Clinical trial NCT03656510
Conditions: Respiratory Syncytial Virus Infections
Sponsor: Janssen Research & Development, LLC
Start date: 2018-11-29; Completion date: 2022-04-18
Enrollment: 246 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The purpose of this study is to evaluate the antiviral activity, clinical outcomes, safety, tolerability, and pharmacokinetic/pharmacodynamic relationships of different oral dose levels of JNJ-53718678 in children greater than or equal to 28 days and less than or equal to 3 years of age with respiratory syncytial virus (RSV) disease (hospitalized participants \[Cohort 1\] or outpatients \[Cohort 2\]).

Detailed description:
JNJ-53718678 is an investigational respiratory syncytial virus (RSV) specific fusion inhibitor and is under development for the treatment of RSV infection, which results in an upper and/or lower respiratory tract illness. The primary hypothesis of this study is that JNJ-53718678 has antiviral activity against RSV (that is, results in a decrease in RSV nasal viral load from immediately prior to first dose of study drug until Day 5). This will be assessed by a positive dose-response relationship of JNJ-53718678 compared to placebo. Besides the RSV nasal viral load through day 5, other timepoints will also be evaluated as well as other nasal viral load related parameters. In addition, the evolution of signs and symptoms of RSV disease will be evaluated. Participants' safety will be monitored throughout the study by evaluating the occurrence and severity of adverse events and by laboratory and electrocardiogram measurements. Study participants will be identified when they are hospitalized or expected to be hospitalized within 24 hours after presentation to the hospital (Cohort 1) or present for medical care as outpatients (Cohort 2) with symptoms of an acute respiratory illness supporting a diagnosis of RSV infection. Eligible participants will be randomized 1:1:1 to receive either a low or a high dose of JNJ 53718678 or placebo and will be receiving study treatment for 7 days. They will be followed up for 3 weeks after the last dose. The total study duration for each participant will be approximately 29 days.

Arms: arm 1: Participants will be randomized to receive JNJ-53718678 2.5 milligram per kilogram (mg/kg) (Age Group 1: greater than or equal to \[\>=\] 28 days and less than \[\<\] 3 months of age), 3 mg/kg (Age Group 2: \>=3 months and \<6 months of age) and 4.5 mg/kg (Age Group 3: \>=6 months and less than or equal to \[\<=3\] years of age) orally twice daily for 7 days. arm 2: Participants will be randomized to receive JNJ-53718678 0.85 mg/kg (Age Group 1: \>=28 days and \<3 months of age), 1 mg/kg (Age Group 2: \>=3 months and \<6 months of age) and 1.5 mg/kg (Age Group 3: \>=6 months and 3 years of age) orally twice daily for 7 days. arm 3: Participants will be randomized to receive matching placebo (i.e. high volume placebo or low volume placebo to match the calculated volume of the JNJ-53718678 for the high dose or low dose) orally twice daily for 7 days.
Interventions: intervention 1: JNJ-53718678 intervention 2: Placebo
Intervention descriptions: intervention 1: Participants will receive JNJ-53718678 (high dose or low dose) orally twice daily for 7 days. intervention 2: Participants will receive matching placebo (high volume or low volume) orally twice daily for 7 days.

Protocol documents:
Prot_000.pdf: 
JNJ-53718678
Clinical Protocol 53718678RSV2002 Amendment 6
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
1
Approved, Date: 1 December 2020
Janssen Research & Development*
Clinical Protocol
A Phase 2, Double-blind, Placebo-controlled Study to Evaluate the Antiviral Activity,
Clinical Outcomes, Safety, Tolerability, and Pharmacokinetic/Pharmacodynamic
Relationships of Different Doses of JNJ-53718678 in Children ≥28 Days and ≤3 Years of
Age With Acute Respiratory Tract Infection Due to Respiratory Syncytial Virus Infection
Protocol 53718678RSV2002; Phase 2
AMENDMENT 6
JNJ-53718678
*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 Pharmaceutica NV; Janssen, Inc; Janssen
Sciences Ireland Unlimited Companies; 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.
This study will be conducted in US sites under US Food & Drug Administration IND regulations
(21 CFR Part 312).
EudraCT NUMBER:2016-003642-93
Status: 
Approved
Date: 
1 December 2020
Prepared by: Janssen Research & Development, a division of Janssen Pharmaceutica NV
EDMS number: 
EDMS-ERI-127967555, 17.0
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.
NCT03656510


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TABLE OF CONTENTS
TABLE OF CONTENTS............................................................................................................................... 2
LIST OF IN-TEXT TABLES AND FIGURES................................................................................................ 5
PROTOCOL AMENDMENTS....................................................................................................................... 6
SYNOPSIS.................................................................................................................................................. 15
TIME AND EVENTS SCHEDULE .............................................................................................................. 37
ABBREVIATIONS...................................................................................................................................... 50
1.
INTRODUCTION................................................................................................................................ 52
1.1. 
Background.................................................................................................................................... 53
1.2. 
Benefit-risk Evaluations.................................................................................................................. 68
1.2.1. 
Known Benefits........................................................................................................................... 68
1.2.2. 
Potential Benefits........................................................................................................................ 68
1.2.3. 
Known Risks............................................................................................................................... 68
1.2.4. 
Potential Risks............................................................................................................................ 68
1.2.5. 
Overall Benefits/Risks................................................................................................................. 70
1.3. 
Overall Rationale for the Study...................................................................................................... 71
2.
OBJECTIVES, ENDPOINTS, AND HYPOTHESIS........................................................................... 72
2.1. 
Objectives and Endpoints .............................................................................................................. 72
2.1.1. 
Objectives ................................................................................................................................... 72
2.1.2. 
Endpoints.................................................................................................................................... 73
2.2. 
Hypothesis ..................................................................................................................................... 76
3.
STUDY DESIGN AND RATIONALE................................................................................................. 76
3.1. 
Overview of Study Design.............................................................................................................. 76
3.2. 
Study Design Rationale.................................................................................................................. 85
4.
SUBJECT POPULATION.................................................................................................................. 89
4.1. 
Inclusion Criteria ............................................................................................................................ 89
4.2. 
Exclusion Criteria ........................................................................................................................... 91
4.3. 
Lifestyle Restrictions ...................................................................................................................... 93
5.
TREATMENT ALLOCATION AND BLINDING................................................................................. 93
6.
DOSAGE AND ADMINISTRATION .................................................................................................. 94
7.
STUDY DRUG COMPLIANCE.......................................................................................................... 96
8.
CONCOMITANT THERAPY.............................................................................................................. 96
9.
STUDY EVALUATIONS.................................................................................................................... 99
9.1. 
Study Procedures........................................................................................................................... 99
9.1.1. 
Overview..................................................................................................................................... 99
9.1.2. 
Screening Phase ...................................................................................................................... 100
9.1.3. 
Double-Blind Treatment Phase ................................................................................................ 101
9.1.4. 
Posttreatment Phase (Follow-Up)............................................................................................ 102
9.2. 
Efficacy Evaluations..................................................................................................................... 103
9.2.1. 
Antiviral Activity......................................................................................................................... 103
9.2.2. 
Clinical Course of RSV Infection .............................................................................................. 105
9.2.3. 
Viral Sequencing....................................................................................................................... 106
9.3. 
Safety Evaluations ....................................................................................................................... 106
9.3.1. 
Specific Toxicities and Safety Topics of Special Interest......................................................... 111


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9.4. 
Pharmacokinetics......................................................................................................................... 112
9.4.1. 
Evaluations ............................................................................................................................... 112
9.4.2. 
Analytical Procedures............................................................................................................... 113
9.5. 
Pharmacokinetic/Pharmacodynamic Evaluations........................................................................ 113
9.6. 
Medical Resource Utilization........................................................................................................ 114
9.7. 
Acceptability and Palatability....................................................................................................... 114
9.8. 
Biomarkers................................................................................................................................... 114
9.9. 
Other Evaluations......................................................................................................................... 114
9.10. 
Sample Collection and Handling.................................................................................................. 114
10. SUBJECT COMPLETION/DISCONTINUATION OF STUDY DRUG/ WITHDRAWAL FROM
THE STUDY..................................................................................................................................... 115
10.1. 
Completion ................................................................................................................................... 115
10.2. 
Stopping Criteria .......................................................................................................................... 115
10.2.1. 
For an Individual Subject.......................................................................................................... 115
10.2.2. 
For the Study............................................................................................................................ 115
10.3. 
Discontinuation of Study Treatment............................................................................................. 115
10.4. 
Withdrawal From the Study.......................................................................................................... 116
10.5. 
Withdrawal From the Use of Samples in Future Research.......................................................... 117
11. STATISTICAL METHODS............................................................................................................... 117
11.1. 
Interim Analyses........................................................................................................................... 117
11.1.1. 
First Interim Analysis ................................................................................................................ 118
11.1.2. 
Second Interim Analysis ........................................................................................................... 118
11.1.3. 
Third Interim Analysis ............................................................................................................... 119
11.1.4. 
Fourth Interim Analysis............................................................................................................. 120
11.2. 
Subject Information ...................................................................................................................... 121
11.3. 
Sample Size Determination ......................................................................................................... 121
11.3.1. 
Primary Objective: Establish Antiviral Activity.......................................................................... 121
11.3.2. 
Key Secondary Objective: Clinical Course Effect..................................................................... 122
11.4. 
Efficacy Analyses......................................................................................................................... 123
11.4.1. 
Antiviral Effect........................................................................................................................... 123
11.4.1.1. 
Primary Endpoint................................................................................................................... 123
11.4.1.2. 
Secondary Endpoints ............................................................................................................ 124
11.4.2. 
Clinical Course of RSV Infection .............................................................................................. 125
11.4.3. 
Correlation Between Antiviral Effect and Clinical Course Endpoints ....................................... 125
11.4.4. 
Viral Sequencing....................................................................................................................... 125
11.5. 
Safety Analyses ........................................................................................................................... 126
11.6. 
Pharmacokinetic Analyses........................................................................................................... 127
11.7. 
Pharmacokinetic/Pharmacodynamic Relationships..................................................................... 127
11.8. 
Medical Resource Utilization Analyses........................................................................................ 128
11.9. 
Acceptability and Palatability....................................................................................................... 128
11.10. Biomarker Analyses ..................................................................................................................... 128
11.11. Other Analyses............................................................................................................................. 128
11.12. Independent Data Monitoring Committee .................................................................................... 128
12. ADVERSE EVENT REPORTING .................................................................................................... 129
12.1. 
Definitions .................................................................................................................................... 129
12.1.1. 
Adverse Event Definitions and Classifications ......................................................................... 129
12.1.2. 
Attribution Definitions................................................................................................................ 130
12.1.3. 
Severity Criteria ........................................................................................................................ 131
12.2. 
Special Reporting Situations........................................................................................................ 131
12.3. 
Procedures................................................................................................................................... 132
12.3.1. 
All Adverse Events.................................................................................................................... 132
12.3.2. 
Serious Adverse Events ........................................................................................................... 133
12.4. 
Contacting Sponsor Regarding Safety......................................................................................... 134
13. PRODUCT QUALITY COMPLAINT HANDLING............................................................................ 134


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13.1. 
Procedures................................................................................................................................... 134
13.2. 
Contacting Sponsor Regarding Product Quality.......................................................................... 134
14. STUDY DRUG INFORMATION....................................................................................................... 134
14.1. 
Physical Description of Study Drug.............................................................................................. 134
14.2. 
Packaging .................................................................................................................................... 135
14.3. 
Labeling........................................................................................................................................ 135
14.4. 
Handling, and Storage ................................................................................................................. 135
14.5. 
Drug Accountability...................................................................................................................... 135
15. STUDY-SPECIFIC MATERIALS..................................................................................................... 136
16. ETHICAL ASPECTS....................................................................................................................... 137
16.1. 
Study-Specific Design Considerations......................................................................................... 137
16.2. 
Regulatory Ethics Compliance..................................................................................................... 137
16.2.1. 
Investigator Responsibilities..................................................................................................... 137
16.2.2. 
Independent Ethics Committee or Institutional Review Board................................................. 138
16.2.3. 
Informed Consent ..................................................................................................................... 139
16.2.4. 
Privacy of Personal Data .......................................................................................................... 140
16.2.5. 
Long-Term Retention of Samples for Additional Future Research .......................................... 140
16.2.6. 
Country Selection ..................................................................................................................... 141
17. ADMINISTRATIVE REQUIREMENTS............................................................................................ 141
17.1. 
Protocol Amendments.................................................................................................................. 141
17.2. 
Regulatory Documentation .......................................................................................................... 141
17.2.1. 
Regulatory Approval/Notification .............................................................................................. 141
17.2.2. 
Required Prestudy Documentation........................................................................................... 141
17.3. 
Subject Identification, Enrollment, and Screening Logs .............................................................. 142
17.4. 
Source Documentation................................................................................................................. 143
17.5. 
Case Report Form Completion .................................................................................................... 144
17.6. 
Pediatric RSV Electronic Severity and Outcomes Rating Scales................................................ 144
17.6.1. 
Clinician .................................................................................................................................... 144
17.6.2. 
Parent(s)/caregiver(s)............................................................................................................... 145
17.7. 
Data Quality Assurance/Quality Control ...................................................................................... 145
17.8. 
Record Retention ......................................................................................................................... 145
17.9. 
Monitoring .................................................................................................................................... 146
17.10. Study Completion/Termination..................................................................................................... 146
17.10.1. Study Completion/End of Study................................................................................................ 146
17.10.2. Study Termination..................................................................................................................... 146
17.11. On-Site Audits.............................................................................................................................. 147
17.12. Use of Information and Publication .............................................................................................. 147
REFERENCES.......................................................................................................................................... 149
ATTACHMENTS....................................................................................................................................... 151
Attachment 1: 
Division of Microbiology and Infectious Diseases (DMID) Pediatric Toxicity
Tables (November 2007; draft).................................................................................................... 151
Attachment 2: 
Cardiovascular Safety –Abnormalities........................................................................ 163
Attachment 3: 
Anticipated Events ....................................................................................................... 165
Attachment 4: 
Clinician PRESORS v7 (24 May 2018)........................................................................ 166
Attachment 5: 
Parent(s)/Caregiver(s) PRESORS v7.1 (9July2018)................................................. 171
Attachment 6: 
Study Medication Log .................................................................................................. 177
Attachment 7: 
Nasal Swab Log........................................................................................................... 178
Attachment 8: 
Temperature Log ......................................................................................................... 179
Attachment 9: 
Study Medication Tolerability Assessment.................................................................. 180
Attachment 10: 
Guidance on Study Conduct During the COVID-19 Pandemic ................................... 181
INVESTIGATOR AGREEMENT............................................................................................................... 184


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Clinical Protocol 53718678RSV2002 Amendment 6
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
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LIST OF IN-TEXT TABLES AND FIGURES
TABLES
Table 1: 
Risk Factors for Severe RSV Disease...................................................................................... 77
Table 2: 
Predicted Geometric Mean AUC24h, Cmax, Ctrough  and QTcI Per Age Group After Day
1 and Day 7............................................................................................................................... 88
Table 3: 
Treatment Overview.................................................................................................................. 95
Table 4: 
Overview of Pharmacokinetic Sampling Windows for Cohort 1 Subjects .............................. 113
Table 5: 
Power (%) to Conclude Dose-response Using MCP-Mod Under Different Assumptions
for the Dose-response Relationship ....................................................................................... 122
FIGURES
Figure 1: Schematic Overview of the Design of Study 53718678RSV2002............................................ 78
Figure 2: Overview of Different Planned Analyses in Study 53718678RSV2002.................................... 85
Figure 3: Candidate Models for RSV Viral Load AUC From Baseline Until Day 5 ................................ 124


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PROTOCOL AMENDMENTS
Protocol Version 
Issue Date
Original Protocol 
13 Jul 2018
Amendment 1 
14 May 2019
Amendment 2 
5 Jul 2019
Amendment 3 
20 Dec 2019
Amendment 4 
26 May 2020
Amendment 5 
10 Jul 2020
Amendment 6 
01 Dec 2020
Amendments are listed beginning with the most recent amendment.
Amendment 6 (01 December 2020)
The overall reason for the amendment:The overall rationale for the changes implemented in the protocol
amendment is to maximize enrollment of subjects with at least moderate RSV disease severity, where potentially
greater treatment benefit can be achieved.
Applicable Section(s) 
Description of Change(s)
Rationale:Inclusion Criterion 4 was changed to maximize enrollment of subjects with at least moderate RSV
disease severity, where potentially greater treatment benefit can be achieved.
SYNOPSIS
3.1 Overview of Study Design
4.1 Inclusion Criteria
Rationale: The typographical error in the low dose for age group 1 was corrected from 0.83 to 0.85 mg
JNJ-53718678/kg bodyweight.
SYNOPSIS
3.1 Overview of Study Design
6 DOSAGE AND ADMINISTRATION
Rationale: A clarification sentence was added regarding compliance with study drug administration.
TIME AND EVENTS SCHEDULE
7 STUDY DRUG COMPLIANCE
9.1.3 Double-Blind Treatment Phase
Rationale:The use of antitussives and mucolytics is recommended to be limited to use in line with the clinical
practice guidelines and package inserts as they can potentially confound the evaluation of RSV signs and
symptoms.
8 CONCOMITANT THERAPY
9.1.1 Overview
9.2.2 Clinical Course of RSV Infection
Rationale:Minor corrections and clarifications were made throughout the document.


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Amendment 5 (10 July 2020)
The overall reason for the amendment:The overall reason for the amendment is to implement
recommendations from Health Authorities (HA). Given that Cohort 1 enrollment has completed and no more
Cohort 1 subjects are ongoing in the study, the changes listed below are only applicable for the newly to be
recruited Cohort 2 subjects.
Applicable Section(s) 
Description of Change(s)
Rationale:A clarification was added to specify the timing of ECG monitoring on Day 3 to be performed at tmax
of JNJ-53718678 at steady state (time to reach Cmax), ie, approximately 1 hour post dose, in line with
recommendations by HA
TIME AND EVENTS SCHEDULE
1.2.5 Overall Benefits/Risks
Rationale:The study intervention discontinuation and withdrawal criterion specific to ECG QT interval changes
was adapted from values >500 ms to values ≥500 ms, in line with recommendations by HA.
9.3 Safety Evaluations
9.3.1 Specific Toxicities and Safety Topics of Special Interest
10.3 Discontinuation of Study Treatment
Rationale:The BCRP inhibitors eltrombopag and curcumin were added to the disallowed concomitant therapy
section. JNJ-53718678 is a substrate for BCRP based on in vitro data. Clinically relevant BCRP inhibitors are
prohibited to avoid potential DDI with JNJ-53718678, in line with recommendations by HA.
1.2.5 Overall Benefits/Risks
8 CONCOMITANT THERAPY
Rationale:Additional flexibility was provided with regards to the day of the Ctrough  sampling, as JNJ-53718678
trough concentrations are determined by the timepoint (at least 4 hours after the AM and before the PM dose)
after dosing, and not by the day of sampling.
SYNOPSIS
TIME AND EVENTS SCHEDULE
3.1 Overview of Study Design
9.4.1 Evaluations
Rationale:Removal of azithromycin as generally allowed medication. Azithromycin is a QT prolonging drug
allowed with restrictions. Correction to an oversight of the previous amendment related to disallowed
concomitant medications with QT-prolonging effects.
8 CONCOMITANT THERAPY
Rationale:Minor corrections and clarifications were made throughout the document.


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Amendment 4 (26 May 2020)
The overall reason for the amendment:The overall reason for the amendment is to implement a risk mitigation
plan following identification of an exposure (Cmax)-related important potential risk of QT interval prolongation
identified in the TQT Study 53718678RSV1009 in healthy adult subjects. Given that Cohort 1 enrollment has
completed and no more Cohort 1 subjects are ongoing in the study, the changes listed below are only applicable
for the newly to be recruited Cohort 2 subjects.
Applicable Section(s) 
Description of Change(s)
Rationale:A new important potential risk of QT interval prolongation was identified from the above-mentioned
TQT study and this was reflected in the benefit-risk section of the protocol.
1.1 Background
1.2.4 Potential Risks
1.2.5 Overall Benefits/Risks
Rationale:Recently available relevant clinical data were included in the introduction. Accordingly, the
Investigator's Brochure Addendum to Edition 06 was added as a reference.
1 INTRODUCTION
1.1 Background
1.2.1 Known Benefits
1.2.2 Potential Benefits
1.2.4 Potential Risks
1.2.5 Overall Benefits/Risks
Rationale: The daily dosing frequency was changed from qd to bid dosing while maintaining the total daily dose
(ie, at each intake half of the total daily dose will be administered). The proposed bid dosing will ensure
mitigation of the important potential risk of QT interval prolongation and the highest potential antiviral effect
while minimizing the risk of development of resistance. The definitions of missing dose and overdose were
adapted accordingly. The generalized Multiple Comparison Procedure-Modeling approach in the statistical
methods has been clarified regarding bid dosing.
SYNOPSIS
TIME AND EVENTS SCHEDULE
1.2.5 Overall Benefits/Risks
1.3 Overall Rationale for the Study
3.1 Overview of Study Design
3.2 Study Design Rationale
6 DOSAGE AND ADMINISTRATION
7 STUDY DRUG COMPLIANCE
9.1.3 Double-Blind Treatment Phase
11.4.1.1 Primary Endpoint
11.4.1.2 Secondary Endpoints
11.4.2 Clinical Course of RSV Infection
Rationale: Changes in PK schedule are required to collect a PK sample at the Cmax  for each patient and a PK
sample in the distribution/elimination phase. This allows the characterization of PK parameters for safety related
to the risk of QT prolongation (Cmax) and efficacy (AUC and Ctrough) in all patients.
SYNOPSIS
TIME AND EVENTS SCHEDULE
3.1 Overview of Study Design
9.4.1 Evaluations
Rationale: The frequency of ECG monitoring was increased by adding measurements at Day 1 (1 hour post
dose) and Day 3 to enhance the cardiac-related safety follow-up.


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Applicable Section(s) 
Description of Change(s)
TIME AND EVENTS SCHEDULE
1.2.5 Overall Benefits/Risks
Rationale: Close monitoring of the use of concomitant medications to be conducted regularly was added as one
of the QT prolongation mitigation measures to ensure the subjects’ safety.
1.2.5 Overall Benefits/Risks
Rationale: Several exclusion criteria related to cardiac safety were added. Exclusion criterion 15 was made more
stringent for children ≤3 years (ie, confirmed QTcF interval >450 ms) to ensure subjects’ safety.
SYNOPSIS
1.2.5 Overall Benefits/Risks
4.2 Exclusion Criteria
Rationale:New physiologically based pharmacokinetics data indicate potential for increase of the JNJ-53718678
Cmax  due to CYP3A4 inhibition which in view of the QT interval prolongation risk needs to be avoided to
maintain the safety margin. Therefore, moderate CYP3A4 inhibitors were added to the disallowed prescription
medications 14 days prior to screening until 3 days after last dose (in addition to the already disallowed strong
CYP3A4 inhibitors) to ensure no effect of the moderate and strong CYP3A4 inhibitors on the study intervention.
Given that the t1/2 of JNJ-53718678 is approximately 10 hours, study intervention is washed out after 3 days.
Therefore, the period for strong CYP3A4 inhibitors being disallowed was aligned with that for moderate ones, ie,
to 3 days after last study intervention intake.
1.2.5 Overall Benefits/Risks
8 CONCOMITANT THERAPY
Rationale:Medications with a known risk to prolong the QT interval cannot be initiated at screening
and/or during the study intervention treatment period in view of the identified potential risk of QT interval
prolongation.
1.2.5 Overall Benefits/Risks
8 CONCOMITANT THERAPY
Rationale: Specific toxicity management for cardiac events potentially related to QT prolongation was added to
ensure the subjects' safety.
1.2.5 Overall Benefits/Risks
9.3.1 Specific Toxicities and Safety Topics of Special Interest
Rationale:A study intervention discontinuation and withdrawal criterion specific to QT interval changes to
values >500 ms on ECG was added to ensure the subjects’ safety.
1.2.5 Overall Benefits/Risks
10.3 Discontinuation of Study Treatment
Rationale: A safety measure regarding hypokalemia and hypomagnesemia was added.
TIME AND EVENTS SCHEDULE
1.2.5 Overall Benefits/Risks
9.3 Safety Evaluations
Rationale:The specific Rash Management section, which is a therapeutic area-specific section that can be
adapted based on emerging data, has been removed as data from both adult and pediatric studies has not indicated
rash-related safety signal.
9.3.1 Specific Toxicities and Safety Topics of Special Interest
10.3 Discontinuation of Study Treatment
ATTACHMENTS
Rationale: A table presenting the risk factors for severe RSV disease was added to avoid stratification errors.


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Applicable Section(s) 
Description of Change(s)
3.1 Overview of Study Design
Rationale: The statement on additional interim analyses (already included in the protocol body) was added to the
synopsis and Section 3.1 for completeness.
SYNOPSIS
3.1 Overview of Study Design
Rationale: A statement was added on sharing selected unblinded data with investigators to support the revised
risk-benefit evaluation for the current study and to support start of Phase 3.
SYNOPSIS
11.1 Interim Analyses
Rationale:A clarification was added (ULN are adult ULN) to the creatinine values of subjects older than 3
months of age in Attachment 1 (DMID Pediatric Toxicity Tables) based on feedback from the DMID Authors.
Attachment 1: 
Division of Microbiology and Infectious Diseases (DMID) Pediatric Toxicity Tables
(November 2007; draft)
Rationale:The medication log was updated given the change in dose regiment from qd to bid. In order to make
efficient updates to the ePRO system, the initial study medication log with slight modification will be repeated to
allow capturing of dose intake information bid.
Attachment 6: 
Study Medication Log
Rationale: The Anticipated Event Review Committee was re-named to Safety Assessment Committee.
Attachment 3: 
Anticipated Events
Rationale: COVID-19-related measures were added to avoid co-infection with SARS-COV-2 as this would
confound evaluation of the clinical course of RSV and to provide guidance on study conduct during the
COVID-19 pandemic.
TIME AND EVENTS SCHEDULE
3.1 Overview of Study Design
4.1 Inclusion Criteria
4.2 Exclusion Criteria
Attachment 10: Guidance on Study Conduct During the COVID-19 Pandemic
Rationale:An inconsistency was corrected from 50 to 55% with regards to the maximum % of subjects enrolled
with time since onset of RSV symptoms of >3 days to ≤5 days at the time of all planned interim or final analyses.
3.2 Study Design Rationale
Rationale:Minor corrections and clarifications were made throughout the document.


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Amendment 3 (20 December 2019)
The overall reason for the amendment:The overall reason for the amendment is to allow unblinding of the
central sponsor team and selected local sponsor representatives from Japan to the data included in the second
interim analysis and to allow unblinding of the sponsor, including the study team, and selected local sponsor
representatives from Japan to all interim analyses planned after the second interim analysis.
Applicable Section(s) 
Description of Change(s)
Rationale: Based on the decision of the Sponsor Committee after the second interim analysis, the sponsor wants
to proceed with further development and start the next JNJ-53718678 pediatric study(ies) in the Northern
Hemisphere season of 2020/2021. Due to the non-confirmatory nature of Study 53718678RSV2002, and the aim
to explore multiple potential clinical endpoints across 2 settings (hospital and community), the central sponsor
team and selected local sponsor representatives from Japan will be unblinded to the data included in the second
interim analysis upon recommendation from the IDMC and the Sponsor Committee to enable preparations for
future study(ies) and to support associated health authority interactions. Any interim analysis planned after the
second interim analysis will be unblinded to the sponsor, including the central study team, and selected local
sponsor representatives from Japan to allow internal decision making and proceeding towards Phase 3.
Investigators, subject(s), and local sponsor representatives (except selected local sponsor representatives from
Japan) will remain blinded during and after all interim analyses.
Medical writers were added to the central sponsor team.
SYNOPSIS
11.1 Interim Analyses
Amendment 2 (5 July 2019)
The overall reason for the amendment:The overall reason for the amendment is to clarify how the required
balance within the symptom onset randomization strata (symptom onset ≤3 days and >3 days to ≤5 days) for each
of the interim analyses as well as for the final analysis will be achieved while allowing some flexibility in view of
RSV seasonality and reducing the recruitment impact of a (temporary) pause in enrollment in one of the strata.
Applicable Section(s) 
Description of Change(s)
Rationale:Clarifications are provided on how the required balance within the symptom onset randomization
strata (symptom onset ≤3 days and >3 days to ≤5 days) for each of the interim analyses as well as for the final
analysis will be achieved while allowing some flexibility in view of RSV seasonality and reducing the
recruitment impact of a (temporary) pause in enrollment in one of the strata. Subjects with symptom onset ≤3
days before randomization must account for a minimum of 45% of all enrolled subjects in Cohorts 1 and 2 (ie,
maximum 55% of subjects can be enrolled in the >3 days to ≤5 days stratum). Enrollment in the >3 days to
≤5 days since symptom onset stratum might be temporarily paused prior to an interim analysis and stopped prior
to the final analysis. Stratum caps and closures are managed separately for each cohort and consider the sample
size of the respective cohort for the interim analysis and the total sample size of each cohort for the final analysis.
Prior to interim analysis 2 (at N=approximately 70-80 in Cohort 1), the temporary pause will occur once the
maximum number of subjects are enrolled in the >3 days to ≤5 days since symptom onset stratum in Cohort 1.
Prior to interim analysis 3 (at N=approximately 70-80 in Cohort 2) and prior to interim analysis 4 (at
N=approximately 150 in the Cohort 2), the temporary pause will occur once the maximum number of subjects are
enrolled in the >3 days to ≤5 days since symptom onset stratum in Cohort 2. Enrollment in the >3 days to
≤5 days since symptom onset stratum will be reopened once the last subject required for the corresponding
interim analysis has been randomized. For the final analysis, enrollment in the >3 days to ≤5 days since symptom
onset stratum will be stopped once the maximum number of subjects are enrolled in this stratum in both cohorts.
Since the number of subjects enrolled in Cohort 2 is the trigger to perform interim analysis 3 and interim
analysis 4, enrollment in Cohort 1 in the >3 days to ≤5 days since symptom onset stratum might be stopped, at
any time after interim analysis 2, once the maximum number of subjects in this stratum are enrolled for the final
analysis.


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Applicable Section(s) 
Description of Change(s)
SYNOPSIS
3.1 Overview of Study Design
3.2 Study Design Rationale
4.1 Inclusion Criteria
5 TREATMENT ALLOCATION AND BLINDING
11.1 Interim Analyses
11.12 Independent Data Monitoring Committee
Rationale: Clarification that the clinical course endpoints will be evaluated in Cohort 1 and Cohort 2 separately,
and will be compared between the 2 cohorts, because of potential differences between the 2 cohorts.
11.3.2 Key Secondary Objective: Clinical Course Effect
11.4.2 Clinical Course of RSV Infection
Rationale: Clarification that clinical evaluation does not have to be repeated in case Cohort 2 Screening and
Randomization occur on the same calendar day, because it is a once daily procedure in the outpatient setting.
TIME AND EVENTS SCHEDULE
Rationale: The PRESORS version 7.1 that was replaced incorrectly by version 7.2 in protocol Amendment 1,
was reversed to PRESORS version 7.1 from the original protocol.
Attachment 6: 
Parent(s)/Caregiver(s) PRESORS v7.1 (9 July 2018)
Rationale: Minor clarifications were made throughout the protocol.
Throughout the protocol
Amendment 1 (14 May 2019)
The overall reason for the amendment:The overall reason for the amendment is to increase the sample size of
Cohort 1 (hospitalized cohort) from 24 to 48 subjects per treatment arm to increase the precision on the estimates
for the clinical course related endpoints in this cohort.
Applicable Section(s) 
Description of Change(s)
Rationale: The sample size of Cohort 1 was increased from 24 to 48 subjects per treatment arm (approximately
144 subjects in total in this cohort) to increase the precision on the estimates for the clinical course related
endpoints in this cohort. Assuming a median time to resolution of symptoms of 3 days in the placebo group, a 1-
day reduction in the active group (ie, ratio ofactive versus placebo of66%), and a scale parameter of 1/0.65, a
sample size of 48 subjects will attain 95% probability to reach an observed effect in the right direction; based on
estimates derived from an accelerated failure time model.
SYNOPSIS
11.3 Sample Size Determination
Rationale: It was clarified that randomization should occur within 48 hours after the collection of the standard of
care (SOC) sample used for RSV diagnosis (instead of having results available), to better standardize the
(pre)screening window  .
SYNOPSIS
TIME AND EVENTS SCHEDULE
3.1 Overview of Study Design
4 SUBJECT POPULATION
4.1 Inclusion Criteria
9.1.2 Screening Phase
9.1.3 Double-Blind Treatment Phase


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Applicable Section(s) 
Description of Change(s)
Rationale: Addition of heel prick for PK-related blood collection to allow sites to use either method as per their
SOC.
SYNOPSIS
TIME AND EVENTS SCHEDULE
1.2.4 Potential Risks
9.4.1 Evaluations
Rationale: An error in Figure 1 was corrected.
3.1 Overview of Study Design
Rationale:Addition of statement to disallow subjects whose mother received an investigational RSV vaccination
during the pregnancy for this child and whose age is <3 months at time of screening, to eliminate any
confounding of the presence of maternal antibodies on the clinical course and antiviral effect.
SYNOPSIS
4.2 Exclusion Criteria
8 CONCOMITANT THERAPY
Rationale: The wording of ‘total blood volume to be collected’ was changed into a maximum regardless of
bodyweight. The total blood volume is in line with the WHO guidance for allowable pediatric blood volume in
clinical research.
9.1 Study Procedures
16.1 Study-Specific Design Considerations
Rationale:Removal of fax-based serious adverse events reporting because of its replacement by a new
electronical reporting system per company process change.
12.3.2 Serious Adverse Events
Rationale:The protocol was updated to indicate that if a study-specific screening nasal mid-turbinate swab was
collected within 8 hours prior to dosing, the leftover of that sample can serve as the baseline sample and should
be shipped to the central laboratory, provided that the study-specific nasal mid-turbinate screening sample was
stored appropriately and has sufficient sample volume available (minimum 4 aliquots of 600 µL each). This will
lessen the burden for subjects by limiting the required number of mid-turbinate nasal swabs.
SYNOPSIS
TIME AND EVENTS SCHEDULE
3.1 Overview of Study Design
9.1.2 Screening Phase
9.3 Safety Evaluations
Rationale:It was clarified that the subject’s diagnosis of RSV infection at screening should be performed using a
preferably rapid PCR- or other molecular-based diagnostic assay (preferred), or a rapid antigen detection assay.
This wording for other molecular-based assay was added to use the more general classification of molecular-
based assays, which includes PCR. In addition, it was clarified that a rapid assay is preferred to allow fast RSV
diagnosis to minimize the screening duration.
SYNOPSIS
TIME AND EVENTS SCHEDULE
3.1 Overview of Study Design
4.1 Inclusion Criteria
9.1.2 Screening Phase


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Applicable Section(s) 
Description of Change(s)
Rationale:The protocol was updated to remove potential for drug-drug-interaction (DDI) as safety topic of
special interest based on the evaluation of newly available nonclinical and clinical data. These data mainly
indicate an increase in JNJ-53718678 exposure when co-administered with strong CYP3A4 inhibitors. Given
safety measures are in place to ensure the subject’s safety in this clinical study and because strong CYP3A4
inhibitors are not allowed as per Section 8, the sponsor no longer considers the potential for DDI a safety topic of
special interest.
1.2.4 Potential Risks
Rationale:The protocol was updated to remove effects on blood coagulation as safety topic of special interest
based on the evaluation of all available data, including most recent nonclinical and clinical data. Based on this
evaluation, no signal with respect to blood coagulation has been observed to date, and hence the sponsor no
longer considers effects on blood coagulation a safety topic of special interest. In line with this decision,
coagulation testing (which requires an additional blood draw) was removed from the Time and Events Schedule.
Consequently, the maximum total blood volume collected decreases.
TIME AND EVENTS SCHEDULE
1.2.4 Potential Risks
9.1.2 Screening Phase
9.3 Safety Evaluations
9.3.1 Specific Toxicities and Safety Topics of Special Interest
Rationale:The protocol was updated to clarify that responses to some of the identifying questions for
parent(s)/caregiver(s) in the eDiary are optional in order to comply with the European regulation on general data
protection.
Attachment 6: 
Parent(s)/Caregiver(s) PRESORS v7.1 (9 July 2018)
Rationale: The protocol was updated to remove any reference to the long-term observational follow-up as this
study is no longer planned as per sponsor’s decision.
SYNOPSIS
3.1 Overview of Study Design
Rationale: The Time and Events Schedule was updated to add the monitoring of the completion of the
parent(s)/caregiver(s) Pediatric RSV Electronic Severity and Outcome Rating Scales (PRESORS) by the site staff
to align with the body of the protocol and for clarification.
TIME AND EVENTS SCHEDULE
Rationale: Minor grammatical, formatting, or spelling changes were made throughout the protocol because
minor errors were noted.
Throughout the protocol and in Attachment 1


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SYNOPSIS
A Phase 2, Double-blind, Placebo-controlled Study to Evaluate the Antiviral Activity, Clinical Outcomes,
Safety, Tolerability, and Pharmacokinetic/Pharmacodynamic Relationships of Different Doses of
JNJ-53718678 in Children ≥28 Days and ≤3 Years of Age With Acute Respiratory Tract Infection Due to
Respiratory Syncytial Virus Infection
JNJ-53718678 is an investigational respiratory syncytial virus (RSV) specific fusion inhibitor belonging to
the indole chemical class and under development for the treatment of RSV infection.
OBJECTIVES, ENDPOINTS, AND HYPOTHESIS
Objectives
Primary Objective
The primary objective is to establish antiviral activity of JNJ-53718678 as measured by RSV viral load in
nasal swab samples by a quantitative reverse transcription polymerase chain reaction (qRT-PCR) assay in
children ≥28 days and ≤3 years of age with RSV disease.
Secondary Objectives
The secondary objectives are to evaluate in children ≥28 days and ≤3 years of age with RSV disease:
 
the dose-response relationship for antiviral activity of JNJ-53718678
 
the impact of JNJ-53718678 on the clinical course of RSV infection
 
the safety and tolerability of JNJ-53718678 after repeated oral doses
 
the pharmacokinetics (PK) of JNJ-53718678 after repeated oral doses
 
medical resource utilization
 
the impact of baseline characteristics on antiviral activity and clinical course, including but not limited
to:
 
time of symptom onset (≤3 days vs >3 days before start of treatment)
 
patient population (hospitalized subjects vs outpatients)
 
baseline viral load
 
disease severity at baseline
 
the relationship between the PK and the pharmacodynamics (PD) (selected antiviral activity, clinical
outcomes, and safety parameters) after repeated dosing of JNJ-53718678
 
the emergence of mutations in the viral genome potentially associated with resistance to JNJ-53718678
 
the acceptability and palatability of the JNJ-53718678 formulation


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Exploratory Objectives
The exploratory objectives are to explore in children ≥28 days and ≤3 years of age with RSV disease:
 
the impact of additional baseline characteristics on antiviral activity and clinical course, including but
not limited to:
 
RSV viral subtype and genotype
 
baseline neutrophil count
 
the occurrence of complications associated with RSV per investigator assessment after initiation of
treatment
 
the need for antibiotics related to complications associated with RSV per investigator assessment
 
the relationship between antiviral activity and clinical outcomes
 
the RSV viral load as measured by a qRT-PCR assay in nasopharyngeal and/or tracheal aspirate
samples in a subgroup of hospitalized subjects (Cohort 1 only) in which these samples are obtained as
part of their standard-of-care (SOC)
 
the RSV infectious virus load as assessed by quantitative culture of RSV (plaque assay) on selected
nasal swab samples (optional objective, pending feasibility of performing such an assay)
Endpoints
Primary Endpoint
The primary efficacy endpoint is the RSV viral load area under the curve (AUC) from immediately prior to
first dose of study drug through Day 5 derived from the RSV viral load as measured by a qRT-PCR assay
in nasal swabs.
Secondary Endpoints
The secondary endpoints are:
 
virologic parameters derived from the RSV viral load as measured by a qRT-PCR assay in nasal swabs
including:
 
RSV viral load and change from baseline over time
 
RSV viral load AUC from immediately prior to first dose of study drug (baseline) through Day 3,
Day 8, and Day 14
 
time to undetectable RSV viral load
 
proportion of subjects with undetectable RSV viral load at each timepoint throughout the study
 
clinical course related endpoints:
 
in hospitalized subjects and outpatients:
o 
following endpoints will be based on the Pediatric RSV Electronic Severity and Outcome
Rating System (PRESORS) assessed throughout the study by  parent(s)/caregiver(s)
(parent[s]/caregiver[s] PRESORS) and by the investigator (clinician PRESORS) during
scheduled visits:
 
duration and severity of signs and symptoms of RSV disease
 
change from baseline in parent(s)/caregiver(s) PRESORS  scores (worsening or
improvement)


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 
change from baseline in clinician PRESORS scores (worsening or improvement)
 
time to resolution (ie, to none or mild) of RSV symptoms
 
time to improvement based on general questions on overall health
 
proportion of subjects with improvement or worsening of RSV disease based on general
questions on overall health
 
time to return to pre-RSV health as rated by the parent(s)/caregiver(s)
o 
respiratory rate, heart rate, body temperature, and peripheral capillary oxygen saturation
(SpO2) over time as measured by the investigator during scheduled visits.
o 
body temperature as measured by parent(s)/caregiver(s) and recorded in the temperature log
(for Cohort 1 after discharge and Cohort 2)
o 
need for (re)hospitalization during treatment and follow-up
 
in hospitalized subjects only:
o 
time to age-adjusted normal values for otherwise healthy and to pre-RSV infection status for
subjects with (a) risk factor(s) for severe RSV disease, for heart rate, respiratory rate, and/or
blood oxygen level (ie, without requirement of supplemental oxygen compared with pre-
RSV infection status)
o 
time to discharge (from initial admission and from initiation of treatment)
o 
time to clinical stability, with clinical stability evaluated by the investigator (from initial
admission and from initiation of treatment)
o 
need for and duration of intensive care unit (ICU) stay; ‘need for ICU stay’ is defined as
follows:
 
being admitted on the ICU (and ICU level of care is required)
 
being admitted on the hospital ward, with or without supplemental oxygen, but deemed
to require ICU level of care (eg, not transferred to ICU due to bed availability)
 
requiring ICU level of care is defined by some specific conditions:
o acute or imminent respiratory failure
o treatment of complicated acid-base or electrolyte imbalances
o cardiogenic shock
o acute congestive heart failure
o hemodynamic instability
 
having other conditions requiring specialized equipment and/or staff competencies only
available in the ICU
o 
need for and duration of supplemental oxygen (regardless of method used); ‘need for
supplemental oxygen’ is defined by:
 
requiring invasive mechanical ventilation
 
requiring any oxygen support requiring intubation or extracorporeal oxygenation
 
receiving invasive mechanical ventilation


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 
receiving supplemental oxygen through a face mask or nasal cannula and not being able
to sustain a blood oxygen saturation of ≥92% when breathing room air for 15 minutes
or less, tested once
o 
need for and duration of noninvasive ventilator support (eg, continuous positive airway
pressure) and/or invasive ventilator support (eg, endotracheal-mechanical ventilation)
o 
need for hydration and/or feeding by intravenous (IV) administration or nasogastric tube,
need for defined by <50% of normal oral intake
o 
time to clinical stability, defined as the time from initiation of study treatment until the time
at which the following criteria are met:
 
return to age-adjusted normal values for otherwise healthy and pre-RSV infection status
for subjects with (a) risk factor(s) for severe RSV disease, for all of the following
signs/symptoms of RSV disease:
 
heart rate; AND
 
respiratory rate; AND
 
blood oxygen level
AND
 
no more oxygen supplementation for otherwise healthy subjects and subjects with (a)
risk factor(s) for severe RSV disease
AND
 
no more IV/nasogastric tube feeding/hydration in otherwise healthy subjects or return
to pre-RSV status of IV/nasogastric tube feeding/hydration in subjects with (a) risk
factor(s) for severe RSV disease
o 
time from initiation of study treatment until SpO2 ≥92% and SpO2≥95% on room air among
subjects who were not on supplemental oxygen prior to the onset of respiratory symptoms
 
safety and tolerability, as assessed by adverse events (AEs), clinical laboratory testing,
electrocardiograms (ECGs), vital signs, throughout the study
 
PK parameters of JNJ-53718678, as determined by population PK (popPK) modeling
 
medical resource utilization
 
acceptability and palatability of the JNJ-53718678 formulation as assessed through a questionnaire
completed by parent(s)/caregiver(s) in the electronic device
 
sequence changes (post baseline) in the RSV F-gene, and other regions of the RSV genome (at the
discretion of the sponsor’s virologist), as compared with the baseline sequence
Exploratory Endpoints
Exploratory endpoints include:
 
the occurrence of complications with onset after treatment initiation that are associated with RSV per
investigator assessment:
 
bacterial superinfections (eg, pneumonia, sinusitis, bronchitis, bacteremia of presumed
respiratory origin per investigator assessment)
 
otitis media, bronchiolitis, viral pneumonia


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exacerbations of underlying pulmonary disease (eg, asthma, cystic fibrosis, bronchopulmonary
dysplasia)
 
exacerbations of underlying cardiovascular conditions
 
the use of antibiotics related to complications associated with RSV per investigator assessment
 
the RSV RNA viral load as measured by a qRT-PCR assay in nasopharyngeal and/or tracheal aspirate
samples in a subgroup of hospitalized subjects in which these samples are obtained as part of their
SOC
 
comparison ofRSV RNA viral load as measured by a qRT-PCR assay in nasal swabs and other samples
(eg, nasopharyngeal and/or tracheal aspirate samples)
 
virologic parameters derived from the RSV viral load as measured by quantitative viral culture
Hypothesis
The primary hypothesis of this study is that JNJ-53718678 has antiviral activity against RSV (ie, a decrease
in RSV viral load AUC from immediately prior to first dose of study drug [baseline] until Day 5), as
assessed by a positive dose-response relationship of JNJ-53718678 compared to placebo.
OVERVIEW OF STUDY DESIGN
This is a Phase 2 multicenter, double-blind, placebo-controlled, randomized study to evaluate the antiviral
activity, clinical outcomes, safety, tolerability, and PK/PD relationships of different oral dose levels of
JNJ-53718678 in children ≥28 days and ≤3 years of age with RSV disease (hospitalized subjects [Cohort 1]
or outpatients [Cohort2]).
Subjects with at least mild RSV disease will be enrolled (ie, at least one symptom of upper respiratory tract
infection, at least one symptom of lower respiratory tract infection, and at least one systemic/general
symptom). Eligible subjects can be otherwise healthy or have a risk factor for severe RSV disease (eg,
prematurity at birth [only for subjects ≥3 months of age at the time of consent] or having a comorbid
condition eg, bronchopulmonary dysplasia, congenital heart disease, other congenital diseases, Down
syndrome, neuromuscular impairment, cystic fibrosis, or recurrent wheezing/asthma). Subjects who are
immunocompromised are excluded.
The total number of subjects is planned to be approximately 294 (approximately 144 in Cohort 1 and
approximately 150 in Cohort 2; approximately 196 subjects receiving JNJ-53718678 and approximately
98 subjects receiving placebo). The sample size of Cohort 2 may be re-estimated to a maximum of 300 in
Cohort 2 based upon results from the third interim analysis (see below).
Study participants will be identified when they are hospitalized or expected to be hospitalized within
24 hours after presentation to the hospital (Cohort 1) or present for medical care as outpatients (Cohort 2)
with symptoms of an acute respiratory illness supporting a diagnosis of RSV infection (eg, nasal congestion,
rhinorrhea, pharyngitis, increased respiratory effort, abnormal breathing sounds [wheezing, rales, or
rhonchi], cyanosis, cough, apnea, fever, feeding difficulties, dehydration). For newly enrolled subjects in
Cohort 2 after Protocol Amendment 6, cough or wheezing should be accompanied by at least one additional
lower respiratory tract infection (LRTI) sign/symptom in order to be eligible. In Cohort 1, a subcohort of 6
subjects >2 and ≤3 years will be included, who will follow in general the same assessment schedule as for
all subjects enrolled in Cohort 1, although with a specific PK sampling schedule, assigned at randomization.
Of note, if the subcohort is fully enrolled, additional subjects >2 and ≤3 years of age can be enrolled in
Cohort 1 and will follow all Cohort 1 procedures.
Overall, for both cohorts, 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 28 [±3]. The total study duration for each subject
will be approximately 29 days (Screening included).


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Screening must be completed as soon as possible. During screening, a study-specific screening sample
(mid-turbinate swab) will be collected for the local diagnosis of RSV infection using a (preferably) rapid
PCR- or other molecular-based diagnostic assay (preferred) or a rapid-antigen-detection assay. Swabs
collected per local SOC testing within 24 hours prior to start of screening may be used in determining study
eligibility. If a rapid-antigen-detection assay is used as part of SOC or study-specifically (with the main
informed consent form [ICF] or with the diagnostic study ICF having been signed), the remainder of the
screening sample used for the RSV diagnostic testing should be sent to the central laboratory for additional
virologic analyses, as applicable.
A (separate) mid-turbinate swab will be collected immediately prior to the first dose for central laboratory
analyses to confirm RSV infection (and subtype), to determine the RSV viral load, to perform viral
sequencing, and to determine the presence of other viral or bacterial pathogens. If a study-specific screening
nasal mid-turbinate swab was collected within 8 hours prior to dosing, the leftover of that sample can serve
as the baseline sample and should be shipped to the central laboratory, provided that the study-specific
nasal mid-turbinate screening sample was stored appropriately and has sufficient sample volume available
(minimum 4 aliquots of 600 µL).
Initially, only hospitalized subjects will be recruited (Cohort 1). After the first interim analysis, an IDMC
will review the interim data and will issue its recommendation to the sponsor, based on which the Sponsor
Committee will decide whether to initiate enrollment in Cohort 2, while hospitalized subjects continue to
be enrolled (see below).
Randomization should occur within 24 hours after start of screening or within 48 hours after collection of
the SOC sample used for local RSV diagnosis (in case swabs collected per local SOC testing were used for
the local diagnosis of RSV infection), whichever comes first. Within each cohort (including the subcohort
of Cohort 1), eligible subjects will be randomized 1:1:1 to receive either a low or a high dose of
JNJ-53718678, or placebo. Those randomized to a placebo regimen will be subsequently randomized in a
1:1 ratio to receive either low or high volume of placebo. This results in an overall randomization scheme
of 2:2:1:1 (low dose JNJ-53718678, high dose JNJ-53718678, low volume placebo, high volume placebo).
Within each cohort, except for the subcohort, randomization will be stratified by time of symptom onset
(≤3 days vs >3 days to ≤5 days before randomization) and by presence of risk factors for severe RSV disease
(otherwise healthy vs presence of [a] risk factor[s] for severe RSV disease as defined above). Subjects with
symptom onset ≤3 days before randomization must account for a minimum of 45% of all enrolled subjects
in Cohorts 1 and 2 (ie, maximum 55% of subjects can be enrolled in the >3 days to ≤5 days stratum). To
guarantee the required balance between strata for the interim analyses, enrollment in the >3 days to ≤5 days
since symptom onset stratum might be temporarily paused prior to an interim analysis and stopped prior to
the final analysis. Stratum caps and closures are managed separately for each cohort and consider the sample
size of the respective cohort for the interim analysis and the total sample size of each cohort for the final
analysis.
Study drug administration should start as soon as possible, but no later than 4 hours after randomization
and within 5 days after symptom onset. For analysis purposes, the day of first study drug intake will be
considered Day 1. Dosing should preferably occur approximately at the same time each day for both intakes
(AM and PM). For subjects who receive only 1 dose of JNJ-53718678 or placebo PM on Day 1, dosing
should continue through the morning (ie, AM) of Day 8 so that all subjects receive 14 consecutive doses in
total. 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. JNJ-53718678/placebo can be administered with/without food. The
study drug will be administered orally using a dosing syringe. For Cohort 1 and during hospitalization, the
study drug can also be administered through a nasogastric tube, if already in place. In this document, both
administration methods are referred to as “oral dosing”, unless specified otherwise.
For dosing purposes, 3 age groups are defined depending on the subject’s age at the time of consent:


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 
Age group 1: ≥28 days and <3 months of age (28 to 91 days of age, extremes included, for interactive
web response system [IWRS] purposes);
 
Age group 2: ≥3 months and <6 months of age (92 to 182 days of age, extremes included, for IWRS
purposes);
 
Age group 3: ≥6 months and ≤3 years of age (183 to 1,096 days, extremes included, for IWRS
purposes).
Study drug will be administered twice daily for 7 days (14 consecutive doses). Doses are based on weight
and age group:
 
High Dose (Cohort 1: n = 48 [target]; Cohort 2: n = 50 [target]):
 
Age group 1: 2.5 mg JNJ-53718678/kg bodyweight
 
Age group 2: 3.0 mg JNJ-53718678/kg bodyweight
 
Age group 3: 4.5 mg JNJ-53718678/kg bodyweight
 
Low Dose (Cohort 1: n = 48 [target]; Cohort 2: n = 50 [target]):
 
Age group 1: 0.85 mg JNJ-53718678/kg bodyweight
 
Age group 2: 1.0 mg JNJ-53718678/kg bodyweight
 
Age group 3: 1.5 mg JNJ-53718678/kg bodyweight
 
Placebo (Cohort 1: n = 48 [target]; Cohort 2: n = 50 [target]): those randomized to a placebo regimen
will be subsequently randomized 1:1 to receive either:
 
High volume placebo:
o 
Age groups 1, 2, and 3: matching placebo (volume of placebo suspension to match  the
calculated volume of the JNJ-53718678 suspension for the high dose)
 
Low volume placebo:
o 
Age groups 1, 2, and 3: matching placebo (volume of placebo suspension to match  the
calculated volume of the JNJ-53718678 suspension for the low dose)
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 salt of
JNJ-53718678-AAA) used in the oral suspension.
In Cohort 1, the study drug will be administered by the study site personnel or by the parent(s)/caregiver(s)
under supervision of the study site personnel during hospitalization. In case the subject is discharged prior
to Day 7, the study drug will continue to be administered at home by the parent(s)/caregiver(s) through
Day 7. In Cohort 2, the first dose of study drug will be administered, by the study site personnel or by the
parent(s)/caregiver(s) under supervision of the study site personnel, at the study site; the study drug will
continue to be administered at home by the parent(s)/caregiver(s) through Day 7 or the morning (AM) of
Day 8 if the first dose was given PM on Day 1. All subjects will receive standard supportive care for RSV
infection as per local SOC considering pre-defined restrictions. All SOC treatment should be recorded as
concomitant medication/treatment.
In Cohort 1, subjects 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 (except for the evening
assessment in case the assessment is to be performed twice daily [bid]). Discharged subjects (Cohort 1) will
be required to attend the scheduled study visits as outpatients with the same visit schedule as Cohort 2
subjects, from time of discharge onward. Cohort 2 subjects will have study visits on Day 3, Day 5, Day 8,
Day 14, and on Day 21. All scheduled study visits can also be done as home visits, if feasible for the study


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site and if allowed per local regulations. On Day 28 (±3), subject’s parent(s)/caregiver(s) will be contacted
by the site staff for a telephone follow up visit, after which the subject completes the study. In case a subject
is experiencing (an) ongoing AE(s) or has clinically significant laboratory or ECG abnormalities at the time
of the Day 21 Follow-Up Visit, parent(s)/caregiver(s) might be requested, at the discretion of the
investigator, to have a Safety Follow-up Visit for the subject at the site (preferred option) or, if feasible for
the study site and if allowed per local regulations, at home on Day 28.
In case subjects prematurely discontinue study drug treatment for any reason (except withdrawal of
consent), the parent(s)/caregiver(s) will be asked to continue with the subject’s remaining study visits and
assessment schedule, or, at a minimum, to return with the subject to the site for a Withdrawal and a Safety
Follow-up Visit. At the Withdrawal and Safety Follow-up Visits, the same assessments as on the Day 8 and
Day 21 visits, respectively, will be performed. In case the subject’s legally acceptable representative(s)
withdraw consent during the treatment or follow-up phase, an optional Withdrawal and Safety Follow-up
Visit will be offered. At these optional Withdrawal and Safety Follow-up Visits, the same assessments as
on the Day 8 and Day 21 visits, respectively, will be performed.
As an evaluation of antiviral activity, the RSV viral load in nasal secretions will be measured at the central
lab using a qRT-PCR assay on mid-turbinate nasal swab specimens, which will be collected at several
timepoints during the study. If feasible, the RSV infectious virus load may also be assessed by quantitative
culture of RSV (plaque assay) on selected nasal swab samples.
Viral resistance will be monitored by sequencing of the F-gene in all baseline samples, and on subsequent
samples upon request of the sponsor’s protocol virologist. Other regions of the RSV genome may also be
sequenced atdiscretion of the sponsor’s virologist. Sequencing data will not be reported to the investigators.
Sequencing results may be presented in a separate report.
Clinical course and severity of RSV infection will be assessed through different measures.
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 subject’s last study-related activity.
Pharmacokinetic assessments during the study will be based on sparse sampling and will be performed
using a popPK model. In the subcohort of Cohort 1, next to randomization to treatment group, within each
treatment arm (high dose, low dose, placebo), the 6 subjects will be randomized 1:1 to 1 of 2 different PK
sampling groups (see table with overview of PK  sampling window below [section Pharmacokinetic
Evaluations]). In Cohort 1, next to randomization to treatment group, the first 12 subjects of each age group
(subcohort not included) will be randomized 1:1 to 1 of 2 different PK sampling groups. Once 12 subjects
of a particular age group have been randomized to the 2 different PK sampling groups, the investigator can
assign the subsequently enrolled subjects to either of the 2 PK sampling groups, but preferably alternating
between 2 different PK sampling groups at this site. For the subjects recruited to Cohort 2 after Protocol
Amendment 4, PK samples will be collected approximately one hour after administration of study drug
(after the ECGs are obtained if applicable) at Day 1 and at least 4 hours after the AM and prior to the PM
dosing on Day 3 or Day 5.
Medical resource utilization and acceptability and palatability of the study drug will be assessed.
Leftover mid-turbinate nasal swab and blood samples collected for other testing may be used for exploratory
biomarker analyses to determine the effects of JNJ-53718678 on markers of RSV disease, at discretion of
the sponsor.
An IDMC will be commissioned for this study and will review unblinded safety data on a regular basis to
ensure subject safety. 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 subjects. The IDMC can recommend to the Sponsor Committee to halt a dose arm due to
safety concerns. The IDMC will also review the data of the interim analyses and provide recommendations


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to the Sponsor Committee. The Sponsor Committee will take a decision considering the IDMC’s
recommendation.
The study will start with Cohort 1 (including the subcohort). The first interim analysis encompassing safety
and tolerability, PK, and antiviral effect is planned when at least 36 subjects from Cohort 1 have completed
the Day 14 assessments (or discontinued earlier). Enrollment in Cohort 1 will continue during the interim
analysis. An IDMC will review the interim data, and will issue its recommendation to the sponsor, based
on which the Sponsor Committee will decide whether to initiate enrollment in Cohort 2 (see below).
A second interim analysis is planned, preferably  at the end of a hemispheric RSV  season, when
approximately 70 to 80 subjects from Cohort 1 (regardless of the number of subjects in the subcohort having
reached the target of 6) have completed the Day 14 assessments (or discontinued earlier). During this
interim analysis, a futility and population enrichment analysis will be performed on antiviral activity and
one clinical endpoint (ie, time to resolution of symptoms, considering data of both cohorts), to terminate
the study for futility, or to enrich the population and limit further enrollment to patients with ≤3 days since
symptom onset. In addition, other clinical course and safety-related endpoints, will be analyzed. The
Sponsor Committee will take a decision considering the IDMC’s recommendation. Depending on
enrollment status of Cohort 2, the second interim analysis will not be performed, if it is later than or too
close to the predicted timing of the planned third interim analysis.
A third interim analysis is planned, preferably at the end of a hemispheric RSV season, when approximately
70 to 80 subjects from Cohort 2 have completed the Day 14 assessments (or discontinued earlier) and will
include all available data from Cohort 1 and Cohort 2. During this interim analysis, a futility and population
enrichment analysis will be performed on antiviral activity (data from both cohorts combined) and clinical
endpoints (Cohort 2 data only), as well as a sample-size re-estimation for clinical endpoints (Cohort 2 data
only). Both the study team and the IDMC will provide their recommendations to the Sponsor Committee,
who will decide, taking all recommendations into account. The maximum number of subjects in Cohort 2
in the study will not exceed 300.
If the study is extended beyond the initially planned sample size in Cohort 2 for the primary analysis
(N=150), a fourth interim analysis will be performed preferably at the end of a hemispheric RSV season,
after approximately 150 subjects in Cohort 2 have completed the Day 14 assessments (or discontinued
earlier), and will include all available data from Cohort 1 and Cohort 2. The primary analysis on antiviral
activity will be performed during this fourthinterim analysis and effects of JNJ-53718678 on clinical course
endpoints, next to endpoints related to safety, PK and PK/PD, will be analyzed to support early Phase 3
preparations, including regulatory interactions. In addition, the futility and population enrichment analysis
will be repeated at this interim analysis. Both the study team and the IDMC will provide their
recommendations to the Sponsor Committee, who will decide, taking all recommendations into account.
The final analysis is planned when all subjects from Cohort 1 and Cohort 2 have completed the study (or
discontinued earlier). If no extension of Cohort 2 is required, the final analysis will coincide with the
primary analysis. Additional interim analyses may be performed at the sponsor’s discretion to support
decision making for further development of JNJ-53718678 and to support interactions with health
authorities.
While recruitment in the subcohort of Cohort 1 is ongoing, subjects >2 and ≤3 years of age are not allowed
to be enrolled in Cohort 2, even if enrollment in that cohort has been opened for the age groups ≤2. After
6 subjects of the subcohort are evaluable for PK analysis and have completed the Day 14 assessments (or
discontinued earlier), safety and PK data will be reviewed by the IDMC, who will issue its recommendation
to the sponsor, based on which the Sponsor Committee will decide whether to also initiate enrollment of
subjects >2 and ≤3 years of age in Cohort 2 when enrollment in that cohort has been opened for the age
groups ≤2. During this IDMC review, additional subjects >2 and ≤3 years of age can be enrolled in Cohort 1
and will follow all Cohort 1 procedures.


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During and after all interim analyses, investigators, subject(s), and local sponsor representatives (except for
selected local sponsor representatives from Japan) will remain blinded. An IDMC will monitor and review
data in an unblinded manner, at all interim analyses. During the first interim analysis, the Sponsor
Committee will be unblinded; the central sponsor team members and local sponsor representatives from
Japan will remain blinded. For the second interim analysis, the Sponsor Committee, central sponsor team
members, and selected local sponsor representatives from Japan will be unblinded upon recommendation
from the IDMC and the Sponsor Committee. During any interim analysis taking place after the second
interim analysis, the sponsor, including the central study team, and selected local sponsor representatives
from Japan will be unblinded. Aggregate unblinded data and certain individual safety events may be shared
with investigators to support the revised risk-benefit evaluation for the current study and to support start of
Phase 3.
A separate substudy may be performed at selected study sites to explore the feasibility of the use of
biosensors for the evaluation of cardio-respiratory parameters (eg, respiratory rate, heart rate, and SpO2).
Details, including objectives and study design, will be described in a separate substudy protocol.
SUBJECT POPULATION
Screening for eligible subjects will be performed as soon as possible after initial presentation at the hospital
(Cohort 1) or after presentation for medical care as outpatients (Cohort 2) such that subjects are randomized
within 5 days of symptom onset. Within each cohort, except for the subcohort, randomization will be
stratified by time of symptom onset (≤3 days vs >3 days to ≤5 days before randomization) and by presence
of risk factors for severe RSV disease (otherwise healthy vs presence of [a] risk factor[s] for severe RSV
disease as defined above).
Key Inclusion Criteria
 
The subject is a boy or girl ≥28 days and ≤3 years at the time of consent.
 
The subject has been diagnosed with RSV infection using a preferably rapid PCR- or other molecular-
based diagnostic assay (preferred) or a rapid-antigen-detection assay.
Note: If a subject had a positive similar RSV diagnostic test from another study for which (s)he was
otherwise ineligible or a SOC 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 confirmation of eligibility.
Randomization should occur within 24 hours after start of screening or within 48 hours after collection
of the SOC sample used for local RSV diagnosis, whichever comes first.
Note: If a rapid antigen detection assay is used as part of SOC or study-specifically (with the main
study ICF or with the diagnostic ICF having been signed), the remainder of the screening sample used
for the RSV diagnostic testing should be sent to the central laboratory for additional virologic analyses,
as applicable.
 
The subject 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, rhinorrhea, pharyngitis, or otitis media; AND
 
LRTI: increased respiratory effort (as evidenced by subcostal, intercostal or tracheosternal
retractions, grunting, head bobbing, nasal flaring or tachypnea), abnormal breathing sounds


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(wheezing, rales or rhonchi), cyanosis, apnea, or cough  (cough or wheezing should be
accompanied by at least one additional LRTI sign/symptom in order to be eligible); 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)
 
The time of onset of RSV symptoms to the anticipated time of randomization must be ≤5 days. Onset
of 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(s) aware of the first sign and/or symptom consistent with respiratory
or systemic/general manifestation ofsymptoms of RSV infection. The time of symptom onset has to
be assessed as accurately as possible.
Note: Subjects with symptom onset ≤3 days before randomization must account for a minimum of
45% of all enrolled subjects in Cohorts 1 and 2 (ie, maximum 55% of subjects could be enrolled in the
>3 days to ≤5 days stratum).
 
Except for the RSV-related illness, the subject 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) in the study population as evaluated by the investigator. This determination must be
recorded in the subject’s source documents and initialed by the investigator.
Key Exclusion Criteria
 
The subject is <3 months postnatal age at screening and was born prematurely (ie, <37 weeks and
0 days of gestation).
 
The subject has major congenital anomalies or known cytogenetic or metabolic disorders other than
the ones allowed above. Note: Isolated open ductus arteriosus and open foramen ovale are not
exclusionary as these are not considered major anomalies. Subjects with congenital heart disease,
cystic fibrosis, congenital diaphragmatic hernia, or Down Syndrome are allowed to participate.
 
The subject is considered by the investigator to be immunocompromised within the past 12 months,
whether due to underlying medical condition (eg, malignancy or genetic disorder other than
immunoglobulin A deficiency, or known human immunodeficiency virus [HIV] infection) or medical
therapy (eg, immunomodulators other than corticosteroids for the treatment of comorbidities,
chemotherapy, radiation, stem cell or solid organ transplant).
 
The subject is being treated with extracorporeal membrane oxygenation (Cohort 1 only).
 
The subject is receiving chronic home oxygen therapy at screening.
 
The subject has 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.
 
The subject has a QT interval corrected for heart rate according to Fridericia's formula (QTcF) interval
>450 ms per the machine read (mean of triplicate) parameter result confirmed by repeat ECG recording
during screening.
 
The subject’s mother received an investigational RSV vaccination during the pregnancy for this child
whose age is <3 months at time of screening.
 
The subject has evidence of one of the following ECG abnormalities per the machine read ECG result
confirmed by repeat ECG recording at screening:
 
Repetitive premature ventricular contractions (>10/min)


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Second- or third-degree heart block
 
Complete or incomplete left bundle branch block or complete right bundle branch block
 
The subject has a personal or first- or second-degree family history of long QT syndrome or sudden
cardiac death.
DOSAGE AND ADMINISTRATION
Within each cohort (including the subcohort of Cohort 1), eligible subjects will be randomized 1:1:1 to
receive either a low or a high dose of JNJ-53718678, or placebo. Subjects randomized to a placebo regimen
are subsequently randomized in a 1:1 ratio to receive placebo matching either the volume of the high or of
the low dose. Doses are based on weight and age group (3 age groups [≥28 days and <3 months; ≥3 months
and <6 months, or ≥6 months and ≤3 years of age] are defined depending on the subject’s age at the time
of consent). An overview of the treatments for Cohort 2 newly recruited subjects is provided in the table
below.
Treatment 
Age Groupa 
Dosing Regimenb,d 
Volume
High dose 
1 
2.5 mg/kg bid on Days 1 to 7 A mLc oral suspension of JNJ-53718678
2 
3.0 mg/kg bid on Days 1 to 7 C mLc oral suspension of JNJ-53718678
3 
4.5 mg/kg bid on Days 1 to 7 E mLc oral suspension of JNJ-53718678
Low dose 
1 
0.85 mg/kg bid on Days 1 to 7 B mLc oral suspension of JNJ-53718678
2 
1.0 mg/kg bid on Days 1 to 7 D mLc oral suspension of JNJ-53718678
3 
1.5 mg/kg bid on Days 1 to 7 F mLc oral suspension of JNJ-53718678
Placebo
Match
high dose
1,2, or 3 
placebo bid on Days 1 to 7 
A, C, or E (respectively) mLb placebo
Match
low dose
1,2, or 3 
placebo bid on Days 1 to 7 
B, D, or F (respectively) mLb placebo
a.
Age Group 1: ≥28 days and <3 months; Age Group 2: ≥3 and <6 months; Age Group 3: ≥6 months and ≤3 years.
b.
Doses are provided for JNJ-53718678-AAA.
c.
A to F represents the volume of oral JNJ-53718678 suspension to obtain the required dose of
JNJ-53718678-AAA or the volume of the matching placebo suspension. JNJ-53718678 is formulated as an oral
suspension containing 23 mg/mL microfine JNJ-53718678-ZCL, the hemi-tartrate salt of JNJ-53718678-AAA,
which is equivalent to 20 mg/mL JNJ-53718678-AAA, to be used depending on the bodyweight of the subject
(and the required volume to be administered). The required volume to be administered per intake will be
calculated by the IWRS and provided to the sites.
d. 
Dosing should preferably occur approximately at the same time each day for both intakes (AM and PM). For
subjects who receive only 1 dose of JNJ-53718678 or placebo PM on Day 1, dosing should continue through the
morning (ie, AM) of Day 8 so that all subjects receive 14 consecutive doses in total.
Study drug administration should start as soon as possible, but no later than 4 hours after randomization
and within 5 days after symptom onset. For analysis purposes, the day of first study drug intake will be
considered Day 1.
Dosing should preferably occur approximately at the same time each day for both intakes (AM and PM).
For subjects who receive only 1 dose of JNJ-53718678 or placebo PM on Day 1, dosing should continue
through the morning (ie, AM) of Day 8 so that all subjects receive 14 consecutive doses in total.
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. The study drug can be administered with/without food. The study drug
will be administered orally using a dosing syringe. For Cohort 1 and during hospitalization, the drug can
also be administered through a nasogastric tube, if already in place.
Note: Prior to Protocol Amendment 4, the total daily dose was the same but the daily dosing frequency was
qd instead of bid.


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 
Cohort 1:
 
During hospitalization: the study drug will be administered by the study site personnel or by the
parent(s)/caregiver(s) under supervision of the study site personnel. Date and time of dosing will
be recorded by the site staff.
 
After Discharge: parent(s)/caregiver(s) will administer study drug at home if the subject is
discharged prior to Day 7. Date and time of dosing will be captured in the study medication log,
to be completed by the parent(s)/caregiver(s) in the provided electronic device.
 
Cohort 2, the first dose of study drug will be administered, by the study site personnel or by the
parent(s)/caregiver(s) under supervision of the study site personnel, at the study site. On Day 1, date
and time of dosing will be recorded by the site staff. At home, date and time of dosing will be captured
in the study medication log, to be completed by the parent(s)/caregiver(s) in the provided electronic
device.
Study site personnel will instruct subjects’ parent(s)/caregiver(s) on how to use and store the study drug for
at-home dosing as per sponsor provided investigational product preparation instruction (IPPI).
EFFICACY EVALUATIONS
Antiviral Activity
As an evaluation of antiviral activity, the RSV viral load in nasal mid-turbinate swab samples will be
measured at the central lab using a qRT-PCR assay. Mid-turbinate swab specimens for the determination
of RSV viral load will be collected at several timepoints during the study. Date and time of sampling will
be collected. Mid-turbinate 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 site staff (nasal swabs
taken on-site) or by parent(s)/caregiver(s) (nasal swabs taken at home).
Additional information about the collection, handling, and shipment of biological samples can be found in
the laboratory manual.
RSV RNA viral load can also be measured by a qRT-PCR assay in nasopharyngeal and/or tracheal aspirate
samples in a subgroup of hospitalized subjects (Cohort 1 only) in which these samples are obtained as part
of their SOC, which may be used to assess virologic parameters.
The RSV infectious virus load as measured by quantitative culture of RSV (plaque assay), if feasible, on
selected nasal swab samples, may be used to assess virologic parameters.
Clinical Severity and Clinical Course of RSV Infection
The study will include the following evaluations of the clinical course of RSV infection:
 
Cohort 1 and Cohort 2:
 
clinical parameters: respiratory rate, heart rate, SpO2 and body temperature as measured by the
investigator during scheduled visits. Note: If the subject is enrolled in the substudy of
Study 53718678RSV2002, the same parameters as assessed by the biosensor will be recorded
from the standard-of-care monitoring/assessments as part of the substudy assessments (refer to
the substudy Clinical Protocol for detailed information).
 
body temperature as measured by parent(s)/caregiver(s) and recorded in the temperature log (for
Cohort 1 after discharge and Cohort 2)
 
evolution and severity of signs and symptoms of RSV disease (fever, cough, sputum, wheezing,
difficulty breathing, nasal congestion, feeding issues) as assessed by the parent(s)/caregiver(s)
(parent[s]/caregiver[s] PRESORS) and the clinician (clinician PRESORS)


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the need for (re)hospitalization
 
the occurrence of complications, bronchiolitis or viral pneumonia with onset after treatment
initiation that are associated with RSV per investigator assessment
 
the need for antibiotics related to complications associated with RSV per Investigator assessment
 
Cohort 1 only:
 
time to discharge (from initial admission and from initiation of treatment)
 
time to clinical stability, with clinical stability  evaluated by the investigator (from initial
admission and from initiation of treatment)
 
level of and duration by level of hospital care (eg, ICU, transitional care unit, ward floor)
 
oxygen requirement type (eg, supplemental oxygen, noninvasive pressure ventilation,
endotracheal-mechanical ventilation), and duration
 
hydration and feeding by IV line/nasogastric tube and duration
Viral Sequencing
Sequencing data will not be reported to the investigators. Viral resistance will be monitored by sequencing
of the F-gene of the viral genome in all baseline 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. The impact of the viral subtype and baseline genotype on the antiviral response will
be explored. Sequencing results may be presented in a separate report.
SAFETY EVALUATIONS
Safety and tolerability will be evaluated throughout the study from signing of the ICF onwards until the last
study-related activity (end of study/early withdrawal).
Any clinically relevant changes occurring during the study must be recorded on the Adverse Event section
of the electronic case report form (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 endpoint is reached.
The study will include the following evaluations of safety and tolerability:
 
Adverse Events
 
Clinical Laboratory Tests
 
Electrocardiogram (ECG)
 
Vital Signs
 
Physical Examination
PHARMACOKINETIC EVALUATIONS
Blood samples for determination of JNJ-53718678 concentrations will be collected through finger prick or
heel stick at predefined timepoints. In the subcohort of Cohort 1, next to randomization to treatment group,
within each treatment arm (high dose, low dose, placebo), the 6 subjects will be randomized 1:1 to 1 of
2 different PK sampling groups (see Table below). In Cohort 1, next to randomization to treatment group,
the first 12 subjects of each age group (subcohort not included) will be randomized 1:1 to 1 of 2 different
PK sampling groups (see Table below). Once 12 subjects of a particular age group have been randomized
to the 2 different PK sampling groups, the investigator can assign the subsequently enrolled subjects to


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either of the 2 PK sampling groups, but preferably alternating between 2 different PK sampling groups at
this site.
Table: Overview of Pharmacokinetic Sampling Windows for Cohort 1 Subjects
Pharmacokinetic 
Sampling Group
Visit Day 1 
Visit Day 2
Time after dose intake at 
Visit 1 
Time before dose intake at 
Visit 2 
Time after dose intake at
Visit 2
X 
2 h –5 h  
- 
30 min –3 h
Y 
5 h –9 h  
3 h –1 min  
-
For the subjects recruited to Cohort 2 after Protocol Amendment 4, PK samples will be collected
approximately one hour after administration of study drug (after the ECGs are obtained if applicable) at
Day 1 and at least 4 hours after the AM and prior to the PM dosing on Day 3 or Day 5.
Samples may also be used for the analysis of metabolites of JNJ-53718678 or endogenous markers for
enzymes or transporters involved in the metabolism and distribution of JNJ-53718678, at the discretion of
the sponsor. Blood samples collected for PK may 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. The subject’s confidentiality will be maintained.
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 parameters.
MEDICAL RESOURCE UTILIZATION
Medical resource utilization data, associated with medical encounters, will be collected in the eCRF for all
subjects 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:
 
Assessments performed as part of the clinical course of RSV infection-related assessments
 
Duration of hospitalization (total days length of stay, including duration by wards level [eg, ICU])
(Cohort 1 only).
 
The number of subjects (proportion) who started antibiotic use after the first dose of study drug
through the last study visit.
 
Requirement for, and duration of, hospital (re)admission for respiratory reasons through the last
study visit.
 
Additional assessments
 
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).
ACCEPTABILITY AND PALATABILITY
Acceptability and palatability of the JNJ-53718678 formulation will be assessed through a questionnaire
completed by parent(s)/caregiver(s) in the electronic device after last dosing.


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BIOMARKERS
Leftover mid-turbinate nasal swab and blood samples collected for other testing may be used for exploratory
biomarker analyses (eg, proteins including cytokines, microbiome), on the premise that these markers may
play a role in the treatment response, safety of JNJ-53718678, or RSV-related disease.
Analyses of biomarkers may be performed at the sponsor’s discretion and reported separately from this
study.
No human deoxyribonucleic acid (DNA) analyses will be performed on these samples.
OTHER EVALUATIONS
Mid-turbinate nasal swabs collected immediately prior to first dosing will be used to determine the presence
of viral (other than RSV) or bacterial pathogens (both by multiplex PCR) at the central laboratory.
STATISTICAL METHODS
Analyses will be performed on the combined dataset of hospital and outpatient subjects, as well as on data
of each cohort separately.
Enrollment will continue during each of the interim analyses.
First Interim Analysis
The first interim analysis encompassing safety and tolerability, PK, and antiviral effect is planned when at
least 36 subjects from Cohort 1 have completed the Day 14 assessments (or discontinued earlier).
Enrollment in Cohort 1 will continue during the interim analysis and IDMC review.
Enrollment in the >3 days to ≤5 days since symptom onset stratum might be temporarily paused prior to
interim analysis 1 (at N=36 in Cohort 1), once the maximum number of subjects are enrolled in the >3 days
to ≤5 days since symptom onset stratum in Cohort 1. Enrollment in the >3 days to ≤5 days since symptom
onset stratum will be reopened once the last subject required for interim analysis 1 has been randomized.
An IDMC will review the interim data, and will issue its recommendation to the sponsor, based on which
the Sponsor Committee will decide whether to initiate enrollment in Cohort 2.
Second Interim Analysis
A second interim analysis is planned, preferably  at the end of a hemispheric RSV  season, when
approximately 70 to 80 subjects from Cohort 1 (regardless of the number of subjects in the subcohort having
reached the target of 6) have completed the Day 14 assessments (or discontinued earlier). Enrollment in the
>3 days to ≤5 days since symptom onset stratum might be temporarily paused prior to interim analysis 2
(at N=approximately 70-80 in Cohort 1), once the maximum number of subjects are enrolled in the >3 days
to ≤5 days since symptom onset stratum in Cohort 1. Enrollment in the >3 days to ≤5 days since symptom
onset stratum will be reopened once the last subject required for interim analysis 2 has been randomized.
During this interim analysis, a futility and population enrichment analysis will be performed on antiviral
activity and one clinical endpoint (ie, time to resolution of symptoms, considering data of both cohorts) to
terminate the study for futility, or to enrich the population and limit further enrollment to patients with ≤3
days since symptom onset. In addition, other clinical course and safety-related endpoints will be analyzed.
The Sponsor Committee will take a decision considering the IDMC’s recommendation. Depending on
enrollment status of Cohort 2, the second interim analysis will not be performed, if it is later than or too
close to the predicted timing of the planned third interim analysis.


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Third Interim Analysis
A thirdinterim analysis is planned, preferablyat the end of a hemispheric RSV season, when approximately
70 to 80 subjects from Cohort 2 have completed the Day 14 assessments (or discontinued earlier) and will
include all available data from Cohort 1 and Cohort 2. Enrollment in the >3 days to ≤5 days since symptom
onset stratum might be temporarily paused prior to interim analysis 3 (at N=approximately 70-80 in Cohort
2), once the maximum number of subjects are enrolled in the >3 days to ≤5 days since symptom onset
stratum in Cohort 2. Enrollment in the >3 days to ≤5 days since symptom onset stratum will be reopened
once the last subject required for interim analysis 3 has been randomized. During this interim analysis, a
futility and population enrichment analysis will be performed on antiviral activity (data from both cohorts
combined) and clinical endpoints (Cohort 2 data only). The rules implement simultaneously a conditional
success probability approach (viral load) and a Go-NoGo approach on multiple clinical endpoints. Both the
study team and the IDMC will review the results of the interim analysis, and may recommend to the Sponsor
Committee an early termination of the study for futility or to enrich the population and limit further
enrollment to patients with ≤3 days since symptom onset, in case the conditional power on the viral load
endpoint is regarded as being too low and/or the success probability of the clinical endpoints is too low.
The Sponsor Committee will take a decision considering the recommendations from the study team and
IDMC. The exact criteria of these non-binding decision rules will be defined in the statistical analysis plan
(SAP).
No clinical endpoints for Phase 3 have been identified yet and the association between the antiviral effect
and clinical course endpoints is not yet established for RSV. A key secondary objective of this Phase 2
study is the evaluation of clinical course endpoints and their dependence on viral load reductions. Results
of this Phase 2 study will inform on discussion and selection of clinical course endpoints and guide the
design for subsequent Phase 3 studies. Therefore, a sample size re-estimation based on clinical course
endpoints (Cohort 2 data only) will be performed during interim analysis 3 and may result in an expansion
of Cohort 2. Based on all available data from Cohort 2 at the cut-off for interim analysis 3, one or more
clinically relevant and sensitive endpoint(s) will be selected for confirmation. Time to resolution (ie, to
none or mild symptoms) and reduction in severity of selected clinical signs/symptoms of RSV-related
illness are currently expected to be the most relevant clinical endpoints for Phase 3 planning. However, data
from this study, in combination with data from other RSV studies within and outside the company, and
knowledge obtained through health authority interaction(s) will be considered in interim analysis 3 for the
endpoint selection and sample size recalculation.
After selection of (a) clinical endpoint(s), the number of subjects in Cohort 2 will be calculated to minimize
the conditional “consider”-probability for clinical endpoints (Go-NoGo-approach) at the end of the study
assuming a required confidence of 90% (one-sided) to exclude the target value and/or the minimal
acceptable value. Both the study team and the IDMC may recommend to the Sponsor Committee an
increase of the sample size for Cohort 2 of the study. The maximum number of subjects in Cohort 2 in the
study will not exceed 300.
Fourth Interim Analysis
If the study is extended beyond the initially planned sample size in Cohort 2 for the primary analysis
(N=150), a fourth interim analysis will be performed preferably at the end of a hemispheric RSV season,
after approximately 150 subjects in Cohort 2 have completed the Day 14 assessments (or discontinued
earlier), and will include all available data from Cohort 1 and Cohort 2. Enrollment in the >3 days to ≤5 days
since symptom onset stratum might be temporarily paused prior to interim analysis 4 (at N=approximately
150 in Cohort 2), once the maximum number of subjects are enrolled in the >3 days to ≤5 days since
symptom onset stratum in Cohort 2. Enrollment in the >3 days to ≤5 days since symptom onset stratum will
be reopened once the last subject required for interim analysis 4 has been randomized. The primary analysis
on antiviral activity will be performed during this fourth interim analysis and effects of JNJ-53718678 on
clinical course endpoints, next to endpoints related to safety, PK and PK/PD, will be analyzed to support
early Phase 3 preparations, including regulatory interactions. In addition, the futility and population


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enrichment analysis will be repeated at this interim analysis. Both the study team and the IDMC will provide
their recommendations to the Sponsor Committee, who will decide, taking all recommendations into
account.
Final Analysis
The final analysis is planned when all subjects from Cohort 1 and Cohort 2 have completed the study (or
discontinued earlier). If no extension of Cohort 2 is required, the final analysis will coincide with the
primary analysis. Enrollment in the >3 days to ≤5 days since symptom onset stratum will be stopped once
the maximum number of subjects are enrolled in this stratum in both cohorts. Since the number of subjects
enrolled in Cohort 2 is the trigger to perform interim analysis 3 and interim analysis 4, enrollment in
Cohort 1 in the >3 days to ≤5 days since symptom onset stratum might be stopped, at any time after interim
analysis 2, once the maximum number of subjects in this stratum are enrolled for the final analysis.
While recruitment in the subcohort of Cohort 1 is ongoing, subjects >2 and ≤3 years of age are not allowed
to be enrolled in Cohort 2, even if enrollment in that cohort has been opened for the age groups ≤2. After
6 subjects of the subcohort are evaluable for PK analysis and have completed the Day 14 assessments (or
discontinued earlier), safety and PK data will be reviewed by the IDMC, who will issue its recommendation
to the sponsor, based on which the Sponsor Committee will decide whether to also initiate enrollment of
subjects >2 and ≤3 years of age in Cohort 2 when enrollment in that cohort has been opened for the age
groups ≤2. During this IDMC review, additional subjects >2 and ≤3 years of age can be enrolled in Cohort 1
and will follow all Cohort 1 procedures.
To account for multiplicity, and to be able to define a robust clinical course endpoint for Phase 3, both
unadjusted and adjusted p-values, with appropriate Type I error control, will be presented in the final
analysis.
Additional interim analyses may be performed at the sponsor’s discretion to support decision making for
further development of JNJ-53718678 and to support interactions with health authorities.
During and after all interim analyses, investigators, subject(s), and local sponsor representatives (except for
selected local sponsor representatives from Japan) will remain blinded. An IDMC will monitor and review
data in an unblinded manner, at all interim analyses. During the first interim analysis, the Sponsor
Committee will be unblinded; the central sponsor team members and local sponsor representatives from
Japan will remain blinded. For the second interim analysis, the Sponsor Committee, central sponsor team
members, and selected local sponsor representatives from Japan will be unblinded upon recommendation
from the IDMC and the Sponsor Committee. During any interim analysis taking place after the second
interim analysis, the sponsor, including the central study team, and selected local sponsor representatives
from Japan will be unblinded. Aggregate unblinded data and certain individual safety events may be shared
with investigators to support the revised risk-benefit evaluation for the current study and to support start of
Phase 3.
Sample Size
The basis of the sample size calculation is the antiviral results of Study 53718678RSV1005. In that study,
the mean difference in RSV viral load AUC from baseline until Day 5 of the placebo group versus active
(adjusted for baseline viral load) was estimated as 105 log10 copies.hour/mL (corresponding to a 25%
reduction) and the standard deviation (SD) on the RSV viral load AUC as 85 log10 copies.hour/mL
(corresponding to a coefficient of variation [CV] of approximately 20%).
Assuming a more conservative reduction in RSV viral load AUC of 20% compared to placebo, considering
a CV of 35% (slightly higher variability than observed in Study 53718678RSV1005), and a 1-sided alpha
of 2.5%; the power to conclude a dose-response using the Multiple Comparison Procedure-Modeling
(MCP-Mod) procedure under different assumptions for the dose-response relationship (linear, Emax, and


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exponential) is provided in the table below. Based on Study 53718678RSV1005 results, no discrimination
between the proposed doses is expected (ie, Emax  dose-response shape was observed).
Table 
Power (%) to Conclude Dose-response Using MCP-Mod Under Different Assumptions for the
Dose-response Relationship
Assumed CV  
Assumed dose-response relationship
Linear 
Emax 
Exponential
Cohort 1 + Cohort 2 (N=74 per treatment arm)
20%  
100.0 
100.0 
100.0
35% 
92.3 
95.3 
96.6
Cohort 2 only (N=50 per treatment arm)
20%  
99.8 
100.0 
100.0
35% 
79.0 
84.0 
86.9
Cohort 1 only (N=24 per treatment arm)
20%  
91.5 
94.7 
96.2
35% 
47.1 
51.2 
54.7
If data of both cohorts are combined (N=74 per treatment arm), the power to conclude dose-response is
more than 90% for all 3 different assumptions for the dose-response relationship. If data from Cohort 1
cannot be combined with data from Cohort 2 (eg, due to inconsistency [means and/or variability] in viral
load data between cohorts per treatment group), the power to conclude a dose-response using the MCP-Mod
procedure in Cohort 2 (N=50 per treatment arm) is at least 79%.
The sample size in Cohort 1 only (n≥24 per treatment arm) will provide sufficient power (approximately
90%) if the reduction in RSV viral load AUC is at least 20% with a CV which is not higher than observed
in Study 53718678RSV1005 (ie, 20%).
In conclusion, a sample size of 72 in Cohort 1 and 150 in Cohort 2 is sufficient to detect with reasonable
power the antiviral effect; even if the data of Cohort 1 cannot be combined with the data of Cohort 2.
Therefore, the primary analysis will be performed after approximately 150 subjects from Cohort 2 have
completed the Day 14 assessments (or discontinued earlier). By that time, it is expected that at least
72 subjects from Cohort 1 will have completed the Day 14 assessments (or discontinued earlier).
During interim analysis 3 (when approximately 70 to 80 subjects from Cohort 2 have completed the Day 14
assessments [or discontinued earlier]), a sample size re-estimation will be performed to allow an extension
of Cohort 2 for the confirmation of the results on selected clinical course endpoints. Based on all clinical
course data from Cohort 2 available at the time of the cut-off for the third interim analysis, one or more
clinically relevant and sensitive endpoint(s) will be selected for confirmation in the final analysis. Time to
resolution (ie, to none or mild symptoms) and reduction in severity of selected clinical signs/symptoms of
RSV-related illness are currently expected to be the most relevant clinical endpoints for Phase 3 planning.
However, data from this study, in combination with data from other RSV studies within and outside the
company, and knowledge obtained through health authority interaction(s) will be considered in interim
analysis 3 for the endpoint selection and sample size recalculation.
After selection of (a) clinical endpoint(s), the number of subjects in Cohort 2 will be calculated that is
required to minimize the conditional “consider”-probability for clinical endpoints (Go-NoGo-approach) at
the end of the study, assuming a required confidence of 90% (1-sided) to exclude the target value and/or
the minimal acceptable value.
Both the study team and the IDMC may recommend to the Sponsor Committee an increase of the sample
size for Cohort 2 of the study. The maximum number of subjects in Cohort 2 in the study will not exceed
300.


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For Cohort 1, assuming a median time to resolution of symptoms of 3 days in the placebo group, a 1-day
reduction in the active group (ie, ratio of 66%), and a scale parameter of 1/0.65, a sample size of 48 subjects
per treatment arm will reach 95% probability to reach an observed effect in the right direction; based on
estimates derived from an accelerated failure time model. This will allow the evaluation ofclinical course
endpoints in the hospital population compared to the outpatients.
Efficacy Analyses
The primary population for the efficacy/antiviral activity analysis will be the intent-to-treat infected
population consisting of all randomized subjects who received at least one dose of study treatment and who
have a centrally confirmed RSV viral load of 1 log10 copies/mL above the lower limit of quantification
(LLOQ) at baseline.
Primary Endpoint
The primary objective is to establish antiviral activity ofJNJ-53718678. The primary efficacy endpoint is
the RSV viral load area under the curve (AUC) from immediately prior to first dose of study drug through
Day 5 derived from the RSV viral load as measured by  a qRT-PCR assay in nasal swabs. A hybrid
methodology that combines aspects of multiple testing with modeling techniques (MCP-Mod) will be used
for evaluating dose-response trends and estimating the dose-response relationships.
A set of 3 candidate models will be used to cover a suitable range of possible dose-response shapes (linear,
Emax, exponential). Doses of the different age groups will be pooled and transformed to the total daily dose
of the oldest age group: low dose (3 mg/kg), high dose (9 mg/kg), and placebo (0 mg/kg) and these will be
used for the “treatment groups” in the analysis.
AUC values with corresponding covariance matrix will be determined by modeling the log10 viral load
values over time using a restricted maximum likelihood-based repeated measures approach. Analyses will
include the fixed, categorical effects of treatment, strata, visit, and treatment-by-visit interaction, as well as
the continuous, fixed covariates of baseline log10 viral load and baseline log10 viral load by-visit interaction.
An unstructured (co)variance structure will be used to model the within subject errors over time. The
Kenward-Roger method will be used to approximate the degrees of freedom.
Each of the dose-response shapes in the candidate set will be tested using the corresponding contrast t-test
statistic, employing a critical value derived for the maximum of the t-test statistics (based on the associated
multivariate t-distribution) to ensure appropriate multiplicity correction that preserves the Type I error rate.
A dose-response trend is established when the maximum of the t-test statistics exceeds the critical value.
Secondary Endpoints
Antiviral Activity
The other antiviral endpoints 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. Kaplan-Meier Curves will be
produced to graphically describe the time to event data.
Differences between treatment groups in viral load will be derived from the same model as for the primary
endpoint using appropriate contrasts deriving least square mean differences, including the 95% 2-sided
confidence intervals (CIs). Other covariates as well as interaction effects might also be investigated.
The time to undetectable RSV viral load will be analyzed using Kaplan-Meier plots and will be modeled
using an accelerated failure time model, adjusted for covariates, such as strata and baseline viral load, to
estimate differences between treatment groups. A generalized MCP-Mod approach will be used to test for
existence of dose-response, if applicable.


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More details regarding the analysis of these data will be described in the SAP.
Clinical Course of RSV Infection
All endpoints 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.
Time to-variables (eg, time to resolution of symptoms, time to clinical stability, length of hospital stay) will
be analyzed using Kaplan-Meier plots and will be modeled using an accelerated failure time model, adjusted
for covariates, such as strata and baseline viral load, to estimate differences between treatment groups. 80%
and 95% 2-sided CIs will be calculated. A generalized MCP-Mod approach defined will be used to test for
existence of dose-response.
Parent(s)/caregiver(s) PRESORS  and clinician PRESORS  scores will be descriptively summarized by
treatment group and compared between treatment groups. 80% and 95% 2-sided CIs will be calculated. A
generalized MCP-Mod approach will be used to test for existence of dose-response on parent(s)/caregiver(s)
PRESORS and clinician PRESORS scores.
More details regarding the analysis of these data will be described in the SAP.
Correlation Between Antiviral Effect and Clinical Course Endpoints
Selected antiviral effect and clinical course endpoints will be subjected to correlation analysis. Various
approaches, including graphical analysis, regression methods but also longitudinal analyses will be utilized.
More details regarding the analysis of these data will be described in the SAP.
Viral Sequencing
The sequencing results of the F-gene (and other regions of the RSV genome, if applicable, at the request of
the protocol virologist) and changes from baseline will be summarized. Sequencing results may be
presented in a separate report.
Safety Analysis
Safety data will be presented descriptively. Statistical testing of safety data, if appropriate, may be presented
in a separate report.
For safety, baseline is defined as the last assessment prior to the first intake of study drug.
The population for the safety analysis will consist of all randomized subjects who received at least 1 dose
of study drug.
Pharmacokinetic Analysis
Population PK analysis of concentration-time data of JNJ-53718678 may 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 subject characteristics (demographics, laboratory variables, 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.
Pharmacokinetic/Pharmacodynamic Relationships
Relationships of JNJ-53718678 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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Medical Resource Utilization Analysis
Medical resource utilization will be descriptively summarized by treatment group.
Acceptability and Palatability Analysis
Data on acceptability and palatability of the JNJ-53718678 formulation will be presented descriptively.
Biomarker Analysis
Analyses may be performed at the sponsor’s discretion and reported separately from this study. Statistical
approaches to explore correlations between clinical outcome, viral load, and biomarkers in blood and mid-
turbinate nasal swabs vary and depend on the different data types of the applied technology platforms, as
well as on the extent of observed differences among study subjects.
Other Analyses
Data on viral (other than RSV) or bacterial pathogens (both by multiplex PCR) determined in mid-turbinate
nasal swabs collected at screening will be listed.
Independent Data Monitoring Committee
An IDMC will be established to monitor and review data in an unblinded manner on a regular basis to
ensure the continuing safety of the subjects enrolled in this study. The committee will meet periodically to
review safety data and results from interim analyses. After the review, the IDMC will provide
recommendations to the Sponsor Committee.
The IDMC will also review the safety and PK data from 6 subjects in the subcohort of Cohort 1 and the
interim analysis data, and will issue its recommendation to the sponsor, based on which the Sponsor
Committee will decide whether to initiate enrollment in Cohort 2. The Sponsor Committee will take a
decision considering the recommendations from the IDMC.








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e. 
Prior to signing the main consent form for the study, subject’s legally acceptable representative may specifically allow for the collection and testing of nasal mid-
turbinate 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.
f. 
Investigators should ensure that all study enrollment criteria have been met at screening. If a subject’s clinical status changes (including any available laboratory
results or receipt of additional medical records) after screening but before the first dose of study drug is given such that they no longer meet all eligibility criteria,
they should be excluded from participation in the study.
g. 
During screening, a study-specific screening sample (mid-turbinate swab) will be collected for the local diagnosis of RSV infection using a preferably rapid PCR-
or other molecular-based diagnostic assay (preferred) or a rapid-antigen-detection assay. Swabs collected per local SOC testing within 24 hours prior to start of
screening may be used in determining study eligibility. If a rapid-antigen-detection assay is used as part of SOC or study-specifically (with the main study ICF or
with the diagnostic ICF having been signed), the remainder of the screening sample used for the RSV diagnostic testing should be sent to the central laboratory for
additional virologic analyses, as applicable.
h. 
Randomization should occur within 24 hours after start of screening or within 48 hours after collection of the SOC sample used for local RSV diagnosis, whichever
comes first. Randomization is to occur predose.
i. 
Study drug administration should start as soon as possible, but no later than 4 hours after randomization and within 5 days after symptom onset. For analysis purposes,
the day of first study drug intake will be considered Day 1. Dosing should preferably occur approximately at the same time each day. The study drug can be
administered with/without food. The study drug will be administered orally using a dosing syringe. The drug can also be administered through a nasogastric tube, if
already in place.
j. 
Study site personnel will instruct subjects’ parent(s)/caregiver(s) on how to use and store the study drug for at-home dosing. Study drug will be provided at day of
discharge in 1 single vial, from which the assigned volume is to be withdrawn each day, for the remainder of the treatment period.
k. 
Clinical evaluation includes measurements/evaluations of respiratory rate, heart rate, body temperature, and SpO2, occurrence of complications, need for antibiotics,
oxygen requirement (type and duration), level of and duration of hospital care, duration of hospitalization, hydration/feeding by IV line/nasogastric tube. In case
antipyretics are used, body temperature should be measured immediately before or >4 hours after giving antipyretics. All clinical assessments should preferably be
done when the infant is calm (ie, not crying or immediately after feeding).
l. 
If the subject is enrolled in the substudy of Study 53718678RSV2002 (see Section 3.1), the same parameters as assessed by the biosensor will be recorded from the
standard-of-care monitoring/assessments as part of the substudy assessments (refer to the substudy Clinical Protocol for detailed information).
m. Only applicable in case of on-site visit.
n. 
The clinician PRESORS (Attachment 4) has to be completed by the clinician on the electronic device.
o. 
An electronic device will be provided to the subject’s parent(s)/caregiver(s) during screening and the investigator/study site personnel will provide sufficient
information to enable the subject’s parent(s)/caregiver(s) to complete these assessments. The first parent(s)/caregiver(s) PRESORS (Attachment 5) assessment of the
bid schedule on Day 1 needs to be completed as close as feasible and prior to the first administration of the study drug. Detailed information is available in
Section 9.2.2.
p. 
The parent(s)/caregiver(s) PRESORS has to be completed by the subject's parent(s)/caregiver(s) during end-of-study visit as the first activity of the visit prior to any
other procedures.
q. 
One mid-turbinate nasal swab will be taken of which aliquots will be used for the central laboratory confirmation of RSV infection, to determine RSV viral load, to
determine mutations in the viral genome potentially associated with resistance to JNJ-53718678, and to determine the presence of other viral or bacterial pathogens.
r. 
Mid-turbinate swabs should be collected from the same nostril throughout the study (unless precluded due to bleeding). Swabs will be collected each day during
hospitalization through Day 13 or until discharge (whichever comes first), and on Day 14 and Day 21 (if still hospitalized). Detailed information on sample collection
is available in Section 9.2.1.
s. 
Leftover mid-turbinate nasal swab samples collected for other testing may be used for exploratory biomarker analyses, at discretion of the sponsor.


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t. 
The baseline mid-turbinate nasal swab should be collected as close as possible and prior to the first administration of study drug (on Day 1). If a study-specific
screening nasal mid-turbinate swab was collected within 8 hours prior to dosing, the leftover of that sample can serve as the baseline sample and should be shipped
to the central laboratory, provided that the study-specific nasal mid-turbinate screening sample was stored appropriately and has sufficient sample volume available
(minimum 4 aliquots of 600 µL each). If feasible, the nasopharyngeal and/or tracheal aspirate sample should be collected as close as possible and prior to the first
administration of study drug (on Day 1).
u. 
Nasopharyngeal and/or tracheal aspirate samples will be collected when aspiration of nasopharyngeal and/or tracheal secretions is performed as part of routine
clinical care while hospitalized (ie, at selected sites only) to assess RSV RNA viral load centrally.
v. 
Systolic and diastolic blood pressure need to be measured sitting or supine (preferably the same position at each measurement) after at least 5 minutes of rest.
w. Physical examination of all body systems includes length and head circumference and body weight measurement and skin examination.
x. 
Directed physical examination includes respiratory system, nose, ear, throat, facial, and neck lymph nodes, and skin examination.
y. 
Triplicate 12-lead ECGs will be obtained, approximately 1 minute apart and preferably  all within 5 minutes. ECGs may be repeated at the discretion of the
investigator. ECGs will be obtained in a supine position after 5 minutes of rest. If an ECG is scheduled at the same timepoint as other assessments, the ECG should
be performed first.
z. 
Samples for clinical laboratory assessments will be collected and analyzed at a central laboratory. Leftover blood samples collected for other testing may be used for
exploratory biomarker analyses, at discretion of the sponsor. Subjects can start treatment before the laboratory results are available (see also Section 9.1.2).
aa. Urinalysis will be performed using dipsticks provided by the central laboratory. In case of abnormalities, the urine sample will be shipped to the central laboratory
for flow cytometric and/or microscopic evaluation(s).
bb. Blood samples for determination of JNJ-53718678 concentrations will be collected through finger prick  or heel stick. In the subcohort of Cohort 1, next to
randomization to treatment group, within each treatment arm (high dose, low dose, placebo), the 6 subjects will be randomized 1:1 to 1 of 2 different PK sampling
groups (see Table 2). In Cohort 1, next to randomization to treatment group, the first 12 subjects of each age group (subcohort not included) will be randomized 1:1
to 1 of 2 different PK sampling groups (see Table 2). Once 12 subjects of a particular age group have been randomized to the 2 different PK sampling groups, the
investigator can assign the subsequently enrolled subjects to either of the 2 PK sampling groups, but preferably alternating between 2 different PK sampling groups
at this site. Detailed information on sample collection is available in Section 9.4.1. Leftover blood samples collected for other testing may be used for exploratory
biomarker analyses, at discretion of the sponsor.
cc. Adverse events related to the use of the biosensor reported during the substudy will be recorded in the eCRF of the main study.






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antipyretics. Parents/caregivers should be instructed accordingly. All clinical assessments should preferably be done when the infant is calm (ie, not crying or
immediately after feeding).
g. 
If the subject is enrolled in the substudy of Study 53718678RSV2002 (see Section 3.1), the same parameters as assessed by the biosensor will be recorded from the
standard-of-care monitoring/assessments as part of the substudy assessments (refer to the substudy Clinical Protocol for detailed information).
h. 
Only applicable in case of on-site visit.
i. 
The clinician PRESORS (Attachment 4) has to be completed by the clinician on the electronic device.
j. 
Detailed information is available in Section 9.2.2.
k. 
The morning assessment needs to be done prior to discharge and the evening one should be done at home.
l. 
If the subject is discharged prior to completion of the last assessment of the bid schedule, this last assessment should be performed at home.
m. The parent(s)/caregiver(s) PRESORS (Attachment 5) has to be completed by the subject's parent(s)/caregiver(s) during end-of-study visit as the first activity of the
visit prior to any other procedures.
n. 
Mid-turbinate swabs should be collected from the same nostril throughout the study (unless precluded due to bleeding). After discharge, swabs will be collected daily
through Day 8 in all subjects. As of Day 8, in subjects who were symptomatic based on the clinician PRESORS at Day 8, daily swabs will be collected through
Day 13 or until the subject becomes asymptomatic based on the parent(s)/caregiver(s) PRESORS, as evaluated by the investigational staff (whichever comes first).
On Day 14 and Day 21, a swab will be collected during the scheduled visit for all subjects. Detailed information on sample collection is available in Section 9.2.1.
o. 
Leftover mid-turbinate nasal swab samples collected for other testing may be used for exploratory biomarker analyses, at discretion of the sponsor.
p. 
To be completed by parent(s)/caregiver(s) on the electronic device (see Attachment 7 [nasal swab log]), if applicable. Refer to Section 9.2.1 for detailed information.
q. 
Body temperature to be measured by parent(s)/caregiver(s) and recorded on the electronic device (see Attachment 8 [temperature log]). In case antipyretics are used,
body temperature should be measured immediately before or >4 hours after giving antipyretics. Parents/caregivers should be instructed accordingly.
r. 
On the day of discharge, if discharged in the morning, only the evening assessment of the bid schedule should be recorded in the temperature log on the electronic
device.
s. 
Systolic and diastolic blood pressure need to be measured sitting or supine (preferably the same position at each measurement) after at least 5 minutes of rest.
t. 
Physical examination of all body systems includes length and head circumference and body weight measurement and skin examination.
u. 
Directed physical examination includes respiratory system, nose, ear, throat, facial, and neck lymph nodes, and skin examination.
v. 
Triplicate 12-lead ECGs will be obtained, approximately 1 minute apart and preferably all within 5 minutes. ECGs may be repeated at the discretion of the
investigator. ECGs will be obtained in a supine position after 5 minutes of rest. If an ECG is scheduled at the same timepoint as other assessments, the ECG should
be performed first.
w. Samples for clinical laboratory assessments will be collected and analyzed at a central laboratory. Leftover blood samples collected for other testing may be used for
exploratory biomarker analyses, at discretion of the sponsor.
x. 
Urinalysis will be performed using dipsticks provided by the central laboratory. In case of abnormalities, the urine sample will be shipped to the central laboratory
for flow cytometric and/or microscopic evaluation(s).
y. 
Adverse events related to the use of the biosensor reported during the substudy will be recorded in the eCRF of the main study.
Note: Additional unscheduled visits in case of lab abnormalities, ECG abnormalities, need for clinical follow-up of (an) AE(s) can be scheduled at the discretion of the
investigator.








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to have a Safety Follow-up Visit for the subject at the site (preferred option) or, if feasible for the study site and if allowed per local regulations, at home on Day 28
(±3). Only clinically relevant assessments will be performed during this visit.
f. 
Prior to signing the main consent form for the study, subject’s legally acceptable representative may specifically allow for the collection and testing of nasal mid-
turbinate 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.
g. 
Investigators should ensure that all study enrollment criteria have been met at screening. If a subject’s clinical status changes (including any available laboratory
results or receipt of additional medical records) after screening but before the first dose of study drug is given such that they no longer meet all eligibility criteria,
they should be excluded from participation in the study.
h. 
During screening, a study-specific screening sample (mid-turbinate swab) will be collected for the local diagnosis of RSV infection using a preferably rapid PCR-
or other molecular-based diagnostic assay (preferred) or a rapid-antigen-detection assay. Swabs collected per local SOC testing within 24 hours prior to start of
screening may be used in determining study eligibility. If a rapid-antigen-detection assay is used as part of SOC or study-specifically (with the main study ICF or
with the diagnostic ICF having been signed), the remainder of the screening sample used for the RSV diagnostic testing should be sent to the central laboratory for
additional virologic analyses, as applicable.
i. 
Randomization should occur within 24 hours after start of screening or within 48 hours after collection of the SOC sample used for local RSV diagnosis, whichever
comes first. Randomization is to occur predose.
j. 
Study drug administration should start as soon as possible, but no later than 4 hours after randomization and within 5 days after symptom onset. For analysis purposes,
the day of first study drug intake will be considered Day 1. Dosing should preferably occur approximately at the same time each day for both intakes (AM and PM).
For subjects who receive only 1 dose of JNJ-53718678 or placebo PM on Day 1, dosing should continue through the morning (ie, AM) of Day 8 so that all subjects
receive 14 consecutive doses in total. 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. The study drug can be administered
with/without food. The study drug will be administered orally using a dosing syringe.
k. 
Study site personnel will instruct subjects’ parent(s)/caregiver(s) on how to use and store the study drug for at-home dosing. Study drug will be provided in 1 single
vial, from which the assigned volume is to be withdrawn each day.
l. 
Date and time of study medication dosing has to be recorded, also in case if it cannot be recorded in the study medication log by the site.
m. Clinical evaluation includes measurements/evaluations of respiratory rate, heart rate, body temperature, and SpO2,need for and duration of hospitalization, occurrence
of complications, need for antibiotics. In case antipyretics are used, body temperature should be measured immediately before or >4 hours after giving antipyretics.
Parents/caregivers should be instructed accordingly. All clinical assessments should preferably be done when the infant is calm (ie, not crying or immediately after
feeding). In case Cohort 2 Screening and Randomization occur on the same calendar day, clinical evaluation does not have to be repeated.
n. 
If the subject is enrolled in the substudy of Study 53718678RSV2002 (see Section 3.1), heart rate, respiratory rate, and SpO2 will be recorded as part of the
substudy assessments (refer to the substudy Clinical Protocol for detailed information).
o. 
Only applicable in case of on-site visit.
p. 
The clinician PRESORS (Attachment 4) has to be completed by the clinician on the electronic device.
q. 
An electronic device will be provided to the subject’s parent(s)/caregiver(s) during screening and the investigator/study site personnel will provide sufficient
information to enable the subject’s parent(s)/caregiver(s) to complete these assessments. The first parent(s)/caregiver(s) PRESORS (Attachment 5) assessment of the
bid schedule on Day 1 needs to be completed as close as feasible and prior to the first administration of study drug. Detailed information is available in Section 9.2.2.
r. 
The parent(s)/caregiver(s) PRESORS has to be completed by the subject's parent(s)/caregiver(s) during end-of-study visit as the first activity of the visit prior to
any other procedures.
s. 
One mid-turbinate nasal swab will be taken of which aliquots will be used for the central laboratory confirmation of RSV infection, to determine RSV viral load, to
determine mutations in the viral genome potentially associated with resistance to JNJ-53718678, and to determine the presence of other viral or bacterial pathogens.


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t. 
Mid-turbinate swabs should be collected from the same nostril throughout the study (unless precluded due to bleeding). Swabs will be collected daily through Day 8
in all subjects. The investigator/study site personnel will train the parent(s)/caregiver(s) to collect the mid-turbinate nasal swab in case collection by an HCP is not
possible. As of Day 8, in subjects who were symptomatic based on the clinician PRESORS at Day 8, daily swabs will be collected through Day 13 or until the subject
becomes asymptomatic based on the parent(s)/caregiver(s) PRESORS, as evaluated by the investigational staff (whichever comes first). On Day 14 and Day 21, a
swab will be collected during the scheduled visit for all subjects. Detailed information on sample collection is available in Section 9.2.1.
u. 
Leftover mid-turbinate nasal swab samples collected for other testing may be used for exploratory biomarker analyses, at discretion of the sponsor.
v. 
The baseline mid-turbinate nasal swab should be collected as close as possible and prior to the first administration of study drug (on Day 1). If a study-specific
screening nasal mid-turbinate swab was collected within 8 hours prior to dosing, the leftover of that sample can serve as the baseline sample and should be shipped
to the central laboratory, provided that the study-specific nasal mid-turbinate screening sample was stored appropriately and has sufficient sample volume available
(minimum 4 aliquots of 600 µL).
w. To be completed by parent(s)/caregiver(s) on the electronic device (see Attachment 7 [nasal swab log]), if applicable. Refer to Section 9.2.1 for detailed information.
x. 
Body temperature to be measured by parent(s)/caregiver(s) and recorded on the electronic device (see Attachment 8 [temperature log]). In case antipyretics are used,
body temperature should be measured immediately before or >4 hours after giving antipyretics. Parents/caregivers should be instructed accordingly.
y. 
Systolic and diastolic blood pressure need to be measured sitting or supine (preferably the same position at each measurement) after at least 5 minutes of rest.
z. 
Complete physical examination of all body systems includes length and head circumference and body weight measurement and skin examination.
aa. Directed physical examination includes respiratory system, nose, ear, throat, facial, and neck lymph nodes, and skin examination.
bb. Triplicate 12-lead ECGs will be obtained, approximately 1 minute apart and preferably all within 5 minutes. ECGs may be repeated at the discretion of the
investigator. ECGs will be obtained in a supine position after 5 minutes of rest. If an ECG is scheduled at the same timepoint as other assessments, the ECG should
be performed first.
cc. Samples for clinical laboratory assessments will be collected and analyzed at a central laboratory. Leftover blood samples collected for other testing may be used for
exploratory biomarker analyses, at discretion of the sponsor. Subjects can start treatment before the laboratory results are available (see also Section 9.1.2).
dd. Urinalysis will be performed using dipsticks provided by the central laboratory. In case of abnormalities, the urine sample will be shipped to the central laboratory
for flow cytometric and/or microscopic evaluation(s).
ee. Blood samples for determination of JNJ-53718678 concentrations will be collected through finger prick or heel stick on Days 3 and 5 at a random timepoint (predose
or postdose) during the visit. Detailed information on sample collection is available in Section 9.4. Leftover blood samples collected for other testing may be used
for exploratory biomarker analyses, at discretion of the sponsor.
ff. 
Adverse events related to the use of the biosensor reported during the substudy will be recorded in the eCRF of the main study.
gg. At Day 1 and Day 3, ECGs should be obtained approximately one hour after administration of study drug. At Day 28, ECGs should be obtained in case abnormal
ECGs at Day 21 or at discretion of the principal investigator. Anytime when it is clinically indicated or for confirmation of abnormal ECG findings, unscheduled
ECGs should be obtained.
hh. Levels of potassium and magnesium will be determined by the central laboratory. In case of hypokalemia or hypomagnesemia at screening or at Day 8, the levels
of potassium and 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.
ii. 
PK samples should be collected approximately one hour after administration of study drug (after the ECGs are obtained if applicable) at Day 1 and at least 4 hours
after the AM and prior to the PM dosing on Day 3 or Day 5.
Note 1: Additional unscheduled visits in case of lab abnormalities, ECG abnormalities, need for clinical follow up of (an) AE(s) can be scheduled at the discretion of
the investigator.
Note 2: Refer to Attachment 10for guidance on study conduct during the COVID 19 pandemic.


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ABBREVIATIONS
AE 
adverse event
ALT  
alanine transaminase
AST  
aspartate aminotransferase
aPTT  
activated partial thromboplastin time
AUC  
area under the RSV viral load-time curve
BCRP  
breast cancer resistance protein
bid 
twice daily
BM 
bone marrow
BW 
body weight
CI 
confidence interval
Cmax  
maximum plasma concentration
Cmin  
minimum plasma concentration
COA  
clinical outcome assessment (paper or electronic as appropriate for this study)
COVID-19 
Coronavirus Disease 2019
CPE 
complete physical examination
(e)CRF  
case report form(s) (paper or electronic as appropriate for this study)
CV  
coefficient of variation
CYP  
cytochrome
DBP  
diastolic blood pressure
DMC  
Data Monitoring Committee
DMID  
Division of Microbiology and Infectious Diseases
DPE 
directed physical exam
EC50 
effective concentration for 50% inhibition
ECG  
electrocardiogram
eDC  
electronic data capture
FC 
food consumption
GCP  
Good Clinical Practice
GGT  
γ-glutamyltransferase
GLP  
Good Laboratory Practice
GPT  
glutamic-pyruvic transaminase
HCP  
healthcare provider
HIV  
human immunodeficiency virus
HP--CD  
2-Hydroxypropyl-beta-cyclodextrin
ICF  
informed consent form
ICH  
International Conference on Harmonisation
ICU  
intensive care unit
IDMC  
independent data monitoring committee
IEC  
Independent Ethics Committee
IPPI 
investigational product preparation instruction
IRB  
Institutional Review Board
IV  
intravenous
IWRS  
interactive web response system
LC-MS/MS  
liquid chromatography/mass spectrometry/mass spectrometry
LLOQ  
lower limit of quantification
LRTI 
lower respiratory tract infection
MATE1 
multidrug and toxin extrusion 1
MCP-Mod 
Multiple Comparison Procedure-Modeling
MDE 
multiple-dose escalation
MedDRA  
Medical Dictionary for Regulatory Activities
MTD  
maximum tolerated dose
NOAEL 
no observed adverse effect level
OAT  
organic anion transporter
OATP  
organic-anion-transporting polypeptide
OCT  
organic cation transporter
PCR  
polymerase chain reaction


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PD 
pharmacodynamic(s)
PK 
pharmacokinetic(s)
PND  
post-natal day
popPK  
population pharmacokinetic(s)
PQC  
Product Quality Complaint
PRESORS  
Pediatric RSV Electronic Severity and Outcome Rating Scales
PRO  
patient-reported outcome(s) (paper or electronic as appropriate for this study)
PT  
prothrombin time
qd 
once daily
qRT-PCR  
quantitative reverse transcription polymerase chain reaction
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 interval
RBC  
red blood cell
RSV  
respiratory syncytial virus
SAE 
serious adverse event
SAP  
statistical analysis plan
SBP 
systolic blood pressure
SDE 
single-dose escalation
SOC  
standard of care
SUSAR  
suspected unexpected serious adverse reaction
TEAE 
treatment-emergent adverse event
TQT  
thorough QT
URTI 
upper respiratory tract infection
WBC  
white blood cell


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1. 
INTRODUCTION
Respiratory syncytial virus (RSV), a negative-stranded ribonucleic acid virus belonging to the
Pneumoviridae family, is considered the most important virus causing acute lower respiratory tract
infection (LRTI). Two subtypes of RSV have been identified ie, subtypes A and B that generally
co-circulate simultaneously, although with a higher prevalence of subtype A.8 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.1,30
In most patients, RSV usually results in upper respiratory tract infections eliciting “common cold”-
like symptoms, which might last up to 2 weeks and are usually self-limiting but hospitalization
does occur, with hospitalizations in the United States for RSV estimated at 55.3/100,000 person-
years between 1993 and 2008 for all ages.31 RSV infection can cause considerable morbidity and
mortality in certain patient populations such as infants22 where RSV can lead to lower respiratory
tract infection (LRTI), with severe respiratory compromise. 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.20,21
RSV is a major cause of hospital admissions and death in young children worldwide.22,25 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.9
In 2015, there were approximately 33.1 million RSV-LRTI episodes in 0 4-year-old children
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.26
On the other hand, among children <5 years of age with RSV infection, 97.7% present for medical
care as outpatients in  emergency departments and in pediatric practices, while 2.7% require
hospitalization.11 It has been estimated that 2.2% (1.7 million visits) of all US primary care visits
of children <5 years of age in the year 2000 resulted from RSV infection.18 These rates of visits
for RSV-associated acute respiratory infections suggest that a major proportion of the burden of
RSV results in outpatient visits among children beyond infancy.11
Despite the large medical and economic burden, no vaccines or antiviral agents have been
approved for the prevention  or treatment of RSV infection  in either adult or pediatric
populations.2,24. In hospitalized patients, the current treatment of RSV infection is often limited to
supportive care, consisting of supplemental oxygen therapy, nutrition, fluids, and, in some cases,
mechanical ventilation.7,28 In an outpatient setting, the standard of care is limited to symptomatic
treatment of the flu-like manifestations of the disease. Overall, the unmet medical need
(prophylactically and therapeutically) is substantial in both children and adults with RSV infection,
whether hospitalized or outpatients.


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The window between the onset of clinical symptoms after RSV exposure followed by infection
(Day 3) and peak viral load (Day 6) is on average 3 days in children and adults4,5,6, which is
sufficiently long to initiate treatment, if diagnosed early. As most hospitalized subjects with RSV
infection already had presented to a primary healthcare provider (HCP) 1 or 2 days prior to
hospitalization6,29, there is indeed an opportunity to initiate treatment in these subjects in a
community setting ie, at the point of the initial HCP contact. Also, studies in the adult and pediatric
population have demonstrated that RSV viral load and severity of disease symptoms are closely
correlated,4,5,6 except for 1 recent study that did not confirm this correlation.27 Together, these data
suggest early initiation of treatment in outpatients is possible, and could result in a decrease of the
viral load, syncytia formation, and in inflammatory reactions following RSV infection, and hence
may improve disease outcomes and shorten the duration and/or severity of the disease, potentially
avoiding hospitalization.
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.3,19 JNJ-53718678 is an investigational RSV specific fusion inhibitor belonging
to the indole chemical class and is under development for the treatment of RSV infection. The
study drug shows in vitro activity against a panel of viruses belonging to both the RSV subfamilies
A or B. In addition, antiviral activity of JNJ-53718678 was demonstrated during clinical studies
in healthy adults inoculated with RSV (Study 53718678RSV2001) and in pediatric subjects
hospitalized due to RSV-infection (Study 53718678RSV1005).
For the most comprehensive nonclinical and clinical information regarding JNJ-53718678, refer
to the latest version of the Investigator's Brochure (IB) and Addendum for JNJ-53718678.17,16
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.
1.1. 
Background
Nonclinical Studies
Nonclinical Pharmacology
The in vitro effective concentration for 50% inhibition (EC50) of RSV was found to be 0.23 ng/mL
(460 pM) as measured in a cellular infectious assay. The in vivo EC50 was 75 ng/mL (150 nM) or
81 ng/mL (160 nM) when the reduction of RSV titer was analyzed in bronchoalveolar fluid or
lavaged-lung tissue, respectively, from cotton rats that received a single dose of different
concentrations of JNJ-53718678, 1 hour before infection. Further efficacy and mechanism of
action studies demonstrated that JNJ-53718678 is a selective and extremely potent small-molecule
RSV fusion inhibitor, capable of significantly reducing the viral titer. Concurrently, a decrease of
the virus-induced pro-inflammatory response was observed in RSV-infected and JNJ-53718678
treated Balb/C mice. Finally, once daily (qd) oral treatment of RSV-infected neonatal lambs with
1-, 5-, and 25-mg/kg doses of JNJ-53718678 resulted in significant concentration-dependent
reductions of the viral titer in both bronchoalveolar lavage fluid (BALF) as well as lavaged-lung
tissue as compared to animals that received vehicle only. There were no differences between


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treatment groups for heart rate, respiratory rate, and temperature. Signs of “illness” (including
abnormal lung sounds, as of Day 1 after inoculation) and/or eye and nasal discharges (as of Day 4
after inoculation) were only observed in the vehicle-treated animals and not in the animals
receiving JNJ-53718678 treatment. Estimated EC50 for the average plasma concentration at steady
state was 753 ng/mL and 296 ng/mL for BALF and lung, respectively, again indicating a potent
antiviral activity. In addition, a dose-dependent reduction of the production of several RSV-
induced pro-inflammatory cytokines and chemokines (ie, interferon [IFN]-γ-induced protein-10
[IP-10], monocyte chemotactic protein-1 [MCP-1], macrophage inflammatory protein-1α
[MIP-1α], and IFN-), RSV-induced gross lung lesion formation and concomitantly, significant
improvement of the general lung condition was observed (eg, reduction of bronchiolitis and lung
neutrophilia). Together, these results demonstrate the efficacy of the study drug to inhibit
RSV-induced lung pathology sequelae.
No in vitro antiviral activity was observed for the JNJ-53718678 metabolites M12
(JNJ-53541683), M19 (JNJ-64564071), and M37 (JNJ-69101045); the EC50 value for M5
(JNJ-54172794) was 7.7 nM.
In high-throughput screening (HTS) ion channel voltage clamp assays, JNJ-53718678 did not
affect cardiac sodium membrane current (INa) up to 10 μM, but slightly to markedly inhibited
cardiac potassium membrane current (IKr) at concentrations starting at 1 μM. In a Good Laboratory
Practice (GLP) human-ether-a-gogo-related (hERG) gene study, with JNJ-53718678, the
IKr-blocking liability was confirmed, and a 50% inhibition concentration (IC50) of 1.9 µM was
estimated. In addition, slight inhibition of the hERG mediated IKr was present at 10 μM M5, but
not at 1 and 3 μM. When JNJ-53718678 was administered IV to anesthetized female guinea pigs,
no significant cardiovascular effects were induced up to the 10-mg/kg dose (cumulative dose:
19.69 mg/kg; median plasma exposure: 7,580 ng/mL). In a first study in male conscious dogs, no
notable effects were found on the cardiovascular and respiratory parameters up to an oral
JNJ-53718678 dose of 100 mg/kg (mean JNJ-53718678 peak plasma exposure: 4,270 ng/mL).
After single JNJ-53718678 doses of 75 and 250 mg/kg and 5-day repeated JNJ-53718678 doses of
250 mg/kg qd in conscious dogs, heart rates (HR) were increased at all doses in most dogs and
blood pressure (BP) was decreased at all dosing occasions in all dogs. Respiratory parameters were
not affected. Mean peak plasma exposure values of JNJ-53718678 after a single JNJ-53718678
dose of 75 mg/kg were 15,400 ng/mL, while they amounted to 31,000 ng/mL after giving repeated
JNJ-53718678 doses of 250 mg/kg qd for 5 days.
Evaluation of neurofunctional integrity of rats revealed minimally and transiently decreased
neuromuscular function, next to minimal effects related to gastrointestinal function, at single
JNJ-53718678 doses of 150 and 1,500 mg/kg in rats. There were no effects at the single
JNJ-53718678 dose of25 mg/kg (maximum plasma concentration [Cmax] 826 ng/mL; area under
the plasma concentration-time curve from 0 to 7 hours [AUC0 7h] 3,380 ng.h/mL).
Pharmacokinetics and Product Metabolism in Animals
Following single IV administration to different preclinical species, JNJ-53718678 clearance (CL)
was high in rats (>100% of hepatic blood flow) and moderate in mice, dogs, and monkeys (~30%


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of hepatic blood flow). The volume of distribution at steady state was moderate in all species
(1-3 L/kg).
Following single oral administration of JNJ-53718678, absorption from the gastrointestinal tract
was rapid in all preclinical species. Mean oral bioavailability was variable across preclinical
species and ranged from 18% (monkey) to 90% (dog). JNJ-53718678 plasma exposure (Cmax,
AUC) increased more than dose-proportionally in male rats and close to dose-proportionally in
monkeys at low doses up to 10 and 5 mg/kg, respectively. Feeding status had minimal to no impact
on oral bioavailability of solution and suspension formulations at 5 mg/kg in dogs.
Following repeated oral administration of JNJ-53718678, plasma exposure was higher in female
than in male rats, while no gender difference in JNJ-53718678 exposure was observed in dogs.
JNJ-53718678 plasma exposure decreased upon repeated dosing in rats, indicating clearance auto-
induction, and increased in dogs and minipigs. These changes in exposure upon repeated dosing
in rats were observed at the mid to high doses tested in the toxicity studies and were minor or not
seen at the lowest dose (25 mg/kg/day).
Following single oral administration of JNJ-53718678 to juvenile preclinical species (1 day of
age), JNJ-53718678 plasma exposure was lower than in adult animals in rats and higher in minipigs
and dogs at the same dose levels.
In rats, upon 3-week repeated dosing from 1 to 21 days of age (pilot study), exposure increased at
low and mid doses (25 and 100 mg/kg) during the first week of dosing, while no consistent change
in exposure was observed throughout administration at the high dose (200 mg/kg). Four-weeks of
repeated dosing in juvenile rats (starting on post-natal day [PND] 4; GLP study) resulted in a more
than dose-proportional increase in exposure parameters, with  Cmax  and AUC between 50 and
150 mg/kg/day and a less than dose-proportional increase between 150 and 400 mg/kg/day. In
minipigs and dogs (pilot studies), exposure increased upon repeated dosing during the first week
of dosing at all doses. Five-weeks of repeated dosing in juvenile minipigs (starting on PND1; GLP
study) resulted in rather flat plasma concentration-time profiles. Exposure values increased
generally more than dose-proportionally over the studied dose range (5-25 mg/kg/day). Exposure
was lower at the end versus the start of the dosing period at 5 mg/kg/day, but remained fairly
similar at 10 and 25 mg/kg/day.
Plasma protein binding of JNJ-53718678 amounted to 88% to 99% in adult preclinical species,
94% in adult humans and 92% to 93% in juvenile preclinical species. JNJ-53718678 binds
preferentially to alfa-1-acid glycoprotein (α-1-AGP). Following single oral administration of
JNJ-53718678 to male Sprague-Dawley rats, the tissue concentration-time profiles of unchanged
JNJ-53718678 showed a pattern similar to the plasma profile with fast distribution to tissues and
parallel concentration decline. Distribution was moderate in most tissues (tissue-to-plasma AUC
ratio ranging from 2 in muscle to 14 in liver), and low in the brain (brain-to-plasma AUC ratio:
0.1). The lung-to-plasma ratio of JNJ-53718678 was 3.5. In male cotton rats, the concentration of
JNJ-53718678 in lung epithelial lining fluid 1 hour after single oral administration at 100 mg/kg
was estimated to be about 1.5-fold higher than the corresponding plasma concentration. In a
quantitative whole-body autoradiography (QWBA) study in male pigmented rats, maximum


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concentrations of total radioactivity in most tissues and in plasma were measured at 24 hours after
the single oral administration of 14C-JNJ-53718678. In the majority of tissues, total radioactivity
concentrations were higher than in whole blood. Tissue-to-blood AUC ratios ranged from
0.36 (eye lens) to 17.6 (stomach wall). 14C-JNJ-53718678 related radioactivity distributed to
pigmented tissues (uveal tract: 12.9; skin 1.0). The lung-to-blood ratio was 1.9.
Following incubation of 14C-JNJ-53718678 in human hepatocytes, metabolites formed via direct
N-glucuronidation (M8) and via N-dealkylation with the loss of the trifluoroethyl moiety (M5)
were the most prominent entities. Three different metabolites formed by addition of 1 oxygen were
observed (M1, M3, M4), and 3 metabolites formed by addition of 1 oxygen combined with
glucuronidation (M7, M9, M10) were also seen. Moreover, N-dealkylation at the level of the
5-chloro-2-methyl-indole nitrogen (M12; JNJ-53541683) was observed. All metabolites observed
in human hepatocytes were also seen following incubation of 14C-JNJ-53718678 in at least
1 preclinical species. The glucuronide M8 was observed in trace amounts in rabbit and human
hepatocytes. In infant human hepatocytes, main metabolites corresponded to those observed in
adult human hepatocytes and in vivo in humans with M5 being by far the major metabolite.
Following single oral administration of 14C-JNJ-53718678 to adult rats, unchanged JNJ-53718678
was the more important entity in plasma both in males and females. M1 and M12 were the main
circulating metabolites. Exposure to M1 and M12 was 2- and 1.4-fold lower than that of unchanged
JNJ-53718678 in male rats, respectively, and 10- and 20-fold lower in female rats, respectively. In
feces, mainly metabolites were observed. Unchanged JNJ-53718678 represented about 13% and
27% of the administered dose. In minipig plasma, unchanged JNJ-53718678 was the most
important entity at early time points with M12 becoming most important later on. In minipig feces,
unchanged drug was the most important entity (around 35% of the dose); main route of metabolic
clearance was oxidation to M1 (around 11% of the dose). M5 and M3 represented less than 5% of
the administered dose. Following single and repeated oral administration of JNJ-53718678 to
juvenile rats of different post-natal ages, circulating entities found in the plasma were unchanged
JNJ-53718678 and oxidative and dealkylation metabolites. Glucuronidation of M1 was an
important metabolite (M7) in the first week of dosing. The ontogeny of the metabolic enzymes in
rat does not impact exposure to JNJ-53718678. Plasma levels of M5 (JNJ-54175794), M12 and
M19 (JNJ-54564071) have been detected in repeated dose toxicology studies conducted in juvenile
and adult dogs and neonatal minipigs.
Cytochrome P450 (CYP)3A4 is the major CYP enzyme involved in JNJ-53718678
phase 1 metabolism  in human hepatocytes. Uridine diphosphate (UDP) glucuronyl transferase
(UGT) 1A3 and UGT1A4 are involved in the formation of the glucuronide M8. In human liver
microsomes, JNJ-53718678 did not show any significant inhibition of CYP1A2, CYP2C8,
CYP2C9, CYP2C19, and CYP2D6 mediated metabolism up to the highest JNJ-53718678
concentration tested (IC50 values >15 µM), while it was shown to be a moderate to strong inhibitor
of CYP3A4 (IC50 1-2 µM). It was also shown to be an inducer of CYP3A4 (≥1.5 µM) and
CYP2B6 (≥5 µM), but not of CYP1A2 (up to 10 µM) in human hepatocytes.
JNJ-53718678 was found to be a substrate, but not an inhibitor, for P-glycoprotein (P-gp; efflux
ratio 9.6) and breast cancer resistance protein (BCRP) in vitro. Based on the observed rapid but


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passive uptake of JNJ-53718678 by suspended human hepatocytes, in vivo clearance of
JNJ-53718678 will likely not be hepatic uptake-limited or sensitive to interactions with hepatic
uptake inhibitors. Further evidence was obtained in human hepatocytes in sandwich cultures
showing similar metabolites with similar relative abundances present in intracellular and bile
canalicular compartments with a low fraction residing in bile canaliculi. In vitro, JNJ-53718678
inhibits organic-anion-transporting polypeptide (OATP)1A2 (IC50 0.6 µM), OATP1B1
(IC50 3.5 µM), organic anion transporter (OAT)3 (IC50 4.2 µM), organic cation transporter (OCT)1
(IC50 3.7 µM), OCT2 (IC50 2.1 µM), but not OAT1 up to 9.6 µM, not OATP1B3 up to 12 µM and
not OATP2B1 up to 10 µM. For multidrug and toxin extrusion (MATE)1 the IC50 was >8.5 µM
and for MATE2-K the IC50 was 8.5 µM. JNJ-53718678 is not a substrate for OATP1A2 and
OATP2B1 up to 15 µM.
Toxicology
Single JNJ-53718678 doses up to 1,500 mg/kg (maximum feasible dose) in rats, up to 150 mg/kg
in dogs and of 50 mg/kg in minipigs were well tolerated. At the highest dose in rats excessive
salivation was seen, while in dogs vomiting and excessive salivation were observed at all doses.
No signs were present in minipigs.
The main findings after giving rats repeated JNJ-53718678 doses for 5 days of 750 mg/kg/day or
for 1 month of 75 and 500 mg/kg/day were rodent-specific adaptive changes (enzyme induction)
in liver, thyroid, pituitary gland, and/or adrenal gland, sometimes accompanied by changes in
serum parameters such as cholesterol, γ-glutamyltransferase (GGT) and protein levels. In addition,
in the 1-month study, dose-related salivation was noted at all doses (25-500 mg/kg/day). Minimal
effects considered non-adverse, related to fibrinogen (decrease) and thrombocytes (increase) were
present from 75 mg/kg/day onwards, and functional coagulation parameters (prothrombin time
[PT] and activated partial thromboplastin time [aPTT]) were prolonged at 500 mg/kg/day, without
increased propensity for bleeding. All changes except for some parameters in females dosed at
500 mg/kg/day reverted to normal. The no observed adverse effect level (NOAEL) was set at
75 mg/kg JNJ-53718678 per day. At this dose, mean Cmax  and AUC0 24h  values for males were
3,240 ng/mL and 11,600 ng.h/mL and for females were 9,240 ng/mL and 52,600 ng.h/mL,
respectively.
JNJ-53718678 doses up to 250 mg/kg/day during 2 weeks given to dogs, resulted in dose-related
vomiting, decreased food intake and salivation at all doses, leading to body weight (BW) loss from
the mid dose (75 mg/kg/day) onwards, and ultimately emaciation in some animals. Small stomach
erosions as a consequence of frequent vomiting were noted at the high dose (250 mg/kg/day). At
ophthalmic examination, miosis was seen in dogs given 250 mg/kg/day. Several dogs dosed at
250 mg/kg/day showed minor to overt increases in liver enzymes (alanine aminotransferase and
aspartate aminotransferase [AST]), which were accompanied by hepatocellular single cell necrosis
in 1 dog. Recovery was evident after 1 month, except for food consumption (FC) in females. The
NOAEL was set at 25 mg/kg/day. At the NOAEL, the mean Cmax  and AUC values of
JNJ-53718678 for males were 4,270 ng/mL and 32,300 ng.h/mL and for females were
3,920 ng/mL and 29,800 ng.h/mL, respectively. Target systems for toxicity are the liver and the
gastrointestinal system.


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A 2-day repeated dose study was conducted in minipigs at doses of 0, 50, 150, and 300 mg/kg/day.
The highest dose was considered above the maximum tolerated dose (MTD) as animals showed
continuous BW loss as a result of decreased FC, which was likely related to the ulceration/necrosis
of the non-glandular stomach. Other findings at this dose level were extensive vomiting, marked
changes in bilirubin which correlated histologically with icterus and cholestasis in the bile ducts
and caniculi in 1 animal. In addition, the animals presented increased bilirubin, aspartate
aminotransferase (AST) and decreased albumin. Red blood cell (RBC) parameters and platelets
were decreased while reticulocytes were increased. Changes in white blood cell subsets and
increased globulin were indicative of an acute inflammatory response. Plasma exposures were high
and did not decline within 72 hours after the second dose was given. Cmax  increased after the
second dose, indicating accumulation after repeated dosing. At this dose the mean Cmax  and
AUC0 24h values after the second dose were 28,100 ng/mL and 622,000 ng.h/mL, respectively. The
animals were sacrificed 1 week after the start of dosing. At the 150-mg/kg/day dose, changes in
bilirubin were obvious and short-lasting, BW loss in relation with decreased food consumption
(FC) was noted. At this dose, almost all changes were reversible. The 50-mg/kg/day dose was well
tolerated with some minor non-adverse changes in clinical pathology. Target organs after dosing
twice up to 300 mg/kg/day were the stomach, the intestinal tract, and the hepatobiliary system.
Oral administration of JNJ-53718678 in minipigs for 2 weeks was well tolerated and without
mortality up to the highest dose of 25 mg/kg/day. Higher BW gain values and minor hematology
and serum chemistry changes were observed, and no target organs were identified after repeated
dosing. High, plateau-like exposure and increasing exposure upon repeated dosing (versus single
dosing) was seen from the mid dose (ie, 10 mg/kg/day) onwards. After 2 weeks of repeated dosing
at 25 mg/kg/day, the mean Cmax  and AUC0 24h values were 4,710 ng/mL and 87,200 ng.h/mL,
respectively. In minipigs dosed for 28 days at the 25 mg/kg/day in a GLP study, findings were
minimal or adaptive in nature in some animals (increased reticulocyte count and hematopoiesis).
Other animals dosed at 25 mg/kg showed exposures overlapping with those observed in animals
of the high dose group that started at a dose of 50 mg/kg/day and were reduced to 35 mg/kg/day
(ie, the 50/35 mg/kg/day dose group). Target organ systems in the 25 and 50/35 mg/kg/day dose
groups were primarily circulating white and red blood cells, leading to hemosiderin deposition in
the liver and adaptive changes in hematopoietic organs (bone marrow [BM], spleen). The effects
on white and red blood cells in animals dosed at 50/35 mg/kg/day after a 28-day dosing-free period
showed signs of ongoing recovery, which was not the case for the liver pigment deposition in
females. The No Observed Effect Level (NOEL) was 10 mg/kg/day with mean Cmax  and AUC
values for male minipigs of 1,510 ng/mL and 21,200 ng.h/mL, and for female minipigs of
1,750 ng/mL and 31,500 ng.h/mL, respectively.
In the first pilot juvenile study in rats, in which pups aged PND1 or PND8 were dosed orally with
JNJ-53718678 up to 200 mg/kg/day for a maximum of 3 weeks, no test article-related mortality or
clinical signs were noted. A transient effect on BW gain was observed after the first dose on PND1
only, without showing a dose relationship. In a second pilot juvenile study in rats, in which pups
aged PND4 were dosed orally with JNJ-53718678 at 300 and 400 mg/kg/day for 7 days, liquid
feces, urogenital erythema, and decreased mean BW gains were observed.


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In the GLP juvenile study in rats, doses of 50 up to 400 mg/kg/day were given for 4 weeks from
PND4 onwards. Excessive salivation (all doses) and a soft distended abdomen were observed, as
well as periodically slightly lower BW gain associated with lowered FC from 150 mg/kg/day
onwards. Some minor changes were observed in serum parameters (triglycerides [all doses],
cholesterol [400 mg/kg/day] and albumin [400 mg/kg/day]). Test item-related histologic findings
comprised of centrilobular hepatocellular hypertrophy from 150 mg/kg/day onwards with
hepatocellular cytoplasmic vacuolation and thyroid follicular hypertrophy at 400 mg/kg/day. A
higher incidence and severity of papillary  mineralization was seen in the kidneys in all
JNJ-53718678 treated groups. None of the findings described above were considered adverse and
all findings were (almost) fully recovered (except triglyceride levels in high dose males) by the
end of the recovery period. Therefore, the NOAEL was set at 400 mg/kg/day. Corresponding Cmax
and AUC0 24h values on Day 0 (PND4) were 28,800 ng/mL and 259,000 ng.h/mL for males and
23,700 ng/mL and 330,000 ng.h/mL for females, respectively. Corresponding Cmax  and AUC0 8h
values on Day 24 (PND28) were 26,800 ng/mL and 170,000 ng.h/mL for males and 31,300 ng/mL
and 171,000 ng.h/mL for females, respectively.
In the pilot juvenile study in dogs, in which puppies aged PND1 were dosed orally with
JNJ-53718678 at 10 up to 75 mg/kg/day during 4 weeks, JNJ-53718678 was well tolerated without
adverse effects. No organ weight changes, gross observations or histological changes were
observed.
In the pilot juvenile study in minipigs, piglets were dosed orally from PND1 onwards with
JNJ-53718678 at 10 up to 75 mg/kg/day for up to 4 weeks. The 75-mg/kg/day dose was
administered to 1 animal and considered to be above the MTD, as the animal was sacrificed, after
showing a poor clinical condition resulting from vomiting. A relationship with the test article
cannot be entirely excluded. Dosing up to 50 mg/kg/day resulted in slightly to overtly lower BW
gains (all doses), and low RBC parameters and increased reticulocyte levels with high total
bilirubin concentrations (from 25 mg/kg/day onwards) as main findings. In  addition, at
50 mg/kg/day slightly increased fibrinogen levels were noted. At 75 mg/kg/day, higher total (direct
and indirect) bilirubin levels and a higher urea concentration were measured. An increase in
extramedullary hematopoiesis in spleen and liver, as well as starry-sky appearance of the splenic
red pulp and BM (from 10 mg/kg/day onwards), lower BM cellularity (at 50 mg/kg/day) and
thymic atrophy (from 25 mg/kg/day onwards) were observed at histopathology.
In the GLP juvenile study in minipigs, doses of 5 up to 25 mg/kg/day were administered from
PND1 onwards for 5 weeks. A dose of 25 mg/kg/day was not well tolerated, and resulted in gastric
ulceration and inflammation, low RBC parameters (RBC count, hemoglobin concentration and
packed cell volume) with reticulocyte response and increased (extramedullary) hematopoiesis,
increased bilirubin levels (both direct and indirect), decreased fibrinogen levels, and BW loss upon
weaning. These findings were (mostly) reversible at the end of the 4-week recovery period. A
minimal to slight, non-adverse increase in tingible body macrophages was noted in the BM of
females dosed at 10 mg/kg/day. The NOAEL in this study was set at 10 mg/kg/day. Corresponding
Cmax  and AUC0 24h  values (PND35) were 4,870 ng/mL and 77,300 ng.h/mL for males and
4,180 ng/mL and 73,300 ng.h/mL for females, respectively.


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JNJ-53718678 did not show any genotoxic potential in a bacterial reverse mutation test, and in in
vitro and in vivo micronucleus tests. Furthermore, it is not irritating to the eye, is not skin
sensitizing and is not phototoxic in vitro. JNJ-53718678 was classified as moderately cytotoxic in
a high content screen assay. JNJ-53718678 did not induce mitochondrial toxicity.
When JNJ-53718678 was spiked with 5% of JNJ-65101335, a potential degradant, the in vitro
micronucleus test in TK6 cells was negative. In the 1-month toxicity study in rats, dosing
JNJ-53718678 up to 150 mg/kg/day with or without 5% of JNJ-65101335 was well tolerated, and
results were similar to previous studies in the rat. No additional toxicity was observed due to
JNJ-65101335.
Clinical Studies
Human Pharmacokinetics and Product Metabolism
Single Dose
In the single-dose escalation (SDE) part of Study 53718678RSV1001, mean Cmax  of
JNJ-53718678 increased proportionally with dose after administration of JNJ-53718678 doses
between 25 mg and 1,000 mg under fasted conditions. Mean AUC from time of administration
extrapolated to infinity  (AUC0 ∞) of JNJ-53718678 increased slightly more than
dose-proportionally with increasing JNJ-53718678 dose from 25 mg to 1,000 mg. Median time to
reach Cmax  (tmax) was 1.00 h, except for the 1,000-mg dose group, in which it was 2.50 h. 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 JNJ-53718678 are similar between Caucasian and
Japanese subjects.
In Study 53718678RSV1009, the effect of JNJ-53718678 on the cardiac repolarization interval in
healthy adult subjects 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 JNJ-53718678 and QT/QTc
interval changes extracted from Holter monitor electrocardiogram (ECG) data. Based on this
analysis, an important potential risk of QT interval prolongation was identified for JNJ-53718678.
The model-predicted mean individual-corrected QT interval (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) JNJ-53718678 was 4.8 ms (4.2; 5.3 ms) and
20.3 ms (18.2; 22.3 ms), respectively. The highest Cmax  at the effect compartment following a
single dose associated with an upper limit of the 90% CI for ΔΔQTcI <10 ms was 4,350 ng/mL,
which corresponds with approximately a single dose of 1,000 mg in an adult. For more details on
the analysis, refer to the IB Addendum.16 A change to a twice daily (bid) dosing regimen (see
Section 6) and several other mitigation measures to safeguard the subjects (see Section 1.2.5) have
been implemented.


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Multiple Dose
Adult Population
In the multiple-dose escalation (MDE) part of Study 53718678RSV1001 in adult subjects under
fed conditions, predose plasma concentrations (Ctrough) reachedsteadystate after 1 day of treatment
with JNJ-53718678. On Day 8, JNJ-53718678 Cmax  and AUC0 24h  increased dose-proportionally
with increasing JNJ-53718678 dose from 250 mg every 24 hours (q24h) to 500 mg q24h.
Fluctuation was lower for the 250 mg twice daily (bid) regimen compared with the 500 mg once
daily (qd) regimen. The total amount of JNJ-53718678 excreted in urine over the dosing interval
at steady state was low, and similar between dose regimens.
In Study 53718678RSV2001 in adult subjects, the PK profile of JNJ-53718678 at multiple doses
of 75 mg, 200 mg, and 500 mg qd for 7 days was evaluated in healthy adult subjects 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 JNJ-53718678.
Interim analysis results from Study 53718678RSV2004 in RSV-infected adult patients
demonstrate that the population (pop)PK model provides an adequate description of most of the
data, however moderate variability existed with exposures greater than expected (~25%) based on
healthy volunteer data. The mean (standard deviation [SD]) Day 7 AUC24h  and Ctrough  following
administration of 500 mg JNJ-53718678 in this study (N 16) were 38,800 (16,600) ng.hr/mL and
698 (546) ng/mL, respectively, compared to 26,520 (7,520) ng.hr/mL and 334 (197) ng/mL,
respectively, observed in Study 53718678RSV2001 (N 17).
Pediatric Population
A popPK model for JNJ-53718678 has been developed using data from Study 53718678RSV1001
in healthy adults and data from Study 53718678RSV1005 in RSV-infected pediatric patients.
Using this popPK model, the JNJ-53718678 PK parameters AUC0 24h, Cmin, and Cmax  were
simulated for Days 1, 3, and 7. At the highest doses of 5, 6, and 9 mg/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 JNJ-53718678 qd in adults.
Food Interaction
In Study 53718678RSV1001, mean Cmax  of JNJ-53718678 was approximately 35% lower and
median tmax increased from 1 h to 3.5 h when JNJ-53718678 was administeredunder fed conditions
compared with fasted conditions. Mean AUC0 of JNJ-53718678 was slightly lower (93%) when
JNJ-53718678 was administered under fed conditions compared with fasted conditions. Therefore,
JNJ-53718678 can be taken with or without food.


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Bioavailability of the JNJ-53718678 oral suspension
The interim PK results from the study part evaluating the oral suspension in
Study 53718678RSV1007 indicated similar bioavailability of the oral suspension compared to the
oral solution formulation, with a relative bioavailability of 109% (Cmax) and 104% (AUC). Mean
Cmax  of JNJ-53718678 was 35% lower when the oral suspension was administered under fed
conditions compared to fasted conditions. The mean fed/fasted ratio was 95% for AUC0 .
Metabolite Profile
Results from the mass balance-study 53718678RSV1008 demonstrated that JNJ-53718678 was
the major metabolite 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 JNJ-53718678 and its metabolites was determined in plasma of healthy
volunteers in Study 53718678RSV1001, similar results were obtained: JNJ-53718678 was the
major 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 JNJ-53718678 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,
JNJ-53718678 is a weak inhibitor and a weak inducer of CYP3A4. JNJ-53718678 had no clinically
significant effect on CYP2C9 and CYP1A2. Single and multiple doses of JNJ-53718678 reduced
the plasma exposure of fexofenadine. The observed decrease in exposure of fexofenadine after
coadministration of a single dose of JNJ-53718678 is due to the inhibition of OATP1A2, an uptake
transporter located in the gut; further reduction of the fexofenadine exposure after repeated dosing
of JNJ-53718678, was likely due to induction of P-gP.
In clinical Study 53718678RSV1006, JNJ-53718678 was coadministered with itraconazole (a
strong CYP3A4 and P-gP inhibitor) and with rifampicin (an inducer of CYP3A4, UGT, and P-gP,
and an inhibitor of OATP). AUC0  of JNJ-53718678 increased approximately 3-fold upon
coadministration with itraconazole 200 mg qd. After coadministration of JNJ-53718678 with a
single dose of rifampicin, no significant change in the total exposure of JNJ-53718678 was
observed, suggesting the OATP transporter is not involved in the disposition of JNJ-53718678.


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However, repeated administration of rifampicin 600 mg qd decreased the exposure of
JNJ-53718678, primarily due to induction of CYP3A4.
Efficacy
Adult Population
In Study 53718678RSV2001 in healthy adult subjects inoculated with RSV-A Memphis 37b virus,
mean and median RSV viral load AUC from baseline until discharge were lower for all
JNJ-53718678 dosing groups (75 mg qd, 200 mg qd, or 500 mg qd JNJ-53718678 for 7 days) as
compared to the placebo group with a large variability observed in each of the JNJ-53718678
dosing groups as well as in the placebo group. No clear dose-response relationship could be
observed. This was paralleled with lower clinical symptom scores and mucus production for the
JNJ-53718678 dosing groups as compared to the placebo group. Hence, antiviral proof-of-concept
for JNJ-53718678 has been established.
Pediatric Population
In Study 53718678RSV1005 in pediatric subjects hospitalized due to RSV-infection, a trend
towards an early antiviral effect of JNJ-53718678 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, 1 of
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 subjects
who had received JNJ-53718678 and those who had received placebo in this limited dataset. No
dose-response relationship was observed across the JNJ-53718678 dose levels.
Safety and Tolerability
Adult Population
Based on combined safety data from studies 53718678RSV1001, 53718678RSV1002,
53718678RSV1004, and 53718678RSV2001 in adult healthy volunteers receiving the oral
solution, no deaths or other serious adverse events (AEs) were reported; 4 subjects discontinued
study treatment due to an AE. Among subjects who received at least 1 dose of JNJ-53718678, 70%
experienced an AE as compared to 46.7% of all subjects who received placebo. All but 1 of the
treatment-emergent AEs reported during these studies were either Grade 1 or Grade 2 in severity;
1 subject who received placebo 
was reported with a Grade 3 headache in
Study 53718678RSV1001. Adverse events observed more frequently (difference in incidence of
≥5%) in subjects who had received at least 1 dose of JNJ-53718678 compared to subjects who
received placebo included diarrhea (20.8% vs 11.1%), dysgeusia (10.8% vs 0.0%), epistaxis
(7.5% vs 0.0%), fatigue (6.7% vs 0.0%), abdominal discomfort (5.0% vs 0.0%), and hot flush
(5.0% vs 0.0%). In general, none of the reported AEs occurred consistently across different studies
and most occurred at a low incidence and low severity. Dysgeusia was frequently reported in
Study 53718678RSV1001 in subjects receiving JNJ-53718678 and in none of the subjects of the
placebo group and was related to the bitter taste of the oral JNJ-53718678 solution. This


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observation led to the initiation of Study 53718678RSV1003 to select an optimized taste of this
formulation for future studies. The reported AEs of diarrhea may be explained by the presence of
2-Hydroxypropyl-beta-cyclodextrin (HP-β-CD) as an excipient in the JNJ-53718678 and placebo
oral formulation, which has been correlated with increased incidences of diarrhea as the main AE.
The observed incidence of epistaxis is consistent with the incidences observed in other RSV
challenge studies. Hot flush was only reported in the MDE part of Study 53718678RSV1001 and
no dose-related incidence was observed.
The incidences of graded and non-graded laboratory abnormalities were generally low in these
studies. All graded laboratory abnormalities were either Grade 1 or Grade 2. Graded and non-
graded laboratory abnormalities observed more frequently in subjects who had received at least
1 dose of JNJ-53718678 compared to subjects who received only placebo (difference in incidence
of ≥5%) included prothrombin activity above normal (non-graded; 72.2% vs 39.1%),
triacylglycerol lipase above normal (non-graded; 19.4% vs 13.0%), increased cholesterol (graded:
15.0% vs 8.9%), and eosinophil/leukocyte ratio below normal (non-graded; 7.5% vs 2.2%). Of
note, the incidences of the graded laboratory abnormality of increased PT and aPTT were similar
between subjects receiving JNJ-53718678 and those receiving placebo (15.8% vs 17.8% and 8.3%
vs 11.1%, respectively).
Changes in heart rate, blood pressure, or respiratory rate were observed in some subjects and were
considered generally clinically insignificant. These were either Grade 1 or Grade 2 in severity,
except for 1 subject from Study 53718678RSV1001 who received 1,000 mg JNJ-53718678 and in
whom a Grade 3 increase in respiratory rate was reported. Considering all of the safety data from
clinical studies, a consistently greater incidence of any of the observed abnormalities in vital signs
parameters was not apparent in subjects receiving JNJ-53718678 compared to subjects receiving
placebo.
No prolongations of the QTcF were reported. Changes in electrocardiographic (ECG) parameters
were few and generally considered clinically insignificant.
Safety results from Study 53718678RSV1006 and Study 53718678RSV1008 were generally
consistent with those from above mentioned studies.
Overall, during these clinical studies in healthy adults or adult subjects inoculated with RSV,
JNJ-53718678 at single doses up to 1,000 mg JNJ-53718678 and multiple doses up to 500 mg
JNJ-53718678 once daily and 250 mg JNJ-53718678 twice daily, were generally safe and well
tolerated. No relation was noted between the incidences of AEs and laboratory/vital signs/ECG
abnormalities and the dose level and/or dose regimen of JNJ-53718678. These studies did not
identify any safety signal for JNJ-53718678.
In subjects (n 12) from the study part evaluating the oral suspension in Study 53718678RSV1007,
10 subjects (76.9%) were reported with at least 1 AE. The incidence of AEs was similar between
the different treatments: 5 (41.7%) subjects receiving the oral solution and 6 (50%) and 4 (30.8%)
subjects receiving the oral suspension under fasted and fed conditions, respectively, were reported
with at least 1 AE. All AEs were either Grade 1 or Grade 2 in severity. The most frequently


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reported AEs (reported in ≥3 subjects) were diarrhea (3 subjects [25.0%] receiving the
JNJ-53718678 oral solution, 1 subject [8.3%] receiving the suspension under fasted conditions,
and 1 subject [7.7%] receiving the suspension under fed conditions) and oropharyngeal pain (1
subject [8.3%] receiving the JNJ-53718678 oral solution and 2 subjects [16.7%] receiving the
suspension under fasted conditions).
The incidences of graded and non-graded laboratory abnormalities were generally low. All graded
laboratory abnormalities were Grade 1 or Grade 2 in severity. Most laboratory abnormalities were
considered clinically insignificant. One subject who received the JNJ-53718678 suspension under
fasted conditions and 1 other subject who received the JNJ-53718678 suspension under fed
conditions had triglyceride plasma concentrations above normal which were reported as AEs of
blood triglycerides increased (Grade 1 and Grade 2, respectively), which were both considered by
the investigator to be doubtfully related to study drug.
Abnormalities in vital signs and ECG-parameters were observed in few subjects (2 subjects at
most) and were considered clinically insignificant. No QTcF prolongation was observed.
Study 53718678RSV1009 evaluated the effect of JNJ-53718678 on the cardiac repolarization
interval in healthy adult subjects. Results from the completed Part 1 (dose escalation) of
Study 53718678RSV1009 demonstrated that a single dose of JNJ-53718678 was generally safe
and well tolerated in these healthy adult subjects. No clinically significant safety findings were
identified in any subjects dosed under fasted conditions with JNJ-53718678, including the
supratherapeutic dose of 4,500 mg. In addition, there were no cardiac AEs and no clinically
significant changes in vital signs, ECGs, or laboratory abnormalities. No deaths, SAEs, AEs of at
least Grade 3, or AEs leading to discontinuation of study treatment were observed. Among subjects
who received 2,000 mg, 3,000 mg, and 4,500 mg doses of JNJ-53718678, 50.0%, 83.3%, and
83.3%, respectively, experienced at least 1 AE as compared to 55.6% of subjects who received
placebo. Diarrhea, nausea, and headache were more frequently observed in subjects who received
JNJ-53718678 compared to subjects who received placebo.
Results from Part 2 (TQT part) of Study 53718678RSV1009 demonstrated that JNJ-53718678 was
generally safe and well tolerated in healthy adult subjects. No SAEs, AEs of at least Grade 3, or
deaths were reported during Part 2 of the study. No clinically significant changes in vital signs or
laboratory abnormalities were reported. An AE leading to early study termination was reported for
3 subjects:
 
One subject was reported with prolonged QTcF (>450 to ≤480 ms), based on findings from
the safety ECG, during JNJ-53718678 (4,500 mg) treatment period, which was considered
moderate in severity and probably related to the study agent. The AE resolved the same day.
 
One subject was reported with the AEs vomiting, nausea, and headache during the 4,500 mg
JNJ-53718678 treatment period. The AEs vomiting and nausea were considered mild in
severity and possibly related to the study agent. The AE headache was considered mild in
severity and doubtfully related to the study agent. A second event of vomiting was reported
on the same day and was considered moderate in severity and possibly related to the study
agent. These AEs resolved the same day.


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 
One subject was reported with a skin reaction during the 400 mg moxifloxacin treatment
period. This AE was considered mild in severity and possibly related to the study agent. The
AE resolved the same day.
At least 1 AE was reported in 12 (52.2%) subjects after receiving 500 mg JNJ-53718678,
22 (88.0%) subjects after receiving 4,500 mg JNJ-53718678, 9 (39.1%) subjects after receiving
placebo, and 12 (50.0%) subjects after receiving 400 mg moxifloxacin. During the treatment
phase, diarrhea, nausea, and headache were more frequently observed in subjects who received
4,500 mg of JNJ-53718678 compared to subjects who received 500 mg of JNJ-53718678, placebo,
or 400 mg of moxifloxacin.
Based on exposure-response analysis, an important potential risk of QT interval prolongation was
identified for JNJ-53718678 (see above). For more details on the analysis, refer to the IB
Addendum.16 A change to a bid dosing regimen (see Section 6) and several other mitigation
measures to safeguard the subjects (see Section 1.2.5) have been implemented.
Mean changes in safety ECG parameters were generally minor, and none of them were considered
clinically relevant except for 1 event of prolonged QTcF in 1 subject, which was reported as AE
and led to study discontinuation (see above). Following moxifloxacin treatment, mean changes in
ECG parameters were consistent with the use of moxifloxacin and were not considered clinically
relevant.
 
Two subjects (4,500 mg JNJ-53718678 and placebo) had an abnormal QTcF value between
450 and 480 ms, leading to early study discontinuation for 1 subject due to AE.
 
Six subjects had an abnormal QTcF change from baseline between 30 and 60 ms (2 [8.0%]
after receiving 4,500 mg JNJ-53718678, 1 [4.3%] after receiving placebo, and 3 [12.5%] after
receiving 400 mg moxifloxacin) but the values remained within normal range. None of the
subjects had an abnormal QTcF change from baseline >60 ms.
Interim analysis results (N 67) from Study 53718678RSV2004 demonstrated that JNJ-53718678
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
Study 53718678RSV2004. Overall, 55.6% of subjects experienced at least 1 treatment-emergent
AE (TEAE), of which diarrhea was the most frequently reported TEAE. The overall incidence of
TEAEs was smaller in the JNJ-53718678 500 mg group (36.4%) than in the placebo group
(59.1%). The highest incidence rate of TEAEs was observed in JNJ-53718678 80 mg group
(73.9%). The incidence of TEAEs leading to study medication discontinuation was higher in
JNJ-53718678 500 mg group (13.6%) than in JNJ-53718678 80 mg group (8.7%), or the placebo
group (4.5%). There were 2 subjects (in JNJ-53718678 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.


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Overall, the oral suspension formulation was generally safe and well tolerated in healthy adult
subjects.
Pediatric Population
In Study 53718678RSV1005 in pediatric subjects receiving the oral solution, no deaths, Grade 4
AEs, or AEs leading to study discontinuation or permanent stop of study drug were reported. Four
serious adverse event (SAE)s were reported, 2 in the JNJ-53718678 (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 drug. The majority of subjects were reported with at least 1 AE, at similar
incidence rates in both treatment arms (28/37 subjects [75.7%] in the JNJ-53718678 (combined)
treatment group vs 6/7 subjects [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 JNJ-53718678 [combined] and placebo group, both were also reported
as SAEs). By body system or organ class, most AEs were related to gastrointestinal disorders and
infections and infestations in the JNJ-53718678 (combined) and placebo group. By dictionary-
derived term, most frequently reported in subjects receiving JNJ-53718678 (reported in ≥10% of
subjects) were vomiting, upper respiratory tract infection, and feces soft. Adverse events reported
in ≥10%  (ie, ≥4 subjects) of subjects receiving JNJ-53718678 that were considered by the
investigator to be at least possibly related to study drug were feces soft (18.9%) and vomiting
(21.6%).
Laboratory abnormalities were infrequently reported and of low severity (maximal Division of
Microbiology and Infectious Diseases [DMID] Grade 2). None were observed more frequently
(difference in incidence of≥5%) in the JNJ-53718678 (combined) group compared to the placebo
group. Six AEs related to (non-)graded laboratory abnormalities were reported during the study,
of which 2 were considered to be at least possibly related to study drug by the investigator (Grade 2
anemia and Grade 2 leukocytosis).
No clinically relevant differences in incidence rates of vital signs abnormalities were observed
between JNJ-53718678 and placebo. One subject (placebo) was reported with the Grade 1 AE of
tachycardia considered not related to study drug by the investigator. ECG abnormalities were
scarce and generally not considered clinically relevant. One subject (active treatment) was reported
during the follow-up phase (1 day after end of treatment) with a Grade 1 AE of QRS axis abnormal
considered to be possibly related to study drug by the investigator. No QTcF prolongation was
reported.
Interim analysis of Study 53718678RSV2002 confirmed the previously established safety profile
of JNJ-53718678. No changes from baseline in QTcF or QT interval corrected for heart rate
according to Bazett's formula (QTcB) of >60 ms were reported.
Overall, treatment with JNJ-53718678 was generally safe and well tolerated in pediatric subjects
and no safety signals arose in pediatric subjects compared to the previously established safety
profile in adults.


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1.2. 
Benefit-risk Evaluations
1.2.1. 
Known Benefits
JNJ-53718678 at daily doses of 75, 200 and 500 mg given for 7 days has shown an antiviral effect
and reduced the signs and symptoms of RSV infection in healthy adults in an RSV human
challenge model. Despite a limited data set, in particular the small placebo group, a trend towards
an early antiviral effect of JNJ-53718678 was observed for viral load change from baseline and
for viral load AUC in the pediatric population based on data from Study 53718678RSV1005
(Section 1.1). However, the clinical benefit of this compound remains to be established.
1.2.2. 
Potential Benefits
Subjects participating in this study might have a benefit regarding the clinical course of their RSV
infection. Treatment with JNJ-53718678 may reduce the severity and duration of RSV signs and
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
subjects’ return to pre-RSV health status. The unequal randomization (2:1 active: placebo in each
age group) affords the majority of subjects the potential benefit of JNJ-53718678 treatment.
Results from the proposed study may be useful in developing a new antiviral therapy for RSV
infection.
1.2.3. 
Known Risks
As a formal adverse drug reaction analysis has not yet been conducted for JNJ-53718678, known
risks associated with JNJ-53718678 have not been identified.
1.2.4. 
Potential Risks
All therapies have the potential to cause adverse experiences.
During completed studies 53718678RSV1001, 53718678RSV1002, 53718678RSV1004,
53718678RSV1006, 53718678RSV1008, and 53718678RSV2001, a total of 190 subjects were
enrolled, of which 156 received at least 1 dose of JNJ-53718678 (oral solution) as single doses up
to 1,000 mg or multiple doses up to a total daily dose of 500 mg (as 500 mg qd or 250 mg twice
daily [bid]) for up to 13 days. Of those, 106 were healthy adult subjects and 50 were healthy adult
subjects who were inoculated with RSV-A Memphis 37b virus. In Study 53718678RSV1003,
12 subjects were enrolled but they were only to taste and not to swallow the oral solutions of
JNJ-53718678.
In the ongoing Study 53718678RSV1007, several oral concept formulations are being evaluated
in separate study parts. In the study part evaluating the oral suspension, 12 subjects received the
JNJ-53718678 oral solution and the JNJ-53718678 oral suspension.
During Study 53718678RSV1005, 44 pediatric subjects hospitalized due to RSV-infection were
enrolled, of which 37 subjects received JNJ-53718678 (oral solution) and 7 received placebo.


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Please refer to Section 1.1 for details on the reported AEs and laboratory/ECG abnormalities in
the studies conducted to date.
Based upon the limited clinical data available and considering the early stage of development of
JNJ-53718678, no AEs or clinically significant (non-)graded laboratory abnormalities,
abnormalities in vital signs parameters, ECG abnormalities, or physical examination findings
indicative of a safety concern have been identified.
Based upon the limited 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.The evaluation of JNJ-53718678 antiviral activity requires nasal swabbing.
However, this is a minimally invasive assessment that at most results in some short-term
discomfort for the subject and is usually well tolerated, though occasionally nose bleeding can
occur.
Study procedures such as blood sampling carry a potential risk (eg, pain, discomfort, hematoma)
to the subject. Therefore, minimal volumes of blood (by venipuncture, heel stick or by finger 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. Other
study assessments are not invasive and investigators are encouraged to minimize the stress and
discomfort to subjects while performing these assessments.
Study treatment will be provided in addition to, not in replacement of, standard-of-care supportive
and symptomatic therapy.
Review of data of the TQT Study 53718678RSV1009 has identified a new important potential risk
of QT prolongation for JNJ-53718678 (see Section 1.1 and the IB Addendum16 for more
information). Therefore, a change in dose regimen (see Section 6) and several other measures to
safeguard the subjects (see Section 1.2.5) 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 subjects. 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
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
JNJ-53718678 on cardiac repolarization is not of regulatory concern, but at doses 1,000 mg an
increase of placebo-corrected change from baseline for the ΔΔQTcI above the threshold of 10 ms
can be expected (Section 1.1).
Available clinical safety data do not indicate any safety signal or concern with regards to the
cardiovascular system (Section 1.1).


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1.2.5. 
Overall Benefits/Risks
Currently the only available treatment for RSV is supportive care for infants and children requiring
hospitalization. Based on the available data and proposed safety measures, the overall risk/benefit
assessment for this study is acceptable for the following reasons:
 
Antiviral effect proof of concept was established in adult healthy volunteers challenged with
a laboratory strain of RSV (Study 53718678RSV2001) as well as in naturally RSV infected
pediatric subjects (Study 53718678RSV1005) (Section 1.1);
 
The completed studies to date identified no safety concerns and most observed AEs and
laboratory abnormalities were mild to moderate in severity and considered not related to
JNJ-53718678 by the investigator (Section 1.1);
 
No safety concerns were identified in the interim analysis of Study 53718678RSV2004 in
non-hospitalized adult participants infected with RSV (Section 1.1);
 
Available final data from the ongoing 53718678RSV1005 study in naturally RSV-infected
pediatric subjects >1 month to ≤24 months of age and from an interim analysis of Study
53718678RSV2002 in children ≥28 days and ≤3 years of age did not indicate safety concerns
(Section 1.1);
 
Several safety measures have been proposed to minimize potential risk to subjects, including:
 
Only subjects who meet all of the inclusion criteria and none of the exclusion criteria
(as specified in the protocol) will be allowed to participate in this study. The selection
criteria include adequate provisions to minimize the risk and protect the well-being of the
subjects in the study.
 
Utilization of study treatment discontinuation criteria and stopping criteria
(see Sections 10.2 and 10.3).
 
Subjects in Cohort 1 are to be hospitalized before treatment initiation allowing for
intensive monitoring of subjects at the beginning of the study, until discharge. After
discharge from the hospital, for the remainder of the study period, a close follow-up (see
Section 9.1.4) is planned with the same visit schedule as Cohort 2 outpatient subjects
(study visits on Day 3, Day 5, Day 8, Day 14, Day 21, and a telephone visit on Day 28,
when the subject completes the study).
 
Safety surveillance in this study will monitor standard safety parameters associated with
investigational drug development and safety topic of special interest of JNJ-53718678 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 subjects.
 
Utilization of result from diagnostic testing (swab) performed as part ofstandard of care.
 
The establishment of an IDMC to monitor data on a regular basis to ensure continuing
safety of the subjects enrolled in this 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


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additional stress as possible for the children 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 1.1,
TQT Study 53718678RSV1009), the following measures have been implemented to minimize
the potential risk to subjects:
 
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 6).
 
Specific cardiovascular and ECG-based criteria were established for eligibility
assessment (see Section 4.2).
 
Close monitoring of the use of concomitant medications will be conducted regularly.
Drugs that are moderate or strong CYP3A4 inhibitors and breast cancer resistance protein
(BCRP) inhibitors will be disallowed (see Section 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
abnormalities will be conducted as per the TIME AND EVENTS SCHEDULE.
Additional unscheduled visits/assessments 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 10.3).
 
Close monitoring ofhypokalemia and hypomagnesemia and corrective actions in case of
laboratory abnormalities for these analytes during the treatment period (see Section 9.3).
 
QT prolonging drugs will be disallowed during the treatment period (see Section 8).
 
Specific toxicity management for cardiac and ECG related events was established (see
Section 9.3.1).
1.3. 
Overall Rationale for the Study
This study will explore the antiviral activity, clinical outcomes, safety, tolerability, and PK/PD
relationships of high and low doses of JNJ-53718678 in children ≥28 days and ≤3 years of age
with acute respiratory tract infection due to RSV, in 2 cohorts ie, hospitalized (Cohort 1) and
outpatients (Cohort 2). The results of this study will enable selection of the dose and clinical
endpoints for subsequent Phase 3 studies.


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2. 
OBJECTIVES, ENDPOINTS, AND HYPOTHESIS
2.1. 
Objectives and Endpoints
2.1.1. 
Objectives
Primary Objective
The primary objective is to establish antiviral activity ofJNJ-53718678 as measured by RSV viral
load in nasal swab samples by a quantitative reverse transcription  polymerase chain reaction
(qRT-PCR) assay in children ≥28 days and ≤3 years of age with RSV disease.
Secondary Objectives
The secondary objectives are to evaluate in children ≥28 days and ≤3 years of age with RSV
disease:
 
the dose-response relationship for antiviral activity of JNJ-53718678
 
the impact of JNJ-53718678 on the clinical course of RSV infection
 
the safety and tolerability of JNJ-53718678 after repeated oral doses
 
the PK of JNJ-53718678 after repeated oral doses
 
medical resource utilization
 
the impact of baseline characteristics on antiviral activity and clinical course, including but
not limited to:
 
time of symptom onset (≤3 days vs >3 days before start of treatment)
 
patient population (hospitalized subjects vs outpatients)
 
baseline viral load
 
disease severity at baseline
 
the relationship between the PK and the PD (selected antiviral activity, clinical outcomes, and
safety parameters) after repeated dosing of JNJ-53718678
 
the emergence of mutations in the viral genome potentially associated with resistance to
JNJ-53718678
 
the acceptability and palatability of the JNJ-53718678 formulation
Exploratory Objectives
The exploratory objectives are to explore in children ≥28 days and ≤3 years of age with RSV
disease:
 
the impact of additional baseline characteristics on antiviral activity and clinical course,
including but not limited to:
 
RSV viral subtype and genotype
 
baseline neutrophil count


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 
the occurrence of complications associated with RSV per investigator assessment after
initiation of treatment
 
the need for antibiotics related to complications associated with RSV per investigator
assessment
 
the relationship between antiviral activity and clinical outcomes
 
the RSV viral load as measured by a qRT-PCR assay in nasopharyngeal and/or tracheal
aspirate samples in a subgroup of hospitalized subjects (Cohort 1 only) in which these samples
are obtained as part of their standard-of-care (SOC)
 
the RSV infectious virus load as assessed by quantitative culture of RSV (plaque assay) on
selected nasal swab samples (optional objective, pending feasibility of performing such an
assay)
2.1.2. 
Endpoints
Primary Endpoint
The primary efficacy endpoint is the RSV viral load area under the curve (AUC) from immediately
prior to first dose of study drug through Day 5 derived from the RSV viral load as measured by a
qRT-PCR assay in nasal swabs.
Secondary Endpoints
The secondary endpoints are:
 
virologic parameters derived from the RSV viral load as measured by a qRT-PCR assay in
nasal swabs including:
 
RSV viral load and change from baseline over time
 
RSV viral load AUC from immediately prior to first dose of study drug (baseline) through
Day 3, Day 8, and Day 14
 
time to undetectable RSV viral load
 
proportion of subjects with undetectable RSV viral load at each timepoint throughout the
study
 
clinical course related endpoints:
 
in hospitalized subjects and outpatients:
o 
following endpoints will be based on the Pediatric RSV Electronic Severity and
Outcome Rating System (PRESORS) assessed throughout the study by
parent(s)/caregiver(s) (parent[s]/caregiver[s] PRESORS) and by the investigator
(clinician PRESORS) during scheduled visits:
 duration and severity of signs and symptoms of RSV disease
 change from baseline in parent(s)/caregiver(s) PRESORS scores (worsening or
improvement)
 change from baseline in clinician PRESORS scores (worsening or improvement)


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 time to resolution (ie, to none or mild) of RSV symptoms
 time to improvement based on general questions on overall health
 proportion of subjects with improvement or worsening of RSV disease based on
general questions on overall health
 time to return to pre-RSV health as rated by the parent(s)/caregiver(s)
o 
respiratory rate, heart rate, body temperature, and peripheral capillary oxygen
saturation (SpO2) over time as measured by the investigator during scheduled visits.
Note: If the subject is enrolled in the substudy of Study 53718678RSV2002 (see
Section 3.1), the same parameters as assessed by the biosensor will be recorded from
the standard-of-care monitoring/assessments as part of the substudy assessments
(refer to the substudy Clinical Protocol for detailed information).
o 
body temperature as measured by the parent(s)/caregiver(s) and recorded in the
temperature log (Attachment 8) on the electronic device
o 
need for (re)hospitalization during treatment and follow-up
 
in hospitalized subjects only:
o 
time to age-adjusted normal values for otherwise healthy and to pre-RSV infection
status for subjects with (a) risk factor(s) for severe RSV disease, for heart rate,
respiratory rate, and/or blood oxygen level (ie, without requirement of supplemental
oxygen compared with pre-RSV infection status)
o 
time to discharge (from initial admission and from initiation of treatment)
o 
time to clinical stability, with clinical stability evaluated by the investigator (from
initial admission and from initiation of treatment)
o 
need for and duration of intensive care unit (ICU) stay; ‘need for ICU stay’ is defined
as follows:
 being admitted on the ICU (and ICU level of care is required)
 being admitted on the hospital ward, with or without supplemental oxygen, but
deemed to require ICU level of care (eg, not transferred to ICU due to bed
availability)
 requiring ICU level of care is defined by some specific conditions:
o acute or imminent respiratory failure
o treatment of complicated acid-base or electrolyte imbalances
o cardiogenic shock
o acute congestive heart failure
o hemodynamic instability
 having other conditions requiring specialized equipment and/or staff
competencies only available in the ICU
o 
need for and duration of supplemental oxygen (regardless of method used); need for
supplemental oxygen’ is defined by:


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 requiring invasive mechanical ventilation
 receiving any oxygen support requiring intubation or extracorporeal
oxygenation
 receiving invasive mechanical ventilation
 receiving supplemental oxygen through a face mask or nasal cannula and not
being able to sustain a blood oxygen saturation of ≥92% when breathing room
air for 15 minutes or less, tested once
o 
need for and duration  of noninvasive ventilator support (eg, continuous positive
airway pressure) and/or invasive ventilator support (eg, endotracheal-mechanical
ventilation)
o 
need for hydration and/or feeding by IV administration or nasogastric tube; need for
defined by <50% of normal oral intake
o 
time to clinical stability, defined as the time from initiation of study treatment until
the time at which the following criteria are met:
 return to age-adjusted normal values for otherwise healthy and pre-RSV
infection status for subjects with (a) risk factor(s) for severe RSV disease, for all
of the following signs/symptoms of RSV disease:
 
heart rate; AND
 
respiratory rate; AND
 
blood oxygen level
AND
 no more oxygen supplementation for otherwise healthy subjects and subjects
with (a) risk factor(s) for severe RSV disease
AND
 no more IV/nasogastric tube feeding/hydration in otherwise healthy subjects or
return to pre-RSV status of IV/nasogastric tube feeding/hydration in subjects
with (a) risk factor(s) for severe RSV disease
o 
time from initiation of study treatment until SpO2 ≥92% and SpO2 ≥95% on room air
among subjects who were not on supplemental oxygen prior to the onset of
respiratory symptoms
 
safety and tolerability, as assessed by adverse events (AEs), clinical laboratory testing,
electrocardiograms (ECGs), vital signs, throughout the study
 
PK parameters of JNJ-53718678, as determined by population PK (popPK) modeling
 
medical resource utilization
 
acceptability and palatability of the JNJ-53718678 formulation as assessed through a
questionnaire completed by parent(s)/caregiver(s) in the electronic device
 
sequence changes (post baseline) in the RSV F-gene, and other regions of the RSV genome
(at the discretion of the sponsor’s virologist), as compared with the baseline sequence


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Exploratory Endpoints
Exploratory endpoints include:
 
the occurrence of complications with onset after treatment initiation that are associated with
RSV per investigator assessment:
 
bacterial superinfections (eg, pneumonia, sinusitis, bronchitis, bacteremia of presumed
respiratory origin per investigator assessment)
 
otitis media, bronchiolitis, viral pneumonia
 
exacerbations of underlying pulmonary disease (eg, asthma, cystic fibrosis,
bronchopulmonary dysplasia)
 
exacerbations of underlying cardiovascular conditions
 
the use of antibiotics related to complications associated with RSV per investigator assessment
 
the RSV RNA viral load as measured by a qRT-PCR assay in nasopharyngeal and/or tracheal
aspirate samples in a subgroup of hospitalized subjects in which these samples are obtained
as part of their SOC
 
comparison of RSV RNA viral load as measured by a qRT-PCR assay in nasal swabs and
other samples (eg, nasopharyngeal and/or tracheal aspirate samples)
 
virologic parameters derived from the RSV viral load as measuredby quantitative viral culture
Refer to Section 9, Study Evaluations for evaluations related to endpoints.
2.2. 
Hypothesis
The primary hypothesis of this study is that JNJ-53718678 has antiviral activity against RSV (ie,
a decrease in RSV viral load AUC from immediately prior to first dose of study drug [baseline]
until Day 5), as assessed by a positive dose-response relationship of JNJ-53718678 compared to
placebo.
3. 
STUDY DESIGN AND RATIONALE
3.1. 
Overview of Study Design
This is a Phase 2 multicenter, double-blind, placebo-controlled, randomized study to evaluate the
antiviral activity, clinical outcomes, safety, tolerability, and PK/PD relationships of different oral
dose levels of JNJ-53718678 in children ≥28 days and ≤3 years of age with RSV disease
(hospitalized subjects [Cohort 1] or outpatients [Cohort2]).
Subjects with at least mild RSV disease will be enrolled (ie, at least one symptom of upper
respiratory tract infection, at least one symptom of lower respiratory tract infection, and at least
one systemic/general symptom; see Section 4.1). Eligible subjects can be otherwise healthy or
have (a) risk factor(s) for severe RSV disease (eg, prematurity at birth [only for subjects ≥3 months
of age at the time of consent] or having a comorbid condition eg, bronchopulmonary dysplasia,
congenital heart disease, other congenital diseases, Down syndrome, neuromuscular impairment,


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cystic fibrosis, or recurrent wheezing/asthma) (see Table 1). Subjects who are
immunocompromised are excluded.
Table 1: 
Risk Factors for Severe RSV Disease
Prematurity at birtha
Bronchopulmonary dysplasia
Congenital heart disease
Down syndrome
Neuromuscular impairment
Cystic fibrosis
Recurrent wheezingb
Asthma
Other congenital disease
a Only for subject ≥ 3 months of age at the time of consent
b Recurrent wheezing is defined as ≥3 episodes of wheezing dyspnea since birth
The total number of subjects is planned to be approximately 294 (approximately 144 in Cohort 1
and approximately 150 in Cohort 2; approximately 196 subjects receiving JNJ-53718678 and
approximately 98 subjects receiving placebo). The sample size of Cohort 2 may be re-estimated to
a maximum of 300 in Cohort 2 based upon results from the third interim analysis (see
Section 11.1.3).
Study participants will be identified when they are hospitalized or expected to be hospitalized
within 24 hours after presentation to the hospital (Cohort 1) or present for medical care as
outpatients (Cohort 2) with symptoms of an acute respiratory illness supporting a diagnosis of RSV
infection (eg, nasal congestion, rhinorrhea, pharyngitis, increased respiratory effort, abnormal
breathing sounds [wheezing, rales, or rhonchi], cyanosis, cough, apnea, fever, feeding difficulties,
dehydration). For newly enrolled subjects in Cohort 2 after Protocol Amendment 6, cough or
wheezing should be accompanied by at least one additional LRTI sign/symptom in order to be
eligible. In Cohort 1, a subcohort of 6 subjects >2 and ≤3 years will be included, who will follow
in general the same assessment schedule as for all subjects enrolled in Cohort 1, although with a
specific PK sampling schedule, assigned at randomization  (see Section 9.4.1). Of note, if the
subcohort is fully enrolled, additional subjects >2 and ≤3 years of age can be enrolled in Cohort 1
and will follow all Cohort 1 procedures.
Overall, for both cohorts, 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 28 [±3]. The total study duration
for each subject will be approximately 29 days (Screening included). A diagram of the study design
is provided in Figure 1.


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Figure 1: 
Schematic Overview of the Design of Study 53718678RSV2002
a 
In case of ongoing adverse event(s)
Note: Age group 1: ≥28 days and <3 months of age; Age group 2: ≥3 months and <6 months; Age group 3:
≥6 months and ≤3 years
Note: Prior to Protocol Amendment 4, the total daily dose was the same but the daily dosing
frequency was qd instead of bid.
Screening must be completed as soon as possible. During screening, a study-specific screening
sample (mid-turbinate swab) will be collected for the local diagnosis of RSV infection using a
preferably rapid polymerase chain reaction (PCR)- or other molecular-based diagnostic assay
(preferred) or a rapid-antigen-detection assay. Swabs collected per local SOC testing within
24 hours prior to start of screening may be used in determining study eligibility. If a
rapid-antigen-detection assay is used as part of SOC or study-specifically (with the main study
ICF or with the diagnostic ICF having been signed), the remainder of the screening sample used
for the RSV diagnostic testing should be sent to the central laboratory for additional virologic
analyses, as applicable.
A separate mid-turbinate swab will be collected immediately prior to the first dose for central
laboratory analyses to confirm RSV infection (and subtype), to determine the RSV viral load, to
perform viral sequencing, and to determine the presence of other viral or bacterial pathogens. If a
study-specific screening nasal mid-turbinate swab was collected within 8 hours prior to dosing,
the leftover of that sample can serve as the baseline sample and should be shipped to the central
laboratory, provided that the study-specific nasal mid-turbinate screening sample was stored
appropriately and has sufficient sample volume available (minimum 4 aliquots of 600 µL each).
Initially, only hospitalized subjects will be recruited (Cohort 1). After the first interim analyses, an
IDMC will review the interim data and will issue its recommendation to the sponsor, based on
which the Sponsor Committee will decide whether to initiate enrollment in Cohort 2, while
hospitalized subjects continue to be enrolled (see below).


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Randomization should occur within 24 hours after start of screening or within 48 hours after
collection of the SOC sample used for local RSV diagnosis, whichever comes first. Within each
cohort (including the subcohort of Cohort 1), eligible subjects will be randomized 1:1:1 to receive
either a low or a high dose of JNJ-53718678, or placebo. Those randomized to a placebo regimen
will be subsequently randomized in a 1:1 ratio to receive either low or high volume of placebo.
This results in an overall randomization scheme of 2:2:1:1 (low dose JNJ-53718678, high dose
JNJ-53718678, low volume placebo, high volume placebo). Within each cohort, except for the
subcohort, randomization will be stratified by time of symptom onset (≤3 days vs >3 days to
≤5 days before randomization) and by presence of risk factors for severe RSV disease (otherwise
healthy vs presence of [a] risk factor[s] for severe RSV disease as defined above) (see Table 1).
Subjects with symptom onset ≤3 days before randomization must account for a minimum of 45%
of all enrolled subjects in Cohorts 1 and 2 (ie, maximum 55% of subjects could be enrolled in the
>3 days to ≤5 days stratum). To guarantee the required balance between strata for the interim
analyses, enrollment in the >3 days to ≤5 days since symptom onset stratum might be temporarily
paused prior to an interim analysis and stopped prior to final analysis (see below). Stratum caps
and closures are managed separately for each cohort and consider the sample size of the respective
cohort for the interim analysis and the total sample size of each cohort for the final analysis.
Study drug administration should start as soon as possible, but no later than 4 hours after
randomization and within 5 days after symptom onset. For analysis purposes, the day of first study
drug intake will be considered Day 1. Dosing should preferably occur approximately at the same
time each day  for both intakes (AM and PM). For subjects who receive only 1 dose of
JNJ-53718678 or placebo PM on Day 1, dosing should continue through the morning (ie, AM) of
Day 8 so that all subjects receive 14 consecutive doses in total. 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. JNJ-53718678/placebo can be administered with/without food. The study drug
will be administered orally using a dosing syringe. For Cohort 1 and during hospitalization, the
study drug can also be administered through a nasogastric tube, if already in place. In this
document, both administration methods are referred to as “oral dosing”, unless specified otherwise.
Note: Prior to Protocol Amendment 4, the total daily dose was the same but the daily dosing
frequency was qd instead of bid.
For dosing purposes, 3 age groups are defined depending on the subject’s age at the time of
consent:
 
Age group 1: ≥28 days and <3 months of age (28 to 91 days of age, extremes included, for
IWRS purposes)
 
Age group 2: ≥3 months and <6 months of age (92 to 182 days of age, extremes included, for
IWRS purposes)
 
Age group 3: ≥6 months and ≤3 years of age (183 to 1,096 days, extremes included, for IWRS
purposes).


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Study drug will be administered twice daily for 7 days (14 consecutive doses). Doses are based on
weight and age group:
 
High Dose (Cohort 1: n  48 [target]; Cohort 2: n  50 [target]):
 
Age group 1: 2.5 mg JNJ-53718678/kg bodyweight
 
Age group 2: 3.0 mg JNJ-53718678/kg bodyweight
 
Age group 3: 4.5 mg JNJ-53718678/kg bodyweight
 
Low Dose (Cohort 1: n  48 [target]; Cohort 2: n  50 [target]):
 
Age group 1: 0.85 mg JNJ-53718678/kg bodyweight
 
Age group 2: 1.0 mg JNJ-53718678/kg bodyweight
 
Age group 3: 1.5 mg JNJ-53718678/kg bodyweight
 
Placebo (Cohort 1: n  48 [target]; Cohort 2: n  50 [target]): those randomized to a placebo
regimen will be subsequently randomized 1:1 to receive either:
 
High volume placebo:
o 
Age groups 1, 2, and 3: matching placebo (volume of placebo suspension to match
the calculated volume of the JNJ-53718678 suspension for the high dose)
 
Low volume placebo:
o 
Age groups 1, 2, and 3: matching placebo (volume of placebo suspension to match
the calculated volume of the JNJ-53718678 suspension for the low dose)
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 salt of
JNJ-53718678-AAA) used in the oral suspension.
In Cohort 1, the study drug will be administered by the study site personnel or by the
parent(s)/caregiver(s) under supervision of the study site personnel during hospitalization. In case
the subject is discharged prior to Day 7, the study drug will continue to be administered at home
by the parent(s)/caregiver(s) through Day 7. In Cohort 2, the first dose of study drug will be
administered, by the study site personnel or by the parent(s)/caregiver(s) under supervision of the
study site personnel, at the study site; the study drug will continue to be administered at home by
the parent(s)/caregiver(s) through Day 7 or the morning (AM) of Day 8 if the first dose was given
PM on Day 1. All subjects will receive standard supportive care for RSV infection as per local
SOC considering the restrictions provided in Section 8. All SOC treatment should be recorded as
concomitant medication/treatment.
In Cohort 1, subjects 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 (except for the
evening assessment in case the assessment is to be performed twice daily [bid]). Discharged
subjects (Cohort 1) will be required to attend the scheduled study visits as outpatients with the
same visit schedule as Cohort 2 subjects, from time of discharge onward. Cohort 2 subjects will
have study visits on Day 3, Day 5, Day 8, Day 14, and on Day 21. All scheduled study visits can


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also be done as home visits, if feasible for the study site and if allowed per local regulations. On
Day 28 (±3), subject’s parent(s)/caregiver(s) will be contacted by the site staff for a telephone
follow up visit, after which the subject completes the study. In case a subject is experiencing (an)
ongoing AE(s) or has clinically significant laboratory or ECG abnormalities at the time of the
Day 21 Follow-Up Visit, parent(s)/caregiver(s) might be requested, at the discretion of the
investigator, to have a Safety Follow-up Visit for the subject at the site (preferred option) or, if
feasible for the study site and if allowed per local regulations, at home on Day 28.
In case subjects prematurely discontinue study drug treatment for any reason (except withdrawal
of consent), the parent(s)/caregiver(s) will be asked to continue with the subject’s remaining study
visits and assessment schedule, or, at a minimum, to return with the subject to the site for a
Withdrawal and a Safety Follow-up Visit (see TIME AND EVENTS SCHEDULE). At the
Withdrawal and Safety Follow-up Visits, the same assessments as on the Day 8 and Day 21 visits,
respectively, will be performed. In case the subject’s legally acceptable representative(s) withdraw
consent during the treatment or follow-up phase, an optional Withdrawal and Safety Follow-up
Visit will be offered. At these optional Withdrawal and Safety Follow-up Visits, the same
assessments as on the Day 8 and Day 21 visits, respectively, will be performed.
As an evaluation of antiviral activity, the RSV viral load in nasal secretions will be measured at
the central lab using a qRT-PCR assay on mid-turbinate nasal swab specimens, which will be
collected at several timepoints during the study as indicated in the TIME AND EVENTS
SCHEDULE (see Section 9.2.1). If feasible, the RSV infectious virus load may also be assessed
by quantitative culture of RSV (plaque assay) on selected nasal swab samples.
Viral resistance will be monitored by sequencing of the F-gene in all baseline samples, and on
subsequent samples upon request of the sponsor’s protocol virologist. Other regions of the RSV
genome may also be sequenced at discretion of the sponsor’s virologist. Sequencing data will not
be reported to the investigators (see Section 9.2.3). Sequencing results may be presented in a
separate report.
Clinical course and severity of RSV infection will be assessed through different measures
(see Section 9.2.2). No well-validated clinical measures are currently available to systematically
evaluate severity of RSV disease in pediatric subjects treated in hospitals or community settings.
The sponsor developed the Pediatric RSV Electronic Severity and Outcomes Rating Scales
(PRESORS) to monitor signs of RSV disease severity observed and rated by clinicians treating
pediatric subjects (clinician PRESORS: Attachment 4) as well as by the subject's
parent(s)/caregiver(s) (parent[s]/caregiver[s] PRESORS: Attachment 5). Parent(s)/caregiver(s)
and clinicians use an electronic device to record and rate problems breathing, coughing, wheezing,
feeding, and other signs of RSV disease observed in the subject.
Safety and tolerability, including AEs, laboratory assessments, electrocardiograms (ECGs), vital
signs, and physical examination will be assessed throughout the study from signing of the ICF
until the subject’s last study-related activity (see Section 9.3).


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Pharmacokinetic assessments during the study will be based on sparse sampling and will be
performed using a popPK model (see Section 9.4). In the subcohort of Cohort 1, next to
randomization to treatment group, within each treatment arm (high dose, low dose, placebo), the
6 subjects will be randomized 1:1 to 1 of 2 different PK sampling groups (see Table 4). In
Cohort 1, next to randomization to treatment group, the first 12 subjects of each age group
(subcohort not included) will be randomized 1:1 to 1 of 2 different PK sampling groups
(see Table 4). Once 12 subjects of a particular age group have been randomized to the 2 different
PK sampling groups, the investigator can assign the subsequently enrolled subjects to either of the
2 PK sampling groups, but preferably alternating between 2 different PK sampling groups at this
site. For the subjects recruited to Cohort 2 after Protocol Amendment 4, PK samples will be
collected approximately one hour after administration of study drug (after the ECGs are obtained
if applicable) at Day 1 and at least 4 hours after the AM and prior to the PM dosing on Day 3 or
Day 5 (see Section 9.4.1).
Medical resource utilization (see Section 9.6) and acceptability and palatability of the study drug
(see Section 9.7 and Attachment 9) will be assessed.
Leftover mid-turbinate nasal swab and blood samples collected for other testing may be used for
exploratory biomarker analyses to determine the effects of JNJ-53718678 on markers of RSV
disease, at discretion of the sponsor (see Section 9.8).
See Attachment 10 for guidance on study conduct during the COVID-19 pandemic.
An IDMC will be commissioned for this study and will review unblinded safety data on a regular
basis throughout the conduct of this study to ensure subject safety. 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 subjects. The IDMC can
recommend to the Sponsor Committee to halt a dose arm due to safety concerns. The IDMC will
also review safety and PK data from 6 subjects in the subcohort of Cohort 1 and the data of the
interim analyses and provide recommendations to the Sponsor Committee. The Sponsor
Committee will take a decision considering the IDMC’s recommendation. Refer to Section 11.12
for details.
The study  will start with Cohort 1 (including the subcohort). The first interim analysis
encompassing safety and tolerability, PK, and antiviral effect is planned when at least 36 subjects
from Cohort 1 have completed the Day 14 assessments (or discontinued earlier). Enrollment in
Cohort 1 will continue during the interim analysis. Enrollment in the >3 days to ≤5 days since
symptom onset stratum might be temporarily paused prior to interim analysis 1 (at N 36 in
Cohort 1), once the maximum number of subjects are enrolled in the >3 days to ≤5 days since
symptom onset stratum in Cohort 1. Enrollment in the >3 days to ≤5 days since symptom onset
stratum will be reopened once the last subject required for interim analysis 1 has been randomized.
An IDMC will review the interim data, and will issue its recommendation to the sponsor, based on
which the Sponsor Committee will decide whether to initiate enrollment in Cohort 2.


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A second interim analysis is planned, preferably at the end of a hemispheric RSV season, when
approximately 70 to 80 subjects from Cohort 1 (regardless of the number of subjects in the
subcohort having reached the target of 6) have completed the Day 14 assessments (or discontinued
earlier). Enrollment in the >3 days to ≤5 days since symptom onset stratum might be temporarily
paused prior to interim analysis 2 (at N approximately 70-80 in Cohort 1), once the maximum
number of subjects are enrolled in the >3 days to ≤5 days since symptom onset stratum in Cohort 1.
Enrollment in the >3 days to ≤5 days since symptom onset stratum will be reopened once the last
subject required for interim analysis 2 has been randomized. During this interim analysis, a futility
and population enrichment analysis will be performed on antiviral activity  and one clinical
endpoint (ie, time to resolution of symptoms, considering data of both cohorts), to terminate the
study for futility, or to enrich the population and limit further enrollment to patients with ≤3 days
since symptom onset. In addition, other clinical course and safety-related endpoints will be
analyzed. The Sponsor Committee will take a decision considering the IDMC’s recommendation.
Depending on enrollment status of Cohort 2, the second interim analysis will not be performed, if
it is later than or too close to the predicted timing of the planned third interim analysis.
A third interim analysis is planned, preferably at the end of a hemispheric RSV season, when
approximately 70 to 80 subjects from Cohort 2 have completed the Day 14 assessments (or
discontinued earlier) and will include all available data from Cohort 1 and Cohort 2. Enrollment
in the >3 days to ≤5 days since symptom onset stratum might be temporarily paused prior to
interim analysis 3 (at N approximately 70-80 in Cohort 2), once the maximum number of subjects
are enrolled in the >3 days to ≤5 days since symptom onset stratum in Cohort 2. Enrollment in the
>3 days to ≤5 days since symptom onset stratum will be reopened once the last subject required
for interim analysis 3 has been randomized. During this interim analysis, a futility and population
enrichment analysis will be performed on antiviral activity (data from both cohorts combined) and
clinical endpoints (Cohort 2 data only), as well as a sample-size re-estimation for clinical endpoints
(Cohort 2 data only). Both the study team and the IDMC will provide their recommendations to
the Sponsor Committee, who will decide, taking all recommendations into account. The maximum
number of subjects in Cohort 2 in the study will not exceed 300.
If the study is extended beyond the initially planned sample size in Cohort 2 for the primary
analysis (N 150), a fourth  interim analysis will be performed preferably at the end of a
hemispheric RSV season, after approximately 150 subjects in Cohort 2 have completed the Day 14
assessments (or discontinued earlier), and will include all available data from Cohort 1 and
Cohort 2. Enrollment in the >3 days to ≤5 days since symptom onset stratum might be temporarily
paused prior to interim analysis 4 (at N approximately 150 in Cohort 2), once the maximum
number of subjects are enrolled in the >3 days to ≤5 days since symptom onset stratum in Cohort 2.
Enrollment in the >3 days to ≤5 days since symptom onset stratum will be reopened once the last
subject required for interim analysis 4 has been randomized. The primary analysis on antiviral
activity will be performed during this fourth  interim analysis and effects of JNJ-53718678 on
clinical course endpoints, next to endpoints related to safety, PK and PK/PD, will be analyzed to
support early Phase 3 preparations, including regulatory interactions. In addition, the futility and
population enrichment analysis will be repeated at this interim analysis. Both the study team and


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the IDMC will provide their recommendations to the Sponsor Committee, who will decide, taking
all recommendations into account.
Enrollment will continue during each of the interim analyses.
The final analysis is planned when all subjects from Cohort 1 and Cohort 2 have completed the
study (or discontinued earlier). If no extension of Cohort 2 is required, the final analysis will
coincide with the primary analysis. Enrollment in the >3 days to ≤5 days since symptom onset
stratum will be stopped once the maximum number of subjects are enrolled in this stratum in both
cohorts. Since the number of subjects enrolled in Cohort 2 is the trigger to perform interim
analysis 3 and interim analysis 4, enrollment in Cohort 1 in the >3 days to ≤5 days since symptom
onset stratum might be stopped, at any time after interim analysis 2, once the maximum number
of subjects in this stratum are enrolled for the final analysis. See Section 11.4 for more information.
More details on (un)blinding can be found in Section 11.1.
While recruitment in the subcohort of Cohort 1 is ongoing, subjects >2 and ≤3 years of age are not
allowed to be enrolled in Cohort 2, even if enrollment in that cohort has been opened for the age
groups ≤2. After 6 subjects of the subcohort are evaluable for PK analysis and have completed the
Day 14 assessments (or discontinued earlier), safety and PK data will be reviewed by the IDMC,
who will issue its recommendation to the sponsor, based on which the Sponsor Committee will
decide whether to also initiate enrollment of subjects >2 and ≤3 years of age in Cohort 2 when
enrollment in that cohort has been opened for the age groups ≤2. During this IDMC review,
additional subjects >2 and ≤3 years of age can be enrolled in Cohort 1 and will follow all Cohort 1
procedures.
An overview of the different planned analyses is shown in Figure 2.


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Figure 2: 
Overview of Different Planned Analyses in Study 53718678RSV2002
Additional interim analyses may be performed at the sponsor’s discretion to support decision
making for further development of JNJ-53718678 and to support interactions with health
authorities.
A separate substudy may be performed at selected study sites to explore the feasibility of the use
of biosensors for the evaluation of cardio-respiratory parameters (eg, respiratory rate, heart rate,
and SpO2). Details, including objectives and study design, will be described in a separate substudy
protocol.
3.2. 
Study Design Rationale
This Phase 2 multicenter, double-blind, placebo-controlled, randomized study is designed to
explore the antiviral activity, clinical outcomes, safety, tolerability, and PK/PD relationships of
high and low doses of JNJ-53718678 twice daily for 7 days in children ≥28 days and ≤3 years of
age with acute respiratory tract infection due to RSV, in 2 cohorts ie, hospitalized (Cohort 1) and
outpatients (Cohort 2). The results of this study will enable selection of the dose and clinical
endpoints for subsequent Phase 3 studies.
Blinding, Control, Study Phase/Periods, Intervention Groups
There is currently no approved treatment routinely used for the treatment of RSV infection.
A placebo control will be used to establish the frequency and magnitude of changes in virologic
and clinical endpoints that may occur in the absence of active treatment. The use of a placebo


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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
JNJ-53718678 vs those related to the underlying disease.
Randomization will be used to minimize bias in the assignment of subjects to treatment groups, to
increase the likelihood that known and unknown subject attributes (eg, demographic and baseline
characteristics) are evenly balanced across treatment groups, and to enhance the validity of
statistical comparisons across treatment groups. Blinded treatment will be used to reduce potential
bias during data collection and evaluation of clinical endpoints.
Within each cohort (including the subcohort of Cohort 1), eligible subjects will be randomized
1:1:1 to receive either a low or a high dose of JNJ-53718678, or placebo (see Section 6). Fordosing
purposes, 3 age groups (≥28 days and <3 months; ≥3 months and <6 months or ≥6 months and ≤3
years of age) are defined depending on the subject’s age at the time of consent, taking into account
the abundancy of specific enzymes (and their maturation) involved in the metabolism of JNJ-
53718678 in these different age groups (see also Study 53718678RSV1005).
Within each cohort, except for the subcohort, randomization will be stratified by time of symptom
onset (≤3 days vs >3 days to ≤5 days before randomization) and by presence of risk factors for
severe RSV disease (otherwise healthy vs presence of [a] risk factor[s] for severe RSV disease as
defined above). Subjects with symptom onset ≤3 days before randomization must account for a
minimum of 45% of all enrolled subjects in Cohorts 1 and 2 (ie, maximum 55% of subjects could
be enrolled in the >3 days to ≤5 days stratum). To guarantee the required balance between strata
for the interim analyses, enrollment in the >3 days to ≤5 days since symptom onset stratum might
be temporarily paused prior to an interim analysis and stopped prior to the final analysis. Stratum
caps and closures are managed separately for each cohort and consider the sample size of the
respective cohort for the interim analysis and the total sample size of each cohort for the final
analysis.
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 subjects with these
conditions.
Duration of symptoms onset is included as stratification factor because it is anticipated that there
will be a larger treatment effect in subjects with onset of symptoms ≤3 days. In order to analyze
the impact of the time since onset ofRSV symptoms on the treatment effect, the number of subjects
enrolled with time since onset of RSV symptoms of >3 days to ≤5 days will be limited to a
maximum of 55% at the time of all planned interim or final analyses.
Population
Subjects in the age group ≥28 days to ≤3 years are targeted, as they are mostly affected by (severe)
RSV disease. Both hospitalized (Cohort 1) and outpatient (Cohort 2) subjects are targeted as RSV
is a major cause of acute LRTI, resulting into either hospitalization or outpatient medical care. The
number of subjects exposed as part of the study has been limited to a minimum to reach the


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objectives of the study. A sample size re-estimation based on clinical course endpoints will be
performed and may results in an extension of Cohort 2.
In Cohort 1, a subcohort of 6 subjects >2 and ≤3 years will be included, who will follow in general
the same assessment schedule as for all subjects enrolled in Cohort 1, although with a specific PK
sampling schedule, assigned at randomization (see Section 9.4.1). Of note, if the subcohort is fully
enrolled, additional subjects >2 and ≤3 years of age can be enrolled in Cohort 1 and will follow all
Cohort 1 procedures.
Dose Selection
The active regimens (high or low dose, adapted to the age groups, see Section 6) evaluated in this
design are selected to provide a range of plasma concentrations of JNJ-53718678 to obtain
information on antiviral activity, clinical outcomes, safety, tolerability, and PK/PD relationships
in the target population of subjects, in the age range of ≥28 days to ≤3 years, infected with RSV.
The high doses (5, 6, and 9 mg/kg, dependent on the age groups) were initially selected based on
the results of the PK analysis performed during Study 53718678RSV1005. Pharmacokinetic
analysis demonstrated that these doses resulted in observed minimum plasma concentration (Cmin)
and maximum plasma concentration (Cmax) values within the range of the target concentrations (ie,
the exposure observed in adults treated with 500 mg JNJ-53718678 once daily), although
associated with slightly higher observed AUC values. Furthermore, based on the safety data from
Study 53718678RSV1005, these doses were generally safe and well tolerated and resulted in
antiviral effect (see also Section 1.1).
Based on the exposure-response analysis conducted in the TQT Study 53718678RSV1009 in
healthy adult subjects, 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 modelling 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 were 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 <36 months of age,
respectively) was selected with disallowance of comedication with moderate or strong CYP3A4
inhibitors. Based on Table 2, the upper limit of the 90% confidence interval for QTcI for the
bid regimen for each of the age groups remains below 10 ms. It is anticipated that the proposed
bid dosing will be in the therapeutic range of JNJ-53718678 for the pediatric population (Ctrough at
least 7 times the protein adjusted at 90% maximal effective concentration), ensuring the highest
potential antiviral effect while minimizing the risk of development of resistance, as well as
mitigating the important potential risk of QT interval prolongation.


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Table 2: 
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 - ≤36 Months
(4.5 mg/kg bid)
AUC24h  Day 1 (ng.hr/mL) 
16,500 
17,200 
17,400
AUC24h  Day 7 (ng.hr/mL) 
32,900 
28,800 
21,600
Cmax  Day 1 (ng/ml) 
1,220 
1,350 
1,690
Cmax  Day 7 (ng/ml) 
1,870 
1,800 
1,840
Ctrough  Day 1 (ng/mL) 
566 
509 
292
Ctrough  Day 7 (ng/mL) 
998 
773 
350
QTcI Day 1 (ms) (90%CI) 
1.95 (0.97-3.66) 
2.09 (1.08-3.98) 
2.37 (1.19-4.62)
QTcI Day 7 (ms) (90%CI) 
3.17 (1.34-6.81) 
2.92 (1.31-6.23) 
2.64 (1.25-5.54)
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 low doses represent one-third of the high dose administered for each age group. These low
doses will result in a mean  exposure sufficiently low to clearly differentiate from the mean
exposure obtained with the high doses, which is required to evaluate the JNJ-53718678 exposure-
response relationship for antiviral activity. In Study 53718678RSV1005, the exposures resulting
from these doses also demonstrated antiviral effect.
Study Duration
The total study duration for each subject will be approximately 29 days (Screening included).
Dosing will last for 7 days (14 consecutive doses) as it has been shown that the duration of viral
shedding upon RSV infection is at least that long.6 Healthy adult volunteers in the challenge study
(Study 53718678RSV2001) and hospitalized pediatric subjects in Study 53718678RSV1005 were
dosed for 7 days and JNJ-53718678 was generally safe and well tolerated (see Section 1.1).
Clinical Outcomes of RSV Treatment
Treatment with JNJ-53718678 may reduce the severity and duration of RSV signs and 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 subjects’
return to pre-RSV health status. The study will compare treatment regimens to evaluate the impact
of treatment with JNJ-53718678 on the clinical course of RSV disease.
Biomarker Collection
Leftover mid-turbinate nasal swab and blood samples collected for other testing may be used for
exploratory biomarker analyses (eg, proteins including cytokines, microbiome), on the premise
that these markers may play a role in the treatment response, safety of JNJ-53718678, or
RSV-related disease.
Analyses of biomarkers may be performed at the sponsor’s discretion and reported separately from
this study.
No human deoxyribonucleic acid (DNA) analyses will be performed on these samples.


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Medical Resource Utilization
Treatment of RSV disease with JNJ-53718678 versus placebo may result in lower utilization of
hospital or outpatient healthcare services; therefore, comparison will be done between intervention
groups.
4. 
SUBJECT POPULATION
Screening for eligible subjects will be performed as soon as possible after initial presentation at
the hospital (Cohort 1) or after presentation for medical care as outpatients (Cohort 2) such that
subjects are randomized within 24 hours after start of screening or within 48 hours after collection
of the SOC sample used for local RSV diagnosis, whichever comes first.
The inclusion and exclusion criteria for enrolling subjects in this study are described in the
following 2 subsections. If there is a question about the inclusion or exclusion criteria below, the
investigator must consult with the appropriate sponsor representative and resolve any issues before
enrolling a subject in the study. Waivers are not allowed.
For a discussion of the statistical considerations of subject selection, refer to Section 11.3, Sample
Size Determination.
4.1. 
Inclusion Criteria
Each potential subject must satisfy all of the following criteria to be enrolled in the study:
1. 
The subject is a boy or girl ≥28 days and ≤3 years at the time of consent.
2. 
Each subject’s legally acceptable representative (ie, parent(s)/legal guardian) must sign
an ICF indicating that he or she 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 (even if not clinically indicated; Cohort 1 only),
and is willing/able to adhere to the lifestyle restrictions specified in the protocol (see
Section 4.3) and study procedures and assessments to be performed by the
parent(s)/caregiver(s) as well as those by the investigator/site staff.
Note: Prior to signing the main consent form for the study, subject’s legally acceptable
representative may specifically allow for the collection and testing of nasal mid-turbinate
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.
3. 
The subject has been diagnosed with RSV infection using a preferably rapid PCR- or
other molecular-based diagnostic assay (preferred) or a rapid-antigen-detection assay.
Note: If a subject had a positive similar RSV diagnostic test from another study for which
(s)he was otherwise ineligible or a SOC 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 confirmation of eligibility. Randomization should occur within 24 hours after


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start of screening or within 48 hours after collection of the SOC sample used for local
RSV diagnosis, whichever comes first.
Note: If a rapid-antigen-detection assay is used as part of SOC or study-specifically (with
the main study ICF or with the diagnostic ICF having been signed), the remainder of the
screening sample used for the RSV diagnostic testing should be sent to the central
laboratory for additional virologic analyses, as applicable.
4. 
Criterion modified per Amendment 6:
4.1 
The subject 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:
 
URTI: nasal congestion, rhinorrhea, pharyngitis, or otitis media; AND
 
LRTI: increased respiratory effort (as evidenced by subcostal, intercostal or
tracheosternal retractions, grunting, head bobbing, nasal flaring or tachypnea),
abnormal breathing sounds (wheezing, rales or rhonchi), cyanosis, apnea, or cough
(cough or wheezing should be accompanied by at least one additional LRTI
sign/symptom in order to be eligible); 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).
5. 
The time of onset of RSV symptoms to the anticipated time of randomization must be
≤5 days. Onset of 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(s) aware of the first sign
and/or symptom consistent with respiratory or systemic/general manifestation of
symptoms of RSV infection. The time of symptom onset has to be assessed as accurately
as possible.
Note: Subjects with symptom onset ≤3 days before randomization must account for a
minimum of 45% of all enrolled subjects in Cohorts 1 and 2 (ie, maximum 55% of
subjects could be enrolled in the >3 days to ≤5 days stratum).
6. 
Except for the RSV-related illness, the subject 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) in the study population as evaluated by the
investigator. This determination must be recorded in the subject’s source documents and
initialed by the investigator.
7. 
The subject must have been assessed per local public health practice and considered not
to have SARS-CoV-2 infection during this respiratory infection.


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4.2. 
Exclusion Criteria
Any potential subject who meets any of the following criteria will be excluded from participating
in the study:
1. 
The subject is <3 months postnatal age at screening and was born prematurely (ie,
<37 weeks and 0 days of gestation).
2. 
The subject weighs <2.4 kg or >16.8 kg.
3. 
The subject had major surgery within the 28 days prior to randomization or planned
major surgery through the course of the study.
4. 
The subject has major congenital anomalies or known cytogenetic or metabolic
disorders other than the ones allowed above (see inclusion criterion 6).
Note: Isolated open ductus arteriosus and open foramen ovale are not exclusionary as
these are not considered major anomalies. Subjects with congenital heart disease,
cystic fibrosis, congenital diaphragmatic hernia, or Down Syndrome are allowed to
participate.
5. 
The subject is considered by the investigator to be immunocompromised within the
past 12 months, whether due to underlying medical condition (eg, malignancy or
genetic disorder other than immunoglobulin A deficiency, or known HIV infection)
or medical therapy (eg, immunomodulators other than corticosteroids for the treatment
of comorbidities, chemotherapy, radiation, stem cell or solid organ transplant).
6. 
The subject has known or clinically suspected hepatitis B or C infection, either acute
or chronic active.
7. 
The subject has known allergies, hypersensitivity, or intolerance to JNJ-53718678 or
to any of the excipients of the JNJ-53718678 or placebo formulation (refer to the IB).17
8. 
The subject is currently participating or planned to participate in another clinical
interventional study, during their participation in this study.
9. 
The subject is unwilling to undergo or the parent(s)/caregiver(s) is/are unwilling to
have the subject undergoing mid-turbinate nasal swab procedures.
10. 
The subject has any physical abnormality which limits the ability to collect regular
nasal specimens.
11. 
The subject 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 drug ingestion or absorption.


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12. 
The subject is being treated with extracorporeal membrane oxygenation (Cohort 1
only).
13. 
The subject is receiving chronic home oxygen therapy at screening.
14. 
Criterion modified per Amendment 4:
14.1 
The subject has 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.
15. 
Criterion modified per Amendment 4:
15.1 
The subject has a QTcF interval >450 ms per the machine read (mean of triplicate)
parameter result confirmed by repeat triplicate ECG recording during screening.
16. 
The subject is using any disallowed medication as listed in Section 8.
17. 
Criterion modified per Amendment 4:
17.1 
The subject’s mother received an investigational RSV vaccination during the
pregnancy for this child whose age is <3 months at time of screening.
18. 
The subject has evidence of one of the following ECG abnormalities per the machine
read ECG result confirmed by repeat ECG recording at screening:
 
Repetitive premature ventricular contractions (>10/min)
 
Second- or third-degree heart block
 
Complete or incomplete left bundle branch block or complete right bundle branch
block
19. 
The subject has a personal or first- or second-degree family history of long QT
syndrome or sudden cardiac death.
20. 
The subject has had ANY of:
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.
Note: Investigators should ensure that all study enrollment criteria have been met at screening. If
a subject's clinical status changes (including any available laboratory results or receipt of additional
medical records) after screening but before the first dose of study drug is given such that he or she
no longer meets all eligibility criteria, then the subject should be excluded from participation in


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the study. Section 17.4, Source Documentation, describes the required documentation to support
meeting the enrollment criteria.
4.3. 
Lifestyle Restrictions
Parent(s)/caregiver(s) must be willing and able to adhere to the prohibitions and restrictions with
regards to the concomitant therapy (see Section 8) during the course of the study for the subject to
be eligible for participation.
5. 
TREATMENT ALLOCATION AND BLINDING
Treatment Allocation
Procedures for Randomization and Stratification
Central randomization will be implemented in this study. Within each cohort (including the
subcohort of Cohort 1), eligible subjects will be randomized 1:1:1 to receive either a low or a high
dose of JNJ-53718678, or placebo. Those randomized to a placebo regimen will be subsequently
randomized in a 1:1 ratio to receive either low or high volume of placebo. This results in an overall
randomization scheme of 2:2:1:1 (low dose JNJ-53718678, high dose JNJ-53718678, low volume
placebo, high volume placebo). Randomization will be based on a computer-generated
randomization schedule prepared before the study by or under the supervision of the sponsor.
In the subcohort of Cohort 1, next to randomization to treatment group, within each treatment arm
(high dose, low dose, placebo), the 6 subjects will be randomized 1:1 to 1 of 2 different PK
sampling groups (see Table 4). In Cohort 1, next to randomization to treatment group, the first
12 subjects of each age group (subcohort not included) will be randomized 1:1 to 1 of 2 different
PK sampling groups (see Table 4). Once 12 subjects of a particular age group have been
randomized to the 2 different PK sampling groups, the investigator can assign the subsequently
enrolled subjects to either of the 2 PK sampling groups, but preferably alternating between
2 different PK sampling groups at this site. In Cohort 2, PK samples will be collected as indicated
in the TIME AND EVENTS SCHEDULE.
The randomization will be balanced by using randomly permuted blocks and will be stratified by
time since symptom onset at randomization (≤3 days and >3 days) and by presence of risk factors
for severe RSV disease (otherwise healthy vs presence of [a] risk factor[s] for severe RSV disease
as defined above, Table 1). Stratification will be applied to each cohort separately, with exception
of the subcohort. Subjects with symptom onset ≤3 days before randomization must account for a
minimum of 45% % of all enrolled subjects in Cohorts 1 and 2 (ie, maximum 55% of all subjects
can be enrolled in the >3 days to ≤5 days stratum). To guarantee the required balance between
strata for the interim analyses, enrollment in the >3 days to ≤5 days since symptom onset stratum
might be temporarily paused prior to an interim analysis and stopped prior to the final analysis
(see Section 11.1). Stratum caps and closures are managed separately for each cohort and consider
the sample size of the respective cohort for the interim analysis and the total sample size of each
cohort for the final analysis. Enrollment in the >3 days to ≤5 days since symptom onset stratum


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will be reopened once the last subject required for the corresponding interim analysis has been
randomized.
The interactive web response system (IWRS) will assign a unique treatment code, which will
dictate the treatment assignment, matching study drug kits (1 bottle per subject) for the subject and
PK sampling group (for the subcohort and for the first 12 subjects in each age group in Cohort 1).
The requestor must use his or her own user identification and personal identification number when
contacting the IWRS, and will then give the relevant subject details to uniquely identify the subject.
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 subject.
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 treatment and control groups will be
disclosed to those authorized and only for those subjects included in the interim analysis.
Otherwise, the blind should be broken only if specific emergency treatment/course of action would
be dictated by knowing the treatment status of the subject. In such cases, the investigator may in
an emergency determine the identity of the treatment by contacting the IWRS. It is recommended
that the investigator contacts 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 and reason for the unblinding must be documented in the
appropriate section of the eCRF. The documentation received from the IWRS indicating the code
break is filed in the central Trial Master File.
6. 
DOSAGE AND ADMINISTRATION
Within each cohort (including the subcohort of Cohort 1), eligible subjects will be randomized
1:1:1 to receive either a low or a high dose of JNJ-53718678, or placebo. Subjects randomized to
a placebo regimen are subsequently randomized in a 1:1 ratio to receive placebo matching either
the volume of the high or of the low dose. Doses are based on weight and age group (3 age groups
[≥28 days and <3 months; ≥3 months and <6 months, or ≥6 months and ≤3 years of age] are defined
depending on the subject’s age at the time of consent). An overview of the treatments for Cohort
2 newly recruited subjects is provided in Table 3.


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Table 3: 
Treatment Overview
Treatment 
Age Groupa 
Dosing Regimenb,d  
Volume
High dose 
1 
2.5 mg/kg bid on Days 1 to 7 A mLc oral suspension of JNJ-53718678
2 
3.0 mg/kg bid on Days 1 to 7 C mLc oral suspension of JNJ-53718678
3 
4.5 mg/kg bid on Days 1 to 7 E mLc oral suspension of JNJ-53718678
Low dose 
1 
0.85 mg/kg bid on Days 1 to 7 B mLc oral suspension of JNJ-53718678
2 
1.0 mg/kg bid on Days 1 to 7 D mLc oral suspension of JNJ-53718678
3 
1.5 mg/kg bid on Days 1 to 7 F mLc oral suspension of JNJ-53718678
Placebo
Match
high dose
1,2, or 3 
placebo bid on Days 1 to 7 
A, C, or E (respectively) mLb placebo
Match
low dose
1,2, or 3 
placebo bid on Days 1 to 7 
B, D, or F (respectively) mLb placebo
a.
Age Group 1: ≥28 days and <3 months; Age Group 2: ≥3 and <6 months; Age Group 3: ≥6 months and ≤3 years.
b.
Doses are provided for JNJ-53718678-AAA.
c.
A to F represents the volume of oral JNJ-53718678 suspension to obtain the required dose of JNJ-53718678-AAA
or the volume of the matching placebo suspension. JNJ-53718678 is formulated as an oral suspension containing
23 mg/mL microfine JNJ-53718678-ZCL, the hemi-tartrate salt of JNJ-53718678-AAA, which is equivalent to
20 mg/mL JNJ-53718678-AAA, to be used depending on the bodyweight of the subject (and the required volume
to be administered). The required volume to be administered per intake will be calculated by the IWRS and
provided to the sites.
d. Dosing should preferably occur approximately at the same time each day for both intakes (AM and PM). For
subjects who receive only 1 dose of JNJ-53718678 or placebo PM on Day 1, dosing should continue through the
morning (ie, AM) of Day 8 so that all subjects receive 14 consecutive doses in total.
Study drug administration should start as soon as possible, but no later than 4 hours after
randomization and within 5 days after symptom onset. For analysis purposes, the day of first study
drug intake will be considered Day 1.
Dosing should preferably occur approximately at the same time each day for both intakes (AM
and PM). For subjects who receive only 1 dose of JNJ-53718678 or placebo PM on Day 1, dosing
should continue through the morning (ie, AM) of Day 8 so that all subjects receive 14 consecutive
doses in total. 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. The study drug can be administered
with/without food. The study drug will be administered orally using a dosing syringe. For Cohort 1
and during hospitalization, the drug can also be administered through a nasogastric tube, if already
in place.
Note: Prior to Protocol Amendment 4, the total daily dose was the same but the daily dosing
frequency was qd instead of bid.
 
Cohort 1:
 
During hospitalization: the study drug will be administered by the study site personnel or
by the parent(s)/caregiver(s) under supervision of the study site personnel. Date and time
of dosing will be recorded by the site staff.
 
After Discharge: parent(s)/caregiver(s) will administer study drug at home if the subject
is discharged prior to Day 7. Date and time of dosing will be captured in the study


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medication log, to be completed by the parent(s)/caregiver(s) in the provided electronic
device.
 
Cohort 2, the first dose of study drug will be administered, by the study site personnel or by
the parent(s)/caregiver(s) under supervision of the study site personnel, at the study site. On
Day 1, date and time of dosing will be recorded by the site staff. At home, date and time of
dosing will be captured in the study medication log, to be completed by the
parent(s)/caregiver(s) in the provided electronic device.
Study site personnel will instruct subjects’ parent(s)/caregiver(s) on how to use and store the study
drug for at-home dosing as per sponsor provided investigational product preparation instruction
(IPPI).
7. 
STUDY DRUG COMPLIANCE
During hospitalization, study drug will be administered orally or via nasogastric tube (if
applicable) under supervision of study-site personnel at the study-site.
After discharge, if this occurs prior to the end of the dosing period, and in Cohort 2, study drug
will be administered orally by the subject’s parent(s)/caregiver(s) at home. At the screening visit,
the subject’s parent(s)/caregiver(s) will receive instructions on compliance with study drug
administration, and this instruction will be repeated atthe time of discharge, if applicable. At home,
dosing will be recorded by the parent(s)/caregiver(s) in the electronic study medication log
(Attachment 6). For Cohort 2, site staff should review the entries of the electronic study medication
log daily to ensure compliance with administration of study drug. During the course of the study,
the investigator or designated study-site personnel will be responsible for providing additional
instruction to re-educate any subject’s parent(s)/caregiver(s) who is (are) not compliant with
administering the study drug.
If the subject vomited, regurgitated, or did not completely swallow the study drug, this information
should be recorded and the subject should not be redosed.
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 timepoint per the initial dosing schedule.
If subjects are rehospitalized (subjects from Cohort 1 after discharge) and or hospitalized (subjects
from Cohort 2) due to worsening of RSV disease during the treatment period, administration of
study drug should continue.
An overdose in this study is defined as the administration of a volume of the study drug above that
of the total daily calculated volume for the respective age and bodyweight-based dose within a 24-
hour time period.
8. 
CONCOMITANT THERAPY
Concomitant medications, except those listed below, are allowed during this study. All
concomitant medications and supportive therapy (prescription or over-the-counter medications,


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including vaccines, vitamins, herbal supplements, and non-pharmacologic therapies such as
electrical stimulation, acupuncture, special diets, physiotherapy) different from the study drug
must be recorded in the eCRF, from the date the ICF is signed through to the end-of-study visit.
Recorded information will include a description of the type of the drug/therapy, treatment duration
(dates of treatment 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 subject into the study; however, if a subject 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 subjects will receive supportive care per local institution standards and applicable
guidelines. While treatment guidelines and standards vary based on local practice and should be
considered in the management of subjects, within the parameters of this study, it is recommended
that supplemental oxygen can be administered or withdrawn, as appropriate, to maintain an SpO2
≥93% as long as it is medically indicated (for subjects whose SpO2 is ≥93% when clinically stable).
Subjects 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. However, in line with
the clinical practice guidelines and package inserts, it is recommended to limit the use of
antitussives and mucolytics, in particular in the younger age group. In case these medications are
used, the PRESORS should report the worst symptom(s) during the recall period.
Subjects whose mother received an investigational RSV vaccination during the pregnancy for this
child and whose age is <3 months at time of screening will not be allowed in the study.
In case antipyretics are used, body  temperature should be measured immediately  before or
>4 hours after giving antipyretics (see Section 9.2.2). Parents/caregivers should be instructed
accordingly.
Fexofenadine is allowed, taking into account its package insert and dosing instructions for use in
children, but JNJ-53718678 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 JNJ-53718678 and/or at least 4 hours after taking
JNJ-53718678, taking into account the local prescribing info for fexofenadine.13,15
Prescription medications intended to treat the symptoms/sequelae of the RSV infection are
permitted, including:
 
inhaled β-agonists or anticholinergics
 
oral/intravenous/intramuscular antibiotics such as β-lactams
Note: The temporary use of over-the-counter medications in the 14 days prior to randomization is
permitted. The use of vitamins and mineral supplements is also permitted.


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The following medications are not permitted during the study and for the time period prior to
screening as noted:
 
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 randomization and during the study except for topically administered products.
 
prescription medications intended to prevent or treat the RSV infection itself (eg, ribavirin,
IV immunoglobulin, palivizumab) within 14 days prior to screening and during the study.
Prescription medications intended to treat the symptoms/sequelae of the RSV infection are
permitted.
 
prescription medication eltrombopag, a known BCRP inhibitor, within  2 days prior to
randomization and during the study.
 
the following prescription medications with 14 days prior to screening, until 3 days after last
dose:
 
Prescription medications which are known to be a moderate or strong inhibitor of
cytochrome P450 (CYP)3A4 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.
 
Medications with a known risk to prolong the QT interval14  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 subject 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.
 
Systemic corticosteroids if used for >7 consecutive days immediately prior to randomization
at doses higher than 2 mg/kg/day of prednisone or equivalent. Subjects 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.
 
Any other investigational drug within 30 days or 5-fold half-lives of that drug (whichever is
longer) prior to screening and during the study.
 
Any investigational vaccine, including investigational RSV vaccines, at any time prior to and
during the study. Routine vaccinations are permitted during the studybut local guidelines have
to be followed.
 
Any investigational medical device.
 
Prior exposure to JNJ-53718678 at the time of screening.


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9. 
STUDY EVALUATIONS
9.1. 
Study Procedures
9.1.1. 
Overview
The TIME AND EVENTS SCHEDULE summarizes the frequency and timing of antiviral effect,
clinical course, safety, PK, biomarker, acceptability and palatability, and medical resource
utilization assessments applicable to this study.
If multiple assessments are scheduled for the same timepoint, it is recommended that procedures
be performed in the following sequence: noninvasive procedures should be collected first before
invasive procedures (ECG first, then vital signs/SpO2, then mid-turbinate nasal swab, and blood
draw last). However, mid-turbinate nasal swabs for RSV RNA viral load should be kept as close
to the specified time as possible. Actual dates and times of assessments will be recorded in the
source documentation and eCRF.
Medical resource utilization  data will be collected. Refer to Section 9.6 [Medical Resource
Utilization] for details.
The maximum amount of blood drawn from each subject in this study will not exceed 9.2 mL over
the duration of the study in line with recommendations collated by the WHO12.
Repeat or unscheduled samples may be taken for safety reasons or for technical issues with the
samples.
An electronic device to be used for the parent(s)/caregiver(s) PRESORS (Attachment 5), study
medication log (Attachment 6), nasal swab log (Attachment 7), temperature log (Attachment 8),
and the Study Medication Tolerability Assessment (Attachment 9) will be provided to the
parent(s)/caregiver(s) at the time of screening to record parent(s)/caregiver(s) ratings of the
severity of the subject's symptoms every day (bid or qd), as specified in the TIME AND EVENTS
SCHEDULE. The investigator/study staff will provide sufficient information (included in the
study manual) to enable the parent(s)/caregiver(s) to complete the different logs and
parent(s)/caregiver(s) PRESORS  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.
In case antipyretics are used, body temperature should be measured immediately before or
>4 hours after giving antipyretics. Parents/caregivers should be instructed accordingly.
In case antitussives and mucolytics are used, the PRESORS should report the worst symptom(s)
during the recall period.
Assessments, which should be performed around the dosing timepoint as per the TIME AND
EVENTS SCHEDULE, should be done prior to actual first dosing on Day 1 and preferably prior
to dosing on the other days.


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9.1.2. 
Screening Phase
The procedures specified in the TIME AND EVENTS SCHEDULE will only be performed after
the parent(s)/caregiver(s)’ written informed consent has been obtained and have to occur before
randomization (refer to Section 16.2.3).
If needed, and depending on the time of presentation, screening/predose assessments and
establishment of eligibility can continue the next calendar day, in which case the first study drug
intake will be on that day, immediately after establishing eligibility. For analysis purposes, the day
of first study drug intake will be considered Day 1.
Screening will be completed and randomization as well as first dosing will be performed within
5 days after the onset of RSV symptoms to ensure the eligibility of the subject. Swabs collected
per local SOC testing within 24 hours prior to start of screening may be used in determining study
eligibility (see below). Randomization should occur within 24 hours after start of screening or
within 48 hours after collection of the SOC sample used for local RSV diagnosis, whichever comes
first.
Blood samples for biochemistry (including creatinine clearance calculated by the GFR formula
(Schwarz equation), hematology and a urine sample for urinalysis will be collected at screening
and analyzed at the central laboratory (for urine samples only in case of dipstick abnormalities).
Given  the absence of safety signals regarding laboratory findings in previous studies, the
importance of starting treatment as soon as possible after symptom onset, and the required turn-
around time for central testing, treatment can be initiated prior to availability of the lab results.
Vital signs (systolic blood pressure [SBP], diastolic blood pressure [DBP], and heart rate) and a
standard triplicate 12-lead ECG will be recorded (approximately 1 minute apart and preferably all
within 5 minutes) as specified in the TIME AND EVENTS SCHEDULE and a complete physical
examination (CPE; including all body systems) will be performed. Physical examination also
includes the collection of body weight, length, and head circumference.
Baseline demographics, medical history, and family history with regards to risk factors for
wheezing/asthma will be recorded in the eCRF of this study.
Concomitant disease and medication will be recorded and AE recording will start.
At screening, a nasal (preferentially mid-turbinate) predose swab will be collected for local RSV
diagnosis using a preferably rapid PCR- or other molecular-based diagnostic assay (preferred), or
a rapid antigen-detection-assay. If a subject had a positive similar RSV diagnostic test from another
study for which (s)he was otherwise ineligible or a SOC 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 confirmation of eligibility. Randomization should occur within 24 hours after start of
screening or within 48 hours after collection of the SOC sample used for local RSV diagnosis,
whichever comes first. If a rapid-antigen-detection assay is used as part of SOC or study-
specifically (with the main  ICF or with the diagnostic study ICF having been signed), the
remainder of the screening sample used for the RSV diagnostic testing should be sent to the central


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laboratory for additional virologic analyses, as applicable. In case the local PCR detects more than
1 virus, the subject is eligible as long as RSV is one of the viruses detected.
After randomization, but immediately predose, a mid-turbinate nasal swab will be collected,
aliquoted and sent to the central lab for:
 
RSV diagnosis confirmation using a PCR-based assay
 
RSV viral load
 
Examination for the presence of viral or bacterial co-infection using multiplex PCR
sequencing
 
Viral sequencing
Note: Leftover samples will be stored in the biobank for biomarker research if warranted.
If a study-specific screening nasal mid-turbinate swab was collected within 8 hours prior to dosing,
the leftover of that sample can serve as the baseline sample and should be shipped to the central
laboratory, provided that the study-specific nasal mid-turbinate screening sample was stored
appropriately and has sufficient sample volume available (minimum 4 aliquots of 600 µL each).
Parent(s)/caregiver(s) will be provided with the electronic device at the time ofscreening and will
be instructed by the site staff on how to complete the different logs and the parent(s)/caregiver(s)
PRESORS, rating the severity of signs of RSV, and noting the impact of RSV on the subject’s
household. Parent(s)/caregiver(s) will complete a brief training on the electronic device on how to
complete the different logs and the parent(s)/caregiver(s) PRESORS before they will be allowed
to complete their first entry in the electronic device.
Clinical evaluation will be performed. For both cohorts, this includes but is not limited to
measurements/evaluations of respiratory rate, body temperature, SpO2, and need for antibiotics.
For Cohort 1, this additionally includes but is not limited to level of and duration of hospital care,
duration of hospitalization, hydration/feeding by IV line/nasogastric tube, while for Cohort 2, this
additionally includes the evaluation of the need for and duration of hospitalization. Note that for
all cohorts, all clinical assessments should preferably be done when the infant is calm (ie, not
crying or immediately after feeding).
9.1.3. 
Double-BlindTreatment Phase
Assessments to be performed during the treatment phase are specified in the TIME AND EVENTS
SCHEDULE
Day 1/Day of Randomization
Eligible subjects will be randomized on Day 1, which is preferable the same calendar day as the
screening visit. Study drug administration should start as soon as possible, but no later than 4 hours
after randomization, which should occur within 5 days after RSV symptom onset and within
24 hours after start of screening or within 48 hours after collection of the SOC sample for local
RSV diagnosis, whichever comes first. All subjects (both cohorts) will be administered the first


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dose of the study drug at the study site on Day 1, by or under supervision of the study site
personnel, immediately after the predose swab.
Dosing should preferably occur approximately at the same time each day for both intakes (AM
and PM). For subjects who receive only 1 dose of JNJ-53718678 or placebo PM on Day 1, dosing
should continue through the morning (ie, AM) of Day 8 so that all subjects receive 14 consecutive
doses in total. 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.
Assessments to be performed on Day 1, and their timing are specified in the TIME AND EVENTS
SCHEDULE.
Day 2 to Day 8 (End of Treatment)
Subjects will receive 14 doses in total, administered twice daily and preferably at approximately
the same time each day for both intakes (see above).
For Cohort 1 (prior to discharge) and for Cohort 2, study-site personnel will instruct subject’s
parent(s)/caregiver(s) on how to use and store the study drug for at-home dosing.
Between Day 2 and Day 8, the assessments that will be performed at predefined timepoints
(different for Cohort 1 and Cohort 2) are specified in the TIME AND EVENTS SCHEDULE. For
Cohort 1, some of these assessments will only be performed if and while the subject is hospitalized
as indicated in the TIME AND EVENTS SCHEDULE.
For Cohort 1 subjects after discharge and for Cohort 2 subjects, some of these assessments will be
performed during on-site visits (Day 3, 5 and 8) as indicated in the TIME AND EVENTS
SCHEDULE. These scheduled study visits if feasible for the study site and if allowed per local
regulations, can also be done as home visits. The subcohort of Cohort 1 will follow in general the
same assessment schedule as for all subjects enrolled in Cohort 1, although with a specific PK
sampling schedule, assigned at randomization (see Section 9.4.1). The first 12 subjects in each age
group (excluding the subcohort) in Cohort 1 will be assigned a specific PK sampling schedule (see
Section 9.4.1)
Investigational staff will review daily the completion of the parent(s)/caregiver(s) PRESORS and
the logs once data is transmitted to the database from the electronic device and will contact the
parent(s)/caregiver(s) in case of incompliance. For Cohort 2, site staff should review the entries of
the electronic study medication log daily to ensure compliance with administration of study drug.
9.1.4. 
Posttreatment Phase (Follow-Up)
For all cohorts, subjects will be evaluated for a total of approximately 28 (±3) days post
randomization
Both Cohort 1 subjects after discharge and Cohort 2 subjects will be required to return to the site
for follow-up assessments as an outpatient on Day 14 and Day 21, as indicated in the TIME AND


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EVENTS SCHEDULE. These scheduled study visits if feasible for the study site and if allowed
per local regulations, can also be done as home visits. On Day 28 (±3), subject’s
parent(s)/caregiver(s) will be contacted by the site staff for a telephone follow-up visit. In case a
subject is experiencing (an) ongoing AE(s) or has clinically significant laboratory or ECG
abnormalities at the time of the Day21 Follow-Up Visit, parent(s)/caregiver(s) might be requested,
at the discretion of the investigator, to have a Safety Follow-up Visit for the subject at the site
(preferred option) or, if feasible for the study site and if allowed per local regulations, at home on
Day 28 (±3). Only clinically relevant assessments will be performed during this visit, as applicable.
During the follow-up phase, for both cohorts, the parent(s)/caregiver(s) will complete the
parent(s)/caregiver(s) PRESORS as of Day 9 through Day 14 twice a day (morning and evening;
see TIME AND EVENTS SCHEDULE. From Day 15 through Day 21, the parent(s)/caregiver(s)
will complete the parent(s)/caregiver(s) PRESORS  once daily, in the evening, with the final
parent(s)/caregiver(s) PRESORS assessment being scheduled at the Day-21 on-site visit (see
TIME AND EVENTS SCHEDULE). Investigational staff will review daily the completion of the
parent(s)/caregiver(s) PRESORS  once data is transmitted to the database from the electronic
device and will contact the parent(s)/caregiver(s) in case of incompliance. Investigational staff will
also instruct parent(s)/caregiver(s) on the continuation of the collection of nasal swabs, as
applicable (see Section 3.1).
For all cohorts, in case subjects prematurely discontinue study drug treatment for any reason
(except withdrawal of consent), the parent(s)/caregiver(s) will be asked to continue with the
subject’s remaining study visits and assessment schedule, or, at a minimum, to return with the
subject to the site for a Withdrawal and a Safety Follow-up Visit. At the Withdrawal and Safety
Follow-up Visits, the same assessments as on the Day 8 and Day 21 visits, respectively, will be
performed. In case the subject’s legally acceptable representative(s) withdraw consent during the
treatment or follow-up phase, an optional Withdrawal and Safety Follow-up Visit will be offered.
At these optional Withdrawal and Safety Follow-up Visits, the same assessments as on the Day 8
and Day 21 visits, respectively, will be performed. Assessments will be performed as indicated in
the TIME AND EVENTS SCHEDULE.
9.2. 
EfficacyEvaluations
9.2.1. 
Antiviral Activity
As an evaluation of antiviral activity, the RSV viral load in nasal mid-turbinate swab samples will
be measured at the central lab using a qRT-PCR assay. Mid-turbinate swab specimens for the
determination of RSV viral load will be collected at several timepoints during the study as
indicated in the TIME AND EVENTS SCHEDULE. Date and time of sampling will be collected.
Mid-turbinate 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 site staff (nasal
swabs taken on-site) or by parent(s)/caregiver(s) (nasal swabs taken at home).
On Day 1, in both cohorts, the mid-turbinate nasal swab should be collected as close as possible
and prior to the first administration of study drug. The next swabs should be collected from the


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same nostril preferably at approximately the same time as the predose swab taken on Day 1 and
preferably prior to dose administration.
 
Cohort 1:
 
During hospitalization: Swabs will continue to be collected each day during
hospitalization through Day 13 or until discharge (whichever comes first).
 
Discharged subjects: After discharge, swabs will be collected daily through Day 8 in all
subjects. As of Day 8, in subjects who were symptomatic based on clinician PRESORS
at Day 8, daily swabs will be collected through Day 13 or until the subject becomes
asymptomatic based on the parent(s)/caregiver(s) PRESORS, as evaluated by the
investigational staff (whichever comes first).
 
Cohort 2: Swabs will be collected daily through Day 8 in all subjects. As of Day 8, in subjects
who were symptomatic based on clinician PRESORS at Day 8, daily swabs will be collected
through Day 13 or until the subject becomes asymptomatic based on the parent(s)/caregiver(s)
PRESORS, as evaluated by the investigational staff(whichever comes first).
On Day 14 and Day 21, a swab will be collected during the scheduled visit for all subjects.
The investigational staff will collect mid-turbinate swabs during the scheduled (on-site) visit
(Cohort 1 after discharge and Cohort 2) or during hospitalization (Cohort 1). When no on-site visit
is scheduled per the TIME AND EVENTS SCHEDULE, it may be agreed between the study site
and parent(s)/caregiver(s) to perform a visit for nasal sampling purposes only, or send an HCP to
the subject's home for collection of the nasal swab sample. In case collection by an HCP is not
possible, the investigator/study site personnel will train the parent(s)/caregiver(s) to collect the
mid-turbinate nasal swab. The training to collect and document nasal swabs will be done at
screening, and repeated before discharge if needed for Cohort 1.
The collection of these nasal swab and date and time of sampling should be recorded for all subjects
in the eCRF or in the nasal swab log on the electronic device (see Attachment 7), as described in
the eCRF completion guidelines and the completion guides for the electronic device, which will
be provided to the investigator (see Section 15).
All parent(s)/caregiver(s), after being properly trained, will be provided with appropriate mid-
turbinate nasal swabs and Universal Transport Medium (same supplies as those used to collect
nasal samples at the sites) to collect mid-turbinate nasal swabs. All swabs collected at home by the
parent(s)/caregiver(s) should be stored immediately between 2°C and 8°C (in the refrigerator) and
brought to the site at the next scheduled visit.
Additional information about the collection, handling, and shipment of biological samples can be
found in the laboratory manual.
RSV RNA viral load can also be measured by a qRT-PCR assay in nasopharyngeal and/or tracheal
aspirate samples in a subgroup of hospitalized subjects (Cohort 1 only) in which these samples are
obtained as part of their SOC, which may be used to assess virologic parameters.


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The RSV infectious virus load as measured by quantitative culture of RSV (plaque assay), if
feasible, on selected nasal swab samples, may be used to assess virologic parameters.
9.2.2. 
Clinical Course of RSV Infection
The study will include the following evaluations of the clinical course of RSV infection:
 
Cohort 1 and Cohort 2:
 
clinical parameters: respiratory rate, heart rate, SpO2, and body temperature as measured
by the investigator during scheduled visits. Note:If the subject is enrolled in the substudy
of Study 53718678RSV2002 (see Section 3.1), the same parameters as assessed by the
biosensor will be recorded from the standard-of-care monitoring/assessments as part of
the substudy assessments (refer to the substudy Clinical Protocol for detailed information)
at the timepoints indicated in the TIME AND EVENTS SCHEDULE.
 
body temperature as measured by parent(s)/caregiver(s) and recorded in the temperature
log (Attachment 8) (for Cohort 1 after discharge and Cohort 2)
 
evolution and severity of signs and symptoms of RSV disease (fever, cough, sputum,
wheezing, difficulty breathing, nasal congestion, feeding issues) as assessed by the
parent(s)/caregiver(s) (parent[s]/caregiver[s] PRESORS) and the clinician (clinician
PRESORS)
 
the need for (re)hospitalization
 
the occurrence of complications, bronchiolitis, or viral pneumonia with onset after
treatment initiation that are associated with RSV per investigator assessment
 
the need for antibiotics related to complications associated with RSV per investigator
assessment
 
Cohort 1 only:
 
time to discharge (from initial admission and from initiation of treatment)
 
time to clinical stability, with clinical stability evaluated by the investigator (from initial
admission and from initiation of treatment)
 
level of and duration by level of hospital care (eg, ICU, transitional care unit, ward floor)
 
oxygen requirement type (eg, supplemental oxygen, noninvasive pressure ventilation,
endotracheal-mechanical ventilation), and duration
 
hydration and feeding by IV line/nasogastric tube and duration
Note: In case antipyretics are used, body temperature should be measured immediately before or
>4 hours after giving antipyretics. Parents/caregivers should be instructed accordingly.
Note: In case antitussives and mucolytics are used, the PRESORS should report the worst
symptom(s) during the recall period.
Clinical outcome assessments as performed separately by the clinician (clinician PRESORS) and
the parent(s)/caregiver(s) (parent[s]/caregiver[s] PRESORS, temperature log) will be captured in
an electronic device. Symptoms reported in these assessments will not be reported as AEs but
constitute a part of the efficacy evaluations.


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An electronic device will be provided to the subject’s parent(s)/caregiver(s) at the time of
screening, after enrollment of the subject. The investigator/study site personnel will provide
sufficient information to enable the subject’s parent(s)/caregiver(s) to complete these assessments.
The parent(s)/caregiver(s) PRESORS assessment should be completed once at screening, then bid
(in the morning and in the evening) from Day 1 (day of first dose) to Day 14 and then once daily
in the evening until the Day 21 visit. The final parent(s)/caregiver(s) PRESORS assessment has to
be completed during the scheduled Day-21 on-site visit (see also TIME AND EVENTS
SCHEDULE). The first parent(s)/caregiver(s) PRESORS of the bid schedule on Day 1 needs to be
completed as close as feasible and prior to the first administration of study drug. The screening
parent(s)/caregiver(s) PRESORS assessment will be accepted as baseline if completed within
4 hours before randomization.
During hospitalization (Cohort 1), body temperature will be measured by the investigator. On the
day of discharge (Cohort 1) or at screening (Cohort 2), the initial measurement of body temperature
should be performed by the investigator. If discharged (Cohort 1) or screened in the morning, only
the evening assessment of the bid schedule for the measurement of body temperature should be
recorded in the temperature log on the electronic device (Attachment 8).
The parent(s)/caregiver(s) PRESORS and temperature log should preferably be completed by the
same person throughout the study. A second parent/caregiver who frequently provides direct care
of the child can be set up as a backup reporter on the electronic device to ensure assessments are
recorded if the primary parent/caregiver is unable to enter information for any reason.
Investigational staff will review daily the completion of the parent(s)/caregiver(s) PRESORS and
logs once data is transmitted to the database from the device. The site will contact the
parent(s)/caregiver(s) in case if parent(s)/caregiver(s) PRESORS and information collected in the
logs are not uploaded according to the schedule, which might be due to issues with the electronic
device or due to non-compliance. The site will monitor and help the parent(s)/caregiver(s) to be
compliant. Investigational staff will also instruct parent(s)/caregiver(s) on the continuation of the
collection of nasal swabs, as applicable.
9.2.3. 
Viral Sequencing
Sequencing data will not be reported to the investigators. Viral resistance will be monitored by
sequencing of the F-gene of the viral genome in all baseline 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. The impact of the viral subtype and baseline
genotype on the antiviral response will be explored. Sequencing results may be presented in a
separate report.
Changes in viral sequence will be evaluated but will not be reported as AEs.
9.3. 
Safety Evaluations
Safety and tolerability will be evaluated throughout the study from signing of the ICF onwards
until the last study-related activity (end of study/early withdrawal).


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Details regarding the IDMC are provided in Section 11.12.
Any clinically relevant changes occurring during the study must be recorded on the Adverse Event
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 endpoint is reached.
The study will include the following evaluations of safety and tolerability according to the time
points provided in the TIME AND EVENTS SCHEDULE:
Adverse Events
Adverse events will be reported by the subject (or, when appropriate, by a caregiver, surrogate, or
the subject's legally acceptable representative) for the duration of the study. Adverse events will
be followed by the investigator as specified in Section 12, Adverse Event Reporting.
Special attention will be paid to those subjects who discontinue the study for an AE, or who
experience an AE of at least Grade 3, or an SAE.
Exacerbations of underlying pulmonary disease occurring after treatment start, otitis media,
bronchiolitis, viral pneumonia, bacterial superinfections of presumed respiratory origin per
investigator assessment, and exacerbations of underlying cardiovascular conditions should be
reported as AE and are considered events of interest (complications associated with RSV per
investigator assessment). For each reported event, investigators will be asked if they consider the
event to be a complication of or associated with RSV. When answered yes, additional data related
to that event is collected when available. Further details on these events of interest will be captured
separately in the eCRF.
Clinical Laboratory Tests
Blood samples for serum chemistry, hematology, and a urine sample for urinalysis will be collected
at the time points indicated in the TIME AND EVENTS SCHEDULE. 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.
In case a Grade 3 or Grade 4 laboratory abnormality occurs, a confirmatory test must be performed
preferably within 48 hours but no later than 72 hours after the results have become available.
Any values that indicate a potential safety concern will be assessed by the investigator and
appropriate follow-up actions, including potential discontinuation from treatment (see also
Section 10.3, will be carried out.
The following tests will be performed by the central laboratory:


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 
Hematology Panel
-hemoglobin  
-WBC differential:
-hematocrit 
* neutrophils
-RBC count 
* lymphocytes
-reticulocyte count 
* monocytes
-RBC parameters: 
* eosinophils
* mean corpuscular hemoglobin (MCH) 
* basophils
* MCH concentration  
-platelet count
* mean corpuscular volume
-WBC count
Note: A white blood cell (WBC) evaluation may include any abnormal cells, which will
then be reported by the laboratory. An RBC evaluation may include abnormalities in the
RBC count, RBC parameters, or RBC morphology, which will then be reported by the
laboratory.
In addition, any other abnormal cells in a blood smear will also be reported.
 
Serum Chemistry Panel
-alkaline phosphatase 
-creatinine
-ALT  
-glucose
-AST  
-potassium
-bicarbonate 
-sodium
-uric acid 
-total bilirubin (direct and indirect)
-chloride 
-urea
-magnesium
 
eGFR will be calculated/reported by the central lab (Schwarz formula)
 
Urinalysis
Dipstick  
Sediment (if dipstick result is
abnormal)
-specific gravity  
-RBC
-pH  
-WBC
-glucose 
-epithelial cells
-protein  
-crystals
-blood 
-casts
-ketones 
-bacteria
-bilirubin
-urobilinogen
-nitrite
-leukocyte esterase
Dipstick will be performed at the site as per the TIME AND EVENTS SCHEDULE. If
dipstick result is abnormal, flow cytometry or microscopy will be used to measure sediment,
in the central lab. In case of discordance between the dipstick results and the flow cytometric
results, the sediment will be examined microscopically. In the microscopic examination,
observations other than the presence of WBC, RBC and casts may also be reported by the
laboratory.


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Levels of potassium and magnesium will be determined by the central laboratory. In case of
hypokalemia or hypomagnesemia at screening or Day 8, the levels of potassium and 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. During the study locally
determined potassium and/or magnesium levels need to be recorded in the eCRF as unscheduled
laboratory visits/assessments.
At Screening (Study Day -1 through 1), a nasal (preferentially mid-turbinate) predose swab will
be collected for RSV diagnosis. Swabs collected per local SOC testing within 24 hours prior to
start of screening may be used in determining study eligibility. If a rapid-antigen-detection assay
is used as part of SOC or study-specifically (with the main ICF or with the diagnostic study ICF
having been signed), the remainder of the screening sample used for the RSV diagnostic testing
should be sent to the central laboratory for additional virologic analyses, as applicable.
After randomization (immediately predose), a mid-turbinate nasal swab will be collected,
aliquoted and sent to the central lab for RSV diagnosis confirmation, assessment of viral load and
for the presence of viral or bacterial co-infection, and viral sequencing. If a study-specific
screening nasal mid-turbinate swab was collected within 8 hours prior to dosing, the leftover of
that sample can serve as the baseline sample and should be shipped to the central laboratory,
provided that the study-specific nasal mid-turbinate screening sample was stored appropriately and
has sufficient sample volume available (minimum 4 aliquots of600 µL).
Electrocardiogram (ECG)
Screening and on-treatment ECGs will be collected at the time points indicated in the TIME AND
EVENTS SCHEDULE.
Electrocardiograms (triplicate 12-lead ECG; approximately 1 minute apart and preferably  all
within 5 minutes) should be performed using procedures commensurate with the subject’s age.
For eligibility determination, the machine read ECG results, printed on the ECG device print-out
of the ECG tracing, will be taken into account. The subject should have a QTcF interval ≤450 ms
per the machine read parameter result (mean  of triplicate). If the QTcF interval is confirmed
>450 ms per the machine read parameter result (mean  of triplicate) by repeat ECG recording
during screening (see Section 4.2), the subject is ineligible.
Central ECG readings will be performed by a central ECG lab. Instructions for ECG acquisition
and ECG transmission will be described in the manual provided by the ECG lab. There will be
2 ECG reports: a preliminary report and a final report. Both ECG reports generated by the central
ECG lab will need to be interpreted for clinical significance, signed and dated by the investigator,
and filed in the subject’s medical record. Clinically relevant abnormalities occurring during the
study should be recorded by the investigator in the AE section of the eCRF.


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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, ECGs 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 subject has a QTcF interval ≥500 ms based on a machine read ECG
result (mean of triplicate), confirmation needs to be obtained by repeat ECG recording during the
same visit day. If confirmed based on the repeat machine read ECG results (mean of triplicate),
the subject needs to be withdrawn from study treatment (see also Sections 9.3.1 and 10.3). In case
other clinically relevant ECG 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.
Vital Signs (blood pressure)
For the duration of hospitalization, vital signs will be assessed for each subject twice daily
preferably at approximately the same time on each scheduled day (see TIME AND EVENTS
SCHEDULE). After discharge, vital signs will be assessed once during the on-site visits (see TIME
AND EVENTS SCHEDULE).
Blood pressure will be assessed sitting or supine (preferably the same position at each
measurement), with a completely automated device. Manual techniques will be used only if an
automated device is not available.
Clinically relevant abnormalities in blood pressure occurring during the study should be recorded
in the AE Section of the eCRF.
Physical Examination
To evaluate the subject’s eligibility, a CPE and measurements of length, head circumference, and
body weight will be performed at screening, and a directed physical examination (DPE) will be
performed at several time points throughout the study (see TIME AND EVENTS SCHEDULE).
A DPE includes respiratory system, nose, ear, throat, facial, and neck lymph nodes, and skin
examination.
A skin examination includes an examination of the mucous membranes, but does not include a
vaginal or rectal exam. However, if the subject develops a cutaneous reaction/rash, vaginal and
rectal exams may be done if clinically relevant.
To obtain the actual body weight, subjects 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 subject.
Any clinically relevant changes occurring during the study must be recorded in the AE Section of
the eCRF.


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9.3.1. 
Specific Toxicities and Safety Topics of Special Interest
The following only applies to AEs starting after initiation of study treatment.
AST and ALT Elevation
Management will be at the discretion of the investigator and should follow generally accepted
medical standards. Grading of AST and alanine transaminase (ALT) elevation will be based on the
DMID Pediatric Toxicity Table (see Attachment 1).
For Grade 3 or 4 laboratory abnormalities, subjects should have a confirmatory measurement,
preferably within 48 hours after the laboratory results become available to the site. The below
management scheme is for confirmed laboratory abnormalities and not for isolated events.
Grade 1 (1.1 to <2.0x ULN), or Grade 2 (≥2.0 to <3.0x ULN)
Subjects may continue the intake of study drug.
Subjects should be followed until resolution (return to baseline) or stabilization of AST/ALT
elevation (to be agreed upon with the sponsor).
Grade 3 (≥3.0 to ≤8.0x ULN), or Grade 4 (>8.0x ULN)
If occurring during the treatment period, subjects will permanently discontinue the intake of study
drug, although with continuation of appropriate safety follow-up visits.
It is recommended that the investigator contacts the sponsor to discuss the case. Subjects should
be followed until resolution (return to baseline) or stabilization of AST/ALT elevation.
RSV-related Complications
Management will be at the discretion of the investigator and should follow generally accepted
medical standards.
Cardiac Events Potentially Related to QTProlongation
Regular cardiac safety monitoring will be done in this study via assessments of AEs, laboratory
abnormalities, and regular ECGs.
A subject's study intervention must be discontinued if the subject has a QTc value ≥500 ms at any
scheduled visit based on a machine read ECG result (mean of triplicate), confirmed by repeat ECG
recording during the same visit day (see Section 9.3). For subjects with a confirmed QTc interval
value ≥500 ms, the following measures should be taken:


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 The cardiac event must be reported to the sponsor within 24 hours.
 The investigator should request urgent cardiology referral, within 24 hours if possible.
 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
central laboratory.
 If hypokalemia or hypomagnesemia is identified, 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) is required. During the study, locally
determined potassium and/or magnesium levels need to be recorded in the eCRF as
unscheduled laboratory visits/assessments.
 An ECG should be repeated every 24 hours until resolution of QTc interval prolongation is
confirmed. The subject’s condition should be followed until resolution (return to baseline) or
stabilization. During the study, these assessments will be captured as unscheduled
visits/assessments.
9.4. 
Pharmacokinetics
Pharmacokinetic assessments during the study will be based on sparse sampling and will be
performed using a population PK approach by means of nonlinear mixed-effects modeling.
9.4.1. 
Evaluations
Blood samples for determination of JNJ-53718678 concentrations will be collected through finger
prick or heel stick at the timepoints indicated in the TIME AND EVENTS SCHEDULE. In the
subcohort of Cohort 1, next to randomization to treatment group, within each treatment arm (high
dose, low dose, placebo), the 6 subjects will be randomized 1:1 to 1 of 2 different PK sampling
groups (see Table 4). In Cohort 1, next to randomization to treatment group, the first 12 subjects
of each age group (subcohort not included) will be randomized 1:1 to 1 of 2 different PK sampling
groups (see Table 4). Once 12 subjects of a particular age group have been randomized to the
2 different PK sampling groups, the investigator can assign the subsequently enrolled subjects to
either of the 2 PK sampling groups, but preferably alternating between 2 different PK sampling
groups at this site.


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Table 4: 
Overview of Pharmacokinetic Sampling Windows for Cohort 1 Subjects
Pharmacokinetic 
Sampling Group
Visit Day 1 
Visit Day 2
Time after dose intake at 
Visit 1 
Time before dose intake at 
Visit 2 
Time after dose intake at
Visit 2
X 
2 h –5 h  
- 
30 min –3 h
Y 
5 h –9 h  
3 h –1 min  
-
For the subjects recruited to Cohort 2 after Protocol Amendment 4, PK samples will be collected
approximately one hour after administration of study drug (after the ECGs are obtained if
applicable) at Day 1 and at least 4 hours after the AM and prior to the PM dosing on Day 3 or Day
5.
Samples may also be used for the analysis of metabolites of JNJ-53718678 or endogenous markers
for enzymes or transporters involved in the metabolism and distribution of JNJ-53718678, at the
discretion of the sponsor. Blood samples collected for PK may 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. The subject’s confidentiality will be maintained.
The following information needs to be recorded on the requisition form and/or eCRF: date and
time of preceding study drug intake, date and time of PK blood sampling, fed status (yes/no, fed
status defined as having a meal 30 minutes before or 30 minutes after dosing), and type of meal
(milk vs. other).
9.4.2. 
Analytical Procedures
Bioanalysis will be performed on these samples (applicable treatment groups only [not the placebo
group]) to determine blood concentrations of JNJ-53718678 using a validated, specific and
sensitive liquid chromatography/mass spectrometry/mass spectrometry (LC-MS/MS) method
under the supervision  of the sponsor’s department of Bioanalysis. If applicable, metabolite
concentrations may be determined using a qualified LC-MS/MS method under the supervision of
the sponsor's department of Bioanalysis.
Based on the individual concentration-time data, using the actual dose taken and the actual
sampling times, PK parameters and exposure information of JNJ-53718678 will be derived using
popPK modeling, including, but not limited to: AUC, Ctrough, and possibly Cmax. Baseline
covariates (eg, body weight, age, sex, race) may be included in the model, if relevant. Other PK
parameters may be determined at the discretion of the sponsor if deemed useful to evaluate the PK
of JNJ-53718678.
PK parameters for other analytes (eg, metabolites, endogenous markers) may be determined at the
discretion of the sponsor and may also be subjected to popPK modeling.
9.5. 
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 parameters.


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9.6. 
Medical Resource Utilization
Medical resource utilization  data, associated with medical encounters, will be collected in the
eCRF for all subjects 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:
 
Assessments performed as part of the clinical course of RSV infection-related assessments
(see Section 9.2.2)
 
Duration of hospitalization (total days length of stay, including duration by wards level
[eg, ICU]) (Cohort 1 only).
 
The number of subjects (proportion) who started antibiotic use after the first dose of study
drug through the last study visit.
 
Requirement for, and duration of, hospital (re)admission for respiratory reasons through
the last study visit.
 
Additional assessments
 
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).
9.7. 
Acceptability and Palatability
Acceptability and palatability of the JNJ-53718678 formulation will be assessed through a
questionnaire completed by parent(s)/caregiver(s) in the electronic device after last dosing. See
Attachment 9.
9.8. 
Biomarkers
Leftover mid-turbinate nasal swab and blood samples collected for other testing may be used for
exploratory biomarker analyses (eg, proteins including cytokines, microbiome), on the premise
that these markers may play a role in the treatment response, safety of JNJ-53718678, or
RSV-related disease.
Analyses of biomarkers may be performed at the sponsor’s discretion and reported separately from
this study.
No human deoxyribonucleic acid (DNA) analyses will be performed on these samples.
9.9. 
Other Evaluations
Mid-turbinate nasal swabs collected immediately prior to first dosing will be used to determine the
presence of viral (other than RSV) or bacterial pathogens (both by multiplex PCR) at the central
laboratory.
9.10. Sample Collection and Handling
The actual dates and times of sample collection will be collected in the eCRF or laboratory
requisition form.


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Refer to the TIME AND EVENTS SCHEDULE  for the timing and frequency of all sample
collections. For mid-turbinate nasal swabs, the date and time of sampling, as well as which nostril
was sampled, should be recorded for all subjects in the eCRF or in the nasal swab log on the
electronic device (see Attachment 7), as described in the eCRF completion guidelines and the
completion guides for the electronic device, which will be provided to the investigator (see
Section 15). For Cohort 1 (prior to discharge) and for Cohort 2 (at screening or Day 1 at the latest),
the investigator/study staff will provide instructions to the parent(s)/caregiver(s) and will train
them on how to document this correctly on the electronic device.
All swabs collected at home by the parent(s)/caregiver(s) should be stored immediately between
2°C and 8°C (in the refrigerator) and brought (cooler bag) to the site at the next scheduled visit.
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.
10. 
SUBJECT COMPLETION/DISCONTINUATION OF STUDY DRUG/
WITHDRAWAL FROM THE STUDY
10.1. Completion
A subject will be considered to have completed the treatment phase if he or she has completed
dosing on the 7 days of the dosing period and the Day 8 visit. A subject is considered to have
completed the study if he or she has also completed assessments of the last follow-up visit on
Day 28.
10.2. Stopping Criteria
10.2.1. 
For an Individual Subject
See Section 10.3, Discontinuation of Study Treatment.
10.2.2. 
For the Study
Further enrollment or dosing in the study will be discontinued by sponsor decision at
recommendation of the IDMC when the IDMC considers an event or multiple events to represent
an unacceptable risk to the health and well-being of subjects.
Further enrollment in the study will be discontinued by sponsor decision at recommendation of the
IDMC based on their review of the interim analysis results for safety, PK and efficacy.
10.3. Discontinuation of Study Treatment
A subject will not be automatically withdrawn from the study if he or she has to discontinue study
drug before the end of the treatment regimen.


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If subjects are rehospitalized (subjects from Cohort 1 after discharge) and or hospitalized (subjects
from Cohort 2) due to worsening of RSV disease during the treatment period, administration of
study drug should continue.
A subject's study treatment must be discontinued if:
 
The investigator believes that for safety reasons or tolerability reasons (eg, adverse event) it
is in the best interest of the subject to discontinue study drug
 
The subject experiences a Grade 3 rash or higher
 
The subject has a QTcF interval ≥500 ms based on a machine read ECG result (mean of
triplicate), confirmed by repeat ECG recording during the same visit day (see Section 9.3.1)
 
The subject is reported with the following laboratory abnormalities: AST or ALT increases
≥3 x ULN in samples taken at screening, confirmed in a repeat test, to be performed within
48 hours of the result being available at the site
 
The subject is reported with any other laboratory abnormality of Grade 3 or 4 at screening,
confirmed in a repeat test, to be performed within 48 hours of the result being available at the
site
 
The subject’s parent(s)/caregiver(s) is/are poorly compliant with 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
If a subject discontinues study drug for any reason before the end of the double-blind treatment
period, follow-up assessments should be obtained (see TIME AND EVENTS SCHEDULE) before
the subject can be withdrawn.
10.4. Withdrawal From the Study
A subject will be withdrawn from the study for any of the following reasons:
 
Lost to follow-up
 
Withdrawal of consent
 
Death
 
The subject’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 subject from the study


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If a subject is lost to follow-up, every reasonable effort must be made by the study-site personnel
to 
contact 
the 
subject 
parent(s)/caregiver(s) 
and 
determine 
the 
reason 
for
discontinuation/withdrawal. The measures taken to follow-up must be documented.
In case subjects prematurely discontinue study drug treatment for any reason (except withdrawal
of consent), the parent(s)/caregiver(s) will be asked to continue with the subject’s remaining study
visits and assessment schedule, or, at a minimum, to return with the subject to the site for a
Withdrawal and a Safety Follow-up Visit. At the Withdrawal and Safety Follow-up Visits, the
same assessments as on the Day 8 and Day 21 visits, respectively, will be performed. In case the
subject’s legally acceptable representative(s) withdraw consent during the treatment or follow-up
phase, an optional Withdrawal and Safety Follow-up Visit will be offered. At these optional
Withdrawal and Safety Follow-up Visits, the same assessments as on the Day 8 and Day 21 visits,
respectively, will be performed.
When a subject’s parent(s)/caregiver(s) withdraw(s) the subject before completing the study, the
reason for withdrawal is to be documented in the eCRF and in the source document. Study drug
assigned to the withdrawn subject may not be assigned to another subject. If a subject is withdrawn
from the study before the end of the double-blind treatment period, every attempt should be made
to obtain follow-up assessments (see TIME AND EVENTS SCHEDULE).
10.5. Withdrawal From the Use of Samples in Future Research
The subject may withdraw consent for use of samples for research (refer to Section 16.2.5, Long-
Term Retention of Samples for Additional Future Research). 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.
11. 
STATISTICAL METHODS
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.
Analyses will be performed on the combined dataset of hospital and outpatient subjects, as well as
on data of each cohort separately.
11.1. Interim Analyses
Up to 4 interim analyses are planned (see Figure 2). During and after all interim analyses,
investigators, subject(s), and local sponsor representatives (except for selected local sponsor
representatives from Japan) will remain blinded. An IDMC will monitor and review data in an
unblinded manner, at all interim analyses. Enrollment will continue during each of the interim
analyses.
During the first interim analysis, the Sponsor Committee will be unblinded; the central sponsor
team members and local sponsor representatives from Japan will remain blinded. For the second
interim analysis, the Sponsor Committee, central sponsor team members, and selected local


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sponsor representatives from Japan will be unblinded upon recommendation from the IDMC and
the Sponsor Committee. During anyinterim analysis taking place after the second interim analysis,
the sponsor, including the central study team, and selected local sponsor representatives from
Japan will be unblinded. Aggregate unblinded data and certain individual safety events may be
shared with investigators to support the revised risk-benefit evaluation for the current study and to
support start of Phase 3.
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
recommendation, and will communicate these decisions to the study team. Details are provided in
the IDMC Charter.
The central sponsor team includes the following functions: clinical leader, statistician, virologist,
PK leader, pharmacometrician, medical writers, and statistical programmers.
Additional interim analyses may be performed at the sponsor’s discretion to support decision
making for further development of JNJ-53718678 and to support interactions with health
authorities.
Further details regarding the interim analyses will be specified in the SAP. Operating
characteristics (power, Type I error, …) of statistical decision procedures and methods at the
interim analyses will be evaluated through computer simulations and summarized in a modeling
& simulation report.
11.1.1. 
First Interim Analysis
The first interim analysis encompassing safety and tolerability, PK, and antiviral effect is planned
when at least 36 subjects from Cohort 1 have completed the Day 14 assessments (or discontinued
earlier). Enrollment in Cohort 1 (including the subcohort) will continue during the interim analysis
and IDMC review.
Enrollment in the >3 days to ≤5 days since symptom onset stratum might be temporarily paused
prior to interim analysis 1 (at N 36 in Cohort 1), once the maximum number of subjects are
enrolled in the >3 days to ≤5 days since symptom onset stratum in Cohort 1. Enrollment in the
>3 days to ≤5 days since symptom onset stratum will be reopened once the last subject required
for interim analysis 1 has been randomized.
An IDMC will review the interim data, and will issue its recommendation to the sponsor, based on
which the Sponsor Committee will decide whether to initiate enrollment in Cohort 2, while
hospitalized subjects continue to be enrolled (see also Section 11.12).
11.1.2. 
Second Interim Analysis
A second interim analysis is planned, preferably at the end of a hemispheric RSV season, when
approximately 70 to 80 subjects from Cohort 1 (regardless of the number of subjects in the
subcohort having reached the target of 6) have completed the Day 14 assessments (or discontinued
earlier). Enrollment in the >3 days to ≤5 days since symptom onset stratum might be temporarily


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paused prior to interim analysis 2 (at N approximately 70-80 in Cohort 1), once the maximum
number of subjects are enrolled in the >3 days to ≤5 days since symptom onset stratum in Cohort 1.
Enrollment in the >3 days to ≤5 days since symptom onset stratum will be reopened once the last
subject required for interim analysis 2 has been randomized. During this interim analysis, a futility
and population enrichment analysis will be performed on antiviral activity  and one clinical
endpoint (ie, time to resolution of symptoms, considering data of both cohorts). In addition, other
clinical course and safety-related endpoints will be analyzed. An IDMC will review the interim
data and will issue its recommendation to the sponsor, based on which the Sponsor Committee
will decide whether to terminate the study for futility, or to terminate the enrollment of the >3 days
since symptom onset population. The decision rules will be defined in the SAP.
Depending on enrollment status of Cohort 2, the second interim analysis will not be performed, if
it is later than or too close to the predicted timing of the planned third interim analysis.
11.1.3. 
ThirdInterim Analysis
A third interim analysis is planned, preferably at the end of a hemispheric RSV season, when
approximately 70 to 80 subjects from Cohort 2 have completed the Day 14 assessments (or
discontinued earlier) and will include all available data from Cohort 1 and Cohort 2. Enrollment
in the >3 days to ≤5 days since symptom onset stratum might be temporarily paused prior to
interim analysis 3 (at N approximately 70-80 in Cohort 2), once the maximum number of subjects
are enrolled in the >3 days to ≤5 days since symptom onset stratum in Cohort 2. Enrollment in the
>3 days to ≤5 days since symptom onset stratum will be reopened once the last subject required
for interim analysis 3 has been randomized. During this interim analysis, a futility and population
enrichment analysis will be performed on antiviral activity (data from both cohorts combined) and
clinical endpoints (Cohort 2 data only). The rules implement simultaneously a conditional success
probability approach (viral load) and a Go-NoGo approach10 on multiple clinical endpoints. Both
the study team and the IDMC will review the results of the interim analysis, and may recommend
to the Sponsor Committee an early termination of the study for futility or to enrich the population
and limit further enrollment to patients with ≤3 days since symptom onset, in case the conditional
power on the viral load endpoint is regarded as being too low and/or the success probability of the
clinical endpoints is too low. The Sponsor Committee will take a decision considering the
recommendation of the study team and the IDMC (see also Section 11.12). The exact criteria of
these non-binding decision rules will be defined in the SAP.
No clinical endpoints for Phase 3 have been identified yet and the association between the antiviral
effect and clinical course endpoints is not yet established for RSV. A key secondary objective of
this Phase 2 study is the evaluation of clinical course endpoints and their dependence on viral load
reductions. Results of this Phase 2 study will inform on discussion and selection of clinical course
endpoints and guide the design for subsequent Phase 3 studies. Therefore, a sample size re-
estimation based on clinical course endpoints (Cohort 2 data only) will be performed during
interim analysis 3 and may result in an expansion of Cohort 2. Based on all available data from
Cohort 2 at the cut-off for interim analysis 3, one or more clinically relevant and sensitive
endpoint(s) will be selected for confirmation. Time to resolution (ie, to none or mild symptoms)
and reduction in severity of selected clinical signs/symptoms of RSV-related illness are currently


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expected to be the most relevant clinical endpoints for Phase 3 planning. However, data from this
study, in combination with data from other RSV studies within and outside the company, and
knowledge obtained through health authority interaction(s) will be considered in interim analysis
3 for the endpoint selection and sample size recalculation.
After selection of (a) clinical endpoint(s), the number of subjects in Cohort 2 will be calculated to
minimize the conditional “consider”-probability for clinical endpoints (Go-NoGo-approach) at the
end of the study assuming a required confidence of 90% (one-sided) to exclude the target value
and/or the minimal acceptable value.
Both the study team and the IDMC may recommend to the Sponsor Committee an increase of the
sample size for Cohort 2 of the study. The maximum number of subjects in Cohort 2 in the study
will not exceed 300.
11.1.4. 
Fourth Interim Analysis
If the study is extended beyond the initially planned sample size in Cohort 2 for the primary
analysis (N 150), a fourth interim analysis will be performed preferably at the end of a
hemispheric RSV season, after approximately 150 subjects in Cohort 2 have completed the Day 14
assessments (or discontinued earlier), and will include all available data from Cohort 1 and Cohort
2. Enrollment in the >3 days to ≤5 days since symptom onset stratum might be temporarily paused
prior to interim analysis 4 (at N approximately 150 in Cohort 2), once the maximum number of
subjects are enrolled in the >3 days to ≤5 days since symptom onset stratum in Cohort 2.
Enrollment in the >3 days to ≤5 days since symptom onset stratum will be reopened once the last
subject required for interim analysis 4 has been randomized. The primary analysis on antiviral
activity will be performed during this fourth interim analysis and effects of JNJ-53718678 on
clinical course endpoints, next to endpoints related to safety, PK and PK/PD, will be analyzed to
support early Phase 3 preparations, including regulatory interactions. In addition, the futility and
population enrichment analysis will be repeated at this interim analysis. Both the study team and
the IDMC will provide their recommendations to the Sponsor Committee, who will decide, taking
all recommendations into account.
The final analysis is planned when all subjects from Cohort 1 and Cohort 2 have completed the
study (or discontinued earlier). If no extension of Cohort 2 is required, the final analysis will
coincide with the primary analysis. Enrollment in the >3 days to ≤5 days since symptom onset
stratum will be stopped once the maximum number of subjects are enrolled in this stratum in both
cohorts. Since the number of subjects enrolled in Cohort 2 is the trigger to perform interim analysis
3 and interim analysis 4, enrollment in Cohort 1 in the >3 days to ≤5 days since symptom onset
stratum might be stopped, at any time after interim analysis 2, once the maximum number of
subjects in this stratum are enrolled for the final analysis.
While recruitment in the subcohort of Cohort 1 is ongoing, subjects >2 and ≤3 years of age are not
allowed to be enrolled in Cohort 2, even if enrollment in that cohort has been opened for the age
groups ≤2. After 6 subjects of the subcohort are evaluable for PK analysis and have completed the
Day 14 assessments (or discontinued earlier), safety and PK data will be reviewed by the IDMC,


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who will issue its recommendation to the sponsor, based on which the Sponsor Committee will
decide whether to also initiate enrollment of subjects >2 and ≤3 years of age in Cohort 2 when
enrollment in that cohort has been opened for the age groups ≤2. During this IDMC review,
additional subjects >2 and ≤3 years of age can be enrolled in Cohort 1 and will follow all Cohort 1
procedures.
To account for multiplicity, and to be able to define a robust clinical course endpoint for Phase 3,
both unadjusted and adjusted p-values, with appropriate Type I error control, will be presented in
the final analysis.
11.2. Subject Information
For all subjects who received at least 1 dose of study drug, descriptive statistics will be provided.
All demographic (eg, age, length, weight, race, gender) and other initial subject 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.
11.3. Sample Size Determination
11.3.1. 
Primary Objective: Establish Antiviral Activity
The basis of the sample size calculation is the antiviral results of Study 53718678RSV1005. In
that study, the mean difference in RSV viral load AUC from baseline until Day 5 of the placebo
group versus active (adjusted for baseline viral load) was estimated as 105 log10 copies.hour/mL
(corresponding to a 25% reduction) and the standard deviation (SD) on the RSV viral load AUC
as 85 log10 copies.hour/mL (corresponding to a CV of approximately 20%).
Assuming a more conservative reduction in RSV viral load AUC of 20% compared to placebo,
considering a CV of 35% (slightly higher variability than observed in Study 53718678RSV1005),
and a1-sidedalpha of 2.5%; the power to conclude a dose-response using the Multiple Comparison
Procedure-Modeling (MCP-Mod) procedure under different assumptions for the dose-response
relationship (linear, Emax, and exponential,) is provided in Table 5. Based on
Study 53718678RSV1005 results, no discrimination between the proposed doses is expected
(ie, Emax dose-response shape was observed).


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Table 5: 
Power (%) to Conclude Dose-response Using MCP-Mod Under Different Assumptions for the
Dose-response Relationship
Assumed CV  
Assumed dose-response relationship
Linear 
Emax 
Exponential
Cohort 1 + Cohort 2 (N=74 per treatment arm)
20%  
100.0 
100.0 
100.0
35% 
92.3 
95.3 
96.6
Cohort 2 only (N=50 per treatment arm)
20%  
99.8 
100.0 
100.0
35% 
79.0 
84.0 
86.9
Cohort 1 only (N=24 per treatment arm)
20%  
91.5 
94.7 
96.2
35% 
47.1 
51.2 
54.7
If data of both cohorts are combined (N 74 per treatment arm), the power to conclude
dose-response is more than 90% for all 3 different assumptions for the dose-response relationship.
If data from Cohort 1 cannot be combined with data from Cohort 2 (eg, due to inconsistency
[means and/or variability] in viral load data between cohorts per treatment group), the power to
conclude a dose-response using the MCP-Mod procedure in Cohort 2 (N 50 per treatment arm) is
at least 79%.
The sample size in Cohort 1 only (N≥24 per treatment arm) will provide sufficient power
(approximately 90%) if the reduction in RSV viral load AUC is at least 20% with a CV which is
not higher than observed in Study 53718678RSV1005 (ie, 20%).
In conclusion, a sample size of 72 in Cohort 1 and 150 in Cohort 2 is sufficient to detect with
reasonable power the antiviral effect; even if the data of Cohort 1 cannot be combined with the
data of Cohort 2. Therefore, the primary analysis will be performed after approximately
150 subjects from Cohort 2 have completed the Day 14 assessments (or discontinued earlier). By
that time, it is expected that at least 72 subjects from Cohort 1 will have completed the Day 14
assessments (or discontinued earlier).
11.3.2. 
Key Secondary Objective: Clinical Course Effect
During interim analysis 3 (when approximately 70 to 80 subjects from Cohort 2 have completed
the Day 14 assessments [or discontinued earlier]; see Section 11.1.3), a sample size re-estimation
will be performed to allow an extension of Cohort 2 for the confirmation of the results on selected
clinical course endpoints. Based on all clinical course data from Cohort 2 available at the time of
the cut-off for the third interim analysis, one or more clinically relevant and sensitive endpoint(s)
will be selected for confirmation in the final analysis. Time to resolution (ie, to none or mild
symptoms) and reduction in severity of selected clinical signs/symptoms of RSV-related illness
are currently expected to be the most relevant clinical endpoints for Phase 3 planning. However,
data from this study, in combination with data from other RSV studies within and outside the
company, and knowledge obtained through health authority interaction(s) will be considered in
interim analysis 3 for the endpoint selection and sample size recalculation for Cohort 2.


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After selection of (a) clinical endpoint(s), the number of subjects in Cohort 2 will be calculated
that is required to minimize the conditional “consider”-probability for clinical endpoints (Go-
NoGo-approach) at the end of the study, assuming a required confidence of 90% (1-sided) to
exclude the target value and/or the minimal acceptable value.
For Cohort 1, assuming a median time to resolution of symptoms of 3 days in the placebo group,
a 1-day reduction in the active group (ie, ratio of 66%), and a scale parameter of 1/0.65, a sample
size of 48 subjects per treatment arm will reach 95% probability to reach an observed effect in the
right direction; based on estimates derived from an accelerated failure time model. This will allow
the evaluation of clinical course endpoints in the hospital population compared to the outpatients.
11.4. Efficacy Analyses
The primary population for the efficacy/antiviral activity analysis will be the intent-to-treat
infected population consisting of all randomized subjects who received at least one dose of study
treatment and who have a centrally confirmed RSV viral load of 1 log10 copies/mL above the
LLOQ at baseline.
11.4.1. 
Antiviral Effect
11.4.1.1. 
Primary Endpoint
The primary objective is to establish antiviral activity of JNJ-53718678. The primary efficacy
endpoint is the RSV viral load area under the curve (AUC) from immediately prior to first dose of
study drug through Day 5 derived from the RSV viral load as measured by a qRT-PCR assay in
nasal swabs. A hybrid methodology that combines aspects of multiple testing with modeling
techniques (MCP-Mod) will be used for evaluating dose-response trends and estimating the
dose-response relationships. Refer to Section 2.1.
A set of 3 candidate models will be used to cover a suitable range of possible dose-response shapes
(linear, Emax, exponential) (see Figure 3). Doses of the different age groups will be pooled and
transformed to the total daily dose of the oldest age group: low dose (3 mg/kg), high dose
(9 mg/kg), and placebo (0 mg/kg) and these will be used for the “treatment groups” in the analysis.


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Figure 3: 
Candidate Models for RSV Viral Load AUC From Baseline Until Day 5
AUC values with corresponding covariance matrix will be determined by modeling the log10 viral
load values over time using a restricted maximum likelihood-based repeated measures approach.
Analyses will include the fixed, categorical effects of treatment, strata, visit, and treatment-by-
visit interaction, as well as the continuous, fixed covariates of baseline log10 viral load and baseline
log10 viral load by-visit interaction. An unstructured (co)variance structure will be used to model
the within subject errors over time. The Kenward-Roger method will be used to approximate the
degrees of freedom.
Each of the dose-response shapes in the candidate set will be tested using the corresponding
contrast t-test statistic, employing a critical value derived for the maximum of the t-test statistics
(based on the associated multivariate t-distribution) to ensure appropriate multiplicity correction
that preserves the Type I error rate. A dose-response trend is established when the maximum of
the t-test statistics exceeds the critical value.
Details will be provided in the SAP that will be finalized before the first formal interim analysis.
11.4.1.2. 
Secondary Endpoints
The other antiviral endpoints 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.
Kaplan-Meier Curves will be produced to graphically describe the time to event data.
Differences between treatment groups in viral load will be derived from the same model as for the
primary endpoint using appropriate contrasts deriving least square mean differences, including the
95% 2-sided CIs. Other covariates as well as interaction effects might also be investigated.


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The time to undetectable RSV viral load will be analyzed using Kaplan-Meier plots and will be
modeled using an accelerated failure time model, adjusted for covariates, such as strata and
baseline viral load, to estimate differences between treatment groups. A generalized MCP-Mod
approach will be used to test for existence of dose-response, if applicable. For the MCP-Mod
approach, doses of the different age groups will be pooled and transformed to the total daily dose
of the oldest age group: low dose (3 mg/kg), high dose (9 mg/kg), and placebo (0 mg/kg) and these
will be used for the "treatment groups" in the analysis.
More details regarding the analysis of these data will be described in the SAP.
11.4.2. 
Clinical Course of RSV Infection
All endpoints 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.
Time to-variables (eg, time to resolution of symptoms, time to clinical stability, length of hospital
stay) will be analyzed using Kaplan-Meier plots and will be modeled using an accelerated failure
time model, adjusted for covariates, such as strata and baseline viral load, to estimate differences
between treatment groups. 80% and 95% 2-sided CIs will be calculated. A generalized MCP-Mod
approach defined as in Section 11.4.1.1 will be used to test for existence of dose-response.
Parent(s)/caregiver(s) PRESORS and clinician PRESORS scores will be descriptively summarized
by treatment group and compared between treatment groups. 80% and 95% 2-sided CIs will be
calculated. A generalized MCP-Mod approach as defined in Section 11.4.1.1 will be used to test
for existence of dose-response on parent(s)/caregiver(s) PRESORS  and clinician PRESORS
scores. For the MCP-Mod approach, doses of the different age groups will be pooled and
transformed to the total daily dose of the oldest age group: low dose (3 mg/kg), high dose
(9 mg/kg), and placebo (0 mg/kg) and these will be used for the "treatment groups" in the analysis.
Clinical course endpoints will be evaluated in Cohort 1 and Cohort 2 separately and will be
compared between the 2 cohorts.
More details regarding the analysis of these data will be described in the SAP.
11.4.3. 
Correlation Between Antiviral Effect and Clinical Course Endpoints
Selected antiviral effect and clinical course endpoints (parent[s]/caregiver[s] PRESORS and
clinician PRESORS  scores) will be subjected to correlation analysis. Various approaches,
including graphical analysis, regression methods but also longitudinal analyses will be utilized.
More details regarding the analysis of these data will be described in the SAP.
11.4.4. 
Viral Sequencing
The sequencing results of the F-gene (and other regions of the RSV genome, if applicable, at the
request of the protocol virologist) and changes from baseline will be summarized. Sequencing
results may be presented in a separate report.


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11.5. Safety Analyses
Safety data will be presented descriptively. Statistical testing of safety data, if appropriate, may be
presented in a separate report.
For safety, baseline is defined as the last assessment prior to the first intake of study drug.
The population for the safety analysis will consist of all randomized subjects who received at least
1 dose of study drug.
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). Treatment-emergent AEs are defined as
AEs with onset during the treatment phase or that are a consequence of a pre-existing condition
that has worsened since baseline. All reported AEs will be included in the analysis. For each AE,
the percentage of subjects who experienced at least 1 occurrence of the given event will be
summarized by treatment group.
Summaries, listings, datasets, or subject narratives may be provided, as appropriate, for those
subjects who died, who discontinued treatment due to an AE, or who experienced a severe or a
serious AE.
Clinical Laboratory Tests
Laboratory data will be summarized by type of laboratory test. Descriptive statistics will be
calculated for each laboratory analyte at baseline and for observed values and changes from
baseline at each scheduled timepoint. Changes from baseline results will be presented in pre-
versus post-treatment cross-tabulations (with classes for below, within, and above normal ranges).
Frequency tabulations of the abnormalities will be made. A listing of subjects with any laboratory
results outside the reference ranges will be provided. A listing of subjects with any markedly
abnormal laboratory result will also be provided.
The laboratory abnormalities will be determined per the criteria specified in the DMID  (see
Attachment 1) pediatric toxicity tables and in accordance with the normal ranges of the clinical
laboratory if no gradings were available.
Results from the central laboratory will be included in summary tables. Local laboratory results
(in case of cardiac events potentially related to QT prolongation) will be listed only.
Electrocardiogram (ECG)
The effects on cardiovascular variables will be evaluated by means of descriptive statistics and
frequency tabulations. These tables will include observed values and changes from baseline values
at each selected timepoint (the screening ECG will be used as baseline). Frequency tabulations of
the abnormalities will be generated.
The ECG variables that will be presented are heart rate, PR interval, QRS interval, QT interval,
QTcF, and QTcB.


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The percentage of subjects with abnormalities will be tabulated.
Changes from baseline results will be presented in pre- versus post-treatment cross-tabulations
(with classes for below, within, and above normal ranges).
Vital Signs
Descriptive statistics of body temperature, heart rate, respiratory rate, SBP, DBP, and SpO2 values
and changes from baseline will be summarized at each scheduled timepoint. The percentage of
subjects with values beyond clinically relevant limits (as defined in the SAP) will be summarized.
Physical Examination
Physical examination findings will be summarized at each scheduled time point.
11.6. Pharmacokinetic Analyses
Population PK analysis of concentration-time data of JNJ-53718678 may 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 subject characteristics (demographics,
laboratory variables, 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 JNJ-53718678 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 subjects with available whole blood concentrations per intervention
group. Subjects 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 drug; 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 subjects 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 JNJ-53718678, and, if applicable, of metabolites
and/or endogenous markers.
11.7. Pharmacokinetic/Pharmacodynamic Relationships
Relationships of JNJ-53718678 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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Results of PK/PD analyses may be presented in a separate report.
11.8. Medical Resource Utilization Analyses
Medical resource utilization will be descriptively summarized by treatment group.
11.9. Acceptability and Palatability
Data on acceptability and palatability of the JNJ-53718678 formulation will be presented
descriptively.
11.10. Biomarker Analyses
Analyses may be performed at the sponsor’s discretion and reported separately from this study.
Statistical approaches to explore correlations between clinical outcome, viral load, and biomarkers
in blood and mid-turbinate nasal swabs vary and depend on the different data types of the applied
technology platforms, as well as on the extent of observed differences among study subjects.
11.11. Other Analyses
Data on viral (other than RSV) or bacterial pathogens (both by multiplex PCR) determined in mid-
turbinate nasal swabs collected at screening will be listed.
11.12. Independent Data Monitoring Committee
An IDMC will be established to monitor and review data in an unblinded manner on a regular
basis to ensure the continuing safety of the subjects enrolled in this study. The committee will meet
periodically to review safety data, safety and PK data of the subcohort of Cohort 1 and results from
interim analyses. In addition, an IDMC analysis of the safety and PK data of the full cohort of
hospitalized subjects (including the full subcohort) is planned after all subjects of Cohort 1 have
completed the study (or discontinued earlier). In case the timing of this IDMC analysis coincides
with that of one of the scheduled interim analyses, it may be performed as part of that interim
analysis. After the review, the IDMC will provide recommendations 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 subjects. The IDMC can recommend to the Sponsor Committee to halt a dose arm due to
safety concerns.
The IDMC will consist of at least one pediatrician, at least one medical expert in infectious
diseases, and at least one statistician. The IDMC responsibilities, authorities, and procedures will
be documented in the IDMC Charter.
Given the challenges of ensuring study site preparation in time to recruit for an acute seasonal
infection like RSV and the delays caused by implementing an amendment during an RSV season,
the following changes will be considered based on the results of any formal interim analysis and
may be modified by recommendation of the IDMC based on the review of this study and data from
other ongoing studies: changes with respect to the time since onset of symptoms and changes with
respect to dose selection. If the IDMC determines that subjects with a time since onset of RSV


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symptoms of 5 days prior to randomization may not achieve benefit based on interim results, they
may recommend that the time of onset of RSV symptoms to the time of randomization is reduced.
Furthermore, if the IDMC determines that subjects with a time since onset of RSV symptoms
longer than 5 days prior to randomization may achieve benefit, this duration may be increased to
up to 7 days (ie, 7 days from symptom onset to randomization). In addition, the requirement that
a minimum of 45% of all enrolled subjects in Cohorts 1 and 2 (ie, maximum 55% of subjects can
be enrolled in the >3 days to ≤5 days stratum) are to have a symptom onset of ≤3 days before
randomization, might be modified based on the recommendation of the IDMC after review of the
interim data. Also, in case the data shows no viral and clinical benefit on the low dose, the IDMC
might recommend to drop the low dose and continue with a 2:1 randomization for high dose versus
placebo. If such modifications are recommended by the IDMC and endorsed by the Sponsor
Committee, these changes will be communicated in writing to investigators, health authorities, and
IEC/IRB and may be implemented without amendment to this protocol. Details are provided in the
IDMC Charter.
12. 
ADVERSE EVENT REPORTING
Timely, accurate, and complete reporting and analysis of safety information from clinical studies
are crucial for the protection of subjects, 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.
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 subject’s parent(s)/caregiver(s) is the preferred method to inquire about
AE occurrence.
12.1. Definitions
12.1.1. 
Adverse Event Definitions and Classifications
Adverse Event
An AE is any untoward medical occurrence in a clinical study subject administered a medicinal
(investigational or non-investigational) product. An adverse event does not necessarily have a
causal relationship with the intervention. An adverse event 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.


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Note: The sponsor collects adverse events starting with the signing of the ICF  (refer to
Section 12.3.1, All Adverse Events, for time of last adverse event recording).
Serious Adverse Event
A serious adverse event 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 subject 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 subject or may require
intervention to prevent one of the other outcomes listed in the definition above. These should
usually be considered serious.
If a serious and unexpected adverse event occurs for which there is evidence suggesting a causal
relationship between the study drug and the event (eg, death from anaphylaxis), the event must be
reported as a serious and unexpected suspected adverse reaction even if it is a component of the
study endpoint (eg, all-cause mortality).
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 JNJ-53718678, the expectedness of an AE will be determined by
whether or not it is listed in the IB.
Adverse Event Associated With the Use of the Intervention
An AE is considered associated with the use of the drug if the attribution is possible, probable, or
very likely by the definitions listed in Section 12.3.1, Attribution Definitions.
12.1.2. 
Attribution Definitions
Not Related
An AE that is not related to the use of the intervention.


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Doubtful
An AE for which an alternative explanation is more likely, eg, concomitant drug(s), concomitant
disease(s), or the relationship in time suggests that a causal relationship is unlikely.
Possible
An AE that might be due to the use of the intervention. An alternative explanation, eg, concomitant
drug(s), concomitant disease(s), is inconclusive. The relationship in time is reasonable; therefore,
the causal relationship cannot be excluded.
Probable
An AE that might be due to the use of the intervention. The relationship in time is suggestive
(eg, confirmed by dechallenge). An alternative explanation is less likely, eg, concomitant drug(s),
concomitant disease(s).
Very Likely
An AE that is listed as a possible adverse reaction and cannot be reasonably explained by an
alternative explanation, eg, concomitant drug(s), concomitant disease(s). The relationship in time
is very suggestive (eg, it is confirmed by dechallenge and rechallenge).
12.1.3. 
Severity Criteria
An assessment of severity grade, as per DMID (see Attachment 1), will be made using the
following general categorical descriptors:
Mild: Awareness of symptoms that are easily tolerated, causing minimal discomfort and not
interfering with everyday activities.
Moderate: Sufficient discomfort is present to cause interference with normal activity.
Severe: Extreme distress, causing significant impairment of functioning or incapacitation.
Prevents normal everyday activities.
The investigator should use clinical judgment in assessing the severity of events not directly
experienced by the subject (eg, laboratory abnormalities).
12.2. Special Reporting Situations
Safety events of interest on a sponsor study drug that may require expedited reporting or safety
evaluation include, but are not limited to:
 
Overdose of a sponsor study drug
 
Suspected abuse/misuse of a sponsor study drug
 
Accidental or occupational exposure to a sponsor study drug
 
Medication error involving a sponsor product (with or without subject/patient exposure to the
sponsor study drug, eg, name confusion)


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Special reporting situations should be recorded in the eCRF. Any special reporting situation that
meets the criteria of a SAE should be recorded on the SAE page of the eCRF.
12.3. Procedures
12.3.1. 
All Adverse Events
All AEs and special reporting situations, whether serious or non-serious, will be reported from the
time a signed and dated ICF  is obtained until completion of the subject's last study-related
procedure, which may include contact for follow-up of safety. Anticipated events will be recorded
and reported as described in Attachment 3. Serious AEs, including those spontaneously reported
to the investigator within 30 days after the last dose of study drug, must be reported using the SAE
Form. The sponsor will evaluate any safety information that is spontaneously reported by an
investigator beyond the time frame specified in the protocol.
All events that meet the definition of a serious adverse event will be reported as serious adverse
events, regardless of whether they are protocol-specific assessments.
All AEs, regardless of seriousness, severity, or presumed relationship to study drug, 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.
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). For anticipated events
reported as individual serious adverse events the sponsor will make a determination of relatedness
in addition to and independent of the investigator’s assessment. The sponsor will periodically
evaluate the accumulating data and, when there is sufficient evidence and the sponsor has
determined there is a reasonable possibility that the intervention caused a serious anticipated event,
they will submit a safety report in narrative format to the investigators (and the head of the
investigational institute where required). The sponsor assumes responsibility for appropriate
reporting of anticipated events to the regulatory authorities according to requirements of the
countries in which the studies are conducted. The investigator (or sponsor where required) must
report SUSARs to the appropriate Independent Ethics Committee/Institutional Review Board
(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.
For all studies with an outpatient phase, including open-label studies, the subject must be provided
with a "wallet (study) card" and instructed to carry this card with them for the duration of the study
indicating the following:


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 
Study number
 
Statement, in the local language(s), that the subject 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 staff only)
 
Site number
 
Subject number
 
Any other information that is required to do an emergency breaking of the blind
12.3.2. 
Serious Adverse Events
All SAEs 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.
Information regarding serious adverse events will be transmitted to the sponsor using the SAE
Form and Safety Report Form of the CRF, 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 a SAE should be transmitted electronically.
All SAEs that have not resolved by the end of the study, or that have not resolved upon
discontinuation of the subject'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 drug or to factors unrelated to study
conduct
 
It becomes unlikely that any additional information can be obtained (subject or health care
practitioner refusal to provide additional information, lost to follow-up after demonstration of
due diligence with follow-up efforts)
Suspected transmission of an infectious agent by a medicinal product will be reported as a serious
adverse event.
Any event requiring hospitalization (or prolongation of hospitalization) that occurs during the
course of a subject's participation in a study must be reported as a SAE, except hospitalizations for
the following:
 
Hospitalizations not intended to treat an acute illness or adverse event (eg, social reasons such
as pending placement in long-term care facility)
 
Surgery or procedure planned before entry into the study (must be documented in the eCRF).
Note: Hospitalizations that were planned before the signing of the ICF, and where the
underlying condition for which the hospitalization was planned has not worsened, will not be


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considered serious adverse events. Any adverse event that results in a prolongation of the
originally planned hospitalization is to be reported as a new serious adverse event.
The cause of death of a subject in a study, whether or not the event is expected or associated with
the study drug, is considered a serious adverse event.
12.4. Contacting Sponsor Regarding Safety
The names (and corresponding telephone numbers) of the individuals who should be contacted
regarding safety issues or questions regarding the study are listed in the Contact Information
page(s), which will be provided as a separate document.
13. 
PRODUCT QUALITY COMPLAINT HANDLING
A product quality complaint (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, or reliability of a product, including its labeling or package integrity. A PQC may have
an impact on the safety and efficacy of the product. Timely, accurate, and complete reporting and
analysis of PQC information from studies are crucial for the protection of subjects, investigators,
and the sponsor, and are mandated by regulatory agencies worldwide. The sponsor has established
procedures in conformity with regulatory requirements worldwide to ensure appropriate reporting
of PQC information; all studies conducted by the sponsor or its affiliates will be conducted in
accordance with those procedures.
13.1. 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.
If the defect is combined with a serious adverse event, the study-site personnel must report the
PQC to the sponsor according to the serious adverse event reporting timelines (refer to
Section 12.3.2, Serious Adverse Events). A sample of the suspected product should be maintained
for further investigation if requested by the sponsor.
13.2. Contacting Sponsor Regarding Product Quality
The names (and corresponding telephone numbers) of the individuals who should be contacted
regarding product quality issues are listed in the Contact Information page(s), which will be
provided as a separate document.
14. 
STUDY DRUG INFORMATION
14.1. Physical Description of Study Drug
JNJ-53718678 supplied for this study is formulated as a powder for oral suspension containing
1,636 mg/bottle of JNJ-53718678-ZCL. After reconstitution with the appropriate volume of
solvent, the final oral suspension is obtained containing 23 mg/mL JNJ-53718678-ZCL
(hemi (L)-tartrate salt form), hydroxypropylmethyl cellulose (2910 5 mPa.s), d-a-tocopheryl
polyethylene glycol-1000 succinate, sucralose, strawberry flavor, sodium methylparaben, sodium


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ethylparaben, 
hydrochloric 
acid, 
simethicone, 
and 
purified 
water. 
23 mg/mL 
of
JNJ-53718678-ZCL is equivalent to 20 mg/mL of JNJ-53718678-AAA and 3 mg/mL tartaric acid.
The pH of the suspension is >3. Refer to the IB additional information on the formulation.
The JNJ‑53718678 placebo powder for oral suspension is supplied as a 4,068-mg/bottle
microcrystalline cellulose and will be reconstituted with an appropriate volume of placebo solvent
to obtain a placebo oral suspension.
All study dugs will be manufactured and provided under the responsibility of the sponsor.
14.2. Packaging
Packaging of study drugs will be done under the responsibility of the sponsor; the clinical release
will be performed by the sponsor.
JNJ-53718678 powder for oral suspension, placebo powder for oral suspension and solvent will
be packed in amber glass bottles containing all study drugs needed for the described dose schedule.
Reconstitution is performed by the study-site pharmacist or study-site staff prior to administration,
as described in the pharmacy manual.
Packaging and labeling of JNJ-53718678 and placebo powder for oral suspension will be done in
a double-blind way. The pharmacist, study site staff or parent(s)/caregiver(s) will draw the
assigned volume from the blinded bottles into the oral dispenser prior to administration to the
subject.
Primary packaging will be child resistant (child resistant screw cap on bottle) to accommodate
outpatient use.
No study drugs can be repacked without prior approval from the sponsor.
14.3. Labeling
Labeling of study drugs will be done under the responsibility of the sponsor. Study drug labels will
contain information to meet the applicable regulatory requirements. No study drugs can be re-
labelled without prior approval from the sponsor.
14.4. Handling, and Storage
All study drug should be stored on site and at home as instructed on the label. Refer to the IPPI for
additional guidance on study drug handling and storage.
14.5. Drug Accountability
The investigator is responsible for ensuring that all study drug received at the site is inventoried
and accounted for throughout the study. The dispensing of study drug to the subject’s
parent(s)/caregiver(s), and the return of study drug (if applicable), must be documented on the drug
accountability form. The subject’s parent(s)/caregiver(s) must be instructed to return all original


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containers, whether empty or containing study drug. All study drug will be stored and disposed of
according to the sponsor's instructions.
Study drug 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 drug, and study drug returned by the subject’s
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 drug, or used returned study
drug for destruction, will be documented on the intervention return form. When the study site is
an authorized destruction unit and study drug supplies are destroyed on-site, this must also be
documented on the drug return form.
Potentially hazardous materials such as used ampules, needles, syringes and vials containing
hazardous liquids, should be disposed of immediately in a safe manner and therefore will not be
retained for drug accountability purposes.
Study drug 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 drug will be supplied only to
subjects participating in the study. Returned study drug must not be dispensed again, even to the
same subject. Study drug may not be relabeled or reassigned for use by other subjects. The
investigator agrees neither to dispense the study drug from, nor store it at, any site other than the
study sites agreed upon with the sponsor.
15. 
STUDY-SPECIFIC MATERIALS
The investigator will be provided with the following supplies:
 
JNJ-53718678 IB and any addenda
 
IWRS Manual
 
eCRF completion guidelines
 
Laboratory manual
 
Electronic device for clinician and parent/caregiver PRESORS, logs and tolerability
questionnaire
 
Completion guides for clinician and parent/caregiver PRESORS, logs and tolerability
questionnaire
 
Study information and instruction sheets for parent(s)/caregivers(s) regarding study
procedures ie, dosing and nasal swabbing
 
Specimen collection kits for PK, safety blood and urine samples as well as nasal swab samples
 
Contact information page(s)
 
Pharmacy manual, including study drug preparation and dispensing instructions
 
Oral dosing syringes
 
ECG machine and manual


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 
Additional ancillary equipment, as needed
16. 
ETHICAL ASPECTS
16.1. Study-Specific Design Considerations
The potential subject’s legally acceptable representative 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 the potential subject’s participation. They will be told that their
consent for the participation of the potential subject 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 they would
otherwise be entitled. Only subjects will be enrolled whose legally acceptable representatives are
fully able to understand the risks, benefits, and potential AEs of the study, and provide their consent
voluntarily.
When referring to the signing of the ICF, the terms legal guardian and legally acceptable
representative refer to the legally appointed guardian of the child with authority to authorize
participation in research. For each subject, 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. Assent must be obtained from children
(minors) capable of understanding the nature of the study, typically subjects 7 years of age and older,
depending on the institutional policies. For the purposes of this study, all references to subjects who
have provided consent (and assent as applicable) refers to the subjects and his or her parent(s) or the
subject's legal guardian(s) or legally acceptable representative(s) who have provided consent
according to this process. Minors who assent to a study and later withdraw that assent should not be
maintained in the study against their will, even if their parent(s) still want them to participate.
The total blood volume to be collected is considered to be in line with generally acceptable
guidelines for the collection of blood samples for this age group.12 The maximum amount of blood
drawn from each subject for study-specific purposes will not exceed 9.2 mL over the duration of
the study. In addition, 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
as possible additional stress for the subject. Use of local anesthetics at the spot of the puncture is
allowed.
16.2. Regulatory Ethics Compliance
16.2.1. 
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 subjects.
Compliance with this standard provides public assurance that the rights, safety, and well-being of


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study subjects are protected, consistent with the principles that originated in the Declaration of
Helsinki, and that the study data are credible.
16.2.2. 
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 subjects)
 
Investigator's Brochure (or equivalent information) and amendments/addenda
 
Sponsor-approved subject recruiting materials
 
Information on compensation for study-related injuries or payment to subjects 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 subjects
 
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
subjects, data or study conduct, unless required locally), the ICF, applicable recruiting materials,
and subject 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 subjects, data or study conduct)
 
Revision(s) to ICF and any other written materials to be provided to subjects
 
If applicable, new or revised subject recruiting materials approved by the sponsor
 
Revisions to compensation for study-related injuries or payment to subjects 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 adverse events that are serious, unlisted/unexpected, and associated with the study
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 
New information that may adversely affect the safety of the subjects or the conduct of the
study
 
Deviations from or changes to the protocol to eliminate immediate hazards to the subjects
 
Report of deaths of subjects 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 subjects, 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).
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.
16.2.3. 
Informed Consent
Each legally acceptable representative 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 subject’s legally acceptable
representative 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 study-site
personnel must explain to the legally acceptable representatives of potential subject’s the aims,
methods, reasonably anticipated benefits, and potential hazards of the study, and any discomfort
participation in the study may entail. Subject’s legally acceptable representatives will be informed
that their participation 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 subject will
receive. Finally, they will be told that the investigator will maintain a subject 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 subject,
to the extent permitted by the applicable law(s) or regulations. By signing the ICF the subject’s
legally acceptable representative is authorizing such access, which includes permission to obtain
information about his or her survival status and agrees to allow his or her study physician to
recontact the subject’s legally acceptable representatives for the purpose of obtaining consent for
additional safety evaluations, if needed.


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The subject’s legally acceptable representative 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 subject's legally acceptable representative's
personally dated signature. After having obtained the consent, a copy of the ICF must be given to
the subject’s legally acceptable representative.
If the subject’s legally acceptable representative is 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
subject’s legally acceptable representative is obtained.
16.2.4. 
Privacy of Personal Data
The collection and processing of personal data from subjects 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 subjects confidential.
The informed consent obtained from the subject’s 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 subject’s legally acceptable representative has the right to request through the investigator
access to his or her 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, and the applicable laws and
regulations.
Exploratory biomarker andPK research is not conducted under standards appropriate for the return
of data to subjects. 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 subject’s legally acceptable representative 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.
16.2.5. 
Long-Term Retention of Samples for Additional Future Research
Samples collected in this study may be stored for up to 15 years (or according to local regulations)
for additional research. Samples will only be used to understand JNJ-53718678, to understand


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RSV infection, to understand differential drug responders, and to develop tests/assays related to
JNJ-53718678 and RSV infection. The research may begin at any time during the study or the
post-study storage period. No human genetic testing will be performed on these samples.
Stored samples will be coded throughout the sample storage and analysis process and will not be
labeled with personal identifiers. The subject’s legally acceptable representative may withdraw
their consent for their samples to be stored for research (refer to Section 10.5, Withdrawal From
the Use of Samples in Future Research).
16.2.6. 
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 16.1, Study-Specific Design
Considerations.
17. 
ADMINISTRATIVE REQUIREMENTS
17.1. Protocol Amendments
The doses or treatment regimen of JNJ-53718678 may be modified by recommendation of the
IDMC and Sponsor Committee decision at any time for PK, efficacy, or safety reasons based on
the review of this and other ongoing studies of JNJ-53718678. If such modifications are
recommended based on IDMC review, these changes will be communicated in writing to
investigators, health authorities, and ethics committees and may be implemented without
amendment to this clinical trial protocol.
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 eCRF and source
documents will reflect any departure from the protocol, and the source documents will describe
this departure and the circumstances requiring it.
17.2. Regulatory Documentation
17.2.1. 
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.
17.2.2. 
Required Prestudy Documentation
The following documents must be provided to the sponsor before shipment of study drug 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, subject 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 subject:
 
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
17.3. Subject Identification, Enrollment, and Screening Logs
The investigator agrees to complete a subject identification and enrollment log to permit easy
identification of each subject during and after the study. This document will be reviewed by the
sponsor study-site contact for completeness.
The subject identification and enrollment log will be treated as confidential and will be filed by
the investigator in the study file. To ensure subject confidentiality, no copy will be made. All
reports and communications relating to the study will identify subjects by subject identification
and age at initial informed consent. In cases where the subject is not randomized into the study,
the date seen and age at initial informed consent will be used.


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The investigator must also complete a subject screening log, which reports on all subjects who
were seen to determine eligibility for inclusion in the study.
17.4. Source Documentation
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:
subject 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 adverse events and follow-up of adverse events; concomitant medication;
intervention receipt/dispensing/return records; study drug administration information; and date of
study completion and reason for early discontinuation of study drug 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).
The following data will be recorded directly into the eCRF and will be considered source data:
 
History of passive smoking all nicotine use, eg, cigarettes (including e-cigarettes or the
equivalent of e-cigarettes),
 
Details of physical examination at screening
The following data will be recorded directly into the electronic device and will be considered
source data:
 
Clinician  PRESORS  and parent(s)/caregiver(s) PRESORS, medication, nasal swabs, and
temperature logs, and the study medication tolerability assessment.
The minimum source documentation requirements for Section 4.1, Inclusion Criteria and
Section 4.2, Exclusion Criteria that specify a need for documented medical history are as follows:
 
Referral letter from treating physician or
 
Complete history of medical notes at the site
Inclusion and exclusion criteria not requiring documented medical history must be verified at a
minimum by parent(s/caregiver(s) interview or other protocol required assessment (eg, physical
examination, laboratory assessment) and documented in the source documents.
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
eCRF in the protocol include the electronic source system but information collected through the


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electronic source system may not be limited to that found in the eCRF. Data in this system may be
considered source documentation.
17.5. Case Report Form Completion
Case report forms are prepared and provided by the sponsor for each subject in electronic format.
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 subject's source documents. Data must be entered into
eCRF in English. The eCRF must be completed as soon as possible after a subject visit and the
forms should be available for review at the next scheduled monitoring visit.
All subjective 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 electronic data capture (eDC) tool. If corrections to
an 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.
17.6. Pediatric RSV Electronic Severity and Outcomes Rating Scales
Pediatric RSV Electronic Severity and Outcomes Rating Scales will be completed by clinician
(clinician PRESORS; Attachment 4) and parent(s)/caregiver(s) (parent[s]/caregiver[s] PRESORS;
Attachment 5), respectively, on an electronic instrument provided at the study-site. Responses
provided will be recorded directly in the electronic database.
17.6.1. 
Clinician
The clinician will provide information about the subject's status, symptoms, and behavior on an
electronic device at time points noted in the TIME AND EVENTS SCHEDULE. Before
completing the first assessment of any subject in the study, the clinician must complete the
assigned electronic clinician PRESORS training. Practical training on the electronic device will be
available on demand.


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17.6.2. 
Parent(s)/caregiver(s)
The subject's parent(s) or caregiver(s) with routine and frequent experience in caring for the subject
will provide information about the subject's status, symptoms, and behaviors as well as the impact
of the subject's RSV disease on the household on an electronic device at time points noted in the
TIME AND EVENTS SCHEDULE. In addition, for the outpatients (Cohort 2) and subjects after
hospital discharge (Cohort 1), the parent(s)/caregiver(s) will record study drug administered,
temperature and (home) nasal swab collection on the electronic device in the medication,
temperature and nasal swab logs, respectively. All parent(s)/caregiver(s) assessments and logs will
be provided in the native language of the parent(s)/caregiver(s). The electronic device will include
instructions and training that will be completed upon first use by the parent(s)/caregiver(s) and
will be available on demand thereafter if parent(s)/caregiver(s) chooses this option.
17.7. 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, direct transmission
ofclinical laboratoryand ECG data from a central laboratory into the sponsor's database and direct
transmission of clinician PRESORS and parent(s)/caregiver(s) PRESOR 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 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.
17.8. 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 subject, 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.


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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/institutionmust permit access to such reports.
17.9. Monitoring
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 the data entered into the eCRF  with the source documents
(eg, hospital/clinic/physician’s office medical records). 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 study-site 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.
17.10. Study Completion/Termination
17.10.1. 
Study Completion/End of Study
The study is considered completed with the last visit for the last subject participating in the study.
The final data from the study site will be sent to the sponsor (or designee) after completion of the
final subject visit at that study site, in the time frame specified in the Clinical Trial Agreement.
17.10.2. 
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
studysite 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 subjects by the investigator
 
Discontinuation of further study drug development
17.11. 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. Subject privacy must, however, be respected.
The investigator and study-site personnel are responsible for being present and available for
consultation during routinely scheduled study-site audit visits conducted by the sponsor or its
designees.
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 he or she has
been contacted by a regulatory agency concerning an upcoming inspection.
17.12. Use of Information and Publication
All information, including but not limited to information regarding JNJ-53718678 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 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 of JNJ-53718678, 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 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 subject identifiers will not be used
in publication of results. Any work created in connection with performance of the study and


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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 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
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 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.




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24. Rivera CA, Gómez RS, Díaz RA, et al. Novel therapies and vaccines against the human respiratory syncytial
virus. Expert Opin Investig Drugs. 2015;24:1613-1630.
25. Rudan I, Boschi-Pinto C, Biloglav Z, Mulholland K, Campbell H. Epidemiology and etiology of childhood
pneumonia. Bull. World Health Organ. 2008; 86(5):408-416.
26. Shi T, McAllister DA, O'Brien KL, et al. Global, regional, and national disease burden estimates of acute lower
respiratory infections due to respiratory syncytial virus in young children in 2015: a systematic review and
modelling study. Lancet. 2017;390:946-958.
27. Thwaites RS, Coates M, Kazuhiro I et al. Reduced nasal viral load and IFN responses in infants with RSV
bronchiolitis and respiratory failure. Am J Respir Crit Care Med. 2018.
28. Wainwright C. Acute viral bronchiolitis in children –a very common condition with few therapeutic options.
Paediatr Respir Rev. 2010; 11(1):39-45.
29. Walsh EE, Peterson DR, Kalkanoglu AE, et al. Viral shedding and immune responses to respiratory syncytial
virus infection in older adults. J Infect Dis. 2013;207:1424-1432.
30. Yusuf S, Piedimonte G, Auais A, et al. The relationship of meteorological conditions to the epidemic activity
of respiratory syncytial virus. Epidemiol Infect. 2007;135:1077-1090.
31. Zhou H, Thompson WW, Viboud CG, et al. Hospitalizations associated with influenza and respiratory
syncytial virus in the United States, 1993-2008. Clin Infect Dis. 2012;54:1427-1436.


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ATTACHMENTS
Attachment 1: 
Division of Microbiology and Infectious Diseases (DMID)
Pediatric Toxicity Tables (November 2007; draft)
DIVISION OF MICROBIOLOGY AND INFECTIOUS
DISEASES (DMID) PEDIATRIC TOXICITY TABLES
NOVEMBER 2007
DRAFT23
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.


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COMMENTS REGARDING THE USE OF THESE TABLES
 
Standardized and commonly used toxicity tables (Division of AIDS, 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/freq 
uency 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


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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/Bradycardi
a;
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/spina
l 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
drug
Sufficiently 
severe to require 
evaluation and 
treatment, 
including at least 
temporary 
suspension of 
study drug 
Life-threatening
severity;
Requires
immediate
evaluation,
treatment, and
usually
hospitalization;
Study drug must
be stopped
immediately and
should not be
restarted until the
abnormality is
clearly felt to be
caused by some
other mechanism
that study drug


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Attachment 2: 
Cardiovascular Safety –Abnormalities
Electrocardiogram
All important abnormalities from the ECG readings will be listed.
Parameter (unit) 
Age class 
Abnormally low  
Abnormally high
PR (msec) 
0 - 2 years 
NA  
>150
2 - <3 years 
<100 
>150
QRS (msec) 
0 - 2 years 
NA  
>79
2 - <3 years 
<40 
>79
QT (msec) 
0 - 2 years 
NA  
>500
2 - <18 years 
<320 
>450
RR (msec) 
0 - 3 months 
<333 
>750
3 - 12 months 
<400 
>860
1 - 2 years 
<430 
>1000
2 - <18 years 
<600 
>1200
Vital Signs
Normal ranges:
Parameter (unit) 
Age class
0 –3 months 
3 –6 months 
6 –12 months 
1 –2 years 
2- <3 years
Diastolic BP (mmHg) 
45 - 55 
50 - 65 
55 - 65 
55 - 70 
45 - 60
Systolic BP (mmHg) 
65 -85 
70 - 80 
80 - 100 
90 - 105 
85 - 100
Heart rate HR (bpm) 
100 - 150 
90 - 120 
80 - 120 
70 - 110 
95 - 125
Respiratory rate 
35 - 55 
30 - 45 
25 - 40 
20 - 30 
22 - 30
Oxygen saturation 
SpO2 (%)
≥96 
≥96 
≥96 
≥96 
≥96
The following clinically relevant abnormalities, measured at rest, will be defined for vital signs:


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Parameter (unit) 
Age class
0 –3 months 3 –12 months 
1 - 2-years 
2- <3 years
Diastolic BP 
(mmHg)
abnormally low
<35 
<40 
<40 
<40
abnormally high  
>65 
>85 
>90 
>70
Systolic BP 
(mmHg)
abnormally low
<60 
<60 
<75 
<80
abnormally high  
>110 
>110 
>120 
>110
Heart rate HR 
(bpm)
abnormally low
<80 
<70 
<60 
<90
abnormally high  
>180 
>150 
>140 
>130
Respiratory rate 
abnormally low
<25 
<20 
<18 
<20
abnormally high  
>70 
>60 
>50 
>35
Oxygen saturation 
SpO2 (%)
abnormally low
<92 
<92 
<92 
<92
References:
http://www.pinterest.com/pin/396316835929288711/
http://www.docstoc.com/docs/88983719/Pediatric-Vital-Signs
http://www.coheadquarters.com/PennLibr/MyPhysiology/Appendix/AppendVital1.htm


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Attachment 3: 
Anticipated Events
Anticipated Event
An anticipated event is an adverse event (serious or non-serious) that commonly occurs as a
consequence of the underlying disease or condition under investigation (disease related) or
background regimen.
For the purposes of this study the following events will be considered anticipated events:
 
Cyanosis
 
Pneumonia
 
Bronchiolitis
 
Respiratory failure
 
Rhinitis
 
Co-infections (bacterial or viral)
Reporting of Anticipated Events
All adverse events will be recorded in the CRF regardless of whether considered to be anticipated
events and will be reported to the sponsor as described in Section 12.3.1, All Adverse Events. Any
anticipated event that meets serious adverse event criteria will be reported to the sponsor as
described in Section 12.3.2, Serious Adverse Events. These anticipated events are exempt from
expedited reporting as individual single cases to Health Authorities. However, if based on an
aggregate review, it is determined that an anticipated event is possibly related to study intervention,
the sponsor will report these events in an expedited manner.
Safety Assessment Committee
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.
Statistical Analysis
Details of statistical analysis of anticipated events, including the frequency of review and threshold
to trigger an aggregate analysis of anticipated events will be provided in a separate Anticipated
Events Safety Monitoring Plan (ASMP).


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Attachment 4: 
Clinician PRESORSv7 (24 May 2018)
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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Attachment 5: 
Parent(s)/Caregiver(s) PRESORSv7.1 (9July2018)
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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CCI








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Attachment 9: 
Study Medication Tolerability 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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Attachment 10: 
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 subjects 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 subject 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 judgement of the
investigator to protect the health and well-being of subjects and site staff. If, at any time, a subject’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, subjects’ parents/caregivers will be interviewed to collect safety data. Key efficacy
endpoint assessments should be performed if required and as feasible. Subjects’ parents/caregivers
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 subjects on study
intervention, including follow up. Modifications to protocol-required assessments may be
permitted after consultation between the subjects’ 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 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 subject has tested positive for COVID-19, the investigator should contact the sponsor’s
responsible medical officer to discuss plans for study intervention and follow-up. 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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GUIDANCE SPECIFIC TO THIS PROTOCOL:
 
These emergency provisions are meant to ensure subject 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 labelled with the
prefix “COVID-19-related” in the eCRF/eSource by the site personnel where needed.
 
Administration of the study intervention:
 
If a subject cannot visit the site in person for the first administration of study intervention
(Day 1), trained delegated staff, in accordance with local regulations, can visit subject’s
home to:
o 
instruct subjects’ parent(s)/caregiver(s) on how to use and store the study drug for
at-home dosing as per sponsor dosing instructions.
o 
administer the first study intervention themselves or supervise the subjects'
parent/caregiver during first study intervention administration.
o 
monitor any AEs related to dosing.
 
The date and time of the study intervention administration at the subject’s home at Day 1
will be documented in the subject’s source documents and in the eCRF.
 
Subject Visits/Assessments:
 
If a subject cannot visit the study site in person at Day 1, the sponsor recommends that
any study assessment that may be captured during home visit (such as but not limited to
ECG, mid turbinate nasal swab, PK blood sample collection, Clinician PRESORS and
clinical evaluation) for that particular visit be collected. These assessments and collection
should be performed at subject’s home by trained delegated site staff or home health
service staff.
 
If required, mid turbinate nasal swab and PK samples collection can be stored and picked
up by site staff or courier. In that case, provision of dry ice is required for PK blood
samples.
 
There are some assessments that could be conducted virtually via telephone (or
videoconference, eg, Facetime, Skype, if possible) with subjects’ 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 parent(s)/caregiver(s)
PRESORS completion and medical resource utilization. Please note, the visit windows
included in the TIME AND EVENTS SCHEDULE  are still applicable. It must be
documented in the eCRF and in the subjects’ source documents when  a visit occurs
virtually due to COVID-19.
 
The study assessments that require investigator judgement should be conducted by a
qualified site member identified on the site delegation log.
 
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.


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 
On-site Monitoring visits:
In case on-site monitoring visits are not be 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 future to catch up on source data
verification. Remote source data verification of electronic records might be performed if
possible and 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 be not 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.
 
When, per local procedures, both caregivers need to provide consent, the sponsor allows
obtaining the second consent remotely (phone or video) if allowed per local guidance.


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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: 
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.


Signature
User 
Date 
Reason
 01-Dec-2020 
15:25:28
(GMT)
Document Approval
PPD

SAP_001.pdf: 
JNJ-53718678
Statistical Analysis Plan Protocol 53718678RSV2002
CONFIDENTIAL – FOIA Exemptions Apply in U.S.
1
Approved, Date: 20 May 2021
Janssen Research & Development
Statistical Analysis Plan
Amendment 3
A Phase 2, Double-blind, Placebo-controlled Study to Evaluate the Antiviral Activity, 
Clinical Outcomes, Safety, Tolerability, and Pharmacokinetic/Pharmacodynamic 
Relationships of Different Doses of JNJ-53718678 in Children ≥28 Days and ≤3 Years of 
Age With Acute Respiratory Tract Infection Due to Respiratory Syncytial Virus Infection
Protocol 53718678RSV2002; Phase 2
JNJ-53718678
Status:
Approved
Date:
20 May 2021
Prepared by:
Janssen Research & Development, a Division of Janssen Pharmaceutica NV.
Document No.: EDMS-ERI-169418770, 5.0
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.
NCT03656510


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TABLE OF CONTENTS
TABLE OF CONTENTS ..................................................................................................... 2
LIST OF IN-TEXT TABLES AND FIGURES...................................................................... 4
AMENDMENT HISTORY.................................................................................................... 5
ABBREVIATIONS ............................................................................................................15
1.
INTRODUCTION......................................................................................................15
1.1.
Trial Objectives ....................................................................................................16
1.2.
Trial Design ..........................................................................................................17
1.3.
Statistical Hypotheses for Trial Objectives...........................................................20
1.4.
Sample Size Justification .....................................................................................20
1.5.
Randomization and Blinding ................................................................................22
2.
GENERAL ANALYSIS DEFINITIONS ....................................................................23
2.1.
Visit Windows and Phase Definitions...................................................................23
2.1.1.
Analysis Phase Definitions ...............................................................................23
2.1.2.
Baseline ............................................................................................................23
2.1.3.
Relative Day .....................................................................................................25
2.1.4.
Analysis Windows for Analysis Visits and Timepoints......................................25
2.2.
Pooling Algorithm for Analysis Centers................................................................30
2.3.
Analysis Sets........................................................................................................31
2.3.1.
All Randomized Analysis Sets..........................................................................31
2.3.1.1.
All Randomized Analysis (RAND) Set...........................................................31
2.3.2.
Efficacy Analysis Set(s) ....................................................................................31
2.3.2.1.
ITT-i Set.........................................................................................................31
2.3.2.2.
PP Set............................................................................................................31
2.3.3.
Safety Analysis Set...........................................................................................32
2.3.3.1.
Safety Analysis Set........................................................................................32
2.4.
Definition of Subgroups........................................................................................32
2.5.
Imputation Rules for Missing AE Date/Time of Onset/Resolution .......................35
3.
INTERIM ANALYSIS AND DATA MONITORING COMMITTEE REVIEW.............36
4.
SUBJECT INFORMATION......................................................................................38
4.1.
Demographics and Baseline Characteristics .......................................................39
4.2.
Disposition Information.........................................................................................42
4.3.
Treatment Compliance.........................................................................................42
4.4.
Protocol Deviations ..............................................................................................43
4.5.
Medical History and Family History......................................................................43
4.6.
Prior and Concomitant Medications .....................................................................43
4.7.
Respiratory Pathogens.........................................................................................46
5.
EFFICACY ...............................................................................................................46
5.1.
Analysis Specifications.........................................................................................49
5.1.1.
Level of Significance.........................................................................................49
5.1.2.
Data Handling Rules.........................................................................................50
5.2.
Primary Efficacy Endpoint(s)................................................................................50
5.2.1.
Definition...........................................................................................................50
5.2.2.
Estimand...........................................................................................................51
5.2.3.
Analysis Method ...............................................................................................51
5.2.3.1.
Sensitivity Analyses.......................................................................................51
5.2.3.2.
Methods to Control the Type I Error for Multiplicity and Adaptations............52
5.3.
Secondary Endpoints...........................................................................................55
5.3.1.
Definitions .........................................................................................................55
5.3.1.1.
RSV RNA Viral Load (qRT-PCR) ..................................................................55
5.3.1.2.
Pediatric RSV Electronic Severity and Outcome Rating System (PRESORS)
.......................................................................................................................57
5.3.1.2.1.
PRESORS Modified Definitions .................................................................58


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5.3.1.3.
Other Clinical Course Parameters.................................................................63
5.3.1.3.1.
Respiratory Rate, Heart Rate, Oxygen Saturation and Body Temperature
...................................................................................................................63
5.3.1.3.2.
Hospitalized Subjects only .........................................................................64
5.3.1.4.
Acceptability and Palatability of the JNJ-53718678 formulation ...................72
5.3.1.5.
Medical Resource Utilization .........................................................................72
5.3.2.
Endpoint-specific analysis methods .................................................................73
5.3.2.1.
RSV RNA Viral Load (qRT-PCR) ..................................................................73
5.3.2.2.
Pediatric RSV Electronic Severity and Outcome Rating System (PRESORS)
.......................................................................................................................76
5.3.2.3.
Other Clinical Course Parameters.................................................................79
5.3.2.3.1.
Respiratory Rate, Heart Rate, Oxygen Saturation and Body Temperature
...................................................................................................................79
5.3.2.3.2.
Hospitalized Subjects only .........................................................................79
5.3.2.4.
Acceptability and Palatability of the JNJ-53718678 formulation ...................82
5.3.2.5.
Medical Resource Utilization .........................................................................82
5.4.
Exploratory Endpoints..........................................................................................83
5.4.1.
Definition...........................................................................................................84
5.4.2.
Analysis Methods..............................................................................................93
5.5.
Correlation Between Antiviral Effect and Clinical Course Endpoints...................96
5.6.
Decision Rules at Interim Analyses .....................................................................97
6.
SAFETY.................................................................................................................104
6.1.
Adverse Events ..................................................................................................105
6.1.1.
Definitions .......................................................................................................105
6.1.2.
Adverse Events of Special Interest.................................................................105
6.1.3.
Analysis Methods............................................................................................106
6.2.
Clinical Laboratory Tests....................................................................................107
6.2.1.
Definitions .......................................................................................................107
6.2.2.
Analysis Methods............................................................................................109
6.3.
Vital Signs and Physical Examination Findings .................................................109
6.3.1.
Definitions .......................................................................................................109
6.3.2.
Analysis Methods............................................................................................110
6.4.
Electrocardiogram..............................................................................................111
6.4.1.
Definitions .......................................................................................................111
6.4.2.
Analysis Methods............................................................................................112
7.
VIROLOGY ............................................................................................................113
7.1.
Definitions ..........................................................................................................113
7.2.
Analysis Methods ...............................................................................................114
7.2.1.
Viral Sequencing.............................................................................................114
8.
IMPACT OF PANDEMIC.......................................................................................115
REFERENCES................................................................................................................116
ATTACHMENTS.............................................................................................................117
ATTACHMENT 1:  DIVISION OF MICROBIOLOGY AND INFECTIOUS DISEASES 
(DMID) PEDIATRIC TOXICITY TABLES (NOVEMBER 2007; DRAFT)..............117
ATTACHMENT 2:  PRESORS OBSRO SCORING SYSTEM .......................................127
ATTACHMENT 3:  PRESORS CLINRO SCORING SYSTEM.......................................131


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LIST OF IN-TEXT TABLES AND FIGURES
TABLES
Table 1:
Power (%) to Conclude Dose-response Using MCP-Mod Under Different 
Assumptions for the Dose-response Relationship..........................................21
Table 2:
Analysis Phases..............................................................................................23
Table 3:
Visit Windows..................................................................................................26
Table 4:
Planned Collection of PRESORS ClinRO, PRESORS ObsRO and Clinical 
Evaluation .......................................................................................................28
Table 5:
Visit Windows for PRESORS ClinRO, PRESORS ObsRO, Clinical Evaluation 
(including SBP/DBP) and Body Temperature.................................................28
Table 6:
Worst per Day.................................................................................................29
Table 7:
Time Slot in a Day for BID Days .....................................................................30
Table 8:
Subgroups.......................................................................................................33
Table 9:
Demographic Variables...................................................................................39
Table 10:
Baseline Characteristics .................................................................................39
Table 11:
Time Slot in a Day...........................................................................................41
Table 12:
Correction Factor for Time Slot in a Day ........................................................41
Table 13:
Prior Use of Medications of Interest................................................................44
Table 14:
Concomitant Use of Medications of Interest...................................................44
Table 15:
Any Use of Medications of Interest.................................................................45
Table 16:
Viral Load Parameters ....................................................................................55
Table 17:
Parameters based on PRESORS ObsRO......................................................58
Table 18:
Parameters based on PRESORS ClinRO ......................................................62
Table 19:
Clinical Course Vital Signs Parameters..........................................................64
Table 20:
Additional Clinical Course Parameters for Hospitalized Subjects ..................64
Table 21:
Acceptability and Palatability Parameter ........................................................72
Table 22:
Exploratory Parameters ..................................................................................84
Table 23:
MAV and TV....................................................................................................98
Table 24:
Cardiac Events Potentially Related to QT Prolongation...............................106
Table 25:
Normal Ranges – Below/Normal (including extremes)/Above......................110
Table 26:
Relevant Abnormalities – Abnormally Low/Normal/Abnormally High...........110
Table 27:
Abnormalities for Body Temperature............................................................110
Table 28:
ECG Abnormalities .......................................................................................112
FIGURES
Figure 1:
Schematic Overview of the Design of Study 53718678RSV2002..................18
Figure 2:
Overview of Different Planned Analyses in Study 53718678RSV2002..........37
Figure 3:
Decision Flowchart........................................................................................104


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AMENDMENT HISTORY
Version
Effective 
Date
Description of Changes
Final version
07DEC2018
Amendment 1
08OCT2019
General clarifications added for:

Section 2.1.1 Phase Definitions: definition of the 
screening phase considering the diagnostic ICF is 
required in some countries as testing for RSV is not 
part of Standard Of Care (SOC).

Section 2.1.2 Baseline: for Viral Load (VL) a sample 
taken at the same date and time of dosing can be 
considered.

Section 2.1.4 Analysis Windows for Analysis Visits 
and Time Points: further details on how to handle 
Table 5 Visit Windows for PRESORS ClinRO, 
PRESORS ObsRO, Clinical Evaluation (including 
SBP/DBP) and Body Temperature and Table 6 Worst 
per Day, secondary selection provided as footnote.

Section 3 Interim Analysis and Data Monitoring 
Committee Review: more details added on the 
endpoints to be provided for each interim analysis.

Section 4.1 Demographics and Baseline: the frequency 
table of mismatches for the stratification factors was 
added for completeness.

Section 5.1 Analysis Specifications: clarified that 
derived stratification factors based on eCRF data will 
be used in the analyses when randomization 
stratification factors referred in the model.

Section 5.2.3 Analysis Methods: the following 
clarifications were added.
o
the numeric dose levels to be used in MCP-
mod.
o
for subgroup analysis the model will include 
the subgroup variable as covariate, subgroup-
by- treatment, subgroup-by-visit and 
subgroup-by-visit-by-treatment interactions.

Section 5.3.1.1 RSV RNA Viral Load: clarification on 
the calculation of the viral load of AUC with missing 
data added. Imputation by carrying last observation 
forward will only be done for a maximum time period 
of 24 hours

Section 5.3.1.2 Pediatric RSV Electronic Severity and 
Outcome Rating System (PRESORS): additional 
clarifications in Table17 were provided: 
o
Score 0-3, the higher the score the worse the 
symptom/concept.
o
for the worst score for the daily summary 
score.
o
Time to event is defined as time to the first 
occurrence of the event.

Section 5.3.2.1 RSV RNA Viral Load (qRT-PCR): 
clarified that:


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o
for subgroup analysis the model will include 
the subgroup variable as covariate, subgroup-
by- treatment, subgroup-by-visit and 
subgroup-by-visit-by-treatment interactions.
o
the comparison of proportions will be carried 
out using the Cochran Mantel Haenszel test 
adjusted for each stratification factor 
separately.
o
for time to virus undetectable, estimates and 
covariances from AFT model will be used in 
MCP-mod analysis.

Section 5.3.2.2 Pediatric RSV Electronic Severity and 
Outcome Rating System (PRESORS): clarified that
o
the restricted maximum likelihood based 
repeated measures model will be performed 
for each instrument concept, maximum
summary scores and daily summary scores.
o
for time to different resolutions, estimates and 
covariances from AFT model will be used in 
MCP-mod analysis.

Section 5.3.2.3.1 Respiratory Rate, Heart Rate, 
Oxygen Saturation and Body Temperature: further 
details on how to identify the worst value per day over 
24h were provided.

Section 5.3.2.3.2 Hospitalized subjects only: for time 
to different resolutions, estimates and covariances 
from AFT model will be used in MCP-mod analysis.

Section 5.6 Decision Rules at Interim Analyses. A 
figure describing the decision rules for futility, based 
on different endpoints was added.

Clinical Laboratory Section 6.2.1 Definitions: not all 
parameters have toxicity grades defined for all age 
groups. Available grading as provided by the central 
laboratory will be used in the analysis.

ECGs Section 6.4.1 Definitions:  abnormal changes 
from baseline were missing in Table 27 and have been 
added.

Attachment 2 PRESORS ObsRO Scoring System: 
clarified derivation of concept scores when a question 
contains information for different concepts.

Attachment 3 PRESORS ClinRO Scoring System: 
clarified derivation of concept scores when a question 
contains information for different concepts and/or is 
assessed at different recall time (e.g. past 12h, now)
Following corrections were made:

Section 1.4 Sample Size Justification: protocol stated 
1-sided alpha of 2.5% which is equivalent to 2-sided 
alpha of 5%; so for consistency the same expression is 
used as in the protocol.

Section 2.1.4 Analysis Windows for Analysis Visits 
and Time Points: In Table 5 correction was done for
time interval 228h (Day 10.5) and 240h (Day 11) 


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where instead of 231h it should be 233h and 234h 
respectively.

Section 5.3.2.2: Pediatric RSV Electronic Severity and 
Outcome Rating System (PRESORS): the following 
corrections were done 
o
in the restricted maximum likelihood based 
repeated measures model:

Baseline score has been added to the 
model as a covariate.

Model modification based on 
covariate significant level has been 
removed because not applicable to the 
repeated measures model.
o
for status of RSV symptoms, status of health, 
status of improvements of RSV symptoms and 
status return to pre-RSV disease health 
(ObsRO), differences in proportions will be 
compared by using CMH instead of Wilson 
test.


: the following corrections were done:
o
Scores for breathing problems as “nostril 
flaring” and “head bobbed back and forth 
when breathing” are considered severe (score 
=3) instead of moderate (score =2).
o
Word “worst” was removed from the general 
instructions on how to derive the summary 
scores. 

Attachment 3: PRESORS CLINRO Scoring System: 
word “worst” was removed from the general 
instructions on how to derive the summary scores. 
Additional information/analysis:

Section 2.3.2.2 Per Protocol Set: Missing PRESORS 
ObsRO at baseline is considered as major protocol 
deviation.

Section 5.2.3 Analysis Method: the following text has 
been added
o
for the restricted maximum likelihood based 
repeated measures model, an unstructured 
(co)variance structure is used to model the 
within-subject errors.
o
a sensitivity analysis for the primary endpoint 
considering randomization stratification 
factors as per IWRS instead of the derived 
randomization stratification factor.

Section 5.3.1.2 Pediatric RSV Electronic Severity and 
Outcome Rating System (PRESORS): added the time 
to improvement of RSV symptoms (ObsRO) variable.

Section 5.3.1.3.2. Hospitalized Subjects Only: added
the time to resolution of RSV other symptoms 
(ClinRO)


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
Section 5.3.2.1 RSV RNA Viral Load (qRT-PCR): for 
time to virus undetectable the following has been 
added:
o
stratified Cox proportional hazard model to 
produce survival curves by stratification 
factors has been added. 
o
Similar Cox model including the subgroup
variable and its interaction with treatment for 
subgroup analysis 
o
A forest plot for subgroups Hazard Ratios 
(HR) will be presented will be presented.

Section 5.3.2.2 Pediatric RSV Electronic Severity and 
Outcome Rating System (PRESORS): the following 
evaluations and analyses have been added:
o
Summary table of the reasons for missing 
PRESORS (ObsRO and ClinRO).
o
Summary overview of the number of 
caregivers per subject.
o
Graphical evaluation of the two different ways 
to define the worst score for the daily 
summary score.
o
sensitivity analyses added for the time to 
resolution of all RSV symptoms (ObsRO) 
endpoint considering different imputation 
methods.
o
For different time to the “events” variables:

the stratified Cox proportional hazard 
model to produce survival curves by 
stratification factors has been added.

Similar Cox model including the 
subgroup variable and its interaction 
with treatment for subgroup analysis 

Forest plot for subgroups HRs
o
time to improvement and time to resolution 
RSV other symptoms analyses have been 
added. 

Section 5.3.2.3.2 Hospitalized Subjects Only: for the 
different time to “events” variables, the following 
analyses have been added 
o
stratified Cox proportional hazard model to 
produce survival curves by stratification 
factors has been added. 
o
Similar Cox model including the subgroup
variable and its interaction with treatment for 
subgroup analysis 
o
Forest plot for subgroups HRs.

Section 5.5 Correlation Between Antiviral Effect and 
Clinical Course Endpoint: a plot of viral load versus 
daily summary key RSV symptom severity score over 
time has been added.
Updates as per CTPA#1 approved 14MAY2019:


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
Section 1.2 Trial Design: increased sample size for 
Cohort 1 72 to approximately 144 subjects. Figure 1
replaced with numbers updated accordingly

Section 1.4 Sample Size Justification: 
o
Rationale and calculations for the increased 
sample size in Cohort 1 was provided.
o
Number of subjects from each cohort to be 
included in the clinical course analyses was 
updated.
o
Clarified that only the information from 
Cohort 2 will be used in the sample size re-
estimation.

Section 3 Interim Analysis and Data Monitoring 
Committee Overview:
o
clarified that each Interim Analysis (IA) will 
be preferably performed at the end of the 
hemispheric season.
o
for IA#2 added that approximately between 
70-80 subjects from Cohort 1 will be included 
in the analysis.
o
for IA#3 clarified that data from both cohorts 
will considered for analyses of antiviral 
activity and that only Cohort 2 data will be 
used for sample size re-estimation.
o
Figure 2 replaced with updated numbers as per 
changes in the sample size.

Section 5.1 Analysis specifications: clarified that 
analyses will be performed both by combining 
information from both cohorts and by cohort 
separately.

Section 5.1.1 Level of Significance: added that for 
clinical course endpoints, both the unadjusted and the 
multiplicity adjusted p-value will be provided.

Section 5.2.3.1 Methods to Control Type I Error for 
Multiplicity and Adaptations has been added.

Section 5.6 Decision Rules at Interim Analyses: added 
that for IA#3 & IA#4 the analysis will be performed 
with all data available from both cohorts and a second 
time with balanced cohorts. Details on how to proceed 
in case of inconsistencies in results were included.

Clinical Laboratory Section 6.2.1 Definitions: note 
added since coagulation will not be analyzed in 
subjects enrolled under this protocol amendment.
Updates as per CTPA#2 approved 05JUL2019:

Section 1.2 Trial Design: clarified that number of 
subjects with symptom onset ≤3 days must be a 
minimum of 45 % of all enrolled subjects in Cohorts 1 
and 2 (i.e. maximum 55% of subjects could be 
enrolled in the >3 days stratum).

Section 1.5 Randomization and Unblinding: subjects 
with symptoms onset ≤3 days must be a minimum of 
45 % of all enrolled subjects.


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
Section 5.6 Decision Rules at Interim Analyses: 
clarified that balanced cohorts will also be considered 
in case of severe imbalance between <=3 days and >3-
5 days symptom onset strata.
Amendment 2
10JUL2020
Following clarifications made:

Amendment History, version section format changed 
to clearly provide amendment identifier rather than 
version number.

In Section 2.3.2.2 Per Protocol Set since subjects who 
early discontinued study medication will be considered 
within the criterion “Subject missed more than one 
dose of study drug”.

Section 5.3.2.2 Pediatric RSV Electronic Severity and 
Outcome Rating System (PRESORS): a full 
description of the analysis model has been included to 
clarify that baseline viral load will not be included in 
the model, but continuous covariates will be included 
for both baseline score and analysis visit -by-baseline 
score.

Section 5.6 Decision Rules at Interim Analyses:
o
Clarification that a balanced analysis should 
only be carried out in the situation that there is 
severe imbalance ( i.e. : >55% subjects in 
symptoms onset  >3-5 days ) between the <=3 
days and >3 days since symptom onset stratum 
AND where are more subjects in the >3-5 day 
stratum than in the <=3 days stratum.
o
Clarification that the conditional power for 
viral load endpoint at IA#3 should be based on 
combined data from Cohort 1 and 2.
o
Clarification that the conditional power for 
clinical course endpoints at IA#3 should be 
based on Cohort 2 only.
Following corrections were made:

Exploratory endpoint “Respiratory infection 
complication” relabeled as “RSV-related 
complication” to avoid misunderstandings since one of 
the subcategories is already respiratory complication.
Corrections done :
o
Section 3 Interim Analysis and Data 
Monitoring Committee
o
Section 5.4.1 Definition in Table 19
o
Section 5.4.2 Analysis Methods
o
Section 5.5 Correlation between Antiviral 
Effect and Clinical Course
Additional information/analyses:

Due to PRESORS validation results available, 
PRESORS analyses will additionally be based on the 
modified scores and resolution definition for:
o
ObsRO concepts: Dehydration, Retractions, 
Cyanosis and Apnea.


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o
ClinRO concepts: Retractions, Cyanosis and 
Apnea
o
Exclusion of Cyanosis and Apnea from the 
derivations of the parameters Overall 
Symptoms, Key RSV Symptoms, Respiratory 
Symptoms and General Illness behavior.
A new Section 5.3.1.2.1 PRESORS adapted 
Definitions has been created providing detailed 
information and Table 15 as well as Attachments 2 
&3, have been updated accordingly.

A modified definition of the RSV-related complication 
has been added in the Section 5.4.1 Exploratory 
Endpoints, Table 19 The RSV-Related Complications 
modified definition has 4 complication categories ( 
respiratory, infectious, cardiovascular and acid-base or 
electrolyte) instead of the 3 complication categories 
(respiratory, non-respiratory and other) as in the 
original definition.

Section 5.6 Decision Rules at Interim Analyses, 
Table 20:
o
The endpoint, ‘Time to resolution of all RSV 
symptoms (ObsRO)’ has been updated to 
‘Time to resolution of key RSV symptoms 
(ObsRO)’.
o
The endpoint ‘Overall RSV severity score 
(ObsRO) at Day 8’ has been updated to 
‘Change from baseline in key RSV severity 
score (ObsRO) at Day 8’.
o
The endpoint ‘Incidence of Respiratory 
Infection Complication’ has been updated to 
‘Incidence of RSV-related Complication’ to 
reflect the updated definition for this endpoint. 
o
The Target Value for ‘Change from baseline in 
key RSV severity score (ObsRO) at Day 8’ 
has been updated to represent a 20% effect on 
the change from baseline rather than a 20% 
effect on the absolute score.

Section 5.6 Decision Rules at Interim Analyses; 
Interim Analysis 3: Additional information has been 
added to describe the calculations of conditional power 
for viral load endpoint and the three key clinical 
course endpoints.
Amendment 3
20 May 2021
Updates included as per CTPA#4 approved 26 May 2020:
Section 1.2 Trial Design: described change in dosing 
regimen from QD to BID and subsequent handling in 
analyses: treatment groups will be analyzed and presented 
regardless of dosing regimen (QD or BID).
Section 2.1.4 Analysis Windows for Analysis Visits and 
Time Points: added that ECG assessments are to be collected 
around 1h post-dose on Study Day 1 and Study Day 3. On 
these days, a time window of 45 min to 90 min will 
additionally be applied after assigning the target day


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Section 6.2.1 Definitions: included reference to levels of 
potassium and magnesium to be determined by the central 
laboratory. In case of hypokalemia or hypomagnesemia, the 
levels of potassium and magnesium are to be monitored 
locally and corrected to prevent cardiac disturbances. Data 
will be listed.
Updates included as per CTPA#6 approved 01 December 
2020:
Section 2.4 Subgroups:
o Cohort (Class 2) defined given change to inclusion 
criterion 4 aimed at maximizing enrollment of subjects 
with at least moderate RSV disease severity.
o Specified that in case of population enrichment decision 
(subjects 
with 
symptom 
onset 
≤3 
days 
before 
randomization), efficacy analyses will focus on those 
subjects 
with 
symptom 
onset 
≤3 
days 
before 
randomization stratum only.
Following notable clarifications and corrections were made:
Applicable revisions/clarifications through various sections:
o Added use of ‘analysis’ to phase (treatment and/or follow-
up) to differentiate between analysis definition and 
protocol-defined study phases.
o Clarified throughout to state that the MCP-Mod test for 
trend in viral load will use a 1-sided 2.5% Type I error rate.
Section 2.1.2 Baseline: baseline derivation for ECG triplicate 
assessments clarified.
Section 2.1.4 Analysis Windows for Analysis Visits and Time 
Points: removed reference to data handling, if for a given 
window both, on-site assessment and home-based assessment 
are available for nasal swab collection (for viral load). Sample 
setting of collection is not considered for the analysis.
Section 2.3.3.1 Safety Set: corrected ‘analyzed as treated’ 
definition to consider active vs placebo in addition to dose 
level.
Section 2.4 Subgroups: revised data handling, subgroups and 
their classifications given development of subgroups through 
completion of previous IAs, in addition to further 
development of other studies in the program. Section has been 
revised to facilitate cross-reference through subsequent 
sections in such a way that any future changes to subgroup
analyses will not necessarily require extensive SAP updates.
Section 4.3 Treatment Compliance: derivations have been 
expanded given the change from QD to BID dosing regimen 
with added clarity regards the derivation of % compliance and 
subsequent categorization.
Section 4.5 Medical History: added tabulation of general 
medical history.


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Section 4.6 Prior and Concomitant Medications: added 
medications of interest, aligned with study RSV3001, to 
assess the use of these medications of special interest and their 
potential impact on the PRESORS assessments.
Section 5.2.3 Analysis Method: added sensitivity analysis 
excluding nasal swab samples identified as: 
o Ribonuclease P (RNAse P [housekeeping gene]): result = 
Target Not Detected AND
o RSV A: result = Target Not Detected AND
o RSV B: result = Target Not Detected
Section 5.3.1.1 RSV RNA Viral Load, 5.3.1.2 PRESORS, 
5.3.1.3 Other Clinical Course Parameters
o Added definitions, derivations and tabulation of missing 
data PRESORS ObsRO/ClinRO.
o Added tabulation of number of caregivers/investigators.
Section 5.3.1.3.2 Hospitalized Subjects only:
o Revised time (hours) to end of supplementation (oxygen 
and/or feeding/hydration) to include up to 72h from first 
hospital discharge specification. Definition was revised, 
based on previous IAs, to ensure accurate derivation of 
resolution per subject and not one confounded by 
continued use of supplementation.
o Clarified that normalization of vital signs (HR and RR) is 
based on investigator evaluation only.
o Added definition, derivations and tabulation of re-
hospitalization.
Section 5.3.2 Endpoint-specific Analysis Methods:
o Streamlined time to event analysis by removing all 
references to COX proportional analysis model as the 
same information can be obtained from the AFT analyses.
o Updated AFT model to exclude baseline log10 RSV RNA 
viral load as covariate for clinical course endpoints.
o Expanded methodology for association between key 
endpoints and baseline indicators of interest
o Revised 
methodology 
for 
comparing 
proportions 
accounting for the randomization stratification factors.
Section 5.4: Exploratory Endpoints: the exploratory efficacy 
endpoints listed in Section 5.4 have additionally been 
included, based on previous IAs with new information 
becoming available during the course of the study. These 
additional exploratory efficacy endpoints support decision-
making for further development of JNJ-53718678 and 
interactions with health authorities.
Section 5.6 Decision Rules at Interim Analyses: the 
calculation of conditional power for the change from baseline 
in key RSV symptoms at Day 8 was corrected to account for 
the correlation between ZTV, the test statistic to test the null 


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hypothesis that the difference between the high dose and the 
placebo group is at least as good as the target value (TV) and 
the ZMAV, the test statistic to test the null hypothesis that the 
difference between the high dose and the placebo group is no 
better than the minimum acceptable value (MAV).
Section 6.1.2 Adverse Events of Special Interest: included 
cardiac events potentially associated with QT prolongation, 
aligned with study RSV3001.
Section 6.3.1 Vital Signs Definitions:
o Clarified that vital signs abnormalities will be identified 
based on subject’s age at the date/time of assessment.
o Clarified that maximum temperature per day of assessment 
will be identified regardless of source of data collection 
(investigator [on-site] vs caregiver [home]) and will be 
used in all subsequent analyses.
Section 6.4.1 Electrocardiogram: clarified that ECG
abnormalities will be identified based on subject’s age at the 
date/time of assessment.
Section 7 Virology:
o Added the NGS-read cut-off frequencies.
o Updated long list of 20 F gene positions of interest to 24 F 
gene 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.
o Viral sequencing analysis methods clarified.
Section 8 Impact of Pandemic: section added with overview 
of data handling to ensure COVID-19 impact transparency.
Additional minor clarifications and corrections were made 
throughout the document to align with clarifications and 
corrections noted above.


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ABBREVIATIONS
AE
adverse event
AFT
accelerated failure time
ALT/SGPT
alanine aminotransferase
AST/SGOT
aspartate aminotransferase
ATC
anatomic and therapeutic Class
AUC
area under the curve
BMI
body mass index
CI
confidence interval
ClinRO
clinician reported outcomes
CPAP
Clinical Pharmacology Analysis Plan
CRF
case report form
CSR
Clinical Study Report
CV
coefficient of variation
DPS
Data Presentation Specifications
ECG
Electrocardiogram
eCRF
electronic case report form
FAS
full analysis set
FDA
Food and Drug Administration
HR
Heart Rate
IA
interim analysis
ICH
International Conference on Harmonization
IDMC
Independent Data Monitoring Committee
ITT-i
Intent-To-Treat-infected
IQ
Interquartile
IQR
interquartile range
IWRS
interactive web-based response system
LLOQ
lower limit of quantification
LOCF
last observation carried forward
MedDRA
Medical Dictionary for Regulatory Activities
ObsRO
observer reported outcomes
PD
pharmacodynamic(s)
PI
principal investigator
PK
pharmacokinetic(s)
PP
per protocol
PRESORS
Pediatric RSV Electronic Symptom and Outcomes Rating System
qRT-PCR
quantitative reverse transcription polymerase chain reaction
RAND
Randomized
RR
Respiratory Rate
RSV
respiratory syncytial virus
RT
Randomized or treated
SAE
serious adverse event
SAP
Statistical Analysis Plan
SC
Sponsor Committee
SD
standard deviation
SE
standard error
SI
International System of Units
SOC
Standard of care
SpO2
peripheral capillary oxygen saturation
TEAE
treatment-emergent adverse event
TD
target detected
TND
target not detected
WHO
World Health Organization
WHO-DD
World Health Organization Drug Dictionary
1.
INTRODUCTION
This Statistical Analysis Plan (SAP) contains definitions of analysis sets, derived variables 
and statistical methods for study RSV2002 including efficacy and safety of the 


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investigational compound JNJ-53718678. The SAP is to be interpreted in conjunction with 
the protocol.
This SAP covers the final analysis, as well as the interim analyses (IAs). Details on the 
Independent Data Monitoring Committee (IDMC) analyses will be provided in a separate 
IDMC SAP.
A 
detailed 
analysis 
plan 
for 
the 
pharmacokinetic
(PK)
and 
pharmacokinetic/pharmacodynamics (PK/PD) data will be described in a Clinical 
Pharmacology Analysis Plan (CPAP).
JNJ-53718678 is an investigational respiratory syncytial virus (RSV) specific fusion 
inhibitor belonging to the indole chemical class and under development for the treatment 
of RSV infection.
1.1.
Trial Objectives
The primary objective is to establish antiviral activity of JNJ-53718678 as measured by 
RSV viral load in nasal swab samples by a quantitative reverse transcription polymerase 
chain reaction (qRT-PCR) assay in children ≥28 days and ≤3 years of age with RSV 
disease.
The secondary objectives are to evaluate in children ≥28 days and ≤3 years of age with 
RSV disease:

the dose-response relationship for antiviral activity of JNJ-53718678

the impact of JNJ-53718678 on the clinical course of RSV infection

the safety and tolerability of JNJ-53718678 after repeated oral doses

the PK of JNJ-53718678 after repeated oral doses

medical resource utilization

the impact of baseline characteristics on antiviral activity and clinical course, including 
but not limited to:

time of symptom onset (≤3 days vs >3 days before start of treatment)

patient population (hospitalized subjects vs outpatients)

baseline viral load

disease severity at baseline

the relationship between the PK and the PD (selected antiviral activity, clinical 
outcomes, and safety parameters) after repeated dosing of JNJ-53718678

the emergence of mutations in the viral genome potentially associated with resistance 
to JNJ-53718678

the acceptability and palatability of the JNJ-53718678 formulation
The exploratory objectives are to explore in children ≥28 days and ≤3 years of age with 
RSV disease:


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
the impact of additional baseline characteristics on antiviral activity and clinical 
course, including but not limited to:
RSV viral subtype and genotype
baseline neutrophil count

the occurrence of complications associated with RSV per investigator assessment after 
initiation of treatment

the need for antibiotics related to complications associated with RSV per investigator 
assessment

the relationship between antiviral activity and clinical outcomes

the RSV viral load as measured by a qRT-PCR assay in nasopharyngeal and/or 
tracheal aspirate samples in a subgroup of hospitalized subjects (Cohort 1 only) in 
which these samples are obtained as part of their standard-of-care (SOC)

the RSV infectious virus load as assessed by quantitative culture of RSV (plaque 
assay) on selected nasal swab samples (optional objective, pending feasibility of 
performing such an assay)
1.2.
Trial Design
This is a Phase 2 multicenter, double-blind, placebo-controlled, randomized study to 
evaluate the antiviral activity, clinical outcomes, safety, tolerability, and PK/PD 
relationships of different oral dose levels of JNJ-53718678 in children ≥28 days and ≤3 
years of age with RSV disease (hospitalized subjects [Cohort 1] or outpatients [Cohort 2]).
Up to 4 IAs are planned for this study. For the full trial design please refer to Section 3.1 
of the protocol.
The total number of subjects is planned to be approximately 294 (approximately 144 in 
Cohort 1 and approximately 150 in Cohort 2; approximately 196 subjects receiving 
JNJ-53718678 and approximately 98 subjects receiving placebo). The sample size of 
Cohort 2 may be re-estimated to a maximum of 300 in Cohort 2 based upon results from 
the third IA.
Overall, for both cohorts, 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 28 [±3]. The 
total study duration for each subject will be approximately 29 days (Screening included). 
A diagram of the study design is provided in Figure 1.


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Figure 1:
Schematic Overview of the Design of Study 53718678RSV2002
In Cohort 1, a subcohort of 6 subjects >2 and ≤3 years will be included, who will follow in 
general the same assessment schedule as for all subjects enrolled in Cohort 1, although 
with a specific PK sampling schedule, assigned at randomization. Of note, if the subcohort 
is fully enrolled, additional subjects >2 and ≤3 years of age can be enrolled in Cohort 1 and 
will follow all Cohort 1 procedures. Within each cohort, except for the subcohort, 
randomization will be stratified by time of symptom onset (≤3 days vs >3 days to ≤5 days 
before randomization) and by presence of risk factors for severe RSV disease (otherwise 
healthy vs presence of [a] risk factor[s] for severe RSV disease). Subjects with symptom 
onset ≤3 days before randomization must account for a minimum of 45 % of all enrolled 
subjects in Cohorts 1 and 2 (i.e. maximum 55% of subjects can be enrolled in the >3 days 
stratum), To guarantee balance between strata for the IA, enrollment in the >3 days since 
symptoms onset stratum might be temporarily paused prior to an interim analysis and 
stopped prior to the final analysis. More details regarding randomization can be found in 
Section 1.5.
For dosing purposes, 3 age groups are defined depending on the subject’s age at the time 
of consent:

Age group 1: ≥28 days and <3 months of age (28 to 91 days of age, extremes included, 
for IWRS purposes)

Age group 2: ≥3 months and <6 months of age (92 to 182 days of age, extremes 
included, for IWRS purposes)

Age group 3: ≥6 months and ≤3 years of age (183 to 1,096 days, extremes included, 
for IWRS purposes)


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Prior to Amendment #4 (dated 26 May 2020): study drug to be administered once daily
(quaque die [QD]) for a planned treatment duration of 7 days. Doses are based on 
bodyweight and age group, but are identical for both cohorts:

High Dose (Cohort 1: n = 48 [target]; Cohort 2: n = 50 [target]):

Age group 1: 5 mg JNJ-53718678/kg bodyweight

Age group 2: 6 mg JNJ-53718678/kg bodyweight

Age group 3: 9 mg JNJ-53718678/kg bodyweight

Low Dose (Cohort 1: n = 48 [target]; Cohort 2: n = 50 [target]):

Age group 1: 1.7 mg JNJ-53718678/kg bodyweight

Age group 2: 2 mg JNJ-53718678/kg bodyweight

Age group 3: 3 mg JNJ-53718678/kg bodyweight

Placebo (Cohort 1: n = 48 [target]; Cohort 2: n = 50 [target]): those randomized to a 
placebo regimen will subsequently be randomized 1:1 to receive either:

High volume placebo:
o
Age groups 1, 2, and 3: matching placebo (volume of placebo suspension to 
match the calculated volume of the JNJ-53718678 suspension for the high 
dose)

Low volume placebo:
o
Age groups 1, 2, and 3: matching placebo (volume of placebo suspension to 
match the calculated volume of the JNJ-53718678 suspension for the low 
dose)
Post-amendment #4 (dated 26 May 2020): Cohort 1 enrollment complete with all 
randomized and treated subjects receiving once daily dosing for a planned treatment 
duration of 7 days. Cohort 2 enrollment continuing with study drug to be administered 
twice daily (bis in die [BID]) for a planned treatment duration of 7 days. Total planned 14 
doses are based on bodyweight and age group, but total daily dose remains identical for 
both cohorts regardless of dosing regimen:

High Dose (Cohort 2: n = 50 [target]):

Age group 1: 2.5 mg JNJ-53718678/kg bodyweight

Age group 2: 3.0 mg JNJ-53718678/kg bodyweight

Age group 3: 4.5 mg JNJ-53718678/kg bodyweight

Low Dose (Cohort 2: n = 50 [target]):

Age group 1: 0.85 mg JNJ-53718678/kg bodyweight

Age group 2: 1.0 mg JNJ-53718678/kg bodyweight

Age group 3: 1.5 mg JNJ-53718678/kg bodyweight


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
Placebo (Cohort 2: n = 50 [target]): those randomized to a placebo regimen will 
subsequently be randomized 1:1 to receive either:

High volume placebo:
o
Age groups 1, 2, and 3: matching placebo (volume of placebo suspension to 
match the calculated volume of the JNJ-53718678 suspension for the high 
dose)

Low volume placebo:
o
Age groups 1, 2, and 3: matching placebo (volume of placebo suspension to 
match the calculated volume of the JNJ-53718678 suspension for the low 
dose)
For analysis purposes, treatment groups will be analyzed and presented regardless of 
dosing regimen (QD or BID).
1.3.
Statistical Hypotheses for Trial Objectives
The primary hypothesis of this study is that JNJ-53718678 has antiviral activity against 
RSV (i.e. a decrease in RSV viral load area under the curve (AUC) from immediately prior 
to first dose of study drug [baseline] until Day 5), as assessed by a positive dose-response 
relationship of JNJ-53718678 compared to placebo.
1.4.
Sample Size Justification
The basis of the sample size calculation are
the antiviral
activity data
of 
Study 53718678RSV1005. In that study, the mean difference in RSV viral load AUC from 
baseline until Day 5 of the placebo group versus active (adjusted for baseline viral load) 
was estimated as 105 log10 copies.hour/mL (corresponding to a 25% reduction) and the 
standard deviation (SD) on the RSV viral load AUC as 85 log10 copies.hour/mL 
(corresponding to a coefficient of variation [CV] of approximately 20%).
Assuming a more conservative reduction in RSV viral load AUC of 20% compared to 
placebo, considering a CV of 35% (slightly higher variability than observed in 
Study 53718678RSV1005), and a 1-sided alpha of 2.5%; the power to conclude a dose-
response using the Multiple Comparison Procedure-Modeling (MCP-Mod) procedure 
under different assumptions for the dose-response relationship (linear, Emax and 
exponential) is provided in Table 1. Based on Study 53718678RSV1005 results, no 
discrimination between the proposed doses is expected (i.e. Emax dose-response shape was 
observed).


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Table 1:
Power (%) to Conclude Dose-response Using MCP-Mod Under Different Assumptions 
for the Dose-response Relationship
Assumed 
CV
Assumed dose-response relationship
Linear
Emax
Exponential
Cohort 1 + Cohort 2 (N=74 per treatment arm)
20%
100.0
100.0
100.0
35%
92.3
95.3
96.6
Cohort 2 only (N=50 per treatment arm)
20%
99.8
100.0
100.0
35%
79.0
84.0
86.9
Cohort 1 only (N=24 per treatment arm)
20%
91.5
94.7
96.2
35%
47.1
51.2
54.7
If data of both cohorts are combined (N=74 per treatment arm), the power to conclude 
dose-response is more than 90% for all 3 different assumptions for the dose-response 
relationship. If data from Cohort 1 cannot be combined with data from Cohort 2 (e.g. due 
to inconsistency [means and/or variability] in viral load data between cohorts per treatment 
group), the power to conclude a dose-response using the MCP-Mod procedure in Cohort 2 
(N=50 per treatment arm) is at least 79%. 
The sample size in Cohort 1 only (n ≥24 per treatment arm) will provide sufficient power 
(approximately 90%) if the reduction in RSV viral load AUC is at least 20% with a CV 
which is not higher than observed in Study 53718678RSV1005 (i.e. 20%).
A sample size of 72 in Cohort 1 and 150 in Cohort 2 is sufficient to detect with reasonable 
power the antiviral effect; even if the data of Cohort 1 cannot be combined with the data 
of Cohort 2. Therefore, the primary analysis will be performed after approximately 
150 subjects from Cohort 2 have completed the Day 14 assessments (or discontinued 
earlier). By that time, it is expected that at least 72 subjects from Cohort 1 will have 
completed the Day 14 assessments (or discontinued earlier).
For Cohort 1, assuming a median time to resolution of symptoms of 3 days in the placebo 
group, a 1-day reduction in the active group (i.e. ratio of 66%), and a scale parameter of 
1/0.65, a sample size of 48 subjects per treatment arm will achieve 95% probability to reach 
an observed effect in the right direction based on estimates derived from an accelerated 
failure time model. This will allow an adequate evaluation of clinical course endpoints in 
the hospital population.
In conclusion, approximately 144 subjects in Cohort 1 (48 subjects per treatment arm) and 
approximately 150 in Cohort 2 (50 subjects per treatment arm) are planned to be recruited. 
The sample size of Cohort 2 may be re-estimated to a maximum of 300 in Cohort 2 based 
upon results from the third IA.
Sample Size Re-estimation
During IA#3 (when approximately 70 to 80 subjects from Cohort 2 have completed the 
Day 14 assessments [or discontinued earlier]), a sample size re-estimation will be 
performed to allow an extension of Cohort 2 for the confirmation of the results on selected 


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clinical course endpoints. Based on all clinical course data from Cohort 2 available at the 
time of the cut-off for the third IA, one or more clinically relevant endpoint(s) will be 
selected for confirmation in the final analysis. Time to resolution (i.e. to none or mild 
symptoms) and reduction in severity of selected clinical signs/symptoms of RSV-related 
illness are currently expected to be the most relevant clinical endpoints for Phase 3 
planning. However, data from this study, in combination with data from other RSV studies 
within and outside the company, and knowledge obtained through health authority 
interaction(s) will be considered in IA#3 for the endpoint selection and sample size 
recalculation for Cohort 2. After selection of (a) clinical endpoint(s), the number of subjects
in Cohort 2 will be calculated that is required to minimize the conditional probability of 
inconclusive results (within the Go-NoGo approach) at the end of the study, assuming a 
required confidence of 80% (2-sided) to exclude the target value and/or the minimum
acceptable value.
1.5.
Randomization and Blinding
Central randomization will be implemented in this study. The codes will be maintained 
within the IWRS, which has the functionality to allow the investigator to break the blind 
for an individual subject. Within each cohort (including the subcohort of Cohort 1), eligible 
subjects will be randomized 1:1:1 to receive either a low or a high dose of JNJ-53718678, 
or placebo. Those randomized to a placebo regimen will be subsequently randomized in a 
1:1 ratio to receive either low or high volume of placebo. This results in an overall 
randomization scheme of 2:2:1:1 (low dose JNJ-53718678, high dose JNJ-53718678, low 
volume placebo, high volume placebo). Randomization will be based on a computer-
generated randomization schedule prepared before the study by or under the supervision of 
the sponsor. 
In the subcohort of Cohort 1, next to randomization to treatment group, within each 
treatment arm (high dose, low dose, placebo), the 6 subjects will be randomized 1:1 to 1 of 
2 different PK sampling groups. In Cohort 1, next to randomization to treatment group, the 
first 12 subjects of each age group (subcohort not included) will be randomized 1:1 to 1 of 
2 different PK sampling groups. Once 12 subjects of a particular age group have been 
randomized to the 2 different PK sampling groups, the investigator can assign the 
subsequently enrolled subjects to either of the 2 PK sampling groups, but preferably 
alternating between 2 different PK sampling groups.
The randomization will be balanced by using randomly permuted blocks and will be 
stratified by time since symptom onset at randomization (≤3 days and >3 days) and by 
presence of risk factors for severe RSV disease (otherwise healthy vs presence of [a] risk 
factor[s] for severe RSV disease as defined above). Stratification will be applied to each 
cohort separately, with exception of the subcohort. Subjects with symptom onset ≤3 days 
before randomization must account for at least 45% of all enrolled subjects in Cohorts 1 
and 2. To guarantee the required balance between strata for the interim analyses, enrollment 
in >3 days to ≤5 days since symptom onset stratum might be temporarily paused prior to 
an interim analysis and stopped prior to the final analysis.




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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.

If none of the above, baseline, and subsequently change from baseline, will be 
considered missing.

For Pediatric RSV Electronic Symptom and Outcome Rating System (PRESORS)
clinician reported outcomes (ClinRO), clinical evaluation and parent/caregiver 
PRESORS observer reported outcomes (ObsRO), the baseline assessment will be 
defined as:

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.

If none of the above, baseline, and subsequently change from baseline, will be 
considered missing.

For electrocardiogram (ECG), triplicate 12-lead ECGs, approximately 1 minute apart 
and preferably all within 5 minutes should be performed. Baseline for continuous ECG 
parameters will be defined as:

Average of the last available complete ECG triplicate assessment prior to first 
dose of study drug.

In the absence of complete triplicate ECGs, the average of the last available ECG 
duplicate assessment will be considered.

In the absence of complete or partial triplicates, the last available single ECG can 
be used.

If none of the above, baseline, and subsequently change from baseline, will be 
considered missing.
A set of complete or partial triplicate ECG assessments is identified per date/time by a 
group identifier. Sequence number, within group identifier, can also be used to uniquely 
identify the relevant set of ECGs to be averaged. For continuous ECG parameters, all 
further analyses will be performed on the averaged ECG assessments only.
Once baseline is assigned, any assessment performed prior to the defined baseline, will be 
assigned to Screening. Screening visits will not be used in by-visit summary tables, only 
in listings. Any assessment performed after first dose of study drug on Day 1 and not 
considered baseline per the aforementioned definitions, will be assigned to Day 1, post-
first dose of study drug (post-baseline).


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2.1.3.
Relative Day
Study Day 1 is defined as the date of first study drug intake. All efficacy and safety 
assessments at all visits will be assigned a day relative to this date.
The relative day will be defined as:
reldy=visit date – reference date+1
for visits on or after Day 1, and 
reldy=visit date – reference date
for visits before Day 1.
There is no ‘Day 0’.
2.1.4.
Analysis Windows for Analysis Visits and Timepoints
Listed below are the visit windows and the target days for each visit defined in the protocol.
In general, the following rules will be applied in order to have only one evaluation per 
subject per analysis visit:

If two assessments fall within the same visit window, the measurement closest to the 
target day will be used (the time of the assessment will be ignored, only the date 
component will be used)

If the assessments are equidistant, the last measurement within the interval will be 
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 RSV RNA viral load (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 RSV RNA viral load per day (regardless of sample 
collection setting [on-site vs homebased] and time of collection). The maximum RSV 
RNA viral load on a day will be used in all subsequent RSV RNA viral load analyses
(e.g. time to undetectable) and for analysis visit windowing. Identified RSV RNA viral 
load, as assigned per analysis visit based on these rules, will be used for all subsequent 
by-visit RSV RNA viral load analyses. Please notice that baseline RSV RNA viral 
load follows the rules described in Section 2.1.2.

Electrocardiogram
In case there is more than one assessment per analysis visit window, the following 
rules will be used for continuous ECG parameters, to assign only one averaged ECG 
assessment per analysis timepoint. Within defined visit windows:

The average of the last available complete ECG triplicate should be considered in
the first instance.












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assay, no heterogeneity of treatment effects across centers is expected. No pooling 
algorithm for analysis centers will be applied.
2.3.
Analysis Sets
2.3.1.
All Randomized Analysis Sets
2.3.1.1.
All Randomized Analysis (RAND) Set
All subjects randomized, regardless of being treated or not.
2.3.2.
Efficacy Analysis Set(s)
The Intent-To-Treat-infected (ITT-i) set will be used to perform the evaluation of all 
efficacy variables including clinical course endpoints.
The primary endpoint (viral load) and key clinical course endpoints (time to resolution of 
key RSV symptoms, rate of RSV-related complications, change from baseline in key RSV 
symptoms) might also be analyzed on the Per Protocol (PP) set.
2.3.2.1.
ITT-i Set
All randomized subjects who received at least one dose of study drug and who have a 
centrally confirmed RSV RNA viral load of 1 log10 copies/mL above the lower limit of 
quantification (LLOQ) of the RSV RT-qPCR assay at baseline. Analyses on the ITT-i set 
will be performed as randomized.
2.3.2.2.
PP Set
All subjects in the ITT-i analysis set with the exclusion of any subjects deemed to have a 
major impact on the assessment of efficacy. The subjects to be excluded will be identified 
and documented prior to database lock based on the following criteria. 

Entered but did not satisfy criteria, violation of: 
o
inclusion criteria 3, 4 or 5, 
AND/OR
o
exclusion criteria 5, 9, 10, 11, 12, 13 or 16
Please see Section 4.1 and 4.2 of the protocol for full description of the criteria.

Received wrong treatment or incorrect dose 
o
The actual treatment not the same as the planned treatment
o
Subjects missed more than 1 dose (including subjects who early 
discontinued study medication)

Other:
o
Unplanned unblinding has taken place during the study
o
Insufficient post-baseline RSV RNA viral load samples collected (should 
have at least baseline and 2 post-dose samples between Day 2 and Day 5)

Received concomitant treatment that may affect the efficacy of the trial medication. 
Complete list of concomitant medications to be considered for major protocol 
violation will be identified and documented before the database lock.


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
Missing PRESORS ObsRO:
o
at baseline 
o
>1 missing for 4 consecutive assessments during BID schedule
o
>1 missing for 3 consecutive assessments during QD schedule
Note that in the PP set subjects will have been treated as randomized by definition. 
Analyses on the PP set will only be performed if >10% subjects in the ITT-i set are 
excluded from the PP set.
2.3.3.
Safety Analysis Set
2.3.3.1.
Safety Analysis Set
The Safety analysis set includes all subjects who received at least 1 dose of study agent, 
and will be analyzed as treated, regardless of the randomized treatment group assigned.
Where ‘analyzed as treated’ is defined as:

Placebo: if only placebo doses received

JNJ-53718678 Low/High dose: if at least one dose of active study drug received
o
Low dose: if majority of active doses received = low
o
High dose: if majority of active doses received = high
The Safety analysis set will be used to perform the evaluation of all safety variables and 
will be used for listings.
2.4.
Definition of Subgroups
Table 8 defines subgroups of interest for investigation across several efficacy, safety, 
virology and other analysis endpoints (type of analysis = data domains). Refer to Section 
5 for a detailed overview of efficacy endpoints (primary, secondary and exploratory).
The following data handling applies to subgroup presentation:

With the exception of Region [Class 1], subgroups will only be presented if, based on 
total number of subjects across treatment groups:
o
Subgroups with two strata: N = 36 in both strata
o
Subgroups with more than two strata: N = 36 in at least one stratum
Aforementioned data handling results in approximately 12 subjects minimum per 
treatment group with data in a stratum. This minimum number of subjects ensures 
sufficient data for meaningful subgroup analysis.

Symptom onset: 
o
Cohort 1: unless otherwise specified for a given endpoint, exploratory endpoints, 
as detailed in Section 5.4, will only be analyzed in the stratum: subjects with 
symptom onset ≤3 days before randomization. Subsequent subgroup analyses will 
be performed within this stratum only and also considering meaningful number of 
subjects as previously described.
o
In case of population enrichment decision (subjects with symptom onset ≤3 days 
before randomization), efficacy analyses will focus on those subjects with 
symptom onset ≤3 days before randomization stratum only. Subsequent subgroup 
analyses will be performed within this stratum only and also considering 
meaningful number of subjects as previously described.








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Completely missing onset dates will not be imputed.
Partial AE resolution dates not marked as ongoing will be imputed as follows:

If the resolution date of an adverse event is missing day only, it will be set to the 
earliest of the last day of the month of occurrence of resolution or the day of the date 
of death, if the death occurred in that month.

If the resolution date of an adverse event is missing both day and month, it will be set 
to the earliest of December 31 of the year or the day and month of the date of death, if 
the death occurred in that year.
Completely missing resolution dates will not be imputed.
AE onset/resolution dates with missing times will be imputed as follows:

A missing time of onset of an adverse event will be set to the earlier of:

00:01 as long as the onset date is after the first dosing of the study medication

The time of the first dosing of the study medication if this is the same day the AE 
occurred.

The missing time of resolution of an adverse event will be set to 23:59.
If a missing time is associated with a partial or missing date, the date will be imputed first 
prior to imputing the time.
3.
INTERIM ANALYSIS AND DATA MONITORING COMMITTEE REVIEW
Up to four IAs are planned for this study (Figure 2):
i.
The first IA will take place when at least 36 subjects from Cohort 1 have completed 
Day 14 assessments (or discontinued earlier) to evaluate safety and tolerability, PK, 
and antiviral effect.
ii.
The second IA will take place preferably at the end of a hemispheric RSV season when 
approximately 70 to 80 subjects from Cohort 1 (regardless of the number of subjects in 
the subcohort having reached the target of 6 subjects) have completed Day 14 
assessments (or discontinued earlier). Depending on enrollment status of Cohort 2, 
second IA will not be performed if later or too close to the estimated timing of the 
planned third IA. A futility and population enrichment analysis will be performed on 
antiviral activity (data from both cohorts combined), to terminate the study for futility, 
or to enrich the population and limit further enrollment to patients with ≤3 days since 
symptom onset. In addition, clinical course and safety-related endpoints, will be 
analyzed.
iii.
The third IA will take place preferably at the end of a hemispheric RSV season, when 
approximately 70 to 80 subjects from Cohort 2 have completed Day 14 assessments (or 
discontinued earlier) and will include data from Cohort 1 and Cohort 2. This IA will 
include a futility and population enrichment analysis on antiviral activity (data from 
both cohorts combined) and clinical endpoints (data from Cohort 2 only), as well as a 
sample-size re-estimation for Cohort 2 based on clinical endpoints.
iv.
The fourth IA will only take place if after third IA, decision is to increase number of 
subjects for Cohort 2. This IA will take place preferably at the end of a hemispheric 


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RSV season, after approximately 150 subjects in Cohort 2 completed Day 14 of 
assessments (or discontinued earlier) and will also include Cohort 1 subjects. The 
primary analysis on antiviral activity will be performed during this fourth IA and effects 
of JNJ-53718678 on clinical course endpoints, next to endpoints related to safety, PK 
and PK/PD, will be analyzed to support early Phase 3 plans.
The final analysis is planned when all subjects from Cohort 1 and Cohort 2 have completed 
the study (or discontinued earlier). If no extension of Cohort 2 is required, the final analysis 
may coincide with the primary analysis.
Figure 2:
Overview of Different Planned Analyses in Study 53718678RSV2002
An IDMC will be commissioned for this study and will review unblinded safety data on a 
regular basis throughout the conduct of this study to ensure subject safety. At any point 
during the study, the IDMC has the authority to recommend modifications to the study 
conduct and/or to the safety assessments, or to halt a dose arm due to safety concerns. 
Based on the recommendations of the IDMC following these IAs/reviews of PK, efficacy, 
and safety data, changes to the study may be implemented. The IDMC will also review 
safety and PK data from the 6 subjects in the subcohort of Cohort 1 and the data of the IAs
and provide recommendations to the Sponsor Committee (SC). The SC will take a decision 
considering the IDMC’s recommendation. Efficacy analyses presented to the IDMC will 
be limited to the primary endpoint (viral load) and key clinical course endpoints (time to 
resolution of key RSV symptoms [ObsRO], rate of RSV-related complications, change 
from baseline in key RSV symptoms [ObsRO]).










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4.2.
Disposition Information
Summaries will be provided for the following disposition information by cohort, by 
treatment group and overall

Subjects randomized:
o
Subjects randomized and not treated
o
Subjects randomized and treated

Subjects in the Safety analysis set 

Subjects in the ITT-i analysis set

Subjects assigned to the PP analysis set

Subjects who completed treatment

Subjects who prematurely discontinued study drug
o
Reasons for premature discontinuation of study drug

Subjects who completed study

Subjects who prematurely discontinued study participation
o
Reasons for premature discontinuation of study participation
Aforementioned summaries will be presented by planned treatment group (as randomized) 
with the exception of subjects assigned to safety- and PP analysis sets where the summaries 
will be presented by actual treatment received.
The following will be presented as part of by-subject data listings:

Screen failure subjects and reasons for screen failure

Subjects who discontinued study drug

Subjects who discontinued study participation

Subjects who were unblinded during the study period following randomization
4.3.
Treatment Compliance
Compliance with study drug administration will be summarized descriptively by cohort, 
by treatment group and overall. The reasons for study drug not administered, vomiting after 
study drug administration and swallowing of full volume of suspension will be listed only. 
Compliance will be derived as:
treatment compliance (%) = 100 x number of doses administered/total number of 
doses planned per actual exposure
Where total number of planned doses are as follows:

Prior to Amendment #4 (dated 26 May 2020): study drug administered once daily:
o
For subjects who complete 7 days of planned treatment, a total number of 7
consecutive doses are to be administered as per protocol.
o
In case of premature discontinuation of study drug, total number of doses will 
be based on the number of days the subject was on treatment (e.g. 1 dose per 


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day is planned per protocol so if subject is treated for 3 days , total number 
of planned doses = 3 [1 day = approximately 24 hours = 1 dose planned]).

Post-amendment #4 (dated 26 May 2020): study drug administered twice daily:
o
For subjects who complete 7 days of planned treatment, a total of 14 
consecutive doses are to be administered as per protocol.
o
In case of premature discontinuation of study drug, total number of doses will 
be based on the number of days the subject was on treatment (e.g. 2 doses per 
day are planned per protocol so if subject is treated for 3 days starting the 
morning of Day 1, total number of planned doses = 6 taking into account the 
time slot of the day of first dose of study drug [1 day = approximately 24 
hours = 2 doses planned]).
Derived study drug compliance (%) will be categorized as follows:

<80 %

≥80 % to ≤100 %

>100 %
4.4.
Protocol Deviations
All major protocol deviations will be tabulated and listed, by cohort, by treatment group 
and overall. Those that may affect the assessment of efficacy will be flagged (see Section 
2.3.2.2).
4.5.
Medical History and Family History
Reported general medical history conditions will be presented as number (n) and 
percentage (%) of subjects according to the Medical Dictionary for Regulatory Activities 
(MedDRA) primary system organ class (SOC) and preferred term (PT). Separate summary 
tables will be provided for subjects with risk factors for severe RSV disease.
Risk factors for severe RSV disease, general medical history and family records will also 
be listed.
4.6.
Prior and Concomitant Medications
Medications taken from the date when the ICF is signed through the end of study will be 
summarized by cohort, by treatment group and overall, by preferred term using the World 
Health Organization-Drug Dictionary as frequency tables for the prior and concomitant 
medications separately: 
1. Prior medication: medication that started before the first dose of study drug, 
regardless of when dosing of the medication ended.
2. Concomitant medication: medication received at or after the first dose of study 
drug, medication that was received before initial dosing and continued after initial 
dosing of study drug, or medication with missing stop date. 
Medication that started before the first dose of study drug and continued after the first dose 
of study drug will be summarized as prior medication and separately as concomitant 






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4.7.
Respiratory Pathogens
Positive/negative results for identified non-RSV pathogens at baseline, as based on 
respiratory pathogens assay, will be presented by the following categories:

Presence of other respiratory pathogens

Presence of other respiratory viruses

Presence of respiratory bacteria
Within each category, number (n) and percentage (%) of subjects with positive/negative 
results per pathogen will be summarized by cohort, by treatment group and overall. In case 
multiple results are available from multiple assays per pathogen, the subject will be 
considered positive for the specific pathogen if one or more results from the multiple assays 
are positive. For example, for Bordetella pertussis: at least two results may be available, 
one from the Pathofinder Respifinder 2SMART assay and one from the Fast Track 
Diagnostics Bordetella assay. If either or both results are positive, the subject will be 
considered positive for the presence of Bordatella pertussis.
5.
EFFICACY
The efficacy analyses include the following primary, secondary and exploratory endpoints. 
Primary Endpoint
The primary efficacy endpoint is the RSV viral load AUC from immediately prior to first 
dose of study drug through Day 5 derived from the RSV viral load as measured by a 
qRT-PCR assay in nasal swabs.
Secondary Endpoints

virologic parameters derived from the RSV viral load as measured by a qRT-PCR 
assay in nasal swabs including:

RSV viral load and change from baseline over time

RSV viral load AUC from immediately prior to first dose of study drug (baseline) 
through Day 3, Day 8, and Day 14

time to undetectable RSV viral load

proportion of subjects with undetectable RSV viral load at each timepoint 
throughout the study

clinical course related endpoints:

in hospitalized subjects and outpatients:
o
following endpoints will be based on the Pediatric RSV Electronic Severity 
and Outcome Rating System (PRESORS) assessed throughout the study by 
parent(s)/caregiver(s) (parent[s]/caregiver[s]
PRESORS) and by the 
investigator (clinician PRESORS) during scheduled visits:

duration and severity of signs and symptoms of RSV disease 

change from baseline in parent(s)/caregiver(s) PRESORS scores
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
change from baseline in clinician PRESORS scores (worsening or 
improvement)

time to resolution (i.e. to none or mild) of RSV symptoms 

time to improvement based on general questions on overall health

proportion of subjects with improvement or worsening of RSV disease 
based on general questions on overall health

time to return to pre-RSV health as rated by the parent(s)/caregiver(s)
o
respiratory rate, heart rate, body temperature, and peripheral capillary oxygen 
saturation (SpO2) over time as measured by the investigator during scheduled 
visits. Note: if the subject is enrolled in the substudy of Study 
53718678RSV2002, the same parameters as assessed by the biosensor will 
be recorded from the standard-of-care monitoring/assessments as part of the 
substudy assessments.
o
body temperature as measured by the parent(s)/caregiver(s) and recorded in 
the temperature log on the electronic device
o
need for (re)hospitalization during treatment and follow-up

in hospitalized subjects only:
o
time to age-adjusted normal values for otherwise healthy and to pre-RSV 
infection status for subjects with (a) risk factor(s) for severe RSV disease, for
heart rate, respiratory rate, and/or blood oxygen level (i.e. without 
requirement of supplemental oxygen compared with pre-RSV infection 
status)
o
time to discharge (from initial admission and from initiation of treatment)
o
time to clinical stability, with clinical stability evaluated by the investigator 
(from initial admission and from initiation of treatment)
o
need for and duration of intensive care unit (ICU) stay; ‘need for ICU stay’ 
is defined as follows:

being admitted on the ICU (and ICU level of care is required)

being admitted on the hospital ward, with or without supplemental 
oxygen, but deemed to require ICU level of care (e.g. not transferred to 
ICU due to bed availability)

requiring ICU level of care is defined by some specific conditions:
o
acute or imminent respiratory failure
o
treatment of complicated acid-base or electrolyte imbalances
o
cardiogenic shock
o
acute congestive heart failure
o
hemodynamic instability 

having other conditions requiring specialized equipment and/or staff 
competencies only available in the ICU
o
need for and duration of supplemental oxygen (regardless of method used); 
need for supplemental oxygen’ is defined by:


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
requiring invasive mechanical ventilation

receiving any oxygen support requiring intubation or extracorporeal 
oxygenation

receiving invasive mechanical ventilation 

receiving supplemental oxygen through a face mask or nasal cannula and 
not being able to sustain a blood oxygen saturation of ≥92% when 
breathing room air for 15 minutes or less, tested once 
o
need for and duration of non-invasive ventilator support (e.g. continuous 
positive airway pressure) and/or invasive ventilator support (e.g.
endotracheal-mechanical ventilation) 
o
need for hydration and/or feeding by IV administration or nasogastric tube; 
need for defined by <50% of normal oral intake
o
time to clinical stability, defined as the time from initiation of study treatment 
until the time at which the following criteria are met:

return to age-adjusted normal values for otherwise healthy and pre-RSV 
infection status for subjects with (a) risk factor(s) for severe RSV 
disease, for all of the following signs/symptoms of RSV disease:

heart rate; AND

respiratory rate; AND

blood oxygen level
AND

no more oxygen supplementation for otherwise healthy subjects and 
subjects with (a) risk factor(s) for severe RSV disease
AND

no more IV/nasogastric tube feeding/hydration in otherwise healthy
subjects
or return to pre-RSV status of IV/nasogastric tube 
feeding/hydration in subjects with (a) risk factor(s) for severe RSV 
disease
o
time from initiation of study treatment until SpO2 ≥92% and SpO2 ≥95% on 
room air among subjects who were not on supplemental oxygen prior to the 
onset of respiratory symptoms

safety and tolerability, as assessed by adverse events (AEs), clinical laboratory testing, 
electrocardiograms (ECGs), vital signs, throughout the study

PK parameters of JNJ-53718678, as determined by population PK (popPK) modeling

medical resource utilization

acceptability and palatability of the JNJ-53718678 formulation as assessed through a 
questionnaire completed by parent(s)/caregiver(s) in the electronic device

sequence changes (post baseline) in the RSV F gene, and other regions of the RSV 
genome (at the discretion of the sponsor’s virologist), as compared with the baseline 
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Exploratory Endpoints

The occurrence of complications with onset after treatment initiation that are 
associated with RSV per investigator assessment:

bacterial superinfections (e.g. pneumonia, sinusitis, bronchitis, bacteremia of 
presumed respiratory origin per investigator assessment)

otitis media, bronchiolitis, viral pneumonia

exacerbations of underlying pulmonary disease (e.g. asthma, cystic fibrosis, 
bronchopulmonary dysplasia)

exacerbations of underlying cardiovascular conditions

the use of antibiotics related to complications associated with RSV per investigator 
assessment

the RSV RNA viral load as measured by a qRT-PCR assay in nasopharyngeal and/or 
tracheal aspirate samples in a subgroup of hospitalized subjects in which these samples 
are obtained as part of their SOC

comparison of RSV RNA viral load as measured by a qRT-PCR assay in nasal swabs 
and other samples (e.g. nasopharyngeal and/or tracheal aspirate samples)

virologic parameters derived from the RSV viral load as measured by quantitative viral 
culture
5.1.
Analysis Specifications
Primary, secondary and exploratory efficacy analyses described in the following sections 
will be analyzed and presented using primarily the ITT-i analysis set, unless otherwise 
specified.
Analyses will be performed combining Cohort 1 (hospitalized subjects) and Cohort 2
(outpatients subjects) as well as in each cohort separately except for IA#1 where data from 
subjects in Cohort 1 only are available. In each IA, the cohort/s information to be 
considered for decision-making is specified in Section 5.6. For subgroup analysis, please 
refer to Section 2.4 for further details.
For all the stratified statistical analyses, the derived randomization stratification factors 
(symptom onset [≤3 days vs >3 days to ≤5 days before randomization] and presence of risk 
factors for severe RSV disease [Yes vs No]) will be used instead of the randomization 
stratification factors as collected in IWRS. Exception is sensitivity analysis of the primary 
efficacy endpoint based on IWRS randomization stratification factors.
In addition to the analyses outlined in the subsequent sections, efficacy parameters and a 
selection of derived efficacy variables will be presented in by-subject data listings.
5.1.1.
Level of Significance
The primary objective is to establish antiviral activity of JNJ-53718678. The primary 
efficacy endpoint is the RSV RNA viral load AUC from immediately prior to first dose of 
study drug through Day 5 (AUCDay 5) derived from the RSV RNA viral load as measured 
by a qRT-PCR assay in nasal swabs. A hybrid methodology that combines aspects of 
multiple testing with modeling techniques (MCP-Mod) will be used for evaluating dose-


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response trends and estimating the dose-response relationships. The dose-response will be 
tested at each (interim) analysis at alpha=2.5% (1-sided).
The primary analysis will only adjust for multiplicity with respect to the candidate models 
included into the MCP-Mod test. Due to the exploratory nature of the study, no adjustment 
for multiplicity due to sub-populations and adaptations will be considered in the primary 
analysis. A secondary analysis approach will be performed to control for multiplicity in the 
clinical course endpoints and for adaptations (see Section 5.2.3.2).
5.1.2.
Data Handling Rules
RSV RNA Viral Load
Rule of maximum: before any imputation is applied, the value for each day is defined as 
the maximum value of all RSV assessments performed on that day. Please notice that this 
rule doesn’t apply for baseline. For baseline details please see Section 2.1.2. 
For analysis purposes, the log10 qRT-PCR RSV RNA viral load will be imputed with the 
midpoint on the log scale between the limit of detection (LOD) and LLOQ of the RSV 
qRT-PCR assay when the result is ‘target detected’ (TD) but non-quantifiable.

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) (i.e. 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 RSV RNA viral load, all the RSV RNA viral load results of the 
RSV type with which the subject 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 RSV RNA viral load from the time the co-infection is detected 
(i.e. 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.
5.2.
Primary Efficacy Endpoint(s)
5.2.1.
Definition
RSV RNA viral load will be measured in mid-turbinate nasal swab specimens using an 
RSV A/B qRT-PCR assay.


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The primary efficacy endpoint is the RSV RNA viral load area under the curve (AUC) 
from immediately prior to first dose of study drug (baseline) through Day 5 (AUCDay 5) 
derived from the RSV RNA viral load as measured by a qRT-PCR assay in nasal swabs.
5.2.2.
Estimand
The primary efficacy endpoint is the RSV RNA viral load AUCDay 5 in subjects from both 
cohorts (hospitalized and outpatient). The presence of a dose-response will be established 
using the model-based trend test (MCP-Mod) among two doses of JNJ53718678 versus 
treatment with placebo, in combination with SOC.
The primary estimates of the AUCDay 5 will be derived from a mixed model (see Section 
5.2.3 for the detailed specification). No explicit imputations of missing data from nasal 
swabs post-baseline will be done in this model, as this mixed model would allow to make 
inferences implicitly imputing the missing data under the missing at random assumption.
5.2.3.
Analysis Method
Mean log10 RSV RNA viral load values over time will be analyzed using a restricted 
maximum likelihood based repeated measures approach (MMRM). The analysis model 
includes fixed (discrete) effect parameters for treatment, randomization stratification 
factors (derived), analysis visit and treatment-by-analysis visit interaction, as well as 
continuous covariates for baseline log10 viral load and baseline log10 viral load-by-analysis 
visit interaction. An unstructured (co)variance structure will be used to model the within-
subject errors. In case this model will not converge, the Toeplitz covariance structure will 
be applied. The Kenward-Roger approximation will be used to estimate the denominator 
degrees of freedom.
For subgroup analyses, the model will also include the subgroup variable as a covariate 
and the subgroup-by-treatment, subgroup-by-analysis visit and subgroup-by-analysis visit-
by-treatment interactions. For details about subgroups please see Section 2.4. 
A generalized MCP-Mod (1) approach at 1-sided alpha-level of 2.5% will be applied based 
on the estimated AUC treatment group effect and variance covariance matrix. Candidate 
models are given by the EMax (0.40428), Exponential (0.36411) and Linear model, with 
the aim to test for existence of drug-related effects. Each of the dose-response shapes in 
the candidate set will be tested using the corresponding contrast t-test statistic, employing 
a critical value derived for the maximum of the t-test statistics (based on the associated 
multivariate t-distribution) to ensure appropriate multiplicity correction that preserves a 1-
sided 0.025 Type I error rate. A dose-response trend is established when the maximum of 
the t-test statistics exceeds the critical value.
MCP-Mod uses dose levels 0, 3 and 9 mg/kg which correspond to Placebo, Low and High 
dose respectively according to the dose/kg for age-group 3 as described in Section 1.2.
5.2.3.1.
Sensitivity Analyses
Utilizing the same methodology as described for the primary efficacy endpoint, three 
sensitivity analyses will be performed as follows:
























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Table 18:
Parameters based on PRESORS ClinRO
As exploratory analysis, this secondary approach will be evaluated 
versus the primary approach ‘average of the worst’.
Status of overall 
condition at each 
timepoint
[categorical]
Each assessment of ‘Do you have any concerns relating to the subject’s 
overall condition’ will be assigned to one of the 3 categories below:
 No concerns (condition is stable or improving)
 Some concerns (may become unstable/requires close observation)
 Extremely concerned (unstable, requires immediate medical review)
Status of health 
at each timepoint
[categorical]
Each assessment of ‘Overall, how would you rate the subject’s current 
health status’ will be assigned to one of the 4 categories below:
 Excellent
 Good
 Fair
 Poor
Health compared 
to the baseline 
assessment?
[categorical]
Clinician’s global rating of change (CGRC) question:
With respect to the child’s RSV infection, how would you describe the 
child’s health now compared to the baseline assessment?
Ordinal scale from -5 to 5 where -5 indicates ‘very much worse’, 0 
indicates ‘unchanged’, and 5 indicates ‘very much better’ 
Missing data: 
clinician 
PRESORS
[binary]
Missing clinician PRESORS: ClinRO assessments per day, from baseline 
to Day 21, will be identified per analysis visit window based on the data 
handling rules described in Section 2.1.4, specifically the assignment of 
worst assessment over a 24-hour period, as detailed in Table 6:
Worst per 
Day where:

Expected: number of subjects with expected assessments per day is 
based on the BID vs QD assessment schedule per protocol, 
hospitalized vs outpatient status and for those subjects still ongoing in 
the study at the timepoint of interest (refer to Table 4:
Planned 
Collection of PRESORS ClinRO, PRESORS ObsRO and Clinical 
Evaluation).

Completed: number of subjects with completed (non-missing) 
assessments per day for those subjects still ongoing in the study at the 
timepoint of interest and taking into account subject status 
(hospitalized vs outpatient). Noting that during the BID assessment 
schedule, if at least one assessment is available for that day, it is 
regarded as sufficient, and subject is considered to have a completed 
assessment.

Total missing: number of subjects with at least one missing 
assessment per day from baseline to Day 21.
Number of 
investigators
Based on the number of raters per subject as indicated in the handheld 
eDevice.
Refer to Section 5.4 for details regards clinician PRESORS ClinRO exploratory 
endpoints and analysis.
5.3.1.3.
Other Clinical Course Parameters
5.3.1.3.1.
Respiratory Rate, Heart Rate, Oxygen Saturation and Body 
Temperature 
Formulae to be used for derived clinical course vital signs parameters, are provided in 
Table 19.




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Table 20:
Additional Clinical Course Parameters for Hospitalized Subjects
time to event (hours) = (date/time of event or censoring – date/time 
of hospital admission)/3600, rounded to one decimal
Time (hours) to clinical 
stability: investigator 
assessment since hospital 
admission [time to event]
The time (hours) from hospital admission to first clinical stability 
(=event), as evaluated by the investigator and captured in the 
Clinical Stability eCRF.
Censoring rules and derivation: as for ‘Time (hours) to hospital 
discharge’
Duration of need for 
intensive care unit (ICU) 
stay (hours) [duration] 
The total number of hours a subject experienced a medical need to 
stay in ICU (=event) from first dose of study drug until study 
termination, calculated as sum of [(end date/time of event – start
date/time of event)/3600], rounded to one decimal for all separate 
events per subject as captured in the ICU eCRF. Based on the 
medical need to stay in ICU start/end date/time.
Where:

If the initial start date/time is prior to the first dose of study 
drug, the duration prior to the first dose of study drug will be 
deducted from the overall duration

If start date/time is missing, it will be imputed using date/time 
of first dose of study drug

If the end date is missing, the end date is considered to be 
after study completion or withdrawal

If the end date/time is after study completion/discontinuation, 
the duration after the date/time of study 
completion/discontinuation will be deducted from the overall 
duration (implies imputation of completion/discontinuation 
date/time)

If start date is available but the start time is not available, it 
will be imputed as 00:00

If end date is available but end time is not available and:
o
End date equals hospital discharge date, end time will be 
imputed as the hospital discharge time (only if hospital 
discharge time is also not an imputed time), else imputed 
as 23:59 (if hospital discharge time is also an imputed 
time)
o
End date does not equal hospital discharge date, end time 
will be imputed worst-case as 23:59
Actual duration of 
intensive care unit (ICU) 
stay (hours) 
[duration] 
For subjects in Cohort 1: total number of hours of actual ICU stay 
experienced by a subject from first dose of study drug until end of 
study (sum of the duration of individual ICU records captured in 
the Hospitalization [Inpatient] eCRF) and is derived as:
time hours = sum [(end date/time –start date/time [of 
encounter])]/3600
Derivation and imputation rules: as for ‘Duration of need for 
intensive care unit (ICU) stay (hours)’


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Table 20:
Additional Clinical Course Parameters for Hospitalized Subjects
Need for ICU stay
[binary]
Was there a medical need for the subject to stay in the ICU after 
first dose of study drug? Categories will be Yes (1) or No (0).
Only derive this parameter for subjects that were not in ICU before 
first dose of study drug (no score will be assigned otherwise).
Duration of oxygen 
supplementation
[duration]
The total number of hours a subject used supplemental oxygen 
(=event) from first dose of study drug until study termination, 
calculated as sum of [(end date/time of event - start date/time of 
event)/3600], rounded to one decimal for all separate events per 
subject
Derivation and imputation rules: as for ‘Duration of need for 
intensive care unit (ICU) stay (hours)’
If the subject required oxygen supplementation prior to the current 
respiratory infection, the end date/time will be the date/time that the 
supplemental oxygen administration returned to the level provided 
prior to the current respiratory infection.
Need for oxygen 
supplementation
[binary]
Does the subject require any oxygen supplementation (non-invasive
or invasive) after first dose of study drug?
Categories will be Yes (1) or No (0).
Only derive this parameter for subjects that did not require oxygen 
supplementation before first dose of study drug (no score will be 
assigned otherwise).
If the subject required supplemental oxygen prior to the current 
respiratory infection, requirement will be defined as having not 
returned to the level provided prior to the current respiratory 
infection.
Requirement for non-
invasive non-mechanical 
ventilation support
[binary]
Does the subject require non-invasive non-mechanical ventilation 
support after first dose of study drug? On the Oxygen 
Supplementation form, oxygen supplementation is indicated but the 
type of supplemental oxygen administration does not equal “Non-
Invasive Mechanical Ventilation” or “Invasive Mechanical 
Ventilation”? 
Categories will be Yes (1) or No (0).
Only derive this parameter for subjects that did not require non-
invasive non-mechanical ventilation before first dose of study drug 
(no score will be assigned otherwise).
Requirement for non-
invasive mechanical 
ventilation support 
[binary]
Does the subject require non-invasive mechanical ventilation 
support after first dose of study drug, as indicated on the Oxygen 
Supplementation form: type of supplemental oxygen administration 
equals “Non-Invasive Mechanical Ventilation”? 
Categories will be Yes (1) or No (0).
Only derive this parameter for subjects that did not require non-
invasive mechanical ventilation support or invasive mechanical 






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Table 20:
Additional Clinical Course Parameters for Hospitalized Subjects
will also be censored at the last timepoint of the censored 
component.
time to event (hours) = (maximum (date/time of event or censoring)
– date/time of first dose of study drug)/3600, rounded to one decimal
Time (hours) to return to 
pre-RSV disease level 
for RR: based on 
investigator evaluation
[time to event]
The time (hours) from first dose of study drug until the date/time to 
return to pre-RSV disease level. The return to pre-RSV disease level 
occurs when the observed value of the parameter is indicated by the 
investigator as normal, and no later observed values are indicated by 
the investigator as abnormal (=event).
Normalization of RR will be derived from the investigator response
to the corresponding question in the Vital Signs eCRF: ‘Is this RR 
value normal for this patient?’
If no deterioration from pre-RSV disease levels occurred, the time 
will be set to time of first dose of study drug and the value will be 
set to 0 hours.
Subjects with an abnormal value at the last assessment will be 
censored at that time. Subjects for which this last assessment is the 
baseline assessment will be censored at time 0 hours.
time to event (hours) = (date/time of event or censoring – date/time 
of first dose of study drug)/3600, rounded to one decimal
Time (hours) to return to 
pre-RSV disease level for 
HR: based on 
investigator evaluation
[time to event]
Censoring rules and derivation: as for ‘Time to return to pre-RSV 
disease level for RR: based on investigator evaluation’’
Normalization of HR will be derived from the investigator response
to the corresponding question in the Vital Signs eCRF: ‘Is this Pulse 
value normal for this patient?’
Time (hours) to SpO2 ≥ 
92% on room air 
[time to event]
The time from first dose of study drug until the time of first SpO2
measurement ≥ 92% on room air, and where no supplemental 
oxygen supplementation is given at or after this timepoint and where 
no value < 92% are measured after this timepoint. 
Subjects with SpO2<92% on room air or who are still on oxygen 
supplementation at the last SpO2 assessment will be censored at the 
date and time of the last SpO2 assessment.
If no oxygen supplementation was necessary post-baseline and the 
subject had SpO2 measurement ≥ 92% on room air at baseline and 
all post-baseline measurements, the value (time to event [hours])
will be set to 0 hours. 
If the subject required supplemental oxygen prior to the current 
respiratory infection, end date/time will be defined as the date/time 
the subject has returned to the level provided prior to the current 
respiratory infection.
time to event (hours) = (date/time of event or censoring – date/time 
of first dose of study drug)/3600, rounded to one decimal


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Table 20:
Additional Clinical Course Parameters for Hospitalized Subjects
Time (hours) to SpO2 ≥ 
95% on room air 
[time to event]
Censoring rules and derivation: as for ‘Time (hours) to SpO2 ≥ 92% 
on room air’
Time (hours) to clinical 
stability: protocol 
definition
[time to event]
Time at which all the following criteria are met:
Return to pre-RSV disease status for otherwise healthy subjects and 
subjects with (a) risk factor(s) for severe RSV disease:

heart rate AND

respiratory rate AND

blood oxygen level
AND
No more oxygen supplementation for otherwise healthy subjects 
and subjects with (a) risk factor(s) for severe RSV disease
AND
No more intravenous (IV)/nasogastric tube feeding/hydration in 
otherwise healthy subjects or return to pre-RSV status of 
IV/nasogastric tube feeding/hydration in subjects with (a) risk 
factor(s) for severe RSV disease
Time to clinical stability (protocol definition) will be evaluated 
using two approaches:
The time from first dose of study drug until the time at which each 
of the following criteria are met (=event): 

Normalization of oxygen supplementation (as in parameter 
Time [hours] to end of oxygen supplementation up to 72h from 
first hospital discharge),

Normalization of feeding/hydration (as in parameter Time
[hours] to end of hydration/feeding supplementation up to 72h 
from first hospital discharge), 

Normalization of RR (as in parameter Time [hours] to return to 
pre-RSV disease level for RR: based on investigator 
evaluation), and

Normalization of HR (as in parameter Time [hours] to return to 
pre-RSV disease level for HR: based on investigator 
evaluation), and

Normalization of blood oxygen level (as in parameter Time
[hours] to SpO2 ≥ 92% on room air)
The time from first dose of study drug until the time at which each 
of the following criteria are met (=event): 


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Table 20:
Additional Clinical Course Parameters for Hospitalized Subjects

Normalization of oxygen supplementation (as in parameter 
Time [hours] to end of oxygen supplementation up to 72h from 
first hospital discharge),

Normalization of feeding/hydration (as in parameter Time
[hours] to end of hydration/feeding supplementation up to 72h 
from first hospital discharge), 

Normalization of RR (as in parameter Time [hours] to return to 
pre-RSV disease level for RR: based on investigator 
evaluation), and

Normalization of HR (as in parameter Time [hours] to return to 
pre-RSV disease level for HR: based on investigator 
evaluation), and

Normalization of blood oxygen level (as in parameter Time
[hours] to SpO2 ≥ 95% on room air)
In case any of the five components are censored, the time to clinical 
stability (protocol definition) will also be censored at the last 
timepoint of the censored component.
time to event (hours) = (maximum (date/time of event criteria or 
censoring) – date/time of first dose of study drug)/3600, rounded to 
one decimal
Need for re-
hospitalization 
[categorical]
If, after being discharged from the hospital (initial hospital 
discharge), subject is re-hospitalized (ward or ICU [inpatient 
status]) due to respiratory or other reasons. Re-hospitalization 
status will be categorized as:

Yes
o
Hospital admission date/time at least 24 hours after initial 
hospital discharge date/time AND
o
Reason for re-hospitalization, as assessed by the 
investigator, indicated on Medical Encounters 
[Inpatient/Outpatient] eCRF as:

AE

Other
If reason for re-hospitalization is indicated as AE, further 
differentiation will be made as follows:

Respiratory AEs:

RSV-related complications: modified definition as 
detailed in Section 5.4

Other respiratory AEs

Non-respiratory AEs
This variable is only derived for those subjects who are re-
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5.3.2.
Endpoint-specific analysis methods
5.3.2.1.
RSV RNA Viral Load (qRT-PCR)
Log10 RSV RNA Viral Load
Descriptive statistics mean (SE) graphs and median (IQR) graphs will be shown for the 
log10 RSV RNA viral load actual values and changes from baseline by analysis visit and 
by treatment group. Descriptive statistics will include the number of subjects, mean, 
standard deviation, standard error, 95% confidence interval, median, range and 
interquartile range. The aforementioned will be presented by the subgroups as defined in 
Section 2.4.
Differences on log10 RSV RNA viral load by qRT-PCR between treatment groups and by 
analysis visit will be determined using appropriate contrasts in a similar mixed effects
model as the one used for the primary efficacy endpoint (see Section 5.2.3). The 95% 2-
sided confidence intervals will be presented.
Association Between Log10 RSV RNA Viral Load and Covariates/Baseline 
Indicators 
The potential association between the log10 RSV RNA viral load and the following
covariates and/or baseline indicators will be explored:
- Baseline log10 RSV RNA viral load
- Presence/absence of risk factors for severe RSV disease
- Days since symptom onset (0,1,2,3,4,5)
- RSV subtype
- Medications of interest:

Any prior/concomitant use

No prior/concomitant use
- Supplemental oxygen at baseline 
- Presence of other respiratory pathogens at baseline
- Presence of other respiratory viruses at baseline
- Age as collected at Screening (as continuous variable)
- Overall RSV symptoms summary score (ObsRO) at baseline
- Overall RSV symptoms summary score (ClinRO) at baseline
- Region [Class 2]
- Cohort [Class 1]
- Baseline neutrophils count (as continuous variable)
To predict the change in log10 RSV RNA viral load over time at Day 3, Day 5 and Day 8
based on the aforementioned set of predictor variables (covariates and/or baseline 
indicators), multiple regression analysis using backward stepwise elimination, will be 
performed initially fitting all predictor variables to identify the prognostic factors. Then 


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factors are deleted one-by-one until a stopping condition is satisfied. At each step, the
factor showing the smallest contribution to the model is eliminated. The parameter 
estimates along with the 95% 2-sided confidence limits by predictor variable will be 
produced. In addition, residual plots and goodness of fit measures will be evaluated, but 
not displayed in output. The SAS® procedure GLM SELECT (selection = backward SLS 
= 0.1) will be used. The procedure removes factors based on significance level and stops 
when all factors in the model are significant at the 0.1 level.
Predictor variables which show a strong association may further be explored as additional 
covariates in the primary efficacy model described in Section 5.2.3.
RSV RNA Viral Load AUC
A similar model as used for the primary analysis will be used for the RSV RNA viral load
AUC until Day 3 and until Day 8. The differences in these AUCs for active versus placebo 
will be derived using appropriate contrasts for both Day 3 and Day 8 and from the same 
model containing all RSV RNA viral load assessments from baseline through Day 8.
Least squares mean estimates of the treatment differences, including the 95% 2-sided
confidence intervals, will be presented.
For subgroup analyses, the model will also include subgroup variable as covariate, 
subgroup-by-treatment, subgroup-by-analysis visit and subgroup-by-analysis visit-by-
treatment interactions. For details about subgroups refer to Section 2.4.
The individual AUCs until Day 14, derived using the trapezoidal method, will be analyzed 
using a generalized linear model with AUCDay14/0-312h as a dependent variable, treatment 
group and randomization stratification factors (derived) as fixed factors, and baseline log10
RSV RNA viral load as fixed covariate. The differences versus placebo will be estimated 
using appropriate contrasts and presented with 95% 2-sided confidence intervals.
Proportion of Subjects with Undetectable RSV RNA Viral Load
The proportion of subjects within the RSV RNA viral load categories (undetectable, 
detectable and quantifiable) will be shown in a frequency tabulation, as well as graphically,
by treatment group and analysis visit. Subjects with missing data at that analysis visit will 
not be counted in the denominator for the proportion. Additionally, 95% 2-sided 
confidence interval for each binomial proportion within the individual categories will be 
presented as based on the Wilson score test.
Based on the binary categorization:

Detectable or quantifiable = Yes (1)

Undetectable = No (0)
the difference in proportion of undetectable between each active treatment group as 
compared to placebo will be investigated. Frequency procedure in SAS® provides 
Newcombe confidence limits with Mantel-Haenszel weights for the common risk 
difference, controlling for the two randomization stratification factors (separately). The 


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difference in proportion of undetectable and 95% 2-sided confidence interval for this point 
estimate, controlling for randomization stratification factors, will be presented.
The aforementioned will be presented overall by treatment group and by the subgroups as 
defined in Section 2.4.
Time to Virus Undetectable [time to event]
With reference to the two time to event approaches, their definitions and derivations 
detailed in Section 5.3.1.1:
The time to event variables will be analyzed using Kaplan-Meier analysis (for both 
approaches). A summary table including number of subjects included in the analysis, 
number of subjects censored, 25th and 75th percentiles and median time to event, with 95% 
2-sided confidence intervals based on Kaplan-Meier transformation method, will be 
presented by treatment group. The data will be presented graphically using the Kaplan-
Meier estimate of the survival function by treatment group.
The aforementioned will be presented overall by treatment group and by the subgroups as 
defined in Section 2.4, for time (hours) to confirmed undetectable viral load only.
As sensitivity analysis, overall summary tables will be presented as described above for 
time (hours) to confirmed undetectable viral load but excluding nasal swab samples as 
previously described (refer to Section 5.2.3).
In addition to the Kaplan-Meier analysis, as described above, time (hours) to confirmed 
undetectable viral load and the differences in time to confirmed undetectable viral load
of active dosing regimens versus placebo treatment, will also be estimated using the 
accelerated failure time (AFT) model, using the log-logistic distribution. The AFT model 
will include the categorical effects for treatment (with placebo as the reference), 
randomization stratification factors (derived) and baseline log10 RSV RNA viral load as 
continuous covariate. A summary of information from the final AFT model will include 
parameter estimates and associated standard errors and covariance matrix of parameter 
estimates, estimated accelerated failure time ratios versus placebo and associated 95% 2-
sided confidence intervals. 
The aforementioned will be presented overall by treatment group and by the subgroups as 
defined in Section 2.4.
The parameter estimates and associated variance matrix resulting from AFT model, will be 
used in a generalized MCP-Mod approach that will test for existence of dose-response, at 
alpha=0.10 (1-sided). The aforementioned will be presented overall by treatment group 
only.
Graphical presentation will include:

Overlay of survival curves with Kaplan-Meier survival function and AFT on one plot

Forest plot of accelerated failure time ratios and resulting confidence intervals for 
subgroups of interest as defined in Section 2.4 including the relevant subgroup variable 
as covariate in the model with subgroup*treatment group interaction.


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5.3.2.2.
Pediatric RSV Electronic Severity and Outcome Rating System 
(PRESORS)
With reference to the definitions and derivations detailed in Section 5.3.1.2.1, the following 
will be presented.
ObsRO Concept, Summary Parameter and Daily Scores; ClinRO Concept, 
Summary Parameter and Daily Scores
Descriptive statistics will be shown for the actual values and changes from baseline by 
analysis visit and by treatment group. Descriptive statistics will include the number of 
subjects, mean, standard deviation, standard error, 95% confidence interval, median, range 
and interquartile range. Descriptive statistics will be presented overall, and by subgroup 
(as defined in Section 2.4). For analyses for which we need at most one assessment per day 
(e.g. for summarizing combined in- and outpatient data captured by the clinician), we take 
the worst over 24 hours according to Table 6.
Graphical presentation of actual values and changes from baseline for individual concept 
scores and/or summary parameters (daily summary score [worst of the average]) over time 
will include:

Mean (SE)

BAR plots including:
o
Baseline PRESORS ObsRO/ClinRO
o
Subset of hospitalized subjects (Cohort 1): last PRESORS ObsRO/ClinRO
concept scores BEFORE hospital discharge
o
Subset of hospitalized subjects (Cohort 1): first PRESORS ObsRO/ClinRO
concept scores AFTER hospital discharge

Individual subject profiles over time: key RSV symptoms
The aforementioned will be presented overall by treatment group and by the subgroups as 
defined in Section 2.4.
To explore the agreement between the two approaches (refer to Table 17 in Section 
5.3.1.2.1), in identifying the worst concept score per day, used in deriving the four 
summary parameter daily summary scores, the actual values and changes from baseline 
summary scores over time will be presented graphically for each summary parameter
individually (x4):

Overlay of primary and secondary approach of Mean±SE daily summary scores over 
time on one plot:
o
Average of the worst (PRIMARY APPROACH)
o
Worst of the average (SECONDARY APPROACH)
The aforementioned will be presented overall by treatment group only.


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Association Between Summary Parameter Score: PRESORS ObsRO Key RSV 
Symptoms and Covariates/Baseline Indicators
The potential association between the change from baseline in summary scores of the
summary parameter, PRESORS ObsRO: key RSV symptoms and the covariates and/or 
baseline indicators of  interest will be explored over time at Day X, Day 8 and Day 10 in a 
similar manner, utilizing multiple regression with backward stepwise elimination, as 
described for the RSV RNA viral load. Refer to Section 5.3.2.1 for details.
Day X is defined as the day when at least 50% of Cohort 1 subjects, across all treatment 
groups, have been discharged from hospital. The day identified will be used for both 
cohorts.
PRESORS ObsRO: Change from Baseline: Mixed Model Repeated Measures
For the summary parameter, PRESORS ObsRO: key RSV symptoms, change from 
baseline over time (average of the worst [primary approach] daily summary scores) will be 
analyzed using a restricted maximum likelihood based repeated measures approach. The 
analysis model will include fixed (discrete) effect parameters for treatment, randomization 
stratification factors (derived), analysis visit and treatment-by-analysis visit interaction, as 
well as continuous covariates for the baseline summary parameter score and baseline 
summary parameter score-by-analysis visit interaction. An unstructured covariance 
structure will be selected to model the within-subject errors. In case this model will not 
converge, the Toeplitz covariance structure will be applied. The Kenward-Roger 
approximation will be used to estimate the denominator degrees of freedom.
Differences between treatment groups and by analysis visit will be determined using 
appropriate contrasts. Both the 80% and 95% 2-sided confidence intervals will be 
presented.
For subgroup analyses, the model will also include the subgroup variable as a covariate 
and the subgroup-by-treatment, subgroup-by-analysis visit and subgroup-by-analysis visit-
by-treatment interactions. For details about subgroups refer to Section 2.4.
Time to Resolution of Symptoms (Concepts) and Four Summary Parameters: Key 
RSV Symptoms, Respiratory Symptoms, General Illness Behavior and Overall RSV 
Symptoms (ObsRO)
For the RSV symptoms (concepts) and four summary parameters, these time to event 
variables will be analyzed using Kaplan-Meier analysis. Both the 80% and 95% 2-sided 
confidence intervals will be presented.
The aforementioned will be presented overall by treatment group and by the subgroups as 
defined in Section 2.4, for summary parameters, key RSV symptoms and overall RSV 
symptoms only.
For time to resolution of summary parameters, key RSV symptoms and overall RSV 
symptoms (ObsRO), sensitivity analyses will be performed considering 4 different 
imputation methods:

Method 1: from first resolution (score 0 or 1) after last unresolved value onwards, 
impute missing data as resolved.


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
Method 2: impute all missing values as unresolved (score >1).

Method 3: impute all missing values in-between resolved observations (score 0 or 1) 
as resolved.

Method 4: impute all missing values as unresolved ( score >1), except when in-
between resolved values where resolved is imputed.
These sensitivity analyses will be provided from IA#3 onwards.
In addition, for the summary parameters, key RSV symptoms and overall RSV symptoms, 
difference in median time (hours) to resolution (event) between each active treatment group 
as compared to placebo will be investigated using the AFT model with log-logistic 
distribution. The model will include class variables treatment group with placebo as 
reference and randomization stratification factors (derived) and baseline summary 
parameter score. Summary will include parameter estimates and associated standard error, 
covariance matrix of parameter estimates, estimated accelerated failure time ratio (as 
compared to placebo) and both 80% and 95% 2-sided confidence intervals.
The aforementioned will be presented overall by treatment group and by the subgroups as 
defined in Section 2.4.
Parameter estimates and associated variance matrix resulting from AFT model, will be 
used in a generalized MCP-Mod approach to test dose-response, at 1-sided alpha 
level=0.10. The aforementioned MCP-Mod will be presented overall by treatment group
only.
Graphical presentation will include:

Overlay of survival curves with Kaplan-Meier survival function and AFT on one plot

Forest plot of accelerated failure time ratios and resulting confidence intervals for 
subgroups of interest as defined in Section 2.4 including the relevant subgroup variable 
as covariate in the model with subgroup*treatment group interaction.
Status of RSV Symptoms, Status of Health, Status of Improvement of RSV 
Symptoms, Status of Return to Pre-RSV Disease Health (ObsRO)
The proportion of subjects within the categories will be shown in a frequency tabulation, 
as well as graphically, per analysis timepoint, per treatment group and analysis visit. 
Subjects with missing data at that analysis visit will not be counted in the denominator for 
the proportion. Additionally, 95% 2-sided confidence interval for each binomial proportion 
within the individual categories will be presented as based on the Wilson score test.
The aforementioned will be presented overall by treatment group and by the subgroups as 
defined in Section 2.4.
Status of Overall Condition, Status of Health, Health Compared to the Baseline 
Assessment (ClinRO)
The proportion of subjects within the categories will be summarized in a similar manner as 
described for aforementioned ObsRO ‘status’ variables.
Missing Data: Caregiver/Clinician PRESORS, Number of Caregivers/Investigators
Summary of the number (n) and percentage (%) of subjects with at least one completed 
assessment by analysis visit window (baseline to Day 21), for subjects still ongoing in the 
study at the timepoint of interest, will be presented overall by treatment group and cohort.


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Total number of subjects with completed assessments from baseline to Day 21 will be 
evaluated relative to the total number of subjects with expected assessments taking into 
account the protocol-required assessment schedule.
Actual number of subjects with assessments missing per analysis visit window, taking into 
account the protocol-required assessment schedule and subject status (hospitalized vs 
outpatient) at the timepoint of interest, will also be presented.
The number of caregivers and investigators per subject, over the entire study course, will 
be presented as a frequency tabulation.
5.3.2.3.
Other Clinical Course Parameters
5.3.2.3.1.
Respiratory Rate, Heart Rate, Oxygen Saturation and Body 
Temperature 
Descriptive statistics will be shown for the actual values and changes from baseline by visit 
and by treatment group. Descriptive statistics will include the number of subjects, mean, 
standard deviation, standard error, 95% confidence interval, median, range and 
interquartile range.
Graphical presentation of the Mean±SE of both actual values and changes from baseline 
vital signs over time will be provided.
The aforementioned will be presented overall by treatment group and by the subgroups as 
defined in Section 2.4.
5.3.2.3.2.
Hospitalized Subjects only
Time to Discharge, Time to Clinical Stability: Protocol Definition, Time to Clinical 
Stability: Investigator Assessment
These time to event variables will be analyzed using Kaplan-Meier analysis. Both the 80% 
and 95% 2-sided confidence intervals will be presented.
The aforementioned will be presented overall by treatment group and by the subgroups as 
defined in Section 2.4
In addition, for time (hours) to hospital discharge (relative to date/time of first dose of study 
drug), the differences in median time of active dosing regimens versus placebo treatment 
will also be estimated using the AFT model. The AFT model will include the categorical 
effects for treatment (with placebo as the reference) and randomization stratification factors
(derived). A summary of information from the final AFT model will include parameter 
estimates and associated standard errors and covariance matrix of parameter estimates, 
estimated accelerated failure time ratios versus placebo and the associated 80% and 95% 
2-sided confidence intervals will be presented.
The aforementioned will be presented overall by treatment group and by the subgroups as 
defined in Section 2.4.
The parameter estimates and associated variance matrix resulting from AFT model, will be 
used in a generalized MCP-Mod approach that will test for existence of dose-response, at 
alpha=0.10 (1-sided). The aforementioned MCP-Mod will be presented overall by 
treatment group only.


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Graphical presentation will include:

Overlay of survival curves with Kaplan-Meier survival function and AFT on one plot

Forest plot of accelerated failure time ratios and resulting confidence intervals for 
subgroups of interest as defined in Section 2.4 including the relevant subgroup variable 
as covariate in the model with subgroup*treatment group interaction.
Association Between Time (hours) to Hospital Discharge and Covariates/Baseline 
Indicators 
For Cohort 1 (hospitalized) subjects, the potential association between the time (hours) to 
hospital discharge (relative to date/time of first dose of study drug) and covariates/baseline 
indicators of interest, as detailed in Section 5.3.2.1, will be explored utilizing a similar AFT 
model as described above but including the relevant subgroup variable as covariate in the 
model with subgroup*treatment group interaction.
RSV-related Re-hospitalization
The proportion (number [n] and percentage [%]) of subjects will be presented as frequency 
tabulation:

Re-hospitalized (any reason): percentage (%) based on total number of hospitalized 
subjects in ITT-i analysis set and treatment group

Re-hospitalized:
o
Adverse event:

Respiratory AEs:

RSV-related complications: modified definition as detailed in Section
5.4

Other respiratory AEs

Non-respiratory AEs
o
Other
In addition, the main reason(s) for re-hospitalization will be summarized descriptively.
Individual subject profiles will be provided for all subjects re-hospitalized.
Time to Discharge Since Hospital Admission, Time to Clinical Stability: Investigator 
Assessment Since Hospital Admission
These time to event variables will be analyzed using Kaplan-Meier analysis. Both the 80% 
and 95% 2-sided confidence intervals will be presented.
The aforementioned will be presented overall by treatment group and by the subgroups as 
defined in Section 2.4.
Need for ICU Stay, Need for Oxygen Supplementation, Requirement for 
Supplemental Feeding/Hydration
With reference to the definitions and derivations detailed in Section 5.3.1.3.2, summary 
includes those subjects not requiring the level of care/support at date/time of first dose of 
study drug.


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The proportion (number [n] and percentage [%]) of subjects with data available will be 
presented, as frequency tabulation, by treatment group. Additionally, 95% 2-sided 
confidence interval for each binomial proportion within the individual categories will be 
presented as based on the Wilson score test.
Based on the categorization (Yes vs No), the difference in proportions between each active 
treatment group as compared to placebo will be investigated. Frequency procedure in SAS®
provides Newcombe confidence limits with Mantel-Haenszel weights for the common risk 
difference (difference in proportion), controlling for the two randomization stratification 
factors (separately). The difference in proportion of ‘Yes’ for any ICU/supplementation 
need and both 80% and 95% 2-sided confidence intervals for this point estimate, 
controlling for randomization stratification factors (derived), will be presented.
Derived duration will be summarized descriptively only.
The aforementioned will be presented overall by treatment group and by the subgroups as 
defined in Section 2.4.
Requirement for Non-invasive Non-mechanical Ventilation Support, Requirement 
for Non-invasive Mechanical Ventilation Support, Requirement for Invasive 
Mechanical Ventilation Support
These need for/requirement parameters will be summarized in similar manner as described 
above and will only be calculated for those subjects that do not require ICU stay or 
supplemental support (depending on the parameter of interest) before the first dose of study 
drug.
Time (hours) to End of Oxygen Supplementation, Time (hours) to End of 
Hydration/Feeding Supplementation, Time (hours) to End of Supplementation (up 
to 72h from first hospital discharge)
These time to event variables will be analyzed using Kaplan-Meier analysis. Both the 80% 
and 95% 2-sided confidence intervals will be presented.
The aforementioned will be presented overall by treatment group and by the subgroups as 
defined in Section 2.4.
In addition, time (hours) to end of oxygen supplementation (up to 72h from first hospital 
discharge), difference in median time (hours) to event between each active treatment group 
as compared to placebo will be investigated using the AFT model with log-logistic 
distribution. The model will include class variables treatment group with placebo as 
reference and randomization stratification factors (derived). Summary will include 
parameter estimates and associated standard error, covariance matrix of parameter 
estimates, estimated accelerated failure time ratio (as compared to placebo) and both 80% 
and 95% 2-sided confidence intervals.
The aforementioned will be presented overall by treatment group and by the subgroups as 
defined in Section 2.4.
Graphical presentation will include:

Overlay of survival curves with Kaplan-Meier survival function and AFT on one plot


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
Forest plot of accelerated failure time ratios and resulting confidence intervals for 
subgroups of interest as defined in Section 2.4 including the relevant subgroup variable 
as covariate in the model with subgroup*treatment group interaction.
Time to Return to Pre-RSV Disease Level for Respiratory Rate, Time to Return to
Pre-RSV Disease Level for Heart Rate, Time to SpO2≥92% on Room Air, Time to 
SpO2≥95% on Room Air
These time to event variables will be analyzed using Kaplan-Meier analysis. Both the 80% 
and 95% 2-sided CIs will be presented.
The aforementioned will be presented overall by treatment group and by the subgroups as 
defined in Section 2.4.
5.3.2.4.
Acceptability and Palatability of the JNJ-53718678 formulation
For the individual categories, the proportion (number [n] and percentage [%]) of ITT-i 
subjects with data available at Day 8 will be presented, as frequency tabulation, by 
treatment group. Additionally, 95% 2-sided confidence interval for each binomial 
proportion within the individual categories will be presented as based on the Wilson score 
test. 
As more than one response can be selected by the caregiver, subjects will be counted in 
each selected response such that the sum of percentages can be >100%.
Similar presentation based on the binary categorization will be provided.
The aforementioned will be presented overall by treatment group and by the subgroups as 
defined in Section 2.4.
5.3.2.5.
Medical Resource Utilization
The proportion (number [n] and percentage [%] based on ITT-i analysis set) of subjects 
with any medical care encounters (Yes vs No) will be presented, as frequency tabulation, 
by treatment group. Additionally, 95% 2-sided confidence interval for each binomial 
proportion within the individual categories will be presented as based on the Wilson score 
test.
Based on the binary categorization, the difference in proportion of subjects with any 
medical care encounters (Yes) between each active treatment group as compared to placebo
will be investigated. Frequency procedure in SAS® provides Newcombe confidence limits 
with Mantel-Haenszel weights for the common risk difference, controlling for the two 
randomization stratification factors (separately). The difference in proportion of ‘Yes’ for 
any medical care encounters and both 80% and 95% 2-sided confidence intervals for this 
point estimate, controlling for randomization stratification factors, will be presented.
Based on those subjects with medical care encounters, the following will be presented 
descriptively only:

Reason for medical care encounters

Type of medical care encounters

Frequency of medical care encounters


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
Type of practitioner
As subjects may have experienced one or more medical care encounters, subjects will be 
counted in each selected category such that the sum of percentages can be >100%.
The aforementioned will be presented overall by treatment group and by the subgroups as 
defined in Section 2.4.
5.4.
Exploratory Endpoints
Section 2.1.2 Endpoints of protocol, Amendment #6 (dated 01 December 2020), includes 
a detailed overview of efficacy and other endpoints (primary, secondary and exploratory) 
as planned per protocol. The exploratory efficacy endpoints listed below are additionally
included, based on previous IAs with new information becoming available during the 
course of the study. These additional exploratory efficacy endpoints support decision-
making for further development of JNJ-53718678 and interactions with health 
authorities.
Unless otherwise specified, the additional exploratory efficacy endpoints listed below, 
will be analyzed and presented primarily for those subjects with symptom onset ≤3 
days before randomization.
Parent/Caregiver PRESORS ObsRO

In hospitalized subjects (Cohort 1): RSV Recovery Scale (RRS): Day 1 to Day 8

Time (hours) to resolution of RSV symptoms (concepts) and four summary parameters
(ObsRO): ‘supplemental-free’ definition (at least 24h oxygen- and hydration/feeding 
supplementation free)
Note: aforementioned time (hours) to resolution (‘supplemental free’ definition) for 
both RSV concepts and summary parameters, developed during the course of the study 
based on new information available, is considered the primary definition of time 
(hours) to resolution for subsequent analyses. The addition of ‘at least 24h 
supplementation free’ requirement is to ensure that evaluation of time (hours) to 
resolution is an accurate reflection of the actual subject’s resolution status rather than 
a time (hours) confounded by possible continued use of supplementation.

Potential association between the time (hours) to resolution of key- and overall RSV 
summary parameters (ObsRO [‘supplemental-free’ definition]) and covariates and/or 
baseline indicators of interest

Time (hours) to resolution of key- and overall RSV summary parameters from hospital 
discharge (ObsRO): ‘supplemental-free’ definition (at least 24h oxygen- and 
hydration/feeding supplementation free)

Resolved status per timepoint: 
o
Day 1 to Day 8
o
BEFORE (last PRESORS ObsRO BEFORE)/AFTER (first PRESORS ObsRO
AFTER) hospital discharge

Sustained resolution of key- and overall RSV summary parameters

AUC from immediately prior to first dose of study drug (baseline) through Day X
(AUCDay X), Day 8 (AUCDay 8) and Day 10 (AUCDay 10): key RSV symptoms






















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Resolved Status Based on PRESORS ObsRO/ClinRO: Day 1 to Day 8, Resolved 
Status Based on PRESORS ObsRO/ClinRO Before/After Hospital Discharge
Proportion (number [n] and percentage [%]) of subjects per individual categories will be 
presented graphically, by treatment group.
The aforementioned will be presented overall by treatment group and by the subgroups as 
defined in Section 2.4.
PRESORS ClinRO: Clinically Resolved Status: Day 1 to Day 8
Clinically resolved status, will be assessed from Day 1 to Day 8. The proportion (number 
[n] and percentage [%]) of subjects per individual categories will be presented, as 
frequency tabulation and graphically, by treatment group and study day. 
A logistic regression model will be used to analyze the binary dependent variable, clinically 
resolved status Day 2 to Day 8, comparing each active treatment group versus placebo. 
Logistic regression model will include treatment group and the two randomization 
stratification factors (derived). Estimate of the treatment difference in proportion of 
clinically resolved status and both 80% and 95% 2-sided confidence intervals for this 
estimate will be obtained from the logistic regression model.
The aforementioned will be presented overall by treatment group and by the subgroups as 
defined in Section 2.4.
A sensitivity analysis will be performed applying the alternative imputed value (Column 
4: Sensitivity analysis imputed value [Section 5.4.1]).
PRESORS ObsRO/ClinRO: Time to Resolution [Supplemental-free Definitions] and 
PRESORS ObsRO: Time to Resolution From Hospital Discharge
For the RSV summary parameters specified in Section 5.4.1, these time to event variables 
will be analyzed using Kaplan-Meier analysis. Both the 80% and 95% 2-sided confidence 
intervals will be presented.
In addition, the RSV summary parameters will be further explored utilizing a similar AFT 
model as detailed for time (hours) to resolution in Section 5.3.2.2.
Graphical presentation will include:

Overlay of survival curves with Kaplan-Meier survival function and AFT on one plot

Forest plot of accelerated failure time ratios and resulting confidence intervals for 
subgroups of interest as defined in Section 2.4 including the relevant subgroup variable 
as covariate in the model with subgroup*treatment group interaction.
The aforementioned will be presented overall by treatment group and by the subgroups as 
defined in Section 2.4.
Association Between PRESORS: ObsRO: Time (hours) to Resolution: 24h 
Supplementation Free Definition and Covariates/Baseline Indicators
The potential association between the time (hours) to resolution: 24h supplementation free 
definition of summary parameter, PRESORS ObsRO: key RSV symptoms and 
covariates/baseline indicators of interest, as detailed in Section 5.3.2.1, will be explored 
utilizing a similar AFT model as described in Section 5.3.2.3.2, but including the relevant 
subgroup variable as covariate in the model with subgroup*treatment group interaction.


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PRESORS ObsRO: Sustained Resolution
Proportion (number [n] and percentage [%]) of subjects per individual categories will be 
presented, as frequency tabulation and graphically, by treatment group. Additionally, 95% 
2-sided confidence interval for each binomial proportion within the individual categories 
will be presented as based on the Wilson score test.
The aforementioned will be presented overall by treatment group and by the subgroups as 
defined in Section 2.4.
PRESORS ObsRO/ClinRO: Key RSV Symptoms: AUC
With reference to Section 5.2.3, a similar model as used for the primary efficacy analysis 
at Day 5 will be used for analysis of Day X (AUCDay X), Day 8 (AUCDay 8) and additionally 
for PRESORS ObsRO, Day 10 (AUCDay 10). Where Day X is defined as the day when at 
least 50% of Cohort 1 subjects, across all treatment groups, have been discharged from 
hospital.
The difference between each active treatment group versus placebo will be derived using 
appropriate contrasts for Day X, Day 8 and Day 10 (PRESORS ObsRO only) from the 
same model containing all PRESORS ObsRO/ClinRO assessments from baseline through 
assessment day of interest (ObsRO: Day 10, ClinRO: Day 8).
The aforementioned will be presented for the subgroups as defined in Section 2.4.
RSV-related Complications
RSV-related complications will be provided based on the original (investigator assessment)
and modified (study physician-identified complications) definitions. 
Original Definition (Investigator Assessment):
The proportion of subjects with a complication (Yes and No) will be shown in a frequency 
tabulation including corresponding 95% CI by treatment as based on the Wilson score test.
Based on the binary categorization (Yes vs No), the difference in proportion of subjects 
with RSV-related complications, as assessed by the investigator, between each active 
treatment group as compared to placebo will be investigated. Frequency procedure in SAS®
provides Newcombe confidence limits with Mantel-Haenszel weights for the common risk 
difference (difference in proportion of subjects with RSV-related complications), 
controlling for the two randomization stratification factors (separately). The difference in 
proportion of subjects with RSV-related complications and 80% and 95% 2-sided 
confidence intervals for this point estimate, controlling for randomization stratification 
factors, will be presented.
Similar frequency tables will be provided for the subcategories.
The aforementioned summary will be presented overall by treatment group and by the 
subgroups as defined in Section 2.4.
Modified Definition (Study Physician-identified Complications):
The number (n) and percentage (%) of subjects in the ITT-i analysis set with RSV-related 
complications (Yes vs No) will be presented, as frequency tabulation. The incidence will 


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be presented for emergent adverse events (treatment phase and follow-up phase), as 
assessed by the study physician (modified definition), occurring during the study and 
treatment phase only.
The number (n) and percentage (%) of subjects, by MedDRA preferred term, in each of the 
subcategories will also be presented.
Based on the binary categorization (Yes vs No), the difference in proportion of subjects 
with RSV-related complications, modified definition, between each active treatment group 
as compared to placebo will be investigated and presented in a similar manner as described 
above.
The aforementioned summary will be presented overall by treatment group and by the 
subgroups as defined in Section 2.4.
Use of Antibiotics for RSV-related Complications: Investigator Assessment
The proportion (number [n] and percentage [%]) of subjects using antibiotics for RSV-
related complications at any time during the study (treatment phase and follow-up phase) 
will be presented, as frequency tabulation and graphically, by treatment group. 
Additionally, 95% 2-sided confidence interval for each binomial proportion within the 
individual categories (Yes vs No) will be presented as based on the Wilson score test.
The aforementioned will be presented overall by treatment group and by the subgroups as 
defined in Section 2.4.
5.5.
Correlation Between Antiviral Effect and Clinical Course Endpoints
For each cohort separately, the relationship between primary antiviral effect endpoints and 
clinical course endpoints will be investigated.
Cohort 1
For antiviral effect endpoints:

Log10 RSV RNA viral load AUCDay 5

Time to confirmed undetectable RSV RNA viral load
For clinical course endpoints:

PRESORS ObsRO summary parameters: key RSV symptoms and overall RSV 
symptoms:

Time (hours) to resolution (ObsRO): 24h supplementation free definition

Change from Baseline in PRESORS ObsRO: key RSV symptoms and overall 
RSV symptoms at Day X, Day 8 and Day 10
o
Where Day X is defined as the day when at least 50% of Cohort 1 subjects, 
across all treatment groups, have been discharged from hospital.

RSV-related complications (Yes vs No): modified definition

RSV recovery scale (RRS) (ObsRO): Day 1 to Day 8

Clinically resolved status (ClinRO): Day 1 to Day 8


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
Time (hours) to hospital discharge from first dose of study drug

Time (hours) to resolution of key RSV symptoms from hospital discharge

Time to end of oxygen supplementation up to 72h from first hospital discharge

Time to end of supplementation (oxygen and/or hydration/feeding) up to 72h from 
first hospital discharge
For each pair of variables (2 antiviral x 9 clinical course endpoints) and depending on data 
type (continuous vs categorical) the following will be used to explore the possible 
relationship:

Spearman rank order correlation coefficients + scatterplots: evaluates the monotonic 
relationship between two continuous or ordinal variables. Ranges from -1 to 1 where 
0 indicates no correlation.

Box plots: graphically presents the association between continuous and binary 
variables.

Kaplan-Meier survival curves: by binary category (if binary variable) or by quartiles 
of a continuous variable.

Plot of log10 RSV RNA viral load vs summary parameter: key RSV symptoms
(ObsRO) (“worst hourly” [refer to Table 6:
Worst per Day and :
Parameters 
based on PRESORS ObsRO]) daily summary score over time.
Similarly, for outpatients (Cohort 2) but including, at a minimum, the relevant clinical 
course endpoints as described below.
Cohort 2
For antiviral effect endpoints:

Log10 RSV RNAviral load AUCDay 5

Time to confirmed undetectable RSV RNA viral load
For clinical course endpoints, at a minimum the following will be explored:

PRESORS ObsRO summary parameters: key RSV symptoms and overall RSV 
symptoms:

Time (hours) to resolution (ObsRO): 24h supplementation free definition

Change from Baseline in PRESORS ObsRO: key RSV symptoms and overall 
RSV symptoms at Day X, Day 8 and Day 10
o
Where Day X is defined as the day when at least 50% of Cohort 1 subjects, 
across all treatment groups, have been discharged from hospital

RSV-related complications (Yes vs No): modified definition
As new information becomes available, additional clinical course endpoints may be 
identified and explored utilizing the above methodology to ascertain possible relationships.
5.6.
Decision Rules at Interim Analyses
During IAs, the primary viral load endpoint and 3 below-mentioned key clinical course 
endpoints are considered. Minimum acceptable value and target value for these key clinical 
course endpoints are defined in Table 23:




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OR
o
95% 2-sided confidence interval on the difference in median time to resolution of 
key RSV symptoms between the high dose and placebo group excludes effects as 
good as the TV (i.e. lower limit of the confidence interval is above TV of ‘-1 day’), 
based on data from Cohort 1 only
The above rule is considered non-binding. If the above pre-defined futility rule is hit, the 
SC will review available viral load and clinical course data, and might ask to perform 
subgroup analysis including, but not limited to, onset of symptoms and age group. Based 
on this, the SC may also consider enriching the population (i.e. limit future enrollment to 
subjects with ≤3 days since symptom onset), if there is evidence that the drug is not 
providing benefit to the subjects whose symptoms onset is >3 days.
Interim analysis 3
The IDMC will consider enriching the population (i.e. limit future enrollment to subjects 
with ≤3 days since symptom onset), if

At least 2 out of 4 endpoints have conditional power <50%, where conditional power 
is defined as:

Viral load: conditional probability to reach success based on the MCP-Mod trend 
test at 1-sided alpha=2.5% at IA#4, based on combined data from Cohort 1 and 
Cohort 2.

Key clinical course endpoints: conditional probability of obtaining results in the 
“Go” region defined by a dual Go/No-Go framework at IA#4, based on data from 
Cohort 2 only.
The IDMC will review the re-calculation of the sample size using Cohort 2 data to limit
the conditional probability of an inconclusive result to 20% on all clinical endpoints at the 
end of the study.
The IDMC will consider stopping the study for futility, if:

The conditional power at IA#4 is <50% to demonstrate antiviral activity of JNJ-
53718678 compared with placebo based on the MCP-Mod trend test on viral load at 
1-sided alpha=2.5% based on combined data from Cohort 1 and Cohort 2.
AND

80% 2-sided confidence interval on at least 2 key clinical course endpoints excludes
effects as good as the TV based on data from Cohort 2 only
AND

None of the 80% 2-sided confidence intervals on any key clinical course endpoint 
excludes effects as bad as the MAV based on data from Cohort 2 only
For viral load, the conditional probability of success at IA#4 using combined data from 
Cohorts 1 and 2 will be calculated assuming i) no enrichment and ii) enrichment as 
described below.  


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In both cases, the conditional probability of success will be set to 1 if the 1-sided p-value 
for the MCP-Mod trend test is less than 2.5% at IA#3, as success has already been reached.  
Otherwise, the conditional Type I error will be calculated using the inverse-normal 
combination approach:
4 = 1 −Φ 5Φ(0.975) −√Φ(1 − .<<)
1 −
=
where:

pFull represents the 1-sided p-value for the MCP-Mod trend test for the full population 
at IA#3

w1 = n1 / n

>1 represents the total number of randomized patients in Cohorts 1 and 2 at the time of 
IA#3

n = 294, the planned total number of randomized patients in Cohorts 1 and 2 at IA#4
Given the conditional Type I error, the critical value for the MCP-Mod test based on new 
data from IA#4 only will be calculated. The conditional probability of success at IA#4 will 
be calculated under the observed test statistic at IA#3 (Z1), adjusted for the sample size of 
the new data at IA#4 as:
*?@ = 1 −?A⋂3
#
CD, ∈(−∞, *GH)IJ
where:
D~L MNO, = P
>
>,@
D,@ , QRSS = QRSSTUV@W
and:

x corresponds to the decision not to enrich / to enrich at IA#3

D,@represents the vector of observed MCP-Mod test statistics at IA#3 (Linear, 
Emax and Exponential models) based on the population of interest (full population 
for no enrichment and the sub-population with symptom onset ≤3 days for 
enrichment).

D represents the vector of observed MCP-Mod test statistics for the second stage.

D, represents the observed MCP-Mod test statistic for the second stage (based on 
the new data at IA#4) for model i.

NO, represents the vector of mean MCP-Mod test statistics for the second stage, 
which is estimated using the observed test statistics at IA#3.


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
>,@ represents the number of randomized patients in Cohorts 1 and 2 at the time of 
IA#3 for the population of interest (full population for no enrichment and sub 
population for enrichment). 

>2 represents the number of additional patients to be included in Cohorts 1 and 2 
up until IA#4 (i.e. 294 - >, .<<, where 294 is the total number of randomized 
subjects in Cohorts 1 and 2 at IA#4).

corrMCPx represents the correlation matrix of the test statistics at IA#3 for the 
population of interest.

CRV describes the critical value at IA#4, which is calculated based on the 
conditional 1-sided Type I error 4, taking the multiplicity adjustment for MCP-Mod 
into account.
For the key clinical course endpoints, the conditional probabilities of obtaining results in 
the “Go”, “Stop” and “Consider” regions at IA#4 and at the end of the study will be 
evaluated for Cohort 2 assuming i) no enrichment and ii) enrichment. Calculations of 
conditional power at IA#4 will assume a total sample size of 150 for Cohort 2 and 
calculations of conditional power at the end of the study will be calculated assuming total 
sample sizes for Cohort 2 of 150, 180, 210, 240, 270 and 300.
Analyses will be conducted as described below for each of the three key clinical course 
endpoints in order to estimate the following p-values at IA#3:

 .<<;YZ and %.[;YZ: 1-sided p-values to test the null hypothesis that the difference 
between the high dose and the placebo group is at least as good as the target value (TV) 
for the full and sub-populations against the alternative hypothesis that the difference 
between the high dose and the placebo group is worse than the TV.

 .<<;T\Z and %.[;T\Z: 1-sided p-values to test the null hypothesis that the difference 
between the high dose and the placebo group is no better than the minimum accepted 
value (MAV) for the full and sub-populations against the alternative hypothesis that 
the difference between the high dose and the placebo group is better than the MAV.
Time to resolution of key RSV symptoms

The time to resolution of key RSV symptoms will be analyzed using an accelerated 
failure time (AFT) model, using the log-logistic distribution as described in Section 
5.3.2.2. However, the term for baseline log10 viral load will be retained whether or not 
it is significant at the 10% significance level. The median time to resolution for the 
placebo group (TP) in days will be estimated based upon this model and the TV that 
corresponds to a 1-day reduction for the high dose group will be calculated as a log 
relative reduction (i.e. as log[(TP-1)/TP]). The MAV of no difference corresponds to a 
log relative reduction of log(TP/TP) = 0. The 1-sided p-values for the tests to compare 
the difference between the high dose and placebo groups versus the TV and MAV will 
be derived using normal approximations for appropriate contrasts, ZTV and ZMAV.
Change from baseline in key RSV symptoms at Day 8

The change from baseline in key RSV symptoms at Day 8 will be analyzed using a 
restricted maximum likelihood repeated measures approach as described in Section 


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5.3.2.2. The adjusted mean reduction from baseline for the placebo group will be 
estimated based upon this model (]V
^^^) and the TV that corresponds to a 20% larger 
change from baseline for the high dose group (i.e. 1.2]V
^^^) will be calculated. The MAV 
corresponds to a difference in the change from baseline of 0 (i.e. 1.0]V
^^^). The 1-sided
p-values for the tests to compare the difference between the high dose and placebo 
groups versus the TV and MAV will be derived using normal approximations for 
appropriate contrasts, ZTV and ZMAV.
Incidence of RSV-related complications

The 1-sided p-values to compare the proportion of subjects with at least one RSV-
related complication between the high dose and placebo groups versus the MAV and 
TV will be derived using a normal approximation to the binomial distribution; where:
̂ −̂~L  −,
`(`)
2`
+
a(a)
2a
&
The TV of an absolute reduction in rate of 10% corresponds to a difference in the 
proportion of subjects with at least one RSV-related complication in high dose 
versus placebo of -0.1. The MAV corresponds to a difference in the proportions of 
0.
For each of the three clinical course endpoints, the conditional probability for the Stop 
decision for the situation without/with enrichment and for each assumed total sample size 
will be calculated as:

*?@;% = 1 −Φ b
cd`(+.e)√f`cd`(ghii;jk)
f`
−l
2a
2`,m ΦA1 −@;YZJn
The conditional probability for the Go decision for the time to resolution of key RSV 
symptoms and the incidence of RSV-related complications will be calculated as:

*?@;o = ΦApq>C*GH YZ −N@;YZ, N@;T\Z −*GHT\ZIJ
where:

*GHYZ =
cd`(+.e)√f`cd`Aghii;jkJ
f`
and *GHT\Z =
cd`(+.e)√f`cd`(ghii;rsk)
f`

N@;YZ = l
2a
2`,m ΦA1 −@;YZJ and N@;T\Z = l
2a
2`,m ΦA1 −@;T\ZJ

x corresponds to the decision not to enrich / to enrich at #IA3

@;YZ and @;T\Z represents p-values for the population of interest (full population for 
no enrichment and sub population for enrichment).

>,@ represents the number of randomized patients in Cohort 2 at the time of IA#3 for 
the population of interest.


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
>2 represents the number of additional patients to be included in Cohort 2 up until the 
end of the study (i.e. N - >, .<<, where N represents the total number of randomized 
subjects in Cohort 2 at the end of the study).

w1 = n1 / nPrimary where nPrimary = 225 is defined as midway between the planned sample 
size (N=150) and the maximum sample size (N=300) for Cohort 2.
The conditional probability of the Go decision for the change from baseline in key RSV 
symptoms at Day 8 needs to take the correlation, ρ, of ZTV and ZMAV into account.
4 = −
t 1
>u,@ + vH ∗x(H
1
>V,@y
tl 1
>u,@ + vH/>V,@y tl 1
>u,@ + x(H/>V,@y
The conditional probability of the Go decision is calculated using a bivariate normal 
distribution where:

*?@;o = PAD@;YZ < *GH YZ ∩D@;T\Z > *GH T\Z; N = (N@;YZ, N@;T\Z), 4J
Where:

>u,@ represents the number of Cohort 2 subjects in the high dose group that were 
included in the analysis at IA#3 for the population of interest.

>V,@ represents the number of Cohort 2 subjects in the placebo treatment group that 
were included in the analysis at IA#3 for the population of interest.

Zx2; TV  represents the test statistic to test the null hypothesis that the difference between 
the high dose and the placebo treatment group is at least as good as the target value 
(TV) at the end of the study (full population for no enrichment and sub population with 
symptom onset ≤ 3 days for enrichment).

Zx2; MAV  represents the test statistic to test the null hypothesis that the difference between 
the high dose and the placebo treatment group is no better than the minimum acceptable
value (MAV) at the end of the study (full population for no enrichment and sub 
population with symptom onset ≤ 3 days for enrichment).
For all clinical course endpoints, the conditional probability of an inconclusive result will 
then be calculated as:
*?@;22<.
 = 1 −*?@;% −*?@;o
Interim analysis 4
The IDMC will consider stopping the study for futility, if:

Viral load did not meet success based on the MCP-Mod trend test at 1-sided 
alpha=2.5% based on combined data from Cohort 1 and Cohort 2
AND


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
80% 2-sided confidence interval on at least 2 key clinical course endpoints excludes
effects as good as the TV based on data from Cohort 2 only
AND

None of the 80% 2-sided confidence intervals on any key clinical course endpoints
excludes effects as bad as the MAV based on data from Cohort 2 only
For IA#3 and IA#4 two separate tests for two study populations are conducted and no 
formal multiplicity adjustments for the multiple study populations were implemented.

Test for full population

Test for subpopulation of patients ≤3 days since symptom onset
The futility rules defined are applied to each population separately. For decision-making, 
results of both populations will be considered. The following figure (refer to Figure 3:
Decision Flowchart) provides an overview of the decision rules based on different 
endpoints to determine whether to stop the study for futility. Study will be stopped for 
futility if futility is reached in both populations.
Figure 3:
Decision Flowchart
TV- Target value; MAV -Minimum Acceptable Value
6.
SAFETY
All safety analyses will be descriptively summarized and based on the Safety analysis set. There 
will be no formal statistical testing for any safety endpoint. Refer to Section 2.4 for further 
details regards subgroup analysis, per the analyses detailed below.


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6.1.
Adverse Events
6.1.1.
Definitions
Coding of AE
The verbatim terms used in the eCRF by investigators to identify AEs will be coded using 
the Medical Dictionary for Regulatory Activities. Events are looked at on the level of their 
preferred term.
Emergent Adverse Event
Emergent AEs are AEs with onset after first study medication intake or that are a 
consequence of a pre-existing condition that has worsened since baseline. All reported 
emergent AEs will be included in the analysis. For each AE, the percentage of subjects 
who experience at least 1 occurrence of the given event will be summarized by treatment 
group.
Emergent AEs are categorized as related to study medication, if assessed, by the 
investigator, as ‘possibly’, ‘probably’, or ‘very likely’ related to the study medication.
Phase Allocation of AE
Adverse events present in the SDTM database are allocated to analysis phases based on 
their start date (refer to Section 2.1). If the start date of an event falls between (or on) the 
analysis phase start date and before- or on analysis phase stop date, the AE is attributed to 
that analysis phase (emergent principle).
Incomplete dates (i.e. time and/or day and/or month and/or year missing) are imputed 
according to the rules in Section 2.5.
6.1.2.
Adverse Events of Special Interest
In addition to RSV-related complications, detailed in Section 5.4, the following adverse 
events of special interest are defined (refer to Table 24:
Cardiac Events Potentially 
Related to QT Prolongation):




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of events identified, as detailed in a separate document (data presentation specifications 
[DPS]).
As part of safety, RSV-related complications during the overall analysis treatment- and 
follow-up phase, based on investigator’s assessment, will be summarized descriptively. As 
RSV-related complications are analyzed as part of exploratory efficacy endpoints, refer to 
Section 5.4 for details regards analysis and presentation of RSV-related complications.
Emergent cardiac events potentially related to QT prolongation, identified based on 
MedDRA preferred term code, will be summarized descriptively by analysis phase (overall 
analysis treatment- and follow-up phase) and by analysis treatment phase only if there are 
at least 5 events identified across all treatment groups.
Listings will be provided for at least the following, depending on the number of events:

All adverse events 

Serious adverse events 

AEs leading to death (based on outcome = fatal)

Toxicity Grade 3 to 4 adverse events

AEs for which study medication was permanently stopped

AEs for which study medication was interrupted

AEs for which study was discontinued prematurely
6.2.
Clinical Laboratory Tests
6.2.1.
Definitions
Laboratory parameters of hematology, serum chemistry, and urinalysis will be
investigated. Analyses will be based on International System of Units (SI) converted values 
as available in the database.
Toxicity grades and abnormalities for laboratory parameters
The laboratory abnormalities will be determined according to the Division of Microbiology 
and Infectious Diseases (DMID) pediatric toxicity tables (see Attachment 1). Toxicity 
grades where available per parameter and age group, will be provided by the central 
laboratory and will be used in the analysis. In case no DMID toxicity grades are defined 
for a test and/or age group, the abnormalities (above/below normal range) will be used.
In determining toxicity grades/abnormalities for each subject the following rules are 
applied:

Worst grades/abnormalities are determined over the whole observational period, per 
phase (analysis treatment, analysis follow-up [separately] and in combination analysis 
treatment + follow-up phase), including scheduled and unscheduled measurements. 

The abnormalities “abnormally low” and “abnormally high” are considered equally 
important, i.e. if a subject has as well an abnormally low as an abnormally high value 
post-baseline, both abnormalities are shown in the tables. This means that the sum of 
the percentages can be more than 100%.


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
If, for a specific test, the grading list provides distinct limits for abnormally low 
(=hypo) values as well as for abnormally high (=hyper) values, this test should be 
repeated for hyper- and hypo- limits separately in cross-tabulations.
For subjects enrolled under original protocol dated 13 July 2018, coagulation function will 
be monitored during this clinical study through evaluation of partial thromboplastin time 
(PTT) and activated partial thromboplastin time (aPTT) in seconds, and calculation of the 
International normalized ratio by the central lab. Grading of abnormalities in these 
parameters (PT and PTT) will be based on the DMID Pediatric Toxicity Table (see 
Attachment 1). Coagulation will not be evaluated in subjects enrolled as of protocol 
amendment 1 (dated 14 May 2019).
Post-amendment #4 (dated 26 May 2020), levels of potassium and magnesium will be 
determined by the central laboratory. In case of hypokalemia or hypomagnesemia at 
Screening or Day 8, the levels of potassium and magnesium are to be monitored locally
and corrected to prevent cardiac disturbances. During the study locally determined 
potassium and/or magnesium levels need to be recorded in the eCRF as unscheduled
laboratory visits/assessments. Data will be listed.
The eGFR will be calculated/reported by the central lab (Schwarz formula) and used as 
such in the analysis.
Emergent definition for toxicity grades and abnormalities
An abnormality (toxicity grade or abnormality based on normal ranges) will be considered 
emergent if it is worse than the baseline abnormality. If the baseline abnormality is missing, 
the abnormality is always considered as emergent. A shift from “abnormally low” at 
baseline to “abnormally high” post baseline (or vice versa) is also emergent. The 
emergence definition applies regardless of analysis phase and within each analysis phase.
In case of missing date or partial dates
Laboratory records with missing assessment date- or time- parts (any: day, month or year) 
will not be used in descriptive statistics, unless the scheduled target day or time is known,
and a unique analysis phase allocation is possible taking this additional information into 
account. These assessments will be allocated to the correct phase using the available 
date/time information, and the information in their assessment schedule. In case it is not 
possible to assign a unique analysis phase (e.g. unscheduled timepoints), the assessment 
will be assigned to all possible active analysis phases based on the available date and time 
information. These cases will be flagged in the respective listings.
Imputations of numerical values expressed as characters
In case a laboratory test result is censored (no numeric value is available, but only a 
verbatim term), the following rules are applied: 

‘<x’ or ‘>x’: a numeric value will be imputed by a value exceeding the cut-off value 
with one unit 

‘≤x’ or ‘≥x’: imputation by x. 


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This also applies to normal limits expressed as such.
No such imputations will be done for urinalysis parameters as these are usually 
character/categorical expressions.
6.2.2.
Analysis Methods
Descriptive statistics (mean, standard deviation, median and range) will be provided for 
the clinical laboratory tests at each scheduled visit. Changes from baseline will be 
summarized by treatment group. Incidence of clinical laboratory tests that meet toxicity 
grades or criteria for abnormality will be tabulated for each treatment group.
A cross-tabulation of the worst toxicity/abnormality versus baseline toxicity/abnormality
will be presented for the combination of analysis treatment- and follow-up phase and for 
analysis treatment phase only. This table will also show the number (n) and percentage (%)
of subjects per worst toxicity/abnormality, the number (n) and percentage (%) of subjects 
per emergent worst toxicity/abnormality and the cumulative number of subjects per 
emergent toxicity/abnormality or worse. 
Mean±SE graphs over time for the actual values and change from baseline will be 
generated for all hematology and clinical chemistry tests by treatment group and by age 
group as assigned at Screening.
A listing of abnormal individual subject hematology, blood coagulation and clinical 
chemistry values from scheduled and unscheduled timepoints will be provided. This listing 
will include all other timepoints for the corresponding subject/parameter. Grade 2 or higher 
toxicity laboratory values will be listed separately. Urinalysis results will be listed only.
6.3.
Vital Signs and Physical Examination Findings
6.3.1.
Definitions
Systolic (SBP) and diastolic blood pressure (DBP), HR, RR, oxygen saturation and body 
temperature will be investigated. A directed physical examination (DPE) will be performed 
at several timepoints throughout the study, which includes respiratory system, nose, ear, 
throat, facial, and neck lymph nodes, and skin examination. Note that heart rate, respiratory 
rate, oxygen saturation (SpO2) and body temperature are also analyzed as part of efficacy
endpoints.
Definitions Grades/Abnormalities
Two sets of abnormality codes for SBP, DBP, HR, RR and oxygen saturation will be 
defined, as indicated in Table 25 and Table 26. Vital signs abnormalities will be identified 
based on subject’s age at the time of the assessment and as follows:
Worst grades/abnormalities are determined over the whole observational period and for 
each analysis phase separately, including post-baseline scheduled and unscheduled
measurements of that analysis phase.

The abnormalities ‘abnormally low’ and ‘abnormally high /grades are considered 
equally important, i.e. if a subject has as well an abnormally low as an abnormally 




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A cross-tabulation of the worst grade/abnormality versus baseline will be presented for the 
combination of analysis treatment- and follow-up phase and for analysis treatment phase 
only. This table will also show the number (n) and percentage (%) of subjects per worst 
grade/abnormality, the number (n) and percentage (%) of subjects per emergent worst 
grade/abnormality. For Respiratory rate, heart rate and body temperature, the maximum 
value will be considered as the worst grade/value while for oxygen saturation, the lowest 
value will be considered the worst one. In determining the maximum body temperature, all 
temperature assessments will be considered regardless of whether obtained during on-site 
visit or measured by caregiver and reported in handheld device.
Mean±SE graphs over time for the actual values and changes from baseline will be 
generated and presented by treatment group and by age group as assigned at Screening. 
A listing of abnormal individual subject vital signs values from scheduled and unscheduled 
timepoints will be provided. This listing will include all other timepoints for the 
corresponding subject/parameter.
6.4.
Electrocardiogram
PR, QT, QRS, QTc intervals and heart rate will be investigated. QTcB and QTcF values 
will be used as reported by the central ECG laboratory, they will not be recalculated.
Overall interpretation will be based on the investigator’s assessment as captured in the 
ECG eCRF and categorized as:
Normal
Abnormal
Not evaluable
6.4.1.
Definitions
Definitions and Abnormalities
The ECG abnormalities will be defined as indicated in Table 28. ECG abnormalities will 
be identified based on subject’s age at the time of the assessment and as follows:
Worst grades/abnormalities are determined over the whole observational period and for 
each analysis phase separately, including post-baseline scheduled and unscheduled 
measurements of that analysis phase.
The abnormalities ‘abnormally low’ and ‘abnormally high’/grades are considered 
equally important, i.e. if a subject has as well an abnormally low as an abnormally 
high or graded value post-baseline, both abnormalities are shown in the tables. This 
means that the sum of the percentages can be more than 100%.




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A cross-tabulation of the worst abnormality versus baseline will be presented for the 
combination of analysis treatment- and follow-up phase and for the analysis treatment 
phase only. This table will also show the number (n) and percentage (%) of subjects per 
worst toxicity/abnormality, the number (n) and percentage (%) of subjects per emergent 
worst toxicity/abnormality. 
A tabulation of the worst QT/QTc change versus baseline per treatment for the combination 
of analysis treatment- and follow-up phase will be presented and for the analysis treatment 
phase only.
Mean±SE graphs over time for the actual values and changes from baseline will be 
generated and presented by treatment group and by age group as assigned at Screening. 
A listing of abnormal individual subject ECG values from scheduled and unscheduled 
timepoints will be provided. This listing will include all other timepoints for the 
corresponding subject/parameter. In addition, ECG: Overall interpretation will also be 
listed.
7.
VIROLOGY
7.1.
Definitions
Viral Strain Typing
The RSV subtype is determined at baseline using the RSV A/B qRT-PCR assay performed 
in the central laboratory.
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 subjects will be sequenced to identify pre-existing genetic 
variations in the F gene. Post-baseline sequencing will be performed on the last evaluable 
on-treatment sample and/or during follow-up for all subjects (if viral load is high enough) 
to identify emerging amino acid substitutions in the 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 
subject’s virus’s 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%.


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
Emerging genetic variation: a genetic variation (amino acid substitution, insertion or 
deletion) that is absent, i.e. an NGS-read frequency <3%, at baseline but detected with 
an NGS-read frequency ≥15% at a later post-baseline timepoint.

Enriched genetic variation: a genetic variation (amino acid substitution, insertion or 
deletion) that is present at baseline with an NGS-read frequency ≥3% and <15%, but
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 timepoints.

RSV F-gene amino acid positions of interest:
o
Short list of 8 F gene 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
o
Long list of 24 F gene 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-53718678 to the RSV pre-fusion F protein: positions 127, 137, 138, 
140, 141, 143, 144, 323, 338, 339, 392, 394, 396, 397, 398, 399, 400, 401, 474, 
486, 487, 488, 489, and 517.
Analysis Timepoints
Virology results will be assigned to the visit windows as described in Sections 2.1.1 and 
2.1.4. In addition to the timepoints corresponding to the visits at which samples for RSV F 
gene sequencing are collected, the below timepoints will be considered: 

Baseline: closest timepoint with sequencing data available prior to the first dose of 
study drug. Ideally, this will be the Day 1 pre-dose sample; however, if RSV F gene 
sequencing data cannot be obtained from this sample, the screening sample may be 
used for sequencing.

Last Evaluable On-treatment Timepoint: last available post-baseline timepoint during 
the study treatment phase with sequencing data available. In case no On-Treatment 
assessment is available, the first assessment during study follow-up phase will be
selected.

Any Post-baseline Timepoint During the Study: all available post-baseline timepoints 
in the study with sequencing data available.
7.2.
Analysis Methods
7.2.1.
Viral Sequencing
Subjects with baseline RSV A+B co-infection will be excluded from the summary tables.
Baseline
The prevalence of baseline genetic variations in the RSV F gene (complete RSV F gene 
or considering the positions of interest), i.e. the number of subjects with baseline genetic 
variations in the RSV F gene, will be tabulated in frequency outputs (n, %).


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Post-baseline
Emerging and enriched genetic variations in the RSV F gene (complete RSV F gene or 
considering the positions of interest) will be tabulated by analysis timepoint in frequency 
outputs (n, %).
Over the study period, amino acid changes from reference sequence at baseline and post-
baseline will be listed for all subjects using an NGS-read frequency cut-off of 3%. For 
subjects with emerging or enriched genetic variations, RSV RNA viral load profiles 
including emerging or enriched genetic variations per timepoint, will be generated. 
Subgroup analyses by the presence of baseline genetic variations or emerging genetic 
variations will be tabulated to evaluate the impact on response (i.e. AUCDay 5 and time to 
confirmed undetectable RSV RNA viral load).
The aforementioned will be presented overall by treatment group and by the subgroups as 
defined in Section 2.4.
8.
IMPACT OF PANDEMIC
With the onset of the global 2019 novel coronavirus (COVID-19) pandemic, impact on 
planned analyses is to be considered in accordance with regulatory guidance. Taking into 
consideration the study status, impact to subject safety, data quality and integrity is 
considered minimal.
With reference to the current version of the COVID-19 standard reporting – guiding 
principles, the following will be evaluated for COVID-19 impact and may be presented in 
a separate listing:

Protocol deviations: deviations due to COVID-19 and can be considered major or 
minor.

Treatment and study disposition: premature discontinuation of treatment/study due to 
COVID-19.

Visit/assessment schedule: missed visits/assessments due to COVID-19.

Adverse events: COVID-19 associated adverse events and deaths.


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REFERENCES
(1) Pinheiro, J., Bornkamp, B. Glimm, E. and Bretz, F. (2013), Model based Dose-
Finding under model-uncertainty using general parametric models. Statistics in 
Medicine. 33. 10. 


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ATTACHMENTS
ATTACHMENT 1:  DIVISION OF MICROBIOLOGY AND INFECTIOUS 
DISEASES (DMID) PEDIATRIC TOXICITY TABLES (NOVEMBER 2007; 
DRAFT)
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.


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COMMENTS REGARDING THE USE OF THESE TABLES

Standardized and commonly used toxicity tables (Division of AIDS, 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.
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
DIVISION OF MICROBIOLOGY AND INFECTIOUS DISEASES (DMID) 
PEDIATRIC TOXICITY TABLES NOVEMBER 2007
(Older than 3 months of age)


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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
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


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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
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/frequency 
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 
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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
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


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DIVISION OF MICROBIOLOGY AND INFECTIOUS DISEASES (DMID) 
PEDIATRIC TOXICITY TABLES NOVEMBER 2007
(Older than 3 months of age)
ELECTROLYTES (continued)
Grade 1
Grade 2
Grade 3
Grade 4
Hematuria 
Microscopic 
<25 cells/hpf
Microscopic 
>25 cells/hpf
----
Gross hematuria
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
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


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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
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


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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 
drug
Sufficiently 
severe to 
require 
evaluation and 
treatment, 
including at 
least 
temporary 
suspension of 
study drug
Life-threatening 
severity; 
Requires 
immediate 
evaluation, 
treatment, and 
usually 
hospitalization; 
Study drug must 
be stopped 
immediately and 
should not be 
restarted until 
the abnormality 
is clearly felt to 
be caused by 
some other 
mechanism that 
study drug


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ATTACHMENT 2:  PRESORS OBSRO SCORING SYSTEM
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CCI


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CCI


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CCI


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ATTACHMENT 3:  PRESORS CLINRO SCORING SYSTEM
CCI


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CCI


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CCI


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CCI