additional information can be obtained (participant or health care
practitioner refusal to provide additional information, lost to follow-up after demonstration of
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Suspected transmission of an infectious agent by a medicinal product will be reported as an SAE.
Any event requiring rehospitalization (or prolongation of hospitalization) that occurs during the
course of a participant's participation in a study must be reported as an SAE.
The cause of death of a participant in the study within 30 days after the last dose of study
intervention, whether or not the event is expected or associated with the study intervention, is
considered an SAE and must be reported using the Serious Adverse Event Form.
Anticipated events:
 Cyanosis
 Pneumonia
 Bronchiolitis
 Respiratory failure
 Rhinitis
 Apnea
 Co-infections (bacterial or viral)
10.4.6. 
Product Quality Complaint Handling
A PQC is defined as any suspicion of a product defect related to manufacturing, labeling, or
packaging, ie, any dissatisfaction relative to the identity, quality, durability, reliability, or
performance of a distributed product, including its labeling, drug delivery system, or package
integrity. A PQC may have an impact on the safety and efficacy of the product. In addition, it
includes any technical complaints, defined as any complaint that indicates a potential quality issue
during manufacturing, packaging, release testing, stability monitoring, dose preparation, storage
or distribution of the product or the drug delivery system.
Procedures
All initial PQCs must be reported to the sponsor by the study site personnel within 24 hours after
being made aware of the event.
A sample of the suspected product should be maintained under the correct storage conditions until
a shipment request is received from the sponsor.
10.4.7. 
Contacting Sponsor Regarding Safety, Including Product Quality
The names (and corresponding telephone numbers) of the individuals who should be contacted
regarding safety issues, PQC, or questions regarding the study are listed in the Contact Information
page(s), which will be provided as a separate document.


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10.5. Appendix 5: Division of Microbiology and Infectious Diseases (DMID)
Pediatric Toxicity Tables (November 2007, draft)
ABBREVIATIONS: Abbreviations utilized in the Table:
ULN = Upper Limit of Normal 
LLN = Lower Limit of Normal
Rx = Therapy 
Req = Required
Mod = Moderate 
IV = Intravenous
ADL = Activities of Daily Living 
Dec = Decreased
ESTIMATING SEVERITY GRADE
For abnormalities NOT found elsewhere in the toxicity tables use the scale below to estimate grade of
severity:
GRADE 1 
Mild: Transient or mild discomfort (<48 hours); no medical intervention/therapy
required
GRADE 2 
Moderate: Mild to moderate limitation in activity - some assistance may be
needed; no or minimal medical intervention/therapy required
GRADE 3 
Severe: Marked limitation in activity, some assistance usually required; medical
intervention/therapy required, hospitalizations possible
GRADE 4 
Life-threatening or death*: Extreme limitation in activity, significant assistance
required; significant medical intervention/therapy required, hospitalization or
hospice care probable
* The draft DMID pediatric toxicity tables characterize death as a Grade 5 event, for the
purposes of this study the sponsor will categorize events into 4 grades and has included
death with life-threatening in the Grade 4 category.
SERIOUS OR LIFE-THREATENING ADVERSE EVENTS
ANY clinical event deemed by the clinician to be serious or life-threatening should be considered a Grade 4
event. Clinical events considered to be serious or life-threatening include, but are not limited to: seizures,
coma, tetany, diabetic ketoacidosis, disseminated intravascular coagulation, diffuse petechiae, paralysis,
acute psychosis, severe depression.
COMMENTS REGARDING THE USE OF THESE TABLES
 
Standardized and commonly used toxicity tables (Division of AIDS, National Cancer Institute’s
[NCI’s] Common Toxicity Criteria [CTC], and WHO) have been adapted for use by the DMID and
modified to better meet the needs of participants in DMID trials.
 
For parameters not included in the following toxicity tables, sites should refer to the “Guide For
Estimating Severity Grade” located above.
 
Criteria are generally grouped by body system.
 
Some protocols may have additional protocol-specific grading criteria, which will supersede the use
of these tables for specified criteria.


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DIVISION OF MICROBIOLOGY AND INFECTIOUS
DISEASES (DMID) PEDIATRIC TOXICITY TABLES
NOVEMBER 2007
(Selected Values for children less than or equal to 3 months of age –does not apply to
preterm infants)
For all parameters not listed in this table, please refer to
the DMID Toxicity Table for children >3 months of age
HEMATOLOGY
Grade 1 
Grade 2 
Grade 3 
Grade 4
Hemoglobin
1-7 days old 
13.0-14.0 g/dL 
12.0-12.9 g/dL 
<12 g/dL 
Cardiac Failure
secondary to
Anemia
8-21 days old 
12.0-13.0 g/dL 
10.0-11.9 g/dL 
<10.0 g/dL 
Cardiac Failure
secondary to
Anemia
22-35 days old 
9.5-10.5 g/dL 
8.0-9.4 g/dL 
<8.0 g/dL 
Cardiac Failure
secondary to
Anemia
36-60 days old 
8.5-9.4 g/dL 
7.0-8.4 g/dL 
<7.0 g/dL 
Cardiac Failure
secondary to
Anemia
61-90 days old 
9.0-9.9 g/dL 
7.0-8.9 g/dL 
<7.0 g/dL 
Cardiac Failure
secondary to
Anemia
Absolute Neutrophil Count
1 day old 
5000-7000/mm3 
3000-4999/mm3 
1500-2999/mm3 
<1500/mm3
2-6 days old 
1750-2500/mm3 
1250-1749/mm3 
750-1249/mm3 
<750/mm3
7-60 days old 
1200-1800/mm3 
900-1199/mm3 
500-899/mm3 
<500/mm3
61-90 days old 
750-1200/mm3 
400-749/mm3 
250-399/mm3 
<250/mm3


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DIVISION OF MICROBIOLOGY AND INFECTIOUS
DISEASES (DMID) PEDIATRIC TOXICITY TABLES
NOVEMBER 2007
(Selected values for children younger than or aged 3 months)
HEMATOLOGY (continued)
Grade 1 
Grade 2 
Grade 3 
Grade 4
Bilirubin (fractionated bilirubin test must be performed when total bilirubin is elevated)
<7 days old 
- 
20-25mg/dL 
26-30 mg/dL 
>30 mg/dL
7-60 days old 
1.1-1.9xN  
2.0-2.9xN  
3.0-7.5xN  
>7.5xN
61-90 days old 
1.1-1.9xN  
2.0-2.9xN  
3.0-7.5xN  
>7.5xN
Creatinine
<7 days old 
1.0-1.7 mg/dL 
1.8-2.4 mg/dL 
2.5-3.0 mg/dL 
>3.0 mg/dL
7-60 days old 
0.5-0.9 mg/dL 
1.0-1.4 mg/dL 
1.5-2.0 mg/dL 
>2.0 mg/dL
61-90 days old 
0.6-0.8 mg/dL 
0.9-1.1 mg/dL 
1.2-1.5 mg/dL 
>1.5 mg/dL
Creatinine Clearance
<7 days old 
35-40 mL/min  
30-34 mL/min  
25-29 mL/min  
<25 mL/min
7-60 days old 
45-50 mL/min  
40-44 mL/min  
35-39 mL/min  
<35 mL/min
61-90 days old 
60-75 mL/min  
50-59 mL/min  
35-49 mL/min  
<35 mL/min
Hypocalcemia
<7 days old 
6.5-6.9 mEq/L 
6.0-6.4 mEq/L 
5.5-5.9 mEq/L 
<5.5 mEq/L
7-60 days old 
7.6-8.0 mEq/L 
7.0-7.5 mEq/L 
6.0-6.9 mEq/L 
<6.0 mEq/L
61-90 days old 
7.8-8.4 mEq/L 
7.0-7.7 mEq/L 
6.0-6.9 mEq/L 
<6.0 mEq/L
Hypercalcemia
<7 days old 
12.0-12.4 mEq/L 
12.5-12.9 mEq/L 
13.0-13.5 mEq/L 
>13.5 mEq/L
7-60 days old 
10.5-11.2 mEq/L 
11.3-11.9 mEq/L 
12.0-13.0 mEq/L 
>13.0 mEq/L
61-90 days old 
10.5-11.2 mEq/L 
11.3-11.9 mEq/L 
12.0-13.0 mEq/L 
>13.0 mEq/L


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DIVISION OF MICROBIOLOGY AND INFECTIOUS
DISEASES (DMID) PEDIATRIC TOXICITY TABLES
NOVEMBER 2007
(Older than 3 months of age)
LOCAL REACTIONS
Grade 1 
Grade 2 
Grade 3 
Grade 4
Induration 
<10 mm  
10-25 mm  
26-50 mm  
>50 mm
Erythema 
<10 mm  
10-25 mm  
26-50 mm  
>50 mm
Edema 
<10 mm  
10-25 mm  
26-50 mm  
>50 mm
Rash at Injection Site 
<10 mm  
10-25 mm  
26-50 mm  
>50 mm
Pruritus 
Slight itching at 
injection site 
Moderate itching
at injection
extremity
Itching at
injection 
extremity and 
other sites
Itching over
entire body
HEMATOLOGY
Grade 1 
Grade 2 
Grade 3 
Grade 4
Hemoglobin for children
older than 3 months and
younger than 2 years of
age
9.0 - 9.9 g/dL 
7.0 - 8.9 g/dL 
<7.0 g/dL 
Cardiac Failure
secondary to
anemia
Hemoglobin for children 
older than 2 years of age 
10 - 10.9 g/dL 
7.0 - 9.9 g/dL 
<7.0 g/dL 
Cardiac Failure
secondary to
anemia
Absolute Neutrophil
Count
750 - 1200/mm3 
400 - 749/mm3 
250 - 399/mm3 
<250/mm3
Platelets 
------- 
50,000 - 
75,000/mm3 
25,000 -
49,999/mm3
<25,000/mm3
Prothrombin Time (PT) 
1.1 - 1.2 x ULN  
1.3 - 1.5 x ULN  
1.6 - 3.0 x ULN  
>3.0 x ULN
Partial Thromboplastin
Time (PTT)
1.1 - 1.6 x ULN  
1.7 - 2.3 x ULN  
2.4 - 3.0 x ULN  
>3.0 x ULN


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DIVISION OF MICROBIOLOGY AND INFECTIOUS
DISEASES (DMID) PEDIATRIC TOXICITY TABLES
NOVEMBER 2007
(Older than 3 months of age)
GASTROINTESTINAL
Grade 1 
Grade 2 
Grade 3 
Grade 4
Bilirubin (when
accompanied by any 
increase in other liver 
function test)
1.1 - <1.25 x 
ULN  
1.25 - <1.5 x
ULN
1.5 - 1.75 x ULN  
>1.75 x ULN
Bilirubin (when other
liver function are in the 
normal range)
1.1 - <1.5 x ULN  1.5 - <2.0 x ULN  2.0 - 3.0 x ULN  
>3.0 x ULN
AST (SGOT) 
1.1 - <2.0 x ULN  
2.0 –<3.0 x
ULN
3.0 - 8.0 x ULN  
>8 x ULN
ALT (SGPT) 
1.1 - <2.0 x ULN  2.0 - <3.0 x ULN  3.0 - 8.0 x ULN  
>8 x ULN
GGT 
1.1 - <2.0 x ULN  2.0 - <3.0 x ULN  3.0 - 8.0 x ULN  
>8 x ULN
Pancreatic Amylase 
1.1 - 1.4 x ULN  
1.5 - 1.9 x ULN  
2.0 - 3.0 x ULN  
>3.0 x ULN
Uric Acid 
7.5 - 9.9 mg/dL 
10 - 12.4 mg/dL 
12.5 - 15.0
mg/dL
>15.0 mg/dL
CPK 
See Neuromuscular Toxicity
Appetite 
- 
Decreased 
appetite 
Appetite very
decreased, no
solid food taken
No solid or liquid
taken
Abdominal Pain 
Mild 
Moderate- No 
Treatment 
Needed 
Moderate- 
Treatment 
Needed 
Severe-
Hospitalized for
treatment
Diarrhea 
Slight change in
consistency
and/or frequency
of stools
Liquid stools 
Liquid stools 
greater that 4x 
the amount or 
number normal 
for this child 
Liquid stools
greater than 8x the
amount or number
normal for this
child


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DIVISION OF MICROBIOLOGY AND INFECTIOUS
DISEASES (DMID) PEDIATRIC TOXICITY TABLES
NOVEMBER 2007
(Older than 3 months of age)
GASTROINTESTINAL (continued)
Grade 1 
Grade 2 
Grade 3 
Grade 4
Constipation 
Slight change in
the 
consistency/frequ  
ency of stool
Hard, dry stools
with a change in 
frequency
Abdominal pain
Distention and
Vomiting
Nausea 
Mild 
Moderate- 
Decreased oral 
intake 
Severe-Little oral
intake
Unable to ingest
food or fluid for
more than 24 hours
Vomiting 
1 episode/day
2-3 episodes per 
day  
4-6 episodes per 
day  
Greater than
6 episodes per day
or Intractable
Vomiting


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DIVISION OF MICROBIOLOGY AND INFECTIOUS
DISEASES (DMID) PEDIATRIC TOXICITY TABLES
NOVEMBER 2007
(Older than 3 months of age)
ELECTROLYTES
Grade 1 
Grade 2 
Grade 3 
Grade 4
CREATININE
Note: ULN are the adult ULN
3 months - 2 years of
age
0.6 - 0.8 x ULN  0.9 - 1.1 x ULN  1.2 - 1.5 x ULN  
>1.5 x ULN
2 years - 12 years of
age
0.7 - 1.0 x ULN  1.1 - 1.6 x ULN  1.7 - 2.0 x ULN  
>2.0 x ULN
Older than 12 years of
age
1.0 - 1.7 x ULN  1.8 - 2.4 x ULN  2.5 - 3.5 x ULN  
>3.5 x ULN
Hypernatremia 
- 
>145 - 149 
mEq/L* 
150 - 155
mEq/L
>155 mEq/L or
abnormal sodium AND
mental status changes
Hyponatremia 
- 
130 - 135 
mEq/L 
129 - 124
mEq/L
<124 mEq/L or
abnormal sodium AND
mental status changes
Hyperkalemia 
5.0 - 5.9 mEq/L 6.0 - 6.4 mEq/L 6.5 - 7.0 mEq/L 
>7.0 mEq/L or abnormal
potassium AND cardiac
arrhythmia
Hypokalemia 
3.0-3-5 mEq/L 
2.5-2.9 mEq/L 
2.0-2.4 mEq/L 
<2.0 mEq/L or abnormal
potassium AND cardiac
arrhythmia
Hypercalcemia 
10.5 - 
11.2mg/dL 
11.3 - 11.9 
mg/dL 
12.0 - 12.9
mg/dL
>13.0 mg/dL
Hypocalcemia 
7.8 - 8.4 mg/dL 
7.0 - 7.7 mg/dL 
6.0 - 6.9 mg/dL 
<6.0 mg/dL
Hypomagnesemia 
1.2 - 1.4 mEq/L 0.9 - 1.1 mEq/L 0.6 - 0.8 mEq/L 
<0.6 mEq/L or abnormal
magnesium AND
cardiac arrhythmia
Hypoglycemia 
55 - 65 mg/dL 
40 - 54 mg/dL 
30 - 39 mg/dL 
<30 mg/dL or abnormal
glucose AND mental
status changes
Hyperglycemia 
116 - 159 
mg/dL 
160 - 249 
mg/dL 
250 - 400 
mg/dL 
>400 mg/dL or
ketoacidosis
Proteinuria 
Tr-1+ or <150 
mg/day  
2+ or 150-499 
mg/day  
3+ or 500-1000 
mg/day  
4+ or Nephrotic
syndrome >1000 mg/day
Hematuria 
Microscopic 
<25 cells/hpf 
Microscopic
≥25 cells/hpf* 
---- 
Gross hematuria


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DIVISION OF MICROBIOLOGY AND INFECTIOUS
DISEASES (DMID) PEDIATRIC TOXICITY TABLES
NOVEMBER 2007
(Older than 3 months of age)
CENTRAL NERVOUS SYSTEM (CNS)
Grade 1 
Grade 2 
Grade 3 
Grade 4
Generalized CNS 
Symptoms 
- 
- 
Dizziness
Hypotonic,
hyporesponsive
episodes;
Seizures;
Apnea/Bradycardia
;
Inconsolable crying
>3 hrs;
Headache 
Mild 
Moderate,
Responds to non- 
narcotic analgesia
Moderate to
Severe, Responds
to narcotic
analgesia
Intractable
Level of Activity 
-
Slightly irritable
OR slightly
subdued
Very irritable OR 
Lethargic 
Inconsolable OR
Obtunded
Visual 
-
Blurriness, 
diplopia, or 
horizontal 
nystagmus of 
<1 hour duration, 
with spontaneous 
resolution  
More than
1 episode of
Grade 2 symptoms
per week, or an
episode of Grade 2
symptoms lasting
more than 1 hour
with spontaneous
resolution by
4 hours or vertical
nystagmus
Decrease in visual
acuity, visual field
deficit, or
oculogyric crisis
Myelopathy 
- 
None 
None 
Myelopathic/spinal
cord symptoms,
such as: pyramidal
tract weakness and
disinhibition,
sensory level, loss
of proprioception,
bladder/bowel
dysfunction


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DIVISION OF MICROBIOLOGY AND INFECTIOUS
DISEASES (DMID) PEDIATRIC TOXICITY TABLES
NOVEMBER 2007
(Older than 3 months of age)
PERIPHERAL NERVOUS SYSTEM
Grade 1 
Grade 2 
Grade 3 
Grade 4
Neuropathy/ Lower 
Motor Neuropathy 
-
Mild transient
Paresthesia only
Persistent or 
progressive 
paresthesias, 
burning sensation 
in feet, or mild 
dysesthesia; no 
weakness; mild to 
moderate deep 
tendon reflex 
changes; no 
sensory loss 
Onset of
significant
weakness,
decrease or loss
of DTRs, sensory
loss in "stocking
glove"
distribution,
radicular sensory
loss, multiple
cranial nerve
involvement;
bladder or bowel
dysfunction,
fasciculations,
respiratory
embarrassment
from chest wall
weakness.
Myopathy or 
Neuromuscular Junction 
Impairment
Normal or mild 
(<2 x ULN) CPK 
elevation  
Mild proximal 
weakness and/or 
atrophy not 
affecting gross 
motor function. 
Mild myalgias, 
+/- mild CPK 
elevation (<2 x 
ULN) 
Proximal muscle
weakness and/or
atrophy affecting
motor function
+/- CPK
elevation; or
severe myalgias
with CPK >2 x
ULN;
Onset of
myasthenia-like
symptoms
(fatigable
weakness with
external, variable
ophthalmoplegia
and/or ptosis), or
neuromuscular
junction blockade
(acute paralysis)
symptoms


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DIVISION OF MICROBIOLOGY AND INFECTIOUS
DISEASES (DMID) PEDIATRIC TOXICITY TABLES
NOVEMBER 2007
(Older than 3 months of age)
OTHER
Grade 1 
Grade 2 
Grade 3 
Grade 4
Allergy 
Pruritus without
Rash
Pruritic Rash  
Mild Urticaria 
Severe Urticaria
Anaphylaxis,
Angioedema
Drug Fever (Rectal) 
-
38.5 - 40.0C 
101.3 –104.0 F 
Greater than 
40.0C 
Greater than 
104.0F 
Sustained Fever:
Equal or greater
than 40.0C
(104.0F) for
longer than
5 days
Cutaneous 
Localized rash  
Diffuse
maculopapular
Rash
Generalized 
urticaria 
Stevens-Johnson
Syndrome or
Erythema
multiforme
Stomatitis 
Mild discomfort 
Painful, difficulty
swallowing, but 
able to eat and 
drink
Painful: unable to
swallow solids
Painful: unable to
swallow liquids;
requires IV fluids
Clinical symptoms not 
otherwise specified in
this table
No therapy; 
monitor condition  
May require
minimal
intervention and
monitoring
Requires medical 
care and possible 
hospitalization  
Requires active
medical
intervention,
hospitalization, or
hospice care
Laboratory values not 
otherwise specified in 
this table 
Abnormal, but 
requiring no 
immediate 
intervention; 
follow  
Sufficiently
abnormal to
require evaluation
as to causality
and perhaps mild
therapeutic
intervention, but
not of sufficient
severity to
warrant
immediate
changes in study
intervention
Sufficiently 
severe to require 
evaluation and 
treatment, 
including at least 
temporary 
suspension of 
study intervention  
Life-threatening
severity;
Requires
immediate
evaluation,
treatment, and
usually
hospitalization;
Study
intervention must
be stopped
immediately and
should not be
restarted until the
abnormality is
clearly felt to be
caused by some
other mechanism
that study
intervention
*Revised by the sponsor




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10.7. Appendix 7: Cardiovascular Safety –Abnormalities
ECG
All important abnormalities from the ECG readings will be listed.
Parameter (unit) 
Age class 
Abnormally low  
Abnormally high
PR (msec) 
0 - 2 yrs 
NA  
>150
>2 - 5 yrs 
NA  
>160
QRS (msec) 
0 - 2yrs 
NA  
>89
>2 - 5 yrs 
NA  
>95
QTc (msec) 
0 - 5 yrs 
NA  
>500
RR (msec) 
0 - 3 mo 
<333 
>750
3 - 12 mo 
<400 
>860
1 - 2 yrs 
<430 
>1,000
2 - 18 yrs 
<600 
>1,200
Vital Signs
The following clinically relevant abnormalities will be defined for vital signs
Parameter (unit) 
Age class
0 –3 mo 
3 –12 mo 
1 –<2 yrs 
2 –<3 yrs 
3 –≤5yrs
Diastolic BP (mmHg) abnormally low  
<35 
<40 
<40 
<40 
<45
abnormally high  
>65 
>85 
>90 
>70 
>85
Systolic BP (mmHg) 
abnormally low  
<60 
<60 
<75 
<80 
<80
abnormally high  
>110 
>110 
>120 
>110 
>125
Heart rate HR (bpm) 
abnormally low  
<80 
<70 
<60 
<90 
<70
abnormally high  
>180 
>150 
>140 
>130 
>130
Respiration rate 
abnormally low  
<25 
<20 
<18 
<20 
<20
abnormally high  
>70 
>60 
>50 
>35 
>45
Oxygen saturation 
SpO2 (%)
abnormally low  
<92 
<92 
<92 
<92 
<92
References:
Fleming S, Thompson M, Stevens R, et al. Normal ranges of heart rate and respiratory rate in children from birth to
18 years of age: a systematic review of observational studies. Lancet. 2011;377(9770):1011-1018.


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10.8. Appendix 8: Liver Safety Plan: Suggested Actions and Follow-up
Assessments
A. STOPPING ALGORITHM
ALT ONLY: Study intervention will be discontinued for a participant if liver chemistry stopping
criteria are met.
Liver Chemistry Stopping Criteria and Increased Monitoring Algorithm
Abbreviations: ALT = alanine transaminase; INR = international normalized ratio; SAE = serious adverse event;
ULN = upper limit of normal.


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10.9. Appendix 9: General Guidelines for Measuring Vital Signs and SpO2
Variability in the measurement of vital signs and SpO2 is to be expected due to a number of reasons;
therefore, general guidelines for measuring vital signs and SpO2 have been developed to have a more
consistent approach across sites and countries related to the methodology for measuring these clinical
parameters. In case the infant/child is crying or not calm or not supine (or lying on their parent’s/caregiver’s
arm), resulting measurements should be recorded as not assessable in the eCRF.
Parameter 
General Instructions
Blood Pressure 
 
While the participant is hospitalized, if possible, use the same blood pressure
measurement methodology for all patients enrolled at the site.
 
Prior to the measurement, the participant needs to be rested for at least
5 minutes and measurement is done preferably when the participant is
sleeping or calm (ie, not crying or immediately after feeding).
 
The participant should be in supine position and the arm should be supported
(eg, with a pillow). Infants can be lying on their parent’s/caregiver’s arm.
 
Blood pressure measurements should preferentially be assessed with a
completely automated device. Manual techniques will be used only if an
automated device is not available.
 
If an automated device is not available, a properly maintained mercury
sphygmomanometer 
is 
preferred 
over 
aneroid 
and 
hybrid
sphygmomanometers. When using a mercury sphygmomanometer, the
mercury column should be deflated at 2 to 3 mm/s, and the first and last
audible sounds should be taken as systolic and diastolic pressure. The column
should be read to the nearest 2 mm Hg.
 
Preferentially, the standard location for blood pressure measurement is the
upper arm, with the stethoscope at the elbow crease over the brachial artery
(with manual technique). Clothing that covers the arm should be removed
prior to the placement of the cuff. The cuff should be fitted for the size of the
participant.
Heart/Pulse Rate 
 
While the participant is hospitalized, if possible, use the same heart/pulse
rate measurement methodology for all patients enrolled at the site.
 
Prior to the measurement, the participant needs to be rested for at least
5 minutes and measurement is done preferably when the participant is
sleeping or calm (ie, not crying or immediately after feeding).
 
The participant should be in supine position. Infants can be lying on their
parent’s/caregiver’s arm.
 
Heart/pulse rate measurements should preferentially be assessed with a
completely automated device.
 
Manual techniques will be used only if an automated device is not available.
 
If manual measurement, auscultation of the heart or pulse (radial, brachial)
determination are considered acceptable.
 
If manual measurement, 30 seconds (minimum) or 1 minute (preferred) count
are considered acceptable.


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Respiratory Rate 
 
While the participant is hospitalized, if possible, use the same respiratory rate
measurement methodology for all patients enrolled at the site.
 
Prior to the measurement, participant needs to be rested for at least 5 minutes
and measurement is done preferably when the participant is sleeping or calm
(ie, not crying or immediately after feeding).
 
The participant should be in supine position. Infants can be lying on their
parent’s/caregiver’s arm.
 
Respiratory rate measurements can be assessed with an automated device or
with manual measurement (no preference).
 
If manual measurement is used, inspection (preferred) or auscultation of the
lungs (alternative) are considered acceptable.
 
If manual measurement, 30 seconds (minimum) or 1 minute (preferred) count
are considered acceptable.
Temperature 
 
While the participant is hospitalized, if possible, use the same type of
temperature measurement methodology for all participants enrolled at the
site.
 
In case antipyretics are used, body temperature should be measured
immediately before or >4 hours after giving antipyretics.
 
Electronic devices (tympanic, oral) are preferred over traditional mercury
thermometers (for oral temperature).
 
Tympanic (preferred) or oral (alternative) temperature measurements are
considered acceptable. Axillary temperature should be avoided since it
provides the worst estimate of core temperature and it is largely influenced
by environmental conditions.
SpO2 
 
While the participant is hospitalized, if possible, use the same type of probe
for all patients enrolled at the site.
 
Prior to the measurement, participant needs to be rested for at least 5 minutes
and measurement is done preferably when the participant is sleeping or calm
(ie, not crying or immediately after feeding).
 
The participant should be in supine position. Infants can be lying on their
parent’s/caregiver’s arm.
 
Pulse oximetry measurements using finger, toe, earlobe or frontal sensors are
considered acceptable. If using the digits, assess for warmth and capillary
refill, since adequate arterial pulse strength is necessary for obtaining
accurate SpO2 measurements.
 
Avoid placing the sensor on sites distal to indwelling arterial catheters, blood
pressure cuffs, or venous engorgement (eg, arteriovenous fistulas, blood
transfusions).
 
For hospitalized participant receiving supplemental O2, the supplemental O2
should be interrupted until the SpO2 drops below 92% and remains stable at
that level for 1 minute, or up to 15 minutes, whichever comes first, before
measuring SpO2 for at least one of the scheduled assessments per day.


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 
If it is determined by the investigator that it is unsafe to remove the
participant’s supplemental O2 for assessment of O2 saturation (eg, participant
is on mechanical ventilation  [invasive or non-invasive] or on high-flow
mask), then SpO2 should be measured while receiving supplemental O2. It
should be recorded in the eCRF that supplemental O2 was not interrupted and
the reason should be documented.


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10.10. Appendix 10: CCI
CCI


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10.11. Appendix 11: CCI
CCI


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_____________________________________________________________________________________
CCI


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CCI


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CCI


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_____________________________________________________________________________________
CCI


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10.12. Appendix 12: CCI
CCI


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10.13. Appendix 13: CCI
CCI


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CCI


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CCI


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10.14. Appendix 14: CCI
CCI


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10.15. Appendix 15: CCI
CCI


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10.16. Appendix 16: Study Medication Acceptability and Palatability Assessment
Study Medication Tolerability –Caregiver Assessment
[NOTE:  Text in bold explains which questions are asked when and to guide implementation
on the eDevice in this protocol; they do not need to be translated.]
This tolerability assessment is used in pediatric clinical treatment trials. It is to be
administered at the time point specified in the study protocol Time and Events Schedule.  For
studies using electronic COA assessments, this assessment should also be included in the
eCOA implementation.
In general, how did the child react when he/she was given the medicine? (note all that apply)
Child took medicine easily [cannot be checked if other options selected]
Disgusted expressions after tasting medicine
Cried after tasting medicine
Would not open mouth or turned head away to avoid medicine
Spit out or coughed out medicine
Gagged
Vomited (within 2 minutes of swallowing medicine)
Thank you!


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10.17. Appendix 17: RSV Symptom Onset to Randomization Calculator
The Symptom Onset to Randomization Calculator uses the 24-hour clock.
Day of 1st RSV 
sign/symptom onset 
Time period of 1st RSV 
sign/symptom onset 
Patient out of window for
randomization
Saturday  
Night (Sunday 00:00-05:59) 
≥ 6:00 Wednesday
Sunday  
Morning (06:00-11:59) 
≥ 12:00 Wednesday
Sunday  
Afternoon (12:00-17:59) 
≥ 18:00 Wednesday
Sunday  
Evening (18:00-23:59) 
≥ 00:00 Thursday
Sunday  
Night (Monday 00:00-05:59) 
≥ 6:00 Thursday
Monday  
Morning (06:00-11:59) 
≥ 12:00 Thursday
Monday  
Afternoon (12:00-17:59) 
≥ 18:00 Thursday
Monday  
Evening (18:00-23:59) 
≥ 00:00 Friday
Monday  
Night (Tuesday 00:00-05:59) 
≥ 6:00 Friday
Tuesday  
Morning (06:00-11:59) 
≥ 12:00 Friday
Tuesday  
Afternoon (12:00-17:59) 
≥ 18:00 Friday
Tuesday  
Evening (18:00-23:59) 
≥ 00:00 Saturday
Tuesday  
Night (Wednesday 00:00-05:59) 
≥ 6:00 Saturday
Wednesday  
Morning (06:00-11:59) 
≥ 12:00 Saturday
Wednesday  
Afternoon (12:00-17:59) 
≥ 18:00 Saturday
Wednesday  
Evening (18:00-23:59) 
≥ 00:00 Sunday
Wednesday  
Night (Thursday 00:00-05:59) 
≥ 6:00 Sunday
Thursday  
Morning (06:00-11:59) 
≥ 12:00 Sunday
Thursday  
Afternoon (12:00-17:59) 
≥ 18:00 Sunday
Thursday  
Evening (18:00-23:59) 
≥ 00:00 Monday
Thursday  
Night (Friday 00:00-05:59) 
≥ 6:00 Monday
Friday  
Morning (06:00-11:59) 
≥ 12:00 Monday
Friday  
Afternoon (12:00-17:59) 
≥ 18:00 Monday
Friday  
Evening (18:00-23:59) 
≥ 00:00 Tuesday
Friday  
Night (Saturday 00:00-05:59) 
≥ 6:00 Tuesday
Saturday  
Morning (06:00-11:59) 
≥ 12:00 Tuesday
Saturday  
Afternoon (12:00-17:59) 
≥ 18:00 Tuesday
Saturday  
Evening (18:00-23:59) 
≥ 00:00 Wednesday


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10.18. Appendix 18: List and Definition/Diagnostic Criteriaof Assessed RSV-
related Complications
AEs occurring after study intervention initiation as reported by investigators with the following
terms:
Note: The diagnostic criteria are provided as guidance in the diagnostic process.43
Respiratory complications:
 
Respiratory failure: Either hypoxemic respiratory failure characterized by an arterial oxygen
tension (PaO2) lower than 60 mmHg with a normal or low arterial carbon dioxide tension
(PaCO2), or hypercapnic respiratory failure characterized by a PaCO2 higher than 50 mmHg.
Diagnostic criteria:PaO2 <60 mmHg with a normal or low PaCO2, or PaCO2 >50 mmHg.
 
Apnoeic attacks: Cessation of breathing for 20 seconds or longer or a shorter pause
accompanied by bradycardia (<100 beats per minute), cyanosis, or pallor.
Diagnostic criteria: Clinical observation or report or biosensor recording of respiratory rate
and heart rate.
 
Bronchiolitis: An acute inflammatory injury of the bronchioles that is usually caused by a
viral infection and characterized by18
a) preceding viral upper respiratory tract infection, cough and/or rhinorrhea
b) exposure to an individual with viral upper respiratory tract infection
c) signs of respiratory illness may also include: Tachypnea, intercostal and/or subcostal
retractions, accessory muscle use, nasal flaring, grunting, color change or apnea,
wheezing or crackles, and/or lower O2 saturations.
Diagnostic criteria: Clinical evaluation with findings of tachypnea, intercostal and/or
subcostal retractions, accessory muscle use, nasal flaring, grunting, color change or apnea,
wheezing or crackles, and/or O2 saturation <96% (measured by oximeter).
 
Bronchial obstruction: Anatomic narrowing or occlusion of bronchioles, resulting in a
decreased ability to move air and characterized by an abnormal forced expiratory volume in
the first second of expiration and its ratio to forced vital capacity (FEV1/FVC) is <80%).7
Diagnostic criteria:Spirometry with FEV1/FVC <80%; oscillometry.
 
Pneumonia: An invasion of the lower respiratory tract, below the larynx by pathogens either
by inhalation, aspiration, respiratory epithelium invasion, or hematogenous spread. Neonates
are at risk for bacterial pathogens present in the birth canal. Pneumonia is characterized by
observation of signs of respiratory distress, including tachypnea, nasal flaring, lower chest in-
drawing, or hypoxia on room air.13
Diagnostic criteria: Clinical evaluation; tachypnea (≥60 breaths in a child aged <2 months;
≥50 breaths/min in a child aged 2 11 months; ≥40 breaths/min in a child aged 1 5 years);
O2 saturation <96% (measured by oximeter); chest auscultation findings (decreased breath
sounds, bronchial breath sounds, crackles, abnormal vocal resonance, or pleural rub); chest
X-ray with airspace opacity, lobar consolidation, or interstitial opacities.


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 
Asthmatic crisis: Common chronic disorder of the airways that is complex and characterized
by variable and recurring symptoms, airflow obstruction, bronchial hyperresponsiveness, and
an underlying inflammation.
Diagnostic criteria: Clinical evaluation with wheezing on expiration (on auscultation or
audible), prolonged expiration, resonant percussion note, hyperinflated chest, rhonchi on
auscultation, lower chest wall in-drawing if severe; improvement on use of bronchodilators.
Infectious complications:
 
Otitis media: Infection of the middle ear space. It is a spectrum of diseases that include acute
otitis media (AOM), chronic suppurative otitis media (CSOM), and otitis media with effusion
(OME), caused by viral, bacterial, or coinfection. Fever, otalgia, headache, irritability, cough,
rhinitis, listlessness, anorexia, vomiting, diarrhea, and pulling at the ears are common, but
nonspecific symptoms.9
Diagnostic criteria:(Pneumatic) otoscopy: detection of middle ear effusion.
 
Bacterial respiratory tract infections: Self-limited irritation and swelling of the upper airways,
caused by bacteria, with associated cough with no proof of pneumonia, lacking a separate
condition to account for the patient symptoms, or with no history of emphysema/chronic
bronchitis.
Diagnostic criteria: Clinical evaluation; sputum culture with identification of bacterial
pathogens.
 
Sepsis: Life-threatening organ dysfunction caused by a dysregulated host response to infection
and characterized by presence of acute fever (>39 °C) and severe illness when no other cause
is found.34
Diagnostic criteria: Acute fever (>39 °C); blood culture with identification of bacterial
pathogens; clinical picture of shock (lethargy, tachypnea, cold, skin, prolonged [>3 seconds]
capillary refill, fast weak pulse, and sometimes low blood pressure).
Cardiovascular complications:
 
Arrhythmia: Absence or disruption of cardiac electrical activity resulting in abnormality in
the heart’s normal rhythmic pattern  and characterized by presentation to the emergency
department with symptoms of palpitations, fatigue and/or syncope.21
Diagnostic criteria:ECG findings; irregular pulse.
 
Cardiogenic shock: Primary cardiac disorder that results in both clinical and biochemical
evidence of tissue hypoperfusion.
Diagnostic criteria: Systolic blood pressure ≤90 mm Hg for ≥30 minutes or support to
maintain systolic blood pressure ≥90 mm Hg; urine output ≤30 mL/hr or cool extremities.
 
Hemodynamic instability: Defined as perfusion failure, represented by clinical features of
circulatory shock and advanced heart failure and characterized by hypotension, abnormal
heart rates, cold extremities, peripheral cyanosis, and mottling together with bedside
measurements of right-sided filling pressure and decreased urine flow.41
Diagnostic criteria: Clinical evaluation; BP and HR measurements abnormal for age of
participant.


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 
Congestive cardiac failure: Complex clinical syndrome that results from any functional or
structural heart disorder, impairing ventricular filling or ejection of blood to the systemic
circulation to meet the systemic needs. It is caused by diseases of the endocardium,
myocardium, pericardium, heart valves, vessels or metabolic disorders. Congestive cardiac
failure is characterized by difficulty in feeding (from prolonged feeding time intake to frank
intolerance), cyanosis, tachypnea, sinus tachycardia, and diaphoresis.33
Diagnostic criteria: Clinical evaluation; tachypnea (≥60 breaths in a child aged <2 months;
≥50 breaths/min in a child aged 2 11 months; ≥40 breaths/min in a child aged 1 5 years);
tachycardia (heart rate >160/min in a child <12 months; >120/min in a child aged 12 months
to 5 years).
Acid-base or electrolyte complications:
 
Metabolic acidosis (serum HCO3 <16): Disturbances in the homeostasis of plasma acidity
which is characterized by increase hydrogen ion concentration in the systemic circulation.
 
Metabolic alkalosis (serum HCO3 >30): Defined as a disease state where the body’s pH is
elevated to greater than 7.45 secondary to some metabolic process.
 
Hyponatremia (Na+ <130 mEq/L).
 
Hypokalemia (K+ <2.9 mEq/L).
 
Hyperkalemia (K+ >6.0 mEq/L).
 
Hypocalcemia (Ca2+ <7.7 mg/dL or equivalent to Grade 2 in children ≤3 months).
 
Hypercalcemia (Ca2+ >11.9 mg/dL or equivalent to Grade 2 in children ≤3 months).
 
Hypoglycemia (glucose <54 mg/dL).
 
Hyperglycemia (glucose >160 mg/dL).
Diagnostic criteria: Laboratory values outside of the values above if considered clinically
significant.


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10.19. Appendix 19: Guidance on Study Conduct during the COVID-19 Pandemic
It is recognized that the Coronavirus Disease 2019 (COVID-19) pandemic may have an impact on
the conduct of this clinical study due to, for example, self-isolation/quarantine by participants and
study site personnel; travel restrictions/limited access to public places, including hospitals; study
site personnel being reassigned to critical tasks.
In alignment with recent health authority guidance, the sponsor will be providing options for study-
related participant management in the event of disruption to the conduct of the study. This guidance
does not supersede any local or government requirements or the clinical judgment of the
investigator to protect the health and well-being of participants and study site personnel. If, at any
time, a participant’s safety is considered to be at risk, study intervention will be discontinued, and
study follow-up will be conducted.
Scheduled visits that cannot be conducted in person at the study site will be performed to the extent
possible remotely/virtually or delayed until such time that on-site visits can be resumed. At each
contact, the participant’s parent(s)/caregiver(s) will be interviewed to collect safety data. Key
efficacy endpoint assessments should be performed if required and as feasible. The participant’s
parent(s)/caregiver(s)will also be questioned regarding general health status to fulfill any physical
examination requirement.
Every effort should be made to adhere to protocol-specified assessments for participants on study
intervention, including follow-up. Modifications to protocol-required assessments may be
permitted after consultation between the participant’s parent(s)/caregiver(s) and investigator, and
with the agreement of the sponsor. Missed assessments/visits will be captured in the clinical trial
management system for protocol deviations. Discontinuations of study interventions and
withdrawal from the study should be documented with the prefix “COVID-19-related” in the case
report form (CRF).
The sponsor will continue to monitor the conduct and progress of the clinical study, and any
changes will be communicated to the sites and to the health authorities according to local guidance.
If a participant has tested positive for COVID-19 during the treatment period and in case the
participant’s safety is considered to be at risk, the investigator should contact the sponsor’s
responsible medical officer to discuss plans for study intervention and follow-up. Additional
follow-up and management of a laboratory-confirmed SARS-CoV-2-infected participant will be
per local standard-of-care, independent to the study visits. Modifications made to the study conduct
as a result of the COVID-19 pandemic should be summarized in the clinical study report.


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STUDY CONDUCT RELATED TO COVID-19 VACCINE DEPLOYMENT FOR
NONCOVID-19 CLINICAL TRIALS
There are no available data suggesting additional risk to participants in rilematovir clinical studies
caused by locally  approved (including emergency use-authorized) COVID-19 vaccines or an
interaction between COVID-19 vaccines and rilematovir. Local package inserts for COVID-19
vaccines, including contra-indications, must be followed as well as local vaccination guidelines.
For participants with signs and symptoms of febrile illness or acute infection, it is recommended
that administration of COVID-19 vaccines be timed to occur after study completion or at least
2 weeks after the last dose of study intervention so that signs and symptoms can be clearly
attributed to RSV infection or vaccination. In case a participant received a COVID-19 vaccine
during study period, the COVID-19 vaccine must be documented on the concomitant therapy page
of the eCRF.
Investigators should make an assessment of the relatedness of any AE reported following
COVID-19 vaccination to study intervention, the underlying RSV infection and/or COVID-19
vaccine (as described in Section 10.4.2). If the event is serious and considered related to both the
COVID-19 vaccine and the study intervention, it is to be recorded as a serious adverse reaction (as
described in Sections 8.3.4 and 10.4.5). Adverse events expectedness is described in
Section 10.4.1.


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GUIDANCE SPECIFIC TO THIS PROTOCOL:
 
These emergency provisions are meant to ensure participant safety on study while site
capabilities are compromised by COVID-19 related restrictions. As restrictions are lifted and
the acute phase of the COVID-19 pandemic resolves, the original protocol procedures should
take preference.
 
Virtual visits, missed assessments/visits, and out-of-window visits will be labeled with the
prefix “COVID-19-related” in the eCRF/eSource by the site personnel where needed.
 
Participant Visits/Assessments:
- In case home visits cannot be performed (either due to institute policy or due to local
regulations), such study assessments that can be performed virtually are accepted.
- There are some assessments that could be conducted virtually via telephone (or
videoconference, 
eg, 
Facetime, 
Skype, 
if 
possible) 
with 
participants’
parent(s)/caregiver(s) in their homes. This methodology can only be used in accordance
with applicable (including local) laws, regulations, guidelines, and procedures. These
virtual assessments include review of AEs, concomitant medications, monitoring of
ObsRO Signs/Symptoms, ObsRO GHQ, and Caregiver Impact Questions completion and
medical resource utilization, and review of parent(s)/caregiver(s) responses to the ObsRO
GHQ. Please note, the visit windows included in the Schedule of Activities are still
applicable. It must be documented in the eCRF and in the participants’ source documents
when a visit occurs virtually due to COVID-19.
- The study assessments that require investigator judgment should be conducted by a
qualified site member identified on the site delegation log.
- If required, nasal MT swab can be stored at home and picked up by study site personnel
or courier.
- In case home visits cannot be performed, nasal MT swabs, if required as per the Schedule
of Activities, may be collected by the parent(s)/caregiver(s). Training and written
instructions to collect the nasal MT swab will be provided to the parent(s)/caregiver(s).
 
On-site Monitoring Visits:
- In case on-site monitoring visits are not possible due to local regulations, restrictions and
guidance, the Site Manager will conduct site monitoring visits and activities remotely.
Additional on-site monitoring visits may be needed in the future to catch up on source
data verification. Remote source data verification of electronic records might be
performed if possible and only if allowed by local/national regulations, restrictions, and
guidance.
- During the COVID-19 pandemic and at the impacted sites, clinical Site GCP Audits with
direct impact/engagement from the clinical investigator team would not be conducted to
comply with national, local and/or organizational social distancing restrictions. Additional
quality assurance activities such as remote audits or focused review of study-related
documents may take place with limited impact/engagement if possible.
- If both caregivers need to provide consent per local regulations, the sponsor allows
obtaining the second consent remotely (phone or video) if allowed per local guidance. In
all cases, the written main ICF will be obtained prior to any study-specific assessments.


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10.20. Appendix 20: Protocol Amendment History
DOCUMENT HISTORY
Document 
Date
Amendment 1 
This document
Original Protocol 
17 August 2020


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11. 
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22. Hermann C, Westergaard T, Pedersen BV, et al. A comparison of risk factors for wheeze and recurrent cough
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INVESTIGATOR AGREEMENT
I have read this protocol and agree that it contains all necessary details for carrying out this study. I will
conduct the study as outlined herein and will complete the study within the time designated.
I will provide copies of the protocol and all pertinent information to all individuals responsible to me who
assist in the conduct of this study. I will discuss this material with them to ensure that they are fully informed
regarding the study intervention, the conduct of the study, and the obligations of confidentiality.
Coordinating Investigator (where required):
Name (typed or printed):
Institution and Address:
Signature: 
Date:
(Day Month Year)
Principal (Site) Investigator:
Name (typed or printed):
Institution and Address:
Telephone Number:
Signature: 
Date:
(Day Month Year)
Sponsor's Responsible Medical Officer:
Name (typed or printed): 
Institution: 
Janssen Research & Development
Signature: [electronic signature appended at the end of the protocol] 
Date:
(Day Month Year)
Note: If the address or telephone number of the investigator changes during the course of the study, written
notification will be provided by the investigator to the sponsor, and a protocol amendment will not be required.
PPD


Signature
User 
Date 
Reason
 
04-May-2021 
09:40:37
(GMT)
Document Approval
PPD

SAP_001.pdf: 
CONFIDENTIAL – FOIA Exemptions Apply in U.S.
1
Status: Approved, Date: 24 May 2022
Janssen Research & Development*
Statistical Analysis Plan
A Phase 3, Randomized, Double-blind, Placebo-controlled Study to Evaluate the Efficacy 
and Safety of Rilematovir in Infants and Children (≥28 Days to ≤5 Years of Age) and 
Subsequently in Neonates (<28 Days of Age), Hospitalized With Acute Respiratory Tract
Infection Due to Respiratory Syncytial Virus (RSV)
Protocol 53718678RSV3001; Phase 3
JNJ-53718678  (rilematovir)
*Janssen Research & Development is a global organization that operates through different legal entities in
various countries. Therefore, the legal entity acting as the sponsor for Janssen Research & Development
studies may vary, such as, but not limited to Janssen Biotech, Inc.; Janssen Products, LP; Janssen Biologics,
BV; Janssen-Cilag International NV; Janssen, Inc; Janssen Pharmaceutica NV; Janssen Sciences Ireland
UC; Janssen Biopharma Inc.; or Janssen Research & Development, LLC. The term “sponsor” is used
throughout the protocol to represent these various legal entities; the sponsor is identified on the Contact
Information page that accompanies the protocol.
Status:
Approved
Date:
24 May 2022
Prepared by:
Janssen Research & Development, a Division of Janssen Pharmaceutica NV
Document No.: EDMS-RIM-305732, 2.0
Compliance: The study described in this report was performed according to the principles of Good Clinical Practice (GCP). 
Confidentiality Statement
The information provided herein contains Company trade secrets, commercial or financial information that the Company 
customarily holds close and treats as confidential.  The information is being provided under the assurance that the recipient
will maintain the confidentiality of the information under applicable statutes, regulations, rules, protective orders or 
otherwise.
NCT04583280


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Statistical Analysis Plan 53718678RSV3001
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Status: Approved, Date: 24 May 2022
TABLE OF CONTENTS
TABLE OF CONTENTS ............................................................................................................................... 2
LIST OF IN-TEXT TABLES AND FIGURES................................................................................................ 3
VERSION HISTORY..................................................................................................................................... 4
1.
INTRODUCTION.................................................................................................................................. 6
1.1.
Objectives and Endpoints ................................................................................................................ 6
1.2.
Study Design.................................................................................................................................. 11
2.
STATISTICAL HYPOTHESES.......................................................................................................... 12
3.
SAMPLE SIZE DETERMINATION.................................................................................................... 13
4.
POPULATIONS (ANALYSIS SETS) FOR ANALYSIS..................................................................... 13
5.
STATISTICAL ANALYSES............................................................................................................... 13
5.1.
General Considerations ................................................................................................................. 13
5.1.1.
Pre-Screening............................................................................................................................. 14
5.1.2.
Baseline ...................................................................................................................................... 15
5.1.3.
Relative Day ............................................................................................................................... 15
5.1.4.
Visit Windows ............................................................................................................................. 15
5.1.5.
Data Handling Rules for RSV RNA Viral Load ........................................................................... 18
5.2.
Participant Dispositions.................................................................................................................. 19
5.3.
Primary Endpoint(s) Analysis......................................................................................................... 20
5.3.1.
Definition of Endpoint(s) ............................................................................................................. 20
5.3.2.
Estimand..................................................................................................................................... 21
5.3.3.
Analysis Methods........................................................................................................................ 21
5.4.
Secondary Endpoint(s) Analysis .................................................................................................... 21
5.4.1.
Key Secondary Endpoint(s)........................................................................................................ 21
5.4.1.1.
Definition of Endpoint(s) .......................................................................................................... 22
5.4.1.2.
Analysis Methods .................................................................................................................... 24
5.4.2.
Supportive Secondary Endpoint(s)............................................................................................. 24
5.4.2.1.
Definitions................................................................................................................................ 24
5.4.2.1.1.
Based on Parent/Caregivers PRESORS (ObsRO).............................................................. 25
5.4.2.1.2.
Based on Clinician PRESORS (ClinRO).............................................................................. 28
5.4.2.1.3.
Other Clinical Course Endpoints.......................................................................................... 30
5.4.2.1.4.
Medical Resource Utilization................................................................................................ 32
5.4.2.1.5.
RSV RNA Viral Load (qRT-PCR)......................................................................................... 32
5.4.2.2.
Analysis Methods .................................................................................................................... 33
5.4.2.2.1.
Based on ObsRO and ClinRO ............................................................................................. 33
5.4.2.2.2.
Other Clinical Course Endpoints.......................................................................................... 34
5.4.2.2.3.
Medical Encounters.............................................................................................................. 34
5.4.2.2.4.
RSV RNA Viral Load (qRT-PCR)......................................................................................... 34
5.5.
Exploratory Endpoint(s) Analysis ................................................................................................... 34
5.5.1.
Definitions ................................................................................................................................... 34
5.5.1.1.
Impact on Parents and Family................................................................................................. 34
5.5.2.
Analysis Methods........................................................................................................................ 35
5.6.
Safety Analyses ............................................................................................................................. 35
5.6.1.
Adverse Events........................................................................................................................... 35
5.6.2.
Additional Safety Assessments .................................................................................................. 36
5.6.2.1.
Clinical Laboratory Tests......................................................................................................... 36
5.6.2.2.
Vital Signs and Physical Examination Findings....................................................................... 37
5.6.2.3.
Electrocardiogram ................................................................................................................... 38
5.7.
Other Analyses............................................................................................................................... 40




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VERSION HISTORY
SAP Version History Summary
SAP Version
Approval Date
Change
Rationale
1
07 April 2022
Not Applicable
Initial release
2
24 May 2022
Table 3. Visit Windows. Footnote was 
updated.
Visit windows to be considered for 
each 
PRESORS 
information 
presentation, were clarified.
In Section 5.4.2.1. Definitions of the 
Supportive Secondary Endpoints, the 
rationale for deriving only the 
summary 
parameter 
Key 
RSV 
signs/symptoms for ObsRO and 
ClinRO is provided. 
The 
related 
Sections 
5.4.2.1.1, 
5.4.2.1.2 and 5.4.2.2.1 have been 
updated accordingly.
Due to an error with ObsRO v9.0  
instructions following 
questions 
related to cough item, caregivers may 
inadvertently skipped the question 
related to feeding problems, and data 
for this item may not be available. 
Table 6. Key Secondary Endpoints. 
The approximate 24h resolution of the 
Key RSV signs/symptoms for the 
endpoint time to resolution of Key 
RSV signs/symptoms after free of 
supplementation for at least 24h, was 
added. Censoring rules were updated.
The definition of the resolution of 
Key RSV signs/symptoms in this time 
to event endpoint is different than 
when defined by study day.
Censoring rules were updated since 
PRESORS are meant to be collected 
up to Day 21(~ 504h) rather than until 
Day 35 (~ 840h). 
Table 7. Parameters based on ObsRO. 
Number of caregivers was removed.
Table 8. Parameters based on ClinRO. 
Number of clinicians was removed.
Summaries planned were removed 
from section 5.4.2.2.1.
Due to an error in data collection, the 
number of different caregivers and 
clinicians per participant will not be 
summarized.
Table 8. Parameters based on ClinRO. 
The 
resolution 
categories 
for 
signs/symptoms 
and 
summary 
parameters were clarified.
The categories to be considered are 
resolved, not resolved and not 
available.
Table 9. Additional Clinical Course 
Parameters. The set of participants for 
which duration of ICU stay and 
supplemental feeding/ hydration will 
be provided, was corrected.
Duration will be provided irrespective 
whether a participant did have any 
stay/use prior to first dose of study 
intervention.
Section 5.6.2.1 Clinical Laboratory
Test. For children younger than or 
aged 3 months, a correction was noted 
to DMID table for calcium toxicity 
ranges.
The correction was implemented in a 
protocol amendment as a note to the 
DMID table but due to early 
termination 
of 
the 
trial, 
the 
amendment was never submitted.
The Table 14. ECG abnormalities was 
adjusted.
Table 
amended 
to 
clarify 
that 
abnormalities for QTC formula are 
for both QTcF and QTcB.
Section 5.7.2 Pharmacokinetics. No 
descriptive summary of rilematovir 
concentrations needed.
Only listing to be provided.
Some adjustments were performed to 
Section 6.10 Appendix 10 Missing 
Data. 
Additional scenarios needed to be 
foreseen 
to 
impute 
missing 
dates/times.


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Status: Approved, Date: 24 May 2022
SAP Version
Approval Date
Change
Rationale
Section 6.13 Appendix 13 Clinician 
PRESORS 
ClinRO, 
concept 
“Tachycardia”. 
Derivation for Tachycardia corrected 
since based on ClinRO questions 4 
and 8.




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Status: Approved, Date: 24 May 2022
Objectives
Endpoints
treatment with respect to clinical 
resolution of RSV disease.
(ClinRO) Signs/Symptomsc,e as assessed on the same 
day as the primary endpoint.

To 
evaluate 
the 
superiority 
of 
rilematovir compared to placebo 
treatment with respect to the time 
from first dosing to resolution of Key 
RSV 
Signs/Symptomsb
including 
supplementation free.

Time from first study dose to resolution of Key RSV 
Signs/Symptoms (absent or mild)d,e
based on 
parent’s/caregiver’s 
Observer 
Rated 
Outcome 
(ObsRO) Signs/Symptoms and supplementation free
(oxygen and feeding/hydration) for at least 24 hours.

To 
evaluate 
the 
superiority 
of 
rilematovir compared to placebo 
treatment with respect to the time 
from discharge to resolution of Key 
RSV Signs/Symptoms.

Time from discharge to resolution of Key RSV 
Signs/Symptomsd,e based on ObsRO Signs/Symptoms 
(only including participants who did not reach 
resolution before first discharge).

To 
evaluate 
the 
superiority 
of 
rilematovir compared to placebo 
treatment with respect to the time 
from first dosing to end of oxygen 
supplementation.

Time from first dosing to
end of oxygen 
supplementation (only including participants who 
were receiving oxygen supplementation at the time of 
first dosing).

To 
evaluate 
the 
superiority 
of 
rilematovir compared to placebo 
treatment 
with 
respect 
to 
the 
incidence of post-baseline RSV-
related complications.

Incidence 
in 
post-baseline 
RSV-related 
complications.
Supportive Efficacy

To evaluate the effect of rilematovir
on the clinical course of RSV disease 
as assessed electronically by ObsRO 
Signs/Symptoms and ObsRO General 
Health Questions (GHQ).

The following endpoints will be based on the ObsRO 
Signs/Symptoms:

time to resolution of signs/symptoms (absent or 
mild)e of RSV disease; 

actual values and changes from baseline in 
scores.

The following endpoint will be based on the ObsRO 
GHQ:

time to improvement.

To evaluate the effect of rilematovir 
on the clinical course of RSV disease 
as assessed electronically by ClinRO 
Signs/Symptoms and ClinRO GHQ.

The following endpoints will be based on the ClinRO 
Signs/Symptoms:

time to resolution of signs/symptoms (absent or 
mild)e of RSV disease; 

actual values and changes from baseline in 
scores;

proportion of participants clinically resolved 
from 
RSV 
disease 
based 
on 
ClinRO 
Signs/Symptomsc,e as assessed each day from 
Day 2 to 8.






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Status: Approved, Date: 24 May 2022
Objectives
Endpoints
b.
Signs are defined as objective evidence of the disease, which are apparent to the physician during 
examination (such as tachycardia, tachypnea, chest wall retractions, grunting, and nasal flaring). Symptoms 
are defined as subjective manifestations of the diseases, reported by the participant or by the 
parent(s)/caregiver(s), but not necessarily apparent to the physician during examination (such as rhinorrhea, 
cough, feeding difficulties, disturbed sleep, and disturbed activity level). Throughout this protocol, the 
notation “signs/symptoms” is used.
c.
Clinical resolution is defined by: free of oxygen supplementation, AND free of supplemental feeding, AND 
no medical need for ICU, AND Key RSV Signs/Symptoms resolved to absent or mild as per the ClinRO 
Signs/Symptoms (see Section 5.4.1).e
d.
Key RSV Signs/Symptoms are: Breathing problems, retractions, tachypnea, cough, wheezing (ClinRO 
Signs/Symptoms only), breathing sounds (ObsRO Signs/Symptoms only), and tachycardia 
e.
See protocol Section 10.13 Appendix 13 and Section 10.14, Appendix 14 for definitions of resolved/not 
resolved.
f.
See Section 5.4.1 for the list of complications assessed.
Given the limited number of participants enrolled in the study, the analyses will be restricted to 
the following endpoints. No hypothesis is tested nor estimands will be derived.
Efficacy:

Primary endpoint: RRS as assessed from baseline to Day 8.

Key secondary endpoints:

clinically resolved from RSV disease based on Clinician Rated Outcome (ClinRO) 
Signs/Symptoms as assessed from baseline to Day 8.

Time from first study dose to resolution of Key RSV signs/symptoms based on 
parent’s/caregiver’s Observer Rated Outcome (ObsRO) Signs/Symptoms and 
supplementation free (oxygen and feeding/hydration) for at least 24 hours.

Incidence in post-baseline RSV-related complications.

Supportive secondary endpoints:

Viral Load
o
RSV viral load and change from baseline over time.
o
Proportion of participants with undetectable RSV viral load at each time point of 
assessment throughout the study.

Duration of hospitalization, ICU stay, and of any type of supplementation (oxygen and/or 
feeding/hydration).

Number and type of medical encounters.

Incidence of use of concomitant medications.

Pediatric RSV Electronic Severity and Outcome Rating Systems (PRESORS)
o
Proportion of participants with signs/symptoms of RSV disease resolved/not 
resolved over time, based on ObsRO and ClinRO separately.


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Status: Approved, Date: 24 May 2022

Other secondary endpoints:

Acceptability and palatability of the rilematovir formulation as assessed through a 
questionnaire.

Sequence changes (post-baseline) in the RSV F gene compared to baseline.
Safety
Safety and tolerability, as assessed by adverse events (AEs), clinical laboratory testing, 
electrocardiograms (ECGs), vital signs throughout the study.
Pharmacokinetics (PK)
Rilematovir PK concentrations.
1.2.
Study Design
This is a Phase 3, randomized, double-blind, placebo-controlled, multicenter, interventional study 
in infants and children (≥28 days to ≤5 years of age) and subsequently in neonates (<28 days of 
age), hospitalized (refers to having planned at least 24 hours with an overnight stay in the hospital) 
with RSV infection. The substudy at specific sites will be initiated only after positive 
recommendation by the IDMC upon review of IA#1 results of the main study. The main study will 
be opened for enrollment of neonates at all sites following completion of the substudy in neonates 
and IDMC positive recommendation. This SAP only describes the analyses to be performed in the 
main study.
Participants with RSV disease (ie, diagnosed with at least 1 sign/symptom of upper respiratory 
tract infection [URTI], at least 1 sign/symptom of lower respiratory tract infection [LRTI], and at 
least 1 systemic/general sign/symptom) will be enrolled.
Approximately 737 hospitalized RSV-infected participants will be randomized in a 2:1 ratio to 
receive either rilematovir or placebo bid.
Randomization should occur within a maximum of 24 hours after start of screening or within 
48 hours after collection of the SOC sample used for local RSV diagnosis, whichever comes first, 
and no later than 3 days after onset of first RSV sign/symptom.
Randomization will be stratified by presence of risk factors for severe RSV disease (otherwise 
healthy vs presence of [a] risk factor[s] for severe RSV disease) and by region (Asia-Oceania, 
EMEA, Northern America, and Latin America-The Caribbean)2.
Dosing will be based on a mg/kg basis per age group and 4 age groups are defined based on the 
participant’s age at the time of consent (see Table 1). Study intervention (oral suspension) will be
administered orally, bid, with a treatment duration of 7 days (14 consecutive doses).


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Status: Approved, Date: 24 May 2022
Table 1: Treatment Overview
Treatment
Age Group
Age Range
Dosing Regimena
Volume Oral 
Suspensionb
Rilematovir
1
≥28 days to <3 months 2.5 mg/kg bid on Days 1 to 7(/8)
A mL 
2
≥3 to <6 months
3 mg/kg bid on Days 1 to 7(/8)
B mL 
3
≥6 months to ≤5 years
4.5 mg/kg bid on Days 1 to 7(/8)
C mL 
4*
birth at term to 
<28 days
Xc mg/kg bid on Days 1 to 7(/8)
Dc mL
Placebo
1,2,3, or 4*
see above
Matching placebo bid on 
Days 1 to 7(/8)
A, B, C, or Dc* 
(respectively) mL placebo
bid = twice daily; IDMC = Independent Data Monitoring Committee; IWRS = interactive web response system.
* After opening of recruitment in neonates in the main study dependent on positive IDMC recommendation after 
completion of a substudy in neonates (see protocol Section 9.6).
a
Doses are provided for JNJ-53718678-AAA.
b
A to D represents the volume of oral rilematovir suspension to obtain the required dose of JNJ-53718678-AAA 
or the volume of the matching placebo suspension. After reconstitution, rilematovir is dosed as an equivalent 
20 mg/mL JNJ-53718678-AAA oral suspension (containing 23 mg/mL JNJ-53718678-ZCL, the hemi-tartrate of 
JNJ-53718678-AAA), to be used depending on the bodyweight of the participant. For neonates (Age Group 4), 
the eq. 20 mg/mL JNJ-53718678-AAA oral suspension is diluted with an appropriate volume of solvent for oral 
suspension to an equivalent 5 mg/mL JNJ-53718678-AAA oral suspension (containing 5.75 mg/mL 
JNJ-53718678-ZCL, the hemi-tartrate of JNJ-53718678-AAA). The required volume to be administered per 
intake will be calculated by the IWRS and provided to the sites.
c
Dose dependent on outcome of the substudy in neonates and following IDMC review and recommendation. The 
dosing regimen will not exceed the exposures simulated for the bid regimen in pediatric participants ≥28 days to 
≤5 years of age and observed for the 250 mg bid regimen in adults.
The study will include a Screening Period (Day -1 to Day 1), a Treatment Period (Day 1 to Day 8), 
and a Follow-up Period (Day 9 to Day 35 [±3]). The total study duration for each participant will 
be approximately 36 days (Screening included).
Participants can be discharged as of Day 2, if deemed appropriate by the investigator and after 
completion of the required investigator-performed assessments for that day, with exception of the 
PM bid assessments. Parent(s)/caregiver(s) of discharged participants are required to follow the 
schedule of activities (SoA) accordingly defined in the protocol. If a participant is re-hospitalized 
after discharged due to worsening of RSV disease during the treatment period, administration of 
study intervention in the bid regimen should continue.
A participant will be considered to have completed the study if (s)he has completed dosing and 
has completed assessments at Day 35 (±3 days) of the follow-up phase.
2.
STATISTICAL HYPOTHESES
The primary hypothesis of this study is that treatment with rilematovir improves clinical outcome 
of RSV infection as compared to placebo in hospitalized pediatric participants as assessed with the 
RRS on the first study day when at least 50% of the participants across treatment arms are 
discharged from the hospital.
Due to early termination of the study, the RRS will be derived from baseline to Day 8, but no 
formal hypothesis testing will be performed.


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3.
SAMPLE SIZE DETERMINATION
Please see protocol Section 9.2 Sample Size Determination.
At the time of study termination, 28 participants were randomized and treated.
4.
POPULATIONS (ANALYSIS SETS) FOR ANALYSIS
Analysis Sets
Description
Enrolled
All participants who signed the main ICF.
Randomized
The randomized analysis set includes all participants 
who were randomized in the study.
Intent-to-Treat infected set (ITT-i)
ITTI-i includes all randomized participants who 
received at least 1 dose of study intervention and had an
RSV infection confirmed* by central laboratory 
analysis. Participants with confirmed SARS-CoV-2 
infection (positive test by central laboratory analysis up 
to day 14) are excluded.
*A participant is considered to have a centrally 
confirmed RSV infection based on the RSV RT-qPCR 
assay if he/she has:

a positive RSV RT-qPCR result from central 
lab at baseline
or 

two positive RSV RT-qPCR results from 
central lab post-baseline up to Day 6
This population will be used for the analysis of efficacy 
endpoints, as randomized.
Safety
The safety analysis set includes all participants who 
received at least 1 dose of study intervention.
This population will be used for the analysis of safety 
endpoints, as treated.
Pharmacokinetics analysis set (PKAS)
PKAS includes participants who have received at least 1
dose of rilematovir and have at least 1 valid blood 
sample drawn for PK analysis.
5.
STATISTICAL ANALYSES
5.1.
General Considerations
All analysis dataset preparations and statistical analyses will be performed using SAS® version 
9.2 (or higher). 
Phases will be constructed as defined in Table 2.




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derivation of any screening nor baseline result. The data may be used to conduct exploratory 
economic analyses.
5.1.2.
Baseline
In general, the baseline record is defined as the last record before the first intake of the study drug, 
except for the following assessments:

RSV RNA viral load (VL):

Last available assessment within the 24 hours (h) prior to or at the same time of first drug 
intake will be considered as baseline.

If no assessment within the 24h prior to or at the same time of first drug intake, but there 
is a result available no later than 1h post first study drug intake, the baseline assessment 
will be the first assessment completed within 1h post first drug intake.

If none of the above assessments are available, but there is an assessment available before
the 24h prior to first drug intake, it will be considered as baseline.

PRESORS:

Last available assessment within the 8h prior to first drug intake.

If no assessment is available within 8h prior to first drug intake, but there is an assessment
completed within 1h post first drug intake, then baseline assessment will be the 
assessment completed within 1h post first drug intake.

If none of the above assessments are available, but there is an assessment available before
the 8h prior to first drug intake, it will be considered as baseline.
5.1.3.
Relative Day
Study Day 1 is the reference day and defined as the date of first study medication intake (there is 
no ‘Day 0’). All efficacy and safety assessments at all visits will be assigned a day relative to this 
date.

The relative day for visits before Day 1 will be defined as:
                                                  Relative day = visit date – reference date

The relative day for visits on or after Day 1 will be defined as:
                                                  Relative day = visit date – reference date+1
5.1.4.
Visit Windows
As participants do not always adhere to the protocol visit schedule, the following rules are applied 
to assign actual visits to analysis visits. Listed below are the visit windows and the target days for 
each visit. The reference day is Study Day 1. 


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
If a participant has 2 or more actual visits in 1 visit window, the visit closest to the target day 
will be used as the protocol visit for that visit window. The other additional visit(s) will not 
be used in the summaries or analyses, but they can be used for determination of clinically 
important endpoints. 

If 2 actual visits are equidistant from the target day within a visit window, the later visit is 
used.

If there are two measurements on the same date and time, then the measurement with the 
highest sequence number will be used.
Exceptions to the general rule:

RSV RNA viral load
For the analyses of VL (scheduled once daily), if multiple nasal swabs were taken on a single 
day, the above rules will only be applied after having determined the maximum viral load per 
day. The maximum viral load on a day will be used for windowing. Please notice that baseline 
viral load follows the rules described in Section 5.1.2.

Electrocardiogram (ECG)
For Day 1 and Day 3, the 1h post-dose assessment is targeted. The dose to be considered as 
reference for each day is as follows: 

Day 1, 1h post-dose ECG will be after first dose of study intervention.

Day 3, 1h post-dose after the last administered dose of study intervention prior to the on-
site visit. This means, the study dose intervention that is closer to ECG reading on the 
target day
On these days, an additional time window of 45-90 minutes post-dose was identified in the 
protocol. The upper bound of the ECG window is expanded up to 120 minutes to be aligned 
with the lower bound of 45 minutes. This was deemed acceptable as plasma concentrations, 
which are the driver behind a possible QTc prolongation, at 120 minutes are similar to plasma 
concentrations at 45 minutes. Therefore, the time window to be applied in the analysis on Day 
1 and Day 3 is 45-120 minutes, and the result to be considered is as follows:

If an ECG recording is available within the target day and after first administration within 
the time window indicated, it will be used for the analysis 1h post-dose.

If one or more ECG recordings are available within the target day and within the time 
window, the closest one to target time will be used in the analysis.

If ECG recording (s) is available within the target day but outside time window indicated, 
it will not be used for any 1h post-dose analysis rather for the general analysis for that 
day where general rules for visit windows will be applied.
Once baseline is assigned, any assessment performed prior to the defined baseline, will be assigned
to Screening. Screening visits will not be used in summary tables, only in listings. 
Any assessment performed after first drug intake not considered baseline but within Day 1, will 
be assigned to Day 1, post-dose. Visit windows for VL and ECG/labs are defined as in Table 3.






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Status: Approved, Date: 24 May 2022

For the RSV-A qRT-PCR assay, the LOD is 620 copies/mL and the LLOQ is 1000 copies/mL, 
a result that is TD will be imputed with 2.90 log10 copies/mL.

For the RSV-B qRT-PCR assay, the LOD is 80 copies/mL and the LLOQ is 250 copies/mL, 
a result that is TD will be imputed with 2.15 log10 copies/mL.
When the result is ‘target not detected’ (TND) (ie., below the LOD), for both RSV A and RSV B 
the value of TND will be imputed with 0 log10 copies/mL. 
For the overall analysis of viral load, all the viral load results of the RSV type with which the 
participant has been infected will be used.
In case of co-infection with both subtypes RSV A and B, the rules below will be applied for the 
overall analyses of viral load from the time the co-infection is detected (ie. result of TD or 
>LLOQ):

In case of two quantifiable results: the log10 of the sum of the RSV A and RSV B results in 
copies/mL will be used.

In case of a quantifiable result and a TD/TND result: use the imputed TD/TND on the 
copies/mL scale value and then use the log10 of the sum of the imputed value and the 
quantifiable result.

In case of two TD results, or one TD and one TND result: use the imputed TD/TND on the 
copies/mL scale values and then use the log10 of the sum of the imputed values.

In case of two TND results: impute as 0 log10.
If RNAse P = Not Detected AND RSV A = Not Detected AND RSV B = Not Detected sample 
will be excluded from the analysis.
5.2.
Participant Dispositions
Screened participants and reason for screen failures will be listed.
The number of participants in the following disposition categories will be summarized throughout 
the study by intervention group and overall:

Participants randomized

Participants who received study intervention (SAF)

Participants randomized who received study intervention

Participants in the ITT-i

Participants who discontinued study intervention  

Reasons for discontinuation of study intervention

Participants who discontinued study  

Reasons for discontinuation of study

Participants who completed the study












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If no coughing reported in question 7a, the subsequent question 7b is not needed. 
Due to an error in the instructions and subsequent eCOA device programming for question 7a, if 
a caregiver reported to coughing in response to question 7a, both question 7b and 8 were skipped. 
Question 8 collects feeding problems.
As a consequence, the changes on the planned analyses are as follows for ObsRO and ClinRO:

feeding problems information will be available at database level but no summaries will be 
provided. 

only the Key RSV signs/symptom summary parameter will be derived and available in the 
summaries.
Due to an error in the eCOA device set up, the role of the different caregivers and clinicians rating 
a participant was not collected therefore, this information cannot be summarized.
5.4.2.1.1.
Based on Parent/Caregivers PRESORS (ObsRO)
The parent/caregiver PRESORS (ObsRO) (please see protocol Section 10.11) is composed of 2 
groups of questions:
ObsRO Section
Question(s) #
Purpose
Signs/Symptoms
1-9
Information 
used 
to 
monitor
specific 
signs/symptoms 
of 
RSV 
disease 
based 
on 
observations by the child’s caregiver.
General Health Questions
10-14
Caregiver’s general impression of the child’s RSV 
disease severity, change in RSV disease severity
since entering the study, overall health status and 
return to usual health.


















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Reason of missing ObsRO and/or ClinRO assessments will be available at database level, but no 
summaries will be provided.
5.4.2.2.2.
Other Clinical Course Endpoints
Duration of Hospitalization, ICU stay, supplemental feeding/hydration and of oxygen 
supplementation
Descriptive summaries for each duration will be provided by intervention group for participants 
with at least one episode.
For the supplementation, summaries will include the different types of each supplementation 
received (eg, for supplemental oxygen: requirement for no-invasive non-mechanical ventilation 
support, non-invasive mechanical ventilation support, or invasive mechanical ventilation support).
All information will be listed including any case of re-hospitalization.
5.4.2.2.3.
Medical Encounters
Information on medical encounters (frequency of visits, type of practitioner) will be listed only.
5.4.2.2.4.
RSV RNA Viral Load (qRT-PCR)
Descriptive statistics for viral load including the number of participants, mean, standard deviation
(SD), standard error (SE), 95% confidence interval, median, range and interquartile range by visit 
and intervention group will be provided.
Mean ± SE graphs over time for the log10 viral load actual values and changes from baseline will 
be generated by visit and intervention group. 
Proportion of participants with undetectable RSV viral load
The proportion of participants within the RSV RNA viral load categories (quantifiable, detectable 
and undetectable) will be shown in a frequency tabulation, as well as graphically, by intervention 
group and visit. Participants with missing data on that analysis visit will not be counted in the 
denominator for the proportion. 
In case of co-infection with both RSV A and B, the worst category will be used for the analysis. 
As higher viral loads denote worse degree of infection, the ordering will be from worst to better 
namely: quantifiable – detectable – undetectable.  
5.5.
Exploratory Endpoint(s) Analysis
5.5.1.
Definitions
5.5.1.1.
Impact on Parents and Family
For the Parent/Caregiver General Impact Questions please refer to question 1-4 in protocol Section
10.12, Appendix 12.




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partial or completely missing, then the event will be considered to be treatment emergent unless it 
is known to be prior to the first administration of study intervention based on partial onset date or 
resolution date. All reported treatment-emergent adverse events will be included in the analysis.  
For each adverse event, the number and percentage of participants who experience at least 
1 occurrence of the given event will be summarized by intervention group.
Summary tables will be provided for treatment-emergent adverse events:

AEs

Serious AEs (SAEs)

AEs by toxicity grade

AEs by relationship to study intervention

SAEs by relationship to study intervention

AEs with grade 3 or 4

AEs leading to discontinuation of study intervention

AEs leading to termination of study participation
In addition to the summary tables, a listing for all AEs will be provided.
Incidence of other treatment-emergent adverse events of special interest will be summarized. See 
Section 6.8 for list of adverse events in each category.
If any death, a listing of participants who died will be provided.
5.6.2.
Additional Safety Assessments 
5.6.2.1.
Clinical Laboratory Tests
Clinical laboratory tests will be displayed for the participants included in the safety analysis set.
Descriptive statistics displays will be presented for clinical chemistry, hematology and urinalysis
laboratory tests at scheduled time points.
Change from baseline to scheduled time points will be summarized for chemistry and hematology 
tests and displayed by intervention group. 
Toxicity grades will be determined according to the Division of Microbiology and Infectious 
Diseases (DMID) pediatric toxicity tables and the Division of AIDS (DAIDS) AE grading for 
Total Bilirubin (see protocol Section 10.5 Appendix 5 and Section 10.6 Appendix 6, respectively)
by the central laboratory and will be attributed to the baseline and postbaseline values.
It was noted that in the DMID table (see protocol Section 10.5 Appendix 5) for children less than 
or equal to 3 months of age, the calcium toxicity ranges (Hypocalcemia, Hypercalcemia) provided 
in mEq/L correspond to the values in mg/dL instead. Due to early termination of the study, no 
protocol amendment was completed for this issue.




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
TE will be concluded if the postbaseline value is above the upper limit and the baseline value 
is below the upper limit (eg, Normal or Low). The same applies to the postbaseline value 
being below the lower limit with the baseline value being above the lower limit (eg, Normal 
or High).

If the baseline value is missing, a postbaseline abnormality will always be considered as TE.
Table 12: Vital Signs Abnormalities – Abnormally Los/Normal/Abnormally High
Parameter (unit)
Abnormality
Age class
0 – 3 months 3 – 12 months
1 - 2-years
2- <3 years
3-6 years
DBP (mmHg)
abnormally low
<35
<40
<40
<40
<45
abnormally high
>65
>85
>90
>70
>80
SBP (mmHg)
abnormally low
<60
<60
<75
<80
<80
abnormally high
>110
>110
>120
>110
>110
Pulse/ HR (bpm)
abnormally low
<80
<70
<60
<90
<80
abnormally high
>180
>150
>140
>130
>120
RR
abnormally low
<25
<20
<18
<20
<17
abnormally high
>70
>60
>50
>35
>30
SpO2 (%) 
abnormally low
<92
<92
<92
<92
<92
Table 13: Abnormalities for Body Temperature
Abnormality Code
Temperature (°C)
Tympanic
Forehead
Oral
Rectal
Axillary
Abnormalities on actual values
Normal
≤ 37.8
≤ 38.0
≤ 38.0
≤ 37.2
≤ 38.0
Abnormally high
> 37.8
>38.0
>38.0
>37.2
>38.0
Only measurements taken while participant was calm, not crying and in supine position for 
temperature, pulse, Systolic Blood Pressure (SBP), Diastolic Blood Pressure (DBP) and RR and 
at room air for SpO2, will be considered in the analyses.
Number and percentage of participants with TE abnormalities will be presented by intervention 
group over time.
For RR, pulse/heart rate and body temperature, the maximum value will be considered as the worst 
grade/value while for SpO2, the lowest value will be considered the worst one.
Mean ± SE graphs over time for the actual values and changes from reference will be generated 
and presented by intervention group and by age groups as assigned at screening.
5.6.2.3.
Electrocardiogram
The ECG parameters that will be analyzed are heart rate, PR interval, RR interval, QRS interval, 
QT interval, and corrected QT (QTc) interval using the following correction methods: Bazett’s 
formula (QTcB), Fridericia’s formula (QTcF). QTcB and QTcF values will be used as reported by 
central ECG lab, they will not be recalculated.


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Descriptive statistics (mean, SD, median and range) of ECG parameters and change from baseline 
will be summarized at each scheduled time point by intervention group.
Abnormality criteria (based on criteria defined below in Table 14) will be applied to baseline and 
postbaseline values.
Postbaseline abnormalities will be compared with their corresponding baseline result:

TE will be concluded if the postbaseline value is above the upper limit and the baseline value 
is below the upper limit (eg, Normal or Low). The same applies to the postbaseline value 
being below the lower limit with the baseline value being above the lower limit (eg, Normal 
or High).

If the baseline value is missing, a postbaseline abnormality will always be considered as TE.
The number and percentage of participants with TE ECG abnormalities will be presented by 
intervention group over time.
Table 14: ECG Abnormalities
Parameter (unit)
Age class
Abnormally low
Abnormally high
PR (msec)
0 - 2 years
NA
>150
>2 - 5 years
NA
>160
QRS (msec)
0 - 2 years
NA
>89
>2 - 5 years
NA
>95
QT (msec)
0 - 5 years
NA
>500
RR (msec)
0 - 3 months
<333
>750
3 - 12 months
<400
>860
1 - 2 years
<430
>1000
2 - <18 years
<600
>1200
Abnormalities on the changes from baseline (∆QTc)
QT corrected
Abnormality Code
Criteria
Borderline QTc change
30 ms < ∆QTc <= 60 ms
Abnormally high QTc change
∆QTc > 60 ms
Abnormalities on actual QTcF values
QT corrected Formula
Abnormally high QTc value
450 ms < QTcF ≤ 480 ms
480 ms < QTcF ≤ 500 ms
>500 ms
A tabulation of the worst QT/QTc change versus baseline by intervention group over time will be 
presented.
Mean ± SE graphs over time for the actual values and changes from reference will be generated 
and presented by intervention group and by age group as assigned at screening. 




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5.7.3.
Virology
5.7.3.1.
Definitions
Viral Strain Typing
The RSV subtype is determined at baseline using the RSV-A/B RT-qPCR assay performed in the 
central lab.
Viral Sequencing
Viral resistance will be evaluated by next-generation sequencing (NGS) of the RSV Fusion (F) 
gene using a read frequency cut-off of 3%. 
Baseline samples from all participants will be sequenced to identify pre-existing genetic variations 
in the RSV F gene. Post-baseline sequencing will be performed on the last evaluable on-treatment 
sample and/or during follow-up for all participants (if viral load is high enough) to identify 
emerging amino acid substitutions in the RSV F gene. Additional post-baseline sequencing can be 
performed on request of the sponsor virologist.
Genetic variations
Genetic variations are defined as changes (on amino acid or nucleotide level) in the participant’s 
viral sequence compared to a reference sequence. Genetic variations can include substitutions, 
insertions and deletions. The reference sequences used will be RSV-A Long strain (GenBank 
Accession number AY911262) for RSV-A samples and RSV-B strain 9320 (GenBank Accession 
number AY353550) for RSV-B samples.  Genetic variations will be reported on amino acid level.

Baseline genetic variation: amino acid difference from the RSV-A or RSV-B reference strain 
detected at baseline with an NGS read frequency ≥15%.

Emerging genetic variation: a genetic variation (amino acid substitution, insertion or 
deletion) that is absent, ie. with a NGS read frequency <3%, at baseline but detected with a 
NGS read frequency ≥15% at a later post-baseline time point.

Enriched genetic variation: a genetic variation (amino acid substitution, insertion or 
deletion) detected at baseline with a NGS read frequency ≥3% and <15%, and with an increase 
in NGS read frequency of at least 15% post-baseline.

Genetic variation profile: a specific genetic variation or combination of genetic variations at 
one or more time points

RSV F protein amino acid positions of interest: 

Short list of 8 F protein positions of interest for JNJ-53718678, based on in vitro selection 
experiments with JNJ-53718678 and/or in vitro reduced susceptibility to JNJ-53718678: 
positions 141, 143, 394, 398, 400, 486, 488, and 489

Long list of 24 F protein positions of interest for the class of RSV fusion inhibitors, based 
on in vitro selection experiments, clinical observations, and/or in vitro reduced 
susceptibility to RSV fusion inhibitors, as well as residues involved in binding of JNJ-




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Over the study period
Amino acid changes from reference sequence at baseline and post-baseline will be listed for all 
participants using a NGS read frequency cut-off of 3%. For participants with emerging or enriched 
genetic variations, RSV RNA viral load profiles including emerging or enriched genetic variations 
per time point, will be generated. 
5.7.4.
Definition of Subgroups
Due to early termination of the study, no subgroups will be defined.
5.8.
Interim Analyses
Please see details in protocol Section 9.5 Interim Analysis.
Due to early termination of the study, no interim analysis will be performed.
5.8.1.
Data Monitoring Committee (DMC) or Other Review Board
Please see details in protocol Section 9.6 Independent Data Monitoring Committee and in 
associated IDMC charter.
Due to early termination of the study, the number of participants required for the first safety review 
was not reached. No further IDMC activities are foreseen nor IDMC SAP will be generated.


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6.
SUPPORTING DOCUMENTATION
6.1.
Appendix 1 List of Abbreviations
AE
adverse event
ALT/SGPT
alanine aminotransferase
APAC
Asia Pacific, Oceania and Japan
AST/SGOT
aspartate aminotransferase
ATC
anatomic and therapeutic class
AUC
area under the curve
bid
twice daily
CGRC
Clinician Global Rating of Change
CI
confidence interval
ClinRO
Clinician Reported Outcome
CRF
case report form
CSR
Clinical Study Report
CV
coefficient of variation
DAIDS
Division of AIDS
DMID
Microbiology and Infectious Diseases
DBP
Diastolic blood pressure
DPS
Data Presentation Specifications
ECG
electrocardiogram
eCRF
electronic case report form
EMEA
Europe, Middle East and Africa
FAS
full analysis set
FDA
Food and Drug Administration
h
hours
HR
Heart rate
IA
Interim Analysis
ICE
Intercurrent event
ICH
International Conference on Harmonisation
ICU
Intensive care unit
IDMC
Independent Data Monitoring Committee
IQ
interquartile
ITT-i
Intent-to-treat infected
IWRS
interactive web response system
KM
Kaplan-Meier
LATAM
Latin America and the Caribbean
LLOQ
lower limit of quantification
LOD
limit of detection
LFTU
lost to follow up
LRTI
Lower Respiratory Tract Infection
MedDRA
Medical Dictionary for Regulatory Activities
NA
North America (Canada and USA)
NGS
Next-generation sequencing
ObsRO
Observer Reported Outcome
PD
Pharmacodynamic(s)
PK
Pharmacokinetic(s)
PKAS
Pharmacokinetics analysis set
QTcB
Bazett’s formula QT
QTcF
Fridericia’s formula QT
RR
respiratory rate
RRS
RSV Recovery Scale
SAE
serious adverse event
SAF
Safety analysis set
SAP
Statistical Analysis Plan
SBP
Systolic blood pressure


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SC
Sponsor Committee
SD
standard deviation
SE
standard error
SMQs
standardised MedDRA queries
SoA
Schedule of Activities
SOC
Standard- of- Care
SpO2
Oxygen saturation
TD
Target detected
TE
Treatment Emergent
TEAE
treatment-emergent adverse event
TND
Target not detected
URTI
Upper Respiratory Tract Infection
V
volume distribution
VL
Viral Load
WHO
World Health Organization
WHO-DD
World Health Organization Drug Dictionary


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6.2.
Appendix 2 Changes to Protocol-Planned Analyses
Please see Section 1.1.




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Table 18: Baseline Characteristics
VARIABLE
SUMMARY TYPE
- Down syndrome
- neuromuscular impairment
- cystic fibrosis
- recurrent wheezing
- asthma
- other congenital disease
Frequency distribution 
with the number and 
percentage of 
participants in each 
category.
Receiving Supplemental Oxygen prior to first intake of study medication 
(no, yes)
Prenatal Smoking by the participant’s mother (no, yes)
Exposed to tobacco smoke in home environment (no, yes)
History of >1 episode of wheezing without a cold (no, yes)
History of atopic dermatitis (eczema) (no, yes)
History of allergy (no, yes)
If yes, type of allergy (allergic dermatitis, allergic rhinitis, allergic 
bronchitis, food allergy)
History of asthma (no, yes)
Contact with HCP before presenting (no, yes)
    If yes, type of HCP (General Practitioner, Pediatrician, Other)
Breastfeeding (no, yes)
Number of siblings within the household (0,1,2 or more)
Routinely attending daycare (no, yes)
Is the known pre-RSV SpO2 <92%? (Yes/No)
Pre-RSV infection oxygen saturation measured on room air
Received palivizumab (no, yes)
Received aerosolized ribavirin (no, yes)
Received IV immunoglobulin (no, yes)
Presence of other respiratory infection (no, yes)
Presence of other respiratory viral infection (no, yes)
Presence of other respiratory bacterial infection (no, yes)
1 Only Nasal Swab type samples to be considered.
2 As per IWRS and based on eCRF data.
3 Prematurely born participants are only eligible for this study if their age corrected for gestational age at birth is ≥28 days at the 
time of consent. After this main study opens to neonate enrollment: prematurity is not allowed for neonates (ie, neonate participants 
should have been born at term, after at least 37 weeks of gestation).


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6.4.
Appendix 4 Protocol Deviations
In general, the following list of major protocol deviations may have the potential to impact 
participants’ rights, safety or well-being, or the integrity and/or result of the clinical study. 
Participants with major protocol deviations will be identified prior to database lock and the 
participants with major protocol deviations will be summarized by category.

PD1- Entered but did not satisfy criteria

PD2- Received a disallowed concomitant treatment

PD3- Received wrong treatment or incorrect dose

PD4- Developed withdrawal criteria but not withdrawn 

PD5- Other
The deviations from the protocol with major impact on the assessment of efficacy will be defined. 
The final set of deviations will be identified and documented prior to database lock based on the 
following criteria.

PD1- Entered but did not satisfy criteria

PD1_IC4: Participant was enrolled, although the participant has not been diagnosed with 
RSV infection

PD1_IC5: Participant was enrolled, although the participant has no acute respiratory 
illness with at least 1 of the signs/symptoms listed in each of the 3 categories within 24 
hours prior to start of screening and at screening

PD1_IC6: Participant was enrolled, although the time of onset of RSV signs/symptoms 
to the anticipated time of randomization was not ≤3 days

PD1_EX3: Participant was enrolled, although the participant is considered by the 
investigator to be immunocompromised

PD1_EX5: Participant was enrolled, although the participant has had confirmed SARS-
CoV-2 infection during the four weeks prior to randomization OR participant was 
enrolled, although the participant has had close contact with a person with COVID-19 
within 14 days prior to randomization

PD1_EX6: Participant was enrolled, although the participant is being treated with 
extracorporeal membrane oxygenation

PD1_EX7: Participant was enrolled, although the participant is receiving chronic (home) 
oxygen therapy at the time of screening

PD1_EX9: Participant was enrolled, although participant’s mother received an 
investigational RSV vaccination during the pregnancy for this child and whose age is <3 
months at time of screening

PD1_EX13: Participant was enrolled, although the participant is unable to take 
medications orally OR participant was enrolled, although the participant has a known 
gastrointestinal-related condition that is considered by the sponsor or investigator to be 
likely to interfere with study intervention ingestion or absorption


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
PD2- Received a disallowed concomitant treatment

PD3- Received wrong treatment or incorrect dose

Participant’s actual intervention not the same as planned one:
o
PD3_1: Receiving wrong medication kit 
o
PD3_2: Receiving incorrect dose 

PD3_6: Participant missed 2 or more doses

PD4- Developed withdrawal criteria but not withdrawn 

PD4_6: Unplanned unblinding has taken place during the study 

PD5- Other

PD5_2: More than 1 of every 4-consecutive scheduled ObsRO are missing between D1-
D7 

PD5_3: More than 1 of every 4-consecutive scheduled ObsRO are missing between D8-
D14 

PD5_4: More than 1 of every 3-consecutive scheduled ObsRO are missing from D15-
D21 

PD5_6: ClinRO at the day of discharge and/or next assessment after discharge is not 
available 


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6.5.
Appendix 5 Prior and Concomitant Medications
Prior and Concomitant medications will be coded using the World Health Organization Drug 
Dictionary (WHO-DD). Prior medications are defined as any therapy used before the day and time 
(if available) of first dose (partial or complete) of study intervention. Concomitant medications are 
defined as any therapy used on or after the same day and time as the first dose of study intervention, 
including those that started before and continue on after the first dose of study intervention.
Summaries of concomitant medications will be presented by ATC class up to level 3, intervention 
group, intervention phase and combination of intervention and follow-up phase. The proportion of 
participants who receive each concomitant medication will be summarized as well as the 
proportion of participants who receive at least 1 concomitant medication. Prior medications will 
be summarized by intervention group and class up to level 3.


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6.6.
Appendix 6 Medical History
A list of risk factors for severe RSV disease by participant will be provided. The medical history 
and family history records will also be listed. 


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6.7.
Appendix 7 Intervention Compliance
Compliance will be summarized descriptively for each intervention group. The reasons for not 
administered doses will be listed
Intervention Compliance (%) = 100 x number of doses of study agent /total doses planned
The total planned doses are as follows:

For participants who complete the 7 days of study intervention, a total of 14 doses will be 
given as per protocol 

For early study intervention discontinuation, total doses will be based on the number of days 
participant was in the intervention period (eg: 2 doses per day are planned by protocol so if 
participant is 3 days in the intervention period, total planned doses are 6).


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6.8.
Appendix 8 Adverse Events of Special Interest
Adverse events of special interest are defined as follows:
Table 19: Hepatobiliary Effects
MedDRA Preferred Term (PT)
MedDRA Code
Drug-induced liver injury
10072268
Hyperbilirubinaemia
10020578
Jaundice
10023126
Ocular icterus
10058117
Yellow skin
10048245
Alanine aminotransferase increased
10001551
Aspartate aminotransferase increased
10003481
Bilirubin conjugated increased
10004685
Bilirubin urine present
10077356
Blood bilirubin increased
10005364
Blood bilirubin unconjugated increased
10005370
Gamma-glutamyltransferase increased
10017693
Blood alkaline phosphatase increased
10059570
Hypoalbuminaemia
10020942
Urobilinogen urine decreased
10070480
Urobilinogen urine increased
10070479
Allergic hepatitis
10071198
Hepatic cytolysis
10049199
Hepatitis
10019717
Hepatitis acute
10019727
Hepatitis cholestatic
10019754
Hepatitis chronic active *
10019755
Hepatitis chronic persistent *
10019759
Hepatitis fulminant
10019772
Hepatitis toxic
10019795
Immune-mediated hepatitis
10078962
Non-alcoholic steatohepatitis
10053219
Steatohepatitis
10076331
*actual represents 'acute on chronic hepatitis'.


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Table 20: Cardiac Events Potentially Related to QT Prolongation1
MedDRA Preferred Term (PT)
MedDRA Code
Electrocardiogram QT interval abnormal 
10063748
Electrocardiogram QT prolonged 
10014387
Long QT syndrome 
10024803
Long QT syndrome congenital 
10057926
Torsade de pointes 
10044066
Ventricular tachycardia 
10047302
Cardiac arrest 
10007515
Cardiac death 
10049993
Cardiac fibrillation 
10061592
Cardio-respiratory arrest 
10007617
Electrocardiogram repolarisation abnormality 
10052464
Electrocardiogram U wave inversion 
10062314
Electrocardiogram U wave present 
10057913
Electrocardiogram U-wave abnormality 
10055032
Loss of consciousness 
10024855
Sudden cardiac death
10049418
Sudden death
10042434
Syncope
10042772
Ventricular arrhythmia
10047281
Ventricular fibrillation
10047290
Ventricular flutter
10047294
Ventricular tachyarrhythmia
10065341


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6.9.
Appendix 9 Laboratory Toxicity Grading
The grading scale use for lab assessments is based on Division of Microbiology and Infectious 
Diseases (DMID) pediatric toxicity tables and the Division of AIDS (DAIDS) AE grading for 
Total Bilirubin (see protocol Section 10.5 Appendix 5 and Section 10.6 Appendix 6, respectively).
Pre-baseline measurements will use the same grading ranges as applied to baseline measurements. 
In case a test has two sets of ranges – one for baseline normal and one for baseline abnormal, the 
one for baseline normal will be applied for all measurements taken pre-baseline and on baseline.


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6.10.
Appendix 10 Missing Data 

Missing SpO2 (or not measured on room air) for the RRS
Missing SpO2 or 
NOT measured-on
room air 
Supplemental 
Oxygen 
episode
Imputation RRS category/status
Yes
4 = Non-ICU Hospitalization, Requiring Supplemental Oxygen AND/OR Supplemental 
Feeding/Hydration
No

If no supplemental feeding 3=Non-ICU Hospitalization, Not Requiring Supplemental 
Oxygen NOR Supplemental Feeding/Hydration

If supplemental feeding 4= Non-ICU Hospitalization, Requiring Supplemental Oxygen 
AND/OR Supplemental Feeding/Hydration 










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6.11.
Appendix 11 RRS derivation
The RRS is evaluated by study day, from Day 1 to Day 8. Day 1 is defined as the day of the first 
dose of study intervention intake. Time of dosing is irrelevant when deriving the RRS for each 
study day.
The RRS categories should be evaluated from worst category (7. Death) to the best one (1. Not 
hospitalized without signs/symptoms). For each study day, first would check if participant died 
and if not then the following category 6 will be evaluated. If participant not in that status either, 
next category 5 will be evaluated and so on until there is one category that participants is allocated 
to.
Please see Section 6.10. 




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CCI


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CCI




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CCI


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CCI


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CCI


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7.
REFERENCES
1.
International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use. ICH
Harmonized Tripartite Guideline E14: Clinical evaluation of QT/QTc interval prolongation and proarrhythmic
potential for non-antiarrhythmic drugs. ICH 12 May 2005
2.
United Nations publication, Standard Country or Area Codes for Statistical Use (M49 standard), 
https://unstats.un.org/unsd/methodology/m49/