Conditions: Respiratory Syncytial Viruses
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 22
Healthy volunteers: no

Brief summary:
The purpose of this two-part designed study is to assess in the setting of a planned early interception of pediatric RSV disease, early viral and disease kinetics (observational stage) and the antiviral effects of an Respiratory Syncytial Virus (RSV) fusion inhibitor, JNJ-53718678 (interventional stage). In the observational stage the infant is closely monitored for early symptoms by the parent(s)/caregiver(s) and thus may be brought in for diagnosis earlier than in the typical setting.

Detailed description:

Arms:
arm 1: Participants will not receive any intervention in the observation phase. All infants will be closely monitored for early signs and symptoms of Respiratory Syncytial Virus (RSV) disease using a mobile RSV application on the parent/caregiver's mobile phone, upon an alert, the RSV will be tested, if RSV negative participants (RSV \[-\] diagnosed at site) will return to the pre-diagnostic phase and RSV positive participants (RSV \[+\] diagnosed at site) can be enrolled in the interventional stage of the study after obtaining informed consent for the interventional stage at that time. RSV (+) participants whose parent(s)/caregiver(s) do not consent for enrollment in the interventional stage and participants who are screening failures in the interventional stage will enter the post-diagnostic phase of the observational stage (hospitalized or outpatients). arm 2: Participants will be randomized to receive either JNJ-53718678 (for Age Group 1 (greater than or equal to \[\>=\] 28 days and less than \[\<\] 3 months): 2.5 milligram per kilogram \[mg/kg\]; for Age Group 2 (\>=3 and \<6 months): 3 mg/kg and for Age Group 3 (\>=6 months): 4.5 mg/kg) or placebo (Age Group 1, 2 and 3) twice daily for 7 days.

Interventions: intervention 1: RSV Mobile Application intervention 2: Placebo intervention 3: JNJ-53718678 2.5 mg/kg intervention 4: JNJ-53718678 3 mg/kg intervention 5: JNJ-53718678 4.5 mg/kg
Intervention descriptions: intervention 1: Participants will not receive any intervention in observational phase of this study. Participant's respiratory symptoms will be captured by RSV mobile application installed in participant's caregiver/parent mobile phone. intervention 2: Participants in each Age Group (1,2,3) will receive matching placebo (volume placebo to match the calculated volume of the JNJ-53718678 dose) orally twice daily for 7 days. intervention 3: JNJ-53718678 will be administered to Age Group 1 twice daily for 7 days. intervention 4: JNJ-53718678 will be administered to Age Group 2 twice daily for 7 days. intervention 5: JNJ-53718678 will be administered to Age Group 3 twice daily for 7 days.

Protocol document:
Prot_000.pdf: 
CONFIDENTIAL – FOIA Exemptions Apply in U.S.
1
Status: Approved,  Date: 13 July 2020
Janssen Research & Development *
A Two-Part Study With a Birth Cohort (Observational Stage) for Early Diagnosis of 
Respiratory Syncytial Virus (RSV), Followed by an Optional Phase 2a, Randomized, 
Double-blind, Placebo-controlled Study (Interventional Stage) to Evaluate the Antiviral 
Activity, Clinical Outcomes, Safety, Tolerability, and Pharmacokinetics of JNJ-53718678 
in Infants With Acute Respiratory Tract Infection due to RSV
Protocol 53718678RSV2006; Phase 2a
AMENDMENT 3
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, Inc; Janssen Pharmaceutica NV; Janssen
Sciences Ireland UC; 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.
EudraCT NUMBER: 2019-001509-25
Status:
Approved
Date:
13 July 2020
Prepared by:
Janssen Research & Development  
EDMS number:
EDMS-ERI-182253307, 13.0
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.
NCT04068792


JNJ-53718678
Clinical Protocol 53718678RSV2006 Amendment 3
CONFIDENTIAL – FOIA Exemptions Apply in U.S.
2
Status: Approved,  Date: 13 July 2020
PROTOCOL AMENDMENT SUMMARY OF CHANGES TABLE
DOCUMENT HISTORY
Document
Date
Amendment 3
13-Jul-2020
Amendment 2
05-Jun-2020
Amendment 1
06-Nov-2019
Original Protocol
23-May-2019
Amendment 3 (13 July 2020)
The overall reason for the Amendment: The overall reason is to implement recommendations from 
Health Authorities (HA).
Section Number
and Name
Description of Change
Brief Rationale
1.3 Schedule of 
Activities (SoA)
2.3.5 Benefit-Risk 
Assessment for Study 
Participation
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.
Given 
that 
potential 
QT 
prolongation is Cmax related, as 
observed 
in 
the 
TQT 
study 
53718678RSV1009, timing of the 
ECG is more specifically aligned 
with the timing of expected Cmax
both after the first dose and at 
steady 
state,
in 
line 
with 
recommendations by HA.
7.1 Discontinuation of 
Study Intervention
8.4.3 Electrocardiograms
8.5 Specific Toxicities 
and Safety Topics of 
Special Interest
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.
2.3.5 Benefit-Risk 
Assessment for Study 
Participation
6.5 Concomitant Therapy
The 
BCRP 
inhibitors
eltrombopag
and 
curcumin were added to the disallowed
concomitant therapies.
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.
1.1 Synopsis
1.3 Schedule of 
Activities (SoA)
8.2.2 Double-blind 
Treatment Phase
8.8 Pharmacokinetics
Flexibility was added in the protocol with 
regard to the day of the specific PK samples to 
be collected at least 4 hours after the AM and 
prior to the PM dosing, ie, either on Day 3 or
Day 5.
Provide additional flexibility in the 
protocol with regard 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.
6.5 Concomitant Therapy
Removal of azithromycin as generally allowed 
medication.
Correction to an oversight of the 
previous amendment related to 
disallowed 
concomitant
medications
with QT-prolonging 
effects.
Azithromycin is a QT 
prolonging 
drug 
allowed 
with 
restrictions.
Throughout
Minor corrections and clarifications were done throughout.


JNJ-53718678
Clinical Protocol 53718678RSV2006 Amendment 3
CONFIDENTIAL – FOIA Exemptions Apply in U.S.
3
Status: Approved,  Date: 13 July 2020
Amendment 2 (05 June 2020)
Overall Rationale for the Amendment: The overall reason for the amendment is to implement a risk 
mitigation plan for the newly recruited participants in the interventional stage following identification of 
an exposure (Cmax)-related important potential risk of QT interval prolongation identified in the TQT 
Study 53718678RSV1009 in healthy adult participants. 
Section Number
and Name
Description of Change
Brief Rationale
2.2 Background
2.3.4 Potential Risks for 
Study Participation
2.3.5 Benefit-Risk 
Assessment for Study 
Participation
The important potential risk of QT interval 
prolongation identified in the TQT study was 
added.
A new important potential risk of 
QT 
interval 
prolongation 
was 
identified 
from 
the 
above-
mentioned TQT study and this was 
reflected in relevant sections of the 
protocol.
2.2 Background
2.3.4 Potential Risks for 
Study Participation
2.3.5 Benefit-Risk 
Assessment for Study 
Participation
11 REFERENCES
Recently available relevant clinical data were 
included in the introduction. Accordingly, the 
Investigator's 
Brochure 
Addendum 
to 
Edition 06 was added as a reference.
Newly available clinical data are
reflected in the relevant sections of 
the protocol.
1.1 Synopsis
1.2 Schema
1.3 Schedule of Activities 
(SoA)
4.1 Overall Design
4.3 Justification for Dose
6.1 Study Interventions
Administered
8.2.2 Double-blind 
Treatment Phase
8.7 Treatment of Overdose
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 
definitions of missing dose and overdose were 
adapted accordingly.
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.
6.5 Concomitant Therapy
Moderate CYP3A4 inhibitors were added to 
the disallowed prescription medications 14 
days prior to screening until 3 days after the 
last study intervention dose (in addition to the 
already 
disallowed 
strong 
CYP3A4 
inhibitors).
The period for strong CYP3A4 inhibitors 
being disallowed was aligned with that for 
moderate ones, ie, to 3 days after last study 
intervention intake.
The increase of
Cmax
due to 
CYP3A4 inhibition needs to be 
avoided in view of the QT interval 
prolongation risk to maintain the 
safety margin.
Given that the t1/2 of JNJ-53718678
is approximately 10 hours, study 
intervention is washed out after 
3 days.
6.5 Concomitant Therapy
Medications with a known risk to prolong the
QT interval cannot be initiated at screening 
and/or during the study intervention treatment 
period.
Part of QT prolongation mitigation 
measures to
ensure participants’ 
safety.
2.3.5 Benefit-Risk 
Assessment for Study 
Participation
Close monitoring of the use of concomitant 
medications to be conducted regularly was 
added. 
Part of QT prolongation mitigation 
measures to ensure participants’ 
safety.
7.1 Discontinuation of 
Study Intervention
8.4.3 Electrocardiograms
8.5 Specific Toxicities and 
Safety Topics of Special 
Interest
A study intervention discontinuation and 
withdrawal criterion specific to QT interval 
changes to values >500 ms on ECG was 
added.
Part of QT prolongation mitigation 
measures to ensure participants’ 
safety.
1.3 Schedule of Activities 
The frequency of ECG monitoring was 
Enhancement of the cardiac-related 


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Status: Approved,  Date: 13 July 2020
Section Number
and Name
Description of Change
Brief Rationale
(SoA)
increased by adding measurements at Day 1 
(1 hour post the first dose) and Day 3 of the 
interventional stage.
safety 
follow-up. Part of QT 
prolongation mitigation measures to 
ensure participants’ safety.
5.2 Exclusion Criteria
8.4.3 Electrocardiograms
Several exclusion criteria related to cardiac 
safety were added. Exclusion criterion 8 was 
made more stringent (ie, confirmed QTcF 
interval >450 ms).
Part of QT prolongation mitigation 
measures to ensure participants’ 
safety.
1.3 Schedule of Activities 
(SoA)
2.3.5 Benefit-Risk 
Assessment for Study 
Participation
9.3.4 Safety Analyses
10.2 Appendix 2: Clinical 
Laboratory Tests
A safety measure regarding hypokalemia and 
hypomagnesemia was added.
Part of QT prolongation mitigation 
measures to ensure participants’ 
safety.
8.5 Specific Toxicities and 
Safety Topics of Special 
Interest
10.8 Appendix 8: Visit 
Schedule for Rash 
Management in Pediatric 
Participants
The specific Rash Management section and 
corresponding Appendix were removed.
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.
8.5 Specific Toxicities and 
Safety Topics of Special 
Interest
9.3.4 Safety Analyses
Specific toxicity management for cardiac 
events potentially related to QT prolongation
was added.
Part of QT prolongation mitigation 
measures to ensure participants’ 
safety.
1.3 Schedule of Activities 
(SoA)
4.1 Overall Design
5.1 Inclusion Criteria
5.2 Exclusion Criteria
7.2 Participant 
Discontinuation/Withdrawal 
From the Study
8.1.2 Diagnostic Phase
10.7 Appendix 7: Guidance 
on Study Conduct During 
the COVID-19 Pandemic
COVID-19-related measures were added.
Added to avoid (co)-infection with 
SARS-COV-2 
as 
this 
would 
confound 
symptom 
evaluation 
during the post-diagnostic phase as 
well as evaluation of the clinical 
course of RSV. These measures
provide guidance on study conduct 
during the COVID-19 pandemic.
1.1 Synopsis
4.1 Overall Design
5 STUDY POPULATION
9.1 Sample Size 
Determination
The maximum sample size of the birth cohort 
was increased to 1,300 participants.
As the start of the study was late in 
the RSV season in Panama where 
the majority of the birth cohort was 
recruited, a relatively low number 
of participants were recruited in the 
interventional 
stage. 
The 
RSV 
season and opportunity to enroll in 
the 
interventional 
stage 
were
missed in Argentina and Taiwan 
due to the temporary hold of the 
interventional stage. To ensure that 
the target of 40 participants in this 
stage is achieved, the maximum 
sample size of the birth cohort was 
increased.
1.3 Schedule of Activities 
(SoA)
Systolic 
and 
diastolic 
blood 
pressure
assessment was added to the RSV-like ARI 
Assessment 
was 
inadvertently
missing from the Schedule of 


JNJ-53718678
Clinical Protocol 53718678RSV2006 Amendment 3
CONFIDENTIAL – FOIA Exemptions Apply in U.S.
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Status: Approved,  Date: 13 July 2020
Section Number
and Name
Description of Change
Brief Rationale
visit.
Activities. 
Alignment 
with the 
eCRF.
1.1 Synopsis
1.3 Schedule of Activities 
(SoA)
8 STUDY ASSESSMENTS 
AND PROCEDURES
8.2.2 Double-blind 
Treatment Phase
8.8 Pharmacokinetics
PK sample on Day 1 approximately 1 hour 
postdose (approximately at Cmax) and after 
ECG measurement was added.
The timing of the Day 3 sample was adjusted 
to at least 4 hours after the AM and prior to 
the PM dosing on Day 3.
Changes in PK schedule 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.
Part of risk mitigation plan to 
ensure participants’ safety.
10.5 Appendix 5: Division 
of Microbiology and 
Infectious Diseases (DMID) 
Pediatric Toxicity Tables 
(November 2007, draft)
A clarification was added (ULN are adult 
ULN) to the creatinine values of participants 
older than 3 months of age in Attachment 1 
(DMID Pediatric Toxicity Tables).
For clarification based on feedback 
from the DMID Authors.
8.6 Adverse Events and 
Serious Adverse Events
8.6.3 Regulatory Reporting 
Requirements for Serious 
Adverse Events
10.2 Appendix 2: 
Anticipated Events
Reference to anticipated events in the 
applicable sections of the protocol and the
Anticipated Events Appendix were removed.
Anticipated events are included for 
studies conducted at US sites due to 
specific FDA guidance on adverse 
event reporting. This study is not 
conducted in the US. 
1.1 Synopsis
9.4 Interim Analysis
A statement was added that interim analyses 
may be performed at the sponsor’s discretion.
To allow for interim analyses to 
support decision making for further 
development of JNJ-53718678 and 
to support interactions with Health 
Authorities.
8 STUDY ASSESSMENTS 
AND PROCEDURES
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.
1.1 Synopsis
4.1 Overall Design
4.4 End of Study Definition
The sentence “For RSV(-) participants who 
consented to the stool sample collection, the 
study ends either when the most relevant RSV 
surveillance data indicate that RSV is out of 
circulation or on the day of stool sample 
collection at the participant’s age of 4 months 
(±2 weeks), whichever is last.” was added.
Added for clarification.
1.3 Schedule of Activities 
(SoA)
8.1.2 Diagnostic Phase
Text was added, that if the diagnostic nasal 
mid-turbinate sample during the RSV-like 
ARI visit is taken within 4 hours from the 
sample for testing at home, the nasal mid-
turbinate swab sample during the RSV-like 
ARI visit should be taken from the other 
nostril. In that case nasal mid-turbinate swab 
samples should be continued to be collected
from the same nostril as used during the RSV-
like ARI visit.
Added for clarification.
1.3 Schedule of Activities 
(SoA)
Clarification that the optional blood sample 
for exploratory biomarker analyses will only 
be collected at the first RSV-like ARI visit.
Added for clarification.


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Clinical Protocol 53718678RSV2006 Amendment 3
CONFIDENTIAL – FOIA Exemptions Apply in U.S.
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Status: Approved,  Date: 13 July 2020
Section Number
and Name
Description of Change
Brief Rationale
1.3 Schedule of Activities 
(SoA)
8.1.2 Diagnostic Phase
8.1.3 Post-diagnostic Phase
Clarification added that the optional stool 
sample at 21 days (+2 weeks) after the ARI 
alert does not need to be collected if this time 
point 
coincides 
(±2 weeks) 
with 
the 
participant’s age of 4 months; in that case only 
1 sample is to be collected.
Clarification to avoid duplicate 
sampling.
1.3 Schedule of Activities 
(SoA)
+21 days was added to the stool sample 
collection at the RSV mobile App alert and 
the sample at the RSV-like ARI visit was 
removed. 
Clarification that the optional stool 
sample
should be collected at 
21 days (+2 weeks) after the ARI 
alert.
Throughout
Minor corrections and clarifications were made.


JNJ-53718678
Clinical Protocol 53718678RSV2006 Amendment 3
CONFIDENTIAL – FOIA Exemptions Apply in U.S.
7
Status: Approved,  Date: 13 July 2020
Amendment 1 (06 Nov 2019)
Overall Rationale for the Amendment: The overall reason is to update the protocol to add the missing 
part of the Visit Schedule for Rash Management in Pediatric Participants in Appendix 8.
Section Number
and Name
Description of Change
Brief Rationale
10.8 Appendix 8: 
Visit Schedule for 
Rash Management 
in Pediatric 
Participants
The protocol was updated to add the missing part 
of Appendix 8.
To correct for the inadvertent 
omission of the second part of the 
visit schedule for rash management
(follow-up through Day 8 and 
further visits) in Appendix 8.
1.3 Schedule of 
Activities (SoA)
4.4 End of Study 
Definition
The protocol was updated to add the allowed 
window (ie, ±3 days) to the end of study visit of 
the observational stage in the Schedule of 
Activities.
The protocol was updated to add a note to clarify 
that the window allowed for the optional stool 
sampling is 21 days (+2 weeks) in the post 
diagnostic stage of the observational stage of the 
study for RSV positive patients who do not enter 
the interventional stage of the study.
To align with the protocol text.
The allowed window (+2 weeks) 
for the collection of the optional 
stool sample is larger than the 
window (±3 days) of the end of 
study 
visit 
(Day 
21) 
of 
the 
observational stage of the study. 
This longer window is required to 
ensure collection of a good quality 
stool sample that is usable for 
subsequent assessments. 
1.3 Schedule of 
Activities (SoA)
In the Schedule of Activities (Part 1: Observational 
Stage – RSV(+) Outpatients NOT Enrolled in 
Interventional Stage; footnote d), the crosslink to 
Section 8.3.2 was replaced with a crosslink to 
Section 8.3.1.
To correct crosslinking. 
6.1 Study 
Interventions
Administered
The protocol was updated to include the
Chemistry, Manufacturing, and Controls (CMC)
summary of the administered study intervention.
To provide more information on the 
study intervention.


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Status: Approved,  Date: 13 July 2020
TABLE OF CONTENTS
PROTOCOL AMENDMENT SUMMARY OF CHANGES TABLE ............................................................... 2
TABLE OF CONTENTS ............................................................................................................................... 8
LIST OF IN-TEXT TABLES AND FIGURES.............................................................................................. 10
1.
PROTOCOL SUMMARY ................................................................................................................... 11
1.1.
Synopsis......................................................................................................................................... 11
1.2.
Schema .......................................................................................................................................... 19
1.3.
Schedule of Activities (SoA)........................................................................................................... 20
2.
INTRODUCTION................................................................................................................................ 38
2.1.
Study Rationale.............................................................................................................................. 39
2.2.
Background .................................................................................................................................... 39
2.3.
Benefit-Risk Assessment ............................................................................................................... 55
2.3.1.
Known Benefits........................................................................................................................... 55
2.3.2.
Potential Benefits........................................................................................................................ 55
2.3.3.
Known Risks............................................................................................................................... 55
2.3.4.
Potential Risks for Study Participation........................................................................................ 55
2.3.5.
Benefit-Risk Assessment for Study Participation ....................................................................... 58
3.
OBJECTIVES AND ENDPOINTS ..................................................................................................... 60
3.1.
Objectives ...................................................................................................................................... 60
3.2.
Endpoints ....................................................................................................................................... 61
4.
STUDY DESIGN ................................................................................................................................ 65
4.1.
Overall Design................................................................................................................................ 65
4.2.
Scientific Rationale for Study Design............................................................................................. 67
4.2.1.
Study-Specific Ethical Design Considerations ........................................................................... 68
4.3.
Justification for Dose...................................................................................................................... 68
4.4.
End of Study Definition................................................................................................................... 69
5.
STUDY POPULATION ...................................................................................................................... 70
5.1.
Inclusion Criteria ............................................................................................................................ 70
5.2.
Exclusion Criteria ........................................................................................................................... 72
5.3.
Lifestyle Considerations................................................................................................................. 73
5.4.
Screen Failures .............................................................................................................................. 74
6.
STUDY INTERVENTION................................................................................................................... 74
6.1.
Study Interventions Administered .................................................................................................. 74
6.2.
Preparation/Handling/Storage/Accountability ................................................................................ 76
6.3.
Measures to Minimize Bias: Randomization and Blinding............................................................. 77
6.4.
Study Intervention Compliance...................................................................................................... 78
6.5.
Concomitant Therapy..................................................................................................................... 79
7.
DISCONTINUATION OF STUDY INTERVENTION AND PARTICIPANT 
DISCONTINUATION/WITHDRAWAL ............................................................................................... 81
7.1.
Discontinuation of Study Intervention ............................................................................................ 81
7.2.
Participant Discontinuation/Withdrawal From the Study................................................................ 81
7.2.1.
Withdrawal From the Use of Research Samples ....................................................................... 82
7.3.
Lost to Follow-up............................................................................................................................ 83
8.
STUDY ASSESSMENTS AND PROCEDURES ............................................................................... 84
8.1.
Part 1: Observational Stage........................................................................................................... 87
8.1.1.
Pre-diagnostic Phase.................................................................................................................. 87
8.1.2.
Diagnostic Phase........................................................................................................................ 88
8.1.3.
Post-diagnostic Phase................................................................................................................ 89


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Status: Approved,  Date: 13 July 2020
8.2.
Part 2: Interventional Stage ........................................................................................................... 90
8.2.1.
Screening Phase ........................................................................................................................ 90
8.2.2.
Double-blind Treatment Phase................................................................................................... 90
8.2.3.
Follow-up Phase......................................................................................................................... 91
8.2.4.
Withdrawal and Safety Follow-up Visits ..................................................................................... 92
8.3.
Viral Kinetics and Clinical Outcome............................................................................................... 92
8.3.1.
Viral Load Kinetics (Observational Stage).................................................................................. 92
8.3.2.
Antiviral Activity (Interventional Stage)....................................................................................... 92
8.3.3.
Clinical Course of RSV Infection ................................................................................................ 93
8.3.4.
Viral Sequencing......................................................................................................................... 94
8.4.
Safety Assessments....................................................................................................................... 94
8.4.1.
Physical Examinations................................................................................................................ 95
8.4.2.
Vital Signs (Blood Pressure)....................................................................................................... 96
8.4.3.
Electrocardiograms..................................................................................................................... 96
8.4.4.
Clinical Safety Laboratory Assessments .................................................................................... 97
8.5.
Specific Toxicities and Safety Topics of Special Interest............................................................... 97
8.6.
Adverse Events and Serious Adverse Events ............................................................................... 98
8.6.1.
Time Period and Frequency for Collecting Adverse Event and Serious Adverse Event 
Information.................................................................................................................................. 99
8.6.2.
Follow-up of Adverse Events and Serious Adverse Events ..................................................... 100
8.6.3.
Regulatory Reporting Requirements for Serious Adverse Events ........................................... 100
8.7.
Treatment of Overdose ................................................................................................................ 100
8.8.
Pharmacokinetics......................................................................................................................... 100
8.8.1.
Evaluations ............................................................................................................................... 101
8.8.2.
Analytical Procedures............................................................................................................... 101
8.8.3.
Pharmacokinetic Parameters and Evaluations......................................................................... 101
8.9.
Pharmacokinetic/Pharmacodynamic Evaluations........................................................................ 101
8.10.
Host Genetic Research................................................................................................................ 101
8.11.
Biomarkers ................................................................................................................................... 102
8.12.
Other Evaluations......................................................................................................................... 102
9.
STATISTICAL CONSIDERATIONS................................................................................................ 102
9.1.
Sample Size Determination ......................................................................................................... 102
9.2.
Populations for Analyses.............................................................................................................. 104
9.3.
Statistical Analyses ...................................................................................................................... 104
9.3.1.
Participant Information.............................................................................................................. 104
9.3.2.
Analyses Specific to the Observational Stage.......................................................................... 104
9.3.3.
Viral Kinetics and Clinical Outcome Analyses.......................................................................... 105
9.3.3.1.
Viral Load Kinetics (Observational Stage)............................................................................. 105
9.3.3.2.
Antiviral Activity (Interventional Stage).................................................................................. 105
9.3.3.3.
Clinical Course of RSV Infection ........................................................................................... 106
9.3.3.4.
Correlation Between Antiviral Effect and Clinical Course Endpoints .................................... 106
9.3.3.5.
Viral Sequencing ................................................................................................................... 106
9.3.4.
Safety Analyses ........................................................................................................................ 107
9.3.5.
Other Analyses ......................................................................................................................... 108
9.3.5.1.
Pharmacokinetic Analyses .................................................................................................... 108
9.3.5.2.
Pharmacokinetic/Pharmacodynamic Analyses ..................................................................... 109
9.3.5.3.
Host Genetic Analyses .......................................................................................................... 109
9.3.5.4.
Biomarkers Analyses............................................................................................................. 109
9.3.5.5.
Other Analyses ...................................................................................................................... 109
9.4.
Interim Analysis............................................................................................................................ 109
9.5.
Independent Data Monitoring Committee .................................................................................... 109
10.
SUPPORTING DOCUMENTATION AND OPERATIONAL CONSIDERATIONS .......................... 111
10.1.
Appendix 1: Abbreviations ........................................................................................................... 111
10.2.
Appendix 2: Clinical Laboratory Tests ......................................................................................... 113
10.3.
Appendix 3: Regulatory, Ethical, and Study Oversight Considerations....................................... 115
REGULATORY AND ETHICAL CONSIDERATIONS............................................................................... 115


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INFORMED CONSENT PROCESS.......................................................................................................... 118
DATA PROTECTION................................................................................................................................ 119
LONG-TERM RETENTION OF SAMPLES FOR ADDITIONAL FUTURE RESEARCH .......................... 120
COMMITTEES STRUCTURE................................................................................................................... 120
PUBLICATION POLICY/DISSEMINATION OF CLINICAL STUDY DATA ............................................... 120
DATA QUALITY ASSURANCE................................................................................................................. 122
CASE REPORT FORM COMPLETION.................................................................................................... 122
SOURCE DOCUMENTS........................................................................................................................... 123
MONITORING........................................................................................................................................... 123
ON-SITE AUDITS ..................................................................................................................................... 124
RECORD RETENTION............................................................................................................................. 124
STUDY AND SITE START AND CLOSURE ............................................................................................ 125
10.4.
Appendix 4: Adverse Events: Definitions and Procedures for Recording, Evaluating, 
Follow-up, and Reporting............................................................................................................. 126
ADVERSE EVENT DEFINITIONS AND CLASSIFICATIONS .................................................................. 126
ATTRIBUTION DEFINITIONS .................................................................................................................. 127
SEVERITY CRITERIA............................................................................................................................... 127
SPECIAL REPORTING SITUATIONS...................................................................................................... 128
PROCEDURES......................................................................................................................................... 128
CONTACTING SPONSOR REGARDING SAFETY ................................................................................. 129
PRODUCT QUALITY COMPLAINT HANDLING ...................................................................................... 130
10.5.
Appendix 5: Division of Microbiology and Infectious Diseases (DMID) Pediatric Toxicity 
Tables (November 2007, draft) .................................................................................................... 131
10.6.
Appendix 6: Cardiovascular Safety – Abnormalities.................................................................... 141
10.7.
Appendix 7: Guidance on Study Conduct During the COVID-19 Pandemic ............................... 142
10.8.
Appendix 8: Protocol Amendment History ................................................................................... 145
11.
REFERENCES................................................................................................................................. 146
INVESTIGATOR AGREEMENT ............................................................................................................... 148
LIST OF IN-TEXT TABLES AND FIGURES
TABLES
Table 1:
Predicted Geometric Mean AUC24h, Cmax, Ctrough and QTcI Per Age Group After Day 
1 and Day 7............................................................................................................................... 69
Table 2:
Treatment Overview.................................................................................................................. 75
Table 3:
Populations for Analyses ........................................................................................................ 104
FIGURES
Figure 1:
Schematic Overview of the Design of the Study ...................................................................... 19
Figure 2:
Illustration of Viral Load over Time by Treatment Assumed in the Sample Size 
Calculation .............................................................................................................................. 103


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1.
PROTOCOL SUMMARY
1.1.
Synopsis
A Two-Part Study With a Birth Cohort (Observational Stage) for Early Diagnosis of Respiratory 
Syncytial Virus (RSV), Followed by an Optional Phase 2a, Randomized, Double-blind, Placebo-
controlled Study (Interventional Stage) to Evaluate the Antiviral Activity, Clinical Outcomes, Safety, 
Tolerability, and Pharmacokinetics of JNJ-53718678 in Infants With Acute Respiratory Tract Infection 
due to RSV
JNJ-53718678 is an investigational respiratory syncytial virus (RSV) specific fusion inhibitor under 
development for the treatment of RSV infection.
STUDY RATIONALE
RSV is considered the most important virus causing acute lower respiratory tract infection (LRTI) and a 
major cause of hospital admissions and death in young children worldwide. Infants born prematurely or 
close to the RSV circulation and/or suffering from bronchopulmonary dysplasia or congenital heart 
disease have the highest risk of developing severe RSV-related acute LRTI. At the time of RSV intercept 
when the infants are brought in (on the parent/caregiver’s initiative) for medical care for an acute 
respiratory infection (ARI), the RSV viral load is mostly already past its peak and declining, whereas the 
disease can still evolve. In order to have a significant effect on the disease severity, treatment needs to be 
started as soon as possible to prevent further replication of the virus and the ensuing inflammatory 
response leading to the clinical signs/symptoms and to maximize the potential for the study medication to 
exert its antiviral effects, thereby affecting the clinical course of the disease.
This study is designed to assess in the setting of a planned early interception of pediatric RSV disease, 
early viral and disease kinetics (observational stage) and the antiviral effects of an RSV fusion inhibitor, 
JNJ-53718678 (interventional stage). In the observational stage the infant is closely monitored for early 
symptoms by the parent(s)/caregiver(s) and thus may be brought in for diagnosis earlier than in the typical 
setting.
To ascertain that children will be recruited with a primary RSV infection at an age where disease severity 
is significant, parent-child pairs will be recruited when the child is less than 4 months old and born after 
the end of the season preceding the initiation of the study.
OBJECTIVES AND ENDPOINTS
Objectives
Part 1: Observational Stage

To evaluate the onset and evolution of clinical symptoms of pediatric RSV disease

To evaluate the relationship between viral load and clinical symptoms at early diagnosis of pediatric 
RSV disease
Part 2: Interventional Stage
The primary objective is to evaluate 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 
an early intervention setting in infants (≤4 months of age at enrollment) recruited from a birth cohort.
The secondary objectives are to assess:

the impact of treatment with JNJ-53718678 on the clinical course of RSV infection


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
the safety and tolerability of JNJ-53718678 after repeated oral doses

the pharmacokinetics (PK) of JNJ-53718678 after repeated oral doses
Endpoints
Part 1: Observational Stage

the total score, over time, of respiratory symptoms as captured by the RSV mobile Application (App)
during the pre-diagnostic phase and the post-diagnostic phase for RSV(+) participants that do not 
enter in the interventional stage

the Pediatric RSV Electronic Severity and Outcome Rating System (PRESORS) scores by the 
clinician (clinician PRESORS) on the day of RSV diagnosis 

RSV viral load kinetics during the pre-diagnostic phase

RSV viral load kinetics from Day 1 to Day 8 after RSV diagnosis over time (if not participating in 
the interventional stage)

the PRESORS scores by parent(s)/caregiver(s) (parent[s]/caregiver[s] PRESORS) over time
Part 2: Interventional Stage
The primary efficacy endpoint is the RSV viral load area under the curve (AUC) from immediately prior 
to first dose of study medication through Day 5 derived from the RSV viral load as measured by a 
qRT-PCR assay in nasal swabs.
Secondary endpoints of the interventional stage can be summarized as follows:a

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 (start of study medication) over time

RSV viral load AUC from immediately prior to first dose of study medication (baseline) 
through Day 3, Day 8, and Day 14

time to undetectable RSV viral load

proportion of participants with undetectable RSV viral load at each time point throughout the 
study

clinical course related endpoints:
o
the following endpoints will be based on the PRESORS assessed throughout the 
interventional stage of 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 assessed throughout the 
study by parent(s)/caregiver(s) PRESORS

change 
from 
baseline 
in 
parent(s)/caregiver(s) 
PRESORS 
(worsening 
or 
improvement)

change from baseline in clinician PRESORS (worsening or improvement)

time to resolution (ie, to none or mild) of RSV symptoms
                                                
a Exploratory objectives and corresponding endpoints are provided in Section 3 of the protocol.


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
time to improvement based on general questions on overall health

proportion of participants with improvement or worsening of RSV disease based on 
general questions on overall health on each study day from screening till Day 21

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 during scheduled visits
o
need for (re)hospitalization during treatment and follow-up

safety and tolerability, as assessed by adverse events (AEs), clinical laboratory testing, 
electrocardiograms (ECGs), and vital signs, throughout the interventional stage of the study

PK parameters of JNJ-53718678, as determined by population PK (popPK) modeling
Hypothesis
Part 1: Observational Stage
For the observational stage no formal hypothesis will be tested.
Part 2: Interventional Stage
The primary hypothesis of this study is that JNJ-53718678 has antiviral activity against RSV as assessed 
by a reduction in RSV viral load AUC (from immediately prior to first dose of study medication 
[baseline] until Day 5) at the 5% level (one-sided) for JNJ-53718678 compared to placebo in participants 
recruited from a birth cohort. 
OVERALL DESIGN
This study is designed to assess the impact of early interception and intervention on antiviral activity and 
the clinical course of the disease. The study consists of 2 parts: an observational stage with a birth cohort
and a Phase 2a, multicenter, randomized, double-blind, placebo-controlled interventional stage.
In the observational pre-diagnostic phase, the study aims to record early signs and symptoms of potential 
RSV infections and is focused on bringing the infant in for assessment at a threshold score that is based 
on a combination of at least one sign of upper respiratory infection, any sign of lower respiratory 
involvement and any sign of systemic impact (eg, feeding difficulty, disturbed sleep, disturbed activity 
level). All infants will be closely monitored for early signs and symptoms of RSV disease using a mobile 
RSV App on the parent/caregiver's mobile phone (pre-diagnostic phase). For those infants with scores 
that cross the threshold score an alert will be sent and they will be brought to the study site for an early 
diagnostic RSV test (diagnostic phase). RSV(-) participants will return to the pre-diagnostic phase and 
will be further closely monitored by the parent(s)/caregiver(s) through the RSV mobile App. There will 
be a 7-day pause in the RSV mobile App for the generation of alerts, after which the alert option will be 
switched back on. RSV(+) participants will be enrolled in the screening phase of the interventional stage 
of the study after obtaining informed consent for the interventional stage at that time. RSV(+) participants 
whose parent(s)/caregiver(s) do not consent for enrollment in the interventional stage and participants 
who are screening failures in the interventional stage will enter the post-diagnostic phase of the 
observational stage (hospitalized or outpatients). Upon an alert, if a participant is SARS-CoV-2 positive 
assessed by local health practice, the participant will be withdrawn from study.
The interventional stage will consist of a screening phase, a treatment phase (hospitalized or outpatients), 
and a posttreatment follow-up phase. Newly recruited participants will be randomized in a 1:1 ratio to 
receive either JNJ-53718678 or placebo twice daily (bid) AM and PM for 7 days (14 consecutive doses). 
For participants 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 participants receive 14 consecutive doses in 


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total. Antiviral activity, clinical outcomes, safety, tolerability, and PK of JNJ-53718678 in infants at early 
stage of an ARI due to RSV will be evaluated.
The observational stage involves nasal swabbing for RSV diagnosis, viral assessments (RSV RNA viral 
load), exploratory biomarker analysis, blood sampling (optional) for exploratory biomarker analyses, 
stool sampling (optional) for microbiome analysis, buccal swab collection (optional) for exploratory host 
genetic analyses, and completion of questionnaires (evaluation questionnaires and PRESORS).
In the post-diagnostic phase of the observational stage, for the RSV(+) participants whose 
parent(s)/caregiver(s) do not consent for enrollment in the interventional stage and participants who are 
screening failures in the interventional stage, the parent(s)/caregiver(s) will be asked to continue with the 
twice daily RSV mobile app and to also complete the PRESORS over the same period. 
The interventional stage involves nasal swabbing, viral assessments (RSV RNA viral load, RSV subtype 
determination, and sequencing), blood sampling for PK, and completion of questionnaires (PRESORS).
Study duration will be approximately 29 (±3) days after RSV(+) diagnosis for participants who enter the 
interventional stage, and 21 (±3) days after RSV(+) diagnosis for participants who do not enter the 
interventional stage (or 21 days [+2 weeks] in case optional stool samples will be collected [the additional 
time is only for optional stool sample assessments]). RSV(-) participants will be considered to have 
completed the study at the end of the RSV circulation. For RSV(-) participants who consented to the stool 
sample collection, the study ends either when the most relevant RSV surveillance data indicate that RSV 
is out of circulation or on the day of stool sample collection at the participant’s age of 4 months 
(±2 weeks), whichever is last.
An Independent Data Monitoring Committee (IDMC) will be commissioned for the interventional stage.
NUMBER OF PARTICIPANTS
A target of 1,300 infants (≤4 months of age at enrollment and asymptomatic for ARI-like symptoms 
requiring medical intervention at the time of consent) is planned to be enrolled globally in the 
observational stage of this study. 
It is anticipated that approximately 40 RSV(+) infants from the observational stage of the study will be 
enrolled in the interventional stage. Participants should be ≥28 days old (or ≥3 months postnatal age for 
prematurely born infants) and at least 2.4 kg to be eligible for enrollment in the interventional stage of the 
study.
The enrollment period for the observational stage will be guided by local RSV epidemiological 
distribution and dynamics. Start and end of the RSV circulation will be dependent on the respective 
country/region where the study will be conducted. The determination by the sponsor to end the study will 
be done on a per-site basis in line with the local seasonality pattern.
INTERVENTION GROUPS AND DURATION
After Amendment 2, newly eligible participants in the interventional stage will be randomized 1:1 to 
receive either JNJ-53718678 or placebo. Randomization should occur within 32 hours after the receipt of 
RSV mobile App alert, and will be stratified based on the time between ARI alert and randomization 
(<24 hours or ≥24 hours). Treatment should start as soon as possible, but within 4 hours after 
randomization. Study medication will be administered bid for 7 days (14 consecutive doses). For 
participants 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 participants 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. Doses are based on body weight and age group. Infants ≥28 days and 


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<3 months of age will receive 2.5 mg/kg bid, infants ≥3 and <6 months of age will receive 3 mg/kg bid, 
and infants ≥6 months of age will receive 4.5 mg/kg bid (or matching placebo).
EFFICACY EVALUATIONS
Antiviral Activity (Interventional Stage)
For the evaluation of antiviral activity, the RSV viral load in nasal secretions will be measured at the 
central laboratory using a qRT-PCR assay on mid-turbinate nasal swab specimens, which will be 
collected at several time points during the study. If feasible, the RSV infectious titer may also be assessed 
by quantitative culture of RSV (plaque assay) on selected nasal swab samples. 
Clinical Course of RSV Infection 
The clinical course of RSV infection will be evaluated for all RSV(+) participants (hospitalized or 
outpatients) during either the post-diagnostic phase of the observational stage (for those who do not enter 
the interventional stage or are screen failure in the interventional stage) or the interventional stage of the 
study, including but not limited to:

respiratory rate, heart rate, SpO2, and body temperature as measured by the investigator 

body temperature as measured by the parent(s)/caregiver(s) 

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 by the investigator (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 disease per investigator assessment

the need for antibiotics related to complications associated with RSV disease per investigator 
assessment

for hospitalized patients only: time to discharge (from initial admission and from initiation of study 
treatment), time to clinical stability, with clinical stability evaluated by the investigator (from initial 
admission and from initiation of study treatment), level of and duration by level of hospital care (eg, 
intensive care unit [ICU], translational care unit, ward floor), oxygen requirement type (eg, 
supplemental oxygen, noninvasive pressure ventilation, endotracheal-mechanical ventilation), and 
duration, and hydration and feeding by intravenous (IV) line/nasogastric tube and duration
Viral Sequencing 
In the interventional stage, 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 presence of baseline RSV F-gene polymorphisms on the 
antiviral response will be explored.
SAFETY EVALUATIONS
During the observational stage of the study, all serious and non-serious AEs related to the study sampling 
procedures and all deaths (including their causality) will be documented from signing of the informed 
consent form (ICF) allowing inclusion in the observational stage onwards. 
Safety and tolerability will be evaluated throughout the interventional stage, ie, from signing of the ICF 
allowing inclusion in the interventional stage onwards until the last study-related activity, and will include 


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the following evaluations: AEs, clinical laboratory tests (local), 12-lead ECG, vital signs, and physical 
examination.
PHARMACOKINETIC EVALUATIONS
For newly recruited participants in the interventional stage, a blood sample for determination of 
JNJ-53718678 concentrations will be collected through finger prick or heel stick approximately 1 hour 
after administration of study drug (after the ECGs are obtained) on Day 1 and at least 4 hours after the 
AM and prior to the PM dosing on Day 3 or Day 5.
BIOMARKER AND PHARMACOGENOMIC (DNA) EVALUATIONS 
Stool samples for microbiome analysis will be optionally collected during the study to assess diversity 
and relative abundance of bacterial species.
In the observational stage, optional blood samples will be used for exploratory biomarker analyses (eg, 
proteins, RNA, immune cell populations), on the premise that these analyses investigate the role of 
biomarkers in RSV-related disease. Leftover mid-turbinate nasal swab samples from samples collected 
during the study may also be used for exploratory biomarker analyses (eg, proteins, RNA, immune cells, 
microbiome).
In the observational stage, host genetic variation analysis (DNA) can be performed only on optional 
samples collected from participants whose parent(s)/caregiver(s) provided informed consent for buccal 
swab collection and human DNA testing.
STATISTICAL METHODS
Sample Size Determination
The sample size of the interventional stage is based on results obtained in an earlier birth cohort study 
(Janssen R&D, data on file) and the specified analysis method using simulated data. Based on 10,000 
simulated datasets of 40 participants, with an assumed 10% drop-out rate and an effect size of early 
treatment of 0.75 log10 copies.day/mL reduction in viral load versus placebo on average, there is a power
of 88% to reject the null hypothesis of no antiviral effect of JNJ-53718678 treatment using a significance 
level of 5% (one-sided).
The sample size of the birth cohort is based on the sample size required for the interventional stage. It is 
assumed based on the results of a previous observational birth cohort study (Janssen R&D, data on file) 
that approximately 10% of the infants participating in the birth cohort will be diagnosed as RSV(+) and 
will develop ARI disease signs compatible with a minimum disease severity threshold for intervention. 
At the stage of the temporary hold of the interventional stage of the study on 2 March 2020, 862 infants 
were enrolled in the birth cohort, leading to 29 infants who were diagnosed as RSV(+) and 20 infants who 
participated in the interventional stage. The incidence of RSV(+) was lower than anticipated, which for a 
large part may be explained by the relatively late in the RSV season start of recruitment for the first 
participating country in the study (Panama). It is assumed that when recruitment into the birth cohort is 
re-initiated in time for the next season, ~10% of participants will be diagnosed as RSV(+). In order to 
maintain the target of 40 participants in the interventional part, the maximum number of infants that may 
be recruited in the birth cohort is set at 1,300. With an additional 438 participants in the birth cohort, an 
assumption of 10% incidence of RSV(+) and a 50% rate of infants who will enter the interventional stage, 
the target of 40 participants in the interventional stage is expected to be reached.
As the sample size of the 2 parts are linked and assumptions have to be made on the percentages of 
RSV(+) and eligibility, the study may continue at the discretion of the sponsor when more than 
40 participants are included in the interventional part (with a maximum of 60) and may also be considered 
completed if at least 32 infants have been included in the interventional part. 


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Viral Kinetics and Clinical Outcome Analyses
Details regarding the analyses will be described in the Statistical Analysis Plan (SAP).
Viral Load Kinetics (Observational Stage)
Viral load kinetics will be determined based on measurements of RSV viral load in nasal secretions by a 
qRT-PCR assay on mid-turbinate nasal swab specimens. These data will be analyzed descriptively and 
graphically. For the RSV viral load assessed before the day of RSV diagnosis and at the diagnosis itself it 
will be investigated if the signs and symptoms observed and captured previous to these RSV viral load 
assessments have predictive value for the absence or presence of the virus as well as for the key 
characteristics of the viral load (eg, peak viral load), when virus is present. The correspondence between 
viral load and signs and symptoms will be investigated graphically by visualizing the viral load and signs 
and symptoms together over a period of time before and after RSV diagnosis. Exploratory analyses and 
details will be described in the SAP.
Antiviral Activity (Interventional Stage)
Viral load kinetics will be determined based on measurements of RSV viral load in nasal secretions by a 
qRT-PCR assay on mid-turbinate nasal swab specimens. These data will be analyzed graphically and 
descriptively. Kaplan-Meier Curves will be produced to describe the time to event data. The primary 
population for the efficacy/antiviral activity analysis will be the intent-to-treat infected population 
consisting of all randomized participants who received at least one dose of study medication and who 
have a centrally confirmed RSV infection with an RSV viral load of ≥1 log10 copies/mL above the lower 
limit of quantification (LLOQ) at baseline.
The primary efficacy endpoint is the RSV viral load AUC from immediately prior to first dose of study 
medication through Day 5 (AUC1-5 days) derived from the RSV viral load as measured by a qRT-PCR 
assay in nasal swabs. Mean log10 viral load values over time will be analyzed using a restricted maximum 
likelihood-based repeated measures approach. Analyses will include the fixed, categorical effects of 
treatment, stratum (time from ARI alert within 24 hours or outside 24 hours), 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. 
Differences between treatment groups in viral load for time points, and the difference in the AUC1-5 days
between treatment groups will be derived using appropriate contrasts deriving least square mean 
differences, including the 90% 2-sided confidence intervals. The primary null hypothesis of worse or no 
treatment effect will be rejected if the viral load AUC1-5 days is significantly lower than placebo using a 
one-sided test at the 0.05 significance level. 
Clinical Course of RSV Infection
Endpoints related to evaluation of the clinical course of RSV infection will be analyzed graphically and 
descriptively. Both scores from the RSV mobile App as well as PRESORS scores will be summarized 
descriptively over time and may be modeled using longitudinal analysis. Relationship between symptoms 
reported on the RSV mobile App and becoming RSV(+) (versus RSV[-]), and need for hospitalization 
(versus outpatient) will be investigated graphically. Also, correlation between symptoms reported on the 
RSV mobile App as predictive of viral load characteristics will be investigated, as well as correlation 
between signs and symptoms and viral load over time. Time-to variables will be analyzed using Kaplan-
Meier plots. For the interventional stage these might be modeled using an accelerated failure time model, 
adjusted for covariates, such as stratum and baseline viral load, to estimate differences between treatment 
groups. Endpoints related to hospital stay will be explored.


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Viral Sequencing
Pre-treatment polymorphisms and relevant post-baseline changes in the RSV F-gene (and other regions of 
the RSV genome, if applicable and on request of the sponsor’s virologist) will be tabulated and described. 
The effect of pre-treatment RSV F-gene polymorphisms and relevant post-baseline RSV F-gene changes 
on antiviral response and/or clinical outcomes will be explored.
Safety Analyses
All safety data will be summarized descriptively. 
Pharmacokinetic Analyses
PK analysis will be performed using a popPK approach by means of nonlinear mixed-effects modeling.
Biomarkers Analyses
Analyses may be conducted at the sponsor’s discretion and reported separately from this study.
Interim Analysis
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.
In case of an interim analysis, investigators, participants’ parents/caregivers, and local sponsor 
representatives will remain blinded. The sponsor leadership team responsible for decisions and the central 
study team required to generate and interpret results will have access to unblinded data.


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1.2.
Schema
Figure 1:
Schematic Overview of the Design of the Study
Note: Prior to Protocol Amendment 2, the total daily dose was the same but the daily dosing frequency was qd instead of bid.
bid=twice daily; ICF=informed consent form; PRESORS= Pediatric RSV Electronic Severity and Outcome Rating System; RSV= respiratory syncytial virus


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1.3.
Schedule of Activities (SoA)
Part 1: Observational Stage – Enrollment to Diagnosis
Phase
Pre-diagnosis
Diagnosis
Period
Enrollment
RSV mobile App alerta
RSV-like ARI Visitb,c
Timeframe
Observational Stage Day 
1 (RSV diagnostic test to 
be performed at site as 
soon as possible but no 
later than 24 hours after 
receipt of RSV mobile 
App alert)
RSV alert day +21 days 
(+2wks)
Study Procedures
Informed consent (ICF)d
X
ICF for optional blood samplinge,f
X
ICF for optional buccal swab collection (for 
genetic analyses)e
X
ICF for optional stool samplinge
X
Demographics
X
Review medical history 
X
Inclusion/exclusion criteria
X
Training parent(s)/caregiver(s) for nasal sampling 
at homeg
X
RSV diagnostic test
X
Systolic and diastolic blood pressureh
X
Complete physical examinationi
X
Clinical evaluationj
X
Use of RSV mobile App by parent(s)/caregiver(s)k
Continuous l
Monitoring of RSV mobile App dashboard by site 
staff, 
and take action where neededm
Continuous l
Completion of questionnaires by 
parent(s)/caregiver(s)
Continuous l
Buccal swab collection (optional)
Xn
Blood sample collection (optional)
Xo
Stool sample collection (optional)
Xp
Xq
Mid-turbinate nasal swabr
at home 
X
at the site 
Xs


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Phase
Pre-diagnosis
Diagnosis
Period
Enrollment
RSV mobile App alerta
RSV-like ARI Visitb,c
Timeframe
Observational Stage Day 
1 (RSV diagnostic test to 
be performed at site as 
soon as possible but no 
later than 24 hours after 
receipt of RSV mobile 
App alert)
RSV alert day +21 days 
(+2wks)
Study Procedures
Concomitant medication
X
X
Adverse eventst
Continuous
Footnotes: 
a
Once the RSV mobile Application (App) is activated, pre-programmed study-related questions (App questionnaires) will be asked via the parent/caregiver’s 
smartphone twice daily (bid). The answers of the parent(s)/caregiver(s) will drive an algorithm that calculates scores in the background of the application, where the 
threshold score is defined on the basis of the presence of the signs and symptoms per eligibility criteria for intervention, thus a combination of an upper and a lower 
respiratory sign and a sign of systemic impact. When the infant starts showing clinical signs compatible with RSV disease, that cross this threshold score in the RSV 
mobile App the parent(s)/caregiver(s) will receive an alert asking them to collect a nasal swab at home and to invite them to present to the site with their infant for a 
study visit as soon as possible, ie, within <24 hours after the receipt of the alert (RSV-like acute respiratory infection [ARI] visit). A mid-turbinate nasal swab will 
be collected at the site by qualified study-site personnel and tested with a study-related RSV molecular-based diagnostic assay to diagnose RSV. 
b
The ARI visit (Observational Stage Day 1) should take place at the study site. 
c
RSV negative participants (RSV[-]) will re-enter and continue in the pre-diagnostic phase and the parent(s)/caregiver(s) will observe the health condition of the 
infant and answer the App questionnaires on the RSV mobile App until the next alert or until the end of the RSV circulation as defined per country/region/site.
d
The ICF for the observational stage of the study must be signed at enrollment and no later than before the first study-related activity is performed. 
e
Refusal to give consent for the optional samples does not exclude a participant from participation in the study.
f
The ICF should preferably be signed at Day 1 but can be signed at any time after consent to participate in the study is given, but before blood sampling is 
performed. 
g
If re-training is needed, this will be performed at a later time point.
h
Systolic and diastolic blood pressure need to be measured supine (preferably the same position at each measurement) after at least 5 minutes of rest.
i
Physical examination of all body systems, including length and head circumference and body weight measurement and skin examination. 
j
Clinical evaluation includes measurements/evaluations of respiratory rate, heart rate, body temperature, and peripheral capillary oxygen saturation (SpO2), need for 
and duration of hospitalization, occurrence of complications, need for antibiotics. In case of hospitalization, the following additional evaluations will be performed: 
oxygen requirement (type and duration), level of and duration of hospital care, hydration/feeding by intravenous (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). 
k
The RSV mobile App will be downloaded on the parent/caregiver’s own smartphone during the enrollment visit or at any time after signing the ICF. The RSV 
mobile App will be used from a predefined date (start date will be country and site dependent) until study completion. 
l
Participants for whom the threshold for an alert for an ARI visit is never reached and participants who are diagnosed RSV(-) after an alert will be followed until the 
end of the RSV circulation. 


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Status: Approved,  Date: 13 July 2020
m
The dashboard will need monitoring by the site staff during the entire period of the study from the activation of the questions in the RSV mobile App until 
completion of the observational part of the study. In case of alerts or incompliances notified in the dashboard, it is the site's responsibility to follow-up with the 
parent(s)/caregiver(s) of the specific participant to discuss compliance to protocol requirements, such as taking nasal sampling, planning site visit, completion of 
questionnaires.
n
An optional buccal swab will be taken from all participants whose parent(s)/caregiver(s) have provided additional consent.
o
An optional blood sample for exploratory biomarker analyses will be collected from all participants that have an RSV-like ARI visit (collection only at the first 
RSV-like ARI visit if multiple), irrespective of RSV(+) or RSV(-) diagnosis, if consent for blood sampling is provided. The blood sample should be obtained by 
phlebotomy/venipuncture.
p
Optional stool samples will be taken from all participants whose parent(s)/caregiver(s) have provided additional consent. Stool samples from the infant will be 
collected by the parent(s)/caregiver(s) in dedicated sampling tubes at enrollment (+2 weeks; healthy baseline) and at the age of 4 months (±2 weeks; unless this age 
coincides with enrollment, ie, within 2-week window; in that case only 1 sample is to be collected) for participants in the observational stage. Information on date 
and time of stool sampling as well as feeding type (liquid vs solid) and composition (eg, milk, vegetables, fruit, meat/fish) will be collected. When participants are 
hospitalized, the collection of samples and information on date and time as well as feeding type and composition will be collected by the site staff.
q
An optional stool sample will be collected for participants with an ARI alert, who did not enter the interventional stage of the study, at 21 days (+2 weeks) after the 
ARI alert unless this time point coincides (±2 weeks) with the participant’s age of 4 months; in that case only 1 sample is to be collected. For RSV(-) participants, in 
case another ARI alert is triggered within 2 weeks after the first alert only 1 stool sample needs to be collected. If this second alert results in a positive RSV 
diagnosis, the stool sample should preferably be collected at 21 days (+2 weeks) after the RSV(+) diagnosis.
r
During the enrollment visit of the infant, the infant’s nostrils will be assessed for septum deviations or malformations by the investigator or his/her designee before 
the first nasal sampling. Mid-turbinate nasal swabs should be collected from the same nostril throughout the study (unless precluded due to bleeding).
s
If the diagnostic nasal mid-turbinate sample during the RSV-like ARI visit is taken within 4 hours from the sample for testing at home, the nasal mid-turbinate swab 
sample during the RSV-like ARI visit should be taken from the other nostril. In that case nasal mid-turbinate swab samples should be continued to be collected from 
the same nostril as used during the RSV-like ARI visit.
t
All serious and non-serious adverse events related to the study sampling procedures and all deaths (including their causality) will be documented and will be 
communicated according to the procedure that will be provided by the sponsor.


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Status: Approved,  Date: 13 July 2020
Part 1: Observational Stage – RSV(+) Outpatientsa NOT Enrolled in Interventional Stage (Including Screen Failures of the Interventional Stage)
Phase
Day of 
Diagnosis
Post-diagnosis
Observational Stage Day
1
2-8
9-14
15-20
21
End-of-study
(±3 days)h
Study Procedures
Administrative
ICF for optional blood samplingb
(X)c
Viral Load Kinetics 
Mid-turbinate nasal swabd,e
X
Clinical Assessments
Clinical evaluationf
(X)c
Clinician PRESORS
X
Parent(s)/caregiver(s) PRESORS
X
bid
bid
X
X
Use of RSV mobile App by 
parent(s)/caregiver(s)
Continuous
Completion of App questionnaires by 
parent(s)/caregiver(s)
Continuous
Monitoring of RSV mobile App dashboard 
and of parent(s)/caregiver(s) PRESORS 
completion by site staff
Continuous
Clinical Laboratory Assessments
Blood sample collection (optional)
(X)c
Stool sample collection (optional)g
X
Ongoing Participant Review
Adverse events
Continuous
Concomitant medication
Continuous
Footnotes:
a.
For outpatients who are hospitalized during the course of the study, the reason for hospitalization should be recorded and every effort should be made by the 
investigator to perform all the assessments as indicated in the Schedule of Activities for RSV(+) hospitalized patients NOT enrolled in interventional stage, if 
practically feasible.
b.
The ICF must be signed before (optional) blood sampling is performed. 
c.
The assessments on the day of diagnosis (Day 1) will only be performed once.
d.
Mid-turbinate nasal swabs should be collected from the same nostril throughout the study (unless precluded due to bleeding). Nasal swabs will be collected daily 
through Observational Stage Day 8 for RSV viral load determination. The time and date of the nasal swab collection will be recorded. The investigator/study site 
personnel will train the parent(s)/caregiver(s) to collect the mid-turbinate nasal swab. Detailed information on sample collection is available in Section 8.3.1.
e.
Leftover mid-turbinate nasal swab samples may be used for exploratory biomarker analyses, at discretion of the sponsor.


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Status: Approved,  Date: 13 July 2020
f.
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. All clinical assessments should preferably be done when the infant is calm (ie, not crying or immediately after feeding). 
g.
Stool samples from the infant will be optionally collected by the parent(s)/caregiver(s) at 21 days (+2 weeks) after the ARI alert unless this time point coincides 
(±2 weeks) with the participant’s age of 4 months; in that case only 1 sample is to be collected. Information on date and time of stool sampling as well as feeding 
type (liquid vs solid) and composition (eg, milk, vegetables, fruit, meat/fish) will be collected.
h.
End of study will be 21 days (+2 weeks) in case optional stool samples will be collected (the additional time is only for optional stool sample assessments).


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Status: Approved,  Date: 13 July 2020
Part 1: Observational Stage – RSV(+) Hospitalized Patientsa NOT Enrolled in Interventional Stage up to Discharge (Including Screen Failures of the 
Interventional Stage)
Phase
Day of 
Diagnosis
Post-diagnosis
Observational Stage Day
1
2-8
9-14
15-20
21
End-of-study
(±3 days)h
Study Procedures
Administrative
ICF for optional blood samplingb
(X)c
Viral Load Kinetics 
Mid-turbinate nasal swabd,e
X
Clinical Assessments
Clinical evaluationf
(X)c
bid
bid
bid
bid
Clinician PRESORS
X
bid
bid
X
X
Parent(s)/caregiver(s) PRESORS
X
bid
bid
X
X
Use of RSV mobile App by 
parent(s)/caregiver(s)
Continuous
Completion of App questionnaires by 
parent(s)/caregiver(s)
Continuous
Monitoring of RSV mobile App dashboard 
and of parent(s)/caregiver(s) PRESORS 
completion by site staff
Continuous
Clinical Laboratory Assessments
Blood sample collection (optional) 
(X)c
Stool sample collection (optional)g
X
Ongoing Participant Review
Adverse events
Continuous
Concomitant medication
Continuous
Footnotes:
a
For participants who are discharged during the course of the study, consecutive assessments should be performed according to the Schedule of Activities for 
RSV(+) outpatients NOT enrolled in interventional stage.
b
The ICF must be signed before blood sampling is performed. 
c
The assessments on the day of diagnosis (Day 1) will only be performed once.
d
Mid-turbinate nasal swabs should be collected from the same nostril throughout the study (unless precluded due to bleeding). Nasal swabs will be collected daily 
through Observational Stage Day 8 for RSV viral load determination. The time and date of the nasal swab collection will be recorded. For RSV(+) patients who are 
hospitalized after Observational Stage Day 8, an additional nasal swab will be collected at day of discharge. Detailed information on sample collection is available 
in Section 8.3.1.


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Status: Approved,  Date: 13 July 2020
e
Leftover mid-turbinate nasal swab samples may be used for exploratory biomarker analyses, at discretion of the sponsor.
f
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).
g
Stool samples from the infant will be optionally collected by the site staff at 21 days (+2 weeks) after the ARI alert unless this time point coincides (±2 weeks) with 
the participant’s age of 4 months; in that case only 1 sample is to be collected. Information on date and time of stool sampling as well as feeding type (liquid vs 
solid) and composition (eg, milk, vegetables, fruit, meat/fish) will be collected by the site staff.
h
End of study will be 21 days (+2 weeks) in case optional stool samples will be collected (the additional time is only for optional stool sample assessments).


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Status: Approved,  Date: 13 July 2020
Part 2: Interventional Stage – Outpatientsa
Phase
Screening 
Phase
Treatment Phase
Follow-upb
Dayc
-1 to 1d
1
2
3
4
5 (±1)
6-7
8 (+1)
9-13
14 
(±1)
15-20
21 (±3)
22-27
28 (±3)
End-of-
study
On-site 
visit
Treat
ment
On-
site
On-
site 
visite
On-
site 
visite
On-
site 
visite
On-
site 
visite
On-site 
visite
Phone 
follow-up/ 
Conditional
f on-site 
visit
Study Procedures
Administrative
ICF for interventional
stage of the study
X
Eligibility criteria
Xg
Participant characteristics 
and demographics
X
Medical history/prior 
medications
X
Randomization
Xh
Study Medication Administration
Dosing study medicationi
bid
bid
bid
bid
bid
bid
Provision of study 
medication for daily use at 
homej
X
Document dosingk
bid
bid
bid
bid
bid
bid
Efficacy Assessments
Clinical evaluationl
X
X
X
X
X
X
(X)m
Clinician PRESORS
X
X
X
X
X
X
X
Parent(s)/caregiver(s) 
PRESORSn
X
bid
bid
bid
bid
bid
bid
bid
bid
bid
X
Xo
Temperature log 
completionp
X
bid
bid
bid
bid
bid
bid
bid
bid
bid
X
X


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Status: Approved,  Date: 13 July 2020
Phase
Screening 
Phase
Treatment Phase
Follow-upb
Dayc
-1 to 1d
1
2
3
4
5 (±1)
6-7
8 (+1)
9-13
14 
(±1)
15-20
21 (±3)
22-27
28 (±3)
End-of-
study
On-site 
visit
Treat
ment
On-
site
On-
site 
visite
On-
site 
visite
On-
site 
visite
On-
site 
visite
On-site 
visite
Phone 
follow-up/ 
Conditional
f on-site 
visit
Monitoring of 
parent(s)/caregiver(s) 
PRESORS completion by 
site staff
Continuous
Mid-turbinate nasal 
swabq,r,s
Xt
X
X
X
X
X
X
X
X
X
Nasal swab log 
completion
X
X
X
X
Safety Assessments
Systolic and diastolic 
blood pressureu
X
X
X
X
X
X
(X)m
Directed physical 
examinationv
X
X
X
X
(X)m
ECG (triplicate 12-lead)w
X
Xx
Xx
X
Xx
(X)m,x
Clinical Laboratory Assessments
Blood sampling for 
hematology and 
biochemistryy
Xy
Xy
Xz
  (X)m,aa
Urinalysisbb
X
X
Xz
 (X)m,aa
Pharmacokinetics
Blood sampling for PK of 
JNJ-53718678cc
X
(X)
(X)
Ongoing Participant Review
Adverse events
Continuous
Concomitant medication
Continuous
(X)m
Footnotes:
a
For outpatients who are hospitalized during the course of the study, the reason for hospitalization should be recorded and every effort should be made by the 
investigator to perform all the assessments as indicated in the Schedule of Activities for hospitalized patients, if practically feasible.


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Status: Approved,  Date: 13 July 2020
b
In case participants prematurely discontinue study medication treatment for any reason (except withdrawal of consent), the parent(s)/caregiver(s) will be asked to 
continue with the participant’s remaining study visits and assessment schedule or, at a minimum, to return with the participant 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 participant’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.
c
Visit windows should be applied only for logistical reasons. There should be at least 1 day between 2 consecutive planned site visits.
d
Screening/predose assessments can only start after signing of the ICF for the interventional stage and before randomization. All screening/predose procedures 
should take place prior to the first study medication intake. For analysis purposes, the day of first study medication intake will be considered Day 1 of the 
interventional stage.
e
If feasible for the study site and if allowed per local regulations, home visits are allowed instead of on-site visits (although on-site visits are preferred).
f
In case a participant is experiencing (an) ongoing adverse event(s) or has clinically significant laboratory 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 participant at the site (preferred option) or, if 
feasible for the study site and if allowed per local regulations, at home on Day 28 (±3).
g
Investigators should ensure that all enrollment criteria for the interventional stage have been met at screening. If a participant’s clinical status changes (including 
any available laboratory results or receipt of additional medical records) after screening but before the first dose of study medication is given such that they no 
longer meet all eligibility criteria, they should be excluded from participation in the interventional stage of the study.
h
Randomization should occur within 32 hours after the receipt of the RSV mobile App alert. Randomization is to occur predose.
i
Study medication administration should start as soon as possible, but within 4 hours after randomization. Dosing should preferably occur approximately at the same 
time each day for both intakes (AM and PM). For participants 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 participants 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 medication can be administered with/without food. The study medication will be administered orally using a dosing syringe. 
j
Study site personnel will train participants’ parent(s)/caregiver(s) on how to use and store the study medication for at home dosing. Study medication will be 
provided at Day 1 in 1 single vial, from which the assigned volume is to be withdrawn each day, for the remainder of the study.
k
Date and time of study medication dosing and volume administered will be recorded in the eCRF or in the study medication log.
l
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. All clinical assessments should preferably be done when the infant is calm (ie, not crying or immediately after feeding).
m
Only applicable in case of on-site visit.
n
The first parent(s)/caregiver(s) PRESORS assessment of the bid schedule on Day 1 needs to be completed as close as feasibly possible and prior to the first 
administration of study medication. Detailed information is available in Section 8.3.3.
o
The parent(s)/caregiver(s) PRESORS have to be completed by the participant's parent(s)/caregiver(s) during Day 21 visit as the first activity of the visit prior to any 
other procedures. 
p
Body temperature to be measured and recorded by parent(s)/caregiver(s). In case antipyretics are used, body temperature should be measured immediately before or 
>4 hours after giving antipyretics.
q
One mid-turbinate nasal swab will be taken of which aliquots will be used for a central laboratory confirmation of RSV infection (Day 1 predose only), 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 co-pathogens (Day 1 predose only).
r
Mid-turbinate nasal swabs should be collected from the same nostril throughout the study (unless precluded due to bleeding). Nasal swabs will be collected daily 


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Status: Approved,  Date: 13 July 2020
through Day 8 in all participants. The investigator/study site personnel will train the parent(s)/caregiver(s) to collect the mid-turbinate nasal swab in case collection 
by a healthcare professional (HCP) is not possible. As of Day 8, in participants who were symptomatic based on the clinician PRESORS at Day 8, daily swabs will 
be collected through Day 13 or until the participant 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 mid-turbinate nasal swab will be collected during the scheduled visit for all participants. Detailed information on 
sample collection is available in Section 8.3.2.
s
Leftover mid-turbinate nasal swab samples may be used for exploratory biomarker analyses, at discretion of the sponsor.
t
The mid-turbinate nasal swab should be collected as close as possible and prior to the first administration of study medication (on Day 1). If the RSV-like ARI visit 
nasal swab taken at the site was taken less than 8 hours prior to start of dosing, then this sample can be used as the Day 1 predose sample, and no additional nasal 
sample needs to be collected at Day 1 predose. 
u
Systolic and diastolic blood pressure need to be measured supine (preferably the same position at each measurement) after at least 5 minutes of rest.
v
Directed physical examination includes respiratory system, nose, ear, throat, facial, and neck lymph nodes, and skin examination.
w
Triplicate 12-lead electrocardiograms (ECGs) will be obtained for central reading. 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 time point as other assessments, the ECG should be performed first.
x
At Day 1 and Day 3, triplicate ECGs should be obtained approximately one hour after administration of study drug. At Day 28, triplicate 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 to confirm abnormal ECG findings, 
unscheduled ECGs should be obtained.
y
Samples for clinical laboratory assessments, including for levels of potassium and magnesium, will be collected and analyzed at the local laboratory at the site. 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 and corrected to 
prevent cardiac disturbances. Appropriate clinical management per local SOC (including but not limited to checking the corrected values) may be required.
z
Assessments will only be performed in case of any clinically significant laboratory abnormalities observed at Day 8.
aa
Only to be performed in case any adverse event observed on Day 21 requires additional clinical laboratory assessments.
bb
Urinalysis will be performed by the local laboratory.
cc
A blood sample for determination of JNJ-53718678 concentrations will be collected by the site staff through finger prick or heel stick on Day 1 and Day 3 or Day 5. 
On Day 1, the PK samples should be collected approximately one hour after first administration of study drug (after the ECGs are obtained). On Day 3 or Day 5, the 
PK samples should be collected at least 4 hours after the AM and prior to the PM dosing on that day. Date and time of study medication intake, date and time of PK 
blood sampling, and time of meal if any in the time window of 30 minutes before and 30 minutes after study medication intake on the day of PK sampling need to 
be recorded. 
Note 1: Additional unscheduled visits in case of lab abnormalities, ECG abnormalities, need for clinical follow-up of (an) adverse event(s) can be scheduled at the
discretion of the investigator.
Note 2: Refer to Section 10.7, Appendix 7 for guidance on study conduct during the COVID-19 pandemic.


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Status: Approved,  Date: 13 July 2020
Part 2: Interventional Stage - Hospitalized Patients up to Dischargea
Phase
Screening 
Phase
Treatment Phase
Follow-upb
Day
-1 to 1c
1
2d
3
4-7
8 (+1)
9-13
14 (±1)
15-20
21 (±3)
22-27
28 (±3)
End-of-study
Phone follow-
up/ 
Conditionale
on-site visit
Study Procedures
Administrative
ICF for interventional stage of the study
X
Eligibility criteria
Xf
Participant characteristics and 
demographics
X
Medical history/prior medications
X
Randomization
Xg
Study Medication Administration
Dosing study medication and document 
dosingh
bid
bid
bid
bid
Provision of study medication or daily 
use at home at discharge, if applicablei
(X)
(X)
(X)
Efficacy Assessments
Clinical evaluationj
bid
bid
bid
bid
bid
bid
bid
bid
bid
(X)k
Clinician PRESORS
X
bid
bid
bid
bid
bid
bid
bid
X
X
Parent(s)/caregiver(s) PRESORSl
X
bid
bid
bid
bid
bid
bid
bid
X
Xm
Monitoring of parent(s)/caregiver(s) 
PRESORS completion by site staff
Continuous
Mid-turbinate nasal swabn,o,p
Xq
X
X
X
X
X
X
X
Safety Assessments
Systolic and diastolic blood pressurer
X
bid
bid
bid
bid
bid
bid
bid
bid
bid
(X)k
Directed physical examinations
X
X
X
X
(X)k
ECG (triplicate 12-lead)t
X
Xu
Xu
X
Xu
(X)k,u
Clinical Laboratory Assessments
Blood sampling for hematology and 
biochemistryv
Xv
Xv
Xw
(X)k,x
Urinalysisy
X
X
Xw
(X)k,x


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Status: Approved,  Date: 13 July 2020
Phase
Screening 
Phase
Treatment Phase
Follow-upb
Day
-1 to 1c
1
2d
3
4-7
8 (+1)
9-13
14 (±1)
15-20
21 (±3)
22-27
28 (±3)
End-of-study
Phone follow-
up/ 
Conditionale
on-site visit
Pharmacokinetics
Blood sampling for PK of 
JNJ-53718678z
X
(X)
(X)
Ongoing Participant Review
Adverse events
Continuous
Concomitant medication
Continuous
(X)k
Footnotes:
a
For participants who are discharged during the course of the study (as of Day 2), consecutive assessments should be performed according to the Schedule of 
Activities for hospitalized patients after discharge.
b
In case participants prematurely discontinue study medication treatment for any reason (except withdrawal of consent), the parent(s)/caregiver(s) will be asked to 
continue with the participant’s remaining study visits and assessment schedule, or, at a minimum, to return with the participant 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 participant’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.
c
Screening/predose assessments can only start after signing of the ICF for the interventional stage and before randomization. All screening/predose procedures 
should take place prior to the first study medication intake. If needed, and depending on the time of hospital admission, screening/predose assessments and 
establishment of eligibility can continue the next calendar day, in which case the first study medication intake will be on that day, immediately after establishing 
eligibility. For analysis purposes, the day of first study medication intake will be considered Day 1 of the interventional stage.
d
Participants can be discharged as of Day 2, if deemed appropriate by the investigator and after completion of the required investigator-performed assessments for 
that day, with exception of the evening bid assessments.
e
Participant’s parent(s)/caregiver(s) will be contacted by site staff for a telephone follow up visit. In case a participant is experiencing (an) ongoing adverse event(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.
f
Investigators should ensure that all enrollment criteria for the interventional stage have been met at screening. If a participant’s clinical status changes (including 
any available laboratory results or receipt of additional medical records) after screening but before the first dose of study medication is given such that they no 
longer meet all eligibility criteria, they should be excluded from participation in the interventional stage of the study.
g
Randomization should occur within 32 hours after the receipt of the RSV mobile App alert. Randomization is to occur predose.
h
Study medication administration should start as soon as possible, but within 4 hours after randomization. Dosing should preferably occur approximately at the same 
time each day for both intakes (AM and PM). For participants 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 participants receive 14 consecutive doses in total. Administration of the second dose may be delayed or brought forward 


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(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 medication can be administered with/without food. The study medication will be administered orally using a dosing syringe. Date and 
time of study medication dosing and volume administered will be recorded in the eCRF.
i
Study site personnel will instruct participants’ parent(s)/caregiver(s) on how to use and store the study medication for at-home dosing on the day of discharge, if 
applicable. Study medication 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 study.
j
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).
k
Only applicable in case of on-site visit.
l
The first parent(s)/caregiver(s) PRESORS assessment of the bid schedule on Day 1 needs to be completed as close as feasible and prior to the first administration of 
study medication. Detailed information is available in Section 8.3.3.
m
The parent(s)/caregiver(s) PRESORS have to be completed by the participant's parent(s)/caregiver(s) during Day 21 visit as the first activity of the visit prior to any 
other procedures. 
n
One mid-turbinate nasal swab will be taken of which aliquots will be used for a central laboratory confirmation of RSV infection (Day 1 predose only), 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 co-pathogens (Day 1 predose only).
o
Mid-turbinate nasal swabs should be collected from the same nostril throughout the study (unless precluded due to bleeding). Nasal 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 8.3.2.
p
Leftover mid-turbinate nasal swab samples may be used for exploratory biomarker analyses, at discretion of the sponsor.
q
The mid-turbinate nasal swab should be collected as close as possible and prior to the first administration of study medication (on Day 1). If the RSV-like ARI visit 
nasal swab taken at the site was taken less than 8 hours prior to start of dosing, then this sample can be used as the Day 1 predose sample, and no additional nasal 
sample needs to be collected at Day 1 predose.
r
Systolic and diastolic blood pressure need to be measured supine (preferably the same position at each measurement) after at least 5 minutes of rest.
s
Directed physical examination includes respiratory system, nose, ear, throat, facial, and neck lymph nodes, and skin examination.
t
Triplicate 12-lead ECGs will be obtained for central reading. 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 time point as other assessments, the ECG should be performed first.
u
At Day 1 and Day 3, triplicate ECGs should be obtained approximately one hour after administration of study drug. At Day 28, triplicate 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 to confirm abnormal ECG findings, 
unscheduled ECGs should be obtained.
v
Samples for clinical laboratory assessments, including for levels of potassium and magnesium, will be collected and analyzed at the local laboratory at the site. 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 and corrected to 
prevent cardiac disturbances. Appropriate clinical management per local SOC (including but not limited to checking the corrected values) may be required.
w
Assessments will only be performed in case of any clinically significant laboratory abnormalities observed at Day 8.
x
Only to be performed in case any adverse event observed on Day 21 requires additional clinical laboratory assessments.
y
Urinalysis will be performed by the local laboratory.
z
A blood sample for determination of JNJ-53718678 concentrations will be collected by the site staff through finger prick or heel stick on Day 1 and on Day 3 or 
Day 5. On Day 1, the PK samples should be collected approximately one hour after first administration of study drug (after the ECGs are obtained). On Day 3 or 


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Day 5, the PK samples should be collected at least 4 hours after the AM and prior to the PM dosing on that day. Date and time of study medication intake, date and 
time of PK blood sampling, and time of meal if any in the time window of 30 minutes before and 30 minutes after study medication intake on the day of PK 
sampling need to be recorded.
Note 1: Additional unscheduled visits in case of lab abnormalities, ECG abnormalities, need for clinical follow-up of (an) adverse event(s) can be scheduled at the 
discretion of the investigator.
Note 2: Refer to Section 10.7, Appendix 7 for guidance on study conduct during the COVID-19 pandemic.


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Part 2: Interventional Stage - Hospitalized Patients after Dischargea
Phase
Treatment Phase
Follow-upb
Day
2
3
4
5 (±1)
6-7
8 (+1)
9-13
14 
(±1)
15-20
21 
(±3)
22-27
28 (±3) 
End-of-study
On-
site 
visitc
On-
site 
visitc
On-
site 
visitc
On-
site 
visitc
On-
site 
visitc
Phone follow-
up/
Conditionald
on-site visitc
Study Procedures
Study Medication Administration
Dosing study medication and document 
dosinge
bid
bid
bid
bid
Efficacy Assessments
Clinical evaluationf
X
X
X
X
X
(X)g
Clinician PRESORS
X
X
X
X
X
Parent(s)/caregiver(s) PRESORS
bidh
bidi
bidi
bidi
bidi
bidi
bidi
bidi
X
Xj
Temperature log completionk
bidh
bidi
bidi
bidi
bidi
bidi
bidi
bidi
X
X
Monitoring of parent(s)/caregiver(s) 
PRESORS completion by site staff
Continuous
Mid-turbinate nasal swabl,m
X
X
X
X
X
X
X
X
Nasal swab log completion
X
X
X
Safety Assessments
Systolic and diastolic blood pressuren
X
X
X
X
X
(X)g
Directed physical examinationo
X
X
X
X
(X)g
ECG (triplicate 12-lead)p
Xq
X
Xq
(X)g,q
Clinical Laboratory Assessments
Blood sampling for hematology and 
biochemistryr
Xr
Xs
(X)g,t
Urinalysisu
X
Xs
(X)g,t
Pharmacokinetics
Blood sampling for PK of 
JNJ-53718678v
(X)
(X)
Ongoing Participant Review
Adverse events
(X)
Continuous
Concomitant medication
(X)
Continuous
(X)g


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Footnotes:
a
When participants are rehospitalized during the course of the study, the reason for hospitalization should be recorded and every effort should be made by the 
investigator to perform all the assessments as indicated in the Schedule of Activities for hospitalized patients, if practically feasible.
b
In case participants prematurely discontinue study medication treatment for any reason (except withdrawal of consent), the parent(s)/caregiver(s) will be asked to 
continue with the participant’s remaining study visits and assessment schedule, or, at a minimum, to return with the participant 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 participant’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.
c
If feasible for the study site and if allowed per local regulations, home visits are allowed instead of on-site visits (although on-site visits are preferred).
d
Participant’s parent(s)/caregiver(s) will be contacted by site staff for a telephone follow up visit. In case a participant is experiencing (an) ongoing adverse event(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 participant 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.
e
Dosing should preferably occur approximately at the same time each day for both intakes (AM and PM). For participants 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 participants receive 14 consecutive doses in total. The study 
medication can be administered with/without food. The study medication will be administered orally using a dosing syringe. Date and time of study medication 
dosing and volume administered will be recorded in the eCRF or in the study medication log.
f
Clinical evaluation includes measurements/evaluations of respiratory rate, heart rate, body temperature, and SpO2, need for and duration of rehospitalization, 
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).
g
Only applicable in case of on-site visit.
h
The morning assessment needs to be done prior to discharge and the evening one should be done at home.
i
If the participant is discharged prior to completion of the last assessment of the bid schedule, this last assessment should be performed at home.
j
The parent(s)/caregiver(s) PRESORS have to be completed by the participant's parent(s)/caregiver(s) during Day 21 visit as the first activity of the visit prior to any 
other procedures.
k
Body temperature to be measured and recorded by parent(s)/caregiver(s). In case antipyretics are used, body temperature should be measured immediately before or 
>4 hours after giving antipyretics.
l
Mid-turbinate swabs should be collected from the same nostril throughout the study (unless precluded due to bleeding). After discharge, nasal swabs will be 
collected daily through Day 8 in all participants. As of Day 8, in participants who were symptomatic based on the clinician PRESORS at Day 8, daily nasal swabs 
will be collected through Day 13 or until the participant 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 mid-turbinate nasal swab will be collected during the scheduled visit for all participants. Detailed 
information on sample collection is available in Section 8.3.2.
m
Leftover mid-turbinate nasal swab samples may be used for exploratory biomarker analyses, at discretion of the sponsor.
n
Systolic and diastolic blood pressure need to be measured supine (preferably the same position at each measurement) after at least 5 minutes of rest.
o
Directed physical examination includes respiratory system, nose, ear, throat, facial, and neck lymph nodes, and skin examination.
p
Triplicate 12-lead ECGs will be obtained for central reading. 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.


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q
At Day 3, triplicate ECGs should be obtained approximately one hour after administration of AM study drug. At Day 28, triplicate 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 to confirm abnormal ECG findings, unscheduled
ECGs should be obtained.
r
Samples for clinical laboratory assessments, including for levels of potassium and magnesium, will be collected and analyzed at the local laboratory at the site. In 
case of hypokalemia or hypomagnesemia at Day 8, the levels of potassium and magnesium should be checked as soon as possible and corrected to prevent cardiac 
disturbances. Appropriate clinical management per local SOC (including but not limited to checking the corrected values) may be required.
s
Assessments will only be performed in case of any clinically significant laboratory abnormalities observed at Day 8.
t
Only to be performed in case any adverse event observed on Day 21 requires additional clinical laboratory assessments.
u
Urinalysis will be performed by the local laboratory.
v
A blood sample for determination of JNJ-53718678 concentrations will be collected by the site staff through finger prick or heel stick on Day 3 or Day 5. The PK 
samples should be collected at least 4 hours after the AM and prior to the PM dosing on that day. Date and time of study medication intake, date and time of PK
blood sampling, and time of meal if any in the time window of 30 minutes before and 30 minutes after study medication intake on the day of PK sampling need to 
be recorded.
Note 1: Additional unscheduled visits in case of lab abnormalities, ECG abnormalities, need for clinical follow-up of (an) adverse event(s) can be scheduled at the 
discretion of the investigator.
Note 2: Refer to Section 10.7, Appendix 7 for guidance on study conduct during the COVID-19 pandemic.


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2.
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.5 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.1,26
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.27 RSV infection can cause 
considerable morbidity and mortality in certain patient populations such as infants19 where RSV 
can lead to 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.17,18
RSV is a major cause of hospital admissions and death in young children worldwide.19,23 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.6
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.24
On the other hand, among children <5 years of age with RSV infection, 97.7% present for 
medical care as outpatients in emergency departments (EDs) and in pediatric practices, while 
2.7% require hospitalization.9 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.15
These rates of visits for RSV-associated acute respiratory infections (ARIs) suggest that a major 
proportion of the burden of RSV results in outpatient visits among children beyond infancy.9
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.1,22 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.4,25 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 


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(prophylactically and therapeutically) is substantial in both children and adults with RSV 
infection, whether hospitalized or outpatients.
RSV-related acute respiratory tract infection in children is often a self-resolving disease that 
mostly occurs at home, imposing a high burden on family and society. Although virtually all 
children will have been infected with RSV at least once by the age of 2 years,8 there is still 
limited parental awareness about RSV disease. 
The duration and level of distress and anxiety of the parent/caregiver due to severe RSV 
infection are underestimated.16 Bronchiolitis symptoms usually peak around Day 3 to Day 5 and 
in case of early presentation (Day 2) at the general practitioner or ED, it can be expected that the 
child may get worse before getting better. Furthermore, about half of the children who develop 
severe disease do so after their first ED visit, often in the absence of clear instructions for parents 
when discharged home.3 Current guidelines recommend that the parents monitor the child at 
home pre- and post-discharge, with focus on severe to very severe symptoms, while most 
children present moderate to severe disease resulting in high discomfort for child and family.20,21
Therefore, there is a need to improve RSV disease symptom awareness and appropriate 
mobilization of parent/caregivers to present their infant for medical care at the onset of disease, 
to allow the optimal timing of new antiviral therapeutic interventions based on primary antiviral 
activity.
2.1.
Study Rationale
RSV is considered the most important virus causing acute LRTI and a major cause of hospital 
admissions and death in young children worldwide.19,23 Infants born prematurely or close to the 
RSV circulation and/or suffering from bronchopulmonary dysplasia or congenital heart disease 
have the highest risk of developing severe RSV-related acute LRTI. At the time of RSV intercept 
when the infants are brought in (on the parent/caregiver’s initiative) for medical care for an ARI, 
the RSV viral load is mostly already past its peak and declining7, whereas the disease can still 
evolve. In order to have a significant effect on the disease severity, treatment needs to be started 
as soon as possible to prevent further replication of the virus and the ensuing inflammatory 
response leading to the clinical signs/symptoms and to maximize the potential for the study 
medication to exert its antiviral effects, thereby affecting the clinical course of the disease.
This study is designed to assess in the setting of a planned early interception of pediatric RSV 
disease, early viral and disease kinetics (observational stage) and the antiviral effects of an RSV 
fusion inhibitor, JNJ-53718678 (interventional stage). In the observational stage the infant is 
closely monitored for early symptoms by the parent(s)/caregiver(s) and thus may be brought in 
for diagnosis earlier than in the typical setting.
2.2.
Background
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.2,17 JNJ-53718678 is an investigational RSV specific fusion inhibitor 
belonging to the indole chemical class and is under development for the treatment of RSV 


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infection. The study medication 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 participants hospitalized due to RSV-infection (Study 
53718678RSV1005).
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 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 medication 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, 


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but not at 1 and 3 μM. When JNJ-53718678 was administered intravenously (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 were increased at all doses 
in most dogs and blood pressure 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 of 25 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% 
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-


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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 
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 


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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 
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 


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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 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.
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 body weight 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, AST and decreased albumin. Red blood cell (RBC) parameters and 
platelets were decreased while reticulocytes were increased. Changes in white blood cell (WBC) 
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, body weight loss in relation with 
decreased 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 body weight gain values and minor 


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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 WBCs and RBCs, leading to 
hemosiderin deposition in the liver and adaptive changes in hematopoietic organs (bone marrow 
[BM], spleen). The effects on WBCs and RBCs 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 body weight 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 body weight
gains were observed.
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 body weight 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 


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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 body weight 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 body weight 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.
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.


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Clinical Studies
Human Pharmacokinetics and Product Metabolism
Single Dose 
In the single-dose escalation 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 participants.
In Study 53718678RSV1009, the effect of JNJ-53718678 on the cardiac repolarization interval 
in healthy adult participants was evaluated with dosing up to 4,500 mg. Part 1 of the study was 
the dose escalation part; based on the PK and safety results of Part 1, the supratherapeutic dose 
of 4,500 mg was selected for Part 2 of the study, the thorough QT (TQT) part. Exposure-
response analysis was performed to determine the relationship between the concentrations of 
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 placebo-corrected change from baseline 
for the 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.14 A change to a twice daily (bid) dosing regimen (see 
Section 4.3) and several other mitigation measures to safeguard the participants (see 
Section 2.3.5) have been implemented.
Multiple Dose
Adult Population
In the multiple-dose escalation part of Study 53718678RSV1001 in adult participants under fed 
conditions, predose plasma concentrations (Ctrough) reached steady state after 1 day of treatment 
with 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 qd 


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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 participants, the pharmacokinetic (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 participants inoculated with RSV-A Memphis 37b virus. The PK results from this 
study were consistent with those from corresponding regimens in Study 53718678RSV1001, 
indicating that viral infection did not affect the PK of 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, minimum plasma concentration (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 hour to 3.5 hours when JNJ-53718678 was administered under 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.
Bioavailability of the JNJ-53718678 Oral Suspension
The interim PK results from the study part evaluating the oral suspension in the ongoing 
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-.


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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. 
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 participants inoculated with RSV-A Memphis 37b 
virus, mean and median RSV viral load AUC from baseline until discharge were lower for all 


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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 participants 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 participants 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 participants receiving the oral 
solution, no deaths or other serious adverse events (AEs) were reported; 4 participants
discontinued study treatment due to an AE. Among participants who received at least 1 dose of 
JNJ-53718678, 70% experienced an AE as compared to 46.7% of all participants 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 participant who received placebo was reported with a Grade 3 
headache in Study 53718678RSV1001. AEs observed more frequently (difference in incidence 
of ≥5%) in participants who had received at least 1 dose of JNJ-53718678 compared to 
participants 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 participants receiving JNJ-53718678 and in 
none of the participants of the placebo group and was related to the bitter taste of the oral 
JNJ-53718678 solution. This 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 multiple 


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dose escalation (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 participants who had received 
at least 1 dose of JNJ-53718678 compared to participants 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 participants 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 participants and 
were considered generally clinically insignificant. These were either Grade 1 or Grade 2 in 
severity, except for 1 participant 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 participants receiving JNJ-53718678 
compared to participants receiving placebo.
No prolongations of the QT interval corrected for heart rate according to Fridericia's formula 
(QTcF) were reported. Changes in 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 participants inoculated with RSV, 
JNJ-53718678 at single doses up to 1,000 mg JNJ-53718678 and multiple doses up to 500 mg 
JNJ-53718678 qd and 250 mg JNJ-53718678 bid, 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 participants (n=12) from the study part evaluating the oral suspension in the ongoing Study 
53718678RSV1007, 10 participants (76.9%) were reported with at least 1 AE. The incidence of 
AEs was similar between the different treatments: 5 (41.7%) participants receiving the oral 
solution and 6 (50%) and 4 (30.8%) participants 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 reported AEs (reported in ≥3 participants) were 
diarrhea (3 participants [25.0%] receiving the JNJ-53718678 oral solution, 1 participant [8.3%] 
receiving the suspension under fasted conditions, and 1 participant [7.7%] receiving the 
suspension under fed conditions) and oropharyngeal pain (1 participant [8.3%] receiving the 


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JNJ-53718678 oral solution and 2 participants [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 participant who received the 
JNJ-53718678 suspension under fasted conditions and 1 other participant 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 
medication. 
Abnormalities in vital signs and ECG-parameters were observed in few participants
(2 participants 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 participants. 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 participants. No clinically significant safety findings 
were identified in any participants 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 
participants 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 participants
who received placebo. Diarrhea, nausea, and headache were more frequently observed in 
participants who received JNJ-53718678 compared to participants who received placebo.
Safety results from Part 2 (TQT part) of Study 53718678RSV1009 demonstrated that JNJ-
53718678 was generally safe and well tolerated in healthy adult participants. 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 participants:

One participant 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 participant 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 participant 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%) participants after receiving 500 mg JNJ-53718678, 
22 (88.0%) participants after receiving 4,500 mg JNJ-53718678, 9 (39.1%) participants after 
receiving placebo, and 12 (50.0%) participants after receiving 400 mg moxifloxacin. During the 
treatment phase, diarrhea, nausea, and headache were more frequently observed in participants
who received 4,500 mg of JNJ-53718678 compared to participants 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.14 A change to a bid dosing regimen (see Section 4.3) and several other mitigation 
measures to safeguard the participants (see Section 2.3.5) 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 participant, 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 participants (4,500 mg JNJ-53718678 and placebo) had an abnormal QTcF value 
between 450 and 480 ms, leading to early study discontinuation for 1 participant due to AE.

Six participants 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 participants 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 the 
study. Overall, 55.6% of participants 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 participants (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 
participants. 
Pediatric Population
In Study 53718678RSV1005 in pediatric participants receiving the oral solution, no deaths, 
Grade 4 AEs, or AEs leading to study discontinuation or permanent stop of study medication
were reported. Four SAEs 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 medication. The majority of participants were reported with at least 1 AE, at 
similar incidence rates in both treatment arms (28/37 participants [75.7%] in the JNJ-53718678 
[combined) treatment group vs 6/7 participants [85.7%] in the placebo group, respectively). Most 
of the reported AEs were Grade 1 or Grade 2 in severity. Two Grade 3 (severe) AEs were 
reported (both bronchiolitis; 1 each in the 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 participants receiving 
JNJ-53718678 (reported in ≥10% of participants) were vomiting, upper respiratory tract 
infection, and feces soft. AEs reported in ≥10% (ie, ≥4 participants) of participants receiving 
JNJ-53718678 that were considered by the investigator to be at least possibly related to study 
medication 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 medication 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 participant (placebo) was reported with the Grade 1 
AE of tachycardia considered not related to study medication by the investigator. ECG 
abnormalities were scarce and generally not considered clinically relevant. One participant
(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 medication by the 
investigator. No QTcF prolongation was reported.
Interim analysis of Study 53718678RSV2002 in RSV-infected children ≥28 days and ≤3 years of
age 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.


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Overall, treatment with JNJ-53718678 was generally safe and well tolerated in pediatric 
participants and no safety signals arose in pediatric participants compared to the previously 
established safety profile in adults.
For the most comprehensive nonclinical and clinical information regarding JNJ-53718678, refer 
to the latest version of the Investigator's Brochure (IB) for JNJ-53718678.13
The term “study medication” throughout the protocol, refers to JNJ-53718678 or placebo.
The term "sponsor" used throughout this document refers to the entities listed in the Contact 
Information page(s), which will be provided as a separate document.
2.3.
Benefit-Risk Assessment
2.3.1.
Known Benefits
The potential benefit for participants participating in the observational stage of the study is to be 
diagnosed early with RSV, with a closer follow-up on respiratory symptoms. Even if not 
participating in the interventional stage, the parent(s)/caregiver(s) gets more awareness about the 
disease and is aware of potential risks if the infant's health condition is getting worse after 
diagnosis.
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 2.2). However, the clinical benefit of this compound remains 
to be established.
2.3.2.
Potential Benefits
Subjects participating in the interventional stage of 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 participants’ return to pre-RSV health status. Results 
from the proposed study may be useful in developing a new antiviral therapy for RSV infection.
2.3.3.
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.
2.3.4.
Potential Risks for Study Participation
All therapies have the potential to cause adverse experiences.


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During completed studies 53718678RSV1001, 53718678RSV1002, 53718678RSV1004, 
53718678RSV1006, 53718678RSV1008, and 53718678RSV2001, a total of 190 participants
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 bid) for up to 13 days. Of those, 106 were healthy adult participants and 50 were healthy 
adult 
participants
who 
were 
inoculated 
with 
RSV-A 
Memphis 
37b 
virus. 
In 
Study 53718678RSV1003, 12 participants 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 participants received 
the JNJ-53718678 oral solution and the JNJ-53718678 oral suspension.
During Study 53718678RSV1005, 44 pediatric participants hospitalized due to RSV-infection 
were enrolled, of which 37 participants received JNJ-53718678 (oral solution) and 7 received 
placebo. 
Please refer to Section 2.2 for details on the reported AEs and laboratory/ECG abnormalities in 
the studies conducted to date.
Based upon the 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.
Review of data of the TQT Study 53718678RSV1009, has identified a new important potential 
risk of QT prolongation for JNJ-53718678 (see Section 2.2 and the IB Addendum14 for more 
information). Therefore, a change in dose regimen (see Section 4.3) and several other measures 
to safeguard the participants (see Section 2.3.5) 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 participants. Most AEs were mild, with diarrhea 
being the most frequently reported AE. No Grade 3 or 4 AEs were reported during this study. 
From a clinical safety perspective, no clinically relevant ECG abnormalities (related to QTcF or 
other) or 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 ΔΔQTcI above the threshold of 10 ms can be expected (Section 2.2).


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Available clinical safety data do not indicate any safety signal or concern with regards to the 
cardiovascular system (Section 2.2).
Study treatment will be provided in addition to, not in replacement of, standard-of-care 
supportive and symptomatic therapy.
Study procedures such as blood sampling carry a potential risk (eg, pain, discomfort, hematoma) 
to the participant. Therefore, minimal volumes of blood (by venipuncture or by finger or heel
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 participants while performing these assessments. 
The risks of (optional) venous blood draws, finger prick, or heel stick include discomfort at the 
site of puncture; possible bruising and swelling around the puncture site; rarely an infection; and 
uncommonly, dizziness, nausea, and vomiting.
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 
participant and is usually well tolerated, though occasionally nose bleeding can occur. Examples 
of other AEs that may occur, but are not considered serious, are: coughing, gagging, nausea, and 
vomiting; and a small amount of pain or discomfort during swabbing.
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 participant. 
The collection of saliva (buccal swab) and stool are not expected to result in AEs, as these are 
non-invasive, patient friendly sampling procedures.
Considering the above, participation in the study does not represent a potential for serious risk to 
the health, safety and welfare of the parent(s)/caregiver(s) nor infant. The parent(s)/caregiver(s)
will be informed that in case of emergency and/or if they have any questions regarding medical 
care or treatment they need to contact the treating physician during the observational stage, and 
the site investigator during the interventional stage directly.
Participation in the observational stage of this study will not interfere with any medical decision, 
such as the decision to hospitalize the infant, or with the infant’s standard-of-care medical 
management. Participants will be treated according to the normal standard of care for their RSV 
infection. The decision of the parent(s)/legally acceptable representative(s) to allow or not allow 
the participation of the infant in the study will have no influence on any clinical decision. Based 
on the data entered by the parent(s)/caregiver(s), the parent(s)/caregiver(s) will be invited to 
perform a study visit with their infant. During that study visit (RSV-like ARI visit) a study-
related rapid RSV molecular-based diagnostic assay will be performed to decide whether to 
initiate daily nose swab sampling over 7 more ensuing days (up to and including Day 8) for 


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investigation of the correlation between viral load and disease evolution. Within this time 
interval, in the majority of patients the RSV disease will have resolved. Study assessments will 
be performed in addition to, not in replacement of, standard-of-care supportive and symptomatic 
therapy.
2.3.5.
Benefit-Risk Assessment for Study Participation
Part 1: Observational Stage
The overall risk/benefit for the observational stage of the study is acceptable, due to the limited 
risk related to the study procedures and sample collection, and the potential benefit related to the 
increased awareness of parents/caregivers of respiratory symptoms. 
Part 2: Interventional Stage
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 participants (Study 53718678RSV1005) (Section 2.2);

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 2.2);

No safety concerns were identified in the interim analysis of Study 53718678RSV2004 in 
non-hospitalized adult participants infected with RSV (Section 2.2);

Available final data from the ongoing 53718678RSV1005 study in naturally RSV-infected 
pediatric participants >1 month to ≤24 months of age and from an interim analysis of Study 
53718678RSV2002 in RSV-infected children ≥28 days and ≤3 years of age did not indicate 
safety concerns (Section 2.2); 

Several safety measures have been proposed to minimize potential risk to participants, 
including:

Only participants who meet all of the inclusion criteria and none of the exclusion 
criteria (as specified in the protocol) will be allowed to participate in the interventional 
stage of the study. The selection criteria include adequate provisions to minimize the 
risk and protect the well-being of the participants in the study.

Utilization of study treatment discontinuation criteria and stopping criteria 
(see Sections 7.1 and 7.2).

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 
participants.


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
The establishment of an Independent Data Monitoring Committee (IDMC) to monitor 
data on a regular basis to ensure continuing safety of the participants enrolled in the 
interventional stage of the study.

Customary measures taken by investigational staff to ensure that study-specific 
assessments such as blood sampling and nasal swabbing are performed with as little 
additional stress as possible for the infants and allowance of the use of local anesthetics 
prior to blood sampling.

In view of the identified important potential risk of QT interval prolongation (see 
Section 2.2, TQT Study 53718678RSV1009), the following measures have been 
implemented to minimize the potential risk to participants:

The selection of the bid dose regimens which, relative to the respective qd dose 
regimens for which no safety concern was identified, will minimize Cmax while still 
maintaining AUC and increasing Ctrough (see Section 4.3).

Specific cardiovascular and ECG-based criteria were established for eligibility 
assessment (see Section 5).

Close monitoring of the use of concomitant medications will be conducted regularly. 
Drugs that are moderate or strong CYP3A4 inhibitors and BCRP inhibitors will be 
disallowed (see Section 6.5).

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 Schedule of Activities (SoA). 
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 7).

Close monitoring of hypokalemia and hypomagnesemia and corrective actions in case 
of laboratory abnormalities for these analytes during the treatment period (see 
Section 8.5).

Newly administered QT prolonging drugs will be disallowed during the treatment 
period (see Section 6.5).

Specific toxicity management for cardiac and ECG related events was established (see 
Section 8.5).
Taking into account the measures taken to minimize risk to participants participating in this 
study, the potential risks identified in association with participation in this study and in 
association with JNJ-53718678 are justified by the anticipated benefits that may be afforded to 
participants with RSV disease.


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3.
OBJECTIVES AND ENDPOINTS
3.1.
Objectives
Part 1: Observational Stage
The objectives applied to the observational stage are to evaluate:

the onset and evolution of clinical symptoms of pediatric RSV disease

the relationship between viral load and clinical symptoms at early diagnosis of pediatric 
RSV disease
The exploratory objectives applied to the observational stage are to evaluate:

the characteristics of the scores that trigger a site-visit in relation to:

RSV diagnosis

the progression of clinical symptoms

viral kinetics

participation in the interventional stage

the correspondence between disease characteristics as assessed at the site with scores as 
assessed by parent(s)/caregiver(s) in the RSV mobile Application (App) and Pediatric RSV 
Electronic Severity and Outcome Rating System (PRESORS)

parent(s)/caregiver(s) baseline characteristics in relation to operational features such as:

enrollment in observational stage

RSV mobile App compliance

protocol adherence

enrollment in interventional stage

the analysis of stool microbiome profiles (in optional samples) in relation to RSV disease
Part 2: Interventional Stage
Primary Objective
The primary objective is to evaluate 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 an early intervention setting in infants (≤4 months of age at 
enrollment) recruited from a birth cohort.
Secondary Objectives
The secondary objectives are to assess:

the impact of treatment with JNJ-53718678 on the clinical course of RSV infection


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
the safety and tolerability of JNJ-53718678 after repeated oral doses

the PK of JNJ-53718678 after repeated oral doses
Exploratory Objectives
The exploratory objectives are to assess:

the impact of baseline characteristics on antiviral activity and clinical course, including but 
not limited to:

baseline viral load

disease severity 

hospitalized participants vs outpatients 

parental history of atopy

randomization within 24 hours of ARI alert vs. ≥24 hours

the relationship between the PK and antiviral activity 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 RSV infectious virus titer as assessed by quantitative culture of RSV (plaque assay) on 
selected nasal swab samples (optional objective, pending feasibility of performing such an 
assay)
3.2.
Endpoints
Part 1: Observational Stage
The endpoints applied to the observational stage:

the total score, over time, of respiratory symptoms as captured by the RSV mobile App 
during the pre-diagnostic phase and the post-diagnostic phase for RSV(+) participants that 
do not enter in the interventional stage

the PRESORS scores by the clinician (clinician PRESORS) on the day of RSV diagnosis 

RSV viral load kinetics during the pre-diagnostic phase

RSV viral load kinetics from Day 1 to Day 8 after RSV diagnosis over time (if not 
participating in the interventional stage)

the PRESORS scores by parent(s)/caregiver(s) (parent[s]/caregiver[s] PRESORS) over time
The endpoints applied to the exploratory objectives of the observational stage are:

the frequency and severity of individual symptoms based on the RSV mobile App, over time 

the frequency and severity of clinician recorded symptoms based on the PRESORS assessed 
by the investigator (clinician PRESORS) on the day of RSV diagnosis 


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
the individual signs and symptoms and total score that triggered the site visit

participation in the interventional stage

correspondence of disease characteristics as assessed by the investigator at the site and 
scores as assessed by parent(s)/caregiver(s)

characteristics of parent(s)/caregiver(s) (optional) and infant at baseline in relation to (but 
not limited to) enrollment rate in birth cohort, RSV mobile App compliance, protocol 
adherence, enrollment in interventional stage
Part 2: Interventional Stage
Primary Endpoint
The primary efficacy endpoint is the RSV viral load area under the curve (AUC) from 
immediately prior to first dose of study medication 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 (start of study medication) over time

RSV viral load AUC from immediately prior to first dose of study medication (baseline) 
through Day 3, Day 8, and Day 14

time to undetectable RSV viral load

proportion of participants with undetectable RSV viral load at each time point throughout 
the study

clinical course related endpoints:
the following endpoints will be based on the PRESORS assessed throughout the interventional 
stage of 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 assessed 
throughout the study by parent(s)/caregiver(s) PRESORS

change from baseline in parent(s)/caregiver(s) PRESORS (worsening or 
improvement)

change from baseline in clinician PRESORS (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 participants with improvement or worsening of RSV disease 
based on general questions on overall health on each study day from screening 
till Day 21

time to return to pre-RSV health as rated by the parent(s)/caregiver(s)


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respiratory rate, heart rate, body temperature, and peripheral capillary oxygen saturation (SpO2) 
over time as measured during scheduled visits
need for (re)hospitalization during treatment and follow-up

safety and tolerability, as assessed by AEs, clinical laboratory testing, ECGs, and vital signs, 
throughout the interventional stage of the study

PK parameters of JNJ-53718678, as determined by popPK modeling
Exploratory Endpoints

clinical course related endpoints:

in hospitalized participants:
time to age-adjusted normal values for otherwise healthy and to pre-RSV infection status for 
participants 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)
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)
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
need for and duration of supplemental oxygen (regardless of method used); ‘need for 
supplemental oxygen’ is defined by:

requiring invasive mechanical ventilation

receiving 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
need for and duration of noninvasive ventilator support (eg, continuous positive airway pressure) 
and/or invasive ventilator support (eg, endotracheal-mechanical ventilation)
need for hydration and/or feeding by IV administration or nasogastric tube; need for defined by 
<50% of normal oral intake
time to clinical stability, defined as the time from initiation of study medication 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 participants 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 participants and 
participants with (a) risk factor(s) for severe RSV disease
AND

no more IV/nasogastric tube feeding/hydration in otherwise healthy 
participants 
or 
return 
to 
pre-RSV 
status 
of 
IV/nasogastric 
tube 
feeding/hydration in participants with (a) risk factor(s) for severe RSV disease
time from initiation of study medication until SpO2 ≥92% and SpO2 ≥95% on room air among 
participants who were not on supplemental oxygen prior to the onset of respiratory symptoms

changes from baseline in the RSV F-gene sequence (and potentially other regions of the 
RSV genome, at the discretion of the sponsor's virologist)

presence of pre-treatment RSV F-gene polymorphisms in relation to treatment outcome 

the occurrence of complications with onset after treatment initiation that are associated with 
RSV disease 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 disease per investigator 
assessment


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
virologic parameters derived from the RSV viral load as measured by quantitative viral 
culture (optional, pending feasibility of performing such an assay)
Refer to Section 8, Study Assessments and Procedures for evaluations related to endpoints.
HYPOTHESIS
Part 1: Observational Stage
For the observational stage no formal hypothesis will be tested.
Part 2: Investigational Stage
The primary hypothesis of this study is that JNJ-53718678 has antiviral activity against RSV as 
assessed by a reduction in RSV viral load AUC (from immediately prior to first dose of study 
medication [baseline] until Day 5) at the 5% level (one-sided) for JNJ-53718678 compared to 
placebo in participants recruited from a birth cohort.
4.
STUDY DESIGN
4.1.
Overall Design
This study is designed to assess the impact of early interception and intervention on antiviral 
activity and the clinical course of the disease. The study consists of 2 parts: an observational 
stage with a birth cohort and a Phase 2a, multicenter, randomized, double-blind, placebo-
controlled interventional stage.
A target of 1,300 infants (≤4 months of age at enrollment and asymptomatic for ARI-like 
symptoms requiring medical intervention at the time of consent) is planned to be enrolled 
globally in the observational stage of this study. In the observational pre-diagnostic phase, the 
study aims to record early signs and symptoms of potential RSV infections and is focused on 
bringing the infant in for assessment at a threshold score that is based on a combination of at 
least one sign of upper respiratory infection, any sign of lower respiratory involvement and any
sign of systemic impact (eg, feeding difficulty, disturbed sleep, disturbed activity level). All 
infants will be closely monitored for early signs and symptoms of RSV disease using a mobile 
RSV application a on the parent/caregiver's mobile phone (pre-diagnostic phase). For those 
infants with scores that cross the threshold score, an alert will be sent and they will be brought to 
the study site for an early diagnostic RSV test (diagnostic phase). Upon an alert, if a participant 
is SARS-CoV-2 positive assessed by local health practice, the participant will be withdrawn
from study. RSV negative participants (RSV[-] diagnosed at site) will return to the pre-
                                                
a Parents/caregivers will be informed that they should not hesitate to engage their physicians on any concerns on the 
health status of the child as the function of the RSV mobile App is to gather study information on disease signs 
and to mobilize infants with a predefined set of disease signs for on-site RSV diagnosis and evaluation if the 
criteria for proposing intervention with the study medication are met. The mobile App is in that respect a study 
tool and not designed as a medical decision instrument. The caretakers should at no moment hesitate to seek 
medical attention with their physician if they have any concerns about the health status of the infant irrespective 
of their involvement with the digital monitoring system in the observation stage of the study.


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diagnostic phase, and will be further closely monitored by the parent(s)/caregiver(s) through the 
RSV mobile App. There will be a 7-day pause in the RSV mobile App for the for the generation 
of alerts, after which the alert option will be switched back on. RSV positive participants 
(RSV[+] diagnosed at site) will be enrolled in the screening phase of the interventional stage of 
the study after obtaining informed consent for the interventional stage at that time. RSV(+) 
participants whose parent(s)/caregiver(s) do not consent for enrollment in the interventional 
stage and participants who are screening failures in the interventional stage will enter the post-
diagnostic phase of the observational stage (hospitalized or outpatients).
The interventional stage will consist of a screening phase, a treatment phase (hospitalized or 
outpatients), and a posttreatment follow-up phase. It is anticipated that approximately 40 RSV(+)
infants from the observational stage of the study will be enrolled in the interventional stage and 
will be randomized in a 1:1 ratio to receive either JNJ-53718678 or placebo bid for 7 days
(14 consecutive doses). For participants 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 
participants receive 14 consecutive doses in total. Antiviral activity, clinical outcomes, safety, 
tolerability, and PK of JNJ-53718678 in infants at early stage of an ARI due to RSV will be 
evaluated.
Study duration will be approximately 29 (±3) days after RSV(+) diagnosis for participants who 
enter the interventional stage, and 21 (±3) days after RSV(+) diagnosis for participants who do 
not enter the interventional stage (or 21 days [+2 weeks] in case optional stool samples will be 
collected [the additional time is only for optional stool sample assessments]). RSV(-) participants 
will be considered to have completed the study at the end of the RSV circulation. For RSV(-) 
participants for whom consent was given for the stool sample collection, the study ends either 
when the most relevant RSV surveillance data indicate that RSV is out of circulation or on the 
day of stool sample collection at the participant’s age of 4 months (±2 weeks), whichever is last.
The enrollment period for the observational stage will be guided by local RSV epidemiological 
distribution and dynamics. Start and end of the RSV circulation differs by region and will be 
dependent on the respective country/region where the study will be conducted. The 
determination by the sponsor to end the study will be done on a per-site basis in line with the 
local seasonality pattern.
The observational stage involves nasal swabbing for RSV diagnosis, viral assessments (RSV 
RNA viral load), exploratory biomarker analysis, blood sampling (optional) for exploratory 
biomarker analyses, stool sampling (optional) for microbiome analysis, buccal swab collection 
(optional) for exploratory host genetic analyses, and completion of questionnaires (evaluation 
questionnaires and PRESORS). PRESORS can be collected on paper or in an electronic device.
In the post-diagnostic phase of the observational stage, for the RSV(+) participants whose 
parent(s)/caregiver(s) do not consent for enrollment in the interventional stage and participants 
who are screening failures in the interventional stage, the parent(s)/caregiver(s) will be asked to 
continue with the twice daily RSV mobile app and to also complete the PRESORS over the same 
period.


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The interventional stage involves nasal swabbing, viral assessments (RSV RNA viral load, RSV 
subtype determination, and sequencing), blood sampling for PK, and completion of 
questionnaires (PRESORS).
An IDMC will be commissioned for this study. Refer to Committees Structure in Appendix 3, 
Regulatory, Ethical, and Study Oversight Considerations for details.
A diagram of the study design is provided in Section 1.2, Schema.
4.2.
Scientific Rationale for Study Design
The birth cohort design is intended to allow early interception and treatment when the 
therapeutic impact on viral proliferation as the initiator of the lung tissue damage occurs at a 
stage before the inflammatory response becomes the dominant driver of disease.
Blinding, Control, Study Phase/Periods, Intervention Groups
For the observational stage, a birth cohort, there will be no blinding and no treatment groups are 
defined. For the interventional stage a placebo control will be used to establish the frequency and 
magnitude of changes in clinical endpoints that may occur in the absence of active intervention. 
Randomization will be used to minimize bias in the assignment of participants to treatment 
groups, to increase the likelihood that known and unknown participant 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.
DNA and Biomarker Collection
Buccal swabs will be collected (optional) for exploratory host genetic analyses. It is recognized 
that genetic variation can be an important contributory factor to interindividual differences in 
intervention distribution and response and can also serve as a marker for disease susceptibility 
and prognosis. Host genetic research may help to explain interindividual variability in clinical 
outcomes and may help to identify population subgroups that respond differently to an 
intervention. The goal of the host genetic research component is to collect DNA to allow the 
identification of genetic factors that may influence the PK, pharmacodynamics (PD), efficacy, 
safety, or tolerability of JNJ-53718678 and to identify genetic factors associated with RSV 
disease. DNA collection is optional.
Biomarker samples (ie, blood and stool samples) will be collected to evaluate the mechanism of 
action of JNJ-53718678 or help to explain or predict interindividual variability in RSV disease 
characteristics and clinical outcomes or may help to identify population subgroups that respond 
differently to an intervention. The goal of the biomarker analyses is to evaluate the PD of 
JNJ-53718678 and aid in evaluating the intervention-clinical response relationship. Blood 
collection for biomarker analysis is optional.
DNA and biomarker samples may be used to help address emerging issues and to enable the 
development of safer, more effective, and ultimately individualized therapies.


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4.2.1.
Study-Specific Ethical Design Considerations
Potential participant’s parent(s)/legally acceptable representative(s) will be fully informed of the 
risks and requirements of each stage of the study and, during the study, they will be given any 
new information that may affect their decision to continue participation of their infant. They will 
be told that their consent to participate in the study is voluntary and may be withdrawn at any 
time with no reason given and without penalty or loss of benefits to which the infant would 
otherwise be entitled. Only infants whose parent(s)/legally acceptable representative(s) is/are 
fully able to understand the risks, benefits, and potential AEs of the study, and provide their 
consent voluntarily will be enrolled.
When referring to the signing of each informed consent form (ICF), the term legally acceptable 
representative(s) refers to the legally appointed guardian of the infant with authority to authorize 
participation in research. For each participant, his or her parent(s) (preferably both parents, if 
available) or legally acceptable representative(s), as required by local regulations, must give 
written consent (permission) according to local requirements after the nature of the study has 
been fully explained and before the performance of any study-related assessments.
The total blood volume to be collected is considered to be in line with generally acceptable 
guidelines for the collection of blood samples for this age group.
4.3.
Justification for Dose
The 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 Cmin and Cmax values within the range of the 
target concentrations (ie, the exposure observed in adults treated with 500 mg JNJ-53718678 qd), 
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 2.2).
Based on the exposure-response analysis conducted in the TQT Study 53718678RSV1009 in 
healthy adult participants, an exposure (Cmax) related important potential risk of QT interval 
prolongation was identified. While no safety signal was observed regarding QT prolongation, 
other ECG abnormalities, or cardiovascular side effects, additional 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 months of age, 
respectively) was selected with disallowance of comedication with moderate or strong CYP3A4 
inhibitors. Based on Table 1, 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 [paEC90]), ensuring 


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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.
Table 1:
Predicted Geometric Mean AUC24h, Cmax, Ctrough and QTcI Per Age Group After Day 1 and 
Day 7
Age Group
(Dose mg/kg bid)
1 - <3 Months
(2.5 mg/kg bid)
3 - <6 Months
(3 mg/kg bid)
≥6 Months
(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 (msec) (90%CI)
1.95 (0.97-3.66)
2.09 (1.08-3.98)
2.37 (1.19-4.62)
QTcI Day 7 (msec) (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.
4.4.
End of Study Definition
End of Study Definition
The end of the study is considered as the last scheduled study assessment shown in the Schedule 
of Activities for the last participant in the study with the determination by the sponsor to end the 
study taken on a per-site basis in line with the local RSV seasonality patterns. The final data 
from the study site (including any unshipped samples) will be sent to the sponsor (or designee) 
after completion of the final participant assessment at that study site.
Study Completion Definition
An RSV(+) participant who will not enter the interventional stage will be considered to have 
completed the observational stage of the study if he or she has completed assessments at Day 21
(±3 days) of the observational stage. Note that the end of study will be 21 days (+2 weeks) in 
case optional stool samples will be collected (the additional time is only for optional stool 
sample assessments).
An RSV(+) participant who will enter the interventional stage will be considered to have 
completed the interventional stage of the study if he or she has completed assessments at Day 28 
(±3 days) of the interventional stage.
An RSV(-) participant will be considered to have completed the study at the end of the RSV 
circulation. Start and end of the RSV circulation differs by region and will be dependent on the 
respective country/region where the study will be conducted. The determination by the sponsor 
to end the study will be done on a per-site basis in line with the local seasonality pattern.
For RSV(-) participants for whom consent was given for the stool sample collection, the study 
ends either when the most relevant RSV surveillance data indicate that RSV is out of circulation 


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or on the day of stool sample collection at the participant’s age of 4 months (±2 weeks), 
whichever is last.
At the end of the RSV circulation, the RSV mobile App will notify the parent(s)/caregiver(s) of 
an RSV(-) participant and will invite them to complete evaluation questions in which, among 
other things, their experience using the RSV mobile App will be documented. The evaluation 
questionnaire from the RSV mobile App will be sent to RSV(+) participants, who did not enter 
the interventional stage, after completion of the last PRESORS. 
5.
STUDY POPULATION
Infants ≤4 months of age are eligible for enrollment in the observational stage of the study. A 
target of 1,300 infants is planned to be enrolled globally in this study. 
The inclusion and exclusion criteria for enrolling participants in the observational stage and 
interventional stage of the study are described below. If there is a question about these criteria, 
the investigator must consult with the appropriate sponsor representative and resolve any issues 
before enrolling a participant in the study. Waivers are not allowed.
For a discussion of the statistical considerations of participant selection, refer to Section 9.1, 
Sample Size Determination.
5.1.
Inclusion Criteria
Part 1: Observational Stage
Each potential participant must satisfy all of the following criteria to be enrolled in the 
observational stage of the study:
1.
The infant is ≤4 months of age at enrollment and asymptomatic for ARI-like symptoms 
requiring medical intervention at the time of consent to participate in the study. 
2.
Participant’s parent(s) (preferably both if available or as per local requirements) or their 
legally acceptable representative(s) must sign an ICF (observational stage) indicating that 
he or she understands the purpose of, and procedures required for, the study and is willing 
to allow the infant to participate in the study and is willing/able to adhere to the study 
procedures and assessments to be performed by the parent(s)/caregiver(s) as well as those 
by the investigator/site staff.
3.
At least 1 parent/caregiver must be able to use the RSV mobile App at home via his/her 
own Android/iOS electronic device (compatible with RSV mobile App).
4.
At least 1 parent/caregiver should be of legal consent age (according to local regulation). 
5.
The participant must have been assessed per local public health practice and considered not 
to have SARS-CoV-2 infection.


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Part 2: Interventional Stage
Each potential participant must satisfy all of the following criteria to be enrolled in the 
interventional stage of the study:
1.
The participant has been diagnosed with RSV infection using a rapid molecular-based 
diagnostic assay. 
2.
Participant’s parent(s) (preferably both if available or as per local requirements) or their 
legally acceptable representative(s) has/have signed an ICF (interventional stage) 
indicating that he or she understands the purpose of, and procedures required for, the 
interventional stage of the study and is willing to allow the infant to be treated with 
JNJ-53718678 or placebo and is willing and able to adhere to the prohibitions and 
restrictions with regards to the concomitant medication (see Section 6.5), the lifestyle 
consideration (see Section 5.3), and study procedures and assessments to be performed by 
the parent(s)/caregiver(s) as well as those by the investigator/site staff.
Refusal to give consent for the interventional stage does not exclude a participant from 
continued participation in the observational stage of the study.
3.
The participant is at least 28 days old at the time of consent.
4.
Prematurely born infant (ie, <37 weeks and 0 days of gestation at birth) is at least 3 months 
postnatal age at time of consent.
5.
The participant weighs more than 2.4 kg.
6.
The participant has an acute respiratory illness during which (s)he experienced a period of 
apnea, 
OR
The participant has an acute respiratory illness with at least 1 of the signs/symptoms listed 
in each of the following categories at the moment of diagnosis, as evaluated by the 
investigator:
nasal congestion, rhinorrhea, pharyngitis, or otitis media; AND
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 or cough; AND
feeding difficulties, defined as <75% intake of normal food amounts; dehydration; 
fever; disturbed sleep or disturbed activity level (irritable/restless/agitated/less 
responsive).
7.
Except for the RSV-related illness, the participant must be medically stable based on 
physical examination, medical history, and vital signs performed at screening. If there are 
abnormalities, they must be consistent with the underlying condition (RSV disease and/or 
present risk factor[s] for severe RSV disease) in the study population as evaluated by the 
investigator. This determination must be recorded in the participant’s source documents 
and initialed by the investigator.
8.
The participant 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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5.2.
Exclusion Criteria
Part 1: Observational Stage
Any potential participant who meets any of the following criteria will be excluded from 
participating in the observational stage of the study:
1.
Inclusion in (maternal) RSV vaccine studies or RSV treatment studies.
2.
During the RSV circulation, the infant is experiencing ARI-like symptoms requiring 
medical intervention on the day of enrollment.
3.
Any condition for which, in the opinion of the investigator, participation would not be in 
the best interest of the participant (eg, compromise the well-being) or that could prevent, 
limit, or confound the protocol-specified assessments.
4.
The participant has any physical abnormality which limits the ability to collect regular 
nasal specimens.
5.
The participant is receiving chronic home oxygen therapy at enrollment.
Part 2: Interventional Stage
Any potential participant who meets any of the following criteria will be excluded from 
participating in the interventional stage of the study:
1.
The participant has major congenital anomalies or known cytogenetic or metabolic 
disorders other than the ones allowed below.
Note: Isolated open ductus arteriosus and open foramen ovale are not exclusionary as 
these are not considered major anomalies. Participants with congenital heart disease, 
cystic fibrosis, congenital diaphragmatic hernia, or Down Syndrome are allowed to 
participate.
2.
The participant is considered by the investigator to be immunocompromised, 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).
3.
The participant has known or clinically suspected hepatitis B or C infection, either acute 
or chronic active.
4.
The participant 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 IB13).
5.
The participant is unable to take medications orally or has a known gastrointestinal-related 
condition that is considered by the sponsor or investigator to be likely to interfere with 
study medication ingestion or absorption.
6.
The participant had major surgery within the 28 days prior to randomization or planned 
major surgery through the course of the study.


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7.
Criterion modified per Amendment 2.
7.1
The participant 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.
8.
Criterion modified per Amendment 2.
8.1
The participant has a QTcF interval >450 ms per the machine read (mean of triplicate) 
parameter result confirmed by repeat triplicate ECG recording during screening.
9.
The participant is using any disallowed medication as listed in Section 6.5.
10.
The participant 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.
11.
The participant has a personal or first- or second-degree family history of long QT 
syndrome or sudden cardiac death.
12.
The participant 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 Coronavirus Disease 2019 (COVID-19) (test 
confirmed or suspected SARS-CoV-2 infection) within 14 days prior to randomization.
Note: Investigators should ensure that all study treatment criteria have been met before the start 
of treatment. If a participant 's clinical status changes (including any available laboratory results 
or receipt of additional medical records) after diagnosis/randomization but before the first dose 
of study medication is given such that he or she no longer meets all eligibility criteria, then the 
participant should be excluded from participation in the study. 
The required source documentation to support meeting the enrollment criteria are noted in 
Appendix 3, Regulatory, Ethical, and Study Oversight Considerations.
5.3.
Lifestyle Considerations
The parent(s)/caregiver(s) has to complete the electronic questionnaire twice daily which takes a 
few minutes a day, depending on the symptoms. There are no other prohibitions or restrictions 
during this study, except with regards to the concomitant medication (Section 6.5).


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5.4.
Screen Failures
Participant Identification, Enrollment, and Screening Logs
The investigator agrees to complete a participant identification and enrollment log to permit easy 
identification of each participant during and after the study. This document will be reviewed by 
the sponsor study-site contact for completeness.
The participant identification and enrollment log will be treated as confidential and will be filed 
by the investigator in the study file. To ensure participant confidentiality, no copy will be made. 
All reports and communications relating to the study will identify participants by participant 
identification and age at initial informed consent. In cases where the participant is not enrolled 
into the study, the date seen and age at initial informed consent will be used.
Individuals who do not meet the criteria for participation in this study (screen failure) will not be 
rescreened. Participants who do not meet the criteria for participation in the interventional stage 
of the study will enter the post-diagnostic phase of the observational stage (hospitalized or 
outpatients).
6.
STUDY INTERVENTION
6.1.
Study Interventions Administered
No treatment is administered in the observational stage of the study.
In the interventional stage, eligible participants will be randomized 1:1 to receive either 
JNJ-53718678 or placebo. Randomization should occur within 32 hours after the receipt of RSV 
mobile App alert. The randomization will be stratified based on the time between ARI alert and 
randomization (<24 hours or ≥24 hours). Study medication administration should start as soon as 
possible, but within 4 hours after randomization. For analysis purposes, the day of first study 
medication intake will be considered Day 1 for the interventional stage. Study medication will be 
administered bid and treatment duration will be 7 days (14 consecutive doses). Doses are based 
on body weight and age group. An overview of the treatments for the newly enrolled participants 
in the interventional stage is provided in Table 2.


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Table 2:
Treatment Overview
Treatment
Age Groupa
Dosing Regimenb,c
Volume
JNJ-53718678
1
2.5 mg/kg bid on Days 1 to 7
A mLd oral suspension of JNJ-53718678 
2
3 mg/kg bid on Days 1 to 7
B mLd oral suspension of JNJ-53718678
3
4.5 mg/kg bid on Days 1 to 7
C mLd oral suspension of JNJ-53718678
Placebo
1,2, or 3
placebo bid on Days 1 to 7
A, B, or C (respectively) mLb placebo
a.
Age Group 1: ≥28 days and <3 months; Age Group 2: ≥3 and <6 months; Age Group 3: ≥6 months.
b.
Doses are provided for JNJ-53718678-AAA.
c.
Dosing should preferably occur approximately at the same time each day for both intakes (AM and PM). For 
participants 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 participants receive 14 consecutive doses in total.
d.
A to C 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 body weight of the 
participant (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.
Note: Prior to Protocol Amendment 2, the total daily dose was the same but the daily dosing 
frequency was qd instead of bid.
Dosing should preferably occur approximately at the same time each day for both intakes (AM 
and PM). For participants 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 participants 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 medication will be 
administered orally using a dosing syringe. During hospitalization, the 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.

Hospitalized participants:

during hospitalization: the study medication 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 and volume administered will be recorded by the site staff.

after discharge: the study medication will continue to be administered at home by the 
parent(s)/caregiver(s) through Day 7 (or Day 8 AM, if applicable). Date and time of 
dosing and volume administered will be captured in the study medication log, to be 
completed by the parent(s)/caregiver(s). 

Participants in outpatient setting: 

the first dose of study medication will be administered at the study site. On Day 1, date 
and time of dosing and volume administered will be recorded by the site staff. 

at home, date and time of dosing and volume administered from the second dose on 
Day 1 through Day 7 (or Day 8 AM, if applicable) will be captured in the study 
medication log, to be completed by the parent(s)/caregiver(s). 


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Study site personnel will instruct participants’ parent(s)/caregiver(s) on how to use and store the
study medication for at home dosing.
If the participant vomited, regurgitated, or did not completely swallow the study medication, this 
information should be recorded and the participant 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 time point per the initial dosing schedule.
If participants are rehospitalized (hospitalized participants after discharge) or hospitalized 
(participants from outpatient setting) due to worsening of RSV disease during the treatment 
period, administration of study medication should continue, and the reason for hospitalization 
should be recorded. Every effort should be made by the investigator to perform all the 
assessments as indicated in the Schedule of Activities for hospitalized patients, if practically 
feasible.
Study medication administration must be captured in the source documents and/or the electronic
case report form (eCRF).
The drug product is supplied as a 1,636-mg/bottle powder and solvent for oral suspension 
(G004-01 and G005, respectively). The powder will be reconstituted with the solvent to obtain a 
23-mg/mL oral suspension (equivalent to 20-mg/mL oral suspension of JNJ-53718678-AAA 
[free form]). 
The placebo drug product is supplied as a 4,068-mg/bottle powder and solvent for oral 
suspension (G006 and G003, respectively). The placebo powder will be reconstituted with the 
solvent to obtain a placebo oral suspension.
JNJ-53718678 will be manufactured and provided under the responsibility of the sponsor. Refer 
to the IB for a list of excipients.13
For a definition of study medication overdose, refer to Section 8.7, Treatment of Overdose.
6.2.
Preparation/Handling/Storage/Accountability
Preparation/Handling/Storage
Refer to the pharmacy manual/study site investigational product and procedures manual for 
additional guidance on study medication preparation, handling, and storage.
Accountability
The investigator is responsible for ensuring that all study medication received at the site is 
inventoried and accounted for throughout the study. 
For outpatients, the dispensing of study medication to the participant, and the return of study 
medication from the participant (if applicable), must be documented on the study medication


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accountability form. Participants’ parent(s)/caregiver(s) must be instructed to return all original 
containers, whether empty or containing study medication. 
For hospitalized patients, the study medication administered to the participant must be 
documented on the study medication accountability form. 
All study medication will be stored and disposed of according to the sponsor's instructions. 
Study-site personnel and parent(s)/caregiver(s) must not combine contents of the study 
medication containers.
Study medication 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 medication, and study medication returned 
by the participant, 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 medication, or used returned 
study medication for destruction, will be documented on the study medication return form. When 
the study site is an authorized destruction unit and study medication supplies are destroyed 
on-site, this must also be documented on the study medication 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 study medication accountability purposes. 
Study medication 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 medication will be 
supplied only to participants participating in the study. Returned study medication must not be 
dispensed again, even to the same participant. Study medication may not be relabeled or 
reassigned for use by other participants. The investigator agrees neither to dispense the study 
medication from, nor store it at, any site other than the study sites agreed upon with the sponsor. 
Further guidance and information for the final disposition of unused study interventions will be 
provided.
6.3.
Measures to Minimize Bias: Randomization and Blinding
Intervention Allocation
Procedures for Randomization and Stratification
Central randomization will be implemented in this study. Participants will be randomly assigned 
to 1 of 2 treatment groups based on a computer-generated randomization schedule prepared 
before the study by or under the supervision of the sponsor. The randomization will be balanced 
by using randomly permuted blocks and will be stratified based on the time between ARI alert 
and randomization (<24 hours or ≥24 hours). The interactive web response system (IWRS) will 
assign a unique treatment code, which will dictate the treatment assignment and matching study 
medication kit for the participant. The requestor must use his or her own user identification and 


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personal identification number when contacting the IWRS, and will then give the relevant 
participant details to uniquely identify the participant.
Blinding
The investigator will not be provided with randomization codes. The codes will be maintained 
within the IWRS, which has the functionality to allow the investigator to break the blind for an 
individual participant.
Data that may potentially unblind the treatment assignment (ie, JNJ-53718678 plasma 
concentrations) will be handled with special care to ensure that the integrity of the blind is 
maintained and the potential for bias is minimized. This can include making special provisions, 
such as segregating the data in question from view by the investigators, clinical team, or others 
as appropriate until the time of database lock and unblinding.
Under normal circumstances, the blind should not be broken until all participants have completed 
the study and the database is finalized. The investigator may in an emergency determine the 
identity of the treatment by contacting the IWRS. While the responsibility to break the treatment
code in emergency situations resides solely with the investigator, it is recommended that the 
investigator contact the sponsor or its designee if possible to discuss the particular situation, 
before breaking the blind. Telephone contact with the sponsor or its designee will be available 
24 hours per day, 7 days per week. In the event the blind is broken, the sponsor must be informed 
as soon as possible. The date, time, and reason for the unblinding must be documented by the 
IWRS and in the source document. The documentation received from the IWRS indicating the 
code break must be retained with the participant's source documents in a secure manner.
For participants who have had their treatment assignment unblinded, the parent(s)/caregiver(s) 
will be asked to continue with the participant’s remaining study visits and assessment schedule, 
or, at a minimum, to return with the participant to the site for a Withdrawal and a Safety Follow-
up Visit.
6.4.
Study Intervention Compliance
The first dose of study medication will be administered by study site personnel or by the 
parent/caregiver under supervision of the study site personnel. Data and time of dosing will be 
recorded by study staff. 
Study site personnel will instruct parents/caregivers on how to use and store the study medication
for home dosing.
Parents/caregivers will complete a study medication log with the date/time of study medication
and volume administered. 
Parents/caregivers will also be asked to record if the patient did not swallow all of the study 
medication or if any of the study medication was regurgitated in the study medication log. 
In addition, missed doses will also be reported using the study medication log. 


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6.5.
Concomitant Therapy
Part 1: Observational Stage
There are no prestudy or concomitant medication restrictions during the observational stage of 
this study. Participants may be treated according to the local standard of care. The use of 
medications with potential impact on RSV viral load (eg, palivizumab [Synagis®] and systemic 
or nasal steroids), and medications that may affect the resolution of symptoms (eg, homeopathic 
or naturopathic medications, bronchodilators, antibiotics, etc.) will be recorded in the eCRF from 
the date the ICF for the observational stage of the study is signed onwards.
Part 2: Interventional Stage
Concomitant medications, except those listed below, are allowed during the interventional stage 
of the study. All concomitant medications and supportive therapy different from the study 
medication must be recorded in the eCRF, from the date the ICF for the interventional stage of 
the study is signed through the end-of-study visit. Recorded information will include a 
description of the type of the drug/therapy, treatment duration (dates 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 participant 
into the interventional stage of the study; however, if a participant has received acute doses of a 
prohibited drug, switching to an alternative drug chosen at the discretion of the investigator will 
be allowed.
All hospitalized participants will receive supportive care per local institution standards and 
applicable guidelines. While treatment guidelines and standards vary based on local practice and 
should be considered in the management of participants, within the parameters of this study, it is 
recommended that supplemental oxygen can be administered or withdrawn, as appropriate, to 
maintain an SpO2 ≥93% as long as it is medically indicated (for participants whose SpO2 is 
≥93% when clinically stable).
Participants can receive medications such as acetaminophen/paracetamol, non-steroidal 
anti-inflammatory drugs, leukotriene antagonists, or antihistamines, considering their respective 
package insert, at the investigator’s discretion prior to and during the study.
In case antipyretics are used during the interventional stage, body temperature should be 
measured immediately before or >4 hours after giving antipyretics. Parent(s)/caregiver(s) 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. 


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Prescription medications intended to treat the symptoms/sequelae of the RSV infection are 
permitted, including:

inhaled β-agonists or anticholinergics

oral/IV/intramuscular antibiotics such as β-lactams 
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.
Routine vaccinations are permitted during study participation but local guidelines should be 
followed. 
The following medications are not permitted during the interventional stage of the study and for 
the indicated time period prior to screening for the interventional stage: 

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.

Systemic corticosteroids if used for >7 consecutive days immediately prior to randomization 
at doses higher than 2 mg/kg/day of prednisone or equivalent. Participants meeting the 
eligibility criteria at screening but requiring initiation or increased doses of systemic 
corticosteroids (>2 mg/kg/day of prednisone or equivalent) for a prolonged period 
(>7 consecutive days) during the study are allowed to continue participation in the study.

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 
interventional stage. 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 within 14 days prior to screening for the 
interventional stage until 3 days after the last dose:

Prescription medications which are known to be a moderate or strong inhibitor of 
CYP3A4 enzymes, such as, but not limited to, macrolide antibiotics.

Prescription medications that are known to be strong inducers of CYP3A4 such as, but 
not limited to, rifampin.

Medications with a known risk to prolong the QT interval11 and not belonging to the class of 
moderate or strong CYP3A4 inhibitors (eg, azithromycin, a mild CYP3A4 inhibitor with 
known QT prolonging risk) can be continued if the participant is already on a stable therapy 
prior to screening for the interventional stage and if the QT interval meets the eligibility 
criteria, however, the use of these medications cannot be initiated at screening for the 
interventional stage and/or during the study intervention treatment period.


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
Any other investigational study medication within 30 days or 5-fold half-lives of that drug 
(whichever is longer) prior to screening and during the study.

Prior exposure to JNJ-53718678 at the time of screening.

Any investigational medical device prior to screening. 
7.
DISCONTINUATION OF STUDY INTERVENTION AND PARTICIPANT 
DISCONTINUATION/WITHDRAWAL
7.1.
Discontinuation of Study Intervention
A participant's study medication must be discontinued if:

The investigator believes that for safety reasons or tolerability reasons (eg, AE) it is in the 
best interest of the participant to discontinue study medication

The participant experiences a Grade 3 rash or higher

The participant 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 8.5)

The participant is reported with the following laboratory abnormalities: AST or alanine 
transaminase (ALT) increases ≥3 × upper limit of normal (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 participant 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 participant’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 participant is withdrawn from the study before the end of the double-blind treatment period, 
every attempt should be made to obtain follow-up assessments.
7.2.
Participant Discontinuation/Withdrawal From the Study
A participant will be withdrawn from the study for any of the following reasons (for both the 
observational and interventional stage):

Lost to follow-up

Withdrawal of consent

Death


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
Participant is SARS-CoV-2 positive at any time during the study assessed by local health 
practice

The participant’s parent(s)/caregiver(s) is poorly compliant with study procedures, visits, 
and assessments, preferably after evaluation and discussion between the investigator and the 
sponsor

Decision by the sponsor to stop or cancel the study

Decision by the investigator to withdraw the participant from the study
If a participant is lost to follow-up, every reasonable effort must be made by the study-site 
personnel to contact the participant’s parent(s)/caregiver(s) and determine the reason for 
discontinuation/withdrawal. The measures taken to follow-up must be documented.
In case a participant prematurely discontinues study medication for any reason (except 
withdrawal of consent), the parent(s)/caregiver(s) will be asked to continue with the participant’s 
remaining study visits and assessment schedule, or, at a minimum, to return with the participant 
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 participant’s legally acceptable representative(s) withdraw consent during 
the treatment or follow-up phase of the interventional stage, 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 participant’s parent(s)/caregiver(s) withdraw(s) the participant before completing the 
study, the reason for withdrawal is to be documented in the eCRF and in the source document. If 
a participant is withdrawn from the study before the end of the double-blind treatment period, 
every attempt should be made to obtain follow-up assessments.
Withdrawal of Consent
A participant’s parent(s)/caregiver(s) declining to return their infant for scheduled visits does not 
necessarily constitute withdrawal of consent. Alternate follow-up mechanisms that the 
participant agreed to when signing the consent form apply as local regulations permit.
7.2.1.
Withdrawal From the Use of Research Samples
A participant’s parent(s)/caregiver(s) who withdraws from the study will have the following 
options regarding the optional research samples:

The collected samples will be retained and used in accordance with the original separate 
informed consent for optional research samples.

Consent for optional research samples may be withdrawn, in which case the samples will be 
destroyed and no further testing will take place. To initiate the sample destruction process, 
the investigator must notify the sponsor study site contact of withdrawal of consent for the 
optional research samples and to request sample destruction. The sponsor study site contact 
will, in turn, contact the biomarker representative to execute sample destruction. If 


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requested, the investigator will receive written confirmation from the sponsor that the 
samples have been destroyed.
Withdrawal From the Optional Research Samples While Remaining in the Main Study
Consent for optional research samples may be withdrawn while the participant remains in the 
study. In such a case, the optional research samples will be destroyed. The sample destruction 
process will proceed as described above.
Withdrawal From the Use of Samples in Future Research
The participant may withdraw consent for use of samples for research (refer to Long-Term 
Retention of Samples for Additional Future Research in Appendix 3, Regulatory, Ethical, and 
Study Oversight Considerations). 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 and in the separate ICF for optional research samples.
7.3.
Lost to Follow-up
A participant will be considered lost to follow-up if the participant’s parent(s)/caregiver(s)
repeatedly fails to return with the infant
for scheduled visits and the participant’s 
parent(s)/caregiver(s) is (are) unable to be contacted by the study site. A participant cannot be 
deemed lost to follow-up until all reasonable efforts made by the study-site personnel to contact 
the participant’s parent(s)/caregiver(s) are deemed futile. The following actions must be taken if 
the participant’s parent(s)/caregiver(s) fails to return with the infant to the study site for a 
required study visit:

The study-site personnel must attempt to contact the participant’s parent(s)/caregiver(s) to 
reschedule the missed visit as soon as possible, to counsel the participant’s 
parent(s)/caregiver(s) on the importance of maintaining the assigned visit schedule, to 
ascertain whether the participant’s parent(s)/caregiver(s) wishes to or should continue to 
have the infant in the study.

Before a participant is deemed lost to follow-up, the investigator or designee must make 
every reasonable effort to regain contact with the participant’s parent(s)/caregiver(s) (where 
possible, 3 telephone calls, e-mails, fax, and, if necessary, a certified letter to the 
participant’s parent(s)/caregiver(s)’s last known mailing address, or local equivalent 
methods. These contact attempts should be documented in the participant’s medical records.

Should the participant’s parent(s)/caregiver(s) continue to be unreachable, they will be 
considered to have withdrawn from the study.
Should a study site close, eg, for operational, financial, or other reasons, and the investigator 
cannot reach the participant’s parent(s)/caregiver(s) to inform them, their contact information 
will be transferred to another study site.


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8.
STUDY ASSESSMENTS AND PROCEDURES
Overview
The Schedule of Activities summarizes the frequency and timing of all measurements applicable 
to this study. Unscheduled visits may be performed based on the investigator’s clinical judgment 
and may include further evaluations, as needed.
If multiple assessments are scheduled for the same timepoint, standard-of-care procedures should 
always take precedence over the study procedures.
In the event that an invasive procedure such as a blood draw or a mid-turbinate nasal swab is 
required at the same time as an assessment of clinical evaluation or vital signs or ECG, these 
latter assessments should be performed first.
All parental study-related assessments will ideally be performed by a single parent (or caregiver) 
throughout the study, if possible. 
Clinical course and severity of RSV infection will be assessed through different measures (see 
Section 8.3.3).
In the interventional stage, 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 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 8.3.4). Sequencing results 
may be presented in a separate report.
Safety and tolerability, including AEs, laboratory assessments, ECGs, vital signs, and physical 
examination will be assessed throughout the study from signing of the ICF until the participant’s 
last study-related activity (see Section 8.4).
Optional blood samples and leftover mid-turbinate nasal swab samples will 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 8.11).
An IDMC will be commissioned for the interventional stage of this study. Throughout the 
conduct of this study, an IDMC will review unblinded safety data on a regular basis to ensure 
participant safety. At any point during the study, the IDMC has the authority to recommend 
modifications to the study conduct and/or safety assessments to the Sponsor Committee to ensure 
the safety of enrolled participants (see Section 9.5). 


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Blood Sample Collection and Handling
The maximum amount of blood drawn from each participant in the observational stage of the
study will be approximately 1 mL (ICF must be signed before optional blood sampling is 
performed).
For the PK samples in the interventional stage, 80 µL of blood is required.
The maximum amount of blood drawn from each participant for study-specific purposes will not 
exceed 9.2 mL over the duration of the study in line with recommendations collated by the 
World Health Organization (WHO)10, or less if per local practice guidelines. Repeat or 
unscheduled samples may be taken for safety reasons or for technical issues with the samples.
Nasal Sample Collection and Handling
For the evaluation of antiviral activity, the RSV viral load in nasal secretions will be measured at
the central lab using a qRT-PCR assay on mid-turbinate nasal swab specimens (see 
Section 8.3.2). If feasible, the RSV infectious virus load may also be assessed by quantitative 
culture of RSV (plaque assay) on selected nasal swab samples. 
The presence of viral (other than RSV) or bacterial co-pathogens will be assessed in the nasal 
swab sample collected at Day 1 predose by using multiplex polymerase chain reaction (PCR) at 
the central lab.
Refer to the Schedule of Activities for the timing and frequency of all sample collections.
Details regarding the sampling procedure, storage and transportation will be provided in the 
Laboratory Manual. Only nasal mid-turbinate swabs provided for this study may be used. Other 
swabs are not acceptable for specimen collection as they may inhibit recovery of the pathogens.
Standard-of-care procedures should always take precedence over the study procedures. If a nasal 
sampling procedure is part of the standard of care, then the standard-of-care procedure should be 
performed prior to the study swabs and study swabs should be performed from the opposite 
nostril than that used for the standard-of-care procedure. The nasal swabs for the study will be 
collected in a single Universal Transport Medium (UTM) tube at time points indicated in the 
Schedule of Activities.
All information regarding sample preparation will be provided in the Laboratory Manual. Date 
and time of sample collection will be documented.
RSV is temperature-sensitive. At site, all specimens must be stored under controlled temperature 
conditions as indicated in the Laboratory Manual. Any mishandling of specimens should be 
documented and added to a Sample Collection Log. 


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Stool Sample Collection and Handling
Refer to the Schedule of Activities for the timing and frequency of all (optional) stool sample 
collections.
Stool samples for microbiome analysis will be optionally collected during the study to assess 
diversity and relative abundance of bacterial species (analysis upon discretion of the sponsor). 
Information on date and time of stool sampling as well as feeding type (liquid vs solid) and 
composition (eg, milk, vegetables, fruit, meat/fish) will be collected. 
Stool samples can be collected at home in special dedicated sampling tubes, and shipped to the 
site within 30 days after sample collection. On site, samples will be stored until shipment to the 
sponsor or to a specialized laboratory assigned by the sponsor for microbiome analysis.
Details regarding the sampling procedure, storage and transportation will be provided in the 
Laboratory Manual. Only stool sample collection kits provided for this study may be used. Other 
collection recipients are not acceptable for specimen collection.
All samples will be shipped to the sponsor or to a central lab storage facility assigned by the 
sponsor following specified timing and shipping procedures and stored for a duration of at most 
15 years (or according to local regulations) before being destroyed (see section on Long-Term 
Retention of Samples in Appendix 3, Regulatory, Ethical, and Study Oversight Considerations).
Study-Specific Materials
The investigator will be provided with the following supplies:

IB

Pharmacy manual/study site investigational product and procedures manual

Laboratory manual

IWRS Manual 

Electronic data capture (eDC) Manual

Sample ICF
The participant’s parent(s)/caregiver(s) will be provided with tools to facilitate/support 
participation, such as:

Sample collection materials (nasal swabs and stool sample collection) 

Thermometer 

Nasal swab collection and storage instructions

IP Dosing Instructions

Parent/Caregiver information booklet

RSV mobile App


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
RSV Educational booklet
8.1.
Part 1: Observational Stage
Infants who are ≤4 months of age and asymptomatic for ARI-like symptoms requiring medical 
intervention at the time of consent are eligible for enrollment in the observational stage of the 
study. Their respiratory condition will be followed before, during, and after acute RSV 
infection(s) and at follow-up during a single RSV epidemic circulation (as defined locally).
8.1.1.
Pre-diagnostic Phase
The investigator or his/her designee will provide detailed information on the study to the 
participant’s parent(s)/caregiver(s) and will obtain written informed consent prior to each 
participant’s participation in the study. The ICF for the observational stage of the study will be 
signed before any study-related activity takes place. 
After verification of the inclusion/exclusion criteria outlined in Sections 5.1 and 5.2, the 
participant’s medical history will be reviewed and documented. Demographic and baseline 
characteristics will also be captured during the enrollment visit. 
An optional buccal swab sample for exploratory host genetic analyses will be collected from the 
infant at enrollment (if consent for this optional sample is provided).
During the enrollment visit, parent(s)/caregiver(s) will be properly trained by the 
investigator/study site personnel to perform the nasal sampling at home. If re-training is needed, 
this will be performed at a later time point.
The RSV mobile App will be downloaded on the parent/caregiver’s own smartphone during the 
enrollment visit or at any time after signing the ICF. The parent(s)/caregiver(s) will also receive 
a specific training on the use of the RSV mobile App. 
At enrollment (+2 weeks; healthy baseline) and at the age of 4 months (±2 weeks) for 
participants in the observational stage, a stool sample for microbiome analysis will be optionally 
collected by the parent(s)/caregiver(s). If both time points fall together only 1 sample is to be 
collected.
Onset of Acute Respiratory Infection (ARI)
The parent(s)/caregiver(s) will observe and record the health condition of the infant at home 
starting from a predefined date (start date will be country and site dependent) for the entire 
duration of the study during a single RSV epidemic circulation. Upon activation of the RSV 
mobile App, pre-programmed study-related questions (App questionnaires) will be asked twice
daily (morning and evening) via the parent/caregiver’s smartphone. The answers of the 
parent(s)/caregiver(s) will drive an algorithm that calculates scores in the background of the 
application, where the threshold score is defined on the basis of the presence of the signs and 
symptoms per eligibility criteria for intervention, thus a combination of an upper and a lower 
respiratory sign and a sign of systemic impact. When the infant starts showing clinical signs 


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compatible with RSV disease that cross this threshold score in the RSV mobile App the 
parent(s)/caregiver(s) will receive an alert asking them to collect a nasal swab at home and to 
invite them to present to the site with their infant for a study visit as soon as possible, ie, within 
<24 hours after the receipt of the alert (RSV-like ARI visit). In addition, a notification will be 
sent to the study-site personnel. The RSV diagnostic test must be performed at the site during the 
RSV-like ARI visit as soon as possible and no later than within 24 hours after the receipt of the 
alert. The nasal swabs at home should preferably be taken by the same parent/caregiver and 
preferably also from the same nostril throughout the study (unless precluded due to bleeding). 
Nasal samples collected at home should be stored until the samples will be picked-up.
8.1.2.
Diagnostic Phase
After the threshold score in the RSV mobile App has triggered an alert and a nasal swab has been 
collected at home, the parent(s)/caregiver(s) and infant will perform a study visit as soon as 
possible and no later than within 24 hours after the alert (Observational Stage Day 1). A second 
mid-turbinate nasal swab will be collected at the site by qualified study-site personnel and tested 
with a study-related RSV molecular-based diagnostic assay for RSV diagnosis. If the diagnostic 
nasal mid-turbinate sample during the RSV-like ARI visit is taken within 4 hours from the 
sample for testing at home, the nasal mid-turbinate swab sample during the RSV-like ARI visit 
should be taken from the other nostril. In that case nasal mid-turbinate swab samples should be 
continued to be collected from the same nostril as used during the RSV-like ARI visit. The RSV 
diagnostic test must be performed as soon as possible and no later than within 24 hours after the 
receipt of the alert. In case of an RSV(+) result, the mid-turbinate nasal swab sample collected at 
site will be sent to the central lab for RSV viral load determination and potentially for viral 
sequencing and/or viral and bacterial co-pathogen analyses. Samples from RSV(-) participants 
will be analyzed at the discretion of the sponsor.
Upon an alert, if a participant is SARS-CoV-2 positive assessed by local health practice, the 
participant will be withdrawn from study.
During the visit, a complete physical examination of all body systems, including length and head 
circumference and body weight measurement and skin examination will be performed. 
On day of diagnosis training will be given, if applicable, on completion of the PRESORS and 
logs.
The parent(s)/caregiver(s) and the clinician will complete the parent(s)/caregiver(s) PRESORS 
and the clinician PRESORS, respectively.
Clinical assessments will be performed by the investigator or his/her designee according to 
routine clinical practice. Study-related information and the outcome of the complete physical 
examination and clinical evaluation will be captured. Depending on the outcome of the clinical 
evaluation, the investigator may decide to hospitalize the infant, per local standard of care. This 
study will not interfere with any medical decision, such as the decision to hospitalize the infant, 
or with the infant’s standard-of-care medical management.


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In case the infant has an RSV diagnosis at the site, the parent(s)/caregiver(s) will be informed on 
details of the interventional stage and can elect to enroll their infant in the interventional stage by 
completion of the informed consent process, regardless of whether the participant is hospitalized
or not. RSV(+) participants whose parent(s)/caregiver(s) do not consent for participation in the 
interventional stage of the study and screen failures in the interventional stage will continue 
participation in the post-diagnostic phase of the observational stage, where nasal samples will be 
collected through Day 8 and the PRESORS will be completed following the same schedule as 
the subjects participating in the interventional stage.
Parent(s)/caregiver(s) of participants not participating in the interventional stage can still consent 
for the optional blood sample for exploratory biomarker analyses at the day of diagnosis in case 
the consent for this optional blood sample was not signed at enrollment.
An optional blood sample for exploratory biomarker analyses will be taken if consent for blood 
sampling is provided. 
For participants that have had an ARI alert but did not enter the interventional stage of the study, 
an optional stool sample is to be collected at 21 days (+2 weeks) after each ARI alert unless this 
time point coincides (±2 weeks) with the participant’s age of 4 months; in that case only 1 
sample is to be collected, if additional consent for stool sampling has been provided.
RSV negative participants (RSV[-] diagnosed at site) will continue to be further closely 
monitored in the observational stage. They will return to the pre-diagnostic phase and the 
parent(s)/caregiver(s) will continue to observe the health condition of the infant and answer the 
App questionnaires twice daily in the RSV mobile App until the next alert, or until the end of the 
RSV circulation (as determined for that site/country). There will be a 7-day pause in the RSV 
mobile App for the generation of alerts, after which the alert option will be switched back on. 
For RSV(-) participants, an optional stool sample will be collected 21 days after each ARI alert, 
if applicable. If for RSV(-) participants another ARI alert is triggered within a 2-week window, 
only 1 stool sample needs to be collected. If this second alert results in a positive RSV diagnosis, 
the stool sample should preferably be collected at 21 days (+2 weeks) after this RSV(+) 
diagnosis unless this time point coincides (±2 weeks) with the participant’s age of 4 months; in 
that case only 1 sample is to be collected.
8.1.3.
Post-diagnostic Phase
For RSV(+) outpatients and hospitalized infants who will NOT be enrolled in the interventional 
stage of the study and for screen failures in the interventional stage a once daily mid-turbinate 
nasal swab will be collected from Observational Stage Day 2 until Observational Stage Day 8 at 
the site (for hospitalized) or at home (and at day of discharge in case hospitalized after 
Observational Stage Day 8). The parent(s)/caregiver(s) will complete the parent(s)/caregiver(s) 
PRESORS as of Observational Stage Day 2 through Observational Stage Day 14 twice daily 
(morning and evening). From Observational Stage Day 15 through Observational Stage Day 21, 
they will complete the parent(s)/caregiver(s) PRESORS once daily, in the evening. 


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The clinician PRESORS will be completed by the clinician for all participants on the day of 
diagnosis. From Observational Stage Day 2 onward it will only be completed for hospitalized 
patients until discharge.
Parent(s)/caregiver(s) will continue completion of the App questionnaires until Day 21 (end-of-
study).
For participants who did not enter the interventional stage of the study, an optional stool sample
is to be collected 21 days (+2 weeks) after the ARI alert unless this time point coincides 
(±2 weeks) with the participant’s age of 4 months; in that case only 1 sample is to be collected.
8.2.
Part 2: Interventional Stage
Participants with diagnosed RSV infection (RSV[+]) at site will be enrolled in the screening 
phase of the interventional stage of the study after obtaining informed consent for the 
interventional stage at that time.
8.2.1.
Screening Phase
The procedures to ensure the eligibility of the participant for the interventional stage of the study 
will only be performed after the parent(s)/caregiver(s) have given their written informed consent. 
At the time of consent, the participants should be at least 28 days old or at least 3 months 
postnatal age for prematurely born infants (ie, <37 weeks and 0 days of gestation at birth) to be 
eligible for enrollment in the interventional stage of the study. 
If needed, and depending on the time of presentation, screening/predose assessments can 
continue the next calendar day, in which case the first study medication intake will be on that 
day, immediately after establishing eligibility. A predose mid-turbinate nasal swab should be 
collected as close as possible and within 8 hours prior to the first administration of study 
medication. The mid-turbinate nasal swab sample collected at site will be sent to the central lab 
for RSV viral load determination and potentially for viral sequencing and/or viral and bacterial 
co-pathogen analyses. If the RSV-like ARI visit nasal swab taken at the site was taken less than 8
hours prior to start of dosing, then this sample can be used as the Day 1 predose sample, and no 
additional nasal sample needs to be collected at Day 1 predose.
8.2.2.
Double-blind Treatment Phase
On Day 1, eligible participants will be randomized in a 1:1 ratio to receive either JNJ-53718678 
or placebo. A participant needs to be randomized within 32 hours after the receipt of the RSV 
mobile App alert. The randomization will be stratified based on the time between ARI alert and 
randomization (<24 hours or ≥24 hours). Study medication administration should start as soon as 
possible, but within 4 hours after randomization. 
Study medication will be administered bid for 7 days (14 consecutive doses). For participants 
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 participants receive 14 consecutive doses in 
total. The doses to be administered are based on body weight and age group (see Table 2). For 


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hospitalized participants, the study medication will be administered by study site personnel or by 
the parent(s)/caregiver(s) under supervision of the study site personnel during hospitalization. In 
outpatients, the first dose of study medication will be administered at the study site. All 
participants will receive standard supportive care for RSV infection as per local standard of care 
considering the disallowed medication provided in Section 6.5.
Hospitalized participants can be discharged as of Day 2 if deemed appropriate by the investigator 
and after completion of the required investigator-performed assessments for that day (except for 
the evening assessment in case the assessment is to be performed twice daily). After discharge, 
the discharged participants will follow the same visit schedule as outpatients. 
For hospitalized participants after discharge and for outpatients, some of the assessments will be 
performed during on-site visits (Day 3, 5 and 8). These scheduled study visits, if feasible for the 
study site and if allowed per local regulations, can also be done as home visits.
Pharmacokinetic assessments during the study will be based on sparse sampling (on Day 1 
approximately 1 hour after administration of study drug [after the ECGs are obtained] and on 
Day 3 or Day 5 at least 4 hours after the AM and prior to the PM dosing) and will be performed 
using a popPK model (see Section 8.8).
Investigational staff will review daily the completion of the parent(s)/caregiver(s) PRESORS and 
the logs. The investigational staff will contact the parent(s)/caregiver(s) in case of incompliance.
8.2.3.
Follow-up Phase
Participants will be evaluated for a total of approximately 28 (±3) days post randomization 
(Days 9 to 28 [±3]).
Both outpatients and hospitalized patients after discharge will be asked to return to the site for 
follow-up assessments as an outpatient on Day 14 and Day 21. If feasible for the study site and if 
allowed per local regulations, these visits can also be done as home visits. On Day 28 (±3), 
participant’s parent(s)/caregiver(s) will be contacted by the site staff for a telephone follow-up 
visit. In case a participant 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 participant 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.
The parent(s)/caregiver(s) will complete the parent(s)/caregiver(s) PRESORS as of Day 9 
through Day 14 bid
(morning and evening). 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. 


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8.2.4.
Withdrawal and Safety Follow-up Visits
In case a participant prematurely discontinues study medication treatment for any reason (except 
withdrawal of consent), the parent(s)/caregiver(s) will be asked to continue with the participant’s 
remaining study visits and assessment schedule, or, at a minimum, to return with the participant 
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 participant’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 Schedule of Activities.
8.3.
Viral Kinetics and Clinical Outcome
8.3.1.
Viral Load Kinetics (Observational Stage) 
Mid-turbinate swab specimens for the determination of RSV viral load will be collected at the 
time points indicated in the Schedule of Activities. 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). Date and time of sampling should be 
recorded for all participants. If the diagnostic nasal mid-turbinate sample during the RSV-like 
ARI visit is taken within 4 hours from the sample for testing at home, the nasal mid-turbinate 
swab sample during the RSV-like ARI visit should be taken from the other nostril. In that case 
nasal mid-turbinate swab samples should be continued to be collected from the same nostril as 
used during the RSV-like ARI visit.
For participants with diagnosed RSV infection who do NOT participate in the interventional 
stage of the study and for screen failures, nasal swabs will be collected once daily through 
Observational Stage Day 8 and nasal swab collection will stop after Observational Stage Day 8 
regardless of hospitalized or outpatient status. For RSV(+) patients who are hospitalized after 
Observational Stage Day 8 one additional nasal swab will be collected at day of discharge.
8.3.2.
Antiviral Activity (Interventional Stage)
The mid-turbinate nasal swab on Day 1 should be collected as close as possible prior to the first 
administration of study medication. If the RSV-like ARI visit nasal swab taken at the site was 
taken less than 8 hours prior to start of dosing, then this sample can be used as the Day 1 predose 
sample, and no additional nasal sample needs to be collected at Day 1 predose. The next nasal 
swabs should be collected preferably at approximately the same time as the predose swab taken 
on Day 1 and preferably prior to dose administration. 
For participants with diagnosed RSV infection who participate in the interventional stage of the 
study, nasal swabs will be collected daily through Day 8 in all participants. As of Day 8, in 
participants who were symptomatic based on clinician PRESORS at Day 8, daily nasal swabs 
will be collected through Day 13 or until the participant becomes asymptomatic based on the 


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parent(s)/caregiver(s) PRESORS, as evaluated by the investigational staff (whichever comes 
first). For hospitalized patients, nasal swabs will be collected each day during hospitalization 
through Day 13 or until discharge (whichever comes first). On Day 14 and Day 21, a nasal swab 
will be collected during the scheduled visit for all participants (outpatient or hospitalized).
For hospitalized participants daily during hospitalization and for outpatients at scheduled visits, 
mid-turbinate nasal swabs will be collected by a healthcare professional (HCP; investigator/study 
site personnel). On days when no visit is scheduled, mid-turbinate swabs are collected at home 
by the parent(s)/caregiver(s). All mid-turbinate swabbing may also be performed at the site if this 
is preferred by the parent(s)/caregiver(s).
All parent(s)/caregiver(s) 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 at home. All nasal swabs collected at home should be stored 
until the samples will be picked-up. Additional information about the collection, handling, and 
shipment of biologic samples can be found in the laboratory manual.
For the evaluation of antiviral activity, the RSV viral load in nasal secretions will be measured at 
the central laboratory using a qRT-PCR assay on mid-turbinate nasal swab specimens. If 
feasible, the RSV infectious titer may also be assessed by quantitative culture of RSV (plaque 
assay) on selected nasal swab samples.
8.3.3.
Clinical Course of RSV Infection 
The study will include the following evaluations of the clinical course of RSV infection for all 
RSV(+) participants (hospitalized or outpatients) during either the post-diagnostic phase of the 
observational stage (for those who do not enter the interventional stage or are screen failure in 
the interventional stage) or the interventional stage of the study:

Hospitalized patients and participants in outpatient setting:

clinical parameters: respiratory rate, heart rate, SpO2, and body temperature as 
measured by the investigator during scheduled visits

body temperature as measured by the parent(s)/caregiver(s) and recorded in the 
temperature log (for outpatients and after discharge of hospitalized patients)

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 by the investigator 
(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 
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
Hospitalized patients 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, translational 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.
Clinical outcome assessments (COAs) as performed separately by the clinician (clinician 
PRESORS) and the parent(s)/caregiver(s) (parent[s]/caregiver[s] PRESORS, temperature log) 
will be captured. Symptoms reported in these assessments will not be reported as AEs but 
constitute a part of the efficacy evaluations.
The parent(s)/caregiver(s) PRESORS assessment should be completed once at predose, then 
twice daily (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 the Schedule 
of Activities). The first parent(s)/caregiver(s) PRESORS of the twice daily schedule on Day 1 
needs to be completed within 4 hours before randomization, or if done after randomization, as 
close as feasible and prior to the first administration of study medication. 
8.3.4.
Viral Sequencing 
In the interventional part, 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 presence of baseline RSV F-gene 
polymorphisms on the antiviral response will be explored. Sequencing results may be presented 
in a separate report. Sequencing data will not be reported to the investigators.
In the observational part, viral sequencing may be performed as an exploratory analysis.
Changes in viral sequence will be evaluated but will not be reported as AEs.
8.4.
Safety Assessments
Part 1: Observational Stage
For the observational stage of the study neither changes in ongoing therapy will be imposed 
through participation in this study, nor any investigational medicinal product will be 


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administered. Hence, the overall safety of the participants in the observational stage will not be 
assessed, but safety information related to study-specific procedures will be collected and 
recorded throughout the observational stage. All serious and non-serious AEs related to the study 
sampling procedures and all deaths (including their causality) will be documented from signing
of the ICF allowing inclusion in the observational stage onwards and will be communicated 
according to the sponsor’s procedure.
Part 2: Interventional Stage
Safety and tolerability will be evaluated throughout the interventional stage, ie, from signing of
the ICF allowing inclusion in the interventional stage onwards until the last study-related 
activity. The following evaluation of safety and tolerability will be included:

Adverse events

Physical examination 

Vital signs

Electrocardiogram (ECG) 

Clinical laboratory tests (local)
Any clinically significant abnormalities persisting at the end of the study/early withdrawal will 
be followed up by the investigator until resolution or until a clinically stable endpoint is reached.
AEs will be reported and followed by the investigator as specified in Section 8.6, Adverse
Events and Serious Adverse Events and Appendix 4, Adverse Events: Definitions and 
Procedures for Recording, Evaluating, Follow-Up, and Reporting.
The study will include the following evaluations of safety and tolerability according to the time 
points provided in the Schedule of Activities.
8.4.1.
Physical Examinations
To evaluate the participant’s eligibility, a complete physical examination of all body systems, 
including length and head circumference and body weight measurement and skin examination
will be performed at the day of RSV diagnosis. 
A directed physical examination will be performed at several time points throughout the study 
(see Schedule of Activities). A directed physical examination 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 participant develops a cutaneous reaction/rash, vaginal 
and rectal exams may be done if clinically relevant.
To obtain the actual body weight, participants are advised to be weighed unclothed with a dry 
diaper only or lightly clothed, with consistency for all visits. Length may be assessed in the 


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supine position and the same position should be used for the subsequent assessments of that 
participant.
Any clinically relevant changes occurring during the study must be recorded in the AE Section 
of the eCRF.
8.4.2.
Vital Signs (Blood Pressure)
For the duration of hospitalization, vital signs will be assessed for each participant twice daily 
preferably at approximately the same time on each scheduled day (see Schedule of Activities). 
After discharge, vital signs will be assessed once during the on-site visits (see Schedule of 
Activities).
Blood pressure will be assessed supine only 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.
8.4.3.
Electrocardiograms
Screening and on-treatment ECGs will be collected at the time points indicated in the Schedule 
of Activities. 
Electrocardiograms (triplicate
12-lead ECG) should be performed using procedures 
commensurate with the participant’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 participant 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 5.2), the participant 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 participant’s medical record. Clinically relevant abnormalities occurring during the study 
should be recorded by the investigator in the AE section of the eCRF. 
In the event that an invasive procedure such as a blood draw or nasal swab and an ECG are 
required at approximately the same time, 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 participant has a QTcF interval ≥500 ms based on the 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 


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triplicate), the participant needs to be withdrawn from study intervention (see also Sections 8.5
and 7.1). In case other clinically relevant ECG abnormalities are observed post start of study 
intervention, a confirmatory ECG must be performed preferably within 48 hours, but no later 
than 72 hours, after the results have become available. Evaluation of clinical relevance should be 
done on confirmed results.
8.4.4.
Clinical Safety Laboratory Assessments
Blood samples for serum chemistry and hematology and a random urine sample for urinalysis 
will be collected as noted in Appendix 2, Clinical Laboratory Tests. The investigator must 
review the laboratory results, document this review, and record any clinically relevant changes 
occurring during the study in the AE section of the eCRF. The laboratory reports must be filed 
with the source documents.
8.5.
Specific Toxicities and Safety Topics of Special Interest
The following only applies to AEs starting after initiation of study medication.
AST and ALT Elevation
Management will be at the discretion of the investigator and should follow generally accepted 
medical standards. Grading of AST and ALT elevation will be based on the DMID Pediatric 
Toxicity Table (see Appendix 5). 
For Grade 3 or 4 laboratory abnormalities, participants 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)
Participants may continue the intake of study medication.
Participants 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, participants will permanently discontinue the intake of 
study medication, although with continuation of appropriate safety follow-up visits.
It is recommended that the investigator contacts the sponsor to discuss the case. Participants
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 
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Cardiac Events Potentially Related to QT Prolongation
Regular cardiac safety monitoring will be done in this study via assessments of AEs, laboratory 
abnormalities, and regular ECGs.
A participant's study intervention must be discontinued if the participant has a QTc value 
≥500 ms at any scheduled visit based on the machine read ECG result (mean of triplicate), 
confirmed by repeat ECG recording during the same visit day (see Section 7.1). For participants
with a confirmed QTc interval value ≥500 ms, the following measures should be taken:
•
The cardiac event must be reported to the sponsor within 24 hours. 
•
The investigator should request urgent cardiology referral, 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 
local laboratory. 
•
If hypokalemia or hypomagnesemia is identified, the levels of potassium and/or magnesium 
should be checked as soon as possible and corrected to prevent cardiac disturbances. 
Appropriate clinical management per local SOC (including but not limited to checking the 
corrected values) is required. 
•
An ECG should be repeated every 24 hours until resolution of QTc interval prolongation is 
confirmed. The participant’s condition should be followed until resolution (return to 
baseline) or stabilization. During the study, these assessments will be captured as 
unscheduled assessments/visits.
8.6.
Adverse Events and Serious Adverse Events
Timely, accurate, and complete reporting and analysis of safety information from clinical studies 
are crucial for the protection of participants, investigators, and the sponsor, and are mandated by 
regulatory agencies worldwide. The sponsor has established Standard Operating Procedures in 
conformity with regulatory requirements worldwide to ensure appropriate reporting of safety 
information; all clinical studies conducted by the sponsor or its affiliates will be conducted in 
accordance with those procedures.
AEs will be reported by the participant (or, when appropriate, by a caregiver, surrogate, or the 
participant's legally acceptable representative) for the duration of the study depending on the 
stage of the study (see Section 8.6.1).
Special attention will be paid to those participants 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 


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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.
For further details on AEs and SAEs (Definitions and Classifications; Attribution Definitions; 
Severity Criteria; Special Reporting Situations; Procedures) as well as product quality 
complaints (PQCs), refer to Appendix 4, Adverse Events: Definitions and Procedures for 
Recording, Evaluating, Follow-Up, and Reporting.
8.6.1.
Time Period and Frequency for Collecting Adverse Event and Serious 
Adverse Event Information
All Adverse Events
For the observational stage of the study only all serious and non-serious AE's related to study 
sampling procedures and all deaths will be reported from the time a signed and dated ICF for the 
observational stage is obtained until completion of the participant's last study-related procedure 
in the observational stage. 
For the interventional stage of the study, all AEs and special reporting situations, whether serious 
or non-serious, will be reported from the time a signed and dated ICF for the interventional stage 
is obtained until completion of the participant's last study-related procedure, which may include 
contact for follow-up of safety. SAEs, including those spontaneously reported to the investigator 
within 30 days after the last dose of study medication, and all deaths must be reported using the 
Serious Adverse Event Form. The sponsor will evaluate any safety information that is 
spontaneously reported by an investigator beyond the time frame specified in the protocol.
Serious Adverse Events
All SAEs occurring during the interventional stage of the study must be reported to the 
appropriate sponsor contact person by study-site personnel within 24 hours of their knowledge of 
the event.
During the observational stage, all deaths including causality must be reported to the appropriate 
sponsor contact person by study site personnel within 24 hours of their knowledge of the event as 
an SAE.
Information regarding SAEs will be transmitted to the sponsor using the Serious Adverse Event 
Form and Safety Report Form of the eCRF, which must be completed and reviewed by a 
physician from the study site, and transmitted to the sponsor within 24 hours. The initial and 
follow-up reports of an SAE should be transmitted electronically.


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8.6.2.
Follow-up of Adverse Events and Serious Adverse Events
AEs will be followed by the investigator as specified in Appendix 4, Adverse Events: Definitions 
and Procedures for Recording, Evaluating, Follow-up, and Reporting.
8.6.3.
Regulatory Reporting Requirements for Serious Adverse Events
The sponsor assumes responsibility for appropriate reporting of AEs to the regulatory authorities. 
The sponsor will also report to the investigator (and the head of the investigational institute 
where required) all suspected unexpected serious adverse reactions (SUSARs). The investigator 
(or sponsor where required) must report SUSARs to the appropriate 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. 
8.7.
Treatment of Overdose
An overdose in this study is defined as the administration of a volume of the study medication
above that of the total daily calculated volume for the respective age and body weight-based dose
within a 24-hour time period.
The sponsor does not recommend specific intervention for an overdose. 
In the event of an overdose, the investigator or treating physician should:

Contact the Medical Monitor immediately.

Closely monitor the participant for AE/SAE and laboratory abnormalities until 
JNJ-53718678 can no longer be detected systemically.

Obtain a plasma sample for PK analysis if requested by the Medical Monitor (determined on 
a case-by-case basis).

Document the quantity of the excess dose as well as the duration of the overdosing in the 
eCRF.
Decisions regarding dose interruptions or modifications will be made by the investigator in 
consultation with the Medical Monitor based on the clinical evaluation of the participant.
8.8.
Pharmacokinetics
Pharmacokinetics are only applicable to the interventional stage of this study.
For newly recruited participants in the interventional stage, a blood sample for determination of 
JNJ-53718678 concentrations will be collected through finger prick or heel stick approximately 
1 hour after administration of study drug (after the ECGs are obtained) on Day 1 and at least 
4 hours after the AM and prior to the PM dosing on Day 3 or Day 5. 


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The following times need to be recorded: date and time of study medication intake, date and time 
of PK blood sampling, and time of meal if any in the time window of 30 minutes before and 
30 minutes after study medication intake on the day of PK sampling.
Additional information about the collection, handling, and shipment of biological samples can be 
found in the Laboratory Manual.
8.8.1.
Evaluations
Samples will be used for determination of JNJ-53718678 concentrations. Samples can also be 
used for the analysis of metabolites of JNJ-53718678, protein binding, 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 participant confidentiality will be 
maintained.
8.8.2.
Analytical Procedures 
Samples will be analyzed (applicable treatment group only [not the placebo group]) to determine 
concentrations of JNJ-53718678 using a validated, specific and sensitive method under the 
supervision of the sponsor.
8.8.3.
Pharmacokinetic Parameters and Evaluations
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. This model will be used to derive the individual PK parameters. 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, gender, creatinine clearance, 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 the analytes in scope. If deemed useful to evaluate the safety or efficacy of 
JNJ-53718678, popPK modeling of other analytes (eg, excipients) may be performed at the 
discretion of the sponsor.
8.9.
Pharmacokinetic/Pharmacodynamic Evaluations
Obtained PK and PD data (selected antiviral activity parameters and safety parameters will be 
used to explore the relationship between the PK and PD.
8.10.
Host Genetic Research
In the observational stage, a buccal swab will be collected from participants who consent 
separately to this component of the study to allow for exploratory host genetic variation analysis 
(DNA) (where local regulations permit).


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Details regarding the handling, storage and transfer procedures will be provided in the 
Laboratory Manual.
Participant participation in host genetic research component of the study is optional.
Host genetic analyses may be conducted at the sponsor’s discretion and reported separately from 
this study. 
8.11.
Biomarkers
Stool samples for microbiome analysis will be optionally collected during the study to assess 
diversity and relative abundance of bacterial species (analysis upon discretion of the sponsor).
In the observational stage, optional blood samples will be used for exploratory biomarker 
analyses (eg, proteins, RNA, immune cell populations), on the premise that these analyses 
investigate the role of biomarkers in RSV-related disease.
Leftover mid-turbinate nasal swab samples from samples collected during the study may also be 
used for exploratory biomarker analyses (eg, proteins, RNA, immune cells, microbiome).
Details regarding the handling, storage and transfer procedures will be provided in the 
Laboratory Manual.
Analyses of biomarkers may be conducted at the sponsor’s discretion and reported separately 
from this study.
8.12.
Other Evaluations
In the interventional stage, the presence of viral (other than RSV) or bacterial co-pathogens will 
be assessed in the nasal swab sample collected at baseline (Day 1 predose) by using multiplex 
PCR at the central lab.
9.
STATISTICAL CONSIDERATIONS
Statistical analysis will be done by the sponsor or under the authority of the sponsor. A general 
description of the statistical methods to be used to analyze the efficacy and safety data is outlined 
below. Specific details will be provided in the Statistical Analysis Plan (SAP).
9.1.
Sample Size Determination
The sample size of the interventional stage is based on results obtained in an earlier birth cohort 
study (Janssen R&D, data on file) and the specified analysis method using simulated data. Based 
on 10,000 simulated datasets of 40 participants, with an assumed 10% drop-out rate and an effect 
size of early treatment of 0.75 log10 copies.day/mL reduction in viral load versus placebo on 
average (as illustrated in Figure 2), there is a power of 88% to reject the null hypothesis of no 
antiviral effect of JNJ-53718678 treatment using a significance level of 5% (one-sided).


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Figure 2:
Illustration of Viral Load over Time by Treatment Assumed in the Sample Size Calculation
The sample size of the birth cohort is based on the sample size required for the interventional 
stage. It is assumed based on the results of a previous observational birth cohort study (Janssen 
R&D, data on file) that approximately 10% of the infants participating in the birth cohort will be 
diagnosed as RSV(+) and will develop ARI disease signs compatible with a minimum disease 
severity threshold for intervention. 
At the stage of the temporary hold of the interventional stage of the study on 2 March 2020, 862 
infants were enrolled in the birth cohort, leading to 29 infants who were diagnosed as RSV(+) 
and 20 infants who participated in the interventional stage. The incidence of RSV(+) was lower 
than anticipated, which for a large part may be explained by the relatively late in the RSV season 
start of recruitment for the first participating country in the study (Panama). It is assumed that 
when recruitment into the birth cohort is re-initiated in time for the next season, ~10% of 
participants will be diagnosed as RSV(+). In order to maintain the target of 40 participants in the 
interventional part, the maximum number of infants that may be recruited in the birth cohort is 
set at 1,300. With an additional 438 participants in the birth cohort, an assumption of 10% 
incidence of RSV(+) and a 50% rate of infants who will enter the interventional stage, the target 
of 40 participants in the interventional stage is expected to be reached.


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As the sample size of the 2 parts are linked and assumptions have to be made on the percentages 
of RSV(+) and eligibility, the study may continue at the discretion of the sponsor when more 
than 40 participants are included in the interventional stage (with a maximum of 60) and may 
also be considered completed if at least 32 infants have been included in the interventional part. 
9.2.
Populations for Analyses
For purposes of analysis, the following populations are defined:
Table 3:
Populations for Analyses
Part 
Population
Description
Observational 
Stage (Part 1)
Enrolledobs
All participants who signed the ICF of the observational stage
ARI visitobs
All participants who had at least one ARI-visit at the site
RSV(+)obs
All participants who were diagnosed RSV positive based on the study-related 
RSV molecular-based diagnostic assay during an ARI-visit at the site
Safetyobs
All participants who had at least one swab or blood draw
Interventional 
Stage (Part 2)
Enrolled
All participants who signed the ICF of the interventional stage 
Randomized
All participants who were randomized in the interventional stage of the study
ITT
All participants who were randomized in the interventional stage and who took at 
least 1 dose of study medication
ITT-i
All participants who were in the ITT population and who were infected with the 
RSV virus and who had a centrally confirmed RSV infection with an RSV viral 
load of ≥1 log10 copies/mL above the lower limit of quantification (LLOQ) at 
baseline
PK-evaluable
All participants who took at least 1 dose of JNJ-53718678 and for whom the 
Day 3 sample was evaluable 
Safety
All participants who took at least 1 dose of study medication
9.3.
Statistical Analyses
9.3.1.
Participant Information
Participant characteristics will be summarized for the observational stage and interventional 
stage separately and by population. Parent/caregiver characteristics will also be summarized.
For the interventional part, all demographic (eg, age, length, weight, race, gender), other initial 
participant characteristics (physical examination, medical and surgical history, family history, 
concomitant diseases), RSV disease characteristics (eg, subtype, time since symptom onset, age 
at RSV[+]) will be tabulated and analyzed descriptively by treatment group and overall, by 
population (if applicable).
9.3.2.
Analyses Specific to the Observational Stage
For all participants of the observational stage that reached the threshold for an ARI-alert, the 
onset and evolution of clinical symptoms of pediatric RSV disease will be analyzed 
descriptively. The signs and symptoms that are captured in the RSV mobile App and by the 
investigator will be compared for those that were diagnosed RSV(-) and RSV(+) (for participants 
that performed an ARI visit). For participants that were RSV(+), the viral load will be 
summarized over time, and viral load will be correlated with disease characteristics as captured 
on the RSV mobile App and as measured at the site.


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For the exploratory endpoints a key variable is the score that triggered the site visit. It will be 
investigated if the RSV mobile App data and other characteristics can predict this score. The 
score itself (and its components) will be used correlate to subsequent parameters such as RSV 
diagnosis (positive/negative), disease progression, viral kinetics, and participation in the 
interventional stage.
To investigate the feasibility of the birth cohort to provide an early diagnosis of RSV, 
characteristics of parent(s)/caregiver(s) will be correlated to components such as (but not limited 
to) RSV mobile App compliance, protocol adherence (eg, site visits), participation in 
interventional stage, randomization within 24 hours of alert. Correspondence of disease 
assessment across parent(s)/caregiver(s) and site will be investigated over time.
For the analysis of viral load kinetics during the observational stage, refer to Section 9.3.3.1.
More details regarding the analysis of these data will be provided in the SAP.
9.3.3.
Viral Kinetics and Clinical Outcome Analyses
Details regarding the analyses will be described in the SAP.
9.3.3.1.
Viral Load Kinetics (Observational Stage)
Viral load kinetics will be determined based on measurements of RSV viral load in nasal 
secretions by a qRT-PCR assay on mid-turbinate nasal swab specimens. These data will be 
analyzed descriptively and graphically. For the RSV viral load assessed before the day of RSV 
diagnosis and at the diagnosis itself it will be investigated if the signs and symptoms observed 
and captured previous to these RSV viral load assessments have predictive value for the absence 
or presence of the virus as well as for the key characteristics of the viral load (eg, peak viral 
load), when virus is present. The correspondence between viral load and signs and symptoms 
will be investigated graphically by visualizing the viral load and signs and symptoms together 
over a period of time before and after RSV diagnosis. Exploratory analyses and details will be
described in the SAP. 
9.3.3.2.
Antiviral Activity (Interventional Stage)
Viral load kinetics will be determined based on measurements of RSV viral load in nasal 
secretions by a qRT-PCR assay on mid-turbinate nasal swab specimens. These data will be 
analyzed graphically and descriptively. Kaplan-Meier Curves will be produced to describe the 
time to event data. The primary population for the efficacy/antiviral activity analysis will be the 
intent-to-treat infected population consisting of all randomized participants who received at least 
one dose of study medication and who have a centrally confirmed RSV infection with an RSV 
viral load of ≥1 log10 copies/mL above the lower limit of quantification (LLOQ) at baseline.
The primary efficacy endpoint is the RSV viral load AUC from immediately prior to first dose of 
study medication through Day 5 (AUC1-5 days) derived from the RSV viral load as measured by a 
qRT-PCR assay in nasal swabs. Mean log10 viral load values over time will be analyzed using a 
restricted maximum likelihood-based repeated measures approach. Analyses will include the 


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fixed, categorical effects of treatment, stratum (time from ARI alert within 24 hours or outside 
24 hours), 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. Differences between 
treatment groups in viral load for time points, and the difference in the AUC1-5 days between 
treatment groups will be derived using appropriate contrasts deriving least square mean 
differences, including the 90% 2-sided confidence intervals. The primary null hypothesis of 
worse or no treatment effect will be rejected if the viral load AUC1-5 days is significantly lower 
than placebo using a one-sided test at the 0.05 significance level. 
9.3.3.3.
Clinical Course of RSV Infection
Endpoints related to evaluation of the clinical course of RSV infection will be analyzed 
graphically and descriptively. Both scores from the RSV mobile App as well as PRESORS 
scores will be summarized descriptively over time and may be modeled using longitudinal 
analysis. Relationship between symptoms reported on the RSV mobile App and becoming 
RSV(+) (versus RSV[-]), and need for hospitalization (versus outpatient) will be investigated 
graphically. Also, correlation between symptoms reported on the RSV mobile App as predictive 
of viral load characteristics will be investigated, as well as correlation between signs and 
symptoms and viral load over time. Time-to variables will be analyzed using Kaplan-Meier 
plots. For the interventional stage these might be modeled using an accelerated failure time 
model, adjusted for covariates, such as stratum and baseline viral load, to estimate differences 
between treatment groups. Endpoints related to hospital stay will be explored.
More details regarding the analysis of these data will be described in the SAP.
9.3.3.4.
Correlation Between Antiviral Effect and Clinical Course Endpoints
Selected antiviral effect and selected clinical course endpoints (eg, RSV mobile App scores and 
PRESORS symptoms and total score) will be subjected to correlation analysis. Various 
approaches, including graphical analysis will be used, and data may be modeled using joint 
analysis and structural equation modeling.
More details regarding the analysis of these data will be described in the SAP.
9.3.3.5.
Viral Sequencing
The results of viral sequencing will be evaluated by the sponsor’s virologist. Pre-treatment 
polymorphisms and relevant post-baseline changes in the RSV F-gene (and other regions of the 
RSV genome, if applicable and on request of the sponsor’s virologist) will be tabulated and 
described. The effect of pre-treatment RSV F-gene polymorphisms and relevant post-baseline 
RSV F-gene changes on antiviral response and/or clinical outcomes will be explored.


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9.3.4.
Safety Analyses
For safety analyses a distinction will be made between the observational stage and the 
interventional stage. For the observational stage all data will be summarized descriptively for all 
participants enrolled. 
For the interventional stage a separate analysis will be performed. 
All safety analyses will be made on the Safety Population as defined in Table 3.
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 AEs 
with onset during the interventional stage 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 participants who experience at least 1 occurrence of the given event will be 
summarized by treatment group.
Summaries, listings, datasets, or participant narratives may be provided, as appropriate, for those 
participants who die, who discontinue treatment due to an AE, or who experience a severe or an
SAE.
Clinical Laboratory Tests
Laboratory data will be summarized by type of laboratory test. Reference ranges and markedly 
abnormal results (specified in the SAP) will be used in the summary of laboratory data. 
The laboratory abnormalities will be determined per the criteria specified in the DMID Pediatric 
Toxicity Tables (version November 2007) and in accordance with the normal ranges of the 
clinical laboratory if no DMID gradings are available.
Descriptive statistics will be calculated for each laboratory analyte at baseline and for observed 
values and changes from baseline at each scheduled time point.
Changes from baseline results will be presented in pre- versus post-treatment cross-tabulations 
(with classes for below, within, and above normal ranges).
A listing of participants with any laboratory results outside the reference ranges will be provided. 
A listing of participants with any markedly abnormal laboratory results will also be provided.
Electrocardiogram
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 (the predose ECG will be used as baseline).
The ECG variables that will be analyzed are heart rate, PR interval, QRS interval, QT interval, 
and corrected QT (QTc) interval using the following correction methods: QTcB and QTcF.12


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Frequency tabulations by treatment group of the abnormalities will be made.
Descriptive statistics of QTc intervals and changes from baseline will be summarized at each 
scheduled time point. The percentage of participants with QTc interval >450 milliseconds, 
>480 milliseconds, or >500 milliseconds will be summarized, as will the percentage of 
participants with QTc interval increases from baseline >30 milliseconds or >60 milliseconds.
All clinically relevant abnormalities in ECG waveform that are changes from the baseline 
readings will be reported (eg, changes in T-wave morphology or the occurrence of U-waves).
Vital Signs
Descriptive statistics of actual values and changes from baseline will be summarized at each 
scheduled time point. The percentage of participants with values beyond clinically relevant limits 
(as defined in the SAP) will be summarized. 
Physical Examinations
Clinically relevant findings resulting from the physical examination will be reported as AEs.
9.3.5.
Other Analyses
9.3.5.1.
Pharmacokinetic Analyses
Pharmacokinetic assessment during the study will be based on sparse sampling and will be 
performed using a popPK approach by means of nonlinear mixed-effects modeling.
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 participant characteristics (demographics, 
laboratory variables, race, etc.) will be tested as potential covariates affecting PK parameters. 
Details will be given in a popPK analysis plan and the results of the popPK 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 popPK analysis. Samples 
collected after the snapshot date will be analyzed at a later date, and may be included in a popPK 
re-analysis when they become available after database lock.
Data will be listed for all participants with available whole blood concentrations. Participants 
will be excluded from the PK analysis if their data do not allow for accurate assessment of the 
PK (eg, incomplete administration of the study medication; missing information of dosing and 
sampling times; concentration data not sufficient for PK parameter calculation). All
concentrations below the lowest quantifiable concentration or missing data will be labeled as 
such in the concentration database. All participants and samples excluded from the analysis will 
be clearly documented in the study report.


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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.
9.3.5.2.
Pharmacokinetic/Pharmacodynamic Analyses
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.
Results of PK/PD analyses may be presented in a separate report.
9.3.5.3.
Host Genetic Analyses
DNA samples will be used for research related to RSV disease susceptibility or severity. 
Genomic research may consist of the analysis of one or more candidate genes or of the analysis 
of genetic markers throughout the genome in relation to RSV.
Analyses may be conducted at the sponsor’s discretion and reported separately from this study.
9.3.5.4.
Biomarkers Analyses
Statistical approaches to explore correlations between clinical outcome, viral load, and 
biomarkers in blood (and potentially in mid-turbinate nasal swab samples and stool samples) 
vary and depend on the different data types of the applied technology platforms, as well as on the 
extent of observed differences among study participants. Analyses may be conducted at the 
sponsor’s discretion and reported separately from this study.
9.3.5.5.
Other Analyses
Data from the viral (other than RSV) and bacterial co-pathogen testing at baseline (Day 1 
predose) in the interventional stage will be listed and tabulated.
9.4.
Interim Analysis
No formal interim analysis has been planned. 
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.
In case of an interim analysis, investigators, participants’ parents/caregivers, and local sponsor 
representatives will remain blinded. The sponsor leadership team responsible for decisions and 
the central study team required to generate and interpret results will have access to unblinded 
data.
9.5.
Independent Data Monitoring Committee
An IDMC, will be established as noted in Committees Structure in Appendix 3, Regulatory, 
Ethical, and Study Oversight Considerations.


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The IDMC will be established to monitor and review data for the interventional stage in an 
unblinded manner on a regular basis to ensure the continuing safety of the participants enrolled 
in this stage. The committee will meet periodically to review safety data. 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 participants.
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. A Sponsor Committee, consisting of senior sponsor 
personnel not involved in the conduct of the study, will be established and will be responsible for 
decision making, considering the IDMC recommendations, and will communicate these 
decisions to the study team. Details are provided in the IDMC Charter.


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10.
SUPPORTING DOCUMENTATION AND OPERATIONAL CONSIDERATIONS
10.1.
Appendix 1: Abbreviations
AE
adverse event
ALT
alanine transaminase
App
application
aPTT
activated partial thromboplastin time
ARC
Anticipated Event Review Committee
ARI
acute respiratory infection
AST
aspartate aminotransferase
AUC
area under the RSV viral load-time curve
AUC0-xh
AUC from time of administration up to time x,
AUC0-∞
AUC from time of administration extrapolated to infinity
AUC1-5 days
AUC from immediately prior to first dose of study medication through Day 5
BALF
bronchoalveolar lavage fluid
BCRP
breast cancer resistance protein
bid
twice daily
BM
bone marrow
BW
body weight
Cmax
maximum plasma concentration
Cmin
minimum plasma concentration
CNS
central nervous system
COVID-19
Coronavirus Disease 2019
CPK
creatine phosphokinase
Ctrough
predose plasma concentration
CYP
Cytochrome P450
DMID
Division of Microbiology and Infectious Diseases
EC50
effective concentration for 50% inhibition
ECG
electrocardiogram
eCRF
electronic case report form
ED
emergency department
eDC
electronic data capture
FC
food consumption
GCP
Good Clinical Practice
GGT
γ-glutamyltransferase
GLP
Good Laboratory Practice
HCP
healthcare professional
hERG
human-ether-a-gogo-related
HIV
human immunodeficiency virus
IB
Investigator's Brochure
IC50
50% inhibition concentration
ICF
informed consent form
ICH
International Conference on Harmonisation of Technical Requirements for Pharmaceuticals for 
Human Use
ICMJE
International Committee of Medical Journal Editors
ICU
intensive care unit
IDMC
Independent Data Monitoring Committee
IEC
Independent Ethics Committee
IFN
interferon
IKr
cardiac potassium membrane current
IRB
Institutional Review Board
IV
intravenous
IWRS
interactive web response system
LLOQ
lower limit of quantification
LRTI
lower respiratory tract infection
MATE
multidrug and toxin extrusion


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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
PD
pharmacodynamic(s)
P-gP
P-glycoprotein
PK
pharmacokinetic(s)
PND
post-natal day
popPK
population pharmacokinetic(s)
PQC
Product Quality Complaint
PRESORS
Pediatric RSV Electronic Severity and Outcome Rating Systems
PT
prothrombin time
q24h
every 24 hours
qd
once daily
QTcB
QT interval corrected for heart rate according to Bazett's formula
QTcF
QT interval corrected for heart rate according to Fridericia's formula
qRT-PCR
quantitative reverse transcription polymerase chain reaction
RBC
red blood cell
RSV
respiratory syncytial virus
SAE
serious adverse event
SAP
statistical analysis plan
SpO2
peripheral capillary oxygen saturation
SUSAR
suspected unexpected serious adverse reaction
TEAE
treatment-emergent AE
tmax
time to reach maximum plasma concentration
TQT
thorough QT
TR
total radioactivity
UGT
glucuronyl transferase
ULN
upper limit of normal
WBC
white blood cell
WHO
World Health Organization


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10.2.
Appendix 2: Clinical Laboratory Tests
The following tests will be performed according to the Schedule of Activities by the local 
laboratory:

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
Note: In case of hypokalemia and/or hypomagnesemia at screening or Day 8, the levels of 
potassium and/or magnesium should be checked as soon as possible and corrected to prevent 
cardiac disturbances.

Estimated glomerular filtration rate (eGFR) will be calculated/reported by the local lab 
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
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 as per the Schedule of Activities (SoA). If dipstick is abnormal, 
microscopic evaluation should be performed, with evaluation of sediment as listed above.
In the microscopic examination, observations other than the presence of WBC, RBC, and
casts may also be reported by the laboratory and need to be captured in the eCRF.


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


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


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
Sponsor-approved ICF (and any other written materials to be provided to the participant’s 
parent[s]/legally acceptable representative[s])

IB (or equivalent information) and amendments/addenda

Sponsor-approved participant recruiting materials

Information on compensation for study-related injuries or payment to participants for 
participation in the study, if applicable

Investigator's curriculum vitae or equivalent information (unless not required, as 
documented by the IEC/IRB)

Information regarding funding, name of the sponsor, institutional affiliations, other potential 
conflicts of interest, and incentives for participants

Any other documents that the IEC/IRB requests to fulfill its obligation
This study will be undertaken only after the IEC/IRB has given full approval of the final 
protocol, amendments (if any, excluding the ones that are purely administrative, with no 
consequences for participants, data or study conduct, unless required locally), the ICF, applicable 
recruiting materials, and participant compensation programs, and the sponsor has received a copy 
of this approval. This approval letter must be dated and must clearly identify the IEC/IRB and 
the documents being approved.
Approval for the collection of optional samples for research and for the corresponding ICFs must 
be obtained from the IEC/IRB. Approval for the protocol can be obtained independent of this 
optional research component. 
During the study the investigator (or sponsor where required) will send the following documents 
and updates to the IEC/IRB for their review and approval, where appropriate:

Protocol amendments (excluding the ones that are purely administrative, with no 
consequences for participants, data or study conduct)

Revision(s) to ICF and any other written materials to be provided to participants

If applicable, new or revised participant recruiting materials approved by the sponsor

Revisions to compensation for study-related injuries or payment to participants for 
participation in the study, if applicable

New edition(s) of the IB and amendments/addenda

Summaries of the status of the study at intervals stipulated in guidelines of the IEC/IRB (at 
least annually)

Reports of AEs that are serious, unlisted/unexpected, and associated with the study 
medication

New information that may adversely affect the safety of the participants or the conduct of 
the study

Deviations from or changes to the protocol to eliminate immediate hazards to the 
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
Report of deaths of participants under the investigator's care

Notification if a new investigator is responsible for the study at the site

Development Safety Update Report and Line Listings, where applicable

Any other requirements of the IEC/IRB
For all protocol amendments (excluding the ones that are purely administrative, with no 
consequences for participants, data or study conduct), the amendment and applicable ICF 
revisions must be submitted promptly to the IEC/IRB for review and approval before 
implementation of the change(s).
At least once a year, the IEC/IRB will be asked to review and reapprove this study, where 
required.
At the end of the study, the investigator (or sponsor where required) will notify the IEC/IRB 
about the study completion.
Country Selection
This study will only be conducted in those countries where the intent is to launch or otherwise 
help ensure access to the developed product if the need for the product persists, unless explicitly 
addressed as a specific ethical consideration in Section 4.2.1, Study-Specific Ethical Design 
Considerations.
Other Ethical Considerations
For study-specific ethical design considerations, refer to Section 4.2.1.
INFORMED CONSENT PROCESS
Each participant’s parent(s)/legally acceptable representative(s) must give written consent 
according to local requirements after the nature of the study has been fully explained. The ICF(s) 
must be signed before performance of any study-related activity. The ICF(s) that is/are used must 
be approved by both the sponsor and by the reviewing IEC/IRB and be in a language that the 
participant’s parent(s)/legally acceptable representative(s) can read and understand. The 
informed consent should be in accordance with principles that originated in the Declaration of 
Helsinki, current ICH and GCP guidelines, applicable regulatory requirements, and sponsor 
policy.
Before enrollment in the study, the investigator or an authorized member of the study-site 
personnel must explain to potential participant’s parent(s)/legally acceptable representative(s) the 
aims, methods, reasonably anticipated benefits, and potential hazards of the study, and any 
discomfort participation in the study may entail. The participant’s parent(s)/legally acceptable 
representative(s) will be informed that the infant’s participation in the study is voluntary and that 
they may withdraw consent to participate at any time. They will be informed that choosing not to 
participate or to withdraw from the study will not affect the care the infant will receive for the 
treatment of his or her disease. Finally, they will be told that the investigator will maintain a 


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participant identification register for the purposes of long-term follow up if needed and that their 
records may be accessed by health authorities and authorized sponsor personnel without 
violating the confidentiality of the infant, to the extent permitted by the applicable law(s) or 
regulations. By signing the ICF the participant’s parent(s)/legally acceptable representative(s) 
is/are authorizing such access.
The participant’s parent(s)/legally acceptable representative(s) will be given sufficient time to 
read the ICF and the opportunity to ask questions. After this explanation and before entry into 
the study, consent should be appropriately recorded by means of the participant’s 
parent(s)/legally acceptable representative(s) personally dated signature. After having obtained 
the consent, a copy of the ICF must be given to the participant’s parent(s)/legally acceptable 
representative(s).
Participant’s parent(s)/legally acceptable representative(s) will be asked for consent to provide 
optional samples for research where local regulations permit. After informed consent for the 
study is appropriately obtained, the participant’s parent(s)/legally acceptable representative(s) 
will be asked to sign and personally date a separate ICF indicating agreement to participate in the 
optional research component. Refusal to participate in the optional research will not result in 
ineligibility for the study. A copy of this signed ICF will be given to the participant’s 
parent(s)/legally acceptable representative(s).
DATA PROTECTION
Privacy of Personal Data
The collection and processing of personal data from participants enrolled in this study will be 
limited to those data that are necessary to fulfill the objectives of the study. No personal data (eg, 
no phone number, e-mail, first/last name, mac address,…) will be stored.
These data must be collected and processed with adequate precautions to ensure confidentiality 
and compliance with applicable data privacy protection laws and regulations. Appropriate 
technical and organizational measures to protect the personal data against unauthorized 
disclosures or access, accidental or unlawful destruction, or accidental loss or alteration must be 
put in place. Sponsor personnel whose responsibilities require access to personal data agree to
keep the identity of participants confidential.
The informed consent obtained from the participant’s parent(s) (or his or her legally acceptable 
representative) includes explicit consent for the processing of personal data and for the 
investigator/institution to allow direct access to the infant’s original medical records (source 
data/documents) for study-related monitoring, audit, IEC/IRB review, and regulatory inspection. 
This consent also addresses the transfer of the data to other entities and to other countries.
The participant’s parent(s)/legally acceptable representative(s) has/have the right to request 
through the investigator access to the infant’s personal data and the right to request rectification 
of any data that are not correct or complete. Reasonable steps will be taken to respond to such a 


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request, taking into consideration the nature of the request, the conditions of the study, and the 
applicable laws and regulations.
Exploratory DNA and biomarker research is not conducted under standards appropriate for the 
return of data to participants. In addition, the sponsor cannot make decisions as to the 
significance of any findings resulting from exploratory research. Therefore, exploratory research 
data will not be returned to participants or investigators, unless required by law or local 
regulations. Privacy and confidentiality of data generated in the future on stored samples will be 
protected by the same standards applicable to all other clinical data.
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 scientific and exploratory DNA and biomarker research if the participant’s 
parent(s)/legally acceptable representative(s) consent. Samples will only be used to understand 
RSV disease. The research may begin at any time during the study or the post-study storage 
period. 
Stored samples will be coded throughout the sample storage and analysis process and will not be 
labeled with personal identifiers. Participants may withdraw their consent for their samples to be 
stored for research (refer to Section 7.2.1, Withdrawal From the Use of Research Samples).
COMMITTEES STRUCTURE
Independent Data Monitoring Committee
The IDMC will be established to monitor and review data for the interventional stage in an 
unblinded manner on a regular basis to ensure the continuing safety of the participants enrolled 
in this stage. The committee will meet periodically to review safety data. 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 participants.
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. A Sponsor Committee, consisting of senior sponsor 
personnel not involved in the conduct of the study, will be established and will be responsible for 
decision making, considering the IDMC recommendations, and will communicate these 
decisions to the study team. Details are provided in the IDMC Charter.
PUBLICATION POLICY/DISSEMINATION OF CLINICAL STUDY DATA
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, including host genetic and exploratory biomarker 
research data, generated as a result of this study, are considered confidential and remain the sole 


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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 host genetic 
and exploratory biomarker analyses performed after the Clinical Study Report has been issued 
will be reported in a separate report and will not require a revision of the Clinical Study Report. 
Study participant identifiers will not be used in publication of results. Any work created in 
connection with performance of the study and contained in the data that can benefit from 
copyright protection (except any publication by the investigator as provided for below) shall be 
the property of the sponsor as author and owner of copyright in such work.
Consistent with Good Publication Practices and International Committee of Medical Journal 
Editors (ICMJE) guidelines, the sponsor shall have the right to publish such primary 
(multicenter) data and information without approval from the investigator. The investigator has 
the right to publish study site-specific data after the primary data are published. If an investigator 
wishes to publish information from the study, a copy of the manuscript must be provided to the 
sponsor for review at least 60 days before submission for publication or presentation. Expedited 
reviews will be arranged for abstracts, poster presentations, or other materials. If requested by 
the sponsor in 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 sub-study 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 of the 
availability of the final data (tables, listings, graphs), 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 


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work or revised it critically for important intellectual content; and given final approval of the 
version to be published; and agreed to be accountable for all aspects of the work in ensuring that 
questions related to the accuracy or integrity of any part of the work are appropriately 
investigated and resolved.
Registration of Clinical Studies and Disclosure of Results
The sponsor will register and disclose the existence of and the results of clinical studies as 
required by law. The disclosure of the final study results will be performed after the end of study 
in order to ensure the statistical analyses are relevant.
DATA QUALITY ASSURANCE
Data Quality Assurance/Quality Control
Steps to be taken to ensure the accuracy and reliability of data include the selection of qualified 
investigators and appropriate study sites, review of protocol procedures with the investigator and 
study-site personnel before the study, periodic monitoring visits by the sponsor, and direct 
transmission of clinical laboratory data from a central laboratory (if applicable) and the data 
transmitted by the participants mobile phone into the sponsor's data base. 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. 
CASE REPORT FORM COMPLETION
Case report forms are prepared and provided by the sponsor for each participant in electronic 
format. All data relating to the study must be recorded in the eCRF. All eCRF entries, 
corrections, and alterations must be made by the investigator or authorized study-site personnel. 
The investigator must verify that all data entries in the eCRF are accurate and correct.
The study data will be transcribed by study-site personnel from the source documents onto an 
eCRF, if applicable. Study-specific data will be transmitted in a secure manner to the sponsor.
Worksheets may be used for the capture of some data to facilitate completion of the eCRF. Any 
such worksheets will become part of the participant's source documents. Data must be entered 
into eCRF in English. The eCRF must be completed as soon as possible after a participant visit 
and the forms should be available for review at the next scheduled monitoring visit.
All participative measurements (eg, pain scale information or other questionnaires) will be 
completed by the same individual who made the initial baseline determinations whenever 
possible.


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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 a query (generated by the eDC tool).

Sponsor or sponsor delegate can generate a query for resolution by the investigator and 
study-site personnel.
SOURCE DOCUMENTS
At a minimum, source documents consistent in the type and level of detail with that commonly 
recorded at the study site as a basis for standard medical care must be available for the following: 
participant identification, eligibility, and study identification; study discussion and date of signed 
informed consent; dates of visits; results of safety and efficacy parameters as required by the 
protocol; record of all AEs and follow-up of AEs; concomitant medication; study medication
receipt/dispensing/return records; study medication administration information; and date of study 
completion and reason for early discontinuation of study medication or withdrawal from the 
study, if applicable. 
The author of an entry in the source documents should be identifiable.
Specific details required as source data for the study and source data collection methods will be 
reviewed with the investigator before the study and will be described in the monitoring 
guidelines (or other equivalent document).
An electronic source system may be utilized, which contains data traditionally maintained in a 
hospital or clinic record to document medical care (eg, electronic source documents) as well as 
the study-specific data fields as determined by the protocol. These data are 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 electronic source system may not be limited to that found in the eCRF. Data in this system 
may be considered source documentation. The following data will be recorded directly on the 
electronic device and will be considered source data:
clinician PRESORS and 
parent(s)/caregiver(s) PRESORS, medication, nasal swabs, and temperature logs.
MONITORING
The sponsor will use a combination of monitoring techniques to monitor this study.
The sponsor will perform on-site monitoring visits as frequently as necessary. The monitor will 
record dates of the visits in a study site visit log that will be kept at the study site. The first post-
initiation visit will be made as soon as possible after enrollment has begun. At these visits, the 
monitor will compare the data entered into the eCRF with the source documents (eg, hospital, 
clinic, and physician’s office medical records); a sample may be reviewed. The nature and 
location of all source documents will be identified to ensure that all sources of original data 


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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.
In addition to on-site monitoring visits, remote contacts can occur. It is expected that during 
these remote contacts, study-site personnel will be available to provide an update on the progress 
of the study at the site.
ON-SITE AUDITS
Representatives of the sponsor's clinical quality assurance department may visit the study site at 
any time during or after completion of the study to conduct an audit of the study in compliance 
with regulatory guidelines and company policy. These audits will require access to all study 
records, including source documents, for inspection. Participant privacy must, however, be 
respected. The investigator and 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.
RECORD RETENTION
In compliance with the ICH/GCP guidelines, the investigator/institution will maintain all eCRF
and all source documents that support the data collected from each participant, as well as all 
study documents as specified in ICH/GCP Section 8, Essential Documents for the Conduct of a 
Clinical Trial, and all study documents as specified by the applicable regulatory requirement(s). 
The investigator/institution will take measures to prevent accidental or premature destruction of 
these documents.
Essential documents must be retained until at least 2 years after the last approval of a marketing 
application in an ICH region and until there are no pending or contemplated marketing 
applications in an ICH region or until at least 2 years have elapsed since the formal 
discontinuation of clinical development of the investigational product. These documents will be 
retained for a longer period if required by the applicable regulatory requirements or by an 


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agreement with the sponsor. It is the responsibility of the sponsor to inform the 
investigator/institution as to when these documents no longer need to be retained.
If the responsible investigator retires, relocates, or for other reasons withdraws from the 
responsibility of keeping the study records, custody must be transferred to a person who will 
accept the responsibility. The sponsor must be notified in writing of the name and address of the 
new custodian. Under no circumstance shall the investigator relocate or dispose of any study 
documents before having obtained written approval from the sponsor.
If it becomes necessary for the sponsor or the appropriate regulatory authority to review any 
documentation relating to this study, the investigator/institution must permit access to such 
reports.
STUDY AND SITE START AND CLOSURE
First Act of Recruitment
The first site open is considered the first act of recruitment and it becomes the study start date.
Study Termination
The sponsor reserves the right to close the study site or terminate the study at any time for any 
reason at the sole discretion of the sponsor. Study sites will be closed upon study completion. A 
study site is considered closed when all required documents and study supplies have been 
collected and a study-site closure visit has been performed.
The investigator may initiate study-site closure at any time, provided there is reasonable cause 
and sufficient notice is given in advance of the intended termination.
Reasons for the early closure of a study site by the sponsor or investigator may include but are 
not limited to:

Failure of the investigator to comply with the protocol, the requirements of the IEC/IRB or 
local health authorities, the sponsor's procedures, or GCP guidelines

Inadequate recruitment of participants by the investigator

Discontinuation of further JNJ-53718678 development


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10.4.
Appendix 4: Adverse Events: Definitions and Procedures for Recording, 
Evaluating, Follow-up, and Reporting
ADVERSE EVENT DEFINITIONS AND CLASSIFICATIONS
Adverse Event
An AE is any untoward medical occurrence in a clinical study participant administered a 
medicinal (investigational or non-investigational) product. An AE does not necessarily have a 
causal relationship with the study medication. An AE can therefore be any unfavorable and 
unintended sign (including an abnormal finding), symptom, or disease temporally associated 
with the use of a medicinal (investigational or non-investigational) product, whether or not 
related to that medicinal (investigational or non-investigational) product. (Definition per 
International Conference on Harmonisation [ICH])
This includes any occurrence that is new in onset or aggravated in severity or frequency from the 
baseline condition, or abnormal results of diagnostic procedures, including laboratory test 
abnormalities.
Note: The sponsor collects AEs starting with the signing of the ICF (refer to All Adverse Events
under Section 8.6.1, Time Period and Frequency for Collecting Adverse Events and Serious 
Adverse Events Information, for time of last AE recording).
Serious Adverse Event
An SAE based on ICH and European Union (EU) Guidelines on Pharmacovigilance for 
Medicinal Products for Human Use is any untoward medical occurrence that at any dose:

Results in death

Is life-threatening
(The participant was at risk of death at the time of the event. It does not refer to an event that 
hypothetically might have caused death if it were more severe.)

Requires inpatient hospitalization or prolongation of existing hospitalization

Results in persistent or significant disability/incapacity

Is a congenital anomaly/birth defect

Is a suspected transmission of any infectious agent via a medicinal product

Is Medically Important*
*Medical and scientific judgment should be exercised in deciding whether expedited reporting is 
also appropriate in other situations, such as important medical events that may not be 
immediately life threatening or result in death or hospitalization but may jeopardize the 
participant or may require intervention to prevent one of the other outcomes listed in the 
definition above. These should usually be considered serious.


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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 Study Medication 
An AE is considered associated with the use of the study medication if the attribution is possible, 
probable, or very likely by the definitions listed below (see Attribution Definitions).
ATTRIBUTION DEFINITIONS
Not Related
An AE that is not related to the use of the study medication.
Doubtful
An AE for which an alternative explanation is more likely, eg, concomitant treatment(s), 
concomitant disease(s), or the relationship in time suggests that a causal relationship with the 
study medication is unlikely.
Possible
An AE that might be due to the use of the study medication. An alternative explanation, 
eg, concomitant treatment(s), concomitant disease(s), is inconclusive. The relationship in time is 
reasonable; therefore, the causal relationship with the study medication cannot be excluded.
Probable
An AE that might be due to the use of the study medication. The relationship in time is 
suggestive (eg, confirmed by dechallenge). An alternative explanation is less likely, 
eg, concomitant treatment(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 treatment(s), concomitant disease(s). The relationship in 
time is very suggestive (eg, it is confirmed by dechallenge and rechallenge).
SEVERITY CRITERIA 
An assessment of severity grade 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.


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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 participant (eg, laboratory abnormalities).
SPECIAL REPORTING SITUATIONS
Safety events of interest on a sponsor study medication that may require expedited reporting or 
safety evaluation include, but are not limited to:

Overdose of a sponsor study medication

Suspected abuse/misuse of a sponsor study medication

Accidental or occupational exposure to a sponsor study medication

Medication error involving a sponsor product (with or without participant/patient exposure 
to the sponsor study medication, eg, name confusion)
Special reporting situations should be recorded in the eCRF. Any special reporting situation that 
meets the criteria of an SAE should be recorded on the Serious Adverse Event page of the eCRF.
PROCEDURES
AEs will be reported by the participant (or, when appropriate, by a caregiver, surrogate, or the 
participant's legally acceptable representative) for the duration of the study depending on the 
stage of the study (see Section 8.6.1).
All Adverse Events
All AEs, regardless of seriousness, severity, or presumed relationship to study medication, must 
be recorded using medical terminology in the source document and the eCRF. Whenever 
possible, diagnoses should be given when signs and symptoms are due to a common etiology 
(eg, cough, runny nose, sneezing, sore throat, and head congestion should be reported as "upper 
respiratory infection"). Investigators must record in the eCRF their opinion concerning the 
relationship of the AE to study therapy. All measures required for AE management must be 
recorded in the source document and reported according to sponsor instructions.
For all studies with an outpatient phase, including open-label studies, the participant 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: 

Study number

Statement, in the local language(s), that the participant is participating in a clinical study

Investigator's name and 24-hour contact telephone number

Local sponsor's name and 24-hour contact telephone number (for medical personnel only)


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
Site number

Participant number

Any other information that is required to do an emergency breaking of the blind
Serious Adverse Events
All SAEs that have not resolved by the end of the study, or that have not resolved upon 
discontinuation of the participant's participation in the study, must be followed until any of the 
following occurs:

The event resolves

The event stabilizes

The event returns to baseline, if a baseline value/status is available

The event can be attributed to agents other than the study medication or to factors unrelated 
to study conduct

It becomes unlikely that any additional information can be obtained (participant or health 
care practitioner refusal to provide additional information, lost to follow-up after 
demonstration of due diligence with follow-up efforts)
Suspected transmission of an infectious agent by a medicinal product will be reported as an SAE. 
Any event requiring hospitalization (or prolongation of hospitalization) that occurs during the 
course of a participant's participation in a study must be reported as an SAE, except 
hospitalizations for the following:

Hospitalizations not intended to treat an acute illness or AE (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 considered SAEs. Any AE that results in a prolongation of the originally planned 
hospitalization is to be reported as a new SAE.
The cause of death of a participant in a study within the study duration of the last dose of study 
medication, whether or not the event is expected or associated with the study medication, is 
considered an SAE.
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.


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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 
participants, 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.
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 an SAE, the study-site personnel must report the PQC to the 
sponsor according to the SAE reporting timelines (refer to Section 8.6.1, Time Period and 
Frequency for Collecting Adverse Event and Serious Adverse Event Information). A sample of 
the suspected product should be maintained for further investigation if requested by the sponsor.
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.


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


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


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


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


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


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


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


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


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


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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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10.6.
Appendix 6: Cardiovascular Safety – Abnormalities
ECG
All important abnormalities from the ECG readings will be listed.
Parameter (unit)
Age class
Abnormally low
Abnormally high
PR (msec)
0 – 2 yrs
NA
>150
QRS (msec)
0 - 2yrs
NA
>79
QT (msec)
0 - 2 years
NA
>500
RR (msec)
0 – 3 mo
<333
>750
3 – 12 mo
<400
>860
1 – 2 years
<430
>1000
Vital Signs
Normal ranges:
Parameter (unit)
Age class
0 – 3 mo
3 – 6 mo
6 – 12 mo
1 – 2 years
Diastolic BP (mmHg)
45 - 55
50 - 65
55 - 65
55 - 70
Systolic BP (mmHg)
65 -85
70 - 80
80 - 100
90 – 105
Heart rate HR (bpm)
100 - 150
90 – 120
80 - 120
70 - 110
Respiration rate 
35 - 55
30 - 45
25 – 40
20 - 30
Oxygen saturation SpO2 (%) 
≥96
≥96
≥96
≥96
The following clinically relevant abnormalities will be defined for vital signs
Parameter (unit)
Age class
0 – 3 mo
3 – 12 mo
1 - 2-years
Diastolic BP (mmHg)
abnormally low
<35
<40
<40
abnormally high
>65
>85
>90
Systolic BP (mmHg)
abnormally low
<60
<60
<75
abnormally high
>110
>110
>120
Heart rate HR (bpm)
abnormally low
<80
<70
<60
abnormally high
>180
>150
>140
Respiration rate 
abnormally low
<25
<20
<18
abnormally high
>70
>60
>50
Oxygen saturation SpO2 (%) 
abnormally low
<92
<92
<92
References:
http://www.docstoc.com/docs/88983719/Pediatric-Vital-Signs
http://www.coheadquarters.com/PennLibr/MyPhysiology/Appendix/AppendVital1.htm


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10.7.
Appendix 7: Guidance on Study Conduct During the COVID-19 Pandemic
It is recognized that the Coronavirus Disease 2019 (COVID-19) pandemic may have an impact
on the conduct of this clinical study due to, for example, self-isolation/quarantine by participants
and study-site personnel; travel restrictions/limited access to public places, including hospitals; 
study site personnel being reassigned to critical tasks. 
In alignment with recent health authority guidance, the sponsor will be providing options for 
study-related participant management in the event of disruption to the conduct of the study. This 
guidance does not supersede any local or government requirements or the clinical judgement of 
the investigator to protect the health and well-being of participants and site staff. If, at any time, 
a participant’s safety is considered to be at risk, study intervention will be discontinued, and 
study follow-up will be conducted.
Scheduled visits that cannot be conducted in person at the study site will be performed to the 
extent possible remotely/virtually or delayed until such time that on-site visits can be resumed. 
At each contact, participants’ parents/caregivers will be interviewed to collect safety data. Key 
efficacy endpoint assessments should be performed if required and as feasible. Participants’ 
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 participants on study 
intervention, including follow up. Modifications to protocol-required assessments may be 
permitted after consultation between the participant’s parent(s)/caregiver(s) and investigator, and 
with the agreement of the sponsor. Missed assessments/visits will be captured in the clinical trial 
management system for protocol deviations. Discontinuations of study interventions and 
withdrawal from the study should be documented with the prefix “COVID-19-related” in the 
CRF.
The sponsor will continue to monitor the conduct and progress of the clinical study, and any 
changes will be communicated to the sites and to the health authorities according to local 
guidance. If a participant has tested positive for COVID-19 during the study, (s)he should be 
withdrawn from the study. 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 participants’ 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 CRF/eSource by the site personnel where needed.

Administration of the study intervention:
-
If a participant 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 participant’s home to:
o
Instruct participants’ 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) [as per sponsor dosing instructions].
o
Administer the first study intervention themselves or supervise the participants’
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 participant’s home at 
Day 1 will be documented in the participant’s source documents and in the CRF.

Participant Visits/Assessments:
-
Upon an ARI alert, parents/caregivers need to take a nasal swab at home. If a study 
specific on-site visit cannot be conducted due to COVID-19 pandemic, a phone visit 
will be conducted by the site staff to assess the participant’s health status remotely. If 
there is a medical need for the participant to have physical contact with a physician or 
for hospital based care, the parent(s)/caregiver(s) and participant will be invited to the 
site for a SOC visit and follow SOC procedures for hospital visit; therefore, no study 
related procedures will be performed, unless site staff and parent(s)/caregiver(s) can 
agree to perform (some of) the study assessments if allowed by local regulations during 
the COVID-19 pandemic. The parent(s)/caregiver(s) will continue answering the mobile 
App until a next alert. The optional stool samples will be collected in case the 
parent(s)/caregiver(s) has/have consented to this.
-
If a participant 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, Clinician PRESORS and clinical evaluation)
for that particular visit is collected. These assessments and collection should be 
performed at participant’s home by trained delegated site staff or home health service 
staff.
-
There are some assessments that could be conducted virtually via telephone (or 
videoconference, 
eg, 
Facetime, 
Skype, 
if 
possible) 
with 
participants’
parent(s)/caregiver(s) in their homes. This methodology can only be used in accordance 


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with applicable (including local) laws, regulations, guidelines and procedures and with 
consent of participants’ parent(s)/caregiver(s). These virtual assessments include review 
of AEs, concomitant medications and monitoring of parent(s)/caregiver(s) PRESORS 
completion. Please note, the visit windows included in the Schedule of Activities are 
still applicable. It must be documented in the CRF and in the participant’s source 
documents if 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.

On-site Monitoring Visits: In case on-site monitoring visits are not possible due to local 
regulations, restrictions and guidance, the Site Manager will conduct site monitoring visits 
and activities remotely. Additional on-site monitoring visits may be needed in 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 not be conducted to 
comply with national, local and/or organizational social distancing restrictions. Additional 
quality assurance activities such as remote audits or focused review of study related 
documents may take place with limited impact/engagement if possible.


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10.8.
Appendix 8: Protocol Amendment History
DOCUMENT HISTORY
Document
Date
Amendment 3
13-Jul-2020
Amendment 2
05-Jun-2020
Amendment 1
06-Nov-2019
Original Protocol
23-May-2019


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11.
REFERENCES
1.
American Academy of Pediatrics, Subcommittee on Diagnosis and Management of Bronchiolitis. Diagnosis 
and Management of Bronchiolitis. Pediatrics. 2006;118:1774-1793.
2.
Colman PM, Lawrence MC. The structural biology of type I viral membrane fusion. Nat. Rev. Mol. Cell Biol. 
2003; 4(4):309-319.
3.
Emergency Medicine Cases. Episode 59: Bronchiolitis. Available at: 
https://emergencymedicinecases.com/episode-59-bronchiolitis/. Accessed 19 March 2019.
4.
Empey KM, Peebles Jr RS, Kolls JK. Pharmacologic Advances in the Treatment and Prevention of 
Respiratory Syncytial Virus. Clin Infect Dis. 2010; 50(9):1258–1267.
5.
Falsey AR, Walsh EE. Respiratory syncytial virus infection in adults. Clin Microbiol Rev. 
2000;13(3):371-384.
6.
Feltes TF, Sondheimer HM. Palivizumab and the prevention of respiratory syncytial virus illness in pediatric 
patients with congenital heart disease. Expert Opin. Biol. Ther. 2007; 7(9):1471-1480.
7.
Garcia-Mauriño C, Moore-Clingenpeel M, Thomas J, Mertz S, Cohen DM, Ramilo O et al. Viral load 
dynamics and clinical disease severity in infants with respiratory syncytial virus infection. J Infect Dis. 
2019;219(8):1207-1215.
8.
Glezen W, Taber L, Frank A, et al. Risk of primary infection and reinfection with respiratory syncytial virus. 
Am J Dis Child. 1986:140;543-546.
9.
Hall C, Weinberg G, Iwane M, et al. The burden of respiratory syncytial virus infection in young children. 
N Engl J Med. 2009;360:588-598.
10.
Howie SR. Blood sample volumes in child health research: review of safe limits. Bull World Health Organ. 
2011 Jan 1;89(1):46-53.
11.
https://www.crediblemeds.org/pdftemp/pdf/CombinedList.pdf
12.
International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals 
for Human Use. ICH Harmonized Tripartite Guideline E14: Clinical evaluation of QT/QTc interval 
prolongation and proarrhythmic potential for non-antiarrhythmic drugs. ICH 12 May 2005.
13.
Investigator's Brochure: JNJ-53718678, Edition 06. Janssen Research & Development (July 2019).
14.
Investigator's Brochure: JNJ-53718678, Addendum to Edition 06. Janssen Research & Development (April 
2020).
15.
Johansson N, Kalin M, Hedlund J. Clinical impact of combined viral and bacterial infection in patients with 
community-acquired pneumonia. Scand J Infect Dis. 2011;43:609-615.
16.
Leidy N, Margolis M, Marcin J, et al. The impact of severe respiratory syncytial virus on the child, caregiver, 
and family during hospitalization and recovery. Pediatrics. 2005;115(6):1536-1546.
17.
Leung AK, Kellner JD, Davies HD. Respiratory Syncytial Virus bronchiolitis. J Natl Med Assoc. 
2005;97:1708-1713.
18.
Lewis S, DeMuro C, Block SL, et al. Development of a novel observer-reported outcome measure for the 
assessment of Respiratory Syncytial Virus (RSV) infection symptoms in pediatric clinical trials. JPRO. 
2018;2:9.
19.
Nair H, Nokes JD, Gessner BD, et al. Global burden of acute lower respiratory infections due to respiratory 
syncytial virus in young children: a systematic review and meta-analysis. Lancet 2010; 375(9725):1545-1555.
20.
Piedra P, Stark A. Patient education: Bronchiolitis (and RSV) in infants and children (beyond the basics). 
Available at: https://www.uptodate.com/contents/bronchiolitis-and-rsv-in-infants-and-children-beyond-the-
basics. Accessed 19 March 2019.
21.
Ralston S, Lieberthal A, Meissner H, et al. Clinical Practice Guideline: The Diagnosis, Management, and 
Prevention of Bronchiolitis. Pediatrics. 2014;134(5):e1474-e1502. Erratum in: Pediatrics. 2015;136(4):782.
22.
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.
23.
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.
24.
Shi T, McAllister D, O'Brien K, et al. for the RSV Global Epidemiology Network. 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(10098):946-958.
25.
Wainwright C. Acute viral bronchiolitis in children – a very common condition with few therapeutic options. 
Paediatr Respir Rev. 2010; 11(1):39-45.


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Status: Approved,  Date: 13 July 2020
26.
Yusuf S, Piedimonte G, Auais A, et al. The relationship of meteorological conditions to the epidemic activity 
of respiratory syncytial virus. Epidemiol Infect. 2007;135:1077-109.
27.
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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Status: Approved,  Date: 13 July 2020
INVESTIGATOR AGREEMENT

SAP_001.pdf: 
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Janssen Research & Development
Statistical Analysis Plan  
A Two-Part Study With a Birth Cohort (Observational Stage) for Early Diagnosis of 
Respiratory Syncytial Virus (RSV), Followed by an Optional Phase 2a, Randomized, 
Double-blind, Placebo-controlled Study (Interventional Stage) to Evaluate the Antiviral 
Activity, Clinical Outcomes, Safety, Tolerability, and Pharmacokinetics of JNJ-53718678 
in Infants With Acute Respiratory Tract Infection due to RSV
JNJ-53718678RSV2006; Phase 2A
JNJ-53718678 (rilematovir)
Status:
Approved
Date:
2 June 2021
Prepared by:
Janssen Research & Development, a Division of Janssen Pharmaceutica NV.
Document No.: EDMS-RIM-346257, 1.0
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.
NCT04068792


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TABLE OF CONTENTS
TABLE OF CONTENTS ............................................................................................................................... 2
LIST OF IN TEXT TABLES .......................................................................................................................... 5
ABBREVIATIONS ........................................................................................................................................ 6
1.
INTRODUCTION.................................................................................................................................. 7
1.1.
Trial Objectives ................................................................................................................................ 7
1.2.
Trial Design ...................................................................................................................................... 8
1.3.
Statistical Hypotheses for Trial Objectives..................................................................................... 11
1.4.
Sample Size Justification ............................................................................................................... 11
1.5.
Randomization and Blinding .......................................................................................................... 12
1.6.
Observational and Interventional Study Stages............................................................................. 13
2.
GENERAL ANALYSIS DEFINITIONS .............................................................................................. 13
2.1.
Visit Windows and Phase Definitions............................................................................................. 13
2.1.1.
Phase Definitions........................................................................................................................ 13
2.1.2.
Baseline ...................................................................................................................................... 14
2.1.3.
Relative Day ............................................................................................................................... 14
2.1.4.
Analysis Windows for Analysis Visits and Time Points .............................................................. 15
2.2.
Pooling Algorithm for Analysis Centers.......................................................................................... 19
2.3.
Analysis Sets.................................................................................................................................. 20
2.3.1.
All Enrolled Analysis Set............................................................................................................. 20
2.3.2.
All Randomized Analysis Set...................................................................................................... 20
2.3.3.
Efficacy Analysis Set(s) .............................................................................................................. 20
2.3.3.1.
ITT-i Set................................................................................................................................... 20
2.3.3.2.
PP Set...................................................................................................................................... 20
2.3.4.
Safety Analysis Set..................................................................................................................... 21
2.3.4.1.
Safety Set ................................................................................................................................ 21
2.4.
Definition of Subgroups.................................................................................................................. 21
2.5.
Definition Treatment group ............................................................................................................ 22
2.6.
Imputation Rules for Missing AE Date/Time of Onset/Resolution ................................................. 22
3.
INTERIM ANALYSIS AND DATA MONITORING COMMITTEE REVIEW....................................... 23
4.
SUBJECT INFORMATION................................................................................................................ 23
4.1.
Demographics and Baseline Characteristics ................................................................................. 23
4.2.
Disposition Information................................................................................................................... 25
4.3.
Treatment Compliance................................................................................................................... 25
4.4.
Protocol Deviations ........................................................................................................................ 25
4.5.
Medical History and Family History................................................................................................ 25
4.6.
Prior and Concomitant Medications ............................................................................................... 25
4.7.
Presence of Other Respiratory Viruses or Bacteria....................................................................... 26
5.
EFFICACY ......................................................................................................................................... 26
5.1.
Hypothesis ..................................................................................................................................... 28
5.2.
Analysis Specifications................................................................................................................... 28
5.2.1.
Level of Significance................................................................................................................... 28
5.2.2.
Data Handling Rules................................................................................................................... 28
5.3.
Primary Efficacy Endpoint(s).......................................................................................................... 29
5.3.1.
Definition..................................................................................................................................... 29
5.3.2.
Analysis Method ......................................................................................................................... 29
5.4.
Secondary Endpoints..................................................................................................................... 29
5.4.1.
Definitions ................................................................................................................................... 29
5.4.1.1.
RSV RNA Viral Load (qRT-PCR) ............................................................................................ 30


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5.4.1.2.
Paediatric RSV Electronic Severity and Outcome Rating System (PRESORS)..................... 31
5.4.1.2.1.
PRESORS Modified Definitions ........................................................................................... 31
5.4.1.3.
Other Clinical Course Parameters........................................................................................... 35
5.4.1.3.1.
Respiratory Rate, Heart Rate, Oxygen Saturation and Body Temperature......................... 35
5.4.2.
Endpoint-specific analysis methods ........................................................................................... 36
5.4.2.1.
RSV RNA Viral Load (qRT-PCR) ............................................................................................ 36
5.4.2.2.
Paediatric RSV Electronic Severity and Outcome Rating System (PRESORS)..................... 37
5.4.2.3.
Other Clinical Course Parameters........................................................................................... 38
5.4.2.3.1.
Respiratory Rate, Heart Rate, Oxygen Saturation and Body Temperature......................... 38
5.4.3.
Definition..................................................................................................................................... 38
5.4.4.
Analysis Methods........................................................................................................................ 39
6.
SAFETY............................................................................................................................................. 39
6.1.
Adverse Events .............................................................................................................................. 39
6.1.1.
Definitions ................................................................................................................................... 39
6.1.2.
Analysis Methods........................................................................................................................ 40
6.2.
Clinical Laboratory Tests................................................................................................................ 42
6.2.1.
Definitions ................................................................................................................................... 42
6.2.2.
Analysis Methods........................................................................................................................ 44
6.3.
Vital Signs and Physical Examination Findings ............................................................................. 45
6.3.1.
Definitions ................................................................................................................................... 45
6.3.2.
Analysis Methods........................................................................................................................ 46
6.4.
Electrocardiogram.......................................................................................................................... 47
6.4.1.
Definitions ................................................................................................................................... 47
6.4.2.
Analysis Methods........................................................................................................................ 48
7.
VIROLOGY ........................................................................................................................................ 49
7.1.
Definitions ...................................................................................................................................... 49
7.2.
Analysis Methods ........................................................................................................................... 50
7.2.1.
Viral Sequencing......................................................................................................................... 50
8.
OBSERVATIONAL STAGE .............................................................................................................. 51
8.1.
General Analysis Definitions .......................................................................................................... 51
8.1.1.
Visit Windows and Phase Definitions ......................................................................................... 51
8.1.2.
Analysis Sets .............................................................................................................................. 53
8.1.3.
Definition of Subgroups .............................................................................................................. 53
8.2.
Subject Information ........................................................................................................................ 54
8.2.1.
Demographic and Subject Characteristics ................................................................................. 54
8.2.2.
Disposition Information ............................................................................................................... 56
8.2.3.
Protocol Deviations..................................................................................................................... 56
8.2.4.
Medical History and Family History ............................................................................................ 56
8.3.
Adverse Events .............................................................................................................................. 56
8.4.
Observational Stage Endpoints and Analysis................................................................................ 56
8.4.1.
Hypothesis .................................................................................................................................. 57
8.4.2.
RSV Mobile App Related Endpoints and Analysis ..................................................................... 58
8.4.2.1.
RSV Mobile App Questions, Answers and Scoring Endpoints................................................ 58
8.4.2.2.
Definitions of RSV Mobile App and ARI Visit Endpoints ......................................................... 61
8.4.2.3.
Definitions of RSV Mobile App Compliance Endpoints ........................................................... 61
8.4.2.4.
Definitions of RSV Mobile App and Nasal Swab at Home Endpoints ..................................... 62
8.4.3.
PRESORS Related Endpoints and Analysis .............................................................................. 62
8.4.4.
RSV Viral Load Kinetics Endpoints and Analysis....................................................................... 64
8.4.5.
RSV(+) Hospitalized Endpoints and Analysis............................................................................. 65
8.4.6.
Correspondence of Disease Characteristic Endpoints and Analysis ......................................... 65
8.4.7.
Interventional Stage Participation Endpoints and Analysis ........................................................ 66
8.4.8.
Parent/Caregiver and Child Characteristics Endpoints and Analysis......................................... 67
8.4.9.
Additional Analysis...................................................................................................................... 68
8.4.10.
Subject Profiles........................................................................................................................... 69


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REFERENCES............................................................................................................................................ 70
ATTACHMENTS......................................................................................................................................... 71
Attachment 1:
Division of Microbiology and Infectious Diseases (DMID) Pediatric Toxicity 
Tables (November 2007; draft)................................................................................... 71
CCI


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LIST OF IN TEXT TABLES
Table 1:
Analysis Phases for Subjects in the Interventional Stage ........................................................ 13
Table 2:
Visit Windows............................................................................................................................ 16
Table 3:
Planned Collection of PRESORS ClinRO, PRESORS ObsRO and Clinical Evaluation .......... 17
Table 4:
Visit Windows for PRESORS ClinRO, PRESORS ObsRO, Clinical Evaluation 
(including SBP/DBP) and Body Temperature........................................................................... 17
Table 5:
Worst per Day........................................................................................................................... 19
Table 6:
Subgroup definitions ................................................................................................................. 21
Table 7:
Demographics........................................................................................................................... 24
Table 8:
Baseline Characteristics ........................................................................................................... 24
Table 9:
Viral Load Parameters .............................................................................................................. 30
Table 10: PRESORS Modified Definitions.................................................................................................. 31
Table 11:
Parameters based on PRESORS............................................................................................. 31
Table 12:
Clinical Course Vital Signs Parameters.................................................................................... 35
Table 13:
Exploratory Parameters ............................................................................................................ 38
Table 14:
Cardiac Events Potentially Related to QT Prolongation........................................................... 41
Table 15:
Clinically relevant abnormalities – abnormally low/normal/abnormally high............................. 45
Table 16:
Abnormalities for body temperature.......................................................................................... 45
Table 17:
ECG Abnormalities ................................................................................................................... 47
Table 18:
Analysis phases for subjects in observational stage ................................................................ 51
Table 19:
Subgroup definitions ................................................................................................................. 53
Table 20:
Demographics at Observational Stage Enrollment................................................................... 54
Table 21:
Subject Characteristics at Observational Stage Enrollment..................................................... 54
Table 22:
Caregiver Information at Observational Stage Enrollment ....................................................... 55
Table 23:
Demographics at ARI Visit for Observational Stage RSV (+) Subjects.................................... 55
Table 24:
Characteristics at ARI Visit for Observational Stage RSV (+) Subjects ................................... 56
Table 25:
RSV Mobile App Compliance ................................................................................................... 61
Table 26:
RSV Mobile App Alerts ............................................................................................................. 62
Table 27:
Interventional Stage Participation Characteristics .................................................................... 67
Table 28:
Child and Parent/Caregiver characteristics for RSV Mobile App Compliance, Protocol 
adherence and Enrolled in interventional stage ....................................................................... 67


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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
TEAE
treatment-emergent adverse event
TD
target detected
TND
target not detected
WHO
World Health Organization
WHO-DD
World Health Organization Drug Dictionary


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1.
INTRODUCTION
This Statistical Analysis Plan (SAP) contains definitions of analysis sets, derived variables and 
statistical methods for study 53718678RSV2006 including efficacy and safety of the 
investigational compound JNJ-53718678. The SAP is to be interpreted in conjunction with the 
protocol.
This SAP covers the analyses for the observational stage and interventional stage of the protocol.
Sections 2 to 7 describe the analyses for the interventional stage. The analyses for the observational 
stage are covered in Section 8. Details on the Independent Data Monitoring Committee (IDMC) 
analyses are provided in a separate IDMC SAP.
There will not be PK/PD modelling in this study given the small sample size. Analysis will be 
limited to listings and no Clinical Pharmacology Analysis Plan (CPAP) will be provided.
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
This study is designed to assess in the setting of a planned early interception of pediatric RSV 
disease, early viral and disease kinetics (observational stage) and the antiviral effects of an RSV 
fusion inhibitor, JNJ-53718678 (interventional stage). The objectives of the study are:
Part 1: Observational Stage
The objectives applied to the observational stage are to evaluate:

the onset and evolution of clinical symptoms of pediatric RSV disease

the relationship between viral load and clinical symptoms at early diagnosis of pediatric RSV 
disease
The exploratory objectives applied to the observational stage are to evaluate:

the characteristics of the scores that trigger a site-visit in relation to:

RSV diagnosis

the progression of clinical symptoms

viral kinetics

participation in the interventional stage

the correspondence between disease characteristics as assessed at the site with scores as 
assessed by parent(s)/caregiver(s) in the RSV mobile Application (App) and Pediatric RSV 
Electronic Severity and Outcome Rating System (PRESORS)

parent(s)/caregiver(s) baseline characteristics in relation to operational features such as:

enrollment in observational stage

RSV mobile App compliance


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
protocol adherence

enrollment in interventional stage

the analysis of stool microbiome profiles (in optional samples) in relation to RSV disease
Part 2: Interventional Stage
The primary objective is to evaluate:

the 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 an early 
intervention setting in infants (≤4 months of age at enrollment) recruited from a birth cohort
The secondary objectives are to assess:

the impact of treatment with 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
The exploratory objectives are to assess:

the impact of baseline characteristics on antiviral activity and clinical course, including but
not limited to:

baseline viral load

disease severity

hospitalized participants vs outpatients

parental history of atopy

randomization within 24 hours of ARI alert vs. ≥24 hours

the relationship between the PK and antiviral activity and safety parameters after repeated
dosing of JNJ-53718678

the emergence of mutations in the viral genome potentially associated with resistance to JNJ-
53718678
1.2.
Trial Design
This study is designed to assess the impact of early interception and intervention on antiviral 
activity and the clinical course of the disease. The study consists of 2 parts: an observational stage 
with a birth cohort and a Phase 2a, multicenter, randomized, double-blind, placebo-controlled 
interventional stage.
In the observational pre-diagnostic phase, the study aims to record early signs and symptoms of 
potential RSV infections and is focused on bringing the infant in for assessment at a threshold 
score. All infants will be closely monitored for early signs and symptoms of RSV disease using a 
mobile RSV App on the parent/caregiver's mobile phone (pre-diagnostic phase). For those infants 
with scores that cross the threshold score an alert will be sent and they will be brought to the study 


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site for an early diagnostic RSV test (diagnostic phase). RSV positive (RSV [+]) participants will 
be enrolled in the screening phase of the interventional stage of the study after obtaining informed 
consent for the interventional stage at that time. RSV (+) participants whose parent(s)/caregiver(s) 
do not consent for enrollment in the interventional stage and participants who are screening failures 
in the interventional stage will enter the post-diagnostic phase of the observational stage 
(hospitalized or outpatients).
The interventional stage will consist of a screening phase (Day -1 to Day 1), a treatment phase 
(Day 1 to Day 8 [±1]), and a post-treatment follow-up phase (Day 9 to Day 28 [±3]). Participants 
will be randomized in a 1:1 ratio to receive either JNJ-53718678 or placebo twice daily (bid) for 
7 days. A diagram of the study design is provided in Figure 1.
A target of 1,300 infants (≤4 months of age at enrollment and asymptomatic for acute respiratory 
infection (ARI)-like symptoms requiring medical intervention at the time of consent) is planned to 
be enrolled globally in the observational stage of this study. It is anticipated that approximately 40 
RSV (+) infants from the observational stage of the study will be enrolled in the interventional 
stage. Participants should be ≥28 days old (or ≥3 months postnatal age for prematurely born 
infants) and at least 2.4 kg to be eligible for enrollment in the interventional stage of the study.
Study duration will be approximately 29 (±3) days after RSV (+) diagnosis for participants who 
enter the interventional stage, and 21 (±3) days after RSV (+) diagnosis for participants who do 
not enter the interventional stage. RSV negative (RSV [-]) participants will be considered to have 
completed the study at the end of the RSV circulation.


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Figure 1:
Schematic Overview of the Design of Study 53718678RSV2006
bid=twice daily; ICF=informed consent form; PRESORS= Pediatric RSV Electronic Severity and Outcome Rating System; RSV= respiratory syncytial virus


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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 (183 days of age or older, 183 included, for IWRS purposes).
Study drug will be administered on a once daily (QD) schedule (before protocol amendment 2) or
a twice daily (BID) schedule (after protocol amendment 2) for 7 days. Doses are based on body 
weight and age group:

JNJ-53718678 Total daily dose (n = 20 [target]):

Age group 1: 2.5 mg JNJ-53718678/kg bodyweight

Age group 2: 3 mg JNJ-53718678/kg bodyweight

Age group 3: 4.5 mg JNJ-53718678/kg bodyweight

Placebo (n = 20 [target]):

Age groups 1, 2, and 3: matching placebo (volume of placebo suspension to match the 
calculated volume of the JNJ-53718678 suspension)
1.3.
Statistical Hypotheses for Trial Objectives
Part 1: Observational Stage
For the observational stage, no formal hypothesis will be tested.
Part 2: Interventional Stage
The primary hypothesis of this study is that JNJ-53718678 has antiviral activity against RSV as 
assessed by a reduction in RSV viral load area under the curve (AUC) (from immediately prior to 
first dose of study medication [baseline] until Day 5) at the 5% level (one-sided) for JNJ-53718678 
compared to placebo in participants recruited from a birth cohort.
1.4.
Sample Size Justification
The sample size of the interventional stage is based on results obtained in an earlier birth cohort
study (Janssen R&D, data on file) and the specified analysis method using simulated data. Based
on 10,000 simulated datasets of 40 participants, with an assumed 10% drop-out rate and an effect
size of early treatment of 0.75 log10 copies.day/mL reduction in viral load versus placebo on
average (as illustrated in Figure 2), there is a power of 88% to reject the null hypothesis of no
antiviral effect of JNJ-53718678 treatment using a significance level of 5% (one-sided).


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Figure 2:
Illustration of Viral Load over Time by Treatment Assumed in the Sample Size    Calculation
The sample size of the birth cohort is based on the sample size required for the interventional stage. 
It is assumed based on the results of a previous observational birth cohort study (Janssen R&D, 
data on file) that approximately 10% of the infants participating in the birth cohort will be 
diagnosed as RSV (+) and will develop ARI disease signs compatible with a minimum disease 
severity threshold for intervention. 
At the stage of the temporary hold of the interventional stage of the study on 2 March 2020, 862 
infants were enrolled in the birth cohort, leading to 29 infants who were diagnosed as RSV (+) and 
20 infants who participated in the interventional stage. The incidence of RSV (+) was lower than 
anticipated at the time of initial protocol writing, which for a large part may be explained by the 
relatively late in the RSV season start of recruitment for the first participating country in the study 
(Panama). It is assumed that when recruitment into the birth cohort is re-initiated in time for the 
next season, ~10% of participants will be diagnosed as RSV (+). In order to maintain the target of 
40 participants in the interventional part, the maximum number of infants that may be recruited in 
the birth cohort is set at 1,300. With an additional 438 participants in the birth cohort, an 
assumption of 10% incidence of RSV (+) and a 50% rate of infants who will enter the 
interventional stage, the target of 40 participants in the interventional stage is expected to be 
reached.
As the sample size of the 2 parts are linked and assumptions have to be made on the percentages
of RSV (+) and eligibility, the study may continue at the discretion of the sponsor when more than 
40 participants are included in the interventional stage (with a maximum of 60) and may also be 
considered completed if at least 32 infants have been included the interventional part. 
1.5.
Randomization and Blinding
Central randomization is 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. Eligible subjects will be randomized 1:1 to receive either JNJ-53718678, or placebo.


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Randomization will be based on a computer-generated randomization schedule prepared before 
the study by or under the supervision of the sponsor. 
The randomization will be balanced by using randomly permuted blocks and will be stratified by 
time from randomization since the ARI alert (<24 hours versus ≥24 hours).
1.6.
Observational and Interventional Study Stages
This study consists of two stages: (1) Observational stage, (2) Interventional stage. Two different 
sets of analysis datasets (interventional datasets and observational datasets) will be created.
Throughout this SAP, definitions and analyses for the interventional stage will be covered in 
Sections 2 to 7. The definitions and the analyses for the observational stage will be covered in 
Section 8 of this SAP.
2.
GENERAL ANALYSIS DEFINITIONS
All analysis dataset preparations and statistical analyses will be performed using SAS® version 9.3
(or higher). Graphical presentations are performed using SAS® version 9.3 (or higher) or R version 
3.6.0 (or higher).
2.1.
Visit Windows and Phase Definitions
2.1.1.
Phase Definitions
Analysis phases for the interventional stage will be constructed as defined in Table 1.
Table 1:
Analysis Phases for Subjects in the Interventional Stage
Analysis Phase
[number]
Start Date/Time
End Date/Time
Observational [0]
00:00 of the date of signing the 
informed consent form for the 
observational stage
23:59 of the date before date of signing the 
informed consent form for the interventional stage 
Screening [1]
00:00 of the date of signing the 
informed consent form for the 
interventional stage
1 minute before the first study drug administration 
in the trial
Treatment [2]
Date/time of first study drug 
administration in the trial
23:59 of the last day of treatment + 3 days
or
23:59 of the cut-off date for the IA, 
whichever comes first
Follow-up [3]
1 minute after the End of 
Treatment Phase
23:59 of the day of trial termination (date of last 
contact) or 
23:59 of the cut-off date for the IA, 
whichever comes first


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Assessments will be assigned to phases based on their datetime, but seconds will be ignored 
overall. If the day part of the start date of the assessment is present but the time part is missing, the 
assessment will be treated as if it started at 00:00 on the day of the event (except for adverse Events 
see details in section 2.4). If the day part of the end date of the assessment is present but the time 
part is missing, the assessment will be treated as if it happened at 23:59 on the day of the event. 
No formal imputation will be done, these rules will only be applied to allocate assessments to 
phases.
2.1.2.
Baseline
In the interventional stage, the baseline record is defined as the last record before the first intake 
of the study drug, except for the following assessments:

For RSV RNA viral load:

Last available assessment within the 24h prior to or at the same time of first drug intake 
will be considered as baseline.

If no assessment within the 24h prior to or at the same time of first drug intake, but there 
is a result available no later than 1h post first study drug intake, the baseline assessment 
will be the first assessment completed within 1h post first drug intake.

If none of the above assessments are available, but there is an assessment available before 
the 24h prior to first drug intake, it will be considered as baseline.

For ePRO, 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.
2.1.3.
Relative Day
In the interventional stage, Study Day 1(reference date) is defined as the date of first study 
medication 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’.


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2.1.4.
Analysis Windows for Analysis Visits and Time Points
The visit windows and the target days are defined for each visit of the protocol.
In general, the following rules will be applied in order to have only one evaluation per subject per
analysis visit: 

If two or more 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 two 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:

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 viral load follows the rules described in Section 2.1.2.

Electrocardiogram
In case there is more than one triplicate ECG per analysis visit window, the following rule 
will be used to have only one evaluation per analysis timepoint:
o
The average of the last available complete ECG triplicate within the window, should 
be considered in first instance except for Day 1 and Day 3.
o
Day 1 and Day 3 measurements closest to 1h post dose will be used.
o
In absence of complete triplicate ECGs, the average of the last available ECG duplicate 
should be considered. For duplicates ECGs the same rule applies as for triplicates 
above.
o
In absence of complete or partial triplicates, the last available single ECG can be used. 
Once baseline is assigned, any assessment performed prior to the defined baseline, will be assigned 
to Screening or observational. Observational stage and Screening visits will not be used in 
summary tables, only in listings. Any assessment performed after first drug intake not considered 
baseline but within Day 1, will be assigned to Day 1, post-dose.
Visit windows for viral load and ECG/laboratory assessments are defined as in Table 2.


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Table 2:
Visit Windows
Analysis Visit
[scheduled 
Analysis Visit No.]
TIME INTERVAL (Day)
[TARGET TIMEPOINT (Day)]
VL
ECG
Laboratory
Baseline^
[0]
<=1
[1]
<=1
[1]
<=1
[1]
Day 1
[1]
>1
[1]
Day 2
[2]
>1 to 2
[2]
Day 3
[3]
3
[3]
3
[3]
Day 4
[4]
4
[4]
Day 5
[5]
5
[5]
Day 6
[6]
6
[6]
Day 7
[7]
7
[7]
Day 8
[8]
8
[8]
8-9
[8]
8-9
[8]
Day 9
[9]
9
[9]
Day 10
[10]
10
[10]
Day 11
[11]
11
[11]
Day 12
[12]
12
[12]
Day 13
[13]
Day 14
[14]
13-15
[14]
13-15$
[14]
Day 15
[15]
Day 16
[16]
Day 17
[17]
Day 18
[18]
Day 19
[19]
Day 20
[20]
Day 21
[21]
18-24
[21]
18-24
[21]
Day 22
[22]
Day 23
[23]
Day 24
[241]


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Table 2:
Visit Windows
Analysis Visit
[scheduled 
Analysis Visit No.]
TIME INTERVAL (Day)
[TARGET TIMEPOINT (Day)]
VL
ECG
Laboratory
Day 25
[25]
Day 26
[26]
Day 27
[27]
Day 28*
[28]
25 to +∞
[28]
25 to +∞
[28]
^ Baseline is defined as the last measurement before first study drug intake. Please also see Section 2.1.2
$ Will only be performed in case of any clinically significant laboratory abnormality observed at Day 8
* At the discretion of the investigator
Visits that occurred outside the windows allocated in the above table (ie. visits not being performed 
per protocol), may be assigned a window for consistency (based on the relative day). However, 
these visits will not be used in summary tables and figures but will only be shown in individual 
listings and figures.
PRESORS ClinRO, Clinical evaluation and PRESORS ObsRO are collected as per Table 3. The 
assessments are performed either BID or QD.
Table 3:
Planned Collection of PRESORS ClinRO, PRESORS ObsRO and Clinical Evaluation
Assessments
Hospitalized patients
Outpatients
During Hospitalization
After Discharge
PRESORS 
ClinRO
BID from Day 1 to Day 14 
and 
QD from Day 15 to Day 21
Once at clinic visits
Once at clinic visits
Clinical 
Evaluation£/
SBP+DBP
BID from Day 1 to Day 21 + 
Day 28
Once at clinic visits + Day 
28*
Once at clinic visits + Day 
28*
PRESORS 
ObsRO 
BID from Day 1 to Day 14 and QD from Day 15 to Day 21
Body Temp
Caregiver
NA
BID from Day 2 to Day 14 
and 
QD from Day 15 to Day 21
BID from Day 1 to Day 14 
and 
QD from Day 15 to Day 21
£ Clinical evaluation includes respiratory rate, heart rate, body temperature, and SpO2.
*only in case of on-site visit
Visit windows for these assessments are defined as in Table 4.
Table 4:
Visit Windows for PRESORS ClinRO, PRESORS ObsRO, Clinical Evaluation (including 
SBP/DBP) and Body Temperature
Analysis Time
Time Interval
Target Time
Baseline
0
12h (Day 1.5)
>0h$; 17h59min
12h
24h (Day 2.0)
18h; 29h 59 min
24h
36h (Day 2.5)
30h; 41h 59min
36h


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Table 4:
Visit Windows for PRESORS ClinRO, PRESORS ObsRO, Clinical Evaluation (including 
SBP/DBP) and Body Temperature
Analysis Time
Time Interval
Target Time
48h (Day 3.0)
42h; 53h 59min
48h
60h (Day 3.5)
54h; 65h 59min
60h
72h (Day 4.0)
66h; 77h 59min
72h
84h (Day 4.5)
78h; 89h 59min
84h
96h (Day 5.0)
90h; 101h 59min
96h
108h (Day 5.5)
102h; 113h 59min
108h
120h (Day 6.0)
114h; 125h 59min
120h
132h (Day 6.5)
126h; 137h 59min
132h
144h (Day 7.0)
138h; 149h 59min
144h
156h (Day 7.5)
150h; 161h 59min
156h
168h (Day 8.0)
162h; 173h 59min
168h
180h (Day 8.5)
174h; 185h 59min
180h
192h (Day 9.0)
186h; 197h 59min
192h
204h (Day 9.5)
198h; 209h 59min
204h
216h (Day 10.0)
210h; 221h 59min
216h
228h (Day 10.5)
222h; 233h 59 min
228h
240h (Day 11.0)
234h; 245h 59min
240h
252h (Day 11.5)
246h; 257h 59min
252h
264h (Day 12.0)
258h; 269h 59min
264h
276h (Day 12.5)
270h; 281h 59min
276h
288h (Day 13.0)
282h; 293h 59 min
288h
300h (Day 13.5)
294h; 305h 59min
300h
312h (Day 14.0)
306h; 317h 59min
312h
Day 15
Day [15]
(2 AM-1:59 AM)
15
Day 16
Day [16]
(2 AM-1:59 AM)
16
Day 17
Day [17]
(2 AM-1:59 AM)
17
Day 18
Day [18]
(2 AM-1:59 AM)
18
Day 19
Day [19]
(2 AM-1:59 AM)
19
Day 20
Day [20]
(2 AM-1:59 AM)
20
Day 21
Day [21]
(2 AM-1:59 AM)
21
Day 22
Day [22]
(2 AM-1:59 AM)
22
Day 23
Day [23]
(2 AM-1:59 AM)
23
Day 24
Day [24]
(2 AM-1:59 AM)
24
Day 28
Day [25, +∞]
(2 AM-1:59 AM)
28
$ post baseline
From Day 15 onwards, relative day (adjusted by timeframe as in the table) will be used to define analysis visits. In case there is 
more than one assessment per analysis visit, the one closest to the target will be used for the summary table per analysis visit. If 
more than one is equally close, then the last one will be considered in the analysis.
Note: in case there is an assessment on Day 14 not covered in the 312h window, it will not be used in summary tables and figures 
but will only be shown in individual listings and figures.


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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 5.
Table 5:
Worst per Day
Analysis time
Primary Selection
(worst hourly)
Secondary Selection*
(worst daily)
TIME INTERVAL (Day)
[TARGET TIMEPOINT (Day)]
Baseline
Day 2
Worst [12h; 24h]
Day 3
Worst [36h; 48h]
3
[3]
Day 4
Worst [60h; 72h]
Day 5
Worst [84h; 96h]
4-6
[5]
Day 6
Worst [108h; 120h]
Day 7
Worst [132h; 144h]
Day 8
Worst [156h; 168h]
8-9
[8]
Day 9
Worst [180h; 192h]
Day 10
Worst [204h; 216h]
Day 11
Worst [228h; 240h]
Day 12
Worst [252h; 264h]
Day 13
Worst [276h; 288h]
Day 14
Worst [300h; 312h]
13-15
[14]
Day 15
Worst as per relative day
(2 AM-1:59 AM)
Relative day
Day 16
Day 17
Day 18
Day 19
Day 20
Day 21
18-24
[21]
Day 28
25 to +∞
[28]
25 to +∞
[28]
Note: For ClinRO and Clinical Evaluation only: the secondary selection approach will be considered in the analysis  if no record 
is assigned to Day 3, Day 5, Day 8, Day 14 and/or Day 21 according to the rules in the primary selection column in Table 5 (for 
hospitalized subjects after discharge, or for outpatientss). 

If worst per day as per primary selection available, same value will be assigned for the secondary selection of worst per 
day.

Otherwise, worst per day as per secondary selection will be derived considering all possible values within the relative 
day window. The worst possible result will be selected regardless of being the closest one to the target day.
Day 28 will always be assigned according to the window “25 to +∞”. The primary and secondary selection for Day 28 will be 
identical as the same interval is used for both.
2.2.
Pooling Algorithm for Analysis Centers
As the primary endpoint is a laboratory assessment (objective endpoint) evaluated by a central 
assay, no heterogeneity of treatment effects across centers is expected. No pooling algorithm for 
analysis centers will be applied.


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2.3.
Analysis Sets
2.3.1.
All Enrolled Analysis Set
All participants who signed the ICF of the interventional stage.
2.3.2.
All Randomized Analysis Set
All subjects who were randomized in the interventional stage of the study regardless of being 
treated or not.
2.3.3.
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 all RSV symptoms, rate of complications, overall RSV 
severity score) might also be analyzed on the Per Protocol (PP) set.
2.3.3.1.
ITT-i Set
All randomized subjects who received at least one dose of study drug and who have a centrally 
confirmed RSV 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.
2.3.3.2.
PP Set
All subjects in the ITT-i analysis set with the exclusion of any subject with protocol deviations 
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: 

inclusion criteria 1 or 6 (interventional stage)
AND/OR

exclusion criteria 2, 5, 9 (from the interventional stage) and 4, 5 (from the observational 
stage)
Please see Sections 5.1 and 5.2 of the protocol for full description of the criteria.

Received wrong treatment or incorrect dose 

The actual treatment not the same as the planned treatment

Subjects missed more than 1 dose (if the subject was randomized before Protocol 
amendment 2) or 2 doses (if the subject was randomized after Protocol amendment 2)
(including subjects who discontinued the study medication earlier)

Other:

Unplanned unblinding has taken place during the study


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
Insufficient post-baseline 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.

Missing PRESORS ObsRO:

at baseline 

>1 missing for 5 consecutive assessments during BID schedule

>1 missing for 4 consecutive assessments during QD schedule
Note that in the PP set subjects will be treated as randomized (by definition). Analyses on the PP 
set will only be performed if at least 4 subjects in the ITT-i set are excluded for the PP set.
2.3.4.
Safety Analysis Set
2.3.4.1.
Safety Set
The Safety set includes all subjects who received at least 1 dose of study drug, 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: if at least one dose of the active study drug received 
The Safety set will be used to perform the evaluation of all safety variables and will be used for 
listings.
2.4.
Definition of Subgroups
The following subgroups will be investigated for efficacy, including the primary endpoint (viral 
load) and key clinical course endpoints (time to resolution of all RSV symptoms, rate of 
complications, overall RSV severity score). For safety, no subgroup analyses will be done. See 
Table 6.
Table 6:
Subgroup definitions
Subgroup
Definition
Symptom Onset

Subjects with symptom onset ≤3 days before randomization 

Subjects with symptom onset >3 days before randomization
RSV Viral Subtype

RSV A

RSV B

RSV A+B
Further subgroup analyses might be performed for the efficacy data if it seems useful to be 
combined with the RSV2002 data. 


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2.5.
Definition Treatment group    
Two treatment schedules were used in this study, QD schedule implemented before protocol 
amendment 2 and BID schedule implemented after amendment 2 but with similar total daily doses. 
Treatment group will be defined based on the total daily dose.
2.6.
Imputation Rules for Missing AE Date/Time of Onset/Resolution
Partial AE onset dates will be imputed as follows:

If the onset date of an adverse event is missing day only, it will be set to:

First day of the month that the AE occurred, if month/year of the onset of AE is different 
than the month/year of first dosing of the study medication 

The day of first dosing of the study medication, if the month/year of the onset of AE is 
the same as month/year of the first dosing of the study medication and month/year of the 
AE resolution date is different

The day of first dosing of the study medication or day of AE resolution date, whichever 
is earliest, if month/year of the onset of AE and month/year of the first dosing of the study 
medication and month/year of the AE resolution date are same

If the onset date of an adverse event is missing both day and month, it will be set to the earliest 
of:

January 1 of the year of onset, as long as this date is on or after the first dosing of the 
study medication

Month and day of the first dosing of the study medication, if this date is the same year 
that the AE occurred

Last day of the year if the year of the AE onset is prior to the year of the first dosing of 
the study medication,

The AE resolution date.
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:


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
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
Unplanned 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. In case of an interim analysis, investigators, participants’ parents/caregivers, and local 
sponsor representatives will remain blinded. The sponsor leadership team responsible for decisions 
and the central study team required to generate and interpret results will have access to unblinded 
data.
An IDMC will be commissioned for this study to monitor and review data for the interventional 
stage in an unblinded manner on a regular basis to ensure the continuing safety of the participants 
enrolled in this stage. The committee will meet periodically to review safety data. 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 participants.
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. A Sponsor Committee, consisting of senior sponsor 
personnel not involved in the conduct of the study, will be established and will be responsible for 
decision making, considering the IDMC recommendations, and will communicate these decisions 
to the study team. The IDMC of this study also functions as the IDMC for 53718678RSV2002 and 
the meetings are combined for both studies. Details are provided in the IDMC Charter.
4.
SUBJECT INFORMATION
All subject information analyses described in the following sections will be done on the ITT-I set 
and safety set, unless otherwise for specific display (in the data presentation specification (DPS) 
document). Subject information will be summarized by treatment group and overall.
4.1.
Demographics and Baseline Characteristics
Table 7 and Table 8 presents demographics and baseline characteristics respectively  that will be 
summarized descriptively by treatment group, and overall. Demographics and baseline 
characteristics will also be summarized by subgroup if appropriate.


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Table 7:
Demographics
Continuous Variables:
Summary Type
Age at randomization (months)
Descriptive statistics (N, mean, standard 
deviation [SD], median and range [minimum 
and maximum]).
Weight at baseline (kg)
Length/Height at baseline (cm)
Head Circumference at baseline (cm)
Categorical Variables
Counts (n, %)
Sex (male, female, unknown, undifferentiated)
Age Group (≥28 days and <3 months, ≥3 months and <6 
months, ≥6 months)
Ethnicitya (Hispanic or Latino, Not Hispanic or Latino, Not 
Reported)
Race (American Indian or Alaska Native, Asian, Black or 
African American, Native Hawaiian or other Pacific Islander, 
White, Multiple, Not Reported)
Country
Setting (Hospitalized, Outpatient)
aIf multiple race categories are indicated, the Race is recorded as 'Multiple'. The specifications of the categories 
‘Other’ and ‘Multiple’ will only be listed.
Table 8:
Baseline Characteristics
Continuous Variables:
Summary Type
Duration of RSV symptoms prior to ARI visit (days)
Descriptive statistics (N, 
mean, standard deviation 
[SD], median and range 
[minimum and maximum]).
Duration of RSV symptoms prior to randomization (days)
RSV Viral Load (log10 copies/ml)
RSV Viral Load (log10 copies/ml) by RSV Subtype 
RSV Viral Load (log10 copies/ml) by symptom onset 
RSV Viral Load (log10 copies/ml) by RSV Subtype and by symptom onset
Respiratory Rate (breaths/min)
Heart Rate (beats/min)
Oxygen Saturation (%) at baseline
Number of other siblings within the household
Categorical Variables
Counts (n, %)
RSV Subtype (RSV A, RSV B, RSV A+B)
Time from ARI alert to randomization (<24 hours, ≥24 hours)
(as derived from CRF)
Symptom onset (≤3 days, >3 days) at randomization
Presence of risk factors for severe RSV disease (no, yes)
Receiving Supplemental Oxygen prior to first intake of study medication (no, 
yes)
Prenatal Smoking by the subject’s mother (no, yes)
Exposed to tobacco smoke in home environment (no, yes)
History of atopy/allergy (no, yes)
Contact with other children (siblings, Kindergarten, daycare) (no, yes)
Mode of delivery (vaginal, C-section, not documented)
Feeding type (only breast milk, only formula, combination breast milk and 
formula, solid food only, solid food combined with milk/formula)
Currently attending daycare (no, yes)
If yes, days per week (1, 2, 3, 4, 5, 6, 7)
If no, will child attend day care in the future (yes, no)
Received palivizumab (no, yes)
Received aerosolized ribavirin (no, yes)


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Table 8:
Baseline Characteristics
Continuous Variables:
Summary Type
Received IV immunoglobulin (no, yes)
Presence of respiratory bacteria (no, yes)
Presence of other respiratory viruses (no, yes) *
*Viral and bacterial respiratory co-pathogens are detected in a baseline nasal mid-turbinate swab sample using the Pathofinder 
Respifinder.  2 SMART assays (allows for detection of Influenza A virus, Influenza A virus H1N1 pdm2009, Influenza B virus, 
human respiratory syncytial virus A, human respiratory syncytial virus B, human metapneumovirus, rhinovirus/enterovirus, 
adenovirus, human parainfluenza virus 1, human parainfluenza virus 2, human parainfluenza virus 3, human parainfluenza virus 
4, bocavirus, coronavirus NL63/HKU1, coronavirus 229E, coronavirus 0C43, severe acute respiratory syndrome coronavirus 2, 
and Middle East respiratory syndrome coronavirus, Chlamydophila pneumoniae, Mycoplasma pneumoniae, Legionella 
pneumophila, and Bordetella pertussis), the Fast Track Diagnostics Bacterial pneumonia_CAP assay (CAP1, allows for detection 
of Streptococcus pneumoniae, Staphylococcus aureus, Haemophilus influenzae and Moraxella catarrhalis), and the Fast Track 
Diagnostics Bordetella assay (allows for detection of Bordetella pertussis and Bordetella parapertussis).
4.2.
Disposition Information
The number of screened subjects and reasons for screen failures will be summarized.
Summaries will be provided for the following disposition information:

Randomized, randomized and treated, Safety set, ITT-I set and PP set

Number of subjects who completed and discontinued treatment and the trial, with a breakdown 
of the reasons for discontinuation.
4.3.
Treatment Compliance
Treatment compliance will be calculated as follows:
Treatment compliance (%) = 100 x number of doses of study medication / planned number of 
doses according to the protocol (7 or 14 doses, depending on the time the subject was randomized 
[before or after Protocol amendment 2]).
Dosing compliance will be summarized descriptively by treatment group. The reasons for not 
administered doses will be listed.
4.4.
Protocol Deviations
All major protocol deviations will be listed. Those that may affect the assessment of efficacy will 
be flagged (see Section 2.3.3.2).
4.5.
Medical History and Family History
The medical history and family history records will be listed.
4.6.
Prior and Concomitant Medications
Medications taken from the date when the ICF (for the interventional stage) is signed through the 
end of study will be summarized by setting, by treatment group, overall, and by preferred term 
using the World Health Organization-Drug Dictionary as frequency tables for the prior and 
concomitant medications separately: 


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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 medication. The 
part on concomitant medication will be shown by ATC class level up to level 3. If a 
prior/concomitant therapy record misses components of its start and/or stop dates (time and/or day 
and/or month and/or year), the following actions will be taken: 
1. In case of partial start or stop datetimes, the concomitant therapy records will be allocated to 
prior/concomitant using the available partial information, without imputations. 
2. In case of a completely missing start date, the prior/concomitant therapy will be considered as 
having started before the trial. 
3. In case of a completely missing end date, the prior/concomitant therapy will be considered as 
ongoing at the end of the trial. 
All prior and concomitant medication will be listed.
4.7.
Presence of Other Respiratory Viruses or Bacteria
Data on other respiratory viruses or bacteria, determined by multiplex PCR in mid-turbinate nasal 
swabs collected at baseline will be listed. Proportions of positive and negative results will be 
tabulated.
5.
EFFICACY
All efficacy endpoints will be analyzed on the ITT-i set (interventional stage of the study). 
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 medication (baseline) 
through Day 3 and Day 8.


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
time to undetectable RSV viral load

proportion of participants with undetectable RSV viral load at each time point throughout 
the study

clinical course related endpoints:
The following endpoints will be based on the PRESORS assessed throughout the 
interventional stage of the study by parent(s)/caregiver(s) (parent[s]/caregiver[s] PRESORS) 
and by the investigator (clinician PRESORS) during scheduled visits:
o
duration and severity of signs and symptoms of RSV disease assessed throughout the 
study by parent(s)/caregiver(s) PRESORS and by clinician PRESORS
o
change from baseline in parent(s)/caregiver(s) PRESORS (worsening or 
improvement)
o
change from baseline in clinician PRESORS (worsening or improvement)
o
time to resolution (ie, to none or mild) of RSV symptoms
o
time to improvement based on general questions on overall health
o
proportion of participants with improvement or worsening of RSV disease based on 
general questions on overall health on each study day from screening till Day 21
o
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 during scheduled visits
o
need for (re)hospitalization during treatment and follow-up

safety and tolerability, as assessed by AEs, clinical laboratory testing, ECGs, and vital signs, 
throughout the interventional stage of the study

Due to limited number of subjects at the end of the study, no modelling will be done. 
Individual PK concentrations will be listed
Exploratory Endpoints
Due to the limited number of subjects at the end of this study not all exploratory endpoints will be 
analyzed. Below are the exploratory endpoints that will be analyzed.

changes from baseline in the RSV F-gene sequence (and potentially other regions of the RSV 
genome, at the discretion of the sponsor's virologist)

the occurrence of complications with onset after treatment initiation that are associated with 
RSV disease 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)


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
exacerbations of underlying cardiovascular conditions
5.1.
Hypothesis
The primary hypothesis of the interventional stage is that JNJ-53718678 has antiviral activity 
against RSV as assessed by a reduction in RSV viral load AUC (from immediately prior to first 
dose of study medication [baseline] until Day 5) at the 5% level (one-sided) for JNJ-53718678 
compared to placebo in participants recruited from birth.
5.2.
Analysis Specifications
The randomization stratification factor (time between ARI alert and randomization [<24 hours or 
≥24 hours]) as derived from CRF will be used in the efficacy analyses.
5.2.1.
Level of Significance
The primary endpoint will be tested at alpha level of 5% (one-sided).
5.2.2.
Data Handling Rules
Viral Load
Rule of maximum: Before any imputation is applied, the value for each Day is defined as the 
maximum value of all RSV viral load 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 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 viral load, all the 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 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.


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
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.
5.3.
Primary Efficacy Endpoint(s)
5.3.1.
Definition
RSV viral load will be measured in mid-turbinate nasal swab specimens using an RSV-A/B qRT-
PCR assay.
The primary efficacy endpoint is the RSV viral load area under the curve (AUC) from immediately 
prior to first dose of study drug (baseline) through Day 5 (AUCDay 1-5) derived from the RSV viral 
load as measured by a qRT-PCR assay in nasal swabs.
5.3.2.
Analysis Method
The primary estimates of the RSV viral load AUCDay1-5 will be derived from a mixed model. No 
explicit imputations of missing data from post-baseline nasal swabs 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.
Mean log10 viral load values over time will be analyzed using a restricted maximum likelihood 
based repeated measures approach. The analysis model includes fixed effect parameters for 
treatment, randomization stratification factor, 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 covariance structure will be selected. In case 
this model doesn’t converge, the Toeplitz covariance structure will be applied. The Kenward-
Roger approximation will be used to estimate the denominator degrees of freedom. The differences 
between the AUCs will be estimated using appropriate contrasts. The primary null hypothesis of 
worse or no treatment effect will be rejected if the RSV viral load AUCDay1-5 is significantly lower 
than placebo using a one-sided test at the 0.05 significance level.
For subgroup analysis, the model will be applied per subgroup.
5.4.
Secondary Endpoints
5.4.1.
Definitions
Formulae to be used for derived variables, including data conversions, are provided in the tables
below. Note that for time-to event variables the actual date times will be used.


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5.4.1.1.
RSV RNA Viral Load (qRT-PCR)
Definitions for the derived viral load parameters are provided in Table 9.
Table 9:
Viral Load Parameters
Measurement
Formula
Log10 viral load actual 
values
Log10 of the actual values as measured with qRT-PCR in nasal swab samples collected 
at the clinic visits and at home
Log10 viral load change 
from baseline
Change = log10 viral load actual value – log10 baseline value
Time to virus undetectable 
(hours) 
[Time-to event]
Time to virus undetectable will be evaluated as below:
The time in hours from initiation of study treatment until the first post-baseline time 
point at which the virus is confirmed undetectable (= event).
A confirmed undetectable sample is defined as the first of at least two 
consecutive samples that are undetectable. The last obtained sample for a 
subject , if undetectable is considered confirmed.
Situation
Censoring
Last record is baseline assessment
time 0h
Last available assessment is 
detectable
(right censored) at last available 
assessment
(Date and time of event or censoring - date and time of first dose of study drug)/3600, 
rounded to one decimal.
Viral load status at each 
time point (categorical)
Each RSV viral load measurement will be assigned to one of the 3 categories below:

Undetectable (<LLOQ TND)

Detectable (<LLOQ TD)

Quantifiable (>= LLOQ)
Viral load status detectable 
at each time point (binary)
Each RSV viral load measurement will be assigned to one of the 2 categories to identify 
if it is detectable.

Detectable or quantifiable = Yes (1)

Undetectable = No (0)
Additionally, AUCDay1-3 and AUCDay1-8 will be analyzed using a mixed model approach (see 
Section 5.3.2).


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5.4.1.2.
Paediatric RSV Electronic Severity and Outcome Rating System 
(PRESORS)
This study includes version 7.1 of the PRESORS. 
The ObsRO scoring system that will be used during this study is available in Attachment 2:
PRESORS ObsRO Scoring System. The ClinRO scoring system that will be used during this study 
is available in Attachment 3: PRESORS CLINRO Scoring System. Some PRESORS parameters 
were modified and will be derived as provided in Table 10.
5.4.1.2.1.
PRESORS Modified Definitions
Based on the PRESORS validation results of 64041575RSV0001 study and the IA of 
53718678RSV2002 (data cut-off 02JAN2020), modified scores were defined implementing the 
following changes for concept scores and definition of resolution:
Table 10: PRESORS Modified Definitions
PRESORS
CONCEPT/
Answer level
ORIGINAL
MODIFIED
Score
Definition
Score
Definition
Caregivers 
(ObsRO)
Dehydration
“Dry Skin or Lips”
2
Not Resolved
1
Resolved
Retractions
“Belly Sucked in while breathing”
1
Resolved
2
Not Resolved
Cyanosis
Any
Any
Not considered
Apnea
Any
Any
Not considered
Clinician 
(ClinRO)
Retractions
“Subcostal Retractions”
1
Resolved
2
Not Resolved
Cyanosis
Any
Any
Not considered
Apnea
Any
Any
Not considered
PRESORS data will be analyzed as follows:

Considering modified concepts scores and modified definition of resolution. 

The modified summary parameters for scores and time to resolution (Overall RSV Symptoms, 
Key RSV Symptoms, Respiratory Symptoms and General Illness Behavior) will be derived 
excluding Cyanosis and Apnea and using modified concepts scores and modified definition 
of resolution (Dehydration and Retractions for ObsRO and Retractions for ClinRO).
All the analyses will be based on the modified definitions. 
Table 11:
Parameters based on PRESORS
Measurement
Formula
PARENT/CAREGIVER PRESORS (ObsRO)
ObsRO concept 
scores + change from 
baseline
Score per concept according to the score system provided in Attachment 2. 
Each concept score ranges from 0 to 3. The higher the score, the worse the symptom/concept.


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Table 11:
Parameters based on PRESORS
Measurement
Formula
ObsRO summary 
scores + change from 
baseline
Average of the different concepts, ranging from 0 to 3. 
Summary scores are key RSV symptom severity score, respiratory symptom severity score, 
general illness behavior and overall RSV severity score and will be calculated as defined in 
Attachment 2.
Daily summary 
scores 
For each ObsRO summary score, a daily summary score will be calculated as follows:
Average of the worst: daily summary score will be the average of the worst score reached 
per concept. Table Worst per Day (see Table 5) timepoints will be applied and as a result 
“worst hourly” and “worst daily” will be calculated. Please notice that unless otherwise 
stated, the daily summary score “worst hourly” is the one considered in the analyses.
Time to resolution of 
all RSV symptoms 
(hours) 
[Time-to event]
Time (in hours) from first dose of study drug until the first time of resolution of all RSV 
Symptoms (concepts from ObsRO). 
Symptoms/Concepts are sleep disturbance, crying, illness behavior, breathing problems, 
retractions, tachypnea, breathing sounds, cough, nasal secretions, tachycardia, feeding, 
dehydration.
Cyanosis and apnea will not be considered when modified definitions applied.
Resolution occurs when all symptoms from the ObsRO are scored as none or mild (score of 
0 or 1, respectively) for at least 24 hours.

Three consecutive recordings indicating resolution are required, if the first (of 
these 3 consecutive) recording is before the second analysis timepoint of the BID 
schedule at Day 14. These 3 consecutive recordings should have been done over 4 
scheduled consecutive analysis timepoints, 1 missing timepoint is allowed. 

Two consecutive recordings indicating resolution are required, if the first (of 
these 2 consecutive) recording is at or after the second analysis timepoint of the 
BID schedule at Day 14. These 2 consecutive recordings should have been done 
over 3 scheduled consecutive analysis timepoints, 1 missing timepoint is allowed
In case RSV symptoms are not resolved, data will be censored.
Censoring will be done as follows:
Situation
Censoring
Last record(s) indicate resolution of 
RSV symptoms but insufficient 
recordings to meet the time to 
resolution
first record of resolution from the last 
series of recordings of resolution of 
RSV symptoms
Last record does not indicate 
resolution of RSV symptoms
after the last observation, at 20:00 on 
the same day if the last observation 
was a morning diary entry (from 
2:00 until 13:59)


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Table 11:
Parameters based on PRESORS
Measurement
Formula
at 8:00 the next day if the last entry 
was an evening diary (from 14:00 
until 01:59). In case the assessment
was between 00:00 and 01:59, they 
will be censored at 08:00 that same 
day
Death (without previous resolution)
date/time of death
missing information to determine 
resolution of symptoms because of 
hospitalization
date/time of hospitalization
(Date and time of event or censoring - date and time of first dose of study drug)/3600, 
rounded to one decimal
Time to resolution of 
key RSV symptoms 
(hours) 
[Time-to event]
Time (in hours) from first dose of study drug until the first time of resolution of key RSV 
symptoms. Concepts are breathing problems, retractions, tachypnea, breathing sounds, , 
cough and tachycardia.
Cyanosis and apnea will not be considered when modified definitions applied.
Resolution occurs when all key RSV symptoms from the ObsRO are scored as none or mild 
(score of 0 or 1, respectively) for at least 24 hours.
Similar rules as for time to resolution of all RSV symptoms will be applied.
Time to resolution of 
respiratory symptoms 
(hours) 
[Time-to event]
Time (in hours) from first dose of study drug until the first time of resolution of respiratory 
symptoms. Concepts are breathing problems, retractions, tachypnea, breathing sounds, 
cough, tachycardia and nasal secretions.
Cyanosis and apnea will not be considered when modified definitions applied.
Resolution occurs when all respiratory symptoms from the ObsRO are scored as none or 
mild (score of 0 or 1, respectively) for at least 24 hours.
Similar rules as for time to resolution of all RSV symptoms will be applied.
Time to resolution of 
general illness 
behavior symptoms 
(hours) 
[Time-to event]
Time (in hours) from first dose of study drug until the first time of resolution of general 
illness behavior symptoms (5 general illness behavior concepts from ObsRO). Concepts are 
sleep disturbance, crying, illness behavior, feeding and dehydration.
Resolution occurs when all general illness behavior symptoms from the ObsRO are scored 
as none or mild (score of 0 or 1, respectively) for at least 24 hours.
Similar rules as for time to resolution of all RSV symptoms will be applied.
Status of RSV 
symptoms at each 
time point 
(categorical)
Each assessment of ‘Keeping in mind all the symptoms you observed [recall period], overall,
how would you rate the child’s RSV symptoms now?’ will be assigned to one of the 6 
categories below:
 None
 Very mild
 Mild
 Moderate
 Severe


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Table 11:
Parameters based on PRESORS
Measurement
Formula
 Very severe
Status of health at 
each time point 
(categorical)
Each assessment of ‘Overall, how is the child’s health now?’ will be assigned to one of the 
6 categories below:
 Excellent
 Very good
 Good
 Fair
 Poor
 Very poor
Status of 
improvement of RSV 
symptoms at each 
time point 
(categorical)
Each assessment of ‘Would you say the child’s RSV symptoms have improved, are about 
the same or are worse than when the child entered the study?’ will be assigned to one of 
the 5 categories below:
 Very much improved
 Much improved
 A little improved
 About the same
 A little worse
 Much worse
 Very much worse
Time to improvement 
of RSV symptoms
(general question)
[Time-to-event]
Time (in hours) from first dose of study drug until first time status of improvement of RSV 
symptoms reported as “very much improved” or “much improved” based on response to 
question ‘Would you say the child’s RSV symptoms have improved, are about the same or 
are worse than when the child entered the study?
Similar rules as for time to resolution of all RSV symptoms will be applied.
Status of return to 
pre-RSV disease 
health at each time 
point 
(binary)
Each assessment of ‘Has the child’s health returned to normal (how it was before RSV)?’ 
will be assigned to one of the 2 categories below:
 No
 Yes
CLINICIAN PRESORS (ClinRO)
ClinRO concept 
scores + change from 
baseline
Score per concept according to the score system provided in attachment 3. Each concept 
score ranges from 0 to 3. The higher the score, the worse the symptom/concept.
ClinRO summary 
scores + change from 
baseline
Average of the different concepts, ranging from 0 to 3. 
Summary scores are key RSV symptom severity score, respiratory symptom severity score, 
general illness behavior and overall RSV severity score and will be calculated as defined in 
attachment 3.
ClinRO daily 
summary scores 
For each ClinRO summary score, a daily summary score will be calculated as follows:
Average of the worst: daily summary score will be the average of the worst score reached 
per concept. Table Worst per Day (see  Table 5) timepoints will be applied and as a result 


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Table 11:
Parameters based on PRESORS
Measurement
Formula
“worst hourly” and “worst daily” will be calculated. Please notice that unless otherwise 
stated, the daily summary score “worst daily” is the one considered in the analyses.
Status of overall 
condition at each ime 
point (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 time point 
(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’ 
5.4.1.3.
Other Clinical Course Parameters
5.4.1.3.1.
Respiratory Rate, Heart Rate, Oxygen Saturation and Body 
Temperature 
Definitions to be used for derived clinical course vital signs parameters are provided in Table 12.
Table 12:
Clinical Course Vital Signs Parameters
Measurement
Formula
Respiratory Rate (RR) actual values + 
changes from baseline
RR as measured by the investigator during scheduled visits
change = (observed post-baseline RR – baseline RR)
Heart Rate (HR) actual values + 
changes from baseline
HR as measured by the investigator during scheduled visits
change = (observed post-baseline HR – baseline HR)
Oxygen Saturation (SpO2) actual 
values + changes from baseline
Oxygen Saturation as measured by the investigator during scheduled 
visits
Body Temperature (clinician) actual 
values + changes from baseline
Body Temperature as measured by the investigator during scheduled 
visits
Change = (observed post-baseline temperature – baseline 
temperature)
Body Temperature (caregiver) actual 
values + changes from baseline
Body Temperature as measured at home 
Change = (observed post-baseline temperature – baseline 
temperature)


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5.4.2.
Endpoint-specific analysis methods
5.4.2.1.
RSV RNA Viral Load (qRT-PCR)
Log10 Viral Load
Descriptive statistics mean (SE) graphs and median (IQR) graphs will be shown for the log10 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, 90% 
confidence interval, median, range and interquartile range. Descriptive statistics will be presented 
overall, and by subgroup (as defined in Section 2.4).
Differences on RSV RNA log10 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 endpoint (see Section 5.3.2). The 90% 2-sided confidence intervals will be 
presented.
RSV viral load AUC
A similar model as used for the primary analysis will be used for the viral load AUC through Day 
3, and through Day 8. The differences in these AUCs for treatment group versus placebo group 
will be derived using appropriate contrasts for both through day 3 and through day 8 and from the 
same model containing all RSV RNAS viral load assessment from baseline through Day 8. Least 
squares mean estimates of treatment differences, including the 90% 2-sided confidence intervals.
For subgroup analyses, the model also will be applied per subgroup. For details about subgroups 
refer to Section 2.4.
Proportion of subjects with undetectable RSV 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 on that analysis visit will not be counted in 
the denominator for the proportion.
In case of co-infection with both RSV A and B, the worst category will be used for the analysis.
As higher viral loads denote worse degree of infection, the ordering will be from worst to better 
namely: quantifiable – detectable – undetectable. 
Time to virus confirmed undetectable [time-to event]
This time-to event variable will be analyzed using Kaplan-Meier analysis (for time to confirmed 
undetectable). 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 confidence intervals 
based on log-log 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. For 
subgroup analysis, Kaplan-Meier plots will be produced per subgroup.


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5.4.2.2.
Paediatric RSV Electronic Severity and Outcome Rating System 
(PRESORS)
ObsRO concept, summary and daily scores; ClinRO concept, summary and daily scores
Descriptive statistics mean (SE) graphs, and median (IQR) graphs will be shown for the actual 
values and changes from baseline by visit and treatment group. Descriptive statistics will include 
the number of subjects, mean, standard deviation, standard error, 90% two-sided 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 5. Graphical presentation of actual values and changes 
from baseline for individual concepts score and /or summary parameters (daily summary 
score[worst of the average]) over time include mean(SE) and Bar plots. 
Time to resolution of all RSV symptoms, Time to resolution of key RSV symptoms, Time to 
resolution of respiratory symptoms, Time to resolution of general illness behavior symptoms 
(ObsRO)
These time-to event variables will be analyzed using Kaplan-Meier analysis. The 90% 2-sided 
confidence intervals will be presented. For subgroup analyses, Kaplan-Meier plots will be 
produced per subgroup.
Time to improvement of RSV symptoms (ObsRO general question)
These time-to event variables will be analyzed using Kaplan-Meier analysis. The 90% 2-sided 
confidence intervals will be presented.
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 time point (with corresponding 90% CIs), per treatment group and 
visit. Subjects with missing data on that analysis visit will not be counted in the denominator for 
the proportion.
Status of overall condition, Status of health, Health compared to the baseline assessment 
(ClinRO)
The proportion of subjects within the categories will be shown in a frequency tabulation, as well 
as graphically, per analysis time point (with corresponding 90% CI), per treatment group and visit. 
Subjects with missing data on that analysis visit will not be counted in the denominator for the 
proportion.


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5.4.2.3.
Other Clinical Course Parameters
5.4.2.3.1.
Respiratory Rate, Heart Rate, Oxygen Saturation and Body 
Temperature 
Descriptive statistics mean (SE) graphs and median (IQR) graphs 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, 90% 2-sided confidence 
interval, median, range and interquartile range.
For analyses for which we need one assessment per day (eg for summarizing combined in and 
outpatient data captured by clinician), we take the worst over 24 hours according to Table 5. For 
respiratory rate, heart rate and body temperature, the worst grade/value would be considered as the 
maximum value while for oxygen saturation, the lowest value will be considered the worst.
5.4.3.
Definition
Table 13:
Exploratory Parameters
Measurement
Formula
RSV-related complication 
(original definition)
Subjects who experienced RSV-related complication after first dose of study drug 
will receive code 1, subjects who did not experience a complication will receive 
code 0.
The overall category will consist of any complication (answer to the question: “Is 
this AE a complication related to the current respiratory infection?”).
The following subcategories will also be analyzed:

Respiratory complications
o
Bacterial complications
o
Viral complications

Non-respiratory infectious complications
o
Bacterial complications
o
Viral complications

Other
RSV-related complication 
(modified definition)
Any subject who experienced at least one treatment emergent adverse event 
(TEAE) included in the list of complications below will receive code 1, subjects 
who did not experience any of the specified TEAE will receive code 0.

Respiratory complications: respiratory failure, respiratory distress, 
apneic attacks, bronchiolitis, bronchial obstruction, pneumonia, 
asthmatic crisis.

Infectious complications: otitis media, bacterial respiratory tract 
infections, sepsis.

Cardiovascular complications: arrhythmia, cardiogenic shock, 
hemodynamic instability, congestive cardiac failure.

Acid-base or electrolyte complications: metabolic acidosis (serum 
HCO3- <16), metabolic alkalosis (serum HCO3- >30)


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Table 13:
Exploratory Parameters
Measurement
Formula
The list of TEAE to be considered as per modified definition of RSV-related 
complication, will be reviewed and documented prior to the final database lock.
The modified definition for RSV-related complication will be the primary 
definition used in the analyses.
5.4.4.
Analysis Methods
Respiratory Infection Complication
The proportion of subjects with a complication (yes and no) will be shown in a frequency 
tabulation.
6.
SAFETY
All safety analyses will be descriptively summarized and based on the Safety set. There will be no 
formal statistical testing for any safety endpoint.
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.
Phase Allocation of AE
Adverse events present in the SDTM database are allocated to phases based on their start date. If 
the start date of an event falls between (or on) the start and stop date of a phase, the AE is attributed 
to that 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


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6.1.2.
Analysis Methods
Treatment-emergent adverse events will be summarized by body system, preferred term and 
treatment group.  
A summary will be provided for the following emergent adverse events by phase (treatment phase
and  treatment phase + follow-up phase combined) and by treatment: 

any adverse events 

serious adverse events

deaths due to AE

adverse events by toxicity grade

AEs at least possibly related to study medication

AEs for which study medication was permanently stopped

AEs for which study was discontinued prematurely

serious adverse events that were at least possibly related to study medication. 
Incidence tabulation will be provided for individual adverse events in the above categories (in case
there are at least 2 events in any group)
In addition to the summary tables, the following listings will be provided for all subjects with: 
Any AEs, serious AEs, AEs leading to death, AEs leading to termination of study participation, 
severe AEs (grade 3-4 AEs).
The summary, incidence tabulation for the individual preferred terms and subject listing will be 
provided for the RSV-related complications.
The following adverse events will be tabulated or listed (in case there are less than 5 events); 
overall: any AE, any RSV-related complications, any grade 3-4 AE, AEs that are at least possibly 
related to study medication, AEs that have at least grade 2 and are at least possibly related to study 
medication, AEs leading to death, serious AEs, AEs leading to permanent stop of study medication
and Cardiac events potentially related to QT prolongation (see Table 14) and Hepatobiliary Events 
(see Table 15 )


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Table 14:
Cardiac Events Potentially Related to QT Prolongation
MedDRA Preferred Term (PT)
MedDRA 
Code
Electrocardiogram QT interval abnormal 
10063748
Electrocardiogram QT prolonged 
10014387
Long QT syndrome 
10024803
Long QT syndrome congenital 
10057926
Torsade de pointes 
10044066
Ventricular tachycardia 
10047302
Cardiac arrest 
10007515
Cardiac death 
10049993
Cardiac fibrillation 
10061592
Cardio-respiratory arrest 
10007617
Electrocardiogram repolarization abnormality 
10052464
Electrocardiogram U wave inversion 
10062314
Electrocardiogram U wave present 
10057913
Electrocardiogram U-wave abnormality 
10055032
Loss of consciousness 
10024855
Electrocardiogram QT interval abnormal 
10063748
Sudden cardiac death
10049418
Sudden death
10042434
Syncope
10042772
Ventricular arrhythmia
10047281
Ventricular fibrillation
10047290
Ventricular flutter
10047294
Ventricular tachyarrhythmia
10065341
Table 15: Hepatobiliary Events
MedDRA Preferred Term (PT)
MedDRA 
Code
Drug-induced liver injury
10072268
Hyperbilirubinaemia
10020578
Jaundice
10023126
Ocular icterus
10058117
Yellow skin
10048245
Hepatitis, non-infectious
20000010
Aspartate aminotransferase increased
10003481
Bilirubin conjugated increased
10004685
Bilirubin urine present
10077356
Blood bilirubin increased
10005364
Blood bilirubin unconjugated increased
10005370
Gamma-glutamyltransferase increased
10017693
Blood alkaline phosphatase increased
10059570


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6.2.
Clinical Laboratory Tests
6.2.1.
Definitions
Laboratory parameters of hematology, serum chemistry, and urinalysis will be investigated: all 
analyses will be done on International System of Units (SI) converted values as available in the 
database.
Units:
The analysis of laboratory data will be done on standard international converted values only 
(Lbstresn/Lbstresu variable) except for GFR.
Estimation of GFR:
The local lab is to report the eGFR using the Schwartz formula [2]. In case the eGFR is not 
provided by the site the GFR will be estimated using the Schwartz method for pediatric subjects 
 = 0.45 ∗ℎℎ
 [
 ]

Where eGFR = estimated Glomular Filtration Rate in mL/min/1.73m²

height = subject height in cm at baseline of interventional stage

CRT = serum creatinine in mg/dL.
In case the creatinine is reported in umol/L in the SDTM, the following formula will be 
applied:
 = 0.00509 ∗ℎℎ
 [

]
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 will be 
computed according to the DMID pediatric toxicity tables (version November 2007) and will be 
used in the analysis. In case no 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 evaluation period, per phase 
(treatment, follow-up and combination treatment + follow-up), including unscheduled 
measurements. 


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
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%)

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. 

The eGFR will be calculated/reported by the 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 is 
applicable in both, the treatment and follow-up 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 
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 
on their assessment schedule. In case it is not possible to assign a unique phase (e.g. unscheduled 
time points), the assessment will be assigned to all possible active 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. 
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.
Missing normal limits:
Missing normal limits in the database will be imputed at analysis level using the values specified 
and approved by the sponsor. This only applies if the missing normal limit is critical to determine 


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a toxicity grade or an abnormality score, i.e. not for tests whose toxicity grade is based on the test 
value itself. Imputations, if applicable, will be flagged as applicable if shown in listings.
Missing Basophils, Eosinophils, Monocytes, Lymfocytes and Neutrophils values:
There are several methods how basophils, eosinophils, monocytes, lymfocytes and neutrophils (or 
polymorphonuclear leukocytes PMN) values are reported in the local labs. Some labs provide both 
the absolute count as well as the percentages as source. However, some sites provide only the one 
or the other as source. In the latter cases, if only the absolute counts are known, the PMN% will 
be calculated as follows:
PMN% = (absolute PMN/absolute leukocytes) *100 
Vice versa, if only the PMN % are provided, the counts will be calculated as follows:
PMN count = (PMN (%) *WBC count)/ (100)
Reference ranges will not be calculated for derived variables. 
6.2.2.
Analysis Methods
All lab parameters with numeric values will be analyzed using descriptive statistics on the actual 
values and changes from baseline over analysis timepoint.
Laboratory toxicity grade, abnormality will be described by frequency and percentage of subjects 
using below methods:

Tabulation of the worst-case treatment-emergent toxicity grade and non-graded abnormalities 
of laboratory parameters per treatment group.

Cross-tabulations of the worst toxicity grades versus baseline

Cross-tabulations of the worst laboratory parameter abnormalities versus baseline
Below plots and graphs will be produced to describe the overall and individual evaluations for 
laboratory parameters by timepoints:

Individual plot for each laboratory parameter by timepoint.

Plots of Mean±SE by treatment group over time for actual values and changes from baseline 
will be generated for all hematology and clinical chemistry tests.
A listing of abnormal individual subject hematology, and clinical chemistry values from scheduled 
and unscheduled time points will be provided. This listing will include all other time points for the 
corresponding subject/parameter. Grade 2 or higher toxicity laboratory values will be listed 
separately. Urinalysis results will be listed.


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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 (caregiver or clinical evaluation) will be investigated.  
Definitions Grades/Abnormalities
Abnormality codes will be defined as indicated in Table 16. Determining the abnormalities, the 
following rules are applied:

Worst grades/abnormalities are determined over the whole evaluation period for each trial 
phase separately, including post-baseline scheduled and unscheduled measurements of that 
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%).
Table 16:
Clinically relevant abnormalities – abnormally low/normal/abnormally high
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
Abnormality codes for body temperature are defined as indicated Table 17.
Table 17:
Abnormalities for body temperature
Abnormality Code
Temperature (°C)
Tympanic
Forehead
Oral
Rectal
Axillary
Abnormalities on actual values
Normal
≤ 37.8
≤ 38.0
≤ 38.0
≤ 37.2
≤ 38.0
Abnormally high
> 37.8
>38.0
>38.0
>37.2
>38.0
if location is missing, we assume ‘Rectal.'


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In case of missing dates or time parts:
Vital signs 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 
phase allocation is possible taking this additional information into account. These assessments will 
be allocated to the right phase using the available date(time) information, and the information on 
their assessment schedule. In case it is not possible to assign a unique phase (e.g. unscheduled time 
points), the assessment will be assigned to all possible active phases based on the available date 
and time information. These cases will be flagged in the respective listings.
For temperature where each BID assessment defined as morning, afternoon or evening 
assessment based on the timing of assessment. The following imputation rule will be applied in 
case of missing time:

VSTPT is pre-populated and if time is missing and for deriving ARELTM, VSTPT is used to 
derive timepoint as below

Morning – 08:00 

Afternoon – 16:00

Evening – 20:00
Emergence definition for grades/abnormalities
A grade/abnormality will be considered emergent if it is worse than baseline. If baseline is missing, 
the grade/abnormality is always considered as emergent. A shift from ‘abnormally low’ at baseline 
to ‘abnormally high’ post baseline (or vice versa) is also emergent.
6.3.2.
Analysis Methods
Incidence of vital signs tests that meet criteria for abnormality will be tabulated for each treatment 
group.
A cross-tabulation of the worst grade/abnormality versus baseline will be presented for the 
combination of analysis Treatment and Follow-up phase. This table will also show the number and 
percentage of subjects per worst grade/abnormality, the number 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 
temperatures 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. 
A listing of abnormal individual subject vital signs values from scheduled and unscheduled time 
points will be provided. This listing will include all other time points for the corresponding 
subject/parameter. 


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Abnormal physical examination findings will be listed.
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 lab, they will not be recalculated.
6.4.1.
Definitions
Definitions Abnormalities
The ECG abnormalities will be defined as indicated in Table 18. ECG abnormalities will be 
identified based on the subject’s age at the time of assessment and as follow: 

Worst grades/abnormalities are determined over the whole evaluation 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%)
Table 18:
ECG Abnormalities
Parameter (unit)
Age class
Abnormally low
Abnormally high
PR (msec)
0 - 2 years
NA
>150
QRS (msec)
0 - 2 years
NA
>79
QT/QTc (msec)
0 - 2 years
NA
>500
RR (msec)
0 - 3 months
<333
>750
3 - 12 months
<400
>860
1 - 2 years
<430
>1000
Abnormalities on the changes from baseline (∆QT/QTc)
Abnormality Code
Criteria
QT/QTc
Borderline QT/QTc change
30 ms < ∆QTc < 60 ms
Abnormality high QT/QTc change
∆QTc > 60 ms
Emergent definition for abnormalities
An abnormality will be considered treatment emergent if it is worse than baseline. If baseline 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 within each analysis phase.


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Triplicate ECG assessments
If not available from the central ECG: For time points on which triplicate ECGs apply (expected 
for all time points), a mean value per triplet cluster, will be calculated per time point before any 
further handling. This mean value will be used through the entire analysis. In the analysis dataset, 
the time of the first triplet member will be retained for this average record.
Rounding
When ECG parameters have to be derived or any operations have to be performed (e.g. averaging 
over many assessments/triplicates), no rounding to the integer/unit will be performed; the 
maximum stored resolution of these derived values in the derived dataset(s) will be limited to 
8 decimal positions. When used in tables, these values will be presented using formats reflecting 
the resolution of the unit applicable to the respective parameter (milliseconds, beats per minute).
6.4.2.
Analysis Methods
Incidence of ECG parameters that meet criteria for abnormality will be tabulated for each treatment 
group.
A cross-tabulation of the worst abnormality versus baseline will be presented for the combination 
of analysis Treatment and follow-up phase. This table will also show the number and percentage 
of subjects per worst toxicity/abnormality, the number and percentage of subjects per emergent 
worst toxicity/abnormality. 
A tabulation of the worst QT/QTc change versus baseline per for the combination of analysis 
treatment and follow-up phase will be presented.
Tabulation of participants per QT/QTc category
for actual values
(]450ms,480ms], 
]480ms,500ms] and more than 500ms) and category for change from baseline (<=30, >30-60, >60) 
will be presented. This table will show the number and percentage of participants in each category
Mean±SE graphs over time for the actual values and changes from baseline will be generated and 
presented by treatment group. 
A listing of abnormal individual subject ECG values from scheduled and unscheduled time points 
will be provided. This listing will include all other time points for the corresponding 
subject/parameter.


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7.
VIROLOGY
7.1.
Definitions
Viral Strain Typing
The RSV subtype is determined at baseline using the RSV-A/B RT-qPCR assay performed in the 
central lab.
Viral Sequencing
Viral resistance will be evaluated by next-generation sequencing (NGS) of the RSV Fusion (F) 
gene using a read frequency cut-off of 3%.
Baseline samples from all subjects will be sequenced to identify pre-existing genetic variations in 
the RSV F gene. Post-baseline sequencing will be performed on the last evaluable on-treatment 
sample and/or during follow-up for all 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 viral
sequence compared to a reference sequence. Genetic variations can include substitutions, 
insertions and deletions. The reference sequences used will be RSV-A Long strain (GenBank 
Accession number AY911262) for RSV-A samples and RSV-B strain 9320 (GenBank Accession 
number AY353550) for RSV-B samples.  Genetic variations will be reported on amino acid level.

Baseline genetic variation: amino acid difference from the RSV-A or RSV-B reference strain 
detected at baseline with an NGS read frequency ≥15%.

Emerging genetic variation: 
a genetic variation (amino acid substitution, insertion or 
deletion) that is absent, i.e. with an NGS read frequency <3%, at baseline but detected with 
an NGS read frequency ≥15% at a later post-baseline time point.

Enriched genetic variation: a genetic variation (amino acid substitution, insertion or 
deletion) detected at baseline with an NGS read frequency ≥3% and <15%, and with an 
increase in NGS read frequency of at least 15% post-baseline.

Genetic variation profile: a specific genetic variation or combination of genetic variations at 
one or more time points

RSV F protein amino acid positions of interest: 

Long list of 24 F protein positions of interest for the class of RSV fusion inhibitors, based 
on in vitro selection experiments, clinical observations, and/or in vitro reduced 
susceptibility to RSV fusion inhibitors, as well as residues involved in binding of JNJ-
53718678 to the RSV prefusion 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.


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Analysis Time Points
Virology results will be assigned to the visit windows as described in Sections 2.1.1 and 2.1.4. In 
addition to the time points corresponding to the visits at which samples for RSV F gene sequencing 
are collected, the below time points will be considered: 

Baseline (BL): Time point with sequencing data available closest prior to the first dose. This 
will be the Day 1 pre-treatment 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 Time Point: Last available post-baseline time point during the 
treatment phase with sequencing data available.

Any post-baseline time point in the study with sequencing data available.
7.2.
Analysis Methods
7.2.1.
Viral Sequencing
Baseline
The prevalence of baseline genetic variations in the RSV F-gene (complete RSV F gene or 
considering the positions of interest), ie the number of subjects with baseline genetic variations in 
the RSV F-gene, will be tabulated in frequency outputs (n, %). 
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 time point 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 a 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 time point, will be generated.


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8.
OBSERVATIONAL STAGE
This section covers analyses related to the observational stage only.
All rules, definitions, and imputations described for the interventional stage also apply on the 
observational stage data unless otherwise described in this section. Rules and definitions of the 
RSV (+) non-interventional subjects are similar to the interventional stage subjects to ensure that 
results can be compared with results from the interventional stage.
8.1.
General Analysis Definitions
8.1.1.
Visit Windows and Phase Definitions
Phase Definitions
Phases will be constructed as defined in Table 19 below:
Table 19:
Analysis phases for subjects in observational stage
Analysis Phase
[number]
Start Date/Time
End Date/Time
Subjects to which Phase 
Applies
Observational 
Screening 
[1]
00:00 of the date of 
signing the informed 
consent form for the 
observational stage
23:59 of the date of signing 
the informed consent form 
for the observational stage
All subjects enrolled in the
observational stage
Observational 
Pre-diagnosis
[2]
1 minute after the End of 
the Screening Phase
Date and time of the RSV 
(+) diagnostic test result or 
trial termination
All subjects enrolled in the
observational stage
Observational 
Post-diagnosis
[3]
1 minute after the End of 
Pre-diagnosis Phase
23:59 of the day of trial 
termination (date of last 
contact) 
RSV (+) subjects not enrolled 
in the interventional stage
Thus a subject without ARI visits and/or with only RSV (-) diagnostic test result(s) will remain in
the Pre-diagnosis Phase until the study ends.
Assessments will be assigned to phases based on their datetime, but seconds will be ignored 
overall. If the day part of the start date of the assessment is present but the time part is missing, the 
assessment will be treated as if it started at 00:00 on the day of the event. If the day part of the end 
date of the assessment is present but the time part is missing, the assessment will be treated as if it 
happened at 23:59 on the day of the event. No formal imputation will be done, these rules will 
only be applied to allocate assessments to phases.
Baseline
In the observational stage, only the RSV (+) subjects will be assigned a baseline record. The 
baseline record is defined as the first record on the day of the RSV (+) ARI visit. If this is not 
available, the first available record after the day of the RSV (+) ARI visit is considered baseline.


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Relative Day
In the observational stage, two relative day variables are defined. All assessments at all visits will 
be assigned a day relative to these dates.

The first relative day variable starts counting from the ICF date (RDobs) and Day 1 is defined 
as the date of signing the informed consent form for the observational stage. 

The second relative day item (RDdiag) starts counting from the RSV (+) ARI visit and Day 1 
is defined as the date of the RSV(+) ARI visit.
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’.
Analysis Windows for Analysis Visits and Time Points
For the RSV (+) subjects, the visit windows and the target days are defined for each visit of the 
protocol using the definition defined for the interventional stage in Section 2.1.4. The same visit 
window mapping is applied to ensure that results of the RSV (+) observational subjects can be 
compared with results from subjects of the interventional stage. Similar rules as in the 
interventional stage will be applied to have only one evaluation per subject per analysis visit.
Please note the following differences in the visit schedule and assessments in the observational 
stage as compared to the interventional stage for the RSV (+) subjects:

Mid-turbinate nasal swabs from Day 1 to Day 8 only.

For RSV (+) outpatients clinician evaluation and clinician PRESORS available on Day 1 only.

No temperature logs are being completed

No safety assessments (blood pressure, directed physical examination, ECG) performed (for 
RSV (+) subjects who did not enroll in the interventional stage and stay in observational stage)
For the RSV Mobile App questionnaire, the morning and evening time point is defined as:
Slot of the Day
Time
Target
Morning
00:00 – 19:59
08:00
Evening
20:00 – 23:59
20:00
Note: these time-windows are defined based on the time when the RSV Mobile App pushes the 
questionnaires to the parents/caregivers of the participants. The Morning questionnaires is pushed 
at 08h00 and parents/caregivers have time until 19h59 to complete it. The Evening questionnaire 
is pushed at 20h00 and is available until 23h59.


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8.1.2.
Analysis Sets
The following analysis sets are defined for the observational stage:

All Enrolled Analysis Set – Observational Stage: All participants who signed the ICF of 
the observational stage and were classified as eligible. 

ARI-Visit Analysis Set – Observational Stage: All the subjects who completed at least one 
study related ARI visit with RSV diagnostic test result available.

RSV (+) Analysis Set – Observational Stage: All the subjects with a positive RSV diagnostic 
test who did not enter the interventional stage.

RSV (+) Analysis Set – Overall: All the subjects with a positive RSV diagnostic test result
in the study (includes both RSV (+) interventional and observational stage subjects).
For the observational stage the Safety Analysis Set is the same as the All-Enrolled Analysis Set.
When referring in the text below to ‘observational stage analysis sets’ this indicates the first 3 
analysis sets defined above: All Enrolled Analysis Set – Observational Stage; ARI-Visit Analysis 
Set – Observational Stage; RSV (+) Analysis Set – Observational Stage.
8.1.3.
Definition of Subgroups
The subgroups defined for the observational stage are similar as those defined in the interventional 
stage. Subgroup analyses is performed for selected viral load outputs. Other subgroup analyses 
could be performed post-hoc if it is deemed useful to be combined with the interventional stage.
Table 20:
Subgroup definitions
Subgroup
Subjects to which it 
applies
Definition
Symptom Onset before ARI 
Visit
Subjects in RSV(+) 
Analysis Set –
Observational stage

Subjects with symptom onset ≤3 days before 
ARI Visit

Subjects with symptom onset >3 days before 
ARI Visit
RSV Subtype
Subjects in RSV(+) 
Analysis Set –
Observational stage

RSV A

RSV B

RSV A+B


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8.2.
Subject Information
8.2.1.
Demographic and Subject Characteristics
Table 21 presents demographics at observational stage enrollment that will be summarized 
descriptively for the observational stage analysis sets and the RSV (+) Analysis Set – Overall. 
Table 22 presents subject characteristics at enrollment that will be summarized descriptively for 
the observational stage analysis sets and the RSV (+) Analysis Set – Overall.
Table 21:
Demographics at Observational Stage Enrollment
Continuous Variables
Summary Type
Age at enrollment (months)
Descriptive statistics (N, mean, standard 
deviation [SD], median and range [minimum 
and maximum]).
Weight at birth (kg)
Length/Height at birth (cm)
Categorical Variables
Sex (male, female, unknown, undifferentiated)
Counts (n, %)
Age Group at enrollment (< 14 days; ≥14 days and <30 days;
≥30 days and <60 days, ≥60 days and ≤4 months)
Ethnicitya (Hispanic or Latino, Not Hispanic or Latino, Not 
Reported)
Race (American Indian or Alaska Native, Asian, Black or 
African American, Native Hawaiian or other Pacific Islander, 
White, Multiple, Not Reported)
Country
aIf multiple race categories are indicated, the Race is recorded as 'Multiple'.
Table 22:
Subject Characteristics at Observational Stage Enrollment
Continuous Variables
Summary Type
Gestational age, if ≥ 37 weeks (weeks)
Descriptive statistics (N, mean, standard 
deviation [SD], median and range [minimum 
and maximum]).
Number of other siblings within the household
Categorical Variables
Prematurely born (i.e. <37 weeks gestational age) (no, yes)
Counts (n, %)
Prenatal Smoking by the subject’s mother (no, yes)
Exposed to tobacco smoke in home environment (no, yes)
Other siblings in household (no, yes)
Contact with other children (siblings,
kindergarten, daycare) (no, yes)
History of atopy/allergy (no, yes)
Feeding type (only breast milk; only formula; combination of 
breast milk and formula; solid food only; solid food combined
with milk/formula)
Breastfeeding ongoing (no, yes)
Currently attending daycare (no, yes)
   If yes, days per week (1, 2, 3, 4, 5, 6, 7)
  If no, will child attend day care in the future (yes, no)
Received Palivizumab (no, yes)
Mode of delivery (vaginal, C-section, not documented)


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Table 23 presents caregiver information at enrollment (collected in the eCRF) that will be 
summarized descriptively for the observational stage analysis sets and the RSV (+) Analysis Set –
Overall.
Table 23:
Caregiver Information at Observational Stage Enrollment
Categorical Variables
Summary Type
Educational level of mother (Did not Complete Secondary 
School or Less than High School; Some Secondary or High 
School Education; High School or Secondary
School Degree Complete; Associate's or Technical Degree
Complete; College or Baccalaureate Degree Complete; 
Doctoral or Post Graduate Education: More than High School;
I do not wish to answer; Unknown; Not Applicable)
Counts (n, %)
Educational level of father (Did not Complete Secondary 
School or Less than High School; Some Secondary or High 
School Education; High School or Secondary
School Degree Complete; Associate's or Technical Degree
Complete; College or Baccalaureate Degree Complete; 
Doctoral or Post Graduate Education: More than High School;
I do not wish to answer; Unknown; Not Applicable)
Educational level of caregiver (Did not Complete Secondary 
School or Less than High School; Some Secondary or High 
School Education; High School or Secondary
School Degree Complete; Associate's or Technical Degree
Complete; College or Baccalaureate Degree Complete; 
Doctoral or Post Graduate Education: More than High School;
I do not wish to answer; Unknown; Not Applicable)
Occupational/employment status mother (Full Time 
Employed; Part Time Employed; Unemployed; I do not wish 
to answer; Not Applicable)
Occupational/employment status father (Full Time Employed; 
Part Time Employed; Unemployed; I do not wish to answer; 
Not Applicable)
Occupational/employment status caregiver (Full Time 
Employed; Part Time Employed; Unemployed; I do not wish 
to answer; Not Applicable)
Table 24 and Table 25 present demographic and baseline characteristics for the observational 
RSV(+) subjects as observed during the RSV(+) ARI Visit. This information will be summarized 
descriptively for the observational stage analysis sets and the RSV (+) Analysis Set – Overall.
Table 24:
Demographics at ARI Visit for Observational Stage RSV (+) Subjects
Continuous Variables
Summary Type
Age at ARI visit (months)
Descriptive statistics (N, mean, standard 
deviation [SD], median and range [minimum 
and maximum]).
Weight at ARI visit (kg)
Length/Height at ARI visit (cm)
Head Circumference at ARI visit (cm)
Categorical Variables
Age Group (≥28 days and <3 months, ≥3 months and <6 
months, ≥6 months)
Counts (n, %)
Setting (Hospitalized, Outpatient)


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Table 25:
Characteristics at ARI Visit for Observational Stage RSV (+) Subjects
Continuous Variables
Summary Type
Duration of RSV symptoms prior to ARI visit (days)
Descriptive statistics (N, 
mean, standard deviation 
[SD], median and range 
[minimum and maximum]).
RSV Viral Load (log10 copies/ml)*
RSV Viral Load (log10 copies/ml)* by RSV Subtype 
RSV Viral Load (log10 copies/ml)* by symptom onset 
Respiratory Rate (breaths/min)
Heart Rate (beats/min)
Oxygen Saturation (%)
Categorical Variables
RSV Subtype (RSV A, RSV B, RSV A+B)
Counts (n, %)
Symptom onset (≤3 days, >3 days) prior to ARI visit
Presence of risk factors for severe RSV disease (no, yes)
Received palivizumab (no, yes) 
Received aerosolized ribavirin (no, yes)
Received IV immunoglobulin (no, yes)
*Only nasal mid-turbinate swab type samples to be considered.
8.2.2.
Disposition Information
Summaries will be provided for the following disposition information:

Number of subjects screened

Number of subjects in respective analysis sets

Number of RSV (+) subjects in study

Enrollment in interventional stage

Not enrolled in interventional stage

Enrollment by country and site

Number of subjects who completed or discontinued the observational stage of the trial, with 
a breakdown of the reasons for discontinuation.
8.2.3.
Protocol Deviations
All major protocol deviations related to the observational stage will be listed.
8.2.4.
Medical History and Family History
The medical history and family history records will be listed for the RSV (+) Analysis Set –
Observational Stage. 
8.3.
Adverse Events
All reported adverse events related to the observational stage will be listed.
8.4.
Observational Stage Endpoints and Analysis 
The analyses include the endpoints related to the observational stage. Definitions of the endpoints 
are similar as in the interventional stage, unless otherwise described here. Analyses of blood, 
buccal swab and stool microbiome samples are out of scope of this Statistical Analysis Plan.


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The endpoints applied to the observational stage: 

the total score, over time, of respiratory symptoms as captured by the RSV mobile App during 
the pre-diagnostic phase and the post-diagnostic phase for RSV(+) participants who do not 
enter in the interventional stage

the PRESORS scores by the clinician (clinician PRESORS) on the day of RSV diagnosis for 
RSV(+) participants who do not enter in the interventional stage

RSV viral load kinetics during the pre-diagnostic phase

RSV viral load kinetics from Day 1 to Day 8 after RSV diagnosis over time for RSV(+) 
participants who do not enter in the interventional stage

the PRESORS scores by parent(s)/caregiver(s) (parent[s]/caregiver[s] PRESORS) over time 
for RSV(+) participants who do not enter in the interventional stage
The endpoints applied to the exploratory objectives of the observational stage are:

the frequency and severity of individual symptoms based on the RSV mobile App, over time

the frequency and severity of clinician recorded symptoms based on the PRESORS (clinician 
PRESORS) on the day of RSV diagnosis for RSV(+) participants who do not enter in the 
interventional stage

the individual signs and symptoms and total score that triggered ARI visit 

participation in the interventional stage

correspondence of disease characteristics as assessed by the investigator at the site (ClinRO 
PRESORS) and scores as assessed by parent(s)/caregiver(s) (ObsRO PRESORS and RSV 
Mobile App)

characteristics of parent(s)/caregiver(s) (optional) and infant at baseline in relation to (but not 
limited to) RSV mobile App compliance, protocol adherence, and enrollment in interventional 
stage
8.4.1.
Hypothesis
For the observational stage, no formal hypothesis will be tested.


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8.4.2.
RSV Mobile App Related Endpoints and Analysis
8.4.2.1.
RSV Mobile App Questions, Answers and Scoring Endpoints
Definitions:
In the RSV Mobile App there are several symptom/sign questionnaires that the parents should 
complete depending on the RSV-status of their child. 

Pre-diagnosis questionnaire: This is the main questionnaire that all parent(s) need to 
complete. It monitors the child's symptoms and has an associated algorithm to calculate the 
disease severity based on a scoring. This questionnaire is active every day, once in the morning
and once in the evening (until a child is diagnosed RSV(+)).

Trigger button questionnaire: During the pre-diagnosis phase, a parent/caregiver can decide 
to self-report besides the two pre-diagnosis questionnaires per day. In such a case, the parents 
receive exactly the same questionnaire as the pre-diagnosis questionnaire.

Hospitalization questionnaire: This questionnaire is active during the hospital stay of a 
RSV(+) subject.

Outpatient questionnaire: This questionnaire should be completed only for RSV(+) subjects
in the outpatient setting (including the subjects who are discharged from the hospital setting).
The type of questionnaires is captured in the database as it is provided by the RSV Mobile App 
vendor.
The following endpoints are defined:

Individual questions and answers on the RSV Mobile App questionnaire during pre-diagnosis
and trigger button:
Question
Question name
Possible Answers
Does the baby have a runny or 
stuffy nose?
RUNSTUF

No

Yes
What is the color of the mucus?
COLOR

Clear mucus, no color

White mucus

Yellow or green mucus

No mucus, just stuffy nose
Does the baby have a cough?
COUGH

No

Yes
How often does the baby cough 
during a period of 5 minutes?
COUGHFR5

Less than once (individual 
coughs)

Between 1 and 10 
times (continuous coughing)

More than 10 times (or more 
than twice per minute) (bouts of 
coughing)
What is the strength of the 
coughing?
COUGHST

Weak 

Strong

Very strong, causing sometimes 
vomiting or interference with 
feeding and sleeping
Does the baby show problems 
breathing?
BABYPRBR

No

Yes


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Did your child pause breathing for 
more than 10 seconds?
BREAT10S

No

Yes
How many breaths does the baby 
take in 30 seconds (Please count)?
BREAT30S
Continuous parameter
Do the baby's nostrils flare out 
when breathing? 
FLARE

No

Yes
While breathing, does the baby’s 
belly pull in and/or does the skin 
pull in below the neck?
SKINPULL

No

Yes
Does the baby make noise while 
breathing?
NOISEBR

No

Yes
What kind of noise does the baby 
make when breathing? 
NOISEMK

None of the below

Whistling / wheezing

Chesty sound

Grunting sound
Does the baby show any of 
following signs of not feeling well?
SGNFEEL

Less activity

Tired more easily 

Less interested in playing with 
toys

Clinging to you or had to be 
held or carried

Not responding to you as usual
How much did the baby eat in the 
last 8 hrs?
EATING8H

As normal

Did not complete 1 of his/her 
regular feedings

Did not complete more of 
his/her regular feedings (+2)

Did not eat at all
Did the baby vomit in the last 8 
hrs?
VMT8H

No

Did vomit once or twice

Did vomit more than twice
Is the baby crying more than usual?
BABYCRY

No

Yes, more than usual 

Yes, a lot more than usual
How easy was the baby calmed 
when held or soothed?
CALMEASY

baby calmed easily

baby was difficult to calm

baby did not calm
How would you assess the color of 
your baby’s skin?
SKNCLR

Normal

Paler than usual
Did the baby have fever?
FEVER

No

Yes
Did the baby receive medication to 
lower the fever?
FEVERMD

No

Yes

Don't know
Did the baby have a wet diaper in 
the last 8hrs?
WET8H

Yes

No

Don't know

Individual questions and answers on the RSV Mobile App hospitalization questionnaire:
RUNSTUF, COLOR, COUGH, COUGHFR5, COUGHST, NOISEBR,
NOISEMK, SGNFEEL, EATING8H, VMT8H, BABYCRY, CALMEASY,


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WET8H

Individual questions and answers on the RSV Mobile App outpatient questionnaire:
RUNSTUF, COLOR, COUGH, COUGHFR5, COUGHST, BREAT10S,
BREAT30S, NOISEBR, NOISEMK, SGNFEEL, EATING8H, VMT8H,
BABYCRY, CALMEASY, SKNCLR, FEVER, FEVERMD, WET8H

Symptom summary scores, domain scores (respiratory signs scores; non-respiratory signs 
score) and total score on the RSV Mobile App questionnaire as described in Attachment 4.
Analysis Methods:

Individual question and answers on the RSV Mobile App questions:

Te proportion of answers within the categories by question will be shown in a frequency 
tabulation, as well as graphically by barplots [by pre-diagnosis, trigger button, 
hospitalization and outpatient questionnaires]

Symptom summary scores:

For the questionnaires that triggered an ARI visit (ARI alerts), the proportion of answers 
within the categories by each symptom summary score will be shown in a frequency 
tabulation, as well as graphically by barplots

Respiratory signs scores, non-respiratory signs score and total score on the RSV Mobile App:

Graphical representation (mean, SE) of the RSV Mobile App respiratory signs score, non-
respiratory signs scores and total score over time before ARI alert [during pre-diagnosis 
stage, 0 to 10 days before ARI alert]. Different colors will be used for RSV (+) and RSV(-
) subjects. ARI alerts that did not lead to an RSV diagnostic test result are not included 
in this analysis.

Graphical representation (mean, SE) of the RSV Mobile App respiratory signs scores, non-
respiratory signs score and total score over time (Day 1 to 21) after RSV(+) diagnosis.

A summary of the total score during the pre-diagnosis stage will be shown in a tabulation:

Number of completed questionnaires

Number of completed questionnaires with total score = 0

Number of completed questionnaires with total score > 0, and the distribution of each 
possible score


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8.4.2.2.
Definitions of RSV Mobile App and ARI Visit Endpoints
Definitions:
The following endpoint is defined:

Time (in hours) between RSV Mobile App alert and RSV diagnostic test at ARI visit:      
     Endpoint = Date/time RSV-diagnostic test – Date/time of ARI alert (in hours)
In case no ARI visit / RSV-diagnostic test was performed or in case the date and/or time of 
the RSV-diagnostic test is not available, this endpoint will be missing.
Analysis Methods:

Time (in hours) between RSV Mobile App alert and RSV diagnostic test at ARI visit:

Number of ARI alerts (N, and unique subjects)

Number of ARI visits (N, and unique subjects)

Number of RSV-diagnostic tests with date/time (N, and unique subjects)
o
Descriptive statistics (N, mean, standard deviation [SD], median, IQR and range 
[minimum and maximum])
o
Categorical: <12 hours; 12 -< 24 hours; 24 -< 48 hours; >=48 hours
o
Graphical representation by histogram [by site]
8.4.2.3.
Definitions of RSV Mobile App Compliance Endpoints
Definitions and Analysis methods:
The following information will be summarized with respect to the completion of the RSV Mobile 
App questionnaires:
Table 26:
RSV Mobile App Compliance
Continuous Variables
Summary Type
Number of completed RSV Mobile App questionnaires by 
subject [overall; by questionnaire type (pre-diagnosis, 
hospitalization, outpatient, trigger button)]
Descriptive statistics (N, mean, standard 
deviation [SD], median and range [minimum 
and maximum]).
Completion rates of RSV Mobile App questionnaire 
(planned/completed*100) by subject [overall; by timepoints 
and questionnaire type (pre-diagnosis, hospitalization, 
outpatient)]
Categorical Variables
Number of subjects with completed RSV Mobile App
questionnaires [overall; by questionnaire type (pre-diagnosis, 
hospitalization, outpatient, trigger button)]
Counts (n, %)
Number of RSV Mobile App questionnaires planned & 
completed [overall; by timepoint and questionnaire type (pre-
diagnosis, hospitalization, outpatient)]

Graphical representation of the RSV Mobile App compliance over time by plotting the 
number of completed RSV Mobile App questionnaires and completion rates [by timepoint; 
by country and timepoint].


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The following information will be summarized with respect to the RSV Mobile App Alerts:
Table 27:
RSV Mobile App Alerts
Continuous Variables:
Summary Type
Number of RSV Mobile App Alerts by subject
Descriptive statistics (N, mean, standard 
deviation [SD], median and range [minimum 
and maximum]).
Categorical Variables
Total number of RSV Mobile App Alerts
n
Total number of unique subjects with at least one RSV Mobile 
App Alert
n, %
Number of RSV Mobile App Alerts per subject:
Number of subjects with 1 RSV Mobile App alert
Number of subjects with 2 RSV Mobile App alert
Etc.
n, %
RSV Mobile App Alert and ARI visit:
ARI visit was not performed
ARI visit took place
n, %
8.4.2.4.
Definitions of RSV Mobile App and Nasal Swab at Home Endpoints
Definitions and Analysis methods:
The following information will be tabulated:

Number of RSV Mobile App Alerts

Number of missing nasal swabs at home at ARI alerts

Number of available nasal swabs at home at ARI alerts
8.4.3.
PRESORS Related Endpoints and Analysis
The ObsRO and ClinRO PRESORS scoring system is similar as defined in the interventional stage.
All the time-to variables are calculated using the start date/time set equal at the date/time of the 
RSV (+) diagnostic test result.
Definitions ObsRO PRESORS Endpoints:
The following defined ObsRO endpoints are considered:

ObsRO concept scores + change from baseline

ObsRO summary scores + change from baseline

Daily summary scores 

Time to resolution of all RSV symptoms (hours) [Time-to event]

Time to resolution of key RSV symptoms (hours) [Time-to event]

Time to resolution of respiratory symptoms (hours) [Time-to event]


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
Time to resolution of general illness behavior symptoms (hours) [Time-to event]

Status of RSV symptoms at each time point (general question) [categorical]

Status of health at each time point (general question) [categorical]

Status of improvement of RSV symptoms at each time point (general question) [categorical]

Time to improvement of RSV symptoms (general question) [Time-to event]

Status of return to pre-RSV disease health at each time point [categorical]
Definitions ClinRO PRESORS Endpoints on the Day of RSV Diagnosis:
The following defined ClinRO endpoints are considered:

ClinRO concept scores

ClinRO summary scores

Status of overall condition [categorical]

Status of health [categorical]
Definitions ClinRO PRESORS Endpoints for the RSV (+) Hospitalized Subjects:
The following analysis is performed in case at least 10 RSV (+) subjects are being hospitalized in 
the observational stage.
The following defined ClinRO endpoints are considered:

ClinRO concept scores + change from baseline

ClinRO summary scores + change from baseline

ClinRO daily summary scores 

Status of overall condition at each time point [categorical]

Status of health at each time point [categorical]

Health compared to the baseline assessment [categorical]
Analysis Methods:

ObsRO concept, summary and daily scores; ClinRO concept, summary and daily scores:

Descriptive statistics and mean (SE) graphs will be shown for the actual values and 
changes from baseline by visit. Descriptive statistics will include the number of subjects, 
mean, standard deviation, standard error, 90% confidence interval, median, range and 
interquartile range. Descriptive statistics will be presented overall. 


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
Time-to-event variables:

Time-to event variables will be analyzed using Kaplan-Meier analysis. The 90% 2-sided 
confidence intervals will be presented. 

Categorical variables:

The proportion of subjects within the categories will be shown in a frequency tabulation, 
as well as graphically, per analysis time point (with corresponding 90% CIs) and visit. 
Subjects with missing data on that analysis visit will not be counted in the denominator 
for the proportion.
8.4.4.
RSV Viral Load Kinetics Endpoints and Analysis
Similar data handling rules for the RSV viral load, as described in Section 5.2.2, for the 
interventional stage are applied for the observational stage.
Definitions RSV viral load kinetics during the pre-diagnostic phase:
The following defined RSV viral load endpoints are:

RSV Viral load categorization of samples collected during the pre-diagnostic phase at home
(can include both RSV(-) and RSV(+)) [categorical: Undetectable; Detectable; Quantifiable]

Log10 RSV viral load actual values of the RSV(+) samples (those with detectable or 
quantifiable RSV viral load) collected during the pre-diagnostic phase at home
Definitions RSV viral load kinetics from Day 1 to Day 8 for RSV(+) subjects:
The following defined RSV viral load endpoints are considered:

Log10 RSV viral load actual values

Log10 RSV viral load change from baseline

RSV Viral load status at each time point [categorical: Undetectable; Detectable; Quantifiable]

Time to virus undetectable (hours) [time-to-event]
Analysis Methods:

Categorical variable:

The proportion of subjects within the RSV viral load categories (undetectable, detectable 
and quantifiable) will be shown in a frequency tabulation, as well as graphically by visit. 
Subjects with missing data on that analysis visit will not be counted in the denominator 
for the proportion.

In case of co-infection with both RSV A and B, the worst category will be used for the 
analysis. As higher RSV viral loads denote worse degree of infection, the ordering will 
be from worst to better namely: quantifiable; detectable; undetectable.

Log10 RSV viral load:

Descriptive statistics and mean (SE) graphs will be shown for the log10 RSV viral load 
actual values and changes from baseline by visit from Day 1 to Day 8. Descriptive 


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statistics will include the number of subjects, mean, standard deviation, standard error, 
90% confidence interval, median, range and interquartile range. Descriptive statistics will 
be presented for the log10 RSV viral load actual values of the RSV(+) samples collected 
during the pre-diagnostic phase at home.

Descriptive statistics and mean (SE) graphs will be shown for the log10 RSV viral load 
actual values and changes from baseline by visit from Day 1 to Day 8 by RSV subtype.

Time to virus undetectable:

This time-to event variable will be analyzed using Kaplan-Meier analysis. 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 confidence intervals based on 
log-log transformation method will be presented. The data will be presented graphically 
using the Kaplan-Meier estimate of the survival function. 
8.4.5.
RSV(+) Hospitalized Endpoints and Analysis
The following analysis is performed in case at least 10 RSV(+) subjects are being hospitalized in 
the observational stage.
Definitions vital signs endpoints: 
The following defined endpoints are considered:

Respiratory Rate (RR) actual values + changes from baseline

Heart Rate (HR) actual values + changes from baseline

Oxygen Saturation (SpO2) actual values + changes from baseline

Body Temperature (clinician) actual values + changes from baseline
Analysis Methods:

Viral sign variables:

Descriptive statistics and mean (SE) graphs will be shown for the actual values and 
changes from baseline by visit. Descriptive statistics will include the number of subjects, 
mean, standard deviation, standard error, 90% confidence interval, median, range and 
interquartile 
range.
8.4.6.
Correspondence of Disease Characteristic Endpoints and Analysis
Definitions:
The following RSV disease characteristics scores are considered for the investigator:

PRESORS ClinRO daily summary scores
The following RSV disease characteristics scores are considered for the parent/caregiver:


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
PRESORS ObsRO daily summary scores

RSV Mobile App respiratory signs score, non-respiratory signs scores and total score
Analysis Methods:
The following analysis is performed for all RSV(+) subjects in the observational stage:

Scatterplot of the ClinRO daily summary scores vs the ObsRO daily summary scores on the 
day of the ARI visit. Spearman correlation will be added to the scatterplot.

Scatterplot of the ClinRO daily summary scores vs the RSV Mobile App scores on the day of 
the ARI visit. Spearman correlation will be added to the scatterplot. (in case multiple RSV 
Mobile App scores are available on that day, the maximum value is used in the scatterplot).

Scatterplot of the ObsRO daily summary scores vs the RSV Mobile App scores on the day of 
the ARI visit. Spearman correlation will be added to the scatterplot. (in case multiple RSV 
Mobile App scores are available on that day, the maximum value is used in the scatterplot).

Scatterplot of the ObsRO daily summary scores vs the RSV Mobile App scores from Day 1 
to Day 21. Spearman correlation will be added to the scatterplot. (in case multiple RSV Mobile 
App scores are available on that day, the maximum value is used in the scatterplot).
The following analysis is performed for all hospitalized RSV(+) subjects in the observational stage 
on the days with at least 10 subjects available:

Scatterplot of the ClinRO daily summary scores vs the ObsRO daily summary score on each 
day (Day 1 to Day 21). Spearman correlation will be added to the scatterplot.

Scatterplot of the ClinRO daily summary scores vs the RSV Mobile App scores on each day 
(Day 1 to Day 21). Spearman correlation will be added to the scatterplot. (in case multiple 
RSV Mobile App scores are available on that day, the maximum value is used in the 
scatterplot).
8.4.7.
Interventional Stage Participation Endpoints and Analysis
Definitions:

The following binary endpoint is created for all study enrolled subjects with a RSV(+) 
diagnostic test [RSV(+) Analysis Set – Overall]: 

Enrolled in interventional stage (Yes, No)
Analysis methods:
Demographic, enrollment characteristics and ARI-visit characteristics split by this binary endpoint 
are presented in Tables 19 - 23. The following information will further be tabulated for the RSV 
Mobile App Scores by the binary endpoint and overall:


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Table 28:
Interventional Stage Participation Characteristics
RSV Mobile App 
Respiratory summary scores
Descriptive statistics (N, mean, standard 
deviation [SD], median and range [minimum 
and maximum]).
Non-respiratory summary score
Descriptive statistics (N, mean, standard 
deviation [SD], median and range [minimum 
and maximum]).
Total score
Descriptive statistics (N, mean, standard 
deviation [SD], median and range [minimum 
and maximum]).
8.4.8.
Parent/Caregiver and Child Characteristics Endpoints and Analysis
Definitions:

The following endpoints are created for all study enrolled subjects: 

RSV Mobile App questionnaire compliance (completed/planned * 100 %): [< 25%; 25 - < 50%; 
50 - <75%; ≥75%]. Trigger button RSV Mobile App questionnaires are not considered.

Protocol adherence: [Yes: no major protocol deviations associated with parent/caregiver of 
subject; No: at least one major protocol deviations associated with parent/caregiver of subject]
o
Note: defining major protocol deviations associated with parent/caregiver of subject 
is performed after database lock based on information provided in Deviation domain.
Analysis methods:
Table 29 presents caregiver information at enrollment that will be summarized for the following 
endpoints by category and overall:

RSV Mobile App Compliance

Protocol adherence
Table 29:
Child and Parent/Caregiver characteristics for RSV Mobile App Compliance, Protocol 
adherence and Enrolled in interventional stage
Categorical Variables:
Summary Type
Educational level of mother (Did not Complete Secondary 
School or Less than High School; Some Secondary or High 
School Education; High School or Secondary
School Degree Complete; Associate's or Technical Degree
Complete; College or Baccalaureate Degree Complete; 
Doctoral or Post Graduate Education: More than High School;
I do not wish to answer; Unknown; Not Applicable)
Counts (n, %)
Educational level of father (Did not Complete Secondary 
School or Less than High School; Some Secondary or High 
School Education; High School or Secondary
School Degree Complete; Associate's or Technical Degree
Complete; College or Baccalaureate Degree Complete; 
Doctoral or Post Graduate Education: More than High School;
I do not wish to answer; Unknown; Not Applicable)
Educational level of caregiver (Did not Complete Secondary 
School or Less than High School; Some Secondary or High 
School Education; High School or Secondary


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Table 29:
Child and Parent/Caregiver characteristics for RSV Mobile App Compliance, Protocol 
adherence and Enrolled in interventional stage
Categorical Variables:
Summary Type
School Degree Complete; Associate's or Technical Degree
Complete; College or Baccalaureate Degree Complete; 
Doctoral or Post Graduate Education: More than High School;
I do not wish to answer; Unknown; Not Applicable)
Occupational/employment status mother (Full Time 
Employed; Part Time Employed; Unemployed; I do not wish 
to answer; Not Applicable)
Occupational/employment status father (Full Time Employed; 
Part Time Employed; Unemployed; I do not wish to answer; 
Not Applicable)
Occupational/employment status caregiver (Full Time 
Employed; Part Time Employed; Unemployed; I do not wish 
to answer; Not Applicable)
Country
Age subject at enrollment (months)
Descriptive statistics (N, mean, standard 
deviation [SD], median and range [minimum 
and maximum]).
Age Group at enrollment (< 14 days, ≥14 days and <30 days, 
≥30 days and <60 days, ≥60 days and ≤4 months)
Counts (n, %)
Number of siblings within the household
Descriptive statistics (N, mean, standard 
deviation [SD], median and range [minimum 
and maximum]).
Prenatal Smoking by the subject’s mother (no, yes)
Counts (n, %)
Exposed to tobacco smoke in home environment (no, yes)
Routinely attending daycare (no, yes)
Other siblings in household (no, yes)
8.4.9.
Additional Analysis
The following analysis are performed:

Summary of the RSV Mobile App evaluation questions. The proportion of subjects within the 
categories of each question will be shown in a frequency tabulation.

Scatterplot of the log10 RSV viral load values vs the RSV Mobile App domain scores on the 
day of the ARI visit. Spearman correlation will be added to the scatterplot.

Scatterplot of the log10 RSV viral load values vs the ClinRO summary score on the day of 
the ARI visit. Spearman correlation will be added to the scatterplot.

Scatterplot of the log10 RSV viral load values vs the ObsRO daily summary score on the day 
of the ARI visit. Spearman correlation will be added to the scatterplot.

Cumulative distribution of enrollment in the study (observational stage) over time, overlaid 
with the cumulative distribution of the ARI alerts over time.

Frequency tabulation of each individual RSV Mobile App question at ARI alert (using the 
symptom summary scores) by RSV +/- diagnosis. ARI alerts without diagnosis are not 
considered. For example, for “What is the strength of the coughing?”


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RSV(-)
N=
RSV(+)
N=
Weak 
n
xx.x %
n
xx.x %
Strong
n
xx.x %
n
xx.x %
Very strong, causing sometimes 
vomiting or interference with 
feeding and sleeping
n
xx.x %
n
xx.x %
8.4.10.
Subject Profiles
Individual profiles of the log10 RSV viral load actual values will be created for each RSV(+) subject
in the observational stage. Values from samples collected during the pre-diagnostic phase at home 
and collected during Day 1 to Day 8 are used.
Individual profiles of respiratory signs scores, non-respiratory signs score and total score on the 
RSV Mobile App will be created for each RSV(+) subject in the observational stage. RSV App 
Scores will be presented from Day -10 to Day 21 of the ARI visit. 
Individual profiles combining the log10 RSV viral load actual values and the RSV App total scores 
will be created for each RSV(+) subject in the observational stage.
Individual profiles combining the daily ObsRO summary scores and the RSV App total scores 
will be created for each RSV(+) subject in the observational stage.


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REFERENCES
1.
Ruvuna F., Flores D, Mikrut B., De La Garza K, Fong S. Generalized Lab Norms for Standardizing Data from 
Multiple Laboratories. Drug Information Journal 2003; 37: 61-79
2.
Schwartz GJ and Work DF. Measurement and estimation of GFR in children and adolescents. J Am Soc 
Nephrol. 2009; Nov; 4(11): 1832-643.


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ATTACHMENTS
Attachment 1: Division of Microbiology and Infectious Diseases (DMID) Pediatric Toxicity Tables 
(November 2007; draft)
ABBREVIATIONS: Abbreviations utilized in the Table:
ULN = Upper Limit of Normal
LLN = Lower Limit of Normal
Rx = Therapy 
Req = Required 
Mod = Moderate 
IV = Intravenous
ADL = Activities of Daily Living
Dec = Decreased
ESTIMATING SEVERITY GRADE
For abnormalities NOT found elsewhere in the toxicity tables use the scale below to estimate grade 
of severity:
GRADE 1
Mild: Transient or mild discomfort (<48 hours); no medical 
intervention/therapy required 
GRADE 2
Moderate: Mild to moderate limitation in activity - some assistance may be 
needed; no or minimal medical intervention/therapy required 
GRADE 3
Severe: Marked limitation in activity, some assistance usually required; 
medical intervention/therapy required, hospitalizations possible 
GRADE 4
Life-threatening or death*: Extreme limitation in activity, significant 
assistance required; significant medical intervention/therapy required, 
hospitalization or hospice care probable
* The draft DMID pediatric toxicity tables characterize death as a Grade 5 event, for the 
purposes of this study the sponsor will categorize events into 4 grades and has included 
death with life-threatening in the Grade 4 category.
SERIOUS OR LIFE-THREATENING ADVERSE EVENTS
ANY clinical event deemed by the clinician to be serious or life-threatening should be considered 
a Grade 4 event. Clinical events considered to be serious or life-threatening include, but are not 
limited to: seizures, coma, tetany, diabetic ketoacidosis, disseminated intravascular coagulation, 
diffuse petechiae, paralysis, acute psychosis, severe depression.
COMMENTS REGARDING THE USE OF THESE TABLES

Standardized and commonly used toxicity tables (Division of AIDS, 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.


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


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


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


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


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