Conditions: Respiratory Syncytial Virus Infections
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 3
Healthy volunteers: no

Brief summary:
The purpose of this study is to evaluate the effect of JNJ-53718678 on the development of respiratory syncytial virus (RSV) lower respiratory tract infection (LRTIs) in adult hematopoietic stem cell transplant (HSCT) recipients with RSV upper RTI.

Detailed description:
RSV is recognized as major respiratory pathogen in infants and young children and causes upper and lower respiratory illness among all age groups, often going undiagnosed. Immunocompromised (IC) participants have a reduced ability to combat infection due to an impaired or weakened immune system. Within the IC population, HSCT recipients are generally regarded as having a particularly high risk for more severe disease caused by RSV, representing a substantial unmet need for antiviral treatment of RSV infections in this participant population. JNJ-53718678 is an investigational, potent, small molecule, respiratory syncytial virus (RSV)-specific fusion inhibitor. The study will include a Screening Period (Day -2 to Day 1), a Treatment Period (Day 1 to Day 21), and a Follow-up Period (1 year). Assessments like chest X-ray, pulse/heart rate, respiratory rate, electrocardiogram (ECG), etc will be performed. Safety and efficacy will be assessed through the study. The total study duration for each participant will be approximately 49 days.

Arms:
arm 1: Participants greater than or equal to (\>=) 18 to less than or equal to (\<=) 75 years of age will receive 250 milligram (mg) JNJ-53718678 twice daily (bid) for 21 days (without coadministration with moderate or strong CYP3A4 inhibitors), or 125 mg JNJ-53718678 bid for 21 days (coadministered with moderate or strong CYP3A4 inhibitors with the exception of posaconazole), or 125 mg once daily (qd) for 21 days (when coadministered with posaconazole), or matching placebo for 21 days. arm 2: Participants \>=13 to \<18 years of age will receive 250 mg JNJ-53718678 bid for 21 days (without coadministration with moderate or strong CYP3A4 inhibitors), or 125 mg JNJ-53718678 bid for 21 days (coadministered with moderate or strong CYP3A4 inhibitors with the exception of posaconazole), or 125 mg qd for 21 days (when coadministered with posaconazole), or matching placebo for 21 days.

Interventions: intervention 1: JNJ-53718678 250 mg intervention 2: Placebo intervention 3: JNJ-53718678 125 mg
Intervention descriptions: intervention 1: JNJ-53718678 250 mg will be administered orally. intervention 2: Matching placebo will be administered orally. intervention 3: JNJ-53718678 125 mg will be administered orally.

Protocol document:
Prot_000.pdf: 
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
1
Status: Approved,  Date: 07 May 2021
Janssen Research & Development *
Clinical Protocol
A Randomized, Double-blind, Placebo-controlled Study to Evaluate the Clinical Outcomes,
Antiviral Activity, Safety, Tolerability, Pharmacokinetics, and
Pharmacokinetics/Pharmacodynamics of JNJ-53718678 in Adult and Adolescent
Hematopoietic Stem Cell Transplant Recipients with Respiratory Syncytial Virus Infection
of the Upper Respiratory Tract
FREESIA
Effects of JNJ-53718678 in Adult and Adolescent Patients Who had a Hematopoietic Stem
Cell Transplantation and Who are Infected With RSV
Protocol 53718678RSV2005; Phase 2
AMENDMENT 6
JNJ-53718678
*Janssen Research & Development is a global organization that operates through different legal entities in
various countries. Therefore, the legal entity acting as the sponsor for Janssen Research & Development
studies may vary, such as, but not limited to Janssen Biotech, Inc.; Janssen Products, LP; Janssen
Biologics, BV; Janssen-Cilag International NV; Janssen, Inc; Janssen Pharmaceutica NV; Janssen
Sciences Ireland Unlimited Company; Janssen Biopharma Inc.; or Janssen Research & Development,
LLC. The term “sponsor” is used throughout the protocol to represent these various legal entities; the
sponsor is identified on the Contact Information page that accompanies the protocol.
This study will be conducted in US under US Food & Drug Administration Investigational New
Drug (IND)regulations (21 CFR Part 312).
EudraCT NUMBER:2019-001551-39
Status: 
Approved
Date: 
07 May 2021
Prepared by: Janssen Research & Development, a division of Janssen Pharmaceutica NV
EDMS number: 
EDMS-ERI-182394418, 17.0
GCP Compliance: This study will be conducted in compliance with Good Clinical Practice, and applicable regulatory
requirements.
Confidentiality Statement
The information provided herein contains Company trade secrets, commercial or financial information that the Company
customarily holds close and treats as confidential. The information is being provided under the assurance that the recipient
will maintain the confidentiality of the information under applicable statutes, regulations, rules, protective orders or
otherwise.
NCT04056611


JNJ-53718678
Clinical Protocol 53718678RSV2005 Amendment 6
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
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Status: Approved,  Date: 07 May 2021
PROTOCOL AMENDMENT SUMMARY OF CHANGES TABLE
DOCUMENT HISTORY
Document 
Date
Amendment 6 
7 May 2021
Amendment 5 
03-Aug-2020
Amendment 4 
10-Jul-2020
Amendment 3 
03-Jun-2020
Amendment 2 
11-Dec-2019
Amendment 1 
21-Jun-2019
Original Protocol 
7-Jun-2019
Amendments below are listed beginning with the most recent amendment.
Amendment 6 (7 May 2021)
Overall Rationale for the Amendment: The overall reason for the amendment is to replace the oral
suspension formulations of JNJ-53718678 and placebo by oral film-coated tablets based on supportive data
from Study 53718678RSV1011, for newly enrolled participants after implementation of Protocol
Amendment 6.
Section Number
and Name
Description of Change 
Brief Rationale
1.1 Synopsis
1.3 Schedules of Activities
2.2 Background
4.1 Overall Design
4.3.1 Study Intervention Dose
5.2 Exclusion Criteria
6.1 Study Intervention(s)
Administered
6.2 Preparation/Handling/Stora
ge/Accountability
6.4 Study Intervention
Compliance
8.1 Overview
The oral suspension (supplied as
powder and solvent) of JNJ-53718678
and placebo are replaced by oral film-
coated tablets for all newly enrolled
participants after implementation of
Protocol Amendment 6.
The switch from the oral
suspension to the oral film-coated
tablet is based on supportive
bioavailability and safety data from
Study 53718678RSV1011.
Additionally, oral film-coated
tablets are more patient-friendly for
the adolescent and adult population
in this study compared to the oral
suspension.
1.3 Schedules of Activities 
The Day 1 and Day 3 ECGs and Day 1
and Day 15 sparse PKsampling were
changed from approximately 1 hour
into approximately 1 to 1.5 hours after
JNJ-53718678 intake under fasted
conditions, for both hospitalized
participants and outpatients.
A window between 1 and 1.5 hours
after drug intake was introduced to
cover both oral suspension and oral
tablet formulations, which have a
median Tmax  between 1 and 1.5
hours.
10.12 Appendix 12: Guidance 
on Study Conduct During the 
COVID-19 Pandemic 
Wording was added to specify the
clinical management of laboratory-
confirmed SARS-CoV-2 infection,
diagnosed during the study, in
participants, ie, per local standard of
care.
Clarification


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Status: Approved,  Date: 07 May 2021
Section Number 
and Name
Description of Change 
Brief Rationale
5.3 Lifestyle Considerations 
6.6 Concomitant Therapy  
10.12 Appendix 12: Guidance 
on Study Conduct During the 
COVID-19 Pandemic
Specifics were added on the 
administration of a locally approved 
(including emergency use-authorized)
COVID-19 vaccine during the study.
Additions were made per recent
Health Authority guidance.
6.6 Concomitant Therapy  
Guidance was added with regard to 
participants who receive seasonal (eg,
influenza) or other routine vaccinations
during the study.
Clarification
1.3 Schedules of Activities 
5.2 Exclusion Criteria 
7.1 Discontinuation of Study 
Intervention  
8.4.7.2 Cardiac Events 
Potentially Related to QT 
Prolongation
Participants with ≥Grade 3 laboratory 
abnormality of hypokalemia of 
<2.5 mEq/L and/or hypomagnesemia of 
<0.9 mEq/L at Screening (or 4 days 
prior to Screening) will be excluded 
from the study.
Language in other relevant protocol
sections was aligned with these
changes.
The wording regarding QT-related
safety measures was made more
specific to and more stringent for
clinically relevant (≥Grade 3)
hypokalemia and hypomagnesemia.
1.1 Synopsis 
9.3 Sample Size Determination  
9.4.2.1Primary Endpoint: 
Development ofRSV Lower 
Respiratory Tract Infection  
9.4.2.2 Key Secondary 
Endpoints 
11 REFERENCES  
Log-binomial model was changed to 
stratified Cochran-Mantel-Haenszel test 
for analysis of the primary endpoint and 
key secondary endpoints on the 
proportion of participants hospitalized, 
and proportion of participants 
progressing to respiratory failure and/or 
death. 
Stratified Cochran-Mantel-
Haenszel test is preferred instead of
log-binomial model to analyze the
binary outcomes. There is a known
risk of non-convergence with log-
binomial models and methods to
overcome the non-convergence
might result in biased estimates of
the treatment effect.
1.3 Schedules of Activities 
4.1 Overall Design  
7.1 Discontinuation of Study 
Intervention  
A recommendation was added for
participants who prematurely
discontinue study intervention for any
reason, ie, to remain compliant to all
study-related procedures including
timely completion of all efficacy
assessments up to Day 49 or at least
through Day 28.
To reduce the amount of missing
data from participants who
prematurely discontinue study
intervention.
9.4.2.3 Clinical Course of RSV
Infection
The total length of hospital stay was
removed from the time-to-event
variable examples.
Correction of error.
The total length of hospital stay is
not considered a time to-event
variable but a duration variable (see
Amendment 2) since participants
might not be hospitalized as of the
beginning of the study, and even
could switch between in-and
outpatient status over the course of
the study. This endpoint will be
analyzed using a Hodges-Lehmann
test.


JNJ-53718678
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Status: Approved,  Date: 07 May 2021
Section Number
and Name
Description of Change 
Brief Rationale 
10.12 Appendix 12: Guidance 
on Study Conduct During the 
COVID-19 Pandemic 
The following updates were made: 
 The blood sample for RSV viremia
was removed from the Day 1 home
visit assessments.
 The requirement for dry ice
provision for transport of RSV
viremia blood samples was
removed.
Correction of errors.
Throughout 
Minor corrections and updates were done throughout.
Amendment 5 (03 August 2020)
Overall Rationale for the Amendment: The overall reason for the amendment is to implement
recommendations by Health Authorities (HA).
Section Number
and Name
Description of Change 
Brief Rationale
1.3 Schedules of Activities
8.4.7.2 Cardiac Events Potentially Related to
QT Prolongation
10.2 Appendix 2: Clinical Laboratory Tests
It was clarified that levels of
potassium and magnesium
should be determined by the
local and by the central
laboratory.
Clarification.
All safety laboratory
assessments are being done by
the central laboratory to
maintain uniformity of assay.
Some assessments are also
performed locally when quick
turnaround time is necessary
for medical decision making.
2.3.3 Benefit-Risk Assessment for Study
Participation
It was clarified that close
monitoring of hypokalemia and
hypomagnesemia and corrective
actions in case of laboratory
abnormalities for these analytes
is also applicable at Screening.
Correction of inconsistency.
2.3.3 Benefit-Risk Assessment for Study
Participation
8.3.3 Electrocardiograms
8.4.7.2 Cardiac Events Potentially Related to
QT Prolongation
It was clarified throughout that
the cardiac safety management
refers to QTcF interval changes.
Correction of inconsistency.
5.2 Exclusion Criteria 
Exclusion criterion #24 was
added to exclude participants
with a personal or family
history of long QT syndrome or
sudden cardiac death.
Part of QT prolongation
mitigation measures to ensure
participants’ safety.
5.2 Exclusion Criteria 
Exclusion criteria #19.1 and
#22 were combined in
exclusion criterion #19.2 as
they were almost identical.
Correction of redundancy.


JNJ-53718678
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Status: Approved,  Date: 07 May 2021
Amendment 4 (10 July 2020)
Overall Rationale for the Amendment: The overall reason for the amendment is to implement
recommendations by Health Authorities (HA).
Section Number 
and Name
Description of Change 
Brief Rationale
1.3 Schedules of Activities 
2.3.3 Benefit-Risk Assessment for Study 
Participation  
8.3.3 Electrocardiograms 
A clarification was added to 
specify the timing of ECG 
monitoring on Day 1 and Day 3 
(steady state) to be performed at 
tmax  of JNJ-53718678 (time to 
reach Cmax), ie, approximately 
1 hour (fasted)or 
approximately 4 hours (fed) 
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.
2.3.3 Benefit-Risk Assessment for Study 
Participation  
7.1 Discontinuation of Study Intervention 
8.3.3 Electrocardiograms 
8.4.7.2 Cardiac Events Potentially Related to 
QT Prolongation 
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.
6.6 Concomitant Therapy  
The BCRP inhibitors 
eltrombopag, rolapitant, 
fostamatinib, teriflunomide, and 
curcumin were added to the 
disallowed concomitant therapy 
section. 
JNJ-53718678 is a substrate
for BCRP based on in vitro
data. Clinically relevant
BCRP inhibitors are
prohibited to avoid potential
DDI with JNJ-53718678, in
line with recommendations by
HA.
6.6 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
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Status: Approved,  Date: 07 May 2021
Amendment 3 (03 June 2020)
Overall Rationale for the Amendment:The overall reason for the amendment is to implement a risk
mitigation plan following 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
2.3.1.2 Potential Risks
2.3.3 Benefit-Risk Assessment for Study
Participation
4.3.1 Study Intervention Dose
The important potential risk of
QT interval prolongation
identified in the TQT study was
added.
New potential risk identified
from a TQT study and
reflected in the relevant
sections of the protocol.
2.2 Background
2.3.2.1 Known Benefits
2.3.2.2 Potential Benefits
2.3.3 Benefit-Risk Assessment for Study
Participation
Recently available relevant
clinical data were included in
the introduction. Accordingly,
the Investigator's Brochure
Addendum to Edition 06 was
added as a reference.
New relevant clinical data
available and reflected in the
relevant sections of the
protocol.
1.1 Synopsis
1.2 Schema
1.3 Schedules of Activities
2.3.3 Benefit-Risk Assessment for Study
Participation
4.1 Overall Design
4.3.1 Study Intervention Dose
6.1 Study Intervention(s) Administered
6.2
Preparation/Handling/Storage/Accountability
6.4 Study Intervention Compliance
6.6 Concomitant Therapy
8.5 Treatment of Overdose
Dose regiment was adjusted to
250 mg bid for participants with
no co-administration of strong
or moderate CYP3A4
inhibitors.
The period during the study
when certain concomitant
medications are disallowed was
aligned with the 3 days wash
out period of the study
intervention.
The definitions of missing dose
and overdose were adapted
accordingly.
The daily dosing frequency
was changed from qd to bid
dosing while maintaining the
total daily dose (ie, at each
intake half of the total daily
dose will be administered).
The proposed bid dosing will
ensure 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.
The t1/2 of JNJ-53718678 is
approximately 10 hours
therefore the study
intervention is washed out
after 3 days.
1.1 Synopsis
1.2 Schema
1.3 Schedules of Activities
2.3.3 Benefit-Risk Assessment for Study
Participation
4.1 Overall Design
4.3.1 Study Intervention Dose
6.1 Study Intervention(s) Administered
6.2
Preparation/Handling/Storage/Accountability
6.5 Dose Modification
6.6 Concomitant Therapy
For participants with
coadministration of moderate or
strong CYP3A4 inhibitors with
the exception of posaconazole,
the dose ofthe study
intervention was reduced to
125 mg bid.
PBPK data indicate potential
for increase of the Cmax  due to
CYP3A4 inhibition. With a
dose reduction to 125 mg bid
when moderate or strong
CYP3A4 inhibitors are
coadministered, this increase
in Cmax  remains below the
threshold for the potential
QT-prolongating effect.
1.1 Synopsis
1.2 Schema
1.3 Schedules of Activities
2.3.3 Benefit-Risk Assessment for Study
Participation
4.1 Overall Design
4.3.1 Study Intervention Dose
For participants with
coadministration of
posaconazole, the dose of the
study intervention was reduced
to 125 mg qd.
JNJ-53718678 steady-state
exposure (AUC) after 250mg
bid dosing without
concomitant use of CYP3A4
inhibitors is similar to that
after 125 mg qd dosing with
coadministration of


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Status: Approved,  Date: 07 May 2021
Section Number
and Name
Description of Change 
Brief Rationale
6.1 Study Intervention(s) Administered
6.2
Preparation/Handling/Storage/Accountability
6.5 Dose Modification
6.6 Concomitant Therapy
posaconazole (400 mg bid)
and similar to that of 125 mg
bid dosing with
coadministration of
voriconazole (200 mg bid),
clarithromycin (500 mg bid),
or itraconazole (200 mg qd).
1.3.4 PK Assessments
8.6 Pharmacokinetics
Timing of PK samples was
changed.
PK sampling was optimized to
obtain a PK sample around
expected Cmax  of
JNJ-53718678 and a PK
sample to collect information
related to Ctrough  in view of the
bid regimen.
1.3 Schedules of Activities
2.3.3 Benefit-Risk Assessment for Study
Participation
8.3.3 Electrocardiograms
The frequency of ECG
monitoring was increased by
adding measurements at Days 1,
8, and 15 to enhance the
cardiac-related safety follow up.
Additional ECG assessments
are to be performed as
unscheduled assessments/visits
preferably 3 days after the start
of coadministration with
moderate or strong CYP3A4
inhibitors during the study
intervention period.
Details on ECG collection were
added.
Part of risk mitigation plan to
ensure participant’s safety.
2.3.3 Benefit-Risk Assessment for Study
Participation
Close monitoring of the use of
concomitant medications to be
conducted regularly was added.
Part of risk mitigation plan to
ensure participant’s safety.
2.3.3 Benefit-Risk Assessment for Study
Participation
5.2 Exclusion Criteria
Specific cardiovascular and
ECG-based criteria were added
for eligibility assessment.
Part of risk mitigation plan to
ensure participant’s safety.
2.3.3 Benefit-Risk Assessment for Study
Participation
7.1 Discontinuation of Study Intervention
8.4.7.2 Cardiac Events Potentially Related to
QT Prolongation
The study intervention
discontinuation criteria specific
to QTc interval changes were
aligned with the increased
frequency of ECG assessments.
Part of risk mitigation plan to
ensure participant’s safety.
2.3.3 Benefit-Risk Assessment for Study
Participation
8.4.7.2 Cardiac Events Potentially Related to
QT Prolongation
Specific toxicity management
for confirmed QTc interval
value >500 ms was added.
Part of risk mitigation plan to
ensure participant’s safety.
1.3 Schedules of Activities
2.3.3 Benefit-Risk Assessment for Study
Participation
8.4.7.2 Cardiac Events Potentially Related to
QT Prolongation
10.2 Appendix 2: Clinical Laboratory Tests
Specific guidance for the
management of hypokalemia
and/or hypomagnesemia was
added.
Part of risk mitigation plan to
ensure participant’s safety.
1.1 Synopsis
1.3.3 Long-term Follow-up
4.1 Overall Design
4.4 End of Study Definition
8.10 Medical Resource Utilization
Longer term follow-up was
implemented.
Sponsor decision to collect
information on longer term
RSV-related clinical outcomes
and medical resource
utilization.


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Section Number
and Name
Description of Change 
Brief Rationale 
9 STATISTICAL CONSIDERATIONS
9.4.9 Health Economics
4.2.6 Study-Specific Ethical Design 
Considerations 
The total blood volume was
adapted to ‘maximum
approximately’ 110 mL.
Adaptation to account for
variability in the actual taken
amount of blood.
8.2.1.2 Lower Respiratory Tract Samples 
'for RSV' was added to central
testing of lower respiratory tract
sample.
A clarification was added that
the central testing that may be
provided is for testing of RSV.
1.3 Schedules of Activities 
4.1 Overall Design  
8.2.3 Antiviral Activity  
A sentence was added to
indicate that another upper
respiratory tract sample than the
study-specific bilateral mid-
turbinate nasal swab sample can
also be used to perform local
testing for RSV detection at
Day 28, if needed based on the
local PCR- or other molecular-
based diagnostic assay.
A clarification was added that
an upper respiratory tract
sample other than the
study-specific bilateral mid-
turbinate nasal swab sample
can also be used for local
testing of RSV detection at
Day 28 to align with local
SOC sampling and testing.
7.1 Discontinuation of Study Intervention 
8.4.7 Management of Adverse Events of 
Interest
8.4.7.1 Rash Management
10 SUPPORTING DOCUMENTATION
AND OPERATIONAL
CONSIDERATIONS
Rash Management was
removed.
The specific Rash
Management section, which is
a therapeutic area-specific
section that can be adapted
based on emerging data, was
removed as data from both
adult and pediatric studies
have not indicated a rash-
related safety signal.
8.6.1 Substudy in Hospitalized Participants 
Removal of requirement of
standardized breakfast prior to
study intervention intake on
intensive PK day.
For practical reasons and to
collect information on PK in
both fed and fasted state.
1.1 Synopsis 
1.3 Schedules of Activities 
7.2 Participant Discontinuation/Withdrawal 
From the Study  
8.9 Biomarkers 
A sentence was added to
indicate that collection of
biomarker research samples is
mandatory, unless local
regulations require these
samples to be optional.
A clarification for the
collection of blood samples
for biomarker research was
added to accommodate for
local regulations for collection
of research samples.
9.4.3 Safety Analyses 
A sentence was added to
indicate tabulation or listing of
central/local laboratory results
and local ECGs.
For clarification.
9.4.8 Other Analyses 
A correction was made to
‘Day 1 predose’.
A correction was done to align
with Section 8.2.3.
10.9 Appendix 9: Respiratory Infection 
Intensity and Impact Questionnaire (RiiQ™) 
The RiiQ Impact Scale was
updated.
The latest copyrighted RiiQ
version was used for the
appendix.
1.3 Schedules of Activities 
4.1 Overall Design  
5.1 Inclusion Criteria 
5.2 Exclusion Criteria 
10.12 Appendix 12: Guidance on Study
Conduct During the COVID-19 Pandemic
COVID-19-related measures 
were added to provide guidance 
on study conduct during the
COVID-19 pandemic.
COVID-19 pandemic ongoing
at time of amendment writing.
Throughout 
Minor corrections and clarifications were done throughout.


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Status: Approved,  Date: 07 May 2021
Amendment 2 (11 December 2019)
Overall Rationale for the Amendment:The overall reason for the amendment is to ensure consistency
between different sections, to clarify, and make minor corrections to different parts of the protocol. In
addition, regulatory feedback from competent authorities was incorporated.
Section Number 
and Name
Description of Change 
Brief Rationale
Throughout 
The references to the Investigator’s Brochure 
(IB) in the text were updated to “the most
recent IB”. The reference to the IB was
updated to the newest version (Edition 6).
More straightforward to refer to
the most recent IB in the text
and specify current version in
the reference.
Throughout 
Minor grammatical, formatting, or spelling
changes were made throughout the protocol.
To correct for minor errors that
were noted in the protocol.
1.1 Synopsis 
3 OBJECTIVES AND 
ENDPOINTS  
The wording “is discarded” was added to the
secondary endpoint “Total length of hospital
stay (time in hospital before first dosing is
discarded) and total time in the intensive care
unit (ICU) (time in ICU before first dosing is
discarded)”.
Alignment for consistency with
wording in Efficacy Analyses in
Synopsis and Section 9.4.2.
1.1 Synopsis 
3 OBJECTIVES AND 
ENDPOINTS
The definition of the abbreviation RiiQ was
added to the footnote of the “Objectives and
Endpoints” table.
The definition was added for
clarification.
1.1 Synopsis 
3 OBJECTIVES AND 
ENDPOINTS  
The wording “as determined by the EAC” was
added to the definition of respiratory syncytial
virus (RSV) lower respiratory tract infection
(LRTI).
Added for completeness.
1.1 Synopsis 
8.9 Biomarkers 
The wording “or other clinical outcomes in
this population” was removed from the
sentence “Analyses of biomarkers may be
conducted at the sponsor’s discretion and
reported separately from this study”.
Wording was introduced by
mistake.
1.1 Synopsis 
9.4.2.2 Key Secondary 
Endpoints 
The method for analyzing the key secondary
endpoints total length of hospital stay and the
number of supplemental O2 free days was
adapted from Gehan-Wilcoxon test to Hodges-
Lehmann test.
The Gehan-Wilcoxon test is
more suitable for time-to-event
data (time to resolution of
symptoms). The duration
parameters (total length of
hospital stay and the number of
supplemental O2 free days) will
be analyzed using the Hodges-
Lehmann test.
1.2 Schema 
The schematic overview of the study was
updated to include inclusion criterion #4
(ALC <1,000 cells/µL).
The schematic overview of the
study was updated for
completeness.


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Section Number 
and Name
Description of Change 
Brief Rationale
1.3 Schedules of Activities 
In Section 1.3.2. (Schedule of Activities for 
Outpatients), provision of study intervention 
for daily use at home on Day 3 was removed. 
Correction. Outpatients are not
provided with study intervention
for daily use at home on Day 3.
They receive 2 bottles covering
6 days of dosing on Day 1.
1.3 Schedules of Activities 
5.1 Inclusion Criteria 
8.1 Overview  
10.2 Appendix 2: Clinical 
Laboratory Tests
“Local” was added to all pregnancy testing, 
including the serum pregnancy test at 
screening. Accordingly, the wording “by the
central laboratory” was removed from the
sentence “The following tests will be
performed according to the Schedule of
Activities” in Appendix 2.
Clarification that the pregnancy
test is to be performed locally.
1.3.1 Hospitalization 
Through Discharge 
The Schedule of Activities for hospitalized 
participants was adjusted (Day 35 and 
Day 49). 
Adjusted to clarify which
assessments are only to be
performed in case abnormalities
are observed at Day 28.
1.3.3 PK Assessments 
8.6.1 Substudy in 
Hospitalized Participants 
The footnotes of Table 1 and Table 2 in 
Section 1.3.3 were adjusted. 
The sentence “Participants in the rich serial 
PKsampling substudy will not participate in 
the sparse PK study” in Section 8.6.1 was 
removed from the protocol and the header of 
Table 1 in Section 1.3.3 was adjusted
accordingly.
Adjusted to clarify timing of
sampling.
Correction, participants in the
rich serial PK sampling substudy
will also participate in the sparse
PK study.
4.3 Justification for Dose 
and Duration 
A justification for the selected dosing regimen 
in adolescents has been added. 
Requested by regulatory
authorities.
5.1 Inclusion Criteria 
Inclusion criterion #14 was updated to add the 
required duration for males to use 
contraception, ie, from Day 1 and for 90 days
after receiving the last dose of study drug.
Requested by regulatory
authorities.
6.5 Concomitant Therapy  
In the concomitant therapy section, the section 
on disallowed prescription medications within 
14 days prior to Screening and during the 
study was updated. Ciprofloxacin, atazanavir, 
and darunavir were removed from the list of 
prohibited strong Cytochrome P450 
(CYP)3A4 inhibitors. Ciprofloxacin was
added to the examples of allowed moderate
CYP3A4 inhibitors.
Telithromycin, nefazodone, posaconazole, 
nelfinavir, saquinavir, and erythromycin were 
removed from the list of prohibited strong 
CYP3A4 inhibitors. The note “In Study  
53718678RSV1009 (Thorough QT Study) and 
other clinical studies, exposures several 
fold above the 500 mg exposure have not led 
to any safety concerns. Strong CYP3A4 
inhibitors posaconazole, telithromycin, 
ceritinib, nefazodone, nelfinavir, 
saquinavir, conivaptan, ribociclib, idelalisib, 
and boceprevir are allowed, as their effect 
on JNJ-53718678 exposure is expected to be 
less than 2-fold” was added. 
Ciprofloxacin, atazanavir, and
darunavir are considered
moderate CYP3A4 inhibitors
based on the University of
Washington Drug Interaction
Database (DIDB).30
The list of CYP34 inhibitors by
DIDB was used as guidance for
disallowed and allowed strong
CYP3A4 inhibitors. Based on
DIDB, CYP isoforms inhibitors
are identified and classified
based on the available area
under the plasma concentration-
time curve (AUC)ratios of
clinical index substrates,
sensitive substrates, and
moderate sensitive substrates,
recommended by the FDA drug-
drug interactions (DDI)
guidance.20


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Section Number
and Name
Description of Change 
Brief Rationale
Addition of a note with respect to 
voriconazole. 
In Study 53718678RSV1006,
JNJ-53718678 was
coadministered with itraconazole
(a strong CYP3A4 and P-gp
inhibitor)and no safety signal
was identified. AUC0-∞ of
JNJ-53718678 increased
3.45-fold. Based on the DIDB,
itraconazole increases
midazolam exposure by 10.80
fold (effect of size itraconazole
on JNJ-53718678 is 0.32
compared to midazolam
[3.45/10.80]).
Based on these clinical data, it
can be calculated for the list of
strong CYP3A4 inhibitors that
the increase in plasma exposure
of JNJ-53718678 is 2-fold or
less due to concomitant
administration of posaconazole,
telithromycin, ceritinib,
nefazodone nelfinavir,
saquinavir, conivaptan,
ribociclib, idelalisib, and
boceprevir. Inclusion of these
strong CYP3A4 inhibitors is
deemed acceptable. Strong
CYP3A4 inhibitors such as
mibefradil, clarithromycin,
tipranavir/ritonavir (rtv),
ritonavir, cobicistat,
ketoconazole, troleandomycin,
telaprevir, danoprevir/rtv,
elvitegravir/rtv, saquinavir/rtv,
itraconazole, and indinavir are
disallowed.
Voriconazole is considered a
strong CYP3A4 inhibitor, but is
allowed as comedication based
on additional physiologically
based PK analysis (PBPK)
analysis, showing a moderate
effect on JNJ-53718678 AUC of
2.86-fold.
7.1 Discontinuation of
Study Intervention
7.2 Participant
Discontinuation/Withdrawal
From the Study
The sentence “At the Withdrawal and Safety 
Follow-up Visits, the same assessments as on 
the Day 28 and Day 35 visits, respectively, 
will be performed” was corrected to “Day 22
and Day 28”.
Alignment between text in
Schedules of Activities and
Sections 7.1 and 7.2.


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Section Number
and Name
Description of Change 
Brief Rationale
8.2.6 Evaluation of RSV
Viremia
The word “respiratory” was removed from the 
sentence “At the discretion of the sponsor, 
these samples may also be used for
exploratory analysis of other respiratory
pathogens in plasma that may play a role in
treatment response, safety, or the status and/or
course of RSV-related disease or other clinical
outcomes in this population.”.
Alignment for consistency with
Section 4.1 and Section 8.2.1.4.
8.4.1 Time Period and
Frequency for Collecting
Adverse Event and Serious
Adverse Event Information
Update to clarify that all adverse events (AEs), 
whether serious or non-serious, whether 
anticipated or not anticipated, will be recorded
and reported.
Clarification following
regulatory authorities request.
8.4.4 Regulatory Reporting
Requirements for Serious
Adverse Events
Rhinitis was removed from the list of 
Anticipated Events (Table 5). 
Correction. Rhinitis will not be
monitored as an anticipated
event.
8.4.4 Regulatory Reporting
Requirements for Serious
Adverse Events
Update to clarify that also individual 
anticipated serious adverse events (SAEs) will 
be reported appropriately, according to the
requirements of the countries in which the
study is conducted.
Clarification following
regulatory authorities request
8.4.6 Disease-Related
Events and Disease-Related
Outcomes not Qualifying as
Adverse Events or Serious
Adverse Events
Update to clarify that if symptoms of RSV 
disease are considered related to the drug 
intervention or meet the definition of
seriousness, they will be reported as an
AE/SAE accordingly.
Requested by regulatory
authorities.
10.2 Appendix 2: Clinical
Laboratory Tests
The term creatinine clearance was replaced by 
eGFRcrea. 
eGFRcrea is a more accurate
terminology when referring to
CKD-EPI formula for
determination of creatinine
clearance.
10.4 Appendix 4: Adverse
Events: Definitions and
Procedures for Recording,
Evaluating, Follow-up, and
Reporting
The protocol was updated to better align 
Section 10.4 Appendix 4: Adverse Events: 
Definitions and Procedures for Recording, 
Evaluating, Follow-up, and Reporting, with 
the Division of Microbiology and Infectious 
Diseases (DMID) Adult Toxicity Table (10.7 
Appendix 7).
For consistency between Section
10.4 Appendix 4 and DMID
Adult Toxicity Table
(Section 10.7 Appendix 7), as
requested by regulatory
authorities.
10.5 Appendix 5:
Contraceptive and Barrier
Guidance and Collection of
Pregnancy Information
Update to remove tubal occlusion/ligation 
from the list of permanent sterilization 
methods while retaining it in the list of 
acceptable contraception for this study. 
Alignment with guidance related
to contraception and pregnancy
testing in clinical trials from the
Clinical Trials Facilitation and
Coordination Group of the
European Heads of Medicines
Agencies, as requested by
regulatory authorities.27


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Amendment 1 (21 June 2019)
Overall Rationale for the Amendment: The overall reasons for this amendment are to correct for an
inconsistency with regard to the classification of CYP3A4 inhibitors and CYP3A4 inducers in the
concomitant therapy section and to update the exclusion criteria to clarify that enrollment of participants
during the follow-up phase of another clinical study is allowed.
Section Number 
and Name
Description of Change 
Brief Rationale
6.5 Concomitant 
Therapy  
In the concomitant therapy section, the section on 
disallowed prescription medications within 14 days 
prior to Screening and during the study was
updated. Cyclosporin and glucocorticoids were
removed from the list of prohibited strong
CYP3A4 inhibitors and CYP3A4 inducers,
respectively, and added to the examples of allowed
moderate CYP3A4 inhibitors and CYP3A4
inducers, respectively. Posaconazole was added to
the list of prohibited strong CYP3A4 inhibitors.
Voriconazole and isavuconazole were added to the
list of moderate CYP3A4 inhibitors, which are
allowed.
The concomitant therapy section of
the protocol was updated because
cyclosporin and glucocorticoids
were incorrectly listed as a strong
CYP3A4 inhibitor and strong
CYP3A4 inducers, respectively.
The antifungal drugs posaconazole,
voriconazole, and isavuconazole,
were added for completeness, as
these are used in the target
population. Note:Voriconazole,
which is a moderate/strong
CYP3A4 inhibitor, is allowed based
on additional physiologically based
PK analysis (PBPK).
5.2 Exclusion
Criteria
6.5 Concomitant
Therapy
Exclusion criteria 12 and 16 were updated. In
exclusion criterion 12, a note that concurrent
enrollment is allowed during the follow-up phase
of another clinical study, was added.
In exclusion criterion 16, the term investigational
drug and its related note were removed as this is
covered in exclusion criterion 12. The concomitant
therapy section was updated for consistency with
exclusion criterion 16.
These exclusion criteria were
updated to clarify that enrollment of
participants during the follow-up
phase of another clinical study is
allowed, given the frequent
participation of HSCT recipients in
other investigational treatment
studies with long follow-up periods.


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TABLE OF CONTENTS
PROTOCOL AMENDMENT SUMMARY OF CHANGES TABLE ............................................................... 2
TABLE OF CONTENTS ............................................................................................................................. 14
LIST OF IN-TEXT TABLES AND FIGURES.............................................................................................. 17
1. 
PROTOCOL SUMMARY................................................................................................................... 18
1.1. 
Synopsis......................................................................................................................................... 18
1.2. 
Schema.......................................................................................................................................... 30
1.3. 
Schedules of Activities ................................................................................................................... 31
1.3.1. 
Hospitalization Through Discharge............................................................................................. 31
1.3.2. 
Outpatients ................................................................................................................................. 38
1.3.3. 
Long-term Follow-up................................................................................................................... 46
1.3.4. 
PK Assessments......................................................................................................................... 47
1.3.4.1. 
Sparse PK Sampling and Assessments.................................................................................. 47
1.3.4.2. 
Rich Serial PK Sampling Substudy Assessments................................................................... 48
2. 
INTRODUCTION................................................................................................................................ 49
2.1. 
Study Rationale.............................................................................................................................. 49
2.2. 
Background .................................................................................................................................... 50
2.3. 
Benefit-Risk Assessment............................................................................................................... 56
2.3.1. 
Risks for Study Participation....................................................................................................... 56
2.3.1.1. 
Known Risks............................................................................................................................ 56
2.3.1.2. 
Potential Risks......................................................................................................................... 56
2.3.2. 
Benefits for Study Participation .................................................................................................. 58
2.3.2.1. 
Known Benefits........................................................................................................................ 58
2.3.2.2. 
Potential Benefits..................................................................................................................... 58
2.3.3. 
Benefit-Risk Assessment for Study Participation ....................................................................... 58
3. 
OBJECTIVES AND ENDPOINTS ..................................................................................................... 60
3.1. 
Hypothesis ..................................................................................................................................... 64
4. 
STUDY DESIGN ................................................................................................................................ 65
4.1. 
Overall Design................................................................................................................................ 65
4.2. 
Scientific Rationale for Study Design............................................................................................. 69
4.2.1. 
Study Population......................................................................................................................... 69
4.2.2. 
Blinding, Control, Study Phase/Periods, Intervention Groups.................................................... 70
4.2.3. 
Biomarker Collection................................................................................................................... 70
4.2.4. 
Medical Resource Utilization ...................................................................................................... 71
4.2.5. 
Participant Input Into Design ...................................................................................................... 71
4.2.6. 
Study-Specific Ethical Design Considerations ........................................................................... 71
4.3. 
Justification for Dose and Duration................................................................................................ 71
4.3.1. 
Study Intervention Dose ............................................................................................................. 71
4.3.2. 
Study Intervention Duration ........................................................................................................ 75
4.4. 
End of Study Definition................................................................................................................... 75
5. 
STUDY POPULATION ...................................................................................................................... 76
5.1. 
Inclusion Criteria............................................................................................................................ 76
5.2. 
Exclusion Criteria........................................................................................................................... 78
5.3. 
Lifestyle Considerations................................................................................................................. 81
5.4. 
Screen Failures.............................................................................................................................. 81
6. 
STUDY INTERVENTION................................................................................................................... 82
6.1. 
Study Intervention(s) Administered................................................................................................ 82
6.2. 
Preparation/Handling/Storage/Accountability ................................................................................ 83
6.3. 
Measures to Minimize Bias: Randomization and Blinding............................................................. 85
6.4. 
Study Intervention Compliance...................................................................................................... 86


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6.5. 
Dose Modification........................................................................................................................... 86
6.6. 
Concomitant Therapy..................................................................................................................... 87
6.7. 
Intervention After the End of the Study.......................................................................................... 92
7. 
DISCONTINUATION OF STUDY INTERVENTION AND PARTICIPANT
DISCONTINUATION/WITHDRAWAL............................................................................................... 92
7.1. 
Discontinuation of Study Intervention ............................................................................................ 92
7.2. 
Participant Discontinuation/Withdrawal From the Study................................................................ 93
7.3. 
Lost to Follow-up............................................................................................................................ 94
8. 
STUDY ASSESSMENTS AND PROCEDURES ............................................................................... 95
8.1. 
Overview ........................................................................................................................................ 95
8.2. 
Efficacy Assessments .................................................................................................................... 96
8.2.1. 
Development of Lower Respiratory Tract Infection/Complications ............................................ 96
8.2.1.1. 
Chest Imaging.......................................................................................................................... 96
8.2.1.2. 
Lower Respiratory Tract Samples........................................................................................... 97
8.2.1.3. 
Bilateral Mid-turbinate Nasal Swab Samples .......................................................................... 97
8.2.1.4. 
Blood Samples for RSV Viremia.............................................................................................. 97
8.2.1.5. 
Collection of Lower Respiratory Tract Infections Source Documentation for Endpoint
Adjudication Committee Review.............................................................................................. 98
8.2.2. 
Clinical Course of RSV Infection ................................................................................................ 98
8.2.3. 
Antiviral Activity........................................................................................................................... 99
8.2.4. 
Health-related Quality of Life Assessment ............................................................................... 100
8.2.5. 
Viral Sequencing....................................................................................................................... 100
8.2.6. 
Evaluation of RSV Viremia....................................................................................................... 101
8.3. 
Safety Assessments..................................................................................................................... 101
8.3.1. 
Physical Examinations.............................................................................................................. 101
8.3.2. 
Vital Signs................................................................................................................................. 102
8.3.3. 
Electrocardiograms................................................................................................................... 102
8.3.4. 
Clinical Safety Laboratory Assessments .................................................................................. 103
8.4. 
Adverse Events and Serious Adverse Events ............................................................................. 103
8.4.1. 
Time Period and Frequency for Collecting Adverse Event and Serious Adverse Event
Information................................................................................................................................ 103
8.4.2. 
Method of Detecting Adverse Events and Serious Adverse Events ........................................ 104
8.4.3. 
Follow-up of Adverse Events and Serious Adverse Events ..................................................... 104
8.4.4. 
Regulatory Reporting Requirements for Serious Adverse Events ........................................... 104
8.4.5. 
Pregnancy................................................................................................................................. 105
8.4.6. 
Disease-Related Events and Disease-Related Outcomes not Qualifying as Adverse
Events or Serious Adverse Events........................................................................................... 106
8.4.7. 
Management of Adverse Events of Interest ............................................................................. 106
8.4.7.1. 
Liver Toxicity.......................................................................................................................... 106
8.4.7.2. 
Cardiac Events Potentially Related to QT Prolongation........................................................ 106
8.4.8. 
Management of Complications or Sequelae of HSCT.............................................................. 107
8.5. 
Treatment of Overdose ................................................................................................................ 108
8.6. 
Pharmacokinetics......................................................................................................................... 108
8.6.1. 
Substudy in Hospitalized Participants ...................................................................................... 108
8.7. 
Pharmacokinetics/Pharmacodynamics........................................................................................ 109
8.8. 
Genetics ....................................................................................................................................... 109
8.9. 
Biomarkers................................................................................................................................... 109
8.10. 
Medical Resource Utilization........................................................................................................ 109
9. 
STATISTICAL CONSIDERATIONS................................................................................................ 110
9.1. 
Statistical Hypotheses.................................................................................................................. 110
9.2. 
Populations for Analyses.............................................................................................................. 110
9.3. 
Sample Size Determination ......................................................................................................... 111
9.4. 
Statistical Analyses ...................................................................................................................... 111
9.4.1. 
Participant Information.............................................................................................................. 112
9.4.2. 
Efficacy Analyses...................................................................................................................... 112


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9.4.2.1. 
Primary Endpoint: Development of RSV Lower Respiratory Tract Infection......................... 112
9.4.2.2. 
Key Secondary Endpoints ..................................................................................................... 113
9.4.2.3. 
Clinical Course of RSV Infection ........................................................................................... 113
9.4.2.4. 
Antiviral Activity ..................................................................................................................... 113
9.4.2.5. 
Health-related Quality of Life Assessment............................................................................ 114
9.4.2.6. 
Correlation Between Antiviral Effect and Clinical Course Endpoints .................................... 114
9.4.2.7. 
Viral Sequencing ................................................................................................................... 114
9.4.3. 
Safety Analyses........................................................................................................................ 114
9.4.4. 
Pharmacokinetic Analyses........................................................................................................ 115
9.4.4.1. 
Substudy in Hospitalized Participants ................................................................................... 116
9.4.5. 
Pharmacokinetic/Pharmacodynamic Analyses ........................................................................ 116
9.4.6. 
Biomarkers Analyses................................................................................................................ 116
9.4.7. 
Medical Resource Utilization .................................................................................................... 116
9.4.8. 
Other Analyses ......................................................................................................................... 116
9.4.9. 
Health Economics..................................................................................................................... 117
9.4.10. 
Interim Analysis ........................................................................................................................ 117
9.5. 
Independent Data Monitoring Committee .................................................................................... 117
9.6. 
Endpoint Adjudication Committee................................................................................................ 118
10. SUPPORTING DOCUMENTATION AND OPERATIONAL CONSIDERATIONS .......................... 119
10.1. 
Appendix 1: Abbreviations ........................................................................................................... 119
10.2. 
Appendix 2: Clinical Laboratory Tests ......................................................................................... 122
10.3. 
Appendix 3: Regulatory, Ethical, and Study Oversight Considerations....................................... 124
REGULATORY AND ETHICAL CONSIDERATIONS ........................................................................ 124
INFORMED CONSENT/ASSENT PROCESS.................................................................................... 127
DATA PROTECTION ......................................................................................................................... 128
LONG-TERM RETENTION OF SAMPLES FOR ADDITIONAL FUTURE RESEARCH.................... 129
COMMITTEES STRUCTURE ............................................................................................................ 129
PUBLICATION POLICY/DISSEMINATION OF CLINICAL STUDY DATA......................................... 129
DATA QUALITY ASSURANCE .......................................................................................................... 130
CASE REPORT FORM COMPLETION ............................................................................................. 131
SOURCE DOCUMENTS .................................................................................................................... 131
MONITORING .................................................................................................................................... 132
ON-SITE AUDITS............................................................................................................................... 133
RECORD RETENTION ...................................................................................................................... 133
STUDY AND SITE START AND CLOSURE...................................................................................... 134
10.4. 
Appendix 4: Adverse Events: Definitions and Procedures for Recording, Evaluating,
Follow-up, and Reporting............................................................................................................. 135
ADVERSE EVENT DEFINITIONS AND CLASSIFICATIONS............................................................ 135
ATTRIBUTION DEFINITIONS............................................................................................................ 136
SEVERITY CRITERIA........................................................................................................................ 136
SPECIAL REPORTING SITUATIONS ............................................................................................... 137
PROCEDURES .................................................................................................................................. 137
CONTACTING SPONSOR REGARDING SAFETY........................................................................... 138
PRODUCT QUALITY COMPLAINT HANDLING................................................................................ 139
10.5. 
Appendix 5: Contraceptive and Barrier Guidance and Collection of Pregnancy Information...... 140
10.6. 
Appendix 6: Liver Safety: Suggested Actions and Follow-up Assessments................................ 142
10.7. 
Appendix 7: Toxicity Tables ......................................................................................................... 145
10.8. 
Appendix 8: General Guidelines for Measuring Vital Signs and SpO2 ........................................ 154
10.9. 
Appendix 9: Respiratory Infection Intensity and Impact Questionnaire (RiiQ™)......................... 156
10.9.1. 
Respiratory Infection Intensity and Impact Questionnaire (RiiQ™) Symptom Scale ............... 156
10.9.2. 
Respiratory Infection Intensity and Impact Questionnaire (RiiQ™) Impact Scales.................. 157
10.10. Appendix 10: Patient Global Impression [PGI] Scales................................................................. 159
10.11. Appendix 11: 5-level EuroQol 5-Dimension Questionnaire (EQ-5D-5L)...................................... 160
10.12. Appendix 12: Guidance on Study Conduct During the COVID-19 Pandemic ............................. 163
10.13. Appendix 13: Protocol Amendment History................................................................................. 167
11. REFERENCES................................................................................................................................. 168


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INVESTIGATOR AGREEMENT............................................................................................................... 172
LIST OF IN-TEXT TABLES AND FIGURES
TABLES
Table 1: 
Sparse PK Sampling in Hospitalized Participants .................................................................... 47
Table 2: 
Sparse PK Sampling in Outpatients ......................................................................................... 47
Table 3: 
Rich Serial PK Sampling Substudy in Hospitalized Participants (N30).................................. 48
Table 4: 
Simulated Effect of Concomitant CYP3A4 Inhibitors on JNJ-8678 PK Parameters................. 73
Table 5: 
Predicted Geometric Mean AUC0-24h, Cmax, Ctrough  and ΔΔQTcI After Day1 and Day 7............ 74
Table 6: 
Treatment Overview.................................................................................................................. 82
Table 7: 
Examples of Commonly Used Medications With CYP3A4 Inhibiting and/or QT
Prolonging Effects Which are Disallowed or Allowed Upon Coadministration with JNJ-
53718678f ................................................................................................................................. 90
Table 8: 
Anticipated Events .................................................................................................................. 105
FIGURES
Figure 1: Schematic Overview of the Study............................................................................................. 30


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1. 
PROTOCOL SUMMARY
1.1. 
Synopsis
A Randomized, Double-blind, Placebo-controlled Study to Evaluate the Clinical Outcomes, Antiviral
Activity, Safety, Tolerability, Pharmacokinetics, and Pharmacokinetics/Pharmacodynamics of JNJ-
53718678 in Adult and Adolescent Hematopoietic Stem Cell Transplant Recipients with Respiratory
Syncytial Virus Infection of the Upper Respiratory Tract
Effects of JNJ-53718678 in Adult and Adolescent Patients Who had a Hematopoietic Stem Cell
Transplantation and Who are Infected With RSV
JNJ-53718678 is an investigational, potent small-molecule respiratory syncytial virus (RSV)-specific
fusion inhibitor belonging to the indole chemical class which targets the F-protein and prevents the
conformational changes of the F-protein required for fusion of the viral envelope with the host cell
membrane, thereby inhibiting viral replication and syncytia formation  .
OBJECTIVES AND ENDPOINTS
Objectives 
Endpoints
Primary
To evaluate the effect of JNJ-53718678 on the 
development of RSV lower tract respiratory 
infections (LRTIs)in adult hematopoietic stem cell 
transplant (HSCT) recipients with RSV upper 
respiratory tract infection (URTI).
The proportion of participants who develop RSV
LRTI (see definition below) per the Endpoint
Adjudication Committee (EAC)’s assessment
through Visit Day 28.
Secondary
To evaluate the effect of JNJ-53718678 on the
development of RSV-associated lower respiratory
tract complications (LRTC)in adult and adolescent
HSCT recipients with RSV URTI.
The proportion of participants who develop
RSV-associated LRTC (see definition below) per
the EAC’s assessment through Visit Day 28.
To evaluate the safety and tolerability of
JNJ-53718678
Safety and tolerability, as assessed by AEs,
clinical laboratory testing, electrocardiograms
(ECGs), vital signs, throughout the study
To evaluate the impact of JNJ-53718678 on
progression to respiratory failure and on all-cause
mortality
 
The proportion of participants progressing to
respiratory failure (of any cause) requiring
mechanical 
ventilation 
(invasive 
or
noninvasive) and/or death, in participants who
develop RSV LRTI or RSV-associated LRTC
per the EAC’s assessment;
 
The proportion of participants progressing to
respiratory failure (of any cause) requiring
mechanical 
ventilation 
(invasive 
or
noninvasive) 
and/or 
death 
(all-cause
mortality);
 
The proportion of participants progressing to
death (all-cause mortality), in participants
who develop RSV LRTI or RSV-associated
LRTC per the EAC’s assessment;


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Objectives 
Endpoints
 
The proportion of participants progressing to
death (all-cause mortality);
 
The proportion of participants progressing to
respiratory failure (of any cause) requiring
mechanical 
ventilation 
(invasive 
or
noninvasive), in participants who develop
RSV LRTI or RSV-associated LRTC per the
EAC’s assessment;
 
The proportion of participants progressing to
respiratory failure (of any cause) requiring
mechanical 
ventilation 
(invasive 
or
noninvasive).
To evaluate the impact of JNJ-53718678 on the 
clinical course of RSV infection
Clinical course-related endpoints:
 
Number of supplemental O2 free days through
Day 28
 
Incidence of O2 requirement, total length and
type (eg, supplemental oxygen, noninvasive
pressure ventilation, invasive mechanical
ventilation [tracheal tube, laryngeal mask, or
tracheostomy])
 
Respiratory rate, heart rate, body temperature,
and peripheral capillary oxygen saturation
(SpO2) over time as measured by the
investigator during scheduled visits
 
Proportion of participants hospitalized (of
participants who were not hospitalized at
baseline), proportion of participants re-
hospitalized (of participants who were
hospitalized at baseline and discharged during
the study and of participants who were not
hospitalized 
at 
baseline, 
required
hospitalization, and were discharged during
the study)
 
Total length of hospital stay (time in hospital
before first dosing is discarded) and total time
in the intensive care unit (ICU) (time in ICU
before first dosing is discarded)
 
Incidence of Grade 3 and Grade 4 adverse
events (AEs) in the Infections and Infestations
System Organ Class
 
Incidence of respiratory and thoracic-related
AEs
 
Incidence of antibiotic use in participants who
develop and in those who do not develop RSV


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Objectives 
Endpoints
LRTI or RSV-associated LRTC  per the
EAC’s assessment
 
Time to resolution of symptoms, assessed
through an instrument for patient-reported
symptoms (Respiratory Infection Intensity
and Impact Questionnaire [RiiQ] Symptom
Scale)
 
Change from baseline through Day 28 in
severity of symptoms reported by subjects in
the RiiQ Symptom Scale
 
Time to resolution of respiratory illness,
through the Patient Global Impression of
Severity (PGI-S) Scale
 
Change in Patient Global Impression of
Health 
(PGI-H) 
and 
Patient 
Global
Impression of Change (PGI-C)Scales through
Day 28
To evaluate the PK of JNJ-53718678 
PK parameters of JNJ-53718678
To evaluate the relationship between the PK of 
JNJ-53718678 and the PD (selected antiviral 
activity, clinical outcomes, and safety parameters) 
after repeated dosing of JNJ-53718678
PK/PD analysis of plasma concentration-time data
of JNJ-53718678 using (non)-linear mixed-effects
modeling
To evaluate the antiviral effect of JNJ-53718678 as 
measured by RSV viral load in bilateral mid- 
turbinate nasal swab samples by quantitative 
reverse transcription polymerase chain reaction
(qRT-PCR) assay  
Virologic parameters derived from the RSV viral
load as measured by a qRT-PCR assay in bilateral
mid-turbinate nasal swab samples including:
 
RSV viral load and change from baseline over
time
 
RSV viral load area under the curve (AUC)
from immediately prior to first dose of study
intervention (baseline) through  Day 8,
Day 11, Day 15, Day 22, and Day 28
 
time to undetectable RSV viral load
 
proportion of participants with undetectable
RSV viral load at each time point throughout
the study
To evaluate the impact of RSV and its treatment on 
health-related quality of life (HRQOL). 
Change from baseline for the HRQOL through
Day 28 (as assessed through the 5-level EuroQol 5-
Dimension [EQ-5D-5L] and RiiQ Impact Scales]
To evaluate the emergence of mutations in the viral 
genome potentially associated with resistance to 
JNJ-53718678 
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)


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Objectives 
Endpoints
Exploratory
The exploratory objectives are to evaluate: 
 
medical 
resource 
utilization 
(MRU), 
including 
hospitalization, 
for 
clinical
management of participants during treatment
and posttreatment follow-up
 
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) 
 
the relationship between antiviral activity and 
clinical course 
 
the impact of the baseline RSV viral subtype 
and genotype on the antiviral activity and
clinical course
 
the incidence of RSV viremia
 
the incidence of graft-versus-host disease
(GVHD) or graft failure
The exploratory endpoints are:
 
MRU
 
RSV viral subtype and presence of
pretreatment RSV F-gene polymorphisms
 
virologic parameters derived from the RSV
viral load as measured by quantitative viral
culture
 
proportion of participants with RSV viremia
(RSV viral load in plasma)
 
proportion of participants with new onset
GVHD
 
proportion of participants with graft failure
EAC: Endpoint Adjudication Committee; ECG: electrocardiogram; EQ-5D-5L: 5-level EuroQol 5-Dimension;
GVDH: graft-versus-host disease; HRQOL: health-related quality of life; LRTC: lower respiratory tract
complication(s); LRTI: lower respiratory tract infection; MRU: medical resource utilization; PD:
pharmacodynamic(s); PGI-C: patient global impression of change; PGI-H: patient global impression of health;
PGI-S: patient global impression of severity; PK: pharmacokinetic(s); qRT-PCR: quantitative reverse
transcription polymerase chain reaction; RiiQ: Respiratory Infection Intensity and Impact Questionnaire; RSV:
respiratory syncytial virus; URTI: upper respiratory tract infection
RSV LRTI will be defined as the development of a lower respiratory sign or symptom (including decrease
in oxygen saturation or increase in supplemental oxygen to maintain oxygen saturation, wheezing, rhonchi,
rales, dyspnea, tachypnea, worsening cough, …) AND
 
Positive RSV test from lower respiratory tract sample (eg, sputum, induced sputum,
bronchoalveolar lavage (BAL), lung biopsy, or autopsy specimen) within ±4 days of a new chest
image finding, compared to baseline, consistent with a lower respiratory tract infection; OR
 
Positive RSV test from lower respiratory tract sample (eg, sputum, induced sputum, BAL, lung
biopsy, or autopsy specimen) only; OR
 
Positive RSV test from upper respiratory tract sample within ±4 days of a new chest image
finding, compared to baseline, consistent with a RSV lower respiratory tract infection
as determined by the EAC.
RSV-associated LRTC will be defined as the development of a lower respiratory sign or symptom
(including decrease in oxygen saturation or increase in supplemental oxygen to maintain oxygen saturation,
wheezing, rhonchi, rales, dyspnea, tachypnea, worsening cough, …) AND falling within one of the
following subcategories as determined by the EAC:
 
RSV LRTI defined as above


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OR
 
Secondary bacterial LRTI defined as:
 
Positive specimen for a clinically significant bacterium from lower respiratory tract source (eg,
sputum, induced sputum, BAL, lung biopsy, or autopsy specimen) within ±4 days of a new chest
image finding, compared to baseline, consistent with a lower respiratory tract infection
OR
 
Secondary LRTI due to unusual pathogens defined as:
 
Positive specimen for a clinically significant unusual organism (eg, atypical bacteria, fungus, or
another respiratory virus) from a lower respiratory tract source (eg, sputum, induced sputum,
BAL, lung biopsy, autopsy specimen) within ±4 days of a new chest image finding, compared to
baseline, consistent with a lower respiratory tract infection
OR
 
Secondary LRTC of unknown etiology defined as:
 
New findings on a chest image, compared to baseline, consistent with a lower respiratory tract
infection, inflammatory process, or some other clinically significant pulmonary process in
absence of a positive specimen or no specimen collected from lower respiratory tract source
within ±4 days of the new chest image finding
Hypothesis
The primary hypothesis of this study is that JNJ-53718678 reduces the proportion of adult HSCT recipients
with RSV URTI who develop RSV LRTI within 28 days after start of treatment as compared to placebo,
assessed through the relative risk.
OVERALL DESIGN
This is a Phase 2, randomized, double-blind, placebo-controlled, multicenter study to evaluate the clinical
outcomes, antiviral activity, safety, tolerability, PK, and PK/PD of JNJ-53718678 in adult (ie, adult cohort)
and adolescent (ie, adolescent cohort)HSCT recipients with an RSV URTI.
An interim analysis will be performed when approximately 50% of the planned participants in the adult
cohort have completed the Day 28 assessments (or discontinued earlier). This interim analysis will include
safety, testing for futility, early superiority, and a sample size re-estimation.
The final analysis is planned after the target number of all participants in the adult cohort has been reached
and when all participants in both cohorts have completed the study (or discontinued earlier).
An Independent Data Monitoring Committee (IDMC) will be established to monitor and review data in an
unblinded manner on a regular basis to ensure the continuing safety of the participants enrolled in this study.
The committee will meet periodically to review safety data and will meet to review the results from the
interim analysis. After the review, the IDMC will provide recommendations to the Sponsor Committee,
who will be responsible for decision making, considering the IDMC recommendation, and who will
communicate these decisions to the study team.
A separate substudy with Qualitative Patient Interviews will be performed at selected study sites by a
qualified person selected by the sponsor in a subset of participants to gain insight in HSCT recipients
experience throughout the clinical course of their RSV infection, and to guide interpretation of treatment
outcomes and study endpoints. Details, including objectives and study design, will be described in a
separate substudy protocol.


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The end of study is considered as the last visit (phone visit or on-site visit) for the last participant in the
study.
NUMBER OF PARTICIPANTS
Participants will be enrolled in either the adult or adolescent cohort:
 
Adult cohort: adult participants ≥18 to ≤75 years of age.
 
Adolescent cohort: adolescent participants ≥13 to <18 years of age.
In the adult cohort, a sample size of approximately 249 participants is targeted, with a maximum of
375 participants. No target sample size was determined for the adolescent cohort.
INTERVENTION GROUPS AND DURATION
The study will include a Screening Period (Day -2 to Day 1), a Treatment Period (Day 1 to Day 21), and a
Follow-up Period (Day 22 to Day 49). On Day 49, participants will complete the study. The total study
duration for each participant will be approximately 49 days (Screening included).
Eligible participants will be randomized 2:1 (active:placebo) within each cohort to receive either
JNJ-53718678 for 21 days or placebo for 21 days. Participants will be administered 250 mg JNJ-53718678
bid for 21 days (without coadministration with moderate or strong CYP3A4 inhibitors), 125 mg bid for
21 days (when coadministered with moderate or strong CYP3A4 inhibitors, with the exception of
posaconazole), and 125 mg qd for 21 days (when coadministered with posaconazole)as oral suspension of
JNJ-53718678, or the same volume of placebo suspension. For newly enrolled participants after
implementation of Protocol Amendment 6, study intervention will be administered as eq. 125 mg oral
film-coated tablets (further referred to as 125 mg oral film-coated tablets) or matching placebo (see Table
below).
Study intervention administration should start as soon as possible, but no later than 4 hours after
randomization and within 4 days after symptom onset of RSV URTI. Dosing should preferably occur
approximately at the same time each day (for the qd dosing and for the AM and PM dosing of the bid
regimen).
For participants on bid dosing, dosing should occur approximately 12 hours apart. For participants who
receive the first dose of study intervention PM of Day 1, dosing should continue through the morning (ie,
AM) of Day 22 so that all participants receive 42 consecutive bid doses in total. Administration of the
second bid 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.
Participants on a 125 mg qd regimen coadministered with posaconazole will receive 21 consecutive doses
in total.


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Table: Treatment Overview
Treatment 
Dosing Regimen  
Formulationd
A 
250 mg JNJ-53718678a twice daily for 21 days 
without coadministration with moderate or strong 
CYP3A4 inhibitors
12.5 mL oral suspensionb of JNJ-53718678
or 2 eq. 125 mg oral film-coated tabletsc
A 
125 mg JNJ-53718678a twice daily for 21 days if 
coadministration with moderate or strong CYP3A4 
inhibitors, with the exception of posaconazole
6.25 mL oral suspension of JNJ-53718678
or 1 eq. 125 mg oral film-coated tabletc
A 
125 mg JNJ-53718678a once daily for 21 days if 
coadministration with posaconazole 
6.25 mL oral suspension of JNJ-53718678
or 1 eq. 125 mg oral film-coated tabletc
B 
Matching placebo twice daily for 21 days 
12.5 mL matching placebo suspension
or 2 matching oral placebo tablets
B 
Matching placebo twice daily for 21 days 
6.25 mL matching placebo suspension
or 1 matching oral placebo tablet
B 
Matching placebo once daily for 21 days 
6.25 mL matching placebo suspension
or 1 matching oral placebo tablet
a) Doses are provided for JNJ 53718678 AAA.
b) JNJ 53718678 is dosed as an oral suspension containing 23 mg/mL JNJ 53718678 ZCL, the hemi tartrate salt of
JNJ 53718678 AAA, which is equivalent to 20 mg/mL JNJ 53718678 AAA.
c) For newly enrolled participants after implementation of Protocol Amendment 6, the drug product is administered as
eq. 125 mg oral film coated tablets (containing 143.75 mg of JNJ 53718678 ZCL, the hemi tartrate of
JNJ 53718678 AAA). Note that the tablet may also be dispersed in water before administration through a
nasogastric tube, if applicable.
d) A participant receiving oral suspension must complete the study with the same formulation.
Study supplies will be delivered in a 2-bottle concept to be reconstituted to an oral suspension prior to
dispensing to the participant. For newly enrolled participants after implementation of Protocol
Amendment 6, study intervention will be supplied as oral film-coated tablets in bottles.
EFFICACY EVALUATIONS
Development of Lower Respiratory Tract Infection/Complications
During the course of the study, it is anticipated that, as part of standard of care (SOC) and strongly
recommended by the sponsor, investigators should perform chest imaging and/or computed tomography
(CT) scans, as well as other SOC assessments, if there is any suspicion of the occurrence of an LRTI, ie,
development of a lower respiratory sign or symptom (including decrease in oxygen saturation or increase
in supplemental oxygen to maintain oxygen saturation, wheezing, rhonchi, rales, dyspnea, tachypnea,
worsening cough), as soon as possible. If there is any suspicion of the occurrence of an LRTI, leading to
chest imaging, per local SOC a lower respiratory tract sample (eg, BAL, induced sputum, or regular sputum)
should be obtained for microbiologic and virologic evaluation to determine the etiology. In addition, a
bilateral mid-turbinate nasal swab sample should be collected and sent to the central lab.
An external blinded Endpoint Adjudication Committee (EAC) will review clinical data to determine
whether an RSV LRTI and/or RSV-associated LRTC has developed.
During the course of the study, the following results and reports from evaluations performed per SOC will
be collected and will be reviewed by an EAC:
 
images and reports from chest imaging, including the reports from the central reader
 
results of all local microbiology and virology tests performed (all bacterial, viral, fungal, parasite, or
other results from any respiratory system-related sample [eg, BAL, sputum, pleural fluid, or lung
tissue] and from blood specimens, including bacterial culture, virology (mostly by polymerase chain
reaction [PCR]), and serology studies)
 
ECG tracings and reports of any ECG performed in relation to a suspected LRTI event


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 
body temperature
 
clinical notes
 
autopsy reports (if applicable)
 
clinical course evaluations, including the specific reason for the repeat imaging
 
other supporting documents, as requested.
Clinical Course of RSV Infection
The study will include the following evaluations of the clinical course of RSV infection clinical parameters:
 
respiratory rate, heart rate, SpO2, and body temperature as measured by the investigator during
scheduled visits
 
respiratory signs and symptoms, including auscultation findings, as evaluated by the investigator
 
requirement for supplemental O2
 
supplemental O2 type (eg, supplemental oxygen, noninvasive pressure ventilation, endotracheal-
mechanical ventilation), and duration
 
(re)hospitalization by level of care during treatment and follow-up
 
duration of (re)hospitalization and duration of ICU use
 
respiratory failure (of any cause) requiring mechanical ventilation (invasive or noninvasive) and all-
cause mortality
 
Grade 3 and Grade 4 AEs in the Infections and Infestations System Organ Class
 
respiratory and thoracic-related AEs
 
the use of antibiotics in participants who develop RSV LRTI per the EAC’s assessment and in
participants who do not develop RSV LRTI
 
duration and severity of RSV signs and symptoms, as assessed by the participant using the RiiQ
Symptom Scale and Patient Global Impression (PGI) questions (ie, PGI of Severity [PGI-S], PGI of
Health [PGI-H], and PGI of Change in Health [PGI-C])
 
occurrence of GVHD or delayed engraftment as evaluated by the investigator
Antiviral Activity
For the evaluation of antiviral activity, the RSV viral load in bilateral mid-turbinate nasal swab samples
will be measured at the central laboratory using an RSV qRT-PCR assay. After randomization on Day 1,
but immediately predose, a bilateral mid-turbinate nasal swab sample will be collected as close as possible
and prior to the first administration of study intervention, aliquoted and sent to the central lab.
During the subsequent visits, a bilateral mid-turbinate nasal swab sample will be collected, preferably at
approximately the same time as the predose bilateral mid-turbinate nasal swab sample taken on Day 1 and
preferably prior to dose administration, if applicable. This sample will be aliquoted and sent to the central
lab.
In case of suspicion of the occurrence of an RSV LRTI, an additional bilateral mid-turbinate nasal swab
sample should be collected. This sample will be aliquoted and sent to the central lab.
For a selected set of bilateral mid-turbinate nasal swab samples, quantitative RSV culture may be
performed, if feasible, for determination of RSV infectious viral titer.


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Health-related Quality of Life
Participants will complete the EQ-5D-5L and RiiQ Impact Scales to characterize the impact of RSV and its
treatment on HRQOL.
Viral Sequencing
Development of viral resistance will be monitored by sequencing of the RSV F-gene in all baseline bilateral
mid-turbinate nasal swab samples and in subsequent bilateral mid-turbinate nasal swab samples upon
request of the sponsor’s virologist. Other regions of the RSV genome may also be sequenced at the
discretion of the sponsor’s virologist.
Evaluation of RSV Viremia
In addition, blood samples for RSV detection and quantification of RSV viral load in plasma will be
collected.
PHARMACOKINETIC EVALUATIONS
Pharmacokinetic assessments during the study will be based on sparse sampling for all participants and a
rich serial PK sampling substudy in approximately 30 hospitalized participants at selected sites.
OTHER EVALUATIONS
Pharmacokinetics/Pharmacodynamics
The PK/PD relationship of JNJ-53718678 exposure with selected efficacy (change in viral load from
baseline and clinical outcomes) and safety (including AEs and laboratory abnormalities)parameters will be
explored. If there is any visual trend in graphical analysis, suitable models will be applied to describe the
exposure-effect relationships.
Biomarkers
Blood samples will be collected for exploratory biomarker analyses (host RNA and/or proteins), on the
premise that these markers may play a role in the treatment response, PK, safety of JNJ-53718678, or the
status and course of RSV-related disease. In addition, leftover bilateral mid-turbinate nasal swab or blood
samples may be used for biomarker analysis. Analyses of biomarkers may be conducted at the sponsor’s
discretion and reported separately from this study. Collection of the blood samples for biomarker research
is mandatory, unless local regulations require these samples to be optional.
Medical Resource Utilization
Medical resource utilization data, associated with medical encounters, will be collected for all participants.
Protocol-mandated procedures, tests, and encounters are excluded. The data collected may be used to
conduct exploratory economic analyses.
Long-term Follow-up
Long-term follow-up data will be collected. Participants or a person designated by participants will be
contacted at Day 100, Month 6, and Month 12 to collect data on survival status, morbidity (particularly
complications related to RSV infection) and hospitalizations/MRU.
SAFETY EVALUATIONS
The study will include the following evaluations of safety and tolerability:
 
AEs


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clinical laboratory tests (central)
 
ECG 12-lead
 
vital signs:
o 
vital signs assessments performed as part of the clinical course of RSV infection-related
assessments (body temperature, heart rate, respiratory rate, and SpO2)
o 
additional vital signs assessments: systolic blood pressure (SBP), diastolic blood pressure
(DBP)
 
physical examination of all body systems (at Screening) (including height and body weight
measurements), direct physical examination, and skin examination
In the event that an invasive procedure such as a blood draw or a bilateral mid-turbinate nasal swab is
required at the same time as an assessment of vital signs or ECG, these latter assessments should be
performed first.
Clinically relevant findings resulting from the physical examination will be reported as AE.
Safety and tolerability will be evaluated throughout the study from signing of the ICF until the last
study-related activity.
STATISTICAL METHODS
Sample Size Calculation
Sample size determination was performed for the adult cohort only. Assuming a progression to RSV LRTI
occurring in 35% of the patients in the placebo arm, a relative risk of 40%, and a 2:1 randomization,
210 patients are needed to obtain 90% power with 2.5% one-sided significance in the primary analysis set
based on a Fisher’s Exact test. Assuming 15% of patients will be excluded from the primary analysis set,
the total sample size becomes 249. Similar power estimates were obtained from simulations using Cochran-
Mantel-Haenszel test and Fisher’s Exact test.
Participants with an ALC <500 cells/µL at Screening should account for at least 50% of all participants in
the adult cohort and participants with an ALC <200 cells/µL at Screening should account for at least 25%
of all enrolled participants, also at the time of the interim analysis. To ensure the prespecified distribution
in the strata for the interim analysis, enrollment in certain lymphopenia strata (≥500 - <1,000 cells/μL or
200 - <500 cells/μL) will be temporarily paused prior to the interim analysis once sufficient patients for the
interim analysis are enrolled in the corresponding stratum.
To ensure the prespecified distribution in the strata for the final analysis, enrollment in certain lymphopenia
strata (≥500 - <1,000 cells/μL or 200 - <500 cells/μL) could be stopped early once sufficient patients for
the final analysis are enrolled in the corresponding stratum.
No target sample size was determined for the adolescent cohort.
Efficacy Analyses
For the adolescent cohort, efficacy analysis will be limited to descriptive statistics.
For the adult cohort, primary analysis of efficacy-related endpoints will be performed in the overall
population, in the population with an ALC <500 cells/µL at Screening, and in the population with an ALC
<200 cells/µL at Screening, applying a multiplicity correction.


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As a confirmatory strategy, to account for multiplicity in the statistical evaluation of the most important
efficacy endpoints, hierarchical testing will be applied to control for overall Type I error. The following
endpoints are included in the confirmatory strategy:
1. 
The proportion of participants who develop RSV LRTI per the EAC’s assessment through Visit Day
28, ie, primary endpoint;
2. 
The proportion of participants who develop an RSV-associated LRTC  per the EAC’s assessment
through Visit Day 28;
3. 
Time to resolution of symptoms, assessed through an instrument for patient-reported symptoms (RiiQ
Symptom Scale);
4. Number of supplemental O2 free days through Day 28;
5. 
Proportion of participants hospitalized (of participants who were not hospitalized at baseline);
6. 
The proportion of participants progressing to respiratory failure (of any cause) requiring mechanical
ventilation (invasive or noninvasive) and/or death (all-cause mortality).
7. 
Total length of hospital stay (time in hospital before first dosing is discarded);
First, the primary endpoint will be testedfor superiority at the 1-sided 2.5% significance level. If superiority
is shown on the primary endpoint, the first secondary endpoint in the sequence as indicated above will be
tested for superiority at the same significance level. If superiority is shown for this secondary endpoint,
further secondary endpoints will be tested for superiority in the sequence as indicated above, and at the
same significance level. In case superiority is not shown for an endpoint, no further endpoints in the
sequence will be tested for superiority.
Primary Endpoint Analysis
The proportion of participants who develop an EAC-confirmed RSV LRTI through Visit Day 28 will be
analyzed using a Cochran-Mantel-Haenszel test stratified by the randomization stratification factors.
Key Secondary Endpoint Analysis
For the hypothesis testing, the following methods will be used:
 
Time to resolution of symptoms will be analyzed using a stratified Gehan-Wilcoxon test (using the
randomization stratification factors).
 
Total length of hospital stay and the number of supplemental O2 free days will be analyzed using a
Hodges-Lehmann test.
 
For the proportion of participants hospitalized, and the proportion of participants progressing to
respiratory failure and/or death, a Cochran-Mantel-Haenszel test stratified by  the randomization
stratification factors, will be used as for the primary analysis.
Safety Analysis
Adverse Events
The verbatim terms used in the eCRF by investigators to identify AEs will be coded using the Medical
Dictionary for Regulatory Activities (MedDRA). 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 intervention group.


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Clinical Laboratory Tests
Laboratory data will be summarized by type of laboratory test. The laboratory abnormalities will be
determined per the criteria specified in the DMID Adult and in accordance with the normal ranges of the
clinical laboratory if no gradings were 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-intervention cross-tabulations (with
classes for below, within, and above normal ranges).
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.
Vital Signs
Descriptive statistics of and blood pressure (systolic and diastolic) values and changes from baseline will
be summarized at each scheduled time point. The percentage of participants with markedly abnormal results
(specified in the SAP) will be summarized.


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1.2. 
Schema
Figure 1: 
Schematic Overview of the Study










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Status: Approved,  Date: 07 May 2021
c. 
Prior to signing the main consent/assent form for the study, the participant may specifically allow for the collection and testing of bilateral mid-turbinate nasal swab
samples (as part of the study-specific Screening assessment) by signing the pre-Screening (diagnostic) ICF. This is not required if an upper respiratory tract sample
is collected per local SOC diagnostic testing.
d. 
One Screening sample (from upper respiratory tract collected per local SOC testing within 24 hours prior to start of Screening or bilateral mid-turbinate nasal swab
as part of the study-specific Screening assessment) will be collected for the local diagnosis of RSV infection using a rapid PCR- or other molecular-based diagnostic
assay.
e. 
The sample will be aliquoted and 1 aliquot will be used for local diagnostic testing and the other aliquots will be sent to the central laboratory for confirmatory
analysis.
f. 
Two mid-turbinate nasal swabs should be collected, one from each nostril, and both swabs should be put in the same universal transport medium tube (ie, a bilateral
mid-turbinate nasal swab sample). Only at times when sampling of both nostrils is not feasible, such as in case of bleeding in one nostril, one mid-turbinate nasal
swab should be collected from one nostril (ie, the non-bleeding nostril). Detailed information on sample collection is available in Section 8.2.3. Leftover bilateral
mid-turbinate nasal swab samples may be used for exploratory biomarker analyses, at the discretion of the sponsor.
g. 
Investigators should ensure that all study enrollment criteria 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 intervention is given such that they no longer meet all eligibility
criteria, they should be excluded from participation in the study.
h. 
For women of childbearing potential only.
i. 
Randomization should occur as soon as possible after confirming eligibility (including the radiologist’s or investigator’s interpretation of a chest X-ray, the
confirmation of ALC <1,000 cells/μL [local testing], and confirmation of RSV positivity). Randomization should preferentially occur within 24 hours after start of
Screening or at the latest within 48 hours after the collection of a chest X-ray and the collection of (local) samples for confirmation of ALC <1,000 cells/μL, and for
confirmation of RSV positivity. Additionally, samples for central laboratory will be collected. Randomization is to occur predose.
j. 
Participants will be administered 250 mg JNJ-53718678 bid for 21 days (without coadministration with moderate or strong CYP3A4 inhibitors), 125 mg bid for
21 days (when coadministered with moderate or strong CYP3A4 inhibitors, with the exception of posaconazole), and 125 mg qd for 21 days (when coadministered
with posaconazole), or placebo. Study intervention administration should start as soon as possible, but no later than 4 hours after randomization and within 4 days
after symptom onset of RSV URTI. For analysis purposes, the day of first study intervention intake will be considered Day 1. Dosing should preferably occur
approximately at the same time each day (for the qd dosing and for the AM and PM dosing of the bid regimen). For participants on bid dosing, dosing should occur
approximately 12 hours apart. For participants who receive the first dose of study intervention PM of Day 1, dosing should continue through the morning (ie, AM)
of Day 22 so that all participants receive 42 consecutive bid doses in total. Administration of the second bid 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.
Participants on a 125 mg qd regimen coadministered with posaconazole will receive 21 consecutive doses in total. The study intervention can be administered with
or without food. The study intervention will be administered orally. Study intervention (oral suspension or oral film-coated tablets dispersed in water) can also be
administered through a nasogastric tube, if already in place
k. 
Study-site personnel will instruct the participants on how to use and store the study intervention for at-home dosing. At the day of discharge, sufficient study
intervention will be provided to bridge the period until the next scheduled on-site visit. Suspended study intervention will be provided to participants in vials, from
which the assigned volume is to be withdrawn each day. Each vial contains study intervention for 3-day dosing period. All study intervention should be stored on
site and at home as instructed on the label (see Section 6.1). For newly enrolled participants after implementation of Protocol Amendment 6, study intervention will
be supplied as oral film-coated tablets in bottles. Each bottle contains a sufficient number of tablets to cover study intervention for at least 7 days.
l. 
Date and time of the study intervention dosing needs to be recorded in the eCRF.
m. See Section 8.2.2 for an overview of assessments included in the clinical evaluation. In case antipyretics are used, body temperature should be measured immediately
before or >4 hours after giving antipyretics.
n. 
Only to be performed if the screening assessment occurred >8 hours before first dosing


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Status: Approved,  Date: 07 May 2021
o. 
A chest X-ray should be performed no more than 48 hours prior to randomization (see footnote i). If a chest X-ray has not been obtained as part of SOC, it must be
obtained during Screening.
p. 
During the course of the study, it is anticipated as part of SOC and strongly recommended by the sponsor that investigators will perform chest imaging and/or CT
scans and obtain lower respiratory tract sample (leftover to be sent to central lab; see Section 8.2.1.2), for determination of presence of RSV, if there is any suspicion
of the occurrence of LRTI (see Section 8.2.1.1)as soon as possible.
q. 
If possible, the leftover of the local lower respiratory tract sample will be sent to the central laboratory for additional virologic analyses.
r. 
If the collection of a sample is planned as part of the scheduled visit, collection of an additional sample in case of suspicion of RSV LRTI is not required.
s. 
See Section 8.2.1.5. This will only apply to randomized participants on suspicion of LRTI.
t. 
A predose bilateral mid-turbinate nasal swab sample will be taken of which aliquots will be used for the central laboratory confirmation of RSV infection, to determine
RSV viral load, to determine mutations in the viral genome potentially associated with resistance to JNJ-53718678, and to determine the presence of other viral or
bacterial pathogens. The bilateral mid-turbinate nasal swab sample should be collected as close as possible and prior to the first administration of study intervention
(on Day 1).
u. 
Local testing for RSV detection should be performed using a rapid PCR- or other molecular-based assay on one aliquot of the study-specific bilateral mid-turbinate
nasal swab sample. A SOC upper respiratory tract sample collected at Day 28 may also be used if needed based on the local rapid PCR- or other molecular-based
assay used.
v. 
In case of positive local test for RSV at Day 28, an additional bilateral mid-turbinate nasal swab sample will be collected at Day 35 (study site visit) for central
analysis.
w. Will be collected once daily postdose (except Day 1 predose) and preferentially PM (RiiQ Symptom Scale and PGI-S/PGI-H) or at the scheduled timepoints and
preferentially PM (RiiQ Impact Scales, PGI-C, and EQ-5D-5L, if applicable), in a language in which the participant is fluent, on electronic devices (eDevice). If a
participant requires assistance entering responses in the eDevice, a caregiver or member of the study team who is trained can interview the participant and enter the
participant’s responses on the eDevice on the participant’s behalf.
x. 
MRU will be recorded in the eCRF (see Section 8.10).
y. 
Systolic and diastolic blood pressure need to be measured sitting or supine (preferably the same position at each measurement) after at least 5 minutes of rest.
z. 
Physical examination of all body systems includes also height measurements and skin examination. Note: documented height (source documents) is allowed for
bedridden participants.
aa. Directed physical examination includes respiratory system, nose, ear, throat, facial, and neck lymph nodes, and skin examination.
bb. Documented body weight (source documents) is allowed for bedridden participants
cc. 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. Additional ECG assessments are to be performed as unscheduled assessments/visits preferably 3 days after the start ofcoadministration with moderate
or strong CYP3A4 inhibitors during the study intervention period. Further, unscheduled ECG assessments/visits can be performed based on the overall clinical
picture as per the investigator’s clinical discretion or to confirm abnormal ECG findings.
dd. At Day1 and Day 3, ECGs should be obtained approximately 1 to 1.5 hours (fasted) or approximately 4 hours (fed) after administration of study drug. Fasted is
defined as no food intake within approximately 2 hours prior to dosing and 2 hours after dosing.
ee. Samples for clinical laboratory assessments will be collected and analyzed at a central laboratory. Leftover blood samples may be used for exploratory biomarker
analyses, at the discretion of the sponsor.
ff. 
Urinalysis will be performed using dipsticks provided by the central laboratory. In case of abnormalities, the urine sample will be shipped to the central laboratory
for flow cytometric and/or microscopic evaluation(s).
gg. In case therapeutic drug monitoring of immunosuppressants (IS)is performed as part of SOC or per protocol instruction, the measured IS exposures are to be captured
in the eCRF.
hh. Only applicable in case a participant is experiencing (an) ongoing AE(s) or has clinically significant laboratory or ECG abnormalities at Day 28.


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ii. 
Levels of potassium and magnesium to be determined by the local and by the central laboratory. In case of hypokalemia and/or hypomagnesemia at screening,
Day 3, Day 8, or Day 15, the levels of potassium and/or magnesium should be corrected taking into account any underlying condition and as soon as possible to
prevent cardiac disturbances. Appropriate clinical management per local SOC (including but not limited to checking the corrected values at the local laboratory)
may be required. See also Section 8.4.7.2 for cardiac safety measures.
jj. 
Mandatory unless local regulations require these to be optional.






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Status: Approved,  Date: 07 May 2021
Phase 
Screening 
Pre-
dose
Treatment Phase 
Follow-upa
Day  
-2 to 1b
1 
2 
3c
(±1)
4 
5c
(±1)
6-7 
8c
(±1)
9-
10
11c
(±1)
12-
14
15c
(±1)
16-
21
22c 
23-
27
28c
(±3)
35
(±3)
49
(±3)
End-
of-
study
Screening
On-site
Pre-
dose
On-
site
Treatment
On-site/
SV 
SV 
SV 
SV 
SV  
SV 
SV 
Phone
follow
-up/
ord
on-site
visitc
Phone
follow
-up/
ord
on-site
visitc
confirmation,
RSV viral load,
presence of other
viral or bacterial
pathogens, viral
sequencingh,x
Bilateral mid
turbinate nasal
swab sample:
RSV viral load,
viral sequencingh
X 
X 
X 
X 
X 
X 
X 
(X)z
Local testing for
RSV detectiony
X
Blood sample for
RSV viremia
X 
X 
X
RiiQ Symptom
Scaleaa
X 
Xq
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X
PGI S/PGI Haa
X 
Xq
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X
RiiQ Impact
Scalesaa
X 
Xq
X 
X 
X
X 
X 
X 
X 
EQ 5D 5Laa
X 
Xq
X 
X 
X 
X 
X 
X 
X
PGI Caa
X 
X 
X 
X 
X 
X 
X
Check ePRO
completion
compliance
Continuously
Medical resource
utilizationbb
Continuously
Chest imaging 
Xr
X (on suspicion of LRTI)s,t






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Status: Approved,  Date: 07 May 2021
e. 
Prior to signing the main consent/assent form for the study, the participant may specifically allow for the collection and testing of bilateral mid-turbinate nasal swab
samples (as part of the study-specific Screening assessment) by signing the pre-Screening (diagnostic) ICF. This is not required if an upper respiratory tract sample
is collected per local SOC testing.
f. 
One Screening sample (from upper respiratory tract collected per local SOC testing within 24 hours prior to start of Screening or bilateral mid-turbinate nasal swab
as part of the study-specific Screening assessment) will be collected for the local diagnosis of RSV infection using a rapid PCR- or other molecular-based diagnostic
assay.
g. 
The sample will be aliquoted and 1 aliquot will be used for local diagnostic testing and the other aliquots will be sent to the central laboratory for confirmatory
analysis
h. 
Two mid-turbinate nasal swabs should be collected, one from each nostril, and both swabs should be put in the same universal transport medium tube (ie, a bilateral
mid-turbinate nasal swab sample) and the sample will be aliquoted. Only at times when sampling of both nostrils is not feasible, such as in case of bleeding in one
nostril, one mid-turbinate nasal swab should be collected from one nostril (ie, the non-bleeding nostril). Detailed information on sample collection is available in
Section 8.2.3. Leftover bilateral mid-turbinate nasal swab samples may be used for exploratory biomarker analyses, at the discretion of the sponsor.
i. 
Investigators should ensure that all study enrollment criteria 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 intervention is given such that they no longer meet all eligibility
criteria, they should be excluded from participation in the study.
j. 
For women of childbearing potential only.
k. 
Randomization should occur as soon as possible after confirming eligibility (including the radiologist’s or investigator’s interpretation of a chest X-ray, the
confirmation of ALC <1,000 cells/μL [local testing], and confirmation of RSV positivity). Randomization should preferentially occur within 24 hours after start of
Screening or at the latest within 48 hours after the collection of a chest X-ray and the collection of (local) samples for confirmation of ALC <1,000 cells/μL, and for
confirmation of RSV positivity. Additionally, samples for central laboratory will be collected. Randomization is to occur predose.
l. 
Participants will be administered 250 mg JNJ-53718678 bid for 21 days (without coadministration with moderate or strong CYP3A4 inhibitors), 125 mg bid for
21 days (when coadministered with moderate or strong CYP3A4 inhibitors, with the exception of posaconazole), and 125 mg qd for 21 days (when coadministered
with posaconazole), or placebo. Study intervention administration should start as soon as possible, but no later than 4 hours after randomization and within 4 days
after symptom onset of RSV URTI. For analysis purposes, the day of first study intervention intake will be considered Day 1. Dosing should preferably occur
approximately at the same time each day (for the qd dosing and for the AM and PM dosing of the bid regimen). For participants on bid dosing, dosing should occur
approximately 12 hours apart. For participants who receive the first dose of study intervention PM of Day 1, dosing should continue through the morning (ie, AM)
of Day 22 so that all participants receive 42 consecutive bid doses in total. Administration of the second bid 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.
Participants on a 125 mg qd regimen coadministered with posaconazole will receive 21 consecutive doses in total. The study intervention can be administered with
or without food. The study intervention will be administered orally.
m. Study-site personnel will instruct the participants on how to use and store the study intervention for at-home dosing. Suspended study intervention will be provided
to participants in vials, from which the assigned volume is to be withdrawn each day. Each vial contains study intervention for 3-day dosing period. All study
intervention should be stored on site and at home as instructed on the label (see Section 6.1). For newly enrolled participants after implementation of Protocol
Amendment 6, study intervention will be supplied as oral film-coated tablets in bottles. Each bottle contains a sufficient number of tablets to cover study intervention
for at least 7 days.
n. 
On Day 1, date and time of the study intervention dosing needs to be recorded in the eCRF. At the subsequent on-site visits, participants will be asked to confirm
intake of study intervention as planned since the previous on-site visit.
o. 
Only applicable in case of on-site visit and to be performed at the discretion of the investigator.
p. 
See Section 8.2.2 for an overview of assessments included in the clinical evaluation. In case antipyretics are used, body temperature should be measured immediately
before or >4 hours after giving antipyretics.


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Status: Approved,  Date: 07 May 2021
q. 
Only to be performed if the screening assessment occurred >8 hours before first dosing
r. 
A chest X-ray should be performed no more than 48 hours prior to randomization (see footnote k). If a chest X-ray has not been obtained as part of SOC, it must be
obtained during Screening.
s. 
During the course of the study, it is anticipated as part of SOC and strongly recommended by the sponsor that investigators will perform chest imaging and/or CT
scans and obtain lower respiratory tract sample (leftover to be sent to central lab; see Section 8.2.1.2), for determination of presence of RSV, if there is any suspicion
of the occurrence of LRTI (see Section 8.2.1.1), as soon as possible.
t. 
Outpatients must be instructed to contact the site immediately when there is a deterioration in their condition and should be invited for an unscheduled visit to be
evaluated for the development of an LRTI.
u. 
If possible, the leftover of the local lower respiratory tract sample will be sent to the central laboratory for additional virologic analyses.
v. 
If the collection of a sample is planned as part of the scheduled visit, collection of an additional sample when the occurrence of LRTI is suspected is not required.
w. See Section 8.2.1.5. This will only apply to randomized participants on suspicion of LRTI.
x. 
A predose bilateral mid-turbinate nasal swab sample will be taken of whichaliquots will be used for the central laboratory confirmation of RSV infection, to determine
RSV viral load, to determine mutations in the viral genome potentially associated with resistance to JNJ-53718678, and to determine the presence of other viral or
bacterial pathogens. The bilateral mid-turbinate nasal swab sample should be collected as close as possible and prior to the first administration of study intervention
(on Day 1).
y. 
Local testing for RSV detection should be performed using a rapid PCR- or other molecular-based assay on one aliquot of the study-specific bilateral mid-turbinate
nasal swab sample. A SOC upper respiratory tract sample collected at Day 28 may also be used if needed based on the local rapid PCR- or other molecular-based
assay used.
z. 
In case of positive local test for RSV at Day 28, an additional bilateral mid-turbinate nasal swab sample will be collected at Day 35 (study site visit) for central
analysis.
aa. Will be collected once daily postdose (except Day 1 predose) and preferentially PM (RiiQ Symptom Scale and PGI-S/PGI-H) or at the scheduled timepoints and
preferentially PM (RiiQ Impact Scales, PGI-C, and EQ-5D-5L, if applicable), in a language in which the participant is fluent, on electronic devices (eDevice). If a
participant requires assistance entering responses in the eDevice, a caregiver or member of the study team who is trained can interview the participant and enter the
participant’s responses on the eDevice on the participant’s behalf.
bb. Study personnel will interview participants during follow-up visits or telephone follow-up to record MRU since the last study visit. Medical resource utilization will
be recorded in the eCRF.
cc. Systolic and diastolic blood pressure need to be measured sitting or supine (preferably the same position at each measurement) after at least 5 minutes of rest.
dd. Physical examination of all body systems includes also height measurements and skin examination.
ee. Directed physical examination includes respiratory system, nose, ear, throat, facial, and neck lymph nodes, and skin examination.
ff. 
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. Additional ECG assessments are to be performed as unscheduled assessments/visits preferably 3 days after the start of coadministration with
moderate or strong CYP3A4 inhibitors during the study intervention period. Further, unscheduled ECG assessments/visits can be performed based on the overall
clinical picture as per the investigator’s clinical discretion or to confirm abnormal ECG findings.
gg. At Day 1 and Day 3, ECGs should be obtained approximately 1 to 1.5 hours (fasted) or approximately 4 hours (fed) after administration of study drug. Fasted is
defined as no food intake within approximately 2 hours prior to dosing and 2 hours after dosing.
hh. Samples for clinical laboratory assessments will be collected and analyzed at a central laboratory. Leftover blood samples may be used for exploratory biomarker
analyses, at the discretion of the sponsor.
ii. 
Urinalysis will be performed using dipsticks provided by the central laboratory. In case of abnormalities, the urine sample will be shipped to the central laboratory
for flow cytometric and/or microscopic evaluation(s).


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Status: Approved,  Date: 07 May 2021
jj. 
In case therapeutic drug monitoring of immunosuppressants (IS) is performed as part of SOC or per protocol instruction, the measured IS exposures are to be captured
in the eCRF.
kk. Levels of potassium and magnesium to be determined by the local and by the central laboratory. In case of hypokalemia and/or hypomagnesemia at screening,
Day 3, Day 8, or Day 15, the levels of potassium and/or magnesium should be corrected taking into account any underlying condition and as soon as possible to
prevent cardiac disturbances. Appropriate clinical management per local SOC (including but not limited to checking the corrected values at the local laboratory)
may be required. See also Section 8.4.7.2 for cardiac safety measures.
ll. 
Mandatory unless local regulations require these to be optional.
Note 1: Additional, unscheduled visits can be scheduled at the discretion of the investigator for work-up of suspected LRTI or follow-up of laboratory
abnormalities, ECG abnormalities, (an) AE(s).
Note 2: See Section 10.12, Appendix 12 for guidance on study conduct during the COVID-19 pandemic.


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Status: Approved,  Date: 07 May 2021
1.3.3. 
Long-term Follow-up
Phase 
Long-term Follow-up
Timepointa 
Day 100 ± 1 Week  
Phone follow upb 
Month 6 ± 1 Week  
Phone follow upb 
Month 12 ± 1 Week
Phone follow upb
Study Procedures
Morbidity including medical eventsc 
X 
X 
X
Medical resource utilizationd 
X 
X 
X
Survival status 
X 
X 
X
a. 
From first dose.
b. 
Preferentially phone call but other appropriate means are also acceptable, eg, Skype, WhatsApp, and others, depending on site preferences and local regulations.
c. 
Medical events, particularly complications related to the RSV infection including respiratory complications, GVHD onset or worsening, extended engraftment
period, relapse.
d. 
Medical resource utilization = hospitalizations as well as data on inpatient rehabilitation, long-term care hospitalization and use of extra skilled nursing (home) will
be collected.


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Status: Approved,  Date: 07 May 2021
1.3.4. 
PK Assessments
1.3.4.1. 
Sparse PK Sampling and Assessments
Table 1: 
Sparse PK Sampling in Hospitalized Participants
Phase 
Pre-
dose
Treatment Phase 
Follow-up
Day  
1 
2 
3 
(±1) 
4 
5
(±1)
6-7 
8
(±1)
9-10 
11
(±1)
12-14 
15
(±1)
16-21 
22
Blood sampling
for JNJ 53718678
pharmacokinetics
(sparse)a
Xb,c 
Xd
Xc,d 
Xb 
Xe
a. 
Venous blood samples for determination of JNJ-53718678 plasma concentrations. Detailed information on sample collection is available in Section 8. Leftover blood
samples collected for other testing may be used for exploratory biomarker analyses, at the discretion of the sponsor.
b. 
One sample approximately 1 to 1.5 hours post dose.
c. 
Sparse samples on Day 1 and Day 8 are not needed for the participants of the rich serial PK sampling substudy.
d. 
At least 4 hours after AM dosing and prior to PM dosing for bid dosing; at least 4 hours after dosing for qd dosing.
e. 
At random time of the day.
Table 2: 
Sparse PK Sampling in Outpatients
Phase 
Pre-
dose
Treatment Phase 
Follow-up
Day  
1 
2 
3
(±1)
4 
5 
(±1) 
6-7 
8 
(±1) 
9-10 
11 
(±1) 
12-14 
15 
(±1)
16-21 
22
Pre- 
dose 
Treatment 
On-site/ 
Site
Visit
(SV)
SV 
SV 
SV 
SV 
SV
Blood sampling
for JNJ 53718678
pharmacokinetics
(sparse)a
Xb 
Xc
Xc 
Xb 
Xc
a. 
Venous blood samples for determination of JNJ-53718678 plasma concentrations. Detailed information on sample collection is available in Section 8. Leftover blood
samples collected for other testing may be used for exploratory biomarker analyses, at the discretion of the sponsor.
b. 
One sample approximately 1 to 1.5 hours post dose.
c. 
At random time of the day.


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Status: Approved,  Date: 07 May 2021
1.3.4.2. 
Rich Serial PK Sampling Substudy Assessments
Table 3: 
Rich Serial PK Sampling Substudy in Hospitalized Participants (N30)
Time of Visit 
Sampling Time (hours)
pre-dose 
dosing
0.5h 
1h 
1.5h 
2h 
4h 
8h 
12h or 24h
Day 1a 
X
(-0.5h)
X 
X 
X 
X 
X 
X 
X
Day 8a 
X
(-0.5h)
X 
X 
X 
X 
X 
X 
X
Venous blood samples for determination of JNJ-53718678 plasma concentrations. Detailed information on sample collection is available in Section 8. Leftover blood
samples collected for other testing may be used for exploratory biomarker analyses, at the discretion of the sponsor. Sampling is preferably to be performed at the
indicated sampling time, although small deviations (up to 10 minutes) are allowed.
a. 
Sparse samples on Day 1 and Day 8 (as outlined in Table 1) are not needed for the participants of the rich serial PK sampling substudy.


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Status: Approved,  Date: 07 May 2021
2. 
INTRODUCTION
JNJ-53718678 is an investigational, potent small-molecule respiratory syncytial virus
(RSV)-specific fusion inhibitor belonging to the indole chemical class which targets the F-protein
and prevents the conformational changes of the F-protein required for fusion of the viral envelope
with the host cell membrane, thereby inhibiting viral replication and syncytia formation.
For the most comprehensive nonclinical and clinical information regarding JNJ-53718678, refer
to the most recent edition of the Investigator's Brochure (IB)and Addenda for JNJ-53718678.34
The term “study intervention” throughout the protocol, refers to the intake of study medication.
The term "sponsor" used throughout this document refers to the entities listed in the Contact
Information page(s), which will be provided as a separate document.
2.1. 
Study Rationale
Respiratory syncytial virus is a negative-stranded ribonucleic acid (RNA) virus belonging to the
Pneumoviridae family. Although RSV is generally recognized as the major respiratory pathogen
in infants and young children,25,41 it frequently causes upper and lower respiratory illness among
all age groups, often going undiagnosed. However, persons with certain high-risk conditions, such
as the frail elderly, patients with chronic lung or cardiac disease, and immunocompromised (IC)
patients are more susceptible to severe disease.19,22
Immunocompromised patients (eg, hematopoietic stem cell transplant [HSCT] recipients, subjects
with congenital immunodeficiency, solid organ transplant recipients, human immunodeficiency
virus [HIV]-infected patients) have a reduced ability to combat infection due to an impaired or
weakened immune system. Within the IC population, HSCT recipients are generally regarded as
having a particularly high risk for more severe disease caused by RSV, representing a substantial
unmet need for antiviral treatment of RSV infections in this patient population.22,32 The highest
risk has been observed in allogenic transplants compared to autologous transplants and in HSCT
recipients with an absolute lymphocyte count (ALC) <200 cells/µL.43,50,53
Progression of RSV infection from upper respiratory tract infection (URTI) to lower respiratory
tract infection (LRTI) occurs in 17% to 84% of RSV-infected patients in the HSCT
population.4,9,24,37,39,44,48,49,51 Subsequently, these LRTIs can result in significant morbidity, often
leading to hospitalizations and intensive care unit (ICU) admissions for supportive care, and are a
major cause of mortality in these patients.18,52
There are currently no direct-acting antiviral agents approved for prevention or treatment of RSV
infections in HSCT recipients. In the HSCT population, despite the lack of well-designed clinical
studies, aerosolized ribavirin has been highlighted as a potential treatment strategy for
RSV-associated LRTI, either as monotherapy or in combination with an immunomodulator.32,51,52
However, ribavirin has teratogenic potential and is logistically difficult to administervia aerosol.1,6
Other therapies for RSV infection, for which even less supportive efficacy data are available, such
as oral or intravenous ribavirin, intravenous immunoglobulin  (IVIG), or anti-RSV-enriched


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Status: Approved,  Date: 07 May 2021
antibody preparations are used at some clinical centers. Due to the significant disease burden and
the lack of effective treatment, the unmet medical need (prophylactically and therapeutically) is
substantial in the RSV-infected HSCT recipient population.
Results from a recent study in HSCT recipients with the fusion inhibitor presatovir
(NCT02254408)8,45 suggest that treatment with a fusion inhibitor may reduce RSV viral load and
the rate of progression from URTI to a lower respiratory tract complication (RSV-associated
LRTC; see Section 3), and as such may positively affect the clinical course.
This study will therefore evaluate the clinical outcomes, antiviral activity, safety, tolerability,
pharmacokinetics (PK), and PK/pharmacodynamics (PD) of JNJ-53718678 (also a fusion
inhibitor) in adult and adolescent RSV-infected HSCT recipients with acute URTI symptoms.
2.2. 
Background
Nonclinical Studies
JNJ-53718678 has been extensively evaluated and characterized in both in vitro and in vivo
pharmacological, PK, and toxicological studies. These nonclinical in vitro and animal in vivo
efficacy data demonstrate that JNJ-53718678 is a selective and potent small-molecule RSV fusion
inhibitor, capable of significantly reducing the viral titer in preclinical RSV models. Concurrently,
a decrease of the virus-induced pro-inflammatory response was observed in RSV-infected and
JNJ-53718678 treated Balb/C mice and neonatal lambs. No in vitro antiviral activity was observed
for the JNJ-53718678 minor metabolites M12 (JNJ-53541683), M19 (JNJ-64564071), and M37
(JNJ-69101045), while activity was observed for M5 (JNJ-54172794) which was lower than the
activity observed for JNJ-53718678. Detailed results of performed nonclinical studies are
described in Section 3 ofthe most recent edition of the IB and any Addenda for JNJ-53718678.34
Clinical Studies
Detailed results of performed clinical studies are described in the most recent edition of the IB and
any Addenda for JNJ-53718678.34 During completed adult studies 53718678RSV1001,
53718678RSV1002, 
53718678RSV1004, 53718678RSV1006, 
53718678RSV1008, and
53718678RSV2001, a total of 190 participants were enrolled, of whom 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 once daily [qd] or 250 mg twice daily [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.
Efficacy
In a challenge model for RSV infection in healthy adults (Study 53718678RSV2001), exposure to
JNJ-53718678 resulted in a reduction of viral load over time in all JNJ-53718678 dose groups
(75 mg, 200 mg, and 500 mg) as compared to the placebo group with no clear dose-response for
the active groups. This was paralleled with lower clinical symptom scores and mucus production


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for the JNJ-53718678 dosing groups as compared to the placebo group. Hence, based on these
efficacy data, antiviral proof-of-concept for JNJ-53718678 has been established.
Interim analysis results of the adult Study 53718678RSV2004 demonstrated positive trends for
time to first confirmed RSV undetectability and time to symptom resolution of Key RSV
Symptoms for JNJ-53718678 compared to placebo. For most analyses, the treatment effects
appeared greater in the subgroup of participants with onset of symptoms ≤3 days compared to the
subgroup with symptom onset >3 to 5 days. In Study 53718678RSV1005 in pediatric participants,
a trend towards an early antiviral effect of JNJ-53718678 was observed, despite a limited data set,
particularly in the placebo arms:
 
effect on viral load change from baseline on Days 2 and 3 (1 to 2 logs difference) compared
to placebo;
 
effect on viral load area under the curve (AUC)on Day 3 and Day 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 could be observed across the JNJ-53718678 dose
levels.
Human Pharmacokinetics
In the single dose escalation part of Study 53718678RSV1001, the mean maximum plasma
concentration (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 appeared to increase slightly
more than dose-proportionally with increasing JNJ-53718678 dose from 25 mg to 1,000 mg.
Median time to maximum plasma concentration (tmax) was 1.0 hour, except for the 1,000-mg dose
group, which was 2.5 hours. Mean half-life (t1/2term) ranged from 9.3 to 10.3 hours for the 75-mg
dose group to the 1,000-mg dose group. Based upon data from Study 53718678RSV1004 and
Study 53718678RSV1001, Cmax and AUC0 ∞for JNJ-53718678 are similar between Caucasian and
Japanese participants.
In the multiple dose escalation part of Study 53718678RSV1001 under fed conditions, steady state
conditions were generally reached after 1 day of treatment with JNJ-53718678. At steady state on
Day 8, JNJ-53718678 exposure expressed as mean predose plasma concentration  (Ctrough),
minimum plasma concentration (Cmin), Cmax  and AUC0 24h  showed a dose-proportional increase
with increasing JNJ-53718678 dose from 250 mg every 24 hours (q24h) to 500 mg q24h. Mean
Ctrough  and Cmin  were somewhat higher for the 250 mg every 12 hours (q12h) dose regimen
compared with the 500 mg q24h dose regimen. Cmax was lower, and average plasma concentration
at steady state over the dosing interval (Cavg) and AUC0 24h  were somewhat lower for the 250 mg
q12h compared with the 500 mg q24h dose regimen. The mean total amount of JNJ-53718678
excreted in urine over the dosing interval at steady state was low, 3.74%, 1.89%, and 1.76% of the
administered dose for respectively 250 mg q24h, 500 mg q24h, and 250 mg q12h. Mean renal
clearance was very low, and similar between dose regimens.


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In Study 53718678RSV2001, the multiple-dose PK results in adult participants inoculated with
RSV-A Memphis 37b virus were in line with those from Study 53718678RSV1001, indicating that
viral infection did not affect the PK of JNJ-53718678.
Results from the mass balance-study 53718678RSV1008 demonstrated that JNJ-53718678 was
the major entity in plasma (44% to 47%), with M12 and M37 being the most abundant metabolites
at 17% to 22% and approximately 10% of AUC0 96h of tissue 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 PK results from the study part evaluating the oral suspension in Study 53718678RSV1007,
indicated similar bioavailability of the oral suspension compared to the oral solution formulation,
with a relative bioavailability of 109% (Cmax) and 104% (AUC).
The 125 mg oral film-coated tablets, to be used after implementation of Protocol Amendment 6,
were evaluated as “oral solid concept formulation G033” in Study 53718678RSV1011. Interim
PK results in 24 healthy participants from Study 53718678RSV1011 (Part 1) demonstrated similar
bioavailability of the oral solid concept formulation compared to the oral suspension formulation
(provided as powder G007 + solvent G005), with a relative bioavailability (90% CI) of 91%
(83-99%) (Cmax) and 98% (93-103%) (AUC) under fasted conditions. The median Tmax  was
1.5 hours under fasted condition and 4 hours under fed condition for the oral film-coated tablets.
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 QTc (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. For more details on the analysis, refer to the most recent version of the
IB and any Addenda.34
A population PK (popPK) model for JNJ-53718678 has been developed using data from Phase 1
studies in healthy adults (Studies 53718678RSV1001, 53718678RSV1007, 53718678RSV1008,
and 53718678RSV1009) and Phase 2a Study 53718678RSV2004 in RSV-infected adults.
Interim analysis results from Study 53718678RSV2004 in RSV-infected adult patients (data
cut-off 23 September 2019) demonstrate that the popPK model provides an adequate description


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of most of the data, however moderate variability existed with exposures greater (~25%) than
expected based on healthy volunteer data. The mean (SD) Day 7 AUC0 24h  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).
Effect of Food
The effect of food on the PK of JNJ-53718678 (oral solution) was assessed following a single dose
of 250 mg JNJ-53718678 in Study 53718678RSV1001. Total exposure (AUC0 ∞) of
JNJ-53718678 was similar between fed and fasted conditions. Additionally, PK results from the
study part evaluating the oral suspension in Study 53718678RSV1007, indicated that the 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 .
Interim PK results from Study 53718678RSV1011 of the oral solid concept formulation G033
(oral film-coated tablet to be used in the current study) demonstrated similar bioavailability
compared to the oral suspension formulation (G007 powder + G005 solvent), with a relative
bioavailability (90% CI) of ~72% (64-82%) (Cmax) and ~94%  (88-100%) (AUC) under fed
conditions. The reduction in Cmax  under fed conditions is similar between  the solid concept
formulation and the oral suspension (demonstrated in Parts 6 & 7 of Study 53718678RSV1007).
Therefore, JNJ-53718678 can be taken with or without food.
Drug-drug Interactions
Based on in vitro data, JNJ-53718678 is a cytochrome P450 (CYP)2B6 inducer, a substrate but
not an inhibitor of P-glycoprotein (P-gp)and breast cancer resistance protein up to 15 µM, and an
inhibitor of organic-anion-transporting polypeptide (OATP)1A2, OATP1B1, organic anion
transporter 3, organic cation transporter (OCT)1, and OCT2. In vivo clearance of JNJ-53718678
will likely not be hepatic uptake-limited or sensitive to interactions with hepatic uptake inhibitors.
To prevent graft-versus-host disease (GVHD), patients are treated with immunosuppressive drugs
to suppress donor T cell function before and after stem cell infusion. Commonly used
immunosuppressive drugs include tacrolimus, sirolimus, and cyclosporine, which are known
CYP3A4 substrates. The potential effect of JNJ-53718678 on the PK of sensitive CYP substrates
was evaluated in the drug-drug interaction Study 53718678RSV1002.12 In this study, the drug
interaction potential of JNJ-53718678 was evaluated at a dose level of 500 mg on a drug cocktail
containing selective CYP probes (CYP3A4 [midazolam], CYP1A2 [caffeine], CYP2C9
[warfarin]), and a non-selective P-gp substrate (fexofenadine). In this study, participants received
JNJ-53718678 500 mg qd for a total of 13 consecutive days. Results of this study suggested a weak
inhibition of CYP3A4 activity in the presence of a single dose of JNJ-53718678 and a weak
induction of CYP3A4 activity after repeated administration of JNJ-53718678. Overall, at
steady-state of JNJ-53718678, the exposure of midazolam is hardly affected by JNJ-53718678 due
to the combined CYP3A4 inhibitory and inductive effect described. Similar effects as for
midazolam are anticipated for sirolimus and tacrolimus, which are also listed as sensitive CYP3A4


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substrates,21 and for cyclosporine, which is primarily metabolized through CYP3A4.
Coadministration of JNJ-53718678 with one of these immunosuppressants may initially (first
dose) increase the exposure of the CYP3A4 substrate, but the exposure of the CYP3A4 substrate
will subsequently gradually decrease and return to baseline due to the compensatory inductive
effect. For most CYP3A4 substrates a less than 2-fold increase in exposure would not have a
clinically relevant effect in terms of efficacy or safety. However, a small temporary increase in
exposure of drugs having a narrow therapeutic index (such as tacrolimus and cyclosporine), may
be clinically relevant. Therefore, therapeutic drug monitoring (see Section 6.6) is recommended to
assure adequate immunosuppressant exposures and to allow for immunosuppressant dose
adjustments. On the other hand, strong inhibitors or inducers of CYP3A4 enzymes, are not
permitted as concomitant medication in the JNJ-53718678 studies (see Section 6.6).
In Study 53718678RSV1002, 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.
Safety
Based upon the limited available clinical data and considering the stage of development of
JNJ-53718678, no AEs or clinically significant laboratory abnormalities, abnormalities in vital
signs parameters, ECG abnormalities, or physical examination findings indicative of a safety
concern have been identified.
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 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, ECG, 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


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who received placebo. Diarrhea, nausea, and headache were more frequently observed in
participants who received JNJ-53718678 compared to participants who received placebo.
Results from Part 2 (TQT part) of Study 53718678RSV1009 demonstrated that JNJ-53718678 was
generally safe and well tolerated in healthy adult 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 QT interval corrected using Fridericia's formula
(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.
 
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 most recent
version of the IB and any Addenda.34 A change to a bid dosing regimen (see Section 4.3.1) and
several other mitigation measures to safeguard the participants (see Section 2.3.3) 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


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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 an AE (diarrhea)
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.
Interim analysis of Study 53718678RSV2002 in pediatric participants (N 155) 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.
2.3. 
Benefit-Risk Assessment
More detailed information about the known and expected benefits and risks of JNJ-53718678 may
be found in the most recent edition of the IB and any Addenda.34
2.3.1. 
Risks for Study Participation
2.3.1.1. 
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.
2.3.1.2. 
Potential Risks
All therapies have the potential to cause adverse experiences. For an overview of the total number
of adult participants (completed studies) receiving one or more doses of JNJ-53718678, refer to
Section 2.2.
Please refer to Section 2.2 and the most recent edition of the IB and any Addenda for details on
the reported AEs and laboratory/ECG abnormalities in the studies conducted to date.34
Based upon currently available clinical data and considering the 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.


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Based upon the limited available clinical data, no risk related to the hepatobiliary system was
identified. However, given the hepatobiliary-related nonclinical findings and because the amount
of clinical data is limited, the sponsor considers hepatobiliary effects to be a safety topic of special
interest and hepatobiliary function will be monitored by routine hepatobiliary function tests during
clinical studies.
The evaluation of JNJ-53718678 antiviral activity requires nasal swabbing. 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. Study procedures such as
blood sampling carry a potential risk (eg, pain, discomfort, hematoma) to the participant.
Study treatment will be provided in addition to, not in replacement of, standard-of-care (SOC)
supportive and symptomatic therapy.
Although currently no clinical data from a 21-day treatment with JNJ-53718678 are available, the
treatment duration of 21 days is considered to be safe. In Study 53718678RSV1002,12 the only
study in which a dosing duration of 13 days was evaluated, steady state conditions were generally
achieved at 8 days of dosing. This 13-day dosing regimen (500 mg qd) was generally safe and well
tolerated (see also Section 4.3).
Lower respiratory tract samples will be obtained as per local standard of care (SOC)(including by
bronchoscopy or inducing sputum) and do not expose the participant to additional risk above that
from SOC.
Imaging procedures performed as part of screening, as well as part of identification of suspected
LRTI, carry a risk related to the radiation exposure associated with the assessment. However, these
assessments would be performed as part of SOC. The additional radiation exposure from the
screening chest X-ray, if not performed as SOC, is limited.
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 most recent version of the IB
and any Addenda34 for more information).
Overall, the oral suspension formulation used in Part 1 and 2 of the TQT study was generally safe
and well tolerated in 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).
Available clinical safety data do not indicate any safety signal or concern with regards to the
cardiovascular system (Section 2.2).


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The safety profile of the oral film-coated tablet is similar to that of the oral suspension (Study
53718678RSV1011; data on file).
2.3.2. 
Benefits for Study Participation
2.3.2.1. 
Known Benefits
JNJ-53718678 at daily doses of 75, 200, and 500 mg given for 7 days has shown an antiviral effect
and reduced the signs and symptoms of RSV infection in healthy adults in an RSV human
challenge model. In addition, 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).
In the ongoing adult Study 53718678RSV2004, the interim analysis (N 67) data demonstrated
positive trends for time to first confirmed RSV undetectability for JNJ-53718678 compared to
placebo. Effects appeared greater in the subgroup of participants with symptom onset ≤3 days
compared to the subgroup with symptom onset >3 to 5 days.
However, the clinical benefit of this compound remains to be established.
2.3.2.2. 
Potential Benefits
The HSCT recipients participating in this study might have a benefit regarding the clinical course
of their RSV infection. Treatment with JNJ-53718678 may reduce the severity and duration of
RSV signs and symptoms and their impact on functioning, reduce the effect of RSV infection on
physiologic parameters, prevent progression to more severe disease status (RSV LRTI), reduce the
need for and duration of supportive care (eg, oxygen supplementation, days of hospitalization),
and accelerate the participants’ return to pre-RSV health status. The unequal randomization (2:1
active: placebo) affords the majority of participants the potential benefit of JNJ-53718678
treatment. Results from the proposed study may be useful in developing a new antiviral therapy
for RSV infection.
In the ongoing adult Study 53718678RSV2004, the interim analysis (N 67) data demonstrated a
positive trend for time to symptom resolution of Key RSV Symptoms for JNJ-53718678 compared
to placebo. Effects appeared greater in the subgroup of participants with symptom onset ≤3 days
compared to the subgroup with symptom onset >3 to 5 days.
2.3.3. 
Benefit-Risk Assessment for Study Participation
Currently the only available treatment for RSV in HSCT recipients is supportive and symptomatic
care, as well as ribavirin and/or IVIG (see Section 2.2).
Based on the available data and proposed safety measures, the overall risk/benefit assessment for
this study is acceptable for the following reasons:


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 
Proof-of-concept antiviral effect 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);
 
Antiviral effect proof-of-concept was established in non-hospitalized adult participants
infected with RSV (interim analysis of Study 53718678RSV2004).
 
No safety concerns were identified in the interim analysis of Study 53718678RSV2004 in
non-hospitalized adult participants infected with RSV.
 
No safety concerns were identified in studies in RSV infected pediatric participants
(Study 53718678RSV1005 in children >1 month to ≤24 months of age and from an interim
analysis of Study 53718678RSV2002 in children ≥28 days and ≤3 years of age)(Section 2.2).
 
No safety concerns were identified in completed studies in adult healthy volunteers to date
and most observed AEs and laboratory abnormalities were mild to moderate in severity and
considered not related to JNJ-53718678 by the investigator (Section 2.2).
 
Several safety measures have been proposed to minimize potential risk to participants,
including:
 
Only participants who meet all eligibility criteria (as specified in the protocol,
Sections 5.1 and 5.2) will be allowed to participate in this study. The selection criteria
include adequate provisions to minimize the risk and protect the well-being of the
participants in the study.
 
Safety data on the total daily dose selected for the current study did not identify any safety
concern (see Section 4.3).
 
Utilization of study intervention  discontinuation criteria (see Section 7.1) and study
discontinuation criteria (see Section 7.2).
 
Safety surveillance in this study will monitor standard safety parameters associated with
investigational drug development (see Section 8.3) and safety topic of special interest of
JNJ-53718678 as part of the study assessments (see Section 8.4.7).
 
Possibility to use the results from diagnostic testing (swab) performed as part of SOC.
 
The establishment of an Independent Data Monitoring Committee (IDMC) (see Section
9.5) to monitor data on a regular basis to ensure continuing safety of the participants
enrolled in this study (see Sections 8.3 and 8.4).
 
Additionally, given the longer dosing duration of JNJ-53718678 used in this study (see
Section 4.2) and the population targeted, the IDMC will perform the first unblinded safety
review prior to (should a safety signal warrant) or after the 18th patient has completed the
Day 21 (end-of-intervention)assessments (or discontinued earlier).
 
In view of the identified important potential risk of QT interval prolongation (see
Section 2.3.1.2, TQT Study 53718678RSV1009), the following measures have been
implemented to minimize the potential risk to participants:
o 
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 4.3.1).


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o 
Dose adjustment to 250 mg bid dose for all participants without coadministration
with moderate or strong CYP3A4 inhibitors. For participants coadministered with
moderate or strong CYP3A4 inhibitors with the exception of posaconazole, the dose
will be reduced to 125 mg bid. For participants coadministered with posaconazole,
the dose will be reduced to 125 mg qd (see Sections 4.3.1, 6.1, 6.5, and 6.6).
o 
Specific cardiovascular and ECG-based criteria have been established for eligibility
assessment (see Section 5.2).
o 
Close monitoring of the use of concomitant medications will be conducted regularly.
o 
Enhanced ECG monitoring (including around tmax on Day 1 and Day 3 [steady state])
will be conducted during the regularonsite visits in the treatment period (ie, at Day 1,
Day 3, Day 8, and Day 15). Additional ECG assessments are to be performed as
unscheduled assessments/visits preferably 3 days after the start of coadministration
with moderate or strong CYP3A4 inhibitors during the study intervention period.
Further, unscheduled ECG assessments/visits can be performed based on the overall
clinical picture as per the investigator’s clinical discretion  (see Schedules of
Activities and Section 8.4.7.2).
o 
Utilization of study intervention discontinuation and withdrawal criteria specific to
QTcF interval changes (see Section 7.1).
o 
Close monitoring of hypokalemia and hypomagnesemia and corrective actions in
case of laboratory abnormalities for these analytes at Screening and during the
treatment period (see Section 8.4.7.2).
o 
Specific toxicity management for confirmed QTcF  interval value ≥500 ms (see
Section 8.4.7.2).
o 
Close follow-up of ECG- and cardiac-related AEs as part of medical monitoring.
Taking into account the measures taken to minimize risk to participants participating in this study,
the potential risks identified in association with  JNJ-53718678 are justified by the anticipated
benefits that may be afforded to adult RSV-infected HSCT recipients with acute URTI symptoms.
3. 
OBJECTIVES AND ENDPOINTS
Objectives 
Endpoints
Primary
To evaluate the effect of JNJ-53718678 on the
development of RSV LRTIs in adult HSCT
recipients with RSV URTI.
The proportion of participants who develop RSV
LRTI (see definition below) per the Endpoint
Adjudication Committee (EAC)’s assessment (see
Section 9.6) through Visit Day 28.
Secondary
To evaluate the effect of JNJ-53718678 on the
development of RSV-associated LRTC  in adult
and adolescent HSCT recipients with RSV URTI.
The proportion of participants who develop RSV-
associated LRTC  (see definition below) per the
EAC’s assessment (see Section 9.6) through Visit
Day 28.
To evaluate the safety and tolerability of
JNJ-53718678
Safety and tolerability, as assessed by AEs,
clinical laboratory testing, ECGs, vital signs,
throughout the study


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Objectives 
Endpoints
To evaluate the impact of JNJ-53718678 on 
progression to respiratory failure and on all-cause 
mortality  
 
The proportion of participants progressing to
respiratory failure (of any cause) requiring
mechanical 
ventilation 
(invasive 
or
noninvasive) and/or death, in participants who
develop RSV LRTI or RSV-associated LRTC
per the EAC’s assessment;
 
The proportion of participants progressing to
respiratory failure (of any cause) requiring
mechanical 
ventilation 
(invasive 
or
noninvasive) 
and/or 
death 
(all-cause
mortality);
 
The proportion of participants progressing to
death (all-cause mortality), in participants
who develop RSV LRTI or RSV-associated
LRTC per the EAC’s assessment;
 
The proportion of participants progressing to
death (all-cause mortality);
 
The proportion of participants progressing to
respiratory failure (of any cause) requiring
mechanical 
ventilation 
(invasive 
or
noninvasive), in participants who develop
RSV LRTI or RSV-associated LRTC per the
EAC’s assessment;
 
The proportion of participants progressing to
respiratory failure (of any cause) requiring
mechanical 
ventilation 
(invasive 
or
noninvasive).
To evaluate the impact of JNJ-53718678 on the 
clinical course of RSV infection
Clinical course-related endpoints:
 
Number of supplemental O2 free days through
Day 28 (see Attachment 10.8 for assessments)
 
Incidence of O2 requirement, total length and
type (eg, supplemental oxygen, noninvasive
pressure ventilation, invasive mechanical
ventilation [tracheal tube, laryngeal mask, or
tracheostomy])
 
Respiratory rate, heart rate, body temperature,
and peripheral capillary oxygen saturation
(SpO2) over time as measured by the
investigator during scheduled visits
 
Proportion of participants hospitalized (of
participants who were not hospitalized at
baseline), proportion of participants re-
hospitalized (of participants who were
hospitalized at baseline and discharged during
the study and of participants who were not


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Objectives 
Endpoints
hospitalized 
at 
baseline, 
required
hospitalization, and were discharged during
the study)
 
Total length of hospital stay (time in hospital
before first dosing is discarded) and total time
in the ICU (time in ICU before first dosing is
discarded)
 
Incidence of Grade 3 and Grade 4 adverse
events (AEs) in the Infections and Infestations
System Organ Class
 
Incidence of respiratory and thoracic-related
AEs
 
Incidence of antibiotic use in participants who
develop and in those who do not develop RSV
LRTI or RSV-associated LRTC  per the
EAC’s assessment
 
Time to resolution of symptoms, assessed
through an instrument for patient-reported
symptoms (Respiratory  Infection  Intensity
and Impact Questionnaire [RiiQ] Symptom
Scale [Appendix 10.9])
 
Change from baseline through Day 28 in
severity of symptoms reported by subjects in
the RiiQ Symptom Scale (Appendix 10.9)
 
Time to resolution of respiratory illness,
through the Patient Global Impression of
Severity (PGI-S) Scale (Appendix 10.10)
 
Change in PGI-H and PGI-C Scales through
Day 28 (Appendix 10.10)
To evaluate the PK of JNJ-53718678 
PK parameters of JNJ-53718678
To evaluate the relationship between the PK of 
JNJ-53718678 and the PD (selected antiviral 
activity, clinical outcomes, and safety parameters) 
after repeated dosing of JNJ-53718678
PK/PD analysis of plasma concentration-time data
of JNJ-53718678 using (non)-linear mixed-effects
modeling
To evaluate the antiviral effect of JNJ-53718678 as 
measured by RSV viral load in  bilateral mid- 
turbinate nasal swab samples by quantitative 
reverse transcription polymerase chain reaction
(qRT-PCR) assay  
Virologic parameters derived from the RSV viral
load as measured by a qRT-PCR assay in bilateral
mid-turbinate nasal swab samples including:
 
RSV viral load and change from baseline over
time
 
RSV viral load AUC from immediately prior
to first dose of study intervention (baseline)
through Day 8, Day 11, Day 15, Day 22, and
Day 28.


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Objectives 
Endpoints
 
time to undetectable RSV viral load
 
proportion of participants with undetectable
RSV viral load at each time point throughout
the study
To evaluate the impact of RSV and its treatment on 
health-related quality of life (HRQOL). 
Change from baseline for the HRQOL through
Day 28 (as assessed through the 5-level EuroQol 5-
Dimension [EQ-5D-5L; Appendix 10.11] and RiiQ
Impact Scales (Appendix 10.9)]
To evaluate the emergence of mutations in the viral 
genome potentially associated with resistance to 
JNJ-53718678 
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)
Exploratory
The exploratory objectives are to evaluate: 
 
medical 
resource 
utilization 
(MRU), 
including 
hospitalization, 
for 
clinical
management of participants during treatment
and posttreatment follow-up
 
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) 
 
the relationship between antiviral activity and 
clinical course 
 
the impact of the baseline RSV viral subtype 
and genotype on the antiviral activity and
clinical course
 
the incidence of RSV viremia
 
the incidence of GVHD or graft failure
The exploratory endpoints are:
 
medical resource utilization
 
RSV viral subtype and presence of
pretreatment RSV F-gene polymorphisms
 
virologic parameters derived from the RSV
viral load as measured by quantitative viral
culture
 
proportion of participants with RSV viremia
(RSV viral load in plasma)
 
proportion of participants with new onset
GVHD
 
proportion of participants with graft failure
EAC: Endpoint Adjudication Committee; ECG: electrocardiogram; EQ-5D-5L: 5-level EuroQol 5-
Dimension; GVDH: graft-versus-host disease; HRQOL: health-related quality of life; LRTC: lower
respiratory tract complication(s); LRTI: lower respiratory tract infection; MRU: medical resource
utilization; PD: pharmacodynamic(s); PGI-C: patient global impression of change; PGI-H: patient global
impression of health; PGI-S: patient global impression of severity; PK: pharmacokinetic(s); qRT-PCR:
quantitative reverse transcription polymerase chain reaction; RiiQ: Respiratory Infection Intensity and
Impact Questionnaire; RSV: respiratory syncytial virus; URTI: upper respiratory tract infection
RSV LRTI will be defined as the development of a lower respiratory sign or symptom (including
decrease in oxygen saturation or increase in supplemental oxygen to maintain oxygen saturation,
wheezing, rhonchi, rales, dyspnea, tachypnea, worsening cough) AND


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Positive RSV test from lower respiratory tract sample (eg, sputum, induced sputum,
bronchoalveolar lavage (BAL), lung biopsy, or autopsy specimen) within ±4 days of a
new chest image finding, compared to baseline, consistent with a LRTI; OR
 
Positive RSV test from lower respiratory tract sample (eg, sputum, induced sputum, BAL,
lung biopsy, or autopsy specimen) only; OR
 
Positive RSV test from upper respiratory tract sample within ±4 days of a new chest
image finding, compared to baseline, consistent with a RSV LRTI
as determined by the EAC.
RSV-associated LRTC will be defined as the development of a lower respiratory sign or symptom
(including decrease in oxygen saturation or increase in supplemental oxygen to maintain oxygen
saturation, wheezing, rhonchi, rales, dyspnea, tachypnea, worsening cough) AND falling within
one of the following subcategories as determined by the EAC:
 
RSV LRTI, as defined as above
OR
 
Secondary bacterial LRTI defined as:
 
Positive specimen for a clinically significant bacterium from lower respiratory tract
source (eg, sputum, induced sputum, BAL, lung biopsy, or autopsy specimen) within
±4 days of a new chest image finding, compared to baseline, consistent with a LRTI
OR
 
Secondary LRTI due to unusual pathogens defined as:
 
Positive specimen for a clinically significant unusual organism (eg, atypical bacteria,
fungus, or another respiratory virus) from a lower respiratory tract source (eg, sputum,
induced sputum, BAL, lung biopsy, autopsy specimen) within ±4 days of a new chest
image finding, compared to baseline, consistent with a LRTI
OR
 
Secondary LRTC of unknown etiology defined as:
 
New findings on a chest image, compared to baseline, consistent with a LRTI,
inflammatory process, or some other clinically significant pulmonary process in absence
of a positive specimen or no specimen collected from lower respiratory tract source within
±4 days of the new chest image finding
Refer to Section 8, Study Assessments and Procedures for evaluations related to endpoints.
3.1. 
Hypothesis
The primary hypothesis of this study is that JNJ-53718678 reduces the proportion of adult HSCT
recipients with RSV URTI, who develop RSV LRTI within 28 days after start of treatment as
compared to placebo, assessed through the relative risk.


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4. 
STUDY DESIGN
4.1. 
Overall Design
This is a Phase 2, randomized, double-blind, placebo-controlled, multicenter study to evaluate the
clinical outcomes, antiviral activity, safety, tolerability, PK, and PK/PD of JNJ-53718678 in adult
(ie, adult cohort) and adolescent (ie, adolescent cohort) HSCT recipients with an RSV URTI.
Participants will be enrolled in either the adult or adolescent cohort:
 
Adult cohort: adult participants ≥18 to ≤75 years of age.
 
Adolescent cohort: adolescent participants ≥13 to <18 years of age.
In the adult cohort, a sample size of approximately 249 participants is targeted, with a maximum
of 375 participants (see Section 9.4.10). No target sample size was determined for the adolescent
cohort (see Section 4.2.1).
The study will include a Screening Period (Day -2 to Day 1), a Treatment Period (Day 1 to Day 21),
and a Follow-up Period (Day 22 to Day 49). On Day 49, participants will complete the study. The
total study duration for each participant will be approximately 49 days (Screening included).
Study participants will be identified when they present for medical care (outpatient or hospital)
with new symptoms of an RSV URTI and/or worsening of chronic (associated with previously
existing diagnosis, eg, chronic rhinorrhea, seasonal allergies, chronic lung disease) respiratory
symptoms consistent with RSV infection. Participants will need to complete Screening and initiate
study intervention  dosing within 4 days after symptom onset of RSV URTI (ie, onset of new
symptoms of an RSV URTI and/or worsening of chronic respiratory symptoms, consistent with
RSV URTI).
During Screening, baseline HSCT-related and RSV-related characteristics will be verified.
Participants need to have ALC <1,000 cells/μL at Screening to be eligible. One Screening sample
(from upper respiratory tract collected per local SOC testing within 24 hours prior to start of
Screening or a bilateral mid-turbinate nasal swab as part of the study-specific Screening
assessment) will be collected for the local diagnosis of RSV infection using a rapid PCR- or other
molecular-based diagnostic assay. A separate bilateral mid-turbinate nasal swab will be collected
immediately prior to the first dose for central laboratory analyses to confirm RSV infection (and
subtype), to determine the RSV viral load, to perform viral sequencing, and to determine the
presence of other viral or bacterial pathogens. A chest X-ray is required for screening purposes to
exclude the presence of an LRTI.
Randomization should occur as soon as possible after confirming eligibility (including the
radiologist’s or investigator’s interpretation of a chest X-ray, the confirmation of ALC
<1,000 cells/μL [local testing], and confirmation of RSV positivity). Randomization should
preferentially occur within 24 hours after start of Screening or at the latest within 48 hours after
the collection of a chest X-ray and the collection of (local) samples for confirmation of ALC


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<1,000 cells/μL, and for confirmation of RSV positivity. Eligible participants will be randomized
2:1 (active: placebo)within each cohort to receive either:
 
250 mg JNJ-53718678 bid for 21 days (without coadministration with moderate or strong
CYP3A4 inhibitors)
 
matching placebo bid for 21 days
OR
 
125 mg JNJ-53718678 bid for 21 days for participants coadministered with moderate orstrong
CYP3A4 inhibitors with the exception of posaconazole
 
matching placebo bid for 21 days
OR
 
125 mg JNJ-53718678 qd for 21 days for participants coadministered with posaconazole
 
matching placebo qd for 21 days
See also Sections 4.3.1, 6.1, 6.5, and 6.6.
Randomization in the adult cohort will be stratified by hospitalization status (yes/no) at the time
of randomization, lymphopenia (<200 cells/µL, 200 - <500 cells/µL, and ≥500 - <1,000 cells/µL)
at Screening, and ribavirin and/or IVIG use (yes/no) at the time of randomization. No stratification
will be applied to the adolescent cohort.
Participants with an ALC <500 cells/µL at Screeningshould account for at least 50% of all enrolled
participants in the adult cohort and participants with an ALC <200 cells/µL at Screening should
account for at least 25% of all enrolled participants in the adult cohort, also at the time of the
interim analysis (see Section 9.4.10).
Study intervention administration should start as soon as possible, but no later than 4 hours after
randomization and within 4 days after symptom onset of RSV URTI. Dosing should preferably
occur approximately at the same time each day (for the qd dosing and for the AM and PM dosing
of the bid regimen).
For participants on bid dosing, dosing should occur approximately 12 hours apart. For participants
who receive the first dose of JNJ-53718678 or placebo PM of Day 1, dosing should continue
through the morning (ie, AM) of Day 22 so that all participants receive 42 consecutive bid doses
in total. Administration of the second bid 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.
Participants on a 125 mg qd regimen coadministered with posaconazole will receive
21 consecutive doses in total.


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JNJ-53718678/placebo can be administered with or without food. The study intervention will be
administered orally. During hospitalization, the study intervention (oral suspension or oral film-
coated tablets dispersed in water) 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. The first dose of study intervention will be administered at the study site.
During (re)hospitalization, study intervention will be administered by the study-site personnel. At
home, or when  the rehospitalization occurs at a non-study site, study intervention  will be
administered by the participant or the caregiver. All participants will receive supportive care for
RSV infection as per local SOC, considering the restrictions provided in Section 6.6.
All scheduled study visits are preferentially done at the site, but can also be done as home visits,
if feasible for the study site and if allowed per local regulations (both options are further referred
to as ‘visit’). On Day 35 and Day 49, participants will be contacted by the site staff for a telephone
follow-up visit, after which the participant completes the study. In case a participant is
experiencing (an) ongoing AE(s) or has clinically significant laboratory or ECG abnormalities at
the time of the Day 28 Follow-Up Visit, participants might be requested, at the discretion of the
investigator, to have a Safety Follow-up Visit, at Day 35 and Day 49. In case a participant tests
positive (locally) for RSV in a mid-turbinate nasal swab sample or other upper respiratory tract
sample at Day 28, (s)he will be requested to have a site visit at Day 35 for virologic assessment.
If a participant prematurely discontinues study intervention for any reason before the end of the
Treatment Phase, the participant is recommended to remain compliant to all study-related
procedures including timely completion of all efficacy assessments up to Day 49 or at least through
Day 28 (see Section 7.1). In case the participant withdraws consent/assent during the treatment or
Follow-up phase, optional Withdrawal and Safety Follow-up Visits will be offered (see
Section 7.2). If the reason for withdrawal from the study is full withdrawal of consent/assent, then
no scheduled (as per Schedules of Activities) additional assessments are allowed.
During the study, the development of RSV LRTIs will be monitored (see Section 8.2.1) and the
clinical course of RSV infection will be assessed (see Section 8.2.2). If there is any clinical
suspicion of the occurrence of an LRTI, ie, development of a lower respiratory sign or symptom
(including decrease in oxygen saturation or increase in supplemental oxygen to maintain oxygen
saturation, wheezing, rhonchi, rales, dyspnea, tachypnea, worsening cough), a bilateral
mid-turbinate nasal swab should be collected for central analysis and it is anticipated as part of
SOC and strongly recommended by the sponsor that investigators should perform chest X-rays
and/or computed tomography (CT)scans as part of the evaluation (see Section 8.2.1.1)and obtain
lower respiratory tract sample consistent with local SOC (leftover to be sent to central lab) to
determine the etiology. A blinded Endpoint Adjudication Committee (EAC) will review clinical
data to determine whether an  RSV LRTI and/or RSV-associated LRTC  has developed (see
Section 9.6).
For the evaluation of antiviral activity, the RSV viral load in bilateral mid-turbinate nasal swab
samples will be measured at the central laboratory  using an RSV qRT-PCR assay. Bilateral
mid-turbinate nasal swab samples will be collected at several timepoints during the study as


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indicated in the Schedules of Activities and on clinical suspicion of RSV LRTI (see Section 8.2.3).
For a selected set of mid-turbinate nasal swab samples, quantitative RSV culture may be
performed, if feasible, for determination of RSV infectious viral titer.
Viral resistance will be monitored by sequencing of the F-gene in all baseline bilateral mid-
turbinate nasal swab samples, and on subsequent bilateral mid-turbinate nasal swab samples upon
request of the sponsor’s protocol virologist. Other regions of the RSV genome may also be
sequenced at the discretion of the sponsor’s virologist. Sequencing data will not be reported to the
investigators (see Section 8.2.5). Sequencing results may be presented in a separate report.
A blood sample for evaluation of RSV viremia will be collected at several timepoints during the
study as indicated in the Schedules of Activities and at clinical suspicion of LRTI. At the discretion
of the sponsor, leftover from these samples may be used for an exploratory analysis of other
pathogens in blood (see Section 8.2.6).
Safety and tolerability, including AEs, laboratory assessments, ECGs, vital signs, and physical
examination will be assessed throughout the study from signing of the informed consent form
(ICF)until the participant’s last study-related activity (see Section 8.3).
Pharmacokinetic assessments during the study will be based on sparse sampling for all participants
and a rich serial PK sampling substudy in approximately 30 hospitalized participants at selected
sites (see Section 8.6).
Medical resource utilization (see Section 8.10) will be assessed.
A blood sample will be collected for exploratory biomarker analyses at several timepoints during
the study, as indicated in the Schedules of Activities. Leftover bilateral mid-turbinate nasal swab
and blood samples obtained for other testing may also be used for exploratory biomarker analysis,
at the discretion of the sponsor (see Section 8.9).
Long-term follow-up data will be collected. Participants, or a person designated by the participant,
will be contacted at Day 100, Month 6, and Month 12 to collect data on survival status, morbidity
(particularly complications related to the RSV  infection, including respiratory complications,
GVHD onset or worsening, extended engraftment period, relapse), and hospitalizations/MRU.
See Section 10.12, Appendix 12 for guidance on study conduct during the COVID-19 pandemic.
An IDMC will be established to monitor and review data in an unblinded manner on a regular
basis to ensure the continuing safety of the participants enrolled in this study. The committee will
meet periodically to review safety data and will meet to review the results from the interim
analysis. After the review, the IDMC will provide recommendations to the Sponsor Committee,
who will be responsible for decision making, considering the IDMC recommendation, and who
will communicate these decisions to the study team. Details are provided in the IDMC Charter
(see Section 9.5). Additionally, given the longer dosing duration of JNJ-53718678 used in this
study and the population targeted, the IDMC will perform the first unblinded safety review prior


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to (should a safety signal warrant) or after the 18th patient has completed the Day 28 assessments
(or discontinued earlier).
An interim analysis will be performed when approximately 50% of the planned participants in the
adult cohort have completed the Day 28 assessments (or discontinued earlier). This interim
analysis will include safety, testing for futility, early superiority, and a sample size re-estimation
(see Section 9.4.10) and will be reviewed by the IDMC.
The final analysis is planned after the target number of all participants in the adult cohort has been
reached and when all participants in both cohorts have completed the study (or discontinued
earlier).
A separate substudy with Qualitative Patient Interviews will be performed at selected study sites
by a qualified person selected by the sponsor in a subset of participants to gain insight in HSCT
recipients experience throughout the clinical course of their RSV infection, and to guide
interpretation of treatment outcomes and study endpoints. Details, including objectives and study
design, will be described in a separate substudy protocol.
A diagram of the study design is provided in Section 1.2.
4.2. 
Scientific Rationale for Study Design
4.2.1. 
Study Population
Immunocompromised patients have a reduced ability to combat RSV infection due to an impaired
or weakened immune system, and are therefore more susceptible to severe infections (see also
Section 2.1). Within the IC population, HSCT recipients are generally regarded as having a
particularly high risk for more severe disease caused by RSV, compared to other IC patients.22,32
Respiratory syncytial virus infection in HSCT recipients, if left untreated, may progress quickly
from RSV URTI to LRTI, which substantially impacts daily functioning.52,56 In these patients,
RSV has been recognized as one of the leading causes of morbidity and mortality, resulting in a
prolonged length of hospitalization, increased rate of ICU admission, poorer overall outcomes, and
reported mortality rates of 17% to 20% on average, although highlyvariable.2,56 Given the absence
of effective prevention and treatment, the unmet medical need in the RSV-infected HSCT recipient
population is substantial. Ideally, new antiviral treatments should target the virus early in the
course of disease and prior to progression from RSV URTI to LRTI, as this would positively affect
the clinical course of RSV infection.36,44
Adolescents who have undergone HSCT are similarly affected by the morbidity and mortality
associated with RSV. Therefore, adolescents ≥13 to <18 years of age, who received a HSCT
transplant, who are infected with RSV, and who meet the eligibility criteria may be enrolled in the
adolescent cohort to allow generating some efficacy and safety data in adolescents, which may be
used to support the use of JNJ-53718678 in adolescents. Furthermore, JNJ-53718678 has already
been studied in the pediatric population with a trend towards an early antiviral effect of
JNJ-53718678 and an acceptable safety profile (see Section 2.2). A Phase 2 study of JNJ-53718678
in the pediatric population is currently ongoing. No target sample size will be determined for the


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adolescent cohort due to the expected low prevalence of such individuals in the overall HSCT
recipient population.3,7,10,57
4.2.2. 
Blinding, Control, Study Phase/Periods, Intervention Groups
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. The use of placebo is considered
important for the proper evaluation of the safety and efficacy of JNJ-53718678 as a treatment for
RSV infection (ICH E10 Guidance 2000). Apart from ribavirin or IVIG, which are not approved
for use in this population, are not commonly used, are of uncertain efficacy, and subject to
stratification (adult cohort only)in this study, no other specific treatments are available. Therefore,
the current SOC  for the treatment of RSV is supportive and may include administration of
bronchodilators by aerosol, fluids, nutrition, and oxygen. A comparison of JNJ-53718678 to
placebo on a background of SOC supportive therapy is thus not only justifiable, but essential to
enable an objective determination of the potential benefits and risks of treatment with JNJ-
53718678. Furthermore, patients randomized to placebo may benefit from the more extensive
clinical care provided within the context of a clinical study.
Randomization within the adult and adolescent cohorts will be used to minimize bias in the
assignment of participants to intervention groups, to increase the likelihood that known and
unknown participant attributes (eg, demographic and baseline characteristics) are evenly balanced
across intervention groups, and to enhance the validity of statistical comparisons across
intervention groups. The current design of this study includes a 2:1 randomization scheme. This
design ensures that the number of participants randomized to the placebo group is minimized,
while still enabling proper assessment of the clinical outcomes, safety, and antiviral activity of
JNJ-53718678. Consequently, most participants in the study will receive JNJ-53718678 and thus
have the potential to benefit from its antiviral activity, while the placebo group will allow
comparison of the safety/tolerability with versus without treatment.
Stratification in the adult cohort will account for baseline characteristics where a significant
treatment effect was seen in the presatovir URTI study  (NCT02254408)8,45 , ie, lymphopenia
(<200, 200 to <500 cells/µL, and 500 to <1000 cells/µL) and hospitalization status at baseline
(yes/no). Additionally, a third stratification factor will be pre-baseline use of ribavirin and/or IVIG
(yes/no), given the uncertain efficacy of ribavirin and/or IVIG in RSV infection and accounting
for the use of ribavirin and/or IVIG as components of SOC for RSV infection in HSCT recipients
at some sites. No stratification will be applied to the adolescent cohort, due to the expected low
number of participants in this cohort.
Blinded intervention will be used to reduce potential bias during data collection and evaluation of
clinical endpoints.
4.2.3. 
Biomarker Collection
Blood samples will be collected for exploratory biomarker analyses (host RNA and/or proteins),
on the premise that these markers may play a role in the treatment response, PK, safety of
JNJ-53718678, or the status and course of RSV-related disease. In addition, leftover bilateral


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mid-turbinate nasal swab or blood samples may be used for biomarker analysis (eg, proteins
including cytokines).
Analyses of biomarkers may be conducted at the sponsor’s discretion and reported separately from
this study.
No human deoxyribonucleic acid (DNA) analyses will be performed on these samples.
4.2.4. 
Medical Resource Utilization
Treatment of RSV disease with JNJ-53718678 may result in lower utilization of hospital or
outpatient healthcare services versus placebo; therefore, comparison will be done across
intervention groups.
4.2.5. 
Participant Input Into Design
Participants were not involved in the design of this study.
4.2.6. 
Study-Specific Ethical Design Considerations
Potential participants will be fully informed of the risks and requirements of the study and, during
the study, participants will be given any new information that may affect their decision to continue
participation. They will be told that their consent/assent 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
they would otherwise be entitled. Only participants who are fully able to understand the risks,
benefits, and potential AEs of the study, and provide their consent/assentvoluntarily will be enrolled.
The primary ethical concern is the use of placebo in this population. The rationale for using placebo
is outlined in Section 4.2.2.
Other ethical concerns are the potential burden with obtaining lower respiratory tract samples (by
bronchoscopy or inducing sputum) and the radiation exposure associated with imaging procedures
(as part of screening and to identify potential RSV LRTI, as specified in Section 9.6). However,
these assessments would be performed as part of SOC and do not expose the participant to
additional risk above that from SOC. The additional radiation exposure from the screening chest
X-ray, if not performed as SOC, is limited.
The total blood volume (maximum approximately 110 mL) to be collected is considered to be
acceptable.
4.3. 
Justification for Dose and Duration
4.3.1. 
Study Intervention Dose
Participants will be administered 250 mg JNJ-53718678 bid for 21 days (without coadministration
with moderate or strong CYP3A4 inhibitors), 125 mg bid for 21 days (when coadministered with
moderate or strong CYP3A4 inhibitors, with the exception of posaconazole), and 125 mg qd for
21 days (when coadministered with posaconazole) as oral suspension of JNJ-53718678, or the
same volume of placebo suspension. For newly enrolled participants after implementation of


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Protocol Amendment 6, study intervention will be administered as 125 mg oral film-coated tablets
or matching placebo (see Section 6.1). Please refer to Section 2.2 for details on the interaction with
CYP3A4 inhibitors and Section 6.6 for details on CYP3A4 inhibitors that are allowed but require
dose adjustment.
The initially selected JNJ-53718678 500 mg qd dosing regimen for Study 53718678RSV2005 was
based on the results of the human challenge Study 53718678RSV2001, in which target
engagement for JNJ-53718678 was demonstrated in immunocompetent adults inoculated with
RSV-A Memphis 17b.14 In Study 53718678RSV2001, exposure to JNJ-53718678 resulted in a
reduction of viral load over time in all three JNJ-53718678 dose groups (75, 200, and 500 mg qd)
as compared to the placebo group, without an apparent exposure-antiviral effect relationship. The
protein-adjusted 90% effective concentration (paEC90) of JNJ-53718678 against the RSV-A
rgRSV224 strain was calculated as 41.0 ng/mL. The doses of 75, 200, and 500 mg qd had mean
Ctrough  levels of 50, 85, and 334 ng/mL and were all above the paEC90. Since all dose regimens
were generally safe and well tolerated, the highest dose of 500 mg qd was selected for this study
to minimize the risk of development of resistance and to ensure the highest potential for antiviral
effect in the HSCT population. Doses of 500 mg qd will provide trough levels of at least 8 to
13-fold higher than paEC90 levels (mean [SD] Ctrough  levels on Day 7 of 550 [477] ng/mL and
334 [197] ng/mL, as observed in Studies 53718678RSV1001 [n 6] and 53718678RSV2001
[n 18], respectively). In addition, as a direct-acting antiviral drug, the antiviral effects of
JNJ-53718678 are projected to be independent of non-PK host factors such as immune status or
age.17 Efficacy of JNJ-53718678 in all populations is assumed to be primarily dependent on
achieving a target plasma exposure. An HSCT recipient may have deficiencies in immune-
mediated clearance of free virions and clearance of infected epithelial cells, processes not affected
by JNJ-53718678. A longer treatment duration (see Section on Study Intervention Duration) is
necessary in the HSCT population to compensate the reduced ability of their immune system to
clear infected cells.
The dose (and qd dosing)initially selected for Study 53718678RSV2005 was also evaluated as the
highest dose in Study 53718678RSV2004, in immunocompetent adults.
Population PK simulations of JNJ-53718678 in adult and pediatric participants (allometric scaling
is included in the model on clearances and distribution volumes) have demonstrated thatadolescent
exposures largely overlap with adult exposures, indicating that 500 mg qd dosing for 21 days is
appropriate for adolescents. Therefore, the dosing regimen in adolescents will be the same as the
one in adults.40
Overall, based on all available data (see also the most recent edition of the IB and any Addenda),34
it was anticipated that the initially proposed dose would be in the therapeutic range of
JNJ-53718678 for HSCT recipients, with a favorable safety profile.
However, due to exposure (Cmax)-related important potential risk of QT interval prolongation
identified from the analysis of the TQT Study 53718678RSV1009, the sponsor has performed
additional modelling to evaluate alternative dose and dosing regimens, which would allow to
maintain the plasma concentration (Ctrough) at effective levels and maintain AUC exposure while


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reducing the Cmax, to mitigate this potential risk. The updated popPK model is suitable for PK
simulations to adequately predict Cmax, AUC, and Ctrough  after single and multiple doses of
JNJ-53718678.
The physiologically-based pharmacokinetic (PBPK) model developed to assess the potential drug-
drug interactions with JNJ-53718678 as victim was updated in SimCYP V19 to investigate the
effect of concomitant administration of strong and moderate CYP3A4 inhibitors on the single-dose
and steady-state Cmax  and AUC of JNJ-53718678 following dosing (Table 4). Based on the
analyses, the use of moderate or strong CYP3A4 inhibitors has a similar effect on steady-state Cmax
(1.5-fold), albeit a different effect on steady-state AUC0 24h (up to 2-fold for moderate CYP3A4
inhibitors and up to 3-fold for strong CYP3A4 inhibitors).
Table 4: 
Simulated Effect of Concomitant CYP3A4 Inhibitors on JNJ-8678 PK Parameters
PK Parameter 
Strong CYP3A4 Inhibitorsa 
Moderate CYP3A4 Inhibitorsb 
Cmax  single dose 
1.5-fold 
1.5-fold
AUC24h  single dose 
3-fold 
2-fold
Cmax  multiple doses 
1.5-fold 
1.5-fold
AUC24h  multiple doses 
2.5-fold 
2-fold
PK: pharmacokinetic, CYP: cytochrome P450, AUC0-24h  = area under the plasma concentration-time curve from
time of administration up to 24 hours postdose, Cmax: maximum plasma concentration.
Note: The effect of strong inhibitors on AUC single dose and AUC multiple dose was also evaluated as 3.5-fold.
(Based on single-dose PK results of Study 53718678RSV1006. In this scenario, the effect of CYP3A4 induction on
comedication is excluded).
a Based on itraconazole simulations.
b Based on eg diltiazem simulations.
Simulations were conducted using the popPK model, the effect of comedication and the ΔΔQTcI
in the model (taking into account variance-covariance matrix of the drug-effect slope, plasma
effect site equilibration rate constant [Ke0] and intercept) with 1,000 virtual adult participants
re-sampled from the 53718678RSV2004 data. The summary statistics of the simulation are
presented in Table 5.


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Table 5: 
Predicted Geometric Mean AUC0-24h, Cmax, Ctrough and ΔΔQTcI After Day1 and Day 7
PK Parameters 
250 mg bid 
125 mg bid + moderate 
CYP3A4 inhibitorsa 
125 mg bid + strong
CYP3A4 inhibitors
AUC0-24h  Day 1 (ng.hr/mL) 
24,700 
23,300 
35,000a/40,800b
AUC0-24h  Day 7 (ng.hr/mL) 
40,700 
35,800 
44,800a/62,700b
Cmax  Day 1 (ng/mL) 
1,950 
1,430 
1,430
Cmax  Day 7 (ng/mL) 
2,560 
1,780 
1,780
Ctrough  Day 1 (ng/mL) 
710 
623 
935
Ctrough  Day 7 (ng/mL) 
1,070 
881 
1,100
ΔΔQTcI Day 1 (ms) (90%CI) 
2.98 (1.69-5.06) 
2.66 (1.49-4.53) 
2.66 (1.49-4.53)
ΔΔQTcI Day 7 (ms) (90%CI) 
4.12 (2.10-7.66) 
2.95 (1.48-5.61) 
2.95 (1.48-5.61)
∆∆QTcI: placebo-corrected change from baseline for the individual-corrected QTc, AUC0-24h: AUC from time of
administration up to 24 hours post dosing, bid: twice daily, CI: confidence interval, Cmax: maximum plasma
concentration, Ctrough: predose plasma concentration, CYP: cytochrome P450, PBPK: physiologically-based
pharmacokinetic(s), PK: pharmacokinetic(s).
a. Based on PBPK modeling.
b. Based on single dose PK results of 53718678RSV1006.
In Study 53718678RSV1001, the 250 mg bid regimen provided Ctrough  levels that are somewhat
higher than those observed with the 500 mg qd regimen (mean [SD] Ctrough  levels on Day 7 of
550 [477] ng/mL and 643 [126] ng/mL [n 6] for 500 mg qd and 250 mg bid, respectively). The
dose regimen of 250 mg bid provides similar exposure levels (AUC0 24h), higher Ctrough levels and
lower Cmax  levels compared to the 500 mg qd regimen, which should translate to at least similar
efficacy of JNJ-53718678 as well as maintain the favorable safety profile.
Based on final PK, QTc, and PBPK modeling (for interaction with moderate and strong CYP3A4
inhibitors), a 21-day dosing regimen of 250 mg bid is selected. The dose is to be reduced to
125 mg bid when patients are coadministered or may require initiation of moderate or strong
CYP3A4 inhibitors, including macrolide antibiotics and antifungals, which are important in the
population with high risk of RSV disease progression and complications. The upper limit of the
90% CI for ΔΔQTcI for the bid regimen in combination with moderate or strong CYP3A4
inhibitors remains below 10 ms for each of the groups (Table 5).
Overall, based on all currently available data, it is anticipated that the selected bid dosing of
JNJ-53718678 will be in the therapeutic range for adults, ensuring the highest potential antiviral
effect while minimizing the risk of development of resistance (resulting from increasing Ctrough
[mean Ctrough  will exceed more than 10 times the paEC90 of 41 ng/mL]), as well as mitigating the
potential risk of QT interval prolongation (by decreasing Cmax).
Based on PBPK analyses, the exposure at steady state of JNJ-53718678 after 250 mg
JNJ-53718678 bid dosing without concomittant use of CYP3A4 inhibitors is similar to 125 mg
once daily dosing with coadministration of posaconazole (400 mg bid) and similar to 125 mg
JNJ-53718678 bid dosing with co-administration of voriconazole (200 mg bid), or clarithromycin
(500 mg bid) or itraconazole (200 mg qd).


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4.3.2. 
Study Intervention Duration
In immunocompetent adult and pediatric participants, a treatment duration of 7 days is used, as
specified in Studies 53718678RSV2004, 53718678RSV2001, 53718678RSV1005, and
53718678RSV2002.13,14,15,16 Because of the prolonged viral shedding3,26 observed in HSCT
recipients, the treatment duration will be 21 days in Study 53718678RSV2005. This is consistent
with the presatovir URTI study (NCT02254408),8 where an every 4-day dosing regimen for 5 total
doses ensured adequate plasma levels for 21 days.
Currently, there are no clinical data available from a 21-day treatment with JNJ-53718678. This
duration, however, is considered to be safe because:
 
In Study 53718678RSV1002,12 in which a dosing duration of 13 days was evaluated, steady
state conditions were generally achieved at 8 days of dosing. This 13-day dosing regimen
(500 mg qd) was generally safe and well tolerated.
 
In Study 53718678RSV1001,11 there was no accumulation of JNJ-53718678 observed in
immunocompetent adult participants at 1 week of dosing. The anticipated exposure in
Study 53718678RSV2005 with 500 mg qd is expected to be similar for HSCT recipients as
has been observed in immunocompetent participants.
 
A duration of 21 days of repeated dosing in patients is supported by 1-month repeat-dose good
laboratory practice toxicology studies in adult rats and minipigs. Repeated dosing for 1 month
in rats resulted in a No Observed Adverse Effect Level (NOAEL) of 75 mg/kg/day, associated
with a mean (SD) maximum plasma concentration  (Cmax) of 3,240 (338)ng/mL and
9,240 (477)ng/mL in male and female rats, respectively, and a mean (SD) AUC24h  of
11,600 (849) ng.h/mL and 52,600 (990)ng.h/mL in male and female rats, respectively. In
minipigs, repeated dosing for 1 month did not result in any treatment related effect (No
Observed Effect Level [NOEL]) at 10 mg/kg/day, associated with a mean (SD) Cmax of 1,510
(440) ng/mL and 1,750 (440)ng/mL in male and female minipigs, respectively, and a mean
(SD) AUC24h  of 21,200 (870) ng.h/mL and 31,500 (8,350)ng.h/mL in male and female
minipigs, respectively. Detailed results of the studies can be found in the most recent edition
of the IB and any Addenda.34 These NOAEL and NOEL exposures are in the same range as
the values that were achieved with 500 mg qd in Study 53718678RSV100111 (mean [SD]
Cmax: 2,655 [591] ng/mL and mean [SD] AUC24h: 31,165 [12,686] ng.h/mL).
 
The IDMC will perform the first unblinded safety review prior to (should a safety signal
warrant) or after the 18th patient has completed the Day 28 assessments (or discontinued
earlier)to assure an early evaluation of the treatment duration.
4.4. 
End of Study Definition
End of Study Definition
The end of study is considered as the last visit (phone visit or on-site visit) for the last participant
in the study. The final data from the study site will be sent to the sponsor (or designee) after
completion of the final participant visit at that study site, in the time frame specified in the Clinical
Trial Agreement.


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Study Completion Definition
A participant will be considered to have completed the study if he or she has completed the 1 year
follow-up visit.
Participants who prematurely discontinue study intervention for any reason before completion of
the double-blind phase (Day 21)will not be considered to have completed the treatment period.
5. 
STUDY POPULATION
The inclusion and exclusion criteria for enrolling participants in this study are described below. If
there is a question about these criteria, the investigator must consult with the appropriate sponsor
representative and resolve any issues before enrolling a participant in the study. Waivers are not
allowed.
Repeat testing, once for laboratory results and once for ECG results, is allowed for individuals
who do not meet the criteria for participation in this study
5.1. 
Inclusion Criteria
Each potential participant must satisfy all of the following criteria to be enrolled in the study:
1. 
Male or female (according to their reproductive organs and functions assigned by
chromosomal complement).
2. 
18 to 75 years of age, inclusive. Subjects ≥13 and <18 years of age may be enrolled in
selected countries and study sites consistent with local regulations.
3. 
Received an autologous or allogeneic HSCT using any conditioning regimen.
4. 
ALC <1,000 cells/µL. The local assessment confirming ALC <1,000 cells/µL should be
performed no more than 48 hours prior to randomization.
5. 
The participant has been diagnosed with RSV infection using a rapid PCR- or other
molecular-based diagnostic assay performed on a bilateral mid-turbinate nasal swab
sample as part of the study-specific screening assessment or on an upper respiratory tract
sample as part of SOC testing.
Note: Results from upper respiratory tract samples collected per local SOC testing within
24 hours prior to start of Screening may also be used for determining study eligibility.
The SOC sample used for RSV diagnosis should have been collected no more than
48 hours prior to randomization.
6. 
New onset of at least 1 of the following respiratory symptoms within 4 days prior to the
anticipated start of dosing (Day 1): nasal congestion, rhinorrhea, cough or pharyngitis
(sore throat), and/or worsening of one of these chronic (associated with previously


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existing diagnosis, eg, chronic rhinorrhea, seasonal allergies, chronic lung disease)
respiratory symptoms within 4 days prior to the anticipated start of dosing (Day 1).
7. 
SpO2 ≥92% on room air.
8. 
No evidence of new abnormalities consistent with LRTI on a chest X-ray relative to the
most recent chest X-ray, as determined by the local radiologist (preferentially) or the
investigator. A chest X-ray  should be performed no more than 48 hours prior to
randomization. If a chest X-ray has not been obtained as part of SOC, it must be obtained
during Screening.
9. 
Willingness to complete necessary study procedures
10. 
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 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.
11. 
Must sign an ICF/assent form indicating that he or she understands the purpose of, and
procedures required for, the study and is willing to participate in the study.
Note: Prior to signing the main consent/assent form for the study, the participant may
specifically allow for the collection and testing of a bilateral mid-turbinate nasal swab
sample by signing the pre-Screening (diagnostic) ICF/assent form. This is not required if
an upper respiratory sample is collected for diagnostic testing per local SOC.
12. 
Criterion modified per Amendment 2.
12.1 
A woman must be (as defined in Appendix 10.5, Contraceptive and Barrier Guidance and
Collection of Pregnancy Information)
a. Not of childbearing potential
b. Of childbearing potential and
o 
Practicing a highly effective, preferably user-independent method of
contraception (failure rate of <1% per year when used consistently and
correctly) and agrees to remain on a highly effective method while receiving
study intervention and until 30 days after last dose - the end of relevant
systemic exposure. Examples of highly effective methods of contraception
are located in  Appendix 10.5. Contraceptive and Barrier Guidance and
Collection of Pregnancy Information.
o 
Have a negative highly sensitive serum (-human chorionic gonadotropin)
local pregnancy test at Screening.


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13. 
A woman must agree not to donate eggs (ova, oocytes) for the purposes of assisted
reproduction during the study and for a period of 30 days after the last dose of study
intervention.
14 
Criterion modified per Amendment 2.
14.1 
From Day 1 during the study and for 90 days after receiving the last dose of study drug,
a male participant must wear a condom when engaging in any activity that allows for
passage of ejaculate to another person throughout the study. Male participants should also
be advised of the benefit for a female partner to use a highly effective method of
contraception as a condom may break or leak.
15. 
A male participant must agree not to donate sperm for the purpose of reproduction during
the study and for a minimum of 90 days after receiving the last dose of study intervention.
16. 
Willing and able to adhere to the lifestyle restrictions specified in this protocol.
17. 
Must have been assessed per local public health practice and considered not to have
SARS-CoV-2 infection during this respiratory infection.
5.2. 
Exclusion Criteria
Any potential participant who meets any of the following criteria will be excluded from
participating in the study:
1. 
Admitted to the hospital primarily for a lower respiratory tract disease of any cause as
determined by the investigator.
2. 
Requires supplemental oxygen  at Screening or any time between Screening and
randomization.
3. 
History of or concurrent illness that in the opinion of the investigator might confound
the results of the study or pose an additional risk in administering study intervention to
the participant or that could prevent, limit, or confound the protocol-specified
assessments.
4. 
Documented to be positive for other respiratory viruses (limited to influenza,
parainfluenza, human rhinovirus, adenovirus, human metapneumovirus, or
coronavirus) within 7 days prior to or at the Screening visit, if determined by local SOC
testing (additional testing is not required).
5. 
Clinically significant bacteremia or fungemia within 7 days prior to or at Screening that
has not been adequately treated, as determined by the investigator.


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6. 
Bacterial, fungal, or viral pneumonia within 2 weeks prior to Screening that has not
been adequately treated, as determined by the investigator.
7. 
Known history of HIV/AIDS with a CD4+-cell count <200 cells/µL within the last
month.
8. 
Known allergies, hypersensitivity, or intolerance to JNJ-53718678 or its excipients
(refer to Investigator's Brochure).
9. 
Had major surgery (other than HSCT) within 28 days prior to randomization or has
planned major surgery through the course of the study.
10. 
Has known aspartate aminotransferase (AST)/alanine aminotransferase (ALT) >3x
upper limit of normal within the 4 weeks prior to Screening.
11. 
Has known or suspected clinically active chronic or acute hepatitis B or C infection.
12. 
Criterion modified per Amendment 1.
12.1 
Current or planned participation in another clinical study where study intervention is
being administered while participating in the current study. Note: Concurrent
enrollment is allowed during the follow-up phase of the other clinical study or in case
the study intervention in the other clinical study is a marketed product already approved
for another indication, and taking into account the restrictions as specified in
Section 6.6.
13. 
Unwilling to undergo bilateral mid-turbinate nasal swab procedures or with any
physical nasal abnormality, which limits the ability to collect regular nasal specimens.
14. 
Criterion modified per Amendment 6.
14.1 
Unable to take medications orally or with a known gastrointestinal-related condition
that is considered by the sponsor or investigator to be likely to interfere with study
intervention  ingestion or absorption. Note: During hospitalization, the drug (oral
suspension or oral film-coated tablets dispersed in water) can be administered through
a nasogastric tube, if already in place.
15. 
Has taken any disallowed therapies as noted in Section 6.6, Concomitant Therapy
before the planned first dose of study intervention.
16. 
Criterion modified per Amendment 1.
16.1 
Received an  investigational RSV vaccine at any time prior to the study or used an
invasive investigational medical device within 30 days prior to the study.


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17. 
Plans to father a child while enrolled in this study or within 90 days after the last dose
of study intervention.
18. 
Criterion modified per Amendment 3.
18.1 
Confirmed QTcF interval >450 milliseconds per the machine read parameter result at
Screening. Presence of an abnormal QTcF interval should be confirmed by repeat ECG
recording during Screening.
19. 
Criterion modified per Amendment 3.
19.1 
Criterion modified per Amendment 5.
19.2 
Clinically significant abnormal ECG findings (other than QTcF interval
>450 milliseconds, see exclusion criterion 18) not consistent with the underlying
condition in the study population, as judged by the investigator based on the machine
read ECG results at Screening.
20. 
Employee of the sponsor, investigator or study site, with direct involvement in the
proposed study or other studies under the direction of that investigator or study site, as
well as direct family members of the employees or the investigator.
21. 
Has evidence of one of the following ECG abnormalities per the machine read ECG
results at Screening confirmed by repeat ECG recording:
 
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
22. 
Criterion combined with exclusion criterion 19 per Amendment 5.
23. 
Has had ANY of:
a) Confirmed SARS-CoV-2 infection (test positive) during the four weeks prior to
randomization, OR
b) Close contact with a person with COVID-19 (test confirmed or suspected
SARS-CoV-2 infection) within 14 days prior to randomization.
24. 
Has a personal orfirst- or second-degree family history of long QT syndrome or sudden
cardiac death.
25. 
Has a ≥Grade 3 laboratory abnormality of hypokalemia of <2.5 mEq/L and/or
hypomagnesemia of <0.9 mEq/L at Screening (or 4 days prior to Screening). If the
Grade 3 laboratory abnormality is not confirmed (repeat local test during Screening),
the participant may be enrolled.


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NOTE: Investigators should ensure that all study enrollment criteria 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 intervention is given
such that he or she no longer meets all eligibility criteria, then the participant should be excluded
from participation in the study. Section 5.4, Screen Failures, describes options for retesting. The
required source documentation to support meeting the enrollment criteria are noted in
Appendix 10.3, Regulatory, Ethical, and Study Oversight Considerations.
5.3. 
Lifestyle Considerations
Potential participants must be willing and able to adhere to the following lifestyle restrictions
during the course of the study to be eligible for participation:
1. 
Agree to follow all requirements that must be met during the study as noted in the
Inclusion and Exclusion Criteria (eg, contraceptive requirements).
2. 
Agree to the daily  completion of the electronic patient-reported outcomes (ePRO)
measures (RiiQ, PGI)and the completion of the other ePRO measures per Schedules of
Activities.
3. 
Concurrent administration of authorized medications or prophylactic vaccines/use of
licensed devices is allowed as supportive therapy or as prophylaxis per local SOC and
package inserts, as long as the medication/vaccine/device will not affect the
participant’s participation in the study and is in accordance with allowed concomitant
therapy (see Section 6.6). Also, an investigational drug from another clinical study is
allowed in case it is a marketed product, ie, approved for another indication.
Refer to Section 6.6 for details regarding prohibited and restricted therapy during the
study.
5.4. 
Screen Failures
Participant Identification, Enrollment, and Screening Logs
The investigator agrees to complete a participant identification and enrollment log to permit easy
identification of each participant during and after the study. This document will be reviewed by
the sponsor study-site contact for completeness.
The participant identification and enrollment log will be treated as confidential and will be filed
by the investigator in the study file. To ensure participant confidentiality, no copy will be made.
All reports and communications relating to the study will identify participants by participant
identification and age at initial informed consent/assent.
Individuals who do not meet the criteria for participation in this study (screen failure) may be
rescreened if they experience a new URTI episode. Rescreened participants should be assigned a
new participant number as for the initial screening.


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6. 
STUDY INTERVENTION
6.1. 
Study Intervention(s) Administered
Eligible participants will be randomized 2:1 (active:placebo) within each cohort to receive either
JNJ-53718678 or placebo for 21 days. Participants will be administered 250 mg JNJ-53718678
bid for 21 days (without coadministration with moderate or strong CYP3A4 inhibitors), 125 mg
bid for 21 days (when coadministered with moderate or strong CYP3A4 inhibitors, with the
exception of posaconazole), and 125 mg qd for 21 days (when coadministered with posaconazole)
as oral suspension of JNJ-53718678, or the same volume of placebo suspension. For newly
enrolled participants after implementation of Protocol Amendment 6, study intervention will be
administered as 125 mg oral film-coated tablets or matching placebo (see Table 6 and Section 6.5).
Please refer to Section 2.2 for details on the interaction with CYP3A4 inhibitors and Section 6.6
for details on CYP3A4 inhibitors that are allowed and coadministration with posaconazole.
Table 6: 
Treatment Overview
Treatment 
Dosing Regimen  
Formulationd
A 
250 mg JNJ-53718678a twice daily for 21 days 
without coadministration with moderate or strong 
CYP3A4 inhibitors
12.5 mL oral suspensionb of JNJ-53718678
or 2 eq. 125 mg oral film-coated tabletsc
A 
125 mg JNJ-53718678a twice daily for 21 days if 
coadministration with moderate or strong CYP3A4 
inhibitors, with the exception of posaconazole
6.25 mL oral suspensionb of JNJ-53718678
or 1 eq. 125 mg oral film-coated tabletc
A 
125 mg JNJ-53718678a once daily for 21 days if 
coadministration with posaconazole 
6.25 mL oral suspensionb of JNJ-53718678
or 1 eq. 125 mg oral film-coated tabletc
B 
Matching placebo twice daily for 21 days 
12.5 mL matching placebo suspension
or 2 matching oral placebo tablets
B 
Matching placebo twice daily for 21 days 
6.25 mL matching placebo suspension
or 1 matching oral placebo tablet
B 
Matching placebo once daily for 21 days 
6.25 mL matching placebo suspension
or 1 matching oral placebo tablet
a. Doses are provided for JNJ-53718678-AAA.
b. JNJ-53718678 is dosed as an oral suspension containing 23 mg/mL JNJ-53718678-ZCL, the hemi-
tartrate salt of JNJ-53718678-AAA, which is equivalent to 20 mg/mL JNJ-53718678-AAA.
c. For newly enrolled participants after implementation of Protocol Amendment 6, the drug product is
administered as eq. 125 mg oral film-coated tablets (containing 143.75 mg of JNJ-53718678-ZCL, the
hemi tartrate of JNJ-53718678-AAA). Note that the tablet may also be dispersed in water before
administration through a nasogastric tube, if applicable.
d. A participant receiving oral suspension must complete the study with the same formulation.
Study intervention administration should start as soon as possible, but no later than 4 hours after
randomization and within 4 days after symptom onset of RSV URTI. For analysis purposes, the
day of first study intervention intake will be considered Day 1.
Study intervention will be administered orally. Dosing should preferably occur approximately at
the same time each day (for the qd dosing and for the AM and PM dosing of the bid regimen).
For participants on bid dosing, dosing should occur approximately 12 hours apart. For participants
who receive the first dose ofstudy intervention PM of Day 1, dosing should continue through the
morning (ie, AM) of Day 22 so that all participants receive 42 consecutive bid doses in total.
Administration of the second bid dose may be delayed or brought forward (by maximum 4 hours)


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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.
Participants on a 125 mg qd regimen coadministered with posaconazole will receive
21 consecutive doses in total.
The study intervention can be administered with or without food. During hospitalization, the drug
(oral suspension or oral film-coated tablets dispersed in water)can also be administered through a
nasogastric tube, if already in place.
The first dose of study intervention will be administered at the study site on Day 1; date and time
of dosing study intervention must be captured in the source documents and the electronic case
report form (eCRF). Other dosing dates will be captured in the eCRF on study visit days. Study-
site personnel will instruct participants on how to store study intervention for at-home use as
indicated for this protocol and how to withdraw the appropriate volume from the vial. For newly
enrolled participants after implementation of Protocol Amendment 6, study intervention will be
supplied as oral film-coated tablets in bottles. Each bottle contains a sufficient number of tablets
to cover study intervention for at least 7 days. During (re)hospitalization, study intervention will
be administered by the study-site personnel. At home, or when the rehospitalization occurs at a
non-study site, study intervention will be administered by the participant or their caregiver.
JNJ-53718678 and matching placebo will be manufactured and provided under the responsibility
of the sponsor.
For a definition of study intervention overdose, refer to Section 8.5, Treatment of Overdose.
6.2. 
Preparation/Handling/Storage/Accountability
Preparation/Handling/Storage
Oral Suspension
The drug product is supplied as a 1,988-mg/bottle powder and solvent for oral suspension (G007
and G005, respectively). The powder (which consist of API only) 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 4,940-mg/bottle microcrystalline cellulose powder and
solvent for oral suspension (G008 and G003, respectively). The placebo powder will be
reconstituted with the solvent to obtain a placebo oral suspension.
For a list of excipients for the solvents for oral suspension, refer to the most recent edition of the
IB and any Addenda for JNJ-53718678.34
Suspended study intervention  will be provided to participants in vials, from which a defined
volume is to be withdrawn (see Table 6). Each vial contains study intervention for at least a 3-day


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dosing period. All study intervention should be stored on site and at home as instructed on the
label.
Refer to the pharmacy manual/study site Investigational Product Preparation Instruction (IPPI) for
additional guidance on study intervention preparation, handling, and storage.
Oral Film-coated Tablets (After Implementation of Protocol Amendment 6)
The drug product is supplied as eq. 125 mg oral film-coated tablets (G033; containing 143.75 mg
of JNJ-53718678-ZCL, the hemi tartrate of JNJ-53718678-AAA, equivalent to 125 mg
JNJ-53718678-AAA, the free from drug substance) or matching oral placebo film-coated tablets
(G037).
For a list of excipients of the tablet, refer to the most recent edition of the IB and any addenda for
JNJ-53718678.34
JNJ-53718678 oral film-coated tablets will be manufactured and provided under the responsibility
of the sponsor.
Study intervention will be provided to participants in bottles. Each bottle contains a sufficient
number of tablets to cover study intervention for at least 7 days.
The tablet may also be dispersed in water before administration through a nasogastric tube, if
applicable. Refer to the pharmacy manual/study site IPPI for additional guidance on study
intervention preparation and handling in case of administration through nasogastric tube.
Accountability
The investigator is responsible for ensuring that all study intervention received at the site is
inventoried and accounted for throughout the study. The dispensing of study intervention to the
participant, and the return of study intervention from the participant (if applicable), must be
documented on the intervention accountability form. Participants must be instructed to return all
original containers, whether empty or containing study intervention. The study intervention
dispensedto the participant must be documented on the intervention accountability form. All study
intervention will be stored and disposed of according to the sponsor's instructions. Study-site
personnel must not combine contents of the study intervention containers.
At the study site, study intervention must be handled in strict accordance with the protocol and the
container label, and must be stored in a limited-access area or in a locked cabinet under appropriate
environmental conditions. Unused study intervention, and study intervention 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 intervention, or used returned study
intervention for destruction, will be documented on the intervention return form. When the study
site is an authorized destruction unit and study intervention supplies are destroyed on-site, this
must also be documented on the intervention return form.


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Study intervention should be dispensed under the supervision of the investigator or a qualified
member of the study-site personnel, or by a hospital/clinic pharmacist. Study intervention will be
supplied only to participants participating in the study. Returned study intervention must not be
dispensed again, even  to the same participant. Study intervention may not be relabeled or
reassigned for use by other participants. The investigator agrees neither to dispense the study
intervention from, nor store it at, any site other than the study sites agreed upon with the sponsor.
Further guidance and information for the final disposition of unused study interventions are
provided in the Study Reference Manual.
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 interventions (Treatments A and B; 2:1 [active: placebo] randomization)groups based on
a computer-generated randomization schedule prepared before the study by or under the
supervision of the sponsor. In the adult cohort, the randomization will be balanced by using
randomly permuted blocks and will be stratified by hospitalization status (yes/no) at the time of
randomization, lymphopenia (<200 cells/µL, 200 - <500 cells/µL, and ≥500 - <1,000 cells/µL) at
Screening, and ribavirin and/or IVIG use (yes/no) at the time of randomization. No stratification
will be applied to the adolescent cohort.
Participants with an ALC <500 cells/µL at Screeningshould account for at least 50% of all enrolled
participants in the adult cohort and participants with an ALC <200 cells/µL at Screening should
account for at least 25% of all enrolled participants in the adult cohort, also at the time of the
interim analysis. To ensure the prespecified distribution in the strata, enrollment in the stratum
ALC >500 cell/µL or 200 - <500 cells/µL may be paused prior to the interim analysis and closed
prior to the final analysis (see Section 9.3).
The interactive web response system (IWRS) will assign a unique intervention code, which will
dictate the intervention assignment and matching study intervention kits for the participant. The
requestor must use his or her own user identification and personal identification number when
contacting the IWRS.
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.
In general, randomization codes will be disclosed fully only if the study is completed and the
clinical database is closed. However, if an interim analysis is specified, the randomization codes
and, if required, the translation of randomization codes into intervention and control groups will
be disclosed to those authorized and only for those participants included in the interim analysis
(see Section 9.4.10).


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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 intervention by contacting the IWRS. While the responsibility to break the
intervention code in emergency situations resides solely with the investigator, it is suggested 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 and reason for the unblinding must be documented in the appropriate
section of the eCRF. The documentation received from the IWRS indicating the code break must
be retained with the participant's source documents in a secure manner.
6.4. 
Study Intervention Compliance
The study intervention will be administered orally. During hospitalization, study intervention will
be administered by the study-site personnel. The study intervention (oral suspension or oral film-
coated tablets dispersed in water) can also be administered through a nasogastric tube, if already
in place.
Outpatients will receive instructions on compliance with study intervention administration. In case
of(re)hospitalization during the study, this instruction will be repeated at the time of discharge, if
applicable. During the course of the study, the investigator or designated study-site personnel will
be responsible for providing additional instruction to re-educate any participant who is not
compliant with taking in the study intervention.
If participants are (re)hospitalized due to worsening of RSV disease during the treatment period,
administration of study intervention should continue.
If the participant vomited shortly after intake of study intervention, the participant should not be
re-dosed for that administration timepoint.
In case a dose was missed, the dose should be given as soon as possible, but:
 
For bid dosing: within 6 hours after the scheduled time. If more than 6 hours have elapsed,
the dose should be skipped, and the next dose should be given at the next scheduled timepoint
per the initial dosing schedule.
 
For qd dosing: within 12 hours after the scheduled time. If more than 12 hours have elapsed,
the dose should be skipped, and the next dose should be given at the next scheduled timepoint
per the initial dosing schedule.
6.5. 
Dose Modification
In case comedication of the class of strong or moderate CYP3A4 inhibitors is started or continued
during study intervention treatment, the dose needs to be adjusted to 125 mg bid unless
comedication of posaconazole is started or continued in which case further dose adjustment to
125 mg qd is needed (see Sections 4.3.1, 6.1, 6.5, and 6.6). When this comedication is stopped
during the study intervention administration period, study intervention dosing must be resumed at


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the 250 mg bid regimen. See Section 8.4.7.2 for the required cardiac safety monitoring in such
cases.
6.6. 
Concomitant Therapy
Concomitant medications, except those listed below, are allowed during this study. All
concomitant medications and supportive therapy (prescription or over-the-counter medications,
including vaccines, vitamins, herbal supplements, or physiotherapy) different from the study
intervention must be recorded in the eCRF, from the date the main study ICF is signed through to
the end-of-study visit. Recorded information will include a description of the type of the
drug/therapy, treatment duration (dates of treatment start and stop), dose regimen, route of
administration, and its indication. 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.
Modification of an  effective pre-existing chronic therapy should not be made for the explicit
purpose of entering a participant into the study.
Immunosuppressants (IS) and other therapy for the treatment of the HSCT status of the participant
should be continued, taking into account the respective package inserts. As JNJ-53718678 is a
weak inducer and a weak inhibitor of CYP3A4, there is a potential for interaction between
JNJ-53718678 and IS drugs that are CYP3A4 substrates (eg, sirolimus, cyclosporine, and
tacrolimus), similar to the time-dependent effects observed with midazolam (see Section 2.2). It is
recommended that therapeutic drug monitoring of such IS is performed to assure adequate
immunosuppressant exposures and to allow for IS dose adjustments. In case therapeutic drug
monitoring is performed as part of SOC or per protocol instruction, the measured IS exposures are
to be captured in the eCRF.
Participants can receive medications such as acetaminophen/paracetamol, non-steroidal
anti-inflammatory drugs, or antihistamines, taking into account their respective package insert, at
the investigator’s discretion. In case antipyretics are used, body temperature should be measured
immediately before or >4 hours after giving antipyretics.
Fexofenadine is allowed, taking into account its package insert and dosing instructions, 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.29,31
Prescription medications intended to treat the symptoms/sequelae of the RSV infection are
permitted, including:
 
inhaled β-agonists or anticholinergics
 
oral/intravenous/intramuscular antibiotics such as β-lactams
Note: The temporary use of over-the-counter medications in the 14 days prior to randomization is
permitted. The use of vitamins and mineral supplements is also permitted.


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The use of ribavirin and IVIG is allowed during the study if considered SOC for the HSCT
recipient population per local guidelines.
As side effects due to seasonal (eg, influenza) or other routine (eg, pneumococcal) vaccination, as
well as due to COVID-19 vaccination (locally-approved [including emergency use-authorized]
vaccines) may impact the evaluation of clinical evolution of RSV symptoms, it is recommended
that administration of these prophylactic vaccines be timed to occur after study completion or at
least 1 week after the last dose of study medication  (study Day 28). Investigator discretion,
considering the vaccine package insert and local clinical practice guidelines, including postponing
the vaccination for participant suffering from acute infection  or febrile illness, and overall
assessment of clinical stability will be relied on if there is a medical need to administer vaccine to
a participant during the study period. Study intervention  administration as well as visits and
assessments can continue as scheduled.
The following medications are not permitted from Screening through 3 days after the last dose of
JNJ-53718678 and for the time period prior to Screening as noted:
 
herbal supplements with active metabolic enzyme inducing components (eg, St. John’s Wort)
within 21 days or breast cancer resistance protein (BCRP, a transporter protein) inhibiting
components (eg, curcumin) within 2 days prior to randomization. This does not apply to herbal
teas, herbal supplements without confirmed strong CYP3A4 inhibitory/inductive activity,
and/or homeopathy.
 
palivizumab, within 5 half-lives (approximately 100 days) prior to screening.
 
any investigational RSV vaccine at any time prior to the study or an invasive investigational
medical device within 30 days before the planned first dose of study intervention.
 
any other study intervention, unless if the study intervention in another clinical study is a
marketed product already approved for another indication. Note: Concurrent enrollment is
allowed during the follow-up phase of another clinical study.
 
prescription medications that are known to be strong inducers of CYP3A4 such as, but not
limited to, carbamazepine, enzalutamide, mitotane, phenobarbital, phenytoin, rifampicin.
Note: moderate inducers such as bosentan, efavirenz, etravirine, glucocorticoids, and
modafinil are allowed.
 
prescription medications that are known to be BCRP inhibitors including eltrombopag,
fostamatinib, rolapitant, and teriflunomide within 5 times their respective half-lives prior to
randomization.
 
prescription medications with a known risk to prolong the QT interval (eg, azithromycin, see
Table 7). Note: these medications can be continued if the participant is already on a stable
therapy prior to screening and if the QT interval meets the eligibility criteria.


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The sponsor must be notified in advance (or as soon as possible thereafter) of any instances in
which prohibited therapies are administered.
 
Prescription medications which are known to be a moderate or strong inhibitor of
CYP3A4 enzymes as listed in Table 7 are allowed with dose reduction. If several
medications for the same indication are available and can be used interchangeably, it is
recommended to administer the drug with the least CYP3A4 inhibitory potency.30.
Note: in case of doubts about the CYP3A4 enzymes inhibitory or inducing capacity, it is
recommended to contact the sponsor.


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Table 7: 
Examples of Commonly Used Medications With CYP3A4 Inhibiting and/or QT Prolonging Effects Which are Disallowed or Allowed Upon
Coadministration with JNJ-53718678f
Drug Class 
CYP3A4 Inhibitors 
Allowed with 
JNJ-53718678 Dose 
Reductiona 
QT Prolonging Drugs 
Allowed with Restrictionsb 
CYP3A4 Inhibitors 
+ QT Prolonging Drugs 
Allowed with 
JNJ-53718678 Dose 
Reduction and 
Restrictionsc
CYP3A4 Inhibitors 
+ QT Prolonging Drugs 
Allowed with 
JNJ-53718678 Dose 
Reductiond
CYP3A4
Inhibitors/Inducers
+/- QT Prolonging Drugs
Disallowede
Antifungals 
itraconazole, 
isavuconazole,
ravuconazole
pentamidine 
fluconazole, voriconazole 
posaconazole 
ketoconazole
Macrolide 
antibiotics 
troleandomycin  
azithromycin  
clarithromycin,
erythromycin
Ketolide antibiotics 
telithromycin
Fluoroquinolones 
levofloxacin, moxifloxacin  
ciprofloxacin,
Antidepressants 
nefazodone
Calcium channel 
blocker
verapamil
Immunomodulators 
cyclosporine
Anti-arrhythmics 
disopyramide, 
procainamide, quinidine, 
sotalol 
amiodarone, flecainide,
mexiletine, propafenone,
systemic lidocaine
Antipsychotics 
haloperidol, thioridazine,
ziprasidone
Antidepressants 
citalopram, escitalopram
Antiemetics 
dolasetron, droperidol,
granisetron, ondansetron
Antihistamines 
astemizole, terfenadine
Gastrointestinal/ 
gastroesophageal
reflux disease
drugs
cisapride


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Table 7: 
Examples of Commonly Used Medications With CYP3A4 Inhibiting and/or QT Prolonging Effects Which are Disallowed or Allowed Upon
Coadministration with JNJ-53718678f
Drug Class 
CYP3A4 Inhibitors 
Allowed with 
JNJ-53718678 Dose 
Reductiona 
QT Prolonging Drugs 
Allowed with Restrictionsb 
CYP3A4 Inhibitors 
+ QT Prolonging Drugs 
Allowed with 
JNJ-53718678 Dose 
Reduction and 
Restrictionsc
CYP3A4 Inhibitors 
+ QT Prolonging Drugs 
Allowed with 
JNJ-53718678 Dose 
Reductiond
CYP3A4
Inhibitors/Inducers
+/- QT Prolonging Drugs
Disallowede
This list is not exhaustive. Investigators must consult with the sponsor for any additions or updates to this list. For medications with a known risk to prolong the QT
interval investigators are referred to the complete list available at https://www.crediblemeds.org/pdftemp/pdf/CombinedList.pdf. Investigators must check regularly for
any additions or updates to this list.
a. 
Dose reduction of JNJ-53718678 required in case ofcomedication of JNJ-53718678 with strong or moderate CYP3A4 inhibitors (see Sections 6.1 and 6.5).
b. Medications with a known risk to prolong the QT interval can be continued if the participant is already on a stable therapy prior to screening and if the QT interval
meets the eligibility criteria, however, the use of these medications cannot be initiated at screening and/or during the study intervention treatment period.
c. Medications with CYP3A4 inhibitory effects in addition to QT  interval prolonging effects are allowed if the participant is already on a stable therapy prior to
screening and if the QT interval meets the eligibility criteria, but this requires dose adjustment of JNJ-53718678 (see Sections 6.1 and 6.5). These medications can
also be started during the treatment intervention period with additional cardiac safety monitoring (see Section 8.4.7.2).
d. Posaconazole is allowed if the participant is already on a stable therapy prior to screening and if the QT interval meets the eligibility criteria, but this requires dose
adjustment of JNJ-53718678 (see Sections 6.1 and 6.5). When posaconasole is started during the treatment intervention period, dose adjustment (see section 6.1 and
6.5) and additional cardiac safety monitoring (see Section 8.4.7.2) must be performed.
e. Disallowed within 14 days prior to screening and during the study.
f. 
If several medications for the same indication are available and can be used interchangeably, it is recommended to administer the drug with the least CYP3A4
inhibitory potency.


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6.7. 
Intervention After the End of the Study
If the information on (an) ongoing AE(s)is obtained via telephone contact, written documentation
of the communication must be available for review in the source documents. If the participant has
died, the date and cause of death will be collected and documented on the eCRF.
Investigators may recontact the participant to obtain long-term follow-up information regarding
the participant's safety or survival status as noted in the ICF (refer to Informed Consent/Assent in
Appendix 10.3, Regulatory, Ethical, and Study Oversight Considerations).
Participants will be instructed that study intervention will not be made available to them after they
have completed/discontinued study intervention  and that they should return to their primary
physician to determine SOC.
7. 
DISCONTINUATION OF STUDY INTERVENTION AND PARTICIPANT
DISCONTINUATION/WITHDRAWAL
7.1. 
Discontinuation of Study Intervention
A participant's study intervention must be discontinued if:
 
The participant withdraws consent or assent to receive study intervention
 
The investigator believes that for safety reasons or tolerability reasons (eg, AE) it is in the
best interest of the participant to discontinue study intervention
 
The participant becomes pregnant
 
The participant has a confirmed QTcF interval ≥500 milliseconds at any scheduled visit, per
the machine read parameter result. Confirmation needs to be obtained as soon as possible
during the same visit by another machine read ECG.
 
The participant has a confirmed (repeat local test) laboratory abnormality of hypokalemia of
<2.5 mEq/L and/or hypomagnesemia of <0.9 mEq/L in samples taken any time throughout
the study intervention treatment period (see also Section 8.4.7.2). Repeat sampling (local
laboratory)to be performed within 24 hours of the result being available at the site.
 
The participantis reported with the following laboratory abnormalities: AST or ALT increases
≥3 x ULN in samples taken at Screening, confirmed in a repeat test, to be performed within
48 hours of the result being available at the site.
 
After start of study intervention, the participant is reported with (confirmed) liver function
related laboratory abnormalities as indicated in Appendix 10.6, unless these are related to
newly developing GVHD per investigator's evaluation.
 
After start of study intervention, and applicable in case ofGVHD, the participant is reported
with the following laboratory abnormalities:
 
AST or ALT increases >5 x ULN and rising with or without total bilirubin increase >2 x
ULN
 
AST or ALT remains >5 x ULN without a change in total bilirubin for more than 2 weeks


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 
After start of study intervention, subject develops Grade 3 rash or higher, which is suspected
to be related to study intervention.
If a participant prematurely discontinues study intervention for any reason before the end of the
Treatment Phase, the participant is recommended to remain compliant to all study-related
procedures including timely completion of all efficacy assessments up to Day 49 or at least through
Day 28 (see Schedules of Activities).
If the reason for discontinuation of study intervention is full withdrawal of consent/assent, refer to
Section 7.2).
Study intervention assigned to the participant who discontinued study intervention may not be
assigned to another participant. Additional participants will not be enrolled.
7.2. 
Participant Discontinuation/Withdrawal From the Study
A participant will be withdrawn from the study for any of the following reasons:
 
Lost to follow-up
 
Withdrawal of consent or assent
 
Death
 
Decision by the sponsor to stop or cancel the study
 
Decision by the investigator to withdraw participant
 
Decision by local regulatory authorities and Independent Ethics Committee (IEC)/
Institutional Review Board (IRB) to stop or cancel the study
When a participant withdraws before study  completion, the reason for withdrawal is to be
documented in the eCRF and in the source document. If the reason for withdrawal from the study
is full withdrawal of consent or assent, then no additional assessments are allowed.
Withdrawal of Consent
A participant declining to return for scheduled visits does not necessarily constitute withdrawal of
consent/assent. Alternate follow-up mechanisms that the participant agreed to when signing the
consent form apply (eg, consult with family members, contacting the participant’s other
physicians, medical records, database searches, use of locator agencies at study completion) as
local regulations permit.
Prior to a participant withdrawing consent/assent for follow-up, the investigator should offer the
participant an opportunity for an optional Withdrawal and Safety Follow-up Visits. At these
optional Withdrawal and Safety Follow-up Visits, the same assessments as on the Day 22 and
Day 28 visits, respectively, will be performed.


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Withdrawal From the Use of Research Samples
The biomarker research samples collected in the study are mandatory, unless local regulations
require these to be optional. In such case, a participant 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 participant's original
separate informed consent/assent for optional research samples.
 
The participant may withdraw consent/assent for optional research samples, 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/assent 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 requested, the investigator will receive written confirmation from the sponsor
that the samples have been destroyed.
Withdrawal From the Use of Samples in Future Research
The participant may withdraw consent/assent for use of samples for research (refer to Long-Term
Retention of Samples for Additional Future Research in Appendix 10.3, 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.
7.3. 
Lost to Follow-up
To reduce the chances of a participant being deemed lost to follow-up, prior to randomization
attempts should be made to obtain contact information from each participant, eg, home, work, and
mobile telephone numbers and email addresses for both the participant as well as appropriate
family members.
A participant will be considered lost to follow-up if he or she repeatedly fails to return for
scheduled visits and is 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 are deemed futile. The following actions must be taken if a participant fails to return to
the study site for a required study visit:
 
The study-site personnel must attempt to contact the participant to reschedule the missed visit
as soon as possible, to counsel the participant on the importance of maintaining the assigned
visit schedule, to ascertain whether the participant wishes to or should continue 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 (where possible, 3 telephone calls,
e-mails, fax, and, if necessary, a certified letter to the participant’s last known mailing address,
or local equivalent methods). These contact attempts should be documented in the
participant’s medical records.
 
Should the participant continue to be unreachable, they will be considered to have withdrawn
from the study.


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8. 
STUDY ASSESSMENTS AND PROCEDURES
8.1. 
Overview
The Schedules of Activities summarize the frequency and timing of efficacy, PK, clinical
laboratory, and safety assessments as well as PRO, biomarker analysis, and MRU, applicable to
this study.
PRO assessments should preferentially be conducted/completed before any tests, procedures, or
other consultations to prevent influencing participant perceptions, with the exception of the
screening assessment, which can take place after clinician assessment of eligibility.
If multiple assessments are scheduled for the same timepoint, it is recommended that procedures
be performed in the following sequence: PRO, ECG, vital signs, bilateral mid-turbinate nasal swab,
blood sampling, and physical examination. Actual dates and times of assessments will be recorded
in the source documentation and eCRF.
Local pregnancy tests will be performed at timepoints indicated in the Schedules of Activities.
Additional serum or urine pregnancy tests may be performed, as determined necessary by the
investigator or required by local regulation, to establish the absence of pregnancy at any time
during the participation in the study and if experiencing a delayed menstrual period (over 1 month
between menstrual cycles) or infrequent or irregular menstrual cycles to confirm absence of
pregnancy.
Medical resource utilization  data will be collected. Refer to Section 8.10, Medical Resource
Utilization for details.
For each participant, the maximum amount of blood drawn from each participant in this study will
not exceed 110 mL over the duration of this study.
Repeat or unscheduled samples may be taken for safety reasons or for technical issues with the
samples.
Sample Collection and Handling
The actual dates and times of sample collection must be recorded in the eCRF or laboratory
requisition form. For hospitalized participants, if blood samples are collected via an indwelling
cannula, an appropriate amount (1 mL) of serosanguineous fluid slightly greater than the dead
space volume of the lock will be removed from the cannula and discarded before each blood
sample is taken.
Refer to the Schedules of Activities for the timing and frequency of all sample collections.
Instructions for the collection, handling, storage, and shipment of samples are found in the
laboratory manual that will be provided. Collection, handling, storage, and shipment of samples
must be under the specified, and where applicable, controlled temperature conditions as indicated
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Study-Specific Materials
The investigator will be provided with the following supplies:
 
JNJ-53718678 IB and any addenda
 
Pharmacy manual, including study IPPI
 
Study intervention
 
Oral dosing syringes (only for oral suspension formulations)
 
Laboratory manual
 
ePRO completion guides
 
ePRO participant information sheets, including FAQs
 
eDevice and instructions for use
 
IWRS Manual
 
eCRF completion guidelines
 
ECG machine and manual
 
Additional auxiliary materials, as needed
 
Specimen collection kits for PK, safety blood, and urine samples as well as bilateral mid-
turbinate nasal swab samples
 
Contact information page(s)
8.2. 
Efficacy Assessments
8.2.1. 
Development of Lower Respiratory Tract Infection/Complications
8.2.1.1. 
Chest Imaging
Evaluation  of a chest X-ray at Screening is required for determining study eligibility  (see
Section 5.1). A chest X-ray should be collected prior to randomization. If a chest X-ray has not
been obtained as part of SOC, it must be obtained during Screening and not more than 48 hours
before randomization.
During the course of the study, it is anticipated that, as part of SOC and strongly recommended by
the sponsor, investigators should perform chest imaging and/or CT scans, as well as other SOC
assessments, if there is any suspicion of the occurrence of an LRTI, ie, development of a lower
respiratory sign or symptom (including decrease in oxygen saturation or increase in supplemental
oxygen to maintain oxygen saturation, wheezing, rhonchi, rales, dyspnea, tachypnea, worsening
cough), as soon as possible. Outpatients must be instructed to contact the site immediately when
there is a deterioration in their condition and should be invited for an unscheduled visit to be
evaluated for the development of an LRTI.
Images and results from local reading for chest X-rays will be used for Screening and eligibility
determination. Local reading should be performed by the local radiologist, unless the turnaround


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time is very long, in which case the investigator can perform the interpretation to determine
eligibility. In such case, the image may be sent to the EAC vendor for confirmatory central reading.
Chest imaging done in randomized participants during the course of the study will be collected
electronically from the site, sent to a central reader for review and interpretation, and stored
electronically. For participants who experienced a suspected LRTI, all available reports (also from
Screening) from the central and local readers and images will be sent for review to the EAC
(see Section 9.6).
8.2.1.2. 
Lower Respiratory Tract Samples
If there is any suspicion of the occurrence of an LRTI, ie, development of a lower respiratory sign
or symptom (including decrease in oxygen saturation or increase in supplemental oxygen to
maintain oxygen saturation, wheezing, rhonchi, rales, dyspnea, tachypnea, worsening cough),
leading to chest imaging, per local SOC a lower respiratory tract sample (eg, BAL, induced
sputum, or regular sputum) should be obtained for microbiologic and virologic evaluation to
determine the etiology. The reports of this evaluation will be provided to the EAC.
The determination of the presence of RSV or other respiratory pathogens in the lower respiratory
tract sample may be performed locally as part of SOC, unless such testing is not locally available,
in which case central testing for RSV may be performed.
If feasible, the leftover of the lower respiratory tract sample will be sent to the central laboratory
for additional virologic analyses.
8.2.1.3. 
Bilateral Mid-turbinate Nasal Swab Samples
In case of clinical suspicion of the occurrence of an LRTI, an additional bilateral mid-turbinate
nasal swab sample should be collected. If the collection of a bilateral mid-turbinate nasal swab
sample is planned as part of the scheduled visit, collection of an additional sample in case of
suspicion of LRTI is not required. This sample will be aliquoted and sent to the central laboratory
for:
 
RSV detection and RSV viral load
 
viral sequencing
For a selected set of bilateral mid-turbinate nasal swab samples, quantitative RSV culture may be
performed, if feasible, for determination of RSV infectious viral titer.
8.2.1.4. 
Blood Samples for RSV Viremia
In case of clinical suspicion of the occurrence of an LRTI, a blood sample for evaluation of RSV
viremia will be collected for central analysis. At the discretion of the sponsor, leftover from these
samples may be used for an exploratory analysis of other pathogens in blood.


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8.2.1.5. 
Collection of Lower Respiratory Tract Infections Source
Documentation for Endpoint Adjudication Committee Review
During the course of the study, the following results and reports from evaluations performed per
SOC will be collected and will be reviewed by an EAC (see Section 9.6):
 
images and reports from chest imaging, including the reports from the central reader (see
Section 8.2.1.1)
 
results of all local microbiology and virology tests performed (all bacterial, viral, fungal,
parasite, or other results from any respiratory system-related sample [eg, BAL, sputum,
pleural fluid, or lung tissue] and from blood specimens, including bacterial culture, virology
[mostly by PCR], and serology studies)
 
ECG tracings and reports of any ECG performed in relation to a suspected LRTI event
 
body temperature
 
clinical notes
 
autopsy reports (if applicable)
 
clinical course evaluations, including the specific reason for the repeat imaging
 
other supporting documents, as requested.
All participant-related documents from the site should be anonymized.
8.2.2. 
Clinical Course of RSV Infection
The study will include the following evaluations of the clinical course of RSV infection at
timepoints indicated in the Schedules of Activities:
 
clinical parameters: respiratory rate, heart rate, SpO2, and body temperature as measured by
the investigator during scheduled visits
 
respiratory signs and symptoms, including auscultation findings, as evaluated by the
investigator
 
requirement for supplemental O2
 
supplemental O2 type (eg, supplemental oxygen, noninvasive pressure ventilation,
endotracheal-mechanical ventilation), and duration
 
(re)hospitalization by level of care during treatment and follow-up
 
duration of (re)hospitalization and duration of ICU use
 
respiratory failure (of any cause) requiring mechanical ventilation (invasive or noninvasive)
and all-cause mortality
 
Grade 3 and Grade 4 AEs in the Infections and Infestations System Organ Class
 
respiratory and thoracic-related AEs
 
the use of antibiotics in participants who develop RSV LRTI per the EAC’s assessment and
in participants who do not develop RSV LRTI


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 
duration and severity of RSV signs and symptoms, as assessed by the participant using the
RiiQ Symptom Scale (see Appendix 10.9)and Patient Global Impression (PGI) questions (ie,
PGI of Severity [PGI-S], PGI of Health [PGI-H], and PGI of Change in Health [PGI-C]; see
Appendix 10.10). Symptoms reported in the RiiQ will not be reported as AEs but constitute a
part of the efficacy evaluations. Note:LRTI symptoms, ie, development of a lower respiratory
sign or symptom (including decrease in oxygen saturation or increase in supplemental oxygen
to maintain oxygen saturation, wheezing, rhonchi, rales, dyspnea, tachypnea, worsening
cough), reported by the participant in the RiiQ, will trigger the evaluation for suspected LRTI
by the investigator.
 
occurrence of GVHD or delayed engraftment as evaluated by the investigator
An electronic device (eDevice) to be used for the ePRO will be provided to the participants at
Screening to record participant’s ratings of the severity of their symptoms, as specified in the
Schedules of Activities. The investigator/study staff will provide sufficient information (included
in the study manual) to enable the participants to complete the ePRO on the eDevice correctly and
on schedule to avoid missing or incorrect data. Prior to completing the screening assessment, the
participant must complete a training module (included on the eDevice) on how to enter responses
to questions on the eDevice. If a participant requires assistance entering responses in the eDevice,
a caregiver or member of the study team who is trained can interview the participant and enter the
participant’s responses on the eDevice on the participant’s behalf.
8.2.3. 
Antiviral Activity
For the evaluation of antiviral activity, the RSV viral load in bilateral mid-turbinate nasal swab
samples will be measured at the central laboratory using an RSV qRT-PCR assay. These bilateral
mid-turbinate nasal swab specimens for the determination of RSV viral load will be collected at
several timepoints during the study as indicated in the Schedules of Activities. Date and time of
sampling will be collected.
Bilateral mid-turbinate nasal swab samples will be collected by combining 2 swabs, one from each
nostril, in the same universal transport medium tube. Only at times when sampling of both nostrils
is not feasible, such as in case of bleeding in one nostril, one mid-turbinate nasal swab should be
collected from one nostril (ie. the non-bleeding nostril).
One Screening sample (from upper respiratory tract collected per local SOC testing within
24 hours prior to start of Screening or bilateral mid-turbinate nasal swab as part of the
study-specific Screening assessment) will be collected for the local diagnosis of RSV infection
using a rapid PCR- or other molecular-based diagnostic assay. The collection of SOC sample, used
for RSV diagnosis should be performed no more than 48 hours prior to randomization.
After randomization on Day 1, but immediately predose, a bilateral mid-turbinate nasal swab
sample will be collected as close as possible and prior to the first administration of study
intervention, aliquoted and sent to the central laboratory for:
 
RSV diagnosis confirmation using a PCR-based assay
 
RSV viral load


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 
examination for the presence of viral or bacterial co-pathogens using multiplex PCR
 
viral sequencing
During the subsequent visits, as indicated in the Schedules of Activities, a bilateral mid-turbinate
nasal swab sample will be collected, preferably at approximately the same time as the predose
bilateral mid-turbinate nasal swab sample taken on Day 1 and preferably prior to dose
administration, if applicable. This sample will be aliquoted and sent to the central laboratory for:
 
RSV viral load
 
viral sequencing
At Day 28, local testing for RSV detection should be performed using a rapid PCR- or other
molecular-based assay on an aliquot of the study-specific bilateral mid-turbinate nasal swab
sample. The bilateral mid-turbinate nasal swab sample (all remaining aliquots) will be sent to the
central laboratory. A SOC upper respiratory tract sample collected at Day 28 may also be used if
needed based on the local rapid PCR- or other molecular-based assay used.
In case of suspicion of the occurrence of an LRTI, an additional bilateral mid-turbinate nasal swab
sample should be collected. If the collection of a bilateral mid-turbinate nasal swab sample is
planned as part of the scheduled visit, collection of an additional sample in case of suspicion of
LRTI is not required. This sample will be aliquoted and sent to the central laboratory for:
 
RSV detection and RSV viral load
 
viral sequencing
For a selected set of bilateral mid-turbinate nasal swab samples, quantitative RSV culture may be
performed, if feasible, for determination of RSV infectious viral titer.
8.2.4. 
Health-related Quality of Life Assessment
Participants will complete the EQ-5D-5L  and RiiQ Impact Scales (Appendix 10.11  and
Appendix 10.9, respectively) at timepoints indicated in the Schedules of Activities to characterize
the impact of RSV and its treatment on HRQOL.
8.2.5. 
Viral Sequencing
Development of viral resistance will be monitored by sequencing of the RSV F-gene in all baseline
bilateral mid-turbinate nasal swab samples and in subsequent bilateral mid-turbinate nasal swab
samples upon request of the sponsor’s virologist. Other regions of the RSV genome may also be
sequenced at the discretion of the sponsor’s virologist. The impact of pretreatment RSV F-gene
polymorphisms and relevant post-baseline F-gene changes on the antiviral response and/or clinical
outcomes will be explored. Sequencing data will not be reported to the investigators. Sequencing
results may be presented in a separate report.
Changes in viral sequence will be evaluated but will not be reported as AEs.


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8.2.6. 
Evaluation of RSV Viremia
Blood samples for RSV detection and quantification of RSV viral load in plasma will be collected
at the time points indicated in the Schedules of Activities, to explore its role in treatment response,
safety, or the status and/or course of RSV-related disease. If the collection of such a blood sample
is planned as part of the scheduled visit, collection of an additional sample for suspected LRTI is
not required. At the discretion of the sponsor, these samples may also be used for exploratory
analysis of other pathogens in plasma that may play a role in treatment response, safety, or the
status and/or course of RSV-related disease or other clinical outcomes in this population.
8.3. 
Safety Assessments
The study will include the following evaluations of safety and tolerability:
 
AEs
 
clinical laboratory tests (central)
 
ECG 12-lead
 
vital signs:
o 
vital signs assessments performed as part of the clinical course of RSV infection-
related assessments (see Section 8.3.2: body temperature, heart rate, respiratory rate,
and SpO2)
o 
additional vital signs assessments: systolic blood pressure (SBP)and diastolic blood
pressure (DBP)
 
physical examination of all body systems (at Screening) (including height and body
weight measurements), directed physical examination (at visits specified in Schedules of
Activities), and skin examination
In the event that an invasive procedure such as a blood draw or a bilateral mid-turbinate nasal swab
is required at the same time as an assessment of vital signs or ECG, these latter assessments should
be performed first.
Clinically relevant findings resulting from the physical examination will be reported as AEs.
Safety and tolerability will be evaluated throughout the study from signing of the ICF until the last
study-related activity.
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.
8.3.1. 
Physical Examinations
A physical examination (including height [only at Screening] and body weight measurements) and
skin examination will be performed at the visits indicated in the Schedules of Activities.
Directed physical examination includes respiratory system, nose, ear, throat, facial, and neck
lymph nodes, and skin examination.


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A skin examination includes an examination of the mucous membranes, but does not include a
vaginal or rectal examination. However, if the participant develops a cutaneous reaction/rash,
vaginal and rectal examinations may be done if clinically relevant.
Any clinically relevant changes occurring during the study must be recorded in the AE Section of
the eCRF. Auscultation findings will be documented separately in the eCRF.
8.3.2. 
Vital Signs
Temperature (same method throughout), pulse/heart rate, respiratory rate, blood pressure, and
SpO2 will be assessed. General guidelines for measuring vital signs and SpO2 can be found in
Appendix 10.8.
Clinically relevant abnormalities occurring during the study should be recorded in the AE section
of the eCRF.
8.3.3. 
Electrocardiograms
Twelve-lead ECGs will be collected at the time points specified in the Schedules of Activities and
when clinically indicated or to confirm abnormal ECG findings. In case the ECG is to be taken
under fasted conditions, fasted is defined as no food intake within approximately 2 hours prior to
dosing and 2 hours after dosing. Additional ECG assessments are to be performed as unscheduled
assessments/visits preferably 3 days after the start of coadministration with moderate or strong
CYP3A4 inhibitors during the study intervention period.
During the collection of ECGs, participants should be in a quiet setting without distractions (eg,
television, cell phones). Participants should rest in a supine position for at least 5 minutes before
ECG collection and should refrain from talking or moving arms or legs. If blood sampling or vital
sign measurement is scheduled for the same time point as ECG recording, the procedures should
be performed in the following order: ECG(s), vital signs, blood draw.
Central ECG readings will be performed by a central ECG laboratory. Instructions for ECG
acquisition and ECG transmission will be described in the manual provided by the ECG laboratory.
There will be 2 ECG reports: 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
emerging during the study should be recorded by the investigator in the AE section of the eCRF.
For eligibility determination, the machine read ECG results, printed on the ECG device print-out
of the ECG tracing, will be taken into account. If post baseline, a participant has a QTcF interval
value ≥500 ms based on the machine read QTcF value, confirmation needs to be obtained as soon
as possible during the same visit by another machine read ECG. If confirmed, the participant needs
to be withdrawn from study intervention (see also Section 7.1) and additional ECGs need to be
performed daily until resolution of the QTcF  interval prolongation is confirmed (see also
Section 8.4.7.2). In case other clinically relevant abnormalities are observed post baseline, a
confirmatory ECG must be performed preferably within 48 hours, but no later than 72 hours, after


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the results have become available. Evaluation of clinical relevance should be done on confirmed
results.
8.3.4. 
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 10.2, 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.
8.4. 
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.
Adverse events will be reported by the participant (or, when appropriate, by a caregiver, surrogate,
or the participant's legally acceptable representative [LAR]) for the duration of the study.
For further details on AEs and serious adverse events (SAEs) (Definitions and Classifications;
Attribution Definitions; Severity Criteria; Special Reporting Situations; Procedures) as well as
product quality complaints, refer to Appendix 10.4 Adverse Events: Definitions and Procedures
for Recording, Evaluating, Follow-Up, and Reporting.
8.4.1. 
Time Period and Frequency for Collecting Adverse Event and Serious
Adverse Event Information
All Adverse Events
All AEs and special reporting situations, whether serious or non-serious, whether anticipated or
not anticipated (see also Section 8.4.4), will be reported from the time a signed and dated main
ICF is obtained until completion of the participant's last study-related procedure, which may
include contact for follow-up of safety. For participants having signed a diagnostic ICF only (ie,
who do not enroll in the study by signing the main ICF), reporting will be limited to AEs considered
related to the sampling procedure. In case a participant is experiencing (an) ongoing AE(s) or has
clinically significant laboratory or ECG abnormalities at the time of the Day 28 Follow-Up Visit,
participants might be requested, at the discretion of the investigator, to have a Safety Follow-up
Visit, at Day 35 and Day 49. Serious AEs, including those spontaneously reported to the
investigator within 30 days after the last dose of study intervention, 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.


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Serious Adverse Events
All serious adverse events occurring during the study must be reported to the appropriate sponsor
contact person by study-site personnel within 24 hours of their knowledge of the event.
Information regarding serious adverse events will be transmitted to the sponsor using the 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 a serious adverse event should be transmitted electronically.
8.4.2. 
Method of Detecting Adverse Events and Serious Adverse Events
Care will be taken not to introduce bias when detecting AEs or SAEs. Open-ended and nonleading
verbal questioning of the participant is the preferred method to inquire about adverse event
occurrence. In addition, for the telephone visits, careful questioning should be undertaken to
collect all AEs and not only SAEs.
8.4.3. 
Follow-up of Adverse Events and Serious Adverse Events
Adverse events, including pregnancy, will be followed by the investigator as specified in
Appendix 10.4, Adverse Events: Definitions and Procedures for Recording, Evaluating, Follow-
up, and Reporting.
8.4.4. 
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 IEC/IRB that approved the
protocol unless otherwise required and documented by the IEC/IRB. A SUSAR will be reported to
regulatory authorities unblinded. Participating investigators and IEC/IRB will receive a blinded
SUSAR summary, unless otherwise specified.
An anticipated event is an AE that commonly occurs in the study population independent of
exposure to the drug under investigation. For the purposes of this study the following serious AEs
will be considered anticipated events:


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Table 8: 
Anticipated Events
Pneumonia 
Mucositis 
Death related to clinical progression of underlying
disease requiring HSCT, or graft failure
Sinusitis 
Chronic Obstructive Pulmonary 
Disease 
Sepsis/Infections (opportunistic, eg,
cytomegalovirus/Epstein-Barr virus, P jiroveci, herpes
zoster virus, candida, aspergillosis, viral hepatitis)
Interstitial 
pneumonitis 
Peri-engraftment respiratory 
distress syndrome
Lymphadenopathy
Acute bronchitis 
Idiopathic pneumonia syndrome 
Neutropenia
Hypothyroidism  
Bronchiolitis obliterans 
Thrombocytopenia
Respiratory failure 
Hepatic veno-occlusive disease 
Anemia
Graft Failure 
Thrombotic microangiopathy  
GVHD
Osteopenia, 
osteoporosis, and
avascular bone
necrosis
Posterior subcapsular cataract 
Alopecia
Bone pain  
Congestive heart failure 
Secondary malignancy (Secondary acute leukemias,
solid tumors, and myelodysplastic syndromes)
Hemorrhagic cystitis Bleeding 
Pancytopenia
Infertility  
Retinopathy, Infectious retinitis, 
and ocular hemorrhage
Diffuse alveolar hemorrhage
These anticipated events will be periodically analyzed in aggregate by the sponsor during study
conduct. The sponsor will prepare a safety report in narrative format if the aggregate analysis
indicates that the anticipated event occurs more frequently in the treatment group than in the
control group and the sponsor concludes there is a reasonable possibility that the drug under
investigation caused the anticipated event.
The plan for monitoring and analyzing the anticipated events is specified in a separate Anticipated
Events Safety Monitoring Plan. The assessment of causality will be made by the sponsor’s
unblinded safety assessment committee.
The sponsor assumes responsibility for appropriate reporting of the listed anticipated events and/or
individual anticipated serious adverse events according to the requirements of the countries in
which the studies are conducted.
8.4.5. 
Pregnancy
All initial reports of pregnancy in female participants or partners of male participants must be
reported to the sponsor by the study-site personnel within 24 hours of their knowledge of the event
using the appropriate pregnancy notification form. Abnormal pregnancy outcomes (eg,
spontaneous abortion, fetal death, stillbirth, congenital anomalies, ectopic pregnancy) are
considered SAE and must be reported using the SAE Form (see Section 7.1).
Because the study drug may have an effect on sperm, pregnancies in partners of male participants
included in the study will be reported as noted above.
Follow-up information regarding the outcome of the pregnancy and any postnatal sequelae in the
infant will be required.


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8.4.6. 
Disease-Related Events and Disease-Related Outcomes not
Qualifying as Adverse Events or Serious Adverse Events
Symptoms of RSV disease, as reported in the RiiQ, will not be reported as AEs but constitute a
part of the efficacy evaluations. However, they will be reported as (S)AE if they are considered
related to the study intervention or fulfill the SAE definition.
‘Disease progression’ should not be recorded as an AE term or SAE term; instead, signs and
symptoms of clinical sequelae resulting from disease progression/lack of efficacy will be reported
if they fulfill the (serious) adverse event definition (refer to Adverse Event Definitions and
Classifications in Appendix 10.4, Adverse Events: Definitions and Procedures for Recording,
Evaluating, Follow-up, and Reporting). This pertains to both the suspected LRTI events (RSV
disease progression) as well as to the progression of the underlying disease (leading to HSCT) or
status of the HSCT.
8.4.7. 
Management of Adverse Events of Interest
Adverse event of interest for JNJ-53718678 based on nonclinical data is liver toxicity.
The following only applies to AEs starting after initiation of study intervention.
8.4.7.1. 
Liver Toxicity
Refer to Appendix 10.2 for protocol-required safety laboratory assessments. The severity grade of
laboratory abnormalities in liver function tests (LFT)is assessed using the criteria specified in the
DMID adult toxicity tables in Appendix 10.7, which is also applicable for adolescents. Refer to
Appendix 10.6 for suggested actions and follow-up assessments in case of abnormal liver function
in participants with normal liver function at screening. Ad hoc assessments (such as alkaline
phosphatase, international normalized ratio [INR], gamma-glutamyltransferase [GGT]) may be
performed at the discretion of the investigator, during unscheduled visits.
If there is suspected development of (acute) GVHD with liver involvement, monitoring and
management should be per local SOC for GVHD. For participants with GVHD with involvement
of the liver at enrollment, but AST/ALT <3x ULN within the 4 weeks prior to Screening, liver
function should be monitored per local SOC.
If AST or ALT increases >5 x ULN and rising with or without total bilirubin increase >2 x ULN
or AST or ALT remains >5 x ULN without a change in total bilirubin for more than 2 weeks,
applicable for GVHD, the study intervention should be discontinued (see Section 7.1).
8.4.7.2. 
Cardiac Events Potentially Related to QT Prolongation
Regular cardiac safety monitoring will be done in this study via assessments of AEs, laboratory
abnormalities, and regular ECGs.
Additional ECG assessments are to be performed as unscheduled assessments/visits preferably
3 days after the start of coadministration with moderate or strong CYP3A4 inhibitors during the
study intervention period.


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A participant's study intervention must be discontinued if the participant has a confirmed QTcF
interval value ≥500 ms at any scheduled visit based on the machine read QTcF value. Confirmation
needs to be obtained as soon as possible during the same visit by another machine read ECG (see
Section 7.1). For participants with a confirmed QTcF  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
ofconcomitant 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
and by the central laboratory at the timepoints specified in the Schedules of Activities.
 
In case of hypokalemia and/or hypomagnesemia at screening, Day 3, Day 8, or Day 15, the
levels of potassium and/or magnesium should be corrected taking into account any underlying
condition and as soon as possible to prevent cardiac disturbances. Appropriate clinical
management per local SOC (including but not limited to checking the corrected values at the
local laboratory) may be required.
 
An ECG should be repeated every 24 hours until resolution of QTcF 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.
For participants with a laboratory abnormality of hypokalemia of <2.5 mEq/L (Grade 3) and/or
hypomagnesemia of <0.9 mEq/L (Grade 3) in samples taken throughout the study intervention
treatment period, the following measures should be taken (see also Section 7.1):
 
Repeat to confirm the results (local test), to be performed within 24 hours of the result
being available at the site.
 
Participant’s study intervention must be discontinued after confirmation of results.
 
Clinical evaluation including assessment of cardiovascular status and ECG must be
conducted.
 
Electrolytes should be repeated (local laboratory) every 24 hours until resolution 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.
8.4.8. 
Management of Complications or Sequelae of HSCT
Management of complications or sequalae of HSCT as well as the underlying disease will be at
the discretion of the investigator and should follow generally accepted medical standards.


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8.5. 
Treatment of Overdose
For this study, any dose ofJNJ-53718678 greater than the total daily dose within a 24-hour time
period will be considered an overdose. The sponsor does not recommend specific intervention for
an overdose.
8.6. 
Pharmacokinetics
For all participants, venous blood samples for determination of JNJ-53718678 plasma
concentrations will be collected at the timepoints indicated in the Schedules of Activities (see
Section 1.3.4). Samples may also be used for the analysis of metabolites of JNJ-53718678 or
endogenous markers for enzymes or transporters involved in the metabolism and distribution of
JNJ-53718678, at the discretion of the sponsor. Blood samples collected for PK may additionally
be used to evaluate safety or efficacy aspects that address concerns arising during or after the study
period. Genetic analyses will not be performed on these samples. The participant’s confidentiality
will be maintained.
Bioanalysis of plasma samples (applicable treatment group only [not the placebo group]) to
determine plasma blood concentrations of JNJ-53718678 and, if applicable, metabolites will be
performed using a validated, specific, and sensitive method by the sponsor or under the sponsor’s
supervision.
PK parameters for other analytes (eg, metabolites, endogenous markers, and concomitant therapy)
may be determined at the discretion of the sponsor and may also be subjected to PK analysis.
The following information needs to be recorded on the requisition form: date and time of preceding
study intervention intake, date and time of PK blood sampling, and fed status (yes/no, fed status
defined as having a meal within 30 minutes before or 30 minutes after dosing).
Other samples (eg, bilateral mid-turbinate nasal swab samples) may be analyzed for JNJ-53718678
using research or scientifically validated bioanalytical assays, at the discretion of the sponsor.
8.6.1. 
Substudy in Hospitalized Participants
In a rich serial PKsampling substudy, performed at selected study sites, rich serial PK blood
sampling for the measurement of plasma concentrations of JNJ-53718678 will be performed in
approximately 30 hospitalized participants. At selected study sites participating in the PK
substudy, the ICF will contain a separate section explaining the PK substudy and separate consent
can be given for this substudy.
Participants in the rich serial PK sampling substudy will undergo rich serial PK sampling at visit
(dosing) Days 1 and 8, at 8 different time points within the dosing interval. The first sample should
be collected before study drug intake (within 0.5 hour before). JNJ-53718678 can be taken with or
without food. Samples 2 to 8 should be collected at 0.5, 1, 1.5, 2, 4, 8, and 12 or 24 hours after
study drug intake. No additional sample is needed to cover the sparse PK sample to be taken during
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the morning. If a participant is discharged prior to Day 8, the sparse PKschedule will be followed,
including for Day 8 (see Table 3).
The following times need to be recorded: actual dates and times of study drug intake and actual
dates and times of PK blood sampling. In addition, it should be documented whether the study
intervention intake (ie, the one closest preceding the PK sample) is taken in fed state (ie, between
1 hour before and 1 hour after completion of a meal).
8.7. 
Pharmacokinetics/Pharmacodynamics
The PK/PD relationship of JNJ-53718678 exposure (area under the plasma concentration-time
curve from time 0 to 24 hours after dosing [AUC24h], maximum plasma concentration [Cmax], or
minimum plasma concentration [Cmin]) with selected efficacy (change in viral load from baseline
and clinical outcomes) and safety (including AEs and laboratory abnormalities) parameters will
be explored. If there is any visual trend in graphical analysis, suitable models will be applied to
describe the exposure-effect relationships.
8.8. 
Genetics
Pharmacogenomics and genetics are not evaluated in this study.
8.9. 
Biomarkers
Blood samples will be collected for exploratory biomarker analyses (host RNA and/or proteins)at
the timepoints indicated in the Schedules of Activities, on the premise that these markers may play
a role in the treatment response, PK, safety of JNJ-53718678, or the status and course of RSV-
related disease. Collection of the blood samples for biomarker research is mandatory, unless local
regulations require these samples to be optional. In addition, leftover bilateral mid-turbinate nasal
swab or blood samples may be used for biomarker analysis (eg, proteins including cytokines).
Analyses of biomarkers may be conducted at the sponsor’s discretion and reported separately from
this study.
No human DNA analyses will be performed on these samples.
8.10. Medical Resource Utilization
Medical resource utilization data, associated with medical encounters, will be collected in the
eCRF for all participants. Protocol-mandated procedures, tests, and encounters are excluded. The
data collected may be used to conduct exploratory economic analyses and will include:
 
Assessments performed as part of the clinical course of RSV infection-related assessments
(see Section 8.2.2):
 
Antibiotic use for the treatment of an RSV LRTI and/or RSV-associated LRTC per the
EAC’s assessment after the first dose of study intervention through the last study visit.
 
Requirement for, and duration of, hospital (re)admission including duration by wards
level (eg, ICU) for respiratory reasons from Screening through the last study visit.
 
Occurrence of GVHD or delayed engraftment.


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 
O2 supplementation.
 
Number and duration of medical care encounters and treatments (including physician or
emergency room visits, tests and procedures, and medications, surgeries and other selected
procedures; inpatient and outpatient).
For the long-term follow-up period, hospitalizations as well as data on inpatient rehabilitation,
long-term care hospitalization and use of extra skilled nursing (home) will be collected. In
addition, occurrence or worsening of GVHD ordelayed engraftment and relapse as well as survival
status will be collected.
9. 
STATISTICAL CONSIDERATIONS
Statistical analysis will be done by the sponsor or under the authority of the sponsor. A general
description of the statistical methods to be used to analyze the efficacy and safety data is outlined
below. Specific details will be provided in the Statistical Analysis Plan (SAP).
The primary analysis will be performed when all randomized participants have completed the
Day 49 study visit or discontinued earlier. The final analysis (for health economics purpose) will
be performed when all randomized participants have completed the long-term follow-up (ie, 1 year
after randomization) or discontinued earlier. Data for this analysis might be collected after
database lock and unblinding for the primary analysis.
9.1. 
Statistical Hypotheses
The primary hypothesis of this study is that JNJ-53718678 reduces the proportion of adult HSCT
recipients with RSV URTI, who develop an RSV LRTI within 28 days after start of treatment as
compared to placebo, assessed through the relative risk.
The primary hypothesis will be evaluated (in the adult cohort) in the overall population, in the
population with an ALC <500 cells/μL at Screening, and in the population with an ALC
<200 cells/μL at Screening. To account for this multiplicity, the theory developed by Spiessens
and Debois55 will be used, allowing all 3 tests to be performed at a pre-fixed significance level,
irrespective of the outcome of the other tests. Assuming 50% of the population will have an ALC
<500 cells/μL at Screening and 25% of the population will have an ALC <200 cells/μL at
Screening, fixing the one-sided significance level for each of these two subgroups at 0.6%, and
using an overall 2.5% one-sided significance level, the full population can be tested using 1.8%
one-sided significance.
The secondary endpoints will be evaluated in the largest population (from the adult cohort) where
superiority was shown on the primary endpoint.
9.2. 
Populations for Analyses
For purposes of analysis, the following populations are defined:


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Population 
Description
Enrolled 
All participants who signed the ICF
Randomized 
All participants who were randomized in the study
Efficacy  
All participants who were randomized, treated (at least 1 dose), and had a RSV infection
confirmed by central laboratory analysis, excluding participants infected with a co-pathogen
(specified in Section 5.2, Exclusion Criteria) at baseline not identified during screening,
analyzed as randomized
Safety  
All randomized participants who took at least 1 dose of study intervention analyzed ‘as
treated’
9.3. 
Sample Size Determination
Sample size determination was performed for the adult cohort only. Assuming a progression to
RSV LRTI occurring in 35% of the patients in the placebo arm, a relative risk of 40%, and a 2:1
randomization, 210 patients are needed to obtain 90% power with 2.5% one-sided significance in
the primary analysis set based on a Fisher’s Exact test. Assuming 15% of patients will be excluded
from the primary analysis set, the total sample size becomes 249. Similar power estimates were
obtained from simulations using Cochran-Mantel-Haenszel test and Fisher’s Exact test.
Participants with an ALC <500 cells/µL at Screening should account for at least 50% of all
participants in the adult cohort and participants with an ALC <200 cells/µL at Screening should
account for at least 25% of all enrolled participants, also at the time of the interim analysis (see
Section 9.2 and Section 9.4.10).
To ensure the prespecified distribution in the strata for the interim analysis, enrollment in certain
lymphopenia strata (≥500 - <1,000 cells/μL or 200 - <500 cells/μL) will be temporarily paused
prior to the interim analysis once sufficient patients for the interim analysis are enrolled in the
corresponding stratum.
No more than 62 participants with ALC ≥500 - <1,000 cells/μL and no more than 93 patients with
ALC ≥200 cells/μL can be enrolled prior to the interim analysis. Once sufficient patients have been
enrolled for the interim analysis, enrollment will continue again in all strata.
Similarly, to ensure the prespecified distribution in the strata for the final analysis, enrollment in
certain lymphopenia strata (≥500 - <1,000 cells/μL or 200 - <500 cells/μL) could be stopped early
once sufficient patients for the final analysis are enrolled in the corresponding stratum.
No target sample size was determined for the adolescent cohort (see Section 4.2.1).
9.4. 
Statistical Analyses
The statistical analysis plan will be finalized prior to first patient first visit and it will include a
more technical and detailed description of the statistical analyses described in this section. This
section is a summary of the planned statistical analyses of the most important endpoints including
primary and key secondary endpoints.
The efficacy analyses will be conducted by cohort. Safety, demographic, and baseline
characteristics data will be analyzed for the overall population (adult and adolescent cohorts
combined).


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9.4.1. 
Participant Information
All demographic (eg, age, height, 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), and HSCT-related characteristics
(eg, donor type, cell source, GVHD history, hospitalization at screening) will be tabulated and
analyzed descriptively by intervention group.
9.4.2. 
Efficacy Analyses
For the adolescent cohort, efficacy analysis will be limited to descriptive statistics.
For the adult cohort, primary analysis of efficacy-related endpoints will be performed in the overall
population, in the population with an ALC <500 cells/µL at Screening, and in the population with
an ALC <200 cells/µL at Screening, applying a multiplicity correction (see Section 9.1).
As a confirmatory strategy, to account for multiplicity in the statistical evaluation of the most
important efficacy endpoints, hierarchical testing will be applied to control for overall Type I error.
The following endpoints are included in the confirmatory strategy:
1. The proportion of participants who develop RSV LRTI per the EAC’s assessment (see
Section 9.6) through Visit Day 28, ie, primary endpoint;
2. The proportion of participants who develop an RSV-associated LRTC  per the EAC’s
assessment (see Section 9.6) through Visit Day 28;
3. Time to resolution of symptoms, assessed through an instrument for patient-reported
symptoms (RiiQ Symptom Scale);
4. Number of supplemental O2 free days through Day 28;
5. Proportion of participants hospitalized (of participants who were not hospitalized at baseline);
6. The proportion of participants progressing to respiratory failure (of any cause) requiring
mechanical ventilation (invasive or noninvasive) and/or death (all-cause mortality);
7. Total length of hospital stay (time in hospital before first dosing is discarded);
First, the primary endpoint will be tested for superiority at the 1-sided 2.5% significance level. If
superiority is shown on the primary endpoint, the first secondary endpoint in the sequence as
indicated above will be tested for superiority at the same significance level. If superiority is shown
for this secondary endpoint, further secondary endpoints will be tested for superiority in the
sequence as indicated above, and at the same significance level. In case superiority is not shown
for an endpoint, no further endpoints in the sequence will be tested for superiority.
9.4.2.1. 
Primary Endpoint: Development of RSV Lower Respiratory Tract
Infection
The proportion of participants who develop an EAC-confirmed RSV LRTI through Visit Day 28
will be analyzed using a Cochran-Mantel-Haenszel test stratified by the randomization
stratification factors.


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9.4.2.2. 
Key Secondary Endpoints
For the hypothesis testing, the following methods will be used:
 
Time to resolution of symptoms will be analyzed using a stratified Gehan-Wilcoxon test
(using the randomization stratification factors).
 
Total length of hospital stay and the number of supplemental O2 free days will be analyzed
using a Hodges-Lehmann test.
 
For the proportion of participants hospitalized, and the proportion of participants progressing
to respiratory failure and/or death, a Cochran-Mantel-Haenszel test stratified by the
randomization stratification factors, will be used as for the primary analysis.
9.4.2.3. 
Clinical Course of RSV Infection
Endpoints related to evaluation of the clinical course of RSV infection will be analyzed graphically
and descriptively. For continuous variables, descriptive statistics (n, mean, SD, median, minimum,
and maximum) will be calculated. For categorical variables, frequency tables will be presented.
Time to-variables (eg, time to resolution of symptoms)will be analyzed using Kaplan-Meier plots
and will be modeled using an accelerated failure time model, adjusted for the randomization
stratification factors, to estimate differences between intervention groups.
Results from the RiiQ Impact Scale and PGI (PGI-S, PGI-C, and PGI-H) assessments will be
descriptively summarized by intervention group.
More details regarding the analysis of these data will be described in the SAP.
9.4.2.4. 
Antiviral Activity
Antiviral activity will be determined based on measurements of RSV viral load in bilateral mid-
turbinate nasal swab samples by a qRT-PCR assay. These data will be analyzed graphically and
descriptively as described in the SAP. For continuous variables, descriptive statistics (n, mean,
SD, median, minimum, and maximum) will be calculated. For categorical variables, frequency
tables will be presented. Kaplan-Meier Curves will be produced to graphically describe the time
to event data.
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
intervention, strata, visit, and intervention-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
intervention groups in viral load, and the difference in the AUCs between intervention groups will
be derived using appropriate contrasts deriving least square mean differences, including the 95%
2-sided confidence intervals.


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9.4.2.5. 
Health-related Quality of Life Assessment
Results from the HRQOL assessment (through EQ-5D-5L and RiiQ Impact Scales) will be
descriptively summarized by intervention group.
More details regarding the analysis of these data will be described in the SAP.
9.4.2.6. 
Correlation Between Antiviral Effect and Clinical Course Endpoints
Selected antiviral effect and selected clinical course endpoints (primary and key secondary
endpoints) will be subjected to correlation analysis and will be presented in a tabular and/or
graphical display.
More details regarding the analysis of these data will be described in the SAP.
9.4.2.7. 
Viral Sequencing
The results of viral sequencing will be evaluated by the sponsor virologist. Pretreatment
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 virologist) will be tabulated and
described. The effect of pretreatment RSV F-gene polymorphisms and relevant post-baseline RSV
F-gene changes on antiviral response and/or clinical outcomes will be explored.
9.4.3. 
Safety Analyses
Safety data will be presented descriptively. For safety, baseline is defined as the last assessment
prior to the first intake of study intervention.
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). Intervention-emergent AEs are AEs
with onset during the intervention phase or that are a consequence of a pre-existing condition that
has worsened since baseline. All reported AEs will be included in the analysis. For each AE, the
percentage of participants who experience at least 1 occurrence of the given event will be
summarized by intervention group.
Summaries, listings, datasets, or participant narratives may be provided, as appropriate, for those
participants who die, who discontinue intervention due to an AE, who experience a severe AE (ie,
at least Grade 3) or a SAE, or who experience anticipated events.
Clinical Laboratory Tests
Laboratory data will be summarized by type of laboratory test. The laboratory abnormalities will
be determined per the criteria specified in the DMID Adult (see Attachment 10.7, also for
adolescents) and in accordance with the normal ranges of the clinical laboratory if no gradings
were 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.


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Changes from baseline results will be presented in pre- versus post-intervention cross-tabulations
(with classes for below, within, and above normal ranges).
A listing of participants with any laboratory results outside the reference ranges will be provided.
A listing of participants with any markedly abnormal laboratory results will also be provided.
Results from the central laboratory will be included in summary tables. Local laboratory results
will be listed only (in case of cardiac events potentially related to QT prolongation).
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 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: QT corrected according to
Bazett's formula, and according to Fridericia’s formula.5,28,33,47
Frequency tabulations by intervention 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 blood pressure (systolic and diastolic) values and changes from baseline
will be summarized at each scheduled time point (see also Section 8.2.2). The percentage of
participants with markedly abnormal results (specified in the SAP) will be summarized.
9.4.4. 
Pharmacokinetic Analyses
The PK samples taken from all participants in the study (see Section 1.3.4.1), as well as the rich
serial PK samples collected in the PK substudy (Section 1.3.4.2) will be used for popPK model
development and/or popPK model update. The PK samples taken from participants in the rich
serial PK substudy will be analyzed as specified in Section 9.4.4.1. PopPK analysis of plasma
concentration-time data of JNJ-53718678 from all participants (including those of rich PK
substudy, see Section 9.4.4.1 for details) will be performed using (non)-linear mixed-effects
modeling. Population PK modeling will be used to describe the concentration-time profiles and
estimate the exposure parameters (AUC24h, Ctrough, and Cmax) of JNJ-53718678. Available baseline
subject characteristics (demographics, body weight, laboratory variables, genotype, etc.) may be
explored as potential covariates affecting PK parameters of JNJ-53718678. Details will be given
in a popPK analysis plan and the results of the popPK analysis will be presented in a separate
popPK report.


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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 drug; missing information of
dosing and sampling times; concentration data not sufficient for PK parameter calculation).
All concentrations below the lowest quantifiable concentration or missing data will be labeled as
such in the concentration database. All participants and samples excluded from the analysis will
be clearly documented in the popPK study report.
For each intervention group, descriptive statistics, including arithmetic mean, SD, coefficient of
variation, median, minimum, and maximum will be calculated for all individual derived PK
parameters of JNJ-53718678, and, if applicable, of metabolites.
9.4.4.1. 
Substudy in Hospitalized Participants
For the intensive PK samples of the rich PK substudy, non-compartmental PK analysis of
JNJ-53718678 will be performed using actual sampling time and plasma concentrations obtained
from rich serial PK blood sampling for approximately 30 participants. Descriptive statistics will
be provided for the PK parameters (Ctrough, Cmax, tmax, Cmin, and AUC24h) derived, including
graphical analyses of the data. Results will be presented in a separate PK report.
9.4.5. 
Pharmacokinetic/Pharmacodynamic Analyses
Relationships of JNJ-53718678 population-derived exposure parameters with selected antiviral
activity parameters, clinical outcomes, and safety endpoints will be explored. In case there is a
relationship, this will be characterized using (non)-linear mixed effect models. These relationships
will be presented in a tabular and/or graphical display.
9.4.6. 
Biomarkers Analyses
Statistical approaches to explore correlations between clinical outcome, viral load, and biomarkers
in blood (and potentially from bilateral mid-turbinate nasal swab samples) vary and depend on the
different data types of the applied technology platforms, as well as on the extent of observed
differences among study participants. Analyses may be conducted at the sponsor’s discretion and
reported separately from this study.
9.4.7. 
Medical Resource Utilization
Medical resource utilization will be descriptively summarized by intervention group.
9.4.8. 
Other Analyses
Data on viral (other than RSV) or bacterial pathogens (both by multiplex PCR) determined in
bilateral mid-turbinate nasal swab samples collected at Day 1 predose (or Screening)will be listed
and tabulated.


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9.4.9. 
Health Economics
A separate analysis for health economics purpose will be performed after completion of the
long-term follow-up. Data on survival status, morbidity and hospitalizations/MRU will be
descriptively summarized per intervention group.
9.4.10. 
Interim Analysis
One interim analysis is planned when approximately 50% of the planned participants from the
adult cohort have completed the Day 28 assessments (or discontinued earlier). At the time of the
interim analysis, participants with an ALC <500 cells/µL at Screening should account for at least
50% of all enrolled participants, and participants with an ALC <200 cells/µL at Screening should
account for at least 25% of all enrolled participants. This interim analysis will include safety,
testing for futility, early superiority, and an unblinded sample size re-estimation. During the
interim analysis, enrollment will continue.
Interim testing for futility will focus on the full population only, using the Go-NoGo framework.23
Interim testing for early superiority will focus on the full population only, using a 0.001%
one-sided significance level.
The unblinded sample size re-estimation will use the observed RSV LRTI rates in the full
population and calculate the required sample size for the adult cohort to obtain 90% power for the
final analysis. This calculated value will be increased based on the proportion of patients in the
efficacy analysis set as observed at interim. The study sample size for the adult cohort will not be
decreased, and not be increased to beyond 375 patients. The new sample size will not be
communicated to the sponsor nor the investigators.
Details on the testing for futility, early superiority, and sample re-estimation will be provided in
the SAP and/or IDMC Charter.
During and after this interim analysis, investigators, participant(s), and sponsor representatives
will remain blinded. An IDMC (see Section 9.5) will monitor and review the results from the
interim analysis in an unblinded manner. A Sponsor Committee, consisting of senior sponsor
personnel not involved in the conduct of the study, will be established and will be responsible for
decision making, considering the IDMC recommendation, and will communicate these decisions
to the study team. Details are provided in the IDMC Charter. During the interim analysis, the
Sponsor Committee will remain blinded.
Further details regarding the interim analysis will be specified in the SAP. Operating
characteristics (eg, power, Type I error) of statistical decision procedures and methods at the
interim analysis will be evaluated through computer simulations and summarized in a modeling
and simulation report.
9.5. 
Independent Data Monitoring Committee
An IDMC will be established to monitor and review data in an unblinded manner on a regular
basis to ensure the continuing safety of the participants enrolled in this study. The committee will


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meet periodically to review safety data and results from the interim analysis. After the review, the
IDMC will provide recommendations to the Sponsor Committee, who will be responsible for
decision making, considering the IDMC recommendation, and who will communicate these
decisions to the study team. Details are provided in the IDMC Charter.
Additionally, given the longer dosing duration of JNJ-53718678 used in this study and the
population targeted, the IDMC will perform the first unblinded safety review prior to (should a
safety signal warrant) or after the 18th  patient has completed the Day 28 assessments (or
discontinued earlier).
The IDMC will consist of at least one hematologist/oncologist, 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.
9.6. 
Endpoint Adjudication Committee
An external blinded EAC will review clinical data (see Section 8.2.1.5 for details) to determine
whether an RSV LRTI and/or RSV-associated LRTC has developed (as defined in Section 3). The
clinical data will be used to determine if the event meets the criteria for any of the categories
defined in Section 3 and excludes other potential causes such as pulmonary embolism, cardiogenic
shock, heart failure, and fluid overload. The EAC advice will be stored electronically.
Additional information will be available in the EAC charter.


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10. 
SUPPORTING DOCUMENTATION AND OPERATIONAL CONSIDERATIONS
10.1. Appendix 1: Abbreviations
AE 
Adverse event
ALC  
Absolute lymphocyte count
AlkP  
alkaline phosphatase
ALT  
alanine aminotransferase
AMA  
anti-mitochondrial antibody
ANA  
antinuclear antibody
Anti-LKM1 
anti-liver kidney microsomal antibody type 1
ASMA  
anti-smooth muscle antibodies
AST  
aspartate aminotransferase
AUC  
area under the curve
AUC0-24h  
AUC from time of administration up to 24 hours post dosing
AUC0-∞ 
AUC from time of administration extrapolated to infinity
BAL 
Bronchoalveolar lavage
BCRP  
breast cancer resistance protein
bid 
twice daily
BMI 
body mass index
CBC 
complete blood count
CHF  
congestive heart failure
Cmax  
maximum plasma concentration
Cmin  
minimum plasma concentration
CMV  
cytomegalovirus
COA  
clinical outcome assessment (paper or electronic as appropriate for this study)
COVID-19 
Coronavirus Disease 2019
CRP  
C-reactive protein
CT  
computed tomography
Ctrough  
Predose plasma concentration
CYP  
Cytochrome P450
DIDB  
Drug Interaction Database
DM  
diabetes mellitus
DMID  
Division OfMicrobiology And Infectious Diseases
DNA  
deoxyribonucleic acid
DTP  
direct-to-patient
EAC  
Endpoint Adjudication Committee
EBV  
Epstein-Barr virus
ECG  
electrocardiogram
eCRF  
electronic case report form
eDC  
electronic data capture
EOI 
end of intervention
EQ-5D-5L 
5-level EuroQol 5-Dimension Questionnaire
ERCP  
endoscopic retrograde cholangiopancreatography
ESR  
erythrocyte sedimentation rate
FSH  
follicle stimulating hormone
GCP  
Good Clinical Practice
GGT  
gamma-glutamyltransferase
GHVD 
graft versus host disease
HAV 
hepatitis A virus
HBsAg 
hepatitis B surface antigen
HCV  
hepatitis C virus
HepB  
hepatitis B virus
HEV  
hepatitis E virus
HIV  
human immunodeficiency virus
HRQOL 
health-related quality of life
HSCT  
Hematopoietic stem cell transplant
ICF  
informed consent form


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ICH  
International Conference on Harmonisation of Technical Requirements for Registration of
Pharmaceuticals for Human Use.
IC  
immunocompromised
ICU  
Intensive care unit
IDMC  
Independent Data Monitoring Committee
IEC  
Independent Ethics Committee
IgM  
immunoglobin M
INR  
international normalized ratio
IPPI 
Investigational Product Preparation Instruction
IRB  
Institutional Review Board
IS  
immunosuppressants
IVIG  
Intravenous immunoglobulin
IWRS  
interactive web response system
LAR  
Legally acceptable representative
LRTC  
Lower respiratory tract complication
LRTI 
Lower respiratory tract infection
LT/LFT  
liver tests/liver function tests
MedDRA  
Medical Dictionary for Regulatory Activities
MRCP  
magnetic resonance cholaniopancreatography
MRI 
magnetic resonance imaging
MRU  
medical resource utilization
NSAID  
non-steroidal anti-inflammatory drugs
OATP  
organic-anion-transporting polypeptide
OCT  
organic cation transporter
OTC  
over the counter
paEC90 
protein-adjusted 90% effective concentration
PBPK 
physiologically-based pharmacokinetic(s)
PCR  
polymerase chain reaction
PD 
pharmacodynamic(s)
PGI 
Patient Global Impression
PGI-C 
Patient Global Impression of Change
PGI-H 
Patient Global Impression of Health
PGI-S 
Patient Global Impression of Severity
PK 
pharmacokinetic(s)
PQC  
Product Quality Complaint
PRO  
patient-reported outcome(s)
PT  
prothrombin time
PTT  
partial thromboplastin time
qd 
Once daily
QTc 
corrected QT interval
QTcB  
QT interval corrected for heart rate according to Bazett's formula
QTcI 
individual-corrected QTc
QTcF  
QT interval corrected using Fridericia's formula
q12h  
every 12 hours
q24h  
every 24 hours
RiiQ  
Respiratory Infection Intensity and Impact Questionnaire
RNA  
ribonucleic acid
RSV  
Respiratory syncytial virus
rtv  
ritonavir
SAE 
Serious adverse event
SD 
Standard deviation
SoA  
Schedule of Activities
SOC  
Standard of care
SUSAR  
suspected unexpected serious adverse reaction
Tbili 
total bilirubin
TEAE 
treatment-emergent AE


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TIBC  
total iron binding capacity
TR 
tissue radioactivity
TQT  
thorough QT
ULN  
upper limit of normal
WBC  
white blood count
Definitions of Terms [if applicable]
Electronic source 
system  
Contains data traditionally maintained in a hospital or clinic record to document medical
care or data recorded in a CRF as determined by the protocol. Data in this system may be
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If dipstick result is abnormal, flow cytometry or microscopy will be used to measure
sediment. In case of discordance between the dipstick results and the flow cytometric
results, the sediment will be examined microscopically.
In the microscopic examination, observations other than the presence of WBC, RBC
and casts may also be reported by the laboratory.
Pregnancy  
Serum (only at Screening) and urine pregnancy testing for all woman.


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


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


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 
Information on compensation for study-related injuries or payment to participants for
participation in the study, if applicable
 
Investigator's curriculum vitae or equivalent information (unless not required, as documented
by the IEC/IRB)
 
Information regarding funding, name of the sponsor, institutional affiliations, other potential
conflicts of interest, and incentives for participants
 
Any other documents that the IEC/IRB requests to fulfill its obligation
This study will be undertaken only after the IEC/IRB has given full approval of the final protocol,
amendments (if any, excluding the ones that are purely administrative, with no consequences for
participants, data or study conduct, unless required locally), the ICF, applicable recruiting
materials, and participant compensation programs, and the sponsor has received a copy of this
approval. This approval letter must be dated and must clearly identify the IEC/IRB and the
documents being approved.
During the study the investigator (or sponsor where required) will send the following documents
and updates to the IEC/IRB for their review and approval, where appropriate:
 
Protocol amendments (excluding the ones that are purely administrative, with no
consequences for participants, data or study conduct)
 
Revision(s) to ICF and any other written materials to be provided to participants
 
If applicable, new or revised participant recruiting materials approved by the sponsor
 
Revisions to compensation for study-related injuries or payment to participants for
participation in the study, if applicable
 
New edition(s) of the IB and amendments/addenda
 
Summaries of the status of the study at intervals stipulated in guidelines of the IEC/IRB (at
least annually)
 
Reports of AEs that are serious, unlisted/unexpected, and associated with the study
intervention
 
New information that may adversely affect the safety of the participants or the conduct of the
study
 
Deviations from or changes to the protocol to eliminate immediate hazards to the participants
 
Report of deaths of participants under the investigator's care
 
Notification if a new investigator is responsible for the study at the site
 
Development Safety Update Report and Line Listings, where applicable
 
Any other requirements of the IEC/IRB
For all protocol amendments (excluding the ones that are purely administrative, with no
consequences for participants, data or study conduct), the amendment and applicable ICF revisions
must be submitted promptly to the IEC/IRB for review and approval before implementation of the
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At least once a year, the IEC/IRB will be asked to review and reapprove this study, where required.
At the end of the study, the investigator (or sponsor where required) will notify the IEC/IRB about
the study completion (if applicable, the notification will be submitted through the head of
investigational institution).
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  4.2.6, Study-Specific Ethical Design
Considerations.
Other Ethical Considerations
For study-specific ethical design considerations, refer to Section 4.2.6.
INFORMED CONSENT/ASSENT PROCESS
Each participant must give written consent/assent 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 can read and understand. The informed
consent/assent 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 participants or their LAR the aims, methods, reasonably
anticipated benefits, and potential hazards of the study, and any discomfort participation in the
study may entail. Participants will be informed that their participation is voluntary and that they
may withdraw consent/assent to participate at any time. They will be informed that choosing not
to participate will not affect the care the participant will receive for the treatment of his or her
disease. Participants will be told that alternative treatments are available if they refuse to take part
and that such refusal will not prejudice future treatment. Finally, they will be told that the
investigator will maintain a participant identification register for the purposes of long-term
follow-up if needed and that their records may be accessed by health authorities and authorized
sponsor personnel without violating the confidentiality of the participant, to the extent permitted
by the applicable law(s) or regulations. By signing the ICF the participant is authorizing such
access, which includes permission to obtain information about his or her survival status. It also
denotes that the participant agrees to allow his or her study physician to recontact the participant
for the purpose of obtaining consent/assent for additional safety evaluations, and subsequent
disease-related treatments, if needed.
The participant 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/assent should be appropriately
recorded by means of the participant's personally dated signature. After having obtained the
consent/assent, a copy of the ICF must be given to the participant.


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A participant who is rescreened is not required to sign another ICF if the rescreening occurs within
30 days from the previous ICF signature date.
If the participant is unable to read or write, an impartial witness should be present for the entire
informed consent/assent process (which includes reading and explaining all written information)
and should personally date and sign the ICF after the oral consent/assent of the participant is
obtained.
Written assent should be obtained from participants who are able to write. A separate assent form
written in language the participant can understand should be developed for adolescents. After
having obtained the assent, a copy of the assent form will be given to the participant, and to the
participant's parent(s) or if applicable LAR.
Minor patients reaching the age of majority (per local regulatory requirements) during the study
will be required to sign an ICF.
DATA PROTECTION
Privacy of Personal Data
The collection and processing of personal data from participants enrolled in this study will be
limited to those data that are necessary to fulfill the objectives of the study.
These data must be collected and processed with adequate precautions to ensure confidentiality
and compliance with applicable data privacy protection laws and regulations. Appropriate
technical and organizational measures to protect the personal data against unauthorized disclosures
or access, accidental or unlawful destruction, or accidental loss or alteration must be put in place.
Sponsor personnel whose responsibilities require access to personal data agree to keep the identity
of participants confidential.
The informed consent/assent obtained from the participant includes explicit consent/assent for the
processing of personal data and for the investigator/institution to allow direct access to his or her
original medical records (source data/documents) for study-related monitoring, audit, IEC/IRB
review, and regulatory inspection. This consent/assent also addresses the transfer of the data to
other entities and to other countries.
The participant has the right to request through the investigator access to his or her personal data
and the right to request rectification of any data that are not correct or complete. Reasonable steps
will be taken to respond to such a request, taking into consideration the nature of the request, the
conditions of the study, and the applicable laws and regulations.
Exploratory biomarkerandPK 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


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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 additional research. Samples will only be used to understand JNJ-53718678, to understand
RSV infection, to understand differential intervention  responders, and to develop tests/assays
related to JNJ-53718678 and RSV infection. The research may begin at any time during the study
or the post-study storage period.
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/assent for their samples
to be stored for research (refer to Section 7.2, Withdrawal From the Use of Research Samples).
COMMITTEES STRUCTURE
An IDMC and EAC will be established as indicated in Section 9.5 and Section 9.6, respectively.
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 exploratory biomarker research data, generated as a
result of this study, are considered confidential and remain the sole property of the sponsor. The
investigator agrees to maintain this information in confidence and use this information only to
accomplish this study and will not use it for other purposes without the sponsor's prior written
consent/assent.
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 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.


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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 substudy approaches, secondary results generally should not be
published before the primary endpoints of a study have been published. Similarly, investigators
will recognize the integrity of a multicenter study by not submitting for publication data derived
from the individual study site until the combined results from the completed study have been
submitted for publication, within 18 months after the study end date, or the sponsor confirms there
will be no multicenter study publication. Authorship of publications resulting from this study will
be based on the guidelines on authorship, such as those described in the ICMJE Recommendations
for the Conduct, Reporting, Editing and Publication of Scholarly Work in Medical Journals, which
state that the named authors must have made a significant contribution to the conception or design
of the work; or the acquisition, analysis, or interpretation of the data for the work; and drafted the
work or revised it critically for important intellectual content; and given final approval of the
version to be published; and agreed to be accountable for all aspects of the work in ensuring that
questions related to the accuracy or integrity of any part of the work are appropriately investigated
and resolved.
Registration of Clinical Studies and Disclosure of Results
The sponsor will register and disclose the existence of and the results of clinical studies as required
by law. The disclosure of the final study results will be performed after the end of study in order
to ensure the statistical analyses are relevant.
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, direct transmission
of clinical laboratory data from a central laboratory, ECG and ePRO (eDevice) vendor 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


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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 eCRF. All eCRF entries, corrections, and
alterations must be made by the investigator or authorized study-site personnel. The investigator
must verify that all data entries in the eCRF are accurate and correct.
The study data will be transcribed by study-site personnel from the source documents onto an
eCRF, if applicable. Study-specific data will be transmitted in a secure manner to the sponsor.
Worksheets may be used for the capture of some data to facilitate completion of the eCRF. Any
such worksheets will become part of the participant's source documents. Data must be entered into
eCRF in English. The eCRF must be completed as soon as possible after a participant visit and the
forms should be available for review at the next scheduled monitoring visit.
All participative measurements (eg, pain scale information or other questionnaires) will be
completed by the same individual who made the initial baseline determinations whenever possible.
If necessary, queries will be generated in the eDC tool. If corrections to an eCRF are needed after
the initial entry into the eCRF, this can be done in either of the following ways:
 Investigator and study-site personnel can make corrections in the eDC tool at their own
initiative or as a response to an auto query (generated by the eDC tool).
 Sponsor or sponsor delegate can generate a query for resolution by the investigator and study-
site personnel.
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/assent; dates of visits; results of safety and efficacy parameters as required by
the protocol; record of all AEs and follow-up of AEs; concomitant medication; intervention
receipt/dispensing/return records; study intervention administration information; and date of study
completion and reason for early discontinuation of study intervention  or withdrawal from the
study, if applicable.
The author of an entry in the source documents should be identifiable.
Specific details required as source data for the study and source data collection methods will be
reviewed with the investigator before the study and will be described in the monitoring guidelines
(or other equivalent document).


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The following data may be recorded directly into the eCRF and will be considered source data:
 Race
 History of smoking and all nicotine use, eg, cigarettes (including e-cigarettes or the equivalent
of e-cigarettes), cigars, chewing tobacco, patch, gum
 Blood pressure and pulse/heart rate
 Height and weight
 Details of physical examination
The minimum source documentation requirements for Section 5.1, Inclusion Criteria and
Section 5.2, Exclusion Criteria that specify a need for documented medical history are as follows:
 Referral letter from treating physician or
 Complete history of medical notes at the site
 Discharge summaries
 Chest X-ray and local radiologist’s or investigator’s interpretation
Inclusion and exclusion criteria not requiring documented medical history must be verified at a
minimum by participant interview or other protocol required assessment (eg, physical
examination, laboratory assessment) and documented in the source documents.
MONITORING
The sponsor will use a combination of monitoring techniques central, remote, or on-site monitoring
to monitor this study.
The sponsor will perform on-site monitoring visits as frequently as necessary. The monitor will
record dates of the visits in a study site visit log that will be kept at the study site. The first post-
initiation visit will be made as soon as possible after enrollment has begun. At these visits, the
monitor will compare the data entered into the eCRF with the source documents
(eg, hospital/clinic/physician’s office medical records). The nature and location of all source
documents will be identified to ensure that all sources of original data required to complete the
eCRF are known to the sponsor and study-site personnel and are accessible for verification by the
sponsor study-site contact. If electronic records are maintained at the study site, the method of
verification must be discussed with the study-site personnel.
Direct access to source documents (medical records) must be allowed for the purpose of verifying
that the recorded data are consistent with the original source data. Findings from this review will
be discussed with the study-site personnel. The sponsor expects that, during monitoring visits, the
relevant study-site personnel will be available, the source documents will be accessible, and a
suitable environment will be provided for review of study-related documents. The monitor will
meet with the investigator on a regular basis during the study to provide feedback on the study
conduct.


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In addition to on-site monitoring visits, remote contacts can occur. It is expected that during these
remote contacts, study-site personnel will be available to provide an update on the progress of the
study at the site.
Central monitoring will take place for data identified by the sponsor as requiring central review.
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 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.


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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 study intervention 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 intervention. An AE can therefore be any unfavorable and unintended sign
(including an abnormal finding), symptom, or disease temporally associated with the use of a
medicinal (investigational or non-investigational) product, whether or not related to that medicinal
(investigational or non-investigational) product. (Definition per ICH)
This includes any occurrence that is new in onset or aggravated in severity or frequency from the
baseline condition, or abnormal results of diagnostic procedures, including laboratory test
abnormalities.
Note: The sponsor collects AEs starting with the signing of the main ICF (refer to All Adverse
Events under Section 8.4.1, Time Period and Frequency for Collecting Adverse Events and Serious
Adverse Events Information, for time of last AE recording). For participants having signed a
diagnostic ICF only (ie, who do not enroll in the study by signing the main ICF), reporting will be
limited to AEs considered related to the sampling procedure.
Serious Adverse Event
A SAE based on ICH and EU Guidelines on Pharmacovigilance for Medicinal Products for Human
Use is any untoward medical occurrence that at any dose:
 
Results in death
 
Is life-threatening
(The participant was at risk of death at the time of the event. It does not refer to an event that
hypothetically might have caused death if it were more severe.)
 
Requires inpatient hospitalization or prolongation of existing hospitalization
 
Results in persistent or significant disability/incapacity
 
Is a congenital anomaly/birth defect
 
Is a suspected transmission of any infectious agent via a medicinal product
 
Is Medically Important*
*Medical and scientific judgment should be exercised in deciding whether expedited reporting is
also appropriate in other situations, such as important medical events that may not be immediately
life-threatening or result in death or hospitalization but may jeopardize the participant or may
require intervention to prevent one of the other outcomes listed in the definition above. These
should usually be considered serious.


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Note: Abnormalities in liver function tests (see Appendix 10.2) are considered as medically
important. Details of liver chemistry stopping criteria and required actions and follow-up
assessments after liver stopping or monitoring event are given in Appendix 10.6 Liver Safety. All
events of ALT 3 × upper limit of normal (ULN) and bilirubin 2 × ULN (>35% direct bilirubin)
or ALT 3 × ULN and international normalized ratio (INR*) >1.5, if INR measured, which may
indicate severe liver injury (possible Hy’s Law), must be reported as a SAE. See also Section 8.4.
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 and any Addenda.34
Adverse Event Associated With the Use of the Intervention
An AE is considered associated with the use of the intervention  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 intervention.
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 is unlikely.
Possible
An AE that might be due to the use of the intervention. An alternative explanation, eg, concomitant
treatment(s), concomitant disease(s), is inconclusive. The relationship in time is reasonable;
therefore, the causal relationship cannot be excluded.
Probable
An AE that might be due to the use of the intervention. The relationship in time is suggestive
(eg, confirmed by dechallenge). An alternative explanation is less likely, eg, concomitant
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:


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Mild: Awareness of symptoms that are easily tolerated, causing minimal discomfort and not
interfering with everyday activities.
Moderate: Sufficient discomfort is present to cause interference with normal activity.
Severe: Extreme distress, causing significant impairment of functioning or incapacitation.
Prevents normal everyday activities.
The investigator should use clinical judgment in assessing the severity of events not directly
experienced by the participant (eg, laboratory abnormalities).
For more details, refer to the DMID severity grading scale (see Appendix 10.7).
SPECIAL REPORTING SITUATIONS
Safety events of interest on a sponsor study intervention in an interventional studythat may require
expedited reporting or safety evaluation include, but are not limited to:
 
Overdose of a sponsor study intervention
 
Suspected abuse/misuse of a sponsor study intervention
 
Accidental or occupational exposure to a sponsor study intervention
 
Medication error involving a sponsor product (with or without participant/patient exposure to
the sponsor study intervention, eg, name confusion)
Special reporting situations should be recorded in the eCRF. Any special reporting situation that
meets the criteria of a SAE should be recorded on the SAE page of the eCRF.
PROCEDURES
All Adverse Events
All AEs, regardless of seriousness, severity, or presumed relationship to study intervention, must
be recorded using medical terminology in the source document and the eCRF. Whenever possible,
diagnoses should be given when signs and symptoms are due to a common etiology (eg, cough,
runny nose, sneezing, sore throat, and head congestion should be reported as "upper respiratory
infection"). Investigators must record in the eCRF their opinion concerning the relationship of the
AE to study therapy. All measures required for AE management must be recorded in the source
document and reported according to sponsor instructions.
For all studies with an outpatient phase, including open-label studies, the participant 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


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 
Local sponsor's name and 24-hour contact telephone number (for medical personnel only)
 
Site number
 
Participant number
 
Any other information that is required to 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 intervention or to factors unrelated
to study conduct
 
It becomes unlikely that any additional information can be obtained (participant or health care
practitioner refusal to provide additional information, lost to follow-up after demonstration of
due diligence with follow-up efforts)
Suspected transmission of an infectious agent by a medicinal product will be reported as a 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 a 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.
Disease progression should not be recorded as an AE term or SAE term; instead, signs and
symptoms of clinical sequelae resulting from disease progression/lack of efficacy will be reported
if they fulfill the SAE definition. Follow-up will end at Day 49; there is no longer term follow-up
planned.
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 a SAE, the study-site personnel must report the PQC to the sponsor
according to the SAE reporting timelines (refer to Section 8.4.1, 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: Contraceptive and Barrier Guidance and Collection of
Pregnancy Information
Participants must follow contraceptive measures as outlined in Section  5.1, Inclusion Criteria.
Pregnancy information will be collected and reported as noted in Section 8.4.5, Pregnancy and
Appendix 10.4, Adverse Events: Definitions and Procedures for Recording, Evaluating, Follow-
up, and Reporting.
Definitions
Woman of Childbearing Potential (WOCBP)
A woman is considered fertile following menarche and until becoming postmenopausal unless
permanently sterile (see below).
Woman Not of Childbearing Potential
 
premenarchal
A premenarchal state is one in which menarche has not yet occurred.
 
postmenopausal
A postmenopausal state is defined as no menses for 12 months without an alternative medical
cause. A high follicle stimulating hormone (FSH) level (>40 IU/L or mIU/mL) in the
postmenopausal range may be used to confirm a postmenopausal state in women not using
hormonal contraception or hormonal replacement therapy (HRT), however in the absence of
12 months 
of 
amenorrhea, 
a 
single 
FSH 
measurement 
is 
insufficient.
If there is a question about menopausal status in women on HRT, the woman will be required
to use one of the non-estrogen-containing hormonal highly effective contraceptive methods if
she wishes to continue HRT during the study.
 
permanently sterile
Permanent sterilization methods include hysterectomy, bilateral salpingectomy, and bilateral
oophorectomy.
 
sterile due to pretransplant conditioning protocols
Note: If the childbearing potential changes after start of the study (eg, a premenarchal woman
experiences menarche) or the risk of pregnancy changes (eg, a woman who is not heterosexually
active becomes active), a woman must begin a highly effective method of contraception, as
described throughout the inclusion criteria.
If reproductive status is questionable, additional evaluation should be considered.
Examples of Contraceptives
EXAMPLES OF CONTRACEPTIVESa ALLOWED DURING THE STUDY INCLUDE:
USER-INDEPENDENT
Highly Effective Methods That Are User-Independent Failure rate of ≤1% per year when used
consistently and correctly.
 Implantable progestogen-only hormone contraception associated with inhibition of ovulationb
 Intrauterine device (IUD)


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 Intrauterine hormone-releasing system (IUS)
 Bilateral tubal occlusion/ligation without reversal operation
 Vasectomized partner
(Vasectomized partner is a highly effective contraceptive method provided that the partner is the
sole sexual partner of the woman of childbearing potential and the absence of sperm has been
confirmed. If not, additional highly effective method of contraception should be used.
Spermatogenesis cycle is approximately 74 days.)
USER DEPENDENT
Highly Effective Methods That Are User Dependent Failure rate of <1% per year when used
consistently and correctly.
 Combined (estrogen- and progestogen-containing) hormonal contraception associated with
inhibition of ovulationb
 oral
 intravaginal
 transdermal
 injectable
 Progestogen-only hormone contraception associated with inhibition of ovulationb
 oral
 injectable
 Sexual abstinence
(Sexual abstinence is considered a highly effective method only if defined as refraining from
heterosexual intercourse during the entire period of risk associated with the study intervention. The
reliability of sexual abstinence needs to be evaluated in relation to the duration of the study and the
preferred and usual lifestyle of the participant.)
NOT ALLOWED AS SOLE METHOD OF CONTRACEPTION DURING THE STUDY (not
considered to be highly effective - failure rate of >1% per year)
 Progestogen-only oral hormonal contraception where inhibition of ovulation is not the primary
mode of action.
 Male or female condom with or without spermicidec
 Cap, diaphragm, or sponge with spermicide
 A combination of male condom with either cap, diaphragm, or sponge with spermicide (double-
barrier methods)c
 Periodic abstinence (calendar, symptothermal, post-ovulation methods)
 Withdrawal (coitus-interruptus)
 Spermicides alone
 Lactational amenorrhea method (LAM)
a) Typical use failure rates may differ from those when used consistently and correctly. Use should be
consistent with local regulations regarding the use of contraceptive methods for participants in
clinical studies.
b) Hormonal contraception may be susceptible to interaction with the study drug, which may reduce
the efficacy of the contraceptive method. In addition, consider if the hormonal contraception may
interact with the study drug.
c) Male condom and female condom should not be used together (due to risk of failure with friction).






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documentation of whether parenteral vitamin K was given, along with the effect of such treatment
on INR. 
If initial LTs and ultrasound do not suggest Gilbert’s syndrome, biliary tract disease or obstruction,
viral hepatitis serology should be obtained including anti-HAV IgM, anti-HAV total, HBsAg, anti-
HBs, anti-HB core total, anti-HB core IgM, anti-HCV, anti-HEV IgM (even if the participant has
not traveled to an endemic area for hepatitis E), EBV, and CMV screen. 
a. If participant is immunosuppressed, test for HCV RNA and HEV RNA by PCR
b. If HBsAg or anti-HB core IgM or anti-HB core IgG positive, also get HBV DNA to detect
active HepB, especially in participants who are immunosuppressed.
c. If all other hepatitis B serologic tests are negative and anti-HBc total is the only positive
test, HBV DNA should be obtained to detect reactivation of hepatitis B.
Assuming that the history, physical, and initial imaging and laboratory have not revealed a cause
of elevated LTs, screen for other causes of liver disease including: total protein and albumin
(estimate globulin fraction and do quantitative immunoglobulins if elevated), ANA, anti-LKM1
(anti liver-kidney microsomal antibodies), ASMA (anti-smooth muscle antibodies), ESR, and
CRP. If the pattern of laboratory abnormalities is not hepatocellular, but cholestatic or a mixed
pattern (see definitions in table above), then GGT, AMA (anti-mitochondrial antibody) and
pANCA (anti-neutrophil cytoplasmic antibody) should also be tested. If there is an indication by
history or elevated baseline LTs that there may be an underlying chronic liver disease possibly
exacerbated by exposure to the study drug in the clinical trial or making the participant more
susceptible to DILI, test iron/TIBC and ferritin (hemochromatosis), and alpha-1-antitrypsin level.
If participant is <50 years of age, ceruloplasmin should also be tested to screen for Wilson’s
disease. If participant is sick enough to be hospitalized and is under age 50, a slit lamp examination
to detect Kayser-Fleischer rings and a 24-hour urine copper should be measured. Consider serum
ethanol and/or acetaminophen level and urine drug screen as clinically appropriate. 
A liver biopsy should be considered if autoimmune hepatitis remains a competing etiology and if
immunosuppressive therapy is contemplated. A liver biopsy may be considered:
a. If there is unrelenting rise in liver biochemistries or signs of worsening liver function
despite stopping the suspected offending agent.
b. If peak ALT level has not fallen by >50% at 30-60 days after onset in cases of
hepatocellular DILI, or if peak AlkP has not fallen by >50% at 180 days in cases of
cholestatic DILI despite stopping the suspected offending agent.
c. In cases of DILI where continued use or re-exposure to the implicated agent is expected. 
d. If liver biochemistry abnormalities persist beyond 180 days to evaluate for the presence
of chronic liver diseases and chronic DILI. 
If pertinent, copies of hospital discharge summary, radiology, pathology, and autopsy reports
should be obtained.


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10.7. Appendix 7: Toxicity Tables
DIVISION OF MICROBIOLOGY AND INFECTIOUS DISEASES (DMID) ADULT
TOXICITY TABLE42 – NOVEMBER 2007
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 Extreme limitation in activity, significant assistance
required; significant medical intervention/therapy required, hospitalization or
hospice care probable
SERIOUS OR LIFE-THREATENING AEs
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 World Health Organization [WHO]) have been adapted for
use by the Division of Microbiology and Infectious Diseases (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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HEMATOLOGY
Grade 1 
Grade 2 
Grade 3 
Grade 4
Hemoglobin  
9.5 - 10.5 gm/dL 
8.0 - 9.4gm/dL 
6.5 - 7.9 gm/dL 
< 6.5 gm/dL
Absolute Neutrophil Count 1,000-1,500/ mm3 
750-999/ mm3 
500-749/ mm3 
<500/ mm3
Platelets 
75,000- 
99,999/ mm3 
50,000- 
74,999/ mm3
20,000-49,999/ mm3 
<20,000/ mm3
WBCs 
11,000-13,000/ 
mm3 
13,000- 
15,000 / mm3 
15,000- 
30,000/ mm3 
>30,000 or
<1,000 / mm3
% Polymorphonuclear 
Leucocytes + Band Cells
> 80%  
90 –95% 
>95%  
----------
Abnormal Fibrinogen  
Low: 
100-200 mg/dL 
High: 
400-600 mg/dL 
Low: 
<100 mg/dL 
High: 
>600 mg/dL 
Low: 
< 50 mg/dL 
---------- 
Fibrinogen
associated with gross
bleeding or with
disseminated
coagulation
Fibrin Split Product 
20-40 mcg/ mL 
41-50 mcg/ mL 
51-60 mcg/ mL 
> 60 mcg/ mL
Prothrombin Time (PT) 
1.01 - 1.25 x ULN  
1.26-1.5 x ULN  
1.51 -3.0 x ULN  
>3 x ULN
Activated Partial 
Thromboplastin (APPT)
1.01 -1.66 x ULN  
1.67 - 2.33 x ULN  
2.34 - 3 x ULN  
> 3 x ULN
Methemoglobin  
5.0 - 9.9 %  
10.0 - 14.9 %  
15.0 - 19.9% 
> 20.0 %


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CHEMISTRIES
Grade 1 
Grade 2 
Grade 3 
Grade 4
Hyponatremia 
130-135 mEq/ L 123-129 mEq/ L 
116-122 mEq/ L 
< 116 mEq/ L or abnormal sodium
with mental
status changes or seizures
Hypernatremia 
146-150 mEq/ L 151-157 mEq/ L 
158-165 mEq/ L 
> 165 mEq/ L or abnormal sodium
with mental
status changes or seizures
Hypokalemia 
3.0 - 3.4 mEq/ L 2.5 - 2.9 mEq/ L 2.0 - 2.4 mEq/ L or 
intensive replacement 
therapy or 
hospitalization 
required
< 2.0 mEq/ L or abnormal
potassium with
paresis, ileus or life-threatening
arrhythmia
Hyperkalemia 
5.6 - 6.0 mEq/ L 6.1 - 6.5 mEq/ L 
6.6 - 7.0 mEq/l 
> 7.0 mEq/ L or abnormal
potassium with life-threatening
arrhythmia
Hypoglycemia 
55-64 mg/dL 
40-54 mg/dL 
30-39 mg/dL 
<30 mg/dL or abnormal glucose
with mental
status changes or coma
Hyperglycemia
(nonfasting and no
prior diabetes)
116 - 160 mg/dL 161- 250 mg/d L 
251 - 500 mg/dL 
> 500 mg/dL or abnormal glucose
with ketoacidosis or seizures
Hypocalcemia
(corrected for
albumin)
8.4 - 7.8 mg/dL 7.7 - 7.0 mg/dL 
6.9 - 6.1 mg/dL 
< 6.1 mg/dL or abnormal
calcium with life-threatening
arrhythmia or tetany


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CHEMISTRIES (continued)
Grade 1 
Grade 2 
Grade 3 
Grade 4
Hypercalcemia (correct for 
albumin) 
10.6 - 11.5 mg/dL 
11.6 - 12.5 
mg/d L 
12.6 - 13.5 mg/dL > 13.5 mg/dL or abnormal
calcium with life-
threatening arrhythmia
Hypomagnesemia 
1.4 - 1.2 mEq/ L 1.1 - 0.9 mEq/ L 
0.8 - 0.6 mEq/ L 
< 0.6 mEq/ L or abnormal
magnesium with life-
threatening arrhythmia
Hypophosphatemia 
2.0 - 2.4 mg/dL 1.5 -1.9 mg/dL or 
replacement Rx 
required 
1.0 -1.4 mg/dL 
intensive therapy or 
hospitalization 
required
< 1.0 mg/dL or abnormal
phosphate with life-
threatening arrhythmia
Hyperbilirubinemia (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
Hyperbilirubinemia (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
BUN  
1.25 - 2.5 x ULN  
2.6 - 5 x ULN  
5.1 - 10 x ULN  
> 10 x ULN
Hyperuricemia (uric acid) 
7.5 –10.0 mg/dL 
10.1 –12.0 
mg/dL
12.1 –15.0 mg/d L 
>15.0 mg/d L
Creatinine 
1.1 - 1.5 x ULN  
1.6 - 3.0 x ULN  
3.1 - 6 x ULN  
>6 x ULN or dialysis
required
ENZYMES
Grade 1 
Grade 2 
Grade 3 
Grade 4
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
Alkaline Phosphatase 
1.1 - <2.0 x ULN  
2.0 –<3.0 x ULN  
3.0 –8.0 x ULN  
> 8 x ULN
Amylase 
1.1 - 1.5 x ULN  
1.6 - 2.0 x ULN  
2.1 - 5.0 x ULN  
> 5.1 x ULN
Lipase 
1.1 - 1.5 x ULN  
1.6 - 2.0 x ULN  
2.1 - 5.0 x ULN  
> 5.1 x ULN


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URINALYSIS
Grade 1 
Grade 2 
Grade 3 
Grade 4
Proteinuria 
1+  
or 
200 mg - 1 gm 
loss/day
2-3+  
or 
1- 2 gm loss/day  
4+ 
or 
2-3.5 gm loss/day  
nephrotic syndrome
or
>3.5 gm loss/day
Hematuria 
microscopic only
<10 rbc/hpf
gross, no clots
>10 rbc/hpf
gross, with or without
clots, OR RBC casts
obstructive or
required
transfusion
CARDIOVASCULAR
Grade 1 
Grade 2 
Grade 3 
Grade 4
Cardiac Rhythm  
asymptomatic, 
transient signs, no 
Rx required 
recurrent/persistent; 
symptomatic Rx 
required 
unstable
dysrhythmia;
hospitalization
and treatment
required
Hypertension  
transient increase 
>20 mm/ Hg; no 
treatment 
recurrent, chronic 
increase 
> 20mm/ Hg 
/treatment required 
acute treatment 
required; outpatient 
treatment or 
hospitalization
possible
end organ damage or
hospitalization
required
Hypotension  
transient orthostatic 
hypotension with 
heart rate increased 
by <20 beat/min or 
decreased by <10 
mm Hg systolic BP, 
No treatment 
required
symptoms due to 
orthostatic 
hypotension or BP 
decreased by <20 
mm Hg systolic; 
correctable with oral 
fluid treatment 
requires IV fluids; no 
hospitalization 
required 
mean arterial
pressure
<60mm/ Hg or end
organ damage or
shock; requires
hospitalization and
vasopressor treatment
Pericarditis 
minimal effusion 
mild/ moderate 
asymptomatic 
effusion, no 
treatment
symptomatic 
effusion; pain; EKG 
changes 
tamponade;
pericardiocentesis or
surgery required
Hemorrhage, Blood Loss 
microscopic/occult mild, no transfusion 
gross blood loss; 
1-2 units transfused 
massive blood loss;
>3 units transfused


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RESPIRATORY
Grade 1 
Grade 2 
Grade 3 
Grade 4
Cough  
transient- no 
treatment 
persistent cough; 
treatment responsive 
Paroxysmal cough; 
uncontrolled with
treatment
--------------------
Bronchospasm, Acute 
transient; no 
treatment; 
70% - 80% FEV1 
of peak flow  
requires 
treatment; normalizes 
with bronchodilator; 
FEV1 50% - 
70% 
(of peak flow)
no normalization 
with bronchodilator; 
FEV1 25% - 50% 
of peak flow; or 
retractions present
cyanosis: FEV1
<25%
of peak flow or
intubation necessary
Dyspnea 
dyspnea on exertion dyspnea with normal 
activity  
dyspnea at rest 
dyspnea requiring
oxygen therapy
GASTROINTESTINAL
Grade 1 
Grade 2 
Grade 3 
Grade 4
Nausea
mild or transient; 
maintains 
reasonable intake 
moderate discomfort; 
intake decreased 
significantly; some
activity limited
no significant intake; 
requires IV flu ids 
hospitalization
required;
Vomiting 
1 episode in 24 hours 
2-5 episodes in  
24 hours 
>6 episodes in 
24 hours or needing 
IV fluids 
physiologic
consequences
requiring
hospitalization or
requiring parenteral
nutrition
Constipation  
requiring stool 
softener or dietary 
modification 
requiring 
laxatives 
obstipation  
requiring manual 
evacuation or enema
obstruction or
toxic megacolon
Diarrhea 
mild or transient; 3-4 
loose 
stools/day or mild 
diarrhea last <1 week  
moderate or 
persistent; 5-7 loose 
stools/day or diarrhea 
lasting >1 week  
>7 loose stools/day  
or bloody diarrhea; or 
orthostatic 
hypotension or 
electrolyte imbalance 
or >2L IV fluids
required
hypotensive shock or
physiologic
consequences
requiring
hospitalization
Oral Discomfort/Dysphagia mild discomfort; no 
difficulty  
swallowing 
some limits on 
eating/drinking 
eating/talking very 
limited; unable to 
swallow solid foods
unable to drink flu
ids; requires IV fluids


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NEUROLOGICAL
Grade 1 
Grade 2 
Grade 3 
Grade 4
Neuro-Cerebellar 
slight incoordination 
dysdiadochokinesis 
intention tremor, 
dysmetria,
slurred speech;
nystagmus
locomotor ataxia 
incapacitated
Psychiatric 
mild anxiety or 
depression  
moderate anxiety or 
depression; therapy 
required; change in 
normal routine 
severe mood changes 
requiring therapy; or 
suicidal ideation; or 
aggressive ideation  
acute psychosis
requiring
hospitalization; or
suicidal
gesture/attempt or
hallucinations
Muscle Strength  
subjective weakness 
no objective 
symptoms/ signs 
mild objective 
signs/symptoms no 
decrease in function
objective weakness 
function limited
paralysis
Paresthesia (burning, 
tingling, etc.) 
mild discomfort; no 
treatment required 
moderate discomfort; 
non-narcotic 
analgesia required 
severe discomfort; or 
narcotic analgesia 
required with 
symptomatic
improvement
incapacitating; or not
responsive to narcotic
analgesia
Neuro-sensory  
mild impairment in 
sensation  
(decreased 
sensation, eg, 
vibratory, pinprick, 
hot/cold in great toes) 
in focal area or 
symmetrical 
distribution; or 
change in taste, 
smell, vision and/or
hearing
moderate 
impairment (mod 
decreased sensation, 
eg, vibratory, 
pinprick, hot/cold to 
ankles) and/or joint 
position or mild 
impairment that is 
not 
symmetrical 
severe impairment 
(decreased or loss of 
sensation to knees or 
wrists) or loss of
sensation of at least
mod degree in
multiple
different body areas
(ie, upper and lower
extremities)
sensory loss involves
limbs and trunk;
paralysis; or seizures


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MUSCULOSKELATEL
Grade 1 
Grade 2 
Grade 3 
Grade 4
Arthralgia (joint pain) 
mild pain not 
interfering with 
function 
moderate pain, 
analgesics and/or pain 
interfering with 
function but not with 
activities of daily 
living
severe pain; pain 
and/or analgesics
interfering with
activities of daily
living
disabling pain
Arthritis 
mild pain with  
inflammation, 
erythema or joint 
swelling –but not 
interfering with  
function 
moderate pain with  
inflammation, 
erythema or joint 
swelling –interfering 
with function, but not 
with activities of 
daily living 
severe pain with  
inflammation, 
erythema or joint 
swelling –and
interfering with
activities of daily
living
permanent and/or
disabling joint
destruction
Myalgia 
Myalgia with no 
limitation of activity  
muscle 
tenderness (at other 
than injection site) or 
with moderate 
impairment of
activity
severe muscle 
tenderness with  
marked impairment
of activity
frank
myonecrosis
SKIN
Grade 1 
Grade 2 
Grade 3 
Grade 4
Mucocutaneous 
erythema; pruritus 
diffuse, 
maculopapular rash, 
dry desquamation  
vesiculation or 
moist desquamation 
or ulceration  
exfoliative
dermatitis, mucous
membrane
involvement or
erythema,
multiforme or
suspected
Stevens-Johnson
or necrosis requiring
surgery
Induration  
<15mm  
15-30 mm  
>30mm
Erythema 
<15mm  
15-30 mm  
>30mm
Edema 
<15mm  
15-30 mm  
>30mm
Rash at Injection Site 
<15mm  
15-30 mm  
>30mm
Pruritus 
slight itching at 
injection site 
moderate itching at 
injection extremity  
itching over entire
body


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SYSTEMIC
Grade 1 
Grade 2 
Grade 3 
Grade 4
Allergic Reaction 
pruritus without rash  localized urticaria generalized urticaria; 
angioedema
anaphylaxis
Headache 
mild, no treatment 
required 
transient, moderate; 
treatment required 
severe; responds to 
initial narcotic 
therapy  
intractable; requires
repeated narcotic
therapy
Fever: oral 
37.7 - 38.5 C or 
100.0 - 101.5 F  
38.6 - 39.5 C or 
101.6 - 102.9 F  
39.6 - 40.5 C or 103 - 
105 F  
>40 C or
>105 F
Fatigue 
normal activity 
reduced < 48 hours 
normal activity 
decreased 25- 
50% > 48 hours 
normal activity  
decreased > 50%
can’t work
unable to care for self


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10.8. Appendix 8: General Guidelines for Measuring Vital Signs and SpO2
Variability in the measurement of vital signs and SpO2 is to be expected due to a number of reasons;
therefore, general guidelines for measuring vital signs and SpO2 have been developed to have a more
consistent approach across sites and countries related to the methodology for measuring these clinical
parameters. General instructions are provided in Section 2 for both inpatient and outpatient level of care.
Parameter 
General Instructions
Blood Pressure 
 
While participant is hospitalized, if possible, use the same blood pressure
measurement methodology for all patients enrolled at the site.
 
Prior to the measurement, participant needs to be rested for at least 5 minutes
and preferably 10 minutes in a quiet setting without distractions.
 
Participant can be in either a sitting or supine position. In the sitting position,
the participant should be comfortably seated, with the legs uncrossed. When
measurements are taken in the supine position, the arm should be supported
with a pillow.
 
Blood pressure measurements should preferentially be assessed with a
completely automated device. Manual techniques will be used only if an
automated device is not available.
 
If an automated device is not available, a properly maintained mercury
sphygmomanometer 
is 
preferred 
over 
aneroid 
and 
hybrid
sphygmomanometers. When using a mercury sphygmomanometer, the
mercury column should be deflated at 2 to 3 mm/s, and the first and last
audible sounds should be taken as systolic and diastolic pressure. The column
should be read to the nearest 2 mm Hg.
 
Preferentially, the standard location for blood pressure measurement is the
upper arm, with the stethoscope at the elbow crease over the brachial artery
(with manual technique). Clothing that covers the arm should be removed
prior to the placement of the cuff.
Heart Rate 
 
While participant is hospitalized, if possible, use the same heart rate
measurement methodology for all patients enrolled at the site.
 
Prior to the measurement, participant needs to be rested for at least 5 minutes,
and preferably 10 minutes in a quiet setting without distractions.
 
Participant can be in either a sitting or supine position.
 
Heart rate measurements should preferentially be assessed with a completely
automated device.
 
Manual techniques will be used only if an automated device is not available.
 
If manual measurement, auscultation of the heart or pulse (radial, brachial)
determination are considered acceptable.
 
If manual measurement, 30 seconds (minimum) or 1 minute (preferred) count
are considered acceptable.
Respiratory Rate 
 
While participant is hospitalized, if possible, use the same respiratory rate
measurement methodology for all patients enrolled at the site.


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 
Prior to the measurement, participant needs to be rested for at least 5 minutes,
and preferably 10 minutes in a quiet setting without distractions.
 
Participant can be in either a sitting or supine position.
 
Respiratory rate measurements can be assessed with an automated device or
with manual measurement (no preference).
 
If manual measurement is used, inspection (preferred) or auscultation of the
lungs (alternative) are considered acceptable.
 
If manual measurement, 30 seconds (minimum) or 1 minute (preferred) count
are considered acceptable.
Temperature 
 
While participant is hospitalized, if possible, use the same type of
temperature measurement methodology for all participants enrolled at the
site.
 
Electronic devices (tympanic, oral) are preferred over traditional mercury
thermometers (for oral temperature).
 
Tympanic (preferred) or oral (alternative) temperature measurements are
considered acceptable. Axillary temperature should be avoided since it
provides the worst estimate of core temperature and it is largely influenced
by environmental conditions.
SpO2 
 
While participant is hospitalized, if possible, use the same type of probe for
all patients enrolled at the site.
 
Prior to the measurement, participant needs to be rested for at least 5 minutes,
and preferably 10 minutes in a quiet setting without distractions.
 
Participant can be in either a sitting or supine position.
 
Pulse oximetry measurements using finger, toe, earlobe or frontal sensors are
considered acceptable. If using the digits, assess for warmth and capillary
refill, since adequate arterial pulse strength is necessary for obtaining
accurate SpO2 measurements.
 
Avoid placing the sensor on sites distal to indwelling arterial catheters, blood
pressure cuffs, or venous engorgement (eg, arteriovenous fistulas, blood
transfusions).
 
For hospitalized participants receiving supplemental O2, the measurement
should be performed after 5 minutes on room air.
 
If it is determined by the investigator that it is unsafe to remove the
participant’s supplemental O2 for assessment of O2 saturation (eg, participant
is on high-flow mask), then it should be recorded in the source documentation
as not assessed and the reason should be documented.


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10.9. Appendix 9: Respiratory Infection Intensity and Impact Questionnaire
(RiiQ™)
10.9.1. 
Respiratory Infection Intensity and Impact Questionnaire (RiiQ™)a
Symptom Scale
Please read each of the following questions and select the answer thinking about when you felt
the worst in the past 24 hours.
1. During the past 24 hours, have you had the following symptoms?
None 
Mild 
Moderate 
Severe
a. Cough 
 
 
 

b. Sore throat 
 
 
 

c. Headache 
 
 
 

d. Nasal congestion 
 
 
 

e. Feeling feverish 
 
 
 

f. Body aches and pains 
 
 
 

g. Fatigue (tiredness) 
 
 
 

h. Neck pain 
 
 
 

i. Interrupted sleep  
 
 
 

j. Wheezing 
 
 
 

k. Coughing up phlegm 
(sputum)
 
 
 

l. Short of breath 
 
 
 

m. Loss of appetite 
 
 
 

a Influenzaintensity and impact questionnaire (Flu iiQ  
TM ) ©RH Osborne (2006). No part of the Flu iiQ  
TM may be copied or
reproduced in any form without written permission from the authors: measuredsolutions@bigpond.com
(English
administration once daily)
Adapted with permission of RH Osborne.


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10.9.2. 
Respiratory Infection Intensity and Impact Questionnaire (RiiQ™)a
Impact Scales
2. During the past 24 hours, how able were you to:
No Difficulty
Some 
Difficulty 
Moderate 
Difficulty 
Great
Difficulty
a. Get out of bed 
 
 
 

b. Prepare meals / get 
your own food
 
 
 

c. Perform usual activities 
 
 
 

d. Leave the home 
 
 
 

e. Concentrate on tasks 
 
 
 

f. Take care of yourself 
 
 
 

g. Go out of the room you 
are in
 
 
 

3. During the past 24 hours, have you felt:
Not at all 
Somewhat 
Moderately 
Extremely
a. Irritable 
 
 
 

b. Helpless 
 
 
 

c. Worried 
 
 
 

d. Frustrated 
 
 
 

a Influenzaintensity and impact questionnaire (Flu iiQ  
TM ) ©RH Osborne (2006). No part of the Flu iiQ  
TM may be copied or
reproduced in any form without written permission from the authors: measuredsolutions@bigpond.com
(English
administration once daily)
Adapted with permission of RH Osborne.


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4. During the past 24 hours, have you been concerned about:
Not at all 
concerned 
Somewhat 
concerned 
Moderately 
concerned 
Extremely
concerned
a. People worrying about you 
 
 
 

b. Being a burden 
 
 
 

c. People being annoyed with 
you
 
 
 

d. Needing to depend on people 
 
 
 

e. People having to do extra 
things for you
 
 
 



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10.10. Appendix 10: Patient Global Impression [PGI] Scales
Patient Global Impression of Severity (PGIS) for RSV studies
Overall, how severe were your respiratory infection symptoms today?
a. No respiratory infection symptoms today
b. Mild
c. Moderate
d. Severe
e. Very Severe
Patient Global Impression of Change (PGIC) for RSV studies
Overall, how were your respiratory infection symptoms today compared to yesterday?
 Much better
 Somewhat better
 A little better
 About the same
 A little worse
 Somewhat worse
 Much worse
Patient Global Impression of Health (PGIH) for RSV studies
In general, how would you rate your physical health today?
 Excellent
 Very good
 Good
 Fair
 Poor


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10.11. Appendix 11: 5-level EuroQol 5-Dimension Questionnaire (EQ-5D-5L)
Health Questionnaire
English version for the USA
USA (English) © 2009 EuroQol Group. EQ 5D™ is a trade mark of the EuroQol Group


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Under each heading, please check the ONE box that best describes your health TODAY
MOBILITY
I have no problems walking 

I have slight problems walking 

I have moderate problems walking 

I have severe problems walking 

I am unable to walk  

SELF-CARE
I have no problems washing or dressing myself 

I have slight problems washing or dressing myself 

I have moderate problems washing or dressing myself 

I have severe problems washing or dressing myself 

I am unable to wash or dress myself 

USUAL ACTIVITIES (e.g. work, study, housework,
family or leisure activities)
I have no problems doing my usual activities 

I have slight problems doing my usual activities 

I have moderate problems doing my usual activities 

I have severe problems doing my usual activities 

I am unable to do my usual activities 

PAIN / DISCOMFORT
I have no pain or discomfort 

I have slight pain or discomfort 

I have moderate pain or discomfort 

I have severe pain or discomfort 

I have extreme pain or discomfort 

ANXIETY / DEPRESSION
I am not anxious or depressed 

I am slightly anxious or depressed 

I am moderately anxious or depressed 

I am severely anxious or depressed 

I am extremely anxious or depressed 

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 We would like to know how good or bad your health is
TODAY.
 This scale is numbered from 0 to 100.
 100 means the best health you can imagine.
0 means the worst health you can imagine.
 Mark an X on the scale to indicate how your health is TODAY.
 Now, please write the number you marked on the scale in the box
below.
YOUR HEALTH TODAY 
USA (English) © 2009 EuroQol Group. EQ 5D™ is a trade mark of the EuroQol Group
10
0
20
30
40
50
60
80
70
90
100
5
15
25
35
45
55
75
65
85
95
The best health 
you can imagine
The worst health
you can imagine


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10.12. Appendix 12: 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 (or their caregivers for adolescents)will be interviewed to collect safety data.
Key efficacy endpoint assessments should be performed if required and as feasible. Participants or
their 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 participants or their caregivers 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 treatment period and in case the
participant’s safety is considered to be at risk, the investigator should contact the sponsor’s
responsible medical officer to discuss plans for study intervention and follow-up. Additional
follow-up and management of laboratory-confirmed SARS-CoV-2 infections, diagnosed during
the study, in participants will be per local standard of care, independent from the study visits.
Modifications made to the study conduct as a result of the COVID-19 pandemic should be
summarized in the clinical study report.


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GUIDANCE SPECIFIC TO THIS PROTOCOL:
Missed assessments will be captured in the clinical trial management system as protocol deviations
(applicable only for Data Managers and the site monitors).
Missed visits, out-of-window visits, and missing assessments will be labelled with the prefix
“COVID-19-related” in the eCRF/eSource by the site personnel where needed.
If a participant is unable to travel to the study site for a scheduled visit where study drug would be
dispensed, the following alternate measures should be discussed with the study monitor and may
be considered to ensure continuity of treatment, upon sponsor’s approval:
 
A caregiver or family member may pick up study intervention on behalf of the participant if
first discussed and agreed by the participant. The conversation with the participant must be
documented in the participant source documents. The participant must name the individual
who will pick up study drug on their behalf. This is necessary for site staff to confirm the
study drug is provided to the appropriate individual, to provide guidance for study intervention
transportation as per dosing instructions, and to maintain participants’ privacy. Identification
of who will pick up the study intervention must be confirmed and documented in the
participant’s source documents.
 
Investigative or home health site staff may deliver study intervention directly to the
participant’s home. Compliance with the guidance for study intervention transportation as per
dosing instructions and transit conditions must be clearly documented within the participant
source documents.
 
If no other alternative is feasible, direct-to-patient (DTP) shipment of study intervention from
the site may be considered with prior approval from the sponsor. Site staff need to obtain
participant’s permission and record this in the participant source documents for direct-to-
patient shipments. It is important to note this process may  not be allowed by the health
authorities and a specific approval process must be followed with the sponsor before moving
forward. If requested by the site, the sponsor will investigate local requirements and confirm
health authority requirements for DTP shipment. If approval is granted by the sponsor,
specific procedures including shipment conditions, preferred courier services, and
documentation requirements will be communicated by the sponsor to the site.
 
The date and time of the study intervention administration at the participant’s home at Day 1
instead of at the study site will be documented in the participant’s source documents and in
the eCRF.
If a participant cannot visit the study site in person at Day 1, the sponsor recommends that any
study assessment that may be captured as home visit [such as but not limited to ECG, bilateral
mid-turbinate nasal swab, RiiQ Symptom Scale, PGI-S/PGI-H, RiiQ Impact Scales, EQ-5D-5L,
clinical evaluation of the course of RSV, chest imaging, LRT sampling] for that particular visit be
collected. These assessments and collection should be performed at participant’s home by trained
delegated site staff or home health service staff.
If required, bilateral mid-turbinate nasal swab, LRT sampling and blood samples for RSV viremia
can be stored and picked up by site staff or courier. If possible, central laboratory testing as outlined


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in the protocol is to be continued. If central laboratory tests cannot be performed, the use of a local
laboratory is allowed for study-related analyses. A copy of the local laboratory report should be
reviewed by the investigator and retained, along with reference ranges, for source documentation
and captured in the eCRF. RSV viremia is sent to central lab only. If imaging is required according
to the current Schedule of Activities and cannot be performed at the site due to COVID-19 related
restrictions, the use of local facilities close to the participant’s home is permitted provided these
facilities can adhere to the protocol requirements, but provision of scans to the investigative site
and central readers should be arranged by the investigator and documented. If imaging is not
possible as outlined in the Schedule of Activities, missed imaging should be documented as a
deviation related to COVID-19 and be done as soon as possible.
There are some assessments that could be conducted virtually via telephone (or videoconference,
eg, Facetime, Skype, if possible) with participants and/or caregivers in their homes, if allowed by
local regulations. These virtual assessments include review of AEs and concomitant medications.
Collection of medical records associated with the diagnosis of RSV LRT and recording of
immunosuppressants exposures as applicable should continue. Please note, the visit windows
included in the Schedule of Activities are still applicable. It must be documented in the eCRF if a
visit occurs virtually due to COVID-19.
In case home visits cannot be performed then such study assessments that can be performed
virtually are accepted.
The study assessments that require investigator judgement should be conducted by a medically
qualified site or home health staff member identified on the site delegation log.
On-site monitoring visits may not be possible due to local regulations, restrictions and guidance.
In these cases, the Site Manager will conduct site monitoring visits and activities remotely.
Additional on-site monitoring visits may be needed in future to catch up on source data
verification. Remote source data verification of electronic records might be performed if possible
and if allowed by local/national regulations, restrictions and guidance.
During the COVID-19 pandemic and at the impacted sites, clinical Site GCP Audits with direct
impact/engagement from the clinical investigator team would be not conducted to comply with
national, local and/or organizational social distancing restrictions. Additional quality assurance
activities such as remote audits or focused review of study related documents may take place with
limited impact/engagement if possible.
For subjects ≥13 and <18 years of age, when, per local procedures, both caregivers need to provide
consent, the sponsor allows obtaining the second consent remotely (phone or video) if allowed per
local guidance.


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STUDY CONDUCT RELATED TO COVID-19 VACCINE DEPLOYMENT
There are no available data suggesting additional risk to participants in JNJ-53718678 clinical
studies caused by locallyapproved (and including emergency use-authorized) COVID-19 vaccines
or an interaction between COVID-19 vaccines and JNJ-53718678.
Local package inserts for COVID-19 vaccines, including contra-indications, must be followed as
well as local vaccination guidelines.
For participants with signs and symptoms of febrile illness or acute infection, it is recommended
that administration of COVID-19 vaccines be timed to occur after study completion or at least
1 week after the last dose of study intervention. Investigator discretion and overall assessment of
clinical stability will be relied on if there is a medical need to administer vaccine during the study
period.
Investigators should make an assessment of the relatedness of any AE reported following
COVID-19 vaccination to study intervention, the underlying RSV infection, the underlying disease
(leading to HSCT), and/or COVID-19 vaccine (as described in Section 10.4). If the event is serious
and considered related to both the COVID-19 vaccine and the study intervention, it is to be
recorded as a serious adverse reaction (as described in Sections 8.4. and 10.4). Adverse Events
Expectedness is described in Sections 8.4. and 10.4.
In case a participant received COVID-19 vaccine during study period, the COVID-19 vaccine must
be documented on the concomitant therapy page of the eCRF (see Section 6.6).


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10.13. Appendix 13: Protocol Amendment History
DOCUMENT HISTORY
Document 
Date
Amendment 6 
7 May 2021
Amendment 5 
03-Aug-2020
Amendment 4 
10-July-2020
Amendment 3 
03-June-2020
Amendment 2 
11-Dec-2019
Amendment 1 
21-Jun-2019
Original Protocol 
7-Jun-2019


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11. 
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JNJ-53718678 at Two Dose Levels in Non-Hospitalized Adult Subjects Infected With Respiratory Syncytial
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INVESTIGATOR AGREEMENT
I have read this protocol and agree that it contains all necessary details for carrying out this study. I will
conduct the study as outlined herein and will complete the study within the time designated.
I will provide copies of the protocol and all pertinent information to all individuals responsible to me who
assist in the conduct of this study. I will discuss this material with them to ensure that they are fully informed
regarding the study intervention, the conduct of the study, and the obligations of confidentiality.
Coordinating Investigator (where required):
Name (typed or printed):
Institution and Address:
Signature: 
Date:
(Day Month Year)
Principal (Site) Investigator:
Name (typed or printed):
Institution and Address:
Telephone Number:
Signature: 
Date:
(Day Month Year)
Sponsor's Responsible Medical Officer:
Name (typed or printed): 
Institution: 
Janssen Research & Development
Signature: 
electronic signature appended at the end of the protocol 
Date:
(Day Month Year)
Note: If the address or telephone number of the investigator changes during the study, written notification will be
provided by the investigator to the sponsor, and a protocol amendment will not be required.
PPD


Signature
User 
Date 
Reason
 07-May-2021 
13:14:59
(GMT)
Document Approval
PPD

SAP_001.pdf: 
CONFIDENTIAL – FOIA Exemptions Apply in U.S.
1
Status: Approved, Date: 28 December 2021
Janssen Research & Development
Statistical Analysis Plan
A Randomized, Double-blind, Placebo-controlled Study to Evaluate the Clinical Outcomes, 
Antiviral Activity, Safety, Tolerability, Pharmacokinetics, and 
Pharmacokinetics/Pharmacodynamics of JNJ-53718678 in Adult and Adolescent 
Hematopoietic Stem Cell Transplant Recipients with Respiratory Syncytial Virus Infection 
of the Upper Respiratory Tract
FREESIA
Effects of JNJ-53718678 in Adult and Adolescent Patients Who had a Hematopoietic Stem 
Cell Transplantation and Who are Infected With RSV
Protocol 53718678RSV2005; Phase 2
JNJ-53718678 (rilematovir)
Status:
Approved
Date:
28 December 2021
Prepared by:
Janssen Research & Development, a division of Janssen Pharmaceutica NV  
Document No.: EDMS-ERI-197113532, 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.
NCT04056611


JNJ-53718678
Statistical Analysis Plan 53718678RSV2005
CONFIDENTIAL – FOIA Exemptions Apply in U.S.
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Status: Approved, Date: 28 December 2021
TABLE OF CONTENTS
TABLE OF CONTENTS ............................................................................................................................... 2
VERSION HISTORY..................................................................................................................................... 4
1.
INTRODUCTION.................................................................................................................................. 5
1.1.
Trial Objectives ................................................................................................................................ 5
1.2.
Trial Design ...................................................................................................................................... 9
1.3.
Statistical Hypotheses for Trial Objectives..................................................................................... 10
1.4.
Sample Size Justification ............................................................................................................... 11
1.5.
Randomization and Blinding .......................................................................................................... 11
2.
GENERAL ANALYSIS DEFINITIONS .............................................................................................. 12
2.1.
Visit Windows and Phase Definitions............................................................................................. 12
2.1.1.
Phase Definitions........................................................................................................................ 12
2.1.2.
Baseline ...................................................................................................................................... 12
2.1.3.
Relative Day ............................................................................................................................... 12
2.1.4.
Analysis Windows for Analysis Visits and Time Points .............................................................. 12
2.2.
Analysis Sets.................................................................................................................................. 13
2.2.1.
All Randomized Analysis Set...................................................................................................... 13
2.3.
Definition of Subgroups.................................................................................................................. 13
2.4.
Imputation Rules for Missing AE Date/Time of Onset/Resolution ................................................. 13
3.
INTERIM ANALYSIS AND DATA MONITORING COMMITTEE REVIEW....................................... 13
4.
PARTICIPANT INFORMATION ........................................................................................................ 13
4.1.
Demographics ................................................................................................................................ 13
4.2.
Baseline and RSV Disease Characteristics................................................................................... 13
4.3.
HSCT-related characteristics ......................................................................................................... 14
4.4.
Disposition Information................................................................................................................... 15
4.5.
Treatment Compliance................................................................................................................... 16
4.6.
Extent of Exposure......................................................................................................................... 16
4.7.
Protocol Deviations ........................................................................................................................ 16
4.8.
Prior and Concomitant Medications ............................................................................................... 16
4.9.
Specific Prior Therapy.................................................................................................................... 17
4.10.
Presence of other respiratory viruses or bacteria .......................................................................... 17
4.11.
Medical History and Family History................................................................................................ 17
5.
EFFICACY ......................................................................................................................................... 17
5.1.
Analysis Specifications................................................................................................................... 17
5.1.1.
Level of Significance................................................................................................................... 17
5.1.2.
Data Handling Rules................................................................................................................... 17
5.2.
Efficacy Endpoint(s) ....................................................................................................................... 17
6.
SAFETY............................................................................................................................................. 20
6.1.
Adverse Events .............................................................................................................................. 20
6.2.
Clinical Laboratory Tests................................................................................................................ 20
6.3.
Vital Signs ...................................................................................................................................... 20
6.4.
Physical Examination..................................................................................................................... 21
6.5.
Electrocardiogram.......................................................................................................................... 21
6.6.
Hepatotox....................................................................................................................................... 22
6.7.
Health Economics .......................................................................................................................... 22
6.8.
Long-term safety follow-up............................................................................................................. 22
7.
VIROLOGY ........................................................................................................................................ 22
8.
SUPPORTING DOCUMENTATION .................................................................................................. 25


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8.1.
Appendix 1 List of Abbreviations.................................................................................................... 25
8.2.
Appendix 2 DMID Toxicity Tables.................................................................................................. 26
8.3.
Appendix 3 Respiratory Infection Intensity and Impact Questionnaire (RiiQ™)............................ 35
9.
REFERENCES................................................................................................................................... 36


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VERSION HISTORY
Table 1:
SAP Version History Summary
SAP Version
Approval Date
Change
Rationale
1
28DEC2021
Not Applicable
Initial release


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1.
INTRODUCTION
On 28-Oct-2021, the Sponsor decided to terminate the FREESIA study (53718678RSV2005) early 
due to the low enrollment. The 2 ongoing participants were allowed to complete the study till study 
Day 49. Although a stable version of the Statistical Analysis Plan (SAP) of the study was ready to 
be endorsed (available in RIMdocs EDMS-ERI-197113532 V0.21), it was decided to simplify and 
to reduce the statistical outputs to individual patient profile because data of only 3 randomized 
participants were collected. Therefore, no summary statistics across participants will be produced, 
and data will be reported as a listing generated for each participant (patient profile).
This SAP contains identification of variables that will be included in patient profile and reported
for the clinical study report (CSR), and definitions of derived variables for the FREESIA study.
The SAP is to be interpreted in conjunction with the protocol. 
This SAP covers the primary analysis. The primary analysis will be performed when all 
randomized participants have completed the Day 49 study visit or discontinued earlier. Participants 
will not continue through the long-term follow-up (LTFU) and so, the final analysis (for health 
economics purpose) will not be performed.
Due 
to 
the 
small 
number 
of 
participants 
no 
pharmacokinetic 
(PK) 
or
pharmacokinetic/pharmacodynamics (PK/PD) analysis will be performed, and only observed 
plasma levels of rilematovir will be reported in the CSR. 
Rilematovir (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 in adults and pediatric population.
1.1.
Trial Objectives
Given the small number of enrolled participants, no analyses will be performed to evaluate the 
study objectives listed in Table 2. Only individual patient profiles will be provided.
Table 2:
Objectives and endpoints
Objectives
Endpoints
Primary
To evaluate the effect of JNJ53718678 on the 
development of RSV Lower Respiratory Tract 
Infections (LRTIs) in adult hematopoietic stem cell 
(HSCT) recipients with RSV Upper Respiratory 
Tract Infections (URTI).
The proportion of participants who develop RSV
LRTI (see definition below Table 2) per the 
Endpoint 
Adjudication 
Committee 
(EAC)’s 
assessment through Visit Day 28. 
Secondary
To evaluate the effect of JNJ-53718678 on the 
development 
of 
RSV-associated 
Lower 
Respiratory Tract Complication (LRTC) in adult 
and adolescent HSCT recipients with RSV URTI.
The proportion of participants who develop RSV-
associated LRTC (see definition below Table 2) 
per the EAC’s assessment through Visit Day 28.
To evaluate the safety and tolerability of 
JNJ-53718678
Safety and tolerability, as assessed by adverse 
events (AE), clinical laboratory testing, 
electrocardiograms (ECGs), vital signs, 
throughout the study


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Table 2:
Objectives and endpoints
Objectives
Endpoints
To evaluate the impact of JNJ-53718678 on 
progression to respiratory failure and on all-cause 
mortality

The proportion of participants progressing to 
respiratory failure (of any cause) requiring 
mechanical 
ventilation 
(invasive 
or 
noninvasive) and/or death, in participants who 
develop RSV LRTI or RSV-associated LRTC 
per the EAC’s assessment;

The proportion of participants progressing to 
respiratory failure (of any cause) requiring 
mechanical 
ventilation 
(invasive 
or 
noninvasive) 
and/or 
death 
(all-cause 
mortality);

The proportion of participants progressing to 
death (all-cause mortality), in participants 
who develop RSV LRTI or RSV-associated 
LRTC per the EAC’s assessment;

The proportion of participants progressing to 
death (all-cause mortality);

The proportion of participants progressing to 
respiratory failure (of any cause) requiring 
mechanical 
ventilation 
(invasive 
or 
noninvasive), in participants who develop 
RSV LRTI or RSV-associated LRTC per the 
EAC’s assessment;

The proportion of participants progressing to 
respiratory failure (of any cause) requiring 
mechanical 
ventilation 
(invasive 
or 
noninvasive).
To evaluate the impact of JNJ-53718678 on the 
clinical course of RSV infection
Clinical course-related endpoints:

Number of supplemental O2 free days through 
Day 28

Incidence of O2 requirement, total length and 
type (eg, supplemental oxygen, noninvasive 
pressure ventilation, invasive mechanical 
ventilation [tracheal tube, laryngeal mask, or 
tracheostomy])

Respiratory rate, heart/pulse
rate, body 
temperature, and peripheral capillary oxygen 
saturation (SpO2) over time as measured by 
the investigator during scheduled visits

Proportion of participants hospitalized (of 
participants who were not hospitalized at 
baseline), proportion of participants re-
hospitalized (of participants who were 


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Table 2:
Objectives and endpoints
Objectives
Endpoints
hospitalized at baseline and discharged during 
the study and of participants who were not 
hospitalized 
at 
baseline, 
required 
hospitalization, and were discharged during 
the study) 

Total length of hospital stay (time in hospital 
before first dosing is discarded) and total time 
in the intensive care unit (ICU) (time in ICU 
before first dosing is discarded)

Incidence of Grade 3 and Grade 4 AEs in the 
Infections and Infestations System Organ 
Class

Incidence of respiratory and thoracic-related 
AEs 

Incidence of antibiotic use in participants who 
develop and in those who do not develop RSV 
LRTI or RSV-associated LRTC per the 
EAC’s assessment 

Time to resolution of symptoms, assessed 
through an instrument for patient-reported 
symptoms (Respiratory Infection Intensity 
and Impact Questionnaire [RiiQ] Symptom 
Scale)

Change from baseline through Day 28 in 
severity of symptoms reported by subjects in 
the RiiQ Symptom Scale

Time to resolution of respiratory illness, 
through the Patient Global Impression of 
Severity (PGI-S) Scale

Change in Patient Global Impression of 
Health
(PGI-H)
and 
Patient 
Global 
Impression of Change (PGI-C) Scales through 
Day 28
To evaluate the PK of JNJ-53718678
PK parameters of JNJ-53718678
To evaluate the relationship between the PK of 
JNJ-53718678 and the PD (selected antiviral 
activity, clinical outcomes, and safety parameters) 
after repeated dosing of JNJ-53718678
PK/PD analysis of plasma concentration-time data 
of JNJ-53718678 using (non)-linear mixed-effects 
modeling 
To evaluate the antiviral effect of JNJ-53718678 as 
measured by RSV viral load in bilateral mid-
turbinate nasal swab samples by quantitative 
reverse transcription polymerase chain reaction 
(qRT-PCR) assay
Virologic parameters derived from the RSV viral 
load as measured by a qRT-PCR assay in bilateral 
mid-turbinate nasal swab samples including:

RSV viral load and change from baseline over 
time


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Table 2:
Objectives and endpoints
Objectives
Endpoints

RSV viral load area under the curve (AUC)
from immediately prior to first dose of study 
intervention (baseline) through Day 8, Day 
11, Day 15, Day 22, and Day 28. 

time to undetectable RSV viral load

proportion of participants with undetectable 
RSV viral load at each time point throughout 
the study
To evaluate the impact of RSV and its treatment on 
health-related quality of life (HRQOL).
Change from baseline for the HRQOL through 
Day 28 (as assessed through the 5-level EuroQol 5-
Dimension [EQ-5D-5L] and RiiQ Impact Scales)
To evaluate the emergence of mutations in the viral 
genome potentially associated with resistance to 
JNJ-53718678
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) 
Exploratory
The exploratory objectives are to evaluate:

medical 
resource 
utilization 
(MRU), 
including 
hospitalization, 
for 
clinical 
management of participants during treatment 
and posttreatment follow-up

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)

the relationship between antiviral activity and 
clinical course

the impact of the baseline RSV viral subtype 
and genotype on the antiviral activity and 
clinical course

the incidence of RSV viremia

the incidence of graft-versus-host disease
(GVHD) or graft failure
The exploratory endpoints are:

medical resource utilization

RSV 
viral 
subtype 
and 
presence 
of 
pretreatment RSV F-gene genetic variations

virologic parameters derived from the RSV 
viral load as measured by quantitative viral 
culture

proportion of participants with RSV viremia 
(RSV viral load in plasma)

proportion of participants with new onset 
GVHD 

proportion of participants with graft failure
Definition
RSV LRTI is defined as the development of a lower respiratory sign or symptom (including 
decrease in oxygen saturation or increase in supplemental oxygen to maintain oxygen saturation, 
wheezing, rhonchi, rales, dyspnea, tachypnea, worsening cough, …) AND

Positive RSV test from lower respiratory tract sample (eg, sputum, induced sputum, 
bronchoalveolar lavage (BAL), lung biopsy, or autopsy specimen) within ±4 days of a 
new chest image finding, compared to baseline, consistent with a LRTI; OR


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
Positive RSV test from lower respiratory tract sample (eg, sputum, induced sputum, BAL, 
lung biopsy, or autopsy specimen) only; OR

Positive RSV test from upper respiratory tract sample within ±4 days of a new chest 
image finding, compared to baseline, consistent with a RSV LRTI
as determined by the EAC.
RSV-associated LRTC is defined as the development of a lower respiratory sign or symptom 
(including decrease in oxygen saturation or increase in supplemental oxygen to maintain oxygen 
saturation, wheezing, rhonchi, rales, dyspnea, tachypnea, worsening cough, …) AND falling 
within one of the following subcategories as determined by the EAC: 

RSV LRTI defined as above
OR

Secondary bacterial LRTI defined as:

Positive specimen for a clinically significant bacterium from lower respiratory tract
source (e.g., sputum, induced sputum, BAL, lung biopsy, or autopsy specimen) within ±4 
days of a new chest image finding, compared to baseline, consistent with a LRTI
OR

Secondary LRTI due to unusual pathogens defined as:

Positive specimen for a clinically significant unusual organism (eg, atypical bacteria, 
fungus, or another respiratory virus) from a lower respiratory tract source (eg, sputum, 
induced sputum, BAL, lung biopsy, autopsy specimen) within ±4 days of a new chest 
image finding, compared to baseline, consistent with a LRTI
OR

Secondary LRTC of unknown etiology defined as:

New findings on a chest image, compared to baseline, consistent with a LRTI, 
inflammatory process, or some other clinically significant pulmonary process in absence 
of a positive specimen or no specimen collected from lower respiratory tract source within 
±4 days of the new chest image finding
Due to the small numbers of participants enrolled, no endpoint adjudication will be performed by 
the EAC.
1.2.
Trial Design
This is a Phase 2, randomized, double-blind, placebo-controlled, multicenter study to evaluate the 
clinical outcomes, antiviral activity, safety, tolerability, PK, and PK/PD of rilematovir in adult (ie, 
adult cohort) and adolescent (ie, adolescent cohort) HSCT recipients with an RSV URTI.
Participants are enrolled in either the adult or adolescent cohort:

Adult cohort: adult participants ≥18 to ≤75 years of age. 


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
Adolescent cohort: adolescent participants ≥13 to <18 years of age.
In the adult cohort, a sample size of approximately 249 participants was targeted, with a maximum 
of 375 participants. No target sample size was determined for the adolescent cohort. 
The study includes a Screening Period (Day -2 to Day 1), a Treatment Period (Day 1 to Day 21), 
a Follow-up Period (Day 22 to Day 49) and a long-term follow-up period (Day 50 to one year). 
On Day 49, participants complete the study follow-up and continue to LTFU for one year. The 
total study duration for each participant is approximately 365 days (Screening included). Due to 
study early termination, participants will not continue through the LTFU and data will be collected 
through Day 49 only.
A diagram of the study design is provided in Figure 1.
Figure 1:
Schematic Overview of the Study
For more information on the trial design, see Section 4 Study Design of the study protocol.
1.3.
Statistical Hypotheses for Trial Objectives
The primary hypothesis of this study is that rilematovir reduces the proportion of adult HSCT 
recipients with RSV URTI, who develop an RSV LRTI within 28 days after start of treatment as 
compared to placebo, assessed by the relative risk.
The primary hypothesis will be evaluated (in the adult cohort) in the overall population, in the 
population with an Absolute lymphocyte count (ALC) <500 cells/μL at Screening, and in the 
population with an ALC <200 cells/μL at Screening, respectively. To account for this multiplicity, 
the theory developed by Spiessens and Debois (Spiessens 2010) will be used, allowing all 3 tests 
to be performed at a pre-fixed significance level, irrespective of the outcome of the other tests. 
Assuming 50% of the population will have an ALC <500 cells/μL at Screening and 25% of the 


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population will have an ALC <200 cells/μL at Screening, fixing the one-sided significance level 
for each of these two subgroups at 0.6%, and using an overall 2.5% one-sided significance level, 
the full population can be tested using 1.8% one-sided significance.
Hierarchical testing of the secondary endpoints will be performed in the largest population only
(from the adult cohort) where superiority was shown on the primary endpoint.
No statistical hypothesis testing will be performed in the adolescent cohort.
1.4.
Sample Size Justification
Sample size determination was performed for the adult cohort only. Assuming a progression to 
RSV LRTI occurring in 35% of the patients in the placebo arm, a relative risk of 40%, and a 2:1 
randomization, 210 patients are needed to obtain 90% power with 2.5% one-sided significance in 
the primary analysis set based on a Fisher’s Exact test. Assuming 15% of patients will be excluded 
from the primary analysis set, the total sample size becomes 249. The sample size computation is
based on an exact procedure (Fisher’s Exact test), which is commonly used when sample sizes are 
small and expected event frequencies low. However, the primary endpoint will be analyzed using 
a stratified Cochran-Mantel-Haenszel (CMH) test which takes into account the randomization 
stratification factors in the analysis. Similar power estimates were obtained from simulations using 
the CMH test and the Fisher’s Exact test.
Participants with an ALC <500 cells/µL at Screening should account for at least 50% of all 
participants in the adult cohort and participants with an ALC <200 cells/µL at Screening should 
account for at least 25% of all enrolled participants, also at the time of the interim analysis (IA).
To ensure the prespecified distribution in the strata for the IA, enrollment in certain lymphopenia 
strata (≥500 - <1,000 cells/μL or 200 - <500 cells/μL) will be temporarily paused prior to the IA 
once sufficient patients for the IA are enrolled in the corresponding stratum.
No more than 62 participants with ALC ≥500 - <1,000 cells/μL and no more than 93 patients with 
ALC ≥200 cells/μL can be enrolled prior to the IA. Once sufficient patients have been enrolled for 
the IA, enrollment will continue again in all strata.
Similarly, to ensure the prespecified distribution in the strata for the primary analysis, enrollment 
in certain lymphopenia strata (≥500 - <1,000 cells/μL or 200 - <500 cells/μL) could be stopped 
early once sufficient patients for the primary analysis are enrolled in the corresponding stratum.
No target sample size was determined for the adolescent cohort
1.5.
Randomization and Blinding
Randomization
Central randomization will be implemented in this study using an interactive web response system 
(IWRS). Participants will be randomly assigned to 1 of 2 interventions (Treatments A and B; 2:1 
[active: placebo] randomization) groups based on a computer-generated randomization schedule 
prepared before the study by or under the supervision of the sponsor. In the adult cohort, the 
randomization will be balanced by using randomly permuted blocks and will be stratified by 
hospitalization status (yes/no) at the time of randomization, lymphopenia (ALC categories: <200 


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cells/µL, 200 - <500 cells/µL, and ≥500 - <1,000 cells/µL) at Screening, and ribavirin and/or 
intravenous immunoglobulin (IVIG) use (yes/no) at the time of randomization. No stratification 
will be applied to the adolescent cohort.
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.
In general, randomization codes will be disclosed fully only if the study is completed, and the 
clinical database is closed. However, after database lock for the IA, the randomization codes and, 
if required, the translation of randomization codes into intervention and control groups will be 
disclosed to those authorized and only for those participants included in the IA. 
The IA will be implemented through an Independent Data Monitoring Committee (IDMC), 
providing recommendations to a Sponsor Committee. Only the IDMC and the independent 
Statistical Support Group will be unblinded to the data. Details are specified in the IDMC charter.
2.
GENERAL ANALYSIS DEFINITIONS
Clinical data will be reported through patient profiles, which will be produced using SAS® version 
9.4 (or higher).
2.1.
Visit Windows and Phase Definitions
2.1.1.
Phase Definitions
Not applicable
2.1.2.
Baseline
Not applicable
2.1.3.
Relative Day
Study Day 1 is defined as the date of first study intervention intake (reference day). All efficacy 
and safety assessments at all visits will be assigned a day relative to this date.
The relative day (reldy) will be defined as:
reldy=visit date – reference date + 1
for visits on or after Day 1,
reldy=visit date – reference date
for visits before Day 1.
Consequently, there is no ‘Day 0’ defined.
2.1.4.
Analysis Windows for Analysis Visits and Time Points
All values collected for the parameters listed below will be considered based on their actual date 
and time.


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2.2.
Analysis Sets
2.2.1.
All Randomized Analysis Set
Patient profiles will be produced for all participants who signed the Informed Consent Form (ICF)
and who were randomized in the study, regardless of being treated or not.
2.3.
Definition of Subgroups
Not applicable
2.4.
Imputation Rules for Missing AE Date/Time of Onset/Resolution
Not applicable
3.
INTERIM ANALYSIS AND DATA MONITORING COMMITTEE REVIEW
Not applicable
4.
PARTICIPANT INFORMATION
4.1.
Demographics 
Table 3 presents the list of demographic variables that will be reported in the patient profiles.
Table 3:
Demographic Variables
Variables
Age (years)
Weight at baseline (kg)
Height at baseline (cm)
Gender (male, female)
Age Group: for adolescent cohort: ≥13 - <18 years
for adult cohort: ≥18 - <65 years, ≥ 65 years
Race (American Indian or Alaska Native, Asian, Black or African American, Native Hawaiian or 
other Pacific Islander, White, Multiple, Not Reported, Unknown)
Ethnicity (Hispanic or Latino, Not Hispanic or Latino, Not Reported)
Country
4.2.
Baseline and RSV Disease Characteristics
Table 4 presents the list of baseline and RSV disease characteristics that will be reported in the 
patient profiles.
Table 4:
Baseline and RSV Disease Characteristics
Variables:
Start date and time of first RSV symptoms/signs
Contact with health care professional (HCP) before presenting (no, yes)
If yes, type of HCP (General Practitioner, Oncologist, Pneumonologist, Other -specify)
History of wheezing associated with acute respiratory infection (no, yes)
Additional risk factor for severe RSV disease (no, yes)
If yes, type

Asthma


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Table 4:
Baseline and RSV Disease Characteristics

Chronic Obstructive Pulmonary Disease (COPD)

Congestive Heart Failure (CHF)

Coronary Artery Disease (CAD)

Diabetes Mellitus

Chronic Kidney Disease (CKD)

Other - specify
History of drug allergy (no, yes)
Family history in the allergic/immunologic body system (no, yes, unknown)
History of Tobacco use (current, former, never) (no, yes)
Presence of other respiratory viruses (no, yes)
If yes, type of virus
Note: based on respiratory pathogens panel assay performed centrally at baseline (influenza, parainfluenza, 
human rhinovirus, adenovirus, human metapneumovirus, bocavirus, or coronavirus)
Presence of respiratory bacteria (no, yes)
If yes, type of bacteria
Note: based on respiratory pathogens panel assay performed centrally at baseline (streptococcus pneumoniae, 
staphylococcus aureaus, haemophilus influenzae, moraxella catarrhalis, legionella, mycoplasma pneumoniae, 
chlamydophila pneumoniae, bordetella pertussis, or bordetella parapertussis)
Presence of SARS-CoV-2 (no, yes)
Note: based on respiratory pathogens panel assay performed centrally at baseline
Other baseline characteristics: ie, RSV viral load and subtype, oxygen saturation, RiiQ Symptom 
Score, respiratory rate and pulse rate will be displayed with actual values over time (see Section 5.2
and Section 6.3).
4.3.
HSCT-related characteristics
Table 5 presents the list of HSCT-related characteristics that will be reported in the patient profiles.
Table 5:
HSCT-related Characteristics
Variables:
Date of receipt of HSCT
Immunoglobulin level (g/L)
ALC at Screening – central lab test (cells/μL)
ALC category at Screening – local lab test (<200 cells/µL, 200 - <500 cells/µL, ≥500 - <1,000 
cells/µL)
ALC category at Screening – central lab test (<200 cells/µL, 200 - <500 cells/µL, ≥500 - <1,000 
cells/µL)
Donor type

Autologous

Allogenic matched, related

Allogenic mismatched, related

Allogenic matched, unrelated

Allogenic mismatched, unrelated
Cell source

Bone marrow

Cord blood

Other - specify


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Table 5:
HSCT-related Characteristics
Underlying disease

Leukemia

Non-Hodgkin lymphoma

Hodgkin disease

Multiple myeloma

Aplastic anemia

Other
If leukemia

Acute lymphocytic

Acute myelogenous

Chronic myelogenous

Other - specify
Underlying disease state at RSV diagnosis
Remission
Minimal Residual Disease
Persistent or Relapse
Unclear
T cell depletion (yes, no)
B cell depletion (yes, no)
Conditioning regimen
Myeloablative
Reduced intensity
4.4.
Disposition Information
Table 6 presents a list of the disposition information variables that will be reported in the patient 
profiles.
Table 6:
Disposition information
Variables
Date of signature on informed consent
Eligibility criteria met (no, yes)
If no, criterion
Date and time of randomization
Stratification factors at randomization:
Hospitalization status (no, yes)
Lymphophenia at Screening:
-
<200 cells/µl
-
200 to < 500 cells/µl
-
>500 to < 1000 cells/µl
Ribavirin and/or IVIG use (no, yes)
If yes, type
-
Ribavirin use at Randomization (no, yes)
-
IVIG use at Randomization (no, yes)
Cohort: (Adolescent/Adult)


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Table 6:
Disposition information
Assigned dosing regimen
250 mg JNJ-53718678 or matching Placebo twice daily for 21 days 
125 mg JNJ-53718678 or matching Placebo twice daily for 21 days 
125 mg JNJ-53718678 or matching Placebo once daily for 21 days
Treatment group: (Placebo/JNJ-53718678)
Completed the study treatment [Completed (date), Discontinued (date)]
If no, reason for treatment discontinuation 
If withdrawal by subject
-
Lost to follow-up
-
Withdrawal of consent or ascent
-
Death
-
Other - specify
Completed the study [Completed (date), Discontinued (date)]
If no, reason for study discontinuation 
If withdrawal by subject
-
Lost to follow-up
-
Withdrawal of consent or ascent
-
Death
-
Other - specify
4.5.
Treatment Compliance
Table 7:
Treatment compliance 
Variables
Date and time of first dose administered
Date and time of last dose administered
Any change in dosing regimen (no, yes)
If yes, study Day and new dosing regimen
Any missed doses (no, yes)
4.6.
Extent of Exposure
Not applicable
4.7.
Protocol Deviations
Protocol deviations will not be reported in the patient profiles.
4.8.
Prior and Concomitant Medications
Medications taken from the date when the main study ICF is signed through the end of study will 
be reported.
In the patient profiles concomitant therapy will be displayed by indication:

Adverse Even (AE number and term)

Medical History (Medical history number and term)

Prophylaxis


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
Therapeutic or Diagnostic Procedure (Procedure number and term)

Trial Indication

Other
Table 8 presents the list of the concomitant medications variables that will be reported in the patient 
profiles.
Table 8:
Concomitant medications
Variables
Medication or Therapy preferred term using the World Health Organization-Drug Dictionary (WHO-DD)
Start date (study day) AND end date (study day) OR ongoing
Dose with unit; route AND frequency
4.9.
Specific Prior Therapy
Corticosteroids related to HSCT, palivizumab, ribavirin, and IV immunoglobulin will be 
reported in the patient profiles as other prior medication/therapy. It will include the specific 
therapy taken 30 days prior screening and not ongoing at screening. Ongoing at screening 
therapy will be reported as concomitant medication.
4.10.
Presence of other respiratory viruses or bacteria
Presence of data on other respiratory viruses (other than RSV) or bacteria (both by multiplex PCR) 
determined in mid-turbinate nasal swabs collected at baseline will be listed (see Table 4). 
4.11.
Medical History and Family History
Table 9 presents the list of the medical history variables that will be reported in the patient profiles.
The family history will not be reported.
Table 9:
Medical History 
Variables
Has/had the subject any medical history on pre-defined conditions (no, yes)
If yes, list the medical history term 
5.
EFFICACY
Given the small number of patients enrolled, no efficacy analyses will be performed, and no 
hypothesis will be tested. The efficacy variables presented in the patient profiles are listed below.
5.1.
Analysis Specifications
5.1.1.
Level of Significance
Not applicable
5.1.2.
Data Handling Rules
Not applicable
5.2.
Efficacy Endpoint(s)
Table 10 presents the list of efficacy variables that will be reported in the patient profiles.


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Table 10:
Efficacy 
Variables
Plot over time: days since first drug intake – all collected values will be displayed
RiiQ symptom score over time for (defined in Table 11):
all (13) items 
the key (7) items, 
the upper respiratory tract disease (URTD) symptoms, 
the lower respiratory tract disease (LRTD) symptoms, 
the body/systemic symptoms
Plot including one line per score
Oxygen saturation (SpO2) [%] over time
Plot including color code for oxygen saturation measured on room air (no, yes), value <95% will be 
flagged.
Log10 RSV RNA viral load actual values (log10 copies/mL) as measured with qRT-PCR in nasal 
swab samples over time.
In case of co-infection (RSV A and B), plot will include one line per RSV type and combined RSV
A and B).
Plot including color code for RSV subtype: ie, RSV A, RSV B and RSV A and B
List
Oxygen supplementation (no, yes):
If yes, type of supplemental oxygen administration AND [start date (study day) – end date (study 
day)]
Hospitalization information: [admission date (study day) – hospital discharge date (study day)]
Graft Versus Host Disease (no, yes):
If yes, 
[start date (study day) – end date (study day)]
Overall severity
Affected Organs
Grade
Table 11:
Clinical Course Parameters
Measurement
Formula
Symptoms (RiiQ Symptom Scale)
RiiQ symptom score
RiiQ Symptom Scale is a 13 items questionnaire (see Appendix 3) 
which ranges from ‘None’ (score=0; symptom free) to ‘Severe’ 
(score=3; severe symptoms). 
Arithmetic mean will be calculated if at least 9 out of 13 items are 
available, otherwise it will be set to missing.
RiiQ Key symptom score 
Arithmetic mean of the following 7 Key items (nasal congestion, 
sore throat, short of breath, wheezing, cough, coughing up phlegm 
[sputum], fatigue [tiredness]) will be calculated if at least 5 out of 
7 items are available, otherwise it will be set to missing.
RiiQ URTD symptoms score 
Arithmetic mean of the following items (nasal congestion, sore 
throat) will be calculated if at least 1 out of 2 items are available, 
otherwise it will be set to missing.


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Table 11:
Clinical Course Parameters
RiiQ LRTD symptoms score
Arithmetic mean of the following items (cough, wheezing, short of 
breath, coughing up phlegm [sputum]) will be calculated if at least 
3 out of 4 items are available, otherwise it will be set to missing.
RiiQ body/systemic
symptoms
score 
Arithmetic mean of the following items (headache, feeling feverish, 
body aches and pains, fatigue, neck pain, interrupted sleep, loss of 
appetite) will be calculated if at least 4 out of 7 items are available, 
otherwise it will be set to missing.


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6.
SAFETY
6.1.
Adverse Events
Table 12 presents a list of the safety variables that will be reported in the patient profiles.
Table 12:
Adverse Events
Variables
Information to be provided for each adverse event
Preferred term/System organ class
Related to the current respiratory infection: (no, yes)
Event type: ie, Respiratory complications, non-respiratory infectious complications, other
Is there a suspicion of LRTI
Onset: [start date (study day)]
Outcome: ie, Fatal, Not recovered or Not resolved, Recovered or resolved, Recovered or 
resolved with sequelae, Recovering or resolving, unknown
End date /ongoing
Duration
Toxicity grade
Seriousness criteria: ie, Death, Life threatening, Prolonged/ required hospitalization, 
Significant disability, Congenital anomaly or birth defect, Other medically important event
Action taken with study treatment
Concomitant or additional therapy
Relationship to study treatment
6.2.
Clinical Laboratory Tests
The laboratory abnormalities will be determined according to the Division of Microbiology and 
Infectious Diseases (DMID) adult toxicity tables (see Appendix 2). In case no toxicity grades are 
defined for a test, the abnormalities (above/below normal range) will be used.
Table 13 presents the list of clinical laboratory tests that will be reported in the patient profiles. 
Table 13:
Clinical Laboratory Tests 
Variables
Plot over time: days since first drug intake – all collected values will be displayed
Clinical hematology tests including absolute neutrophil count
For clinical chemistry tests especially eGFR, creatinine, liver function tests (AST, ALT, 
direct/indirect/total bilirubin and ALP), cardiac electrolytes: ie, potassium, magnesium, calcium, 
chloride, phosphorus):
Actual values with toxicity/abnormality flagged will be plotted over time
6.3.
Vital Signs 
The vital signs abnormalities will be defined as indicated in Table 14.


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Table 14:
Clinically Important Abnormalities in Vital Signs
Vital Sign
Abnormality Code
Criteria
Systolic blood 
pressure
Abnormally low
≤ 90 mmHg
Grade 1 or mild
> 140 mmHg - < 160 mmHg
Grade 2 or moderate
≥ 160 mmHg - < 180 mmHg
Grade 3 or severe
≥ 180 mmHg
Diastolic blood 
pressure
Abnormally low
≤ 50 mmHg
Grade 1 or mild
> 90 mmHg - < 100 mmHg
Grade 2 or moderate
≥ 100 mmHg - < 110 mmHg
Grade 3 or severe
≥ 110 mmHg
Respiratory rate
Grade 1 or mild
17-20 breaths per minute
Grade 2 or moderate
21-25 breaths per minute
Grade 3 or severe
> 25 breaths per minute
Grade 4 or potentially 
life threatening
intubation
Temperature
Abnormally high
> 38.0 o C
Pulse/Heart Rate
Abnormally low
≤ 45 bpm
Abnormally high
≥ 120 bpm
Table 15 presents a list of vital signs that will be reported in the patient profiles. 
Table 15:
Vital signs 
Variables
Plot over time: days since first drug intake – all collected values will be displayed
For vital signs parameters including systolic and diastolic blood pressure, heart/pulse rate, 
respiratory rate, body temperature:
Actual values with abnormality flagged will be plotted over time
6.4.
Physical Examination 
Not applicable
6.5.
Electrocardiogram
The ECG abnormalities will be defined as indicated in Table 16.


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Table 16:
ECG Abnormalities 
ECG parameter
Abnormality Code
Criteria
Abnormalities on actual values
Heart Rate
Abnormally low
≤ 45 bpm
Abnormally high
≥ 120 bpm
PR
Abnormally high
≥ 210 ms
QRS
Abnormally high
≥ 120 ms
QTcorrected
Borderline prolonged QT
450 ms < QTc < 480 ms
Prolonged QT
480 ms < QTc < 500 ms
Pathologically prolonged QT
QTc > 500 ms
Abnormalities on changes from baseline (∆QTc)
QTcorrected
Normal QTc change
∆QTc <= 30 ms
Borderline QTc change
30 ms < ∆QTc < 60 ms
Abnormally high QTc change
∆QTc > 60 ms
Table 17 presents the list of ECG parameters that will be reported in the patient profiles. 
Table 17:
ECG parameters 
Variables
Plot over time: days since first drug intake – all collected values will be displayed
For ECG parameters including PR, QT, QTc intervals, and heart rate
Actual values with abnormality flagged will be plotted over time
List
ECG overall interpretation per visit: ie, Normal, Abnormal, Not evaluable
6.6.
Hepatotox 
Any safety information collected in case of hepatotox will be reported in patient profile.
6.7.
Health Economics
Not applicable
6.8.
Long-term safety follow-up 
Not applicable.
7.
VIROLOGY
RSV viral load and RSV subtype will be reported as described in Section 5.2.
Viral Sequencing
Viral resistance will be evaluated by next-generation sequencing (NGS) of the RSV Fusion (F) 
gene using a read frequency cut-off of 3%. 
Baseline samples from all participants will be sequenced to identify pre-existing genetic variations
in the F gene. Post-baseline sequencing will be performed during treatment, on the last evaluable 
on-treatment sample and/or during follow-up for all participants (if viral load is high enough) to 


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identify emerging amino acid substitutions in the RSV F gene. Additional post-baseline 
sequencing can be performed on request of the sponsor virologist.
Genetic variations
Genetic variations are defined as changes (on amino acid or nucleotide level) in the participant’s 
viral sequence compared to a reference sequence. Genetic variations can include substitutions, 
insertions and deletions. The reference sequences used will be RSV-A Long strain (GenBank 
Accession number AY911262) for RSV-A samples and RSV-B strain 9320 (GenBank Accession 
number AY353550) for RSV-B samples. Genetic variations will be reported on amino acid level. 

Baseline genetic variation: amino acid difference from the RSV-A or RSV-B reference strain 
detected at baseline with an NGS read frequency > 15%.

Emerging genetic variation: a genetic variation (amino acid substitution, insertion or 
deletion) that is absent, ie, with a NGS read frequency < 3%, at baseline but detected with a 
NGS read frequency > 15% at a later post-baseline time point.

Enriched genetic variation: a genetic variation (amino acid substitution, insertion or 
deletion) detected at baseline with a NGS read frequency ≥3% and <15%, and with an increase 
in NGS read frequency of at least 15% post-baseline.

Genetic variation profile: a specific genetic variation or combination of genetic variations at 
one or more time points.

RSV F-gene amino acid positions of interest: 

Long list of 24 RSV 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.
Analysis Time Points 
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 
study treatment phase with sequencing data available. In case no On-Treatment assessment is 
available, the first assessment during Follow-Up is selected instead.

Any post-baseline time point in the study with sequencing data available
Table 18 presents the list of virology parameters that will be reported in the patient profiles. 


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Table 18:
Virology parameters 
Variables
List
Indicating genetic variations at the 24 RSV F protein positions with enriched/emerging genetic 
variation flag


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8.
SUPPORTING DOCUMENTATION
8.1.
Appendix 1 List of Abbreviations
AE
adverse event
ALC
Absolute lymphocyte count
AUC
Area under the curve
BMI
body mass index
CAD
Coronary Artery Disease
CHF
Congestive Heart Failure
CKD
Chronic Kidney Disease
CMH
Cochran-Mantel-Haenszel
COPD
Chronic Obstructive Pulmonary Disease
CSR
Clinical study report
DMID
Division of Microbiology and Infectious Diseases
EAC
Endpoint Adjudication Committee
ECG
electrocardiogram
eCRF
electronic case report form
ePRO
electronic Patient-Reported Outcome
EQ-5D
EuroQol 5-Dimension
EQ-5D-5L
5-level EuroQol 5-Dimension
GVHD
graft-versus-host disease
HCP
Health care professional
HRQOL
health-related quality of life
HSCT
Hematopoietic Stem Cell Transplant
IA
Interim Analysis
ICF
Informed Consent Form
ICU
Intensive Care Unit
IDMC
Independent Data Monitoring Committee
IVIG
intravenous immunoglobulin
IWRS
interactive web response system
LLOQ
lower limit of quantification
LRTC
Lower Respiratory Tract Complication
LRTD
Lower Respiratory Tract Disease
LRTI
Lower Respiratory Tract Infection
LTFU
Long-term follow-up
MRU
medical resource utilization
NGS
next-generation sequencing
PD
pharmacodynamic(s)
PGIC
Patient Global Impression of Change
PGIH
Patient Global Impression of Health
PGIS
Patient Global Impression of Severity
PK
pharmacokinetic(s)
qRT-PCR
quantitative reverse transcription polymerase chain reaction
RiiQ
Respiratory Infection Intensity and Impact Questionnaire
RSV
Respiratory Syncytial Virus
SAE
serious adverse event
SAP
Statistical Analysis Plan
SARS-CoV-2
Severe acute respiratory syndrome coronavirus 2
SBP
Systolic Blood Pressure
SOC
Standard-of-care
SpO2
Peripheral capillary oxygen saturation
UN
United Nations
URTD
Upper Respiratory Tract Disease
URTI
Upper Respiratory Tract Infection
VL
Viral load
WHO-DD
World Health Organization Drug Dictionary


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8.2.
Appendix 2 DMID Toxicity Tables
DIVISION OF MICROBIOLOGY AND INFECTIOUS DISEASES (DMID) ADULT 
TOXICITY TABLE – NOVEMBER 2007
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 Extreme limitation in activity, significant assistance 
required; significant medical intervention/therapy required, hospitalization or 
hospice care probable
SERIOUS OR LIFE-THREATENING AEs
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 World Health Organization [WHO]) have been adapted for use by the 
Division of Microbiology and Infectious Diseases (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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HEMATOLOGY
Grade 1
Grade 2
Grade 3
Grade 4
Hemoglobin
9.5 - 10.5 gm/dL
8.0 - 9.4gm/dL
6.5 - 7.9 gm/dL
< 6.5 gm/dL
Absolute Neutrophil Count
1,000-1,500/ mm3
750-999/ mm3
500-749/ mm3
<500/ mm3
Platelets
75,000-
99,999/ mm3
50,000-
74,999/ mm3
20,000-49,999/ mm3
<20,000/ mm3
WBCs
11,000-13,000/
mm3
13,000-
15,000 / mm3
15,000-
30,000/ mm3
>30,000 or
<1,000 / mm3
% Polymorphonuclear
Leucocytes + Band Cells
> 80%
90 – 95%
>95%
----------
Abnormal Fibrinogen
Low:
100-200 mg/dL
High:
400-600 mg/dL
Low:
<100 mg/dL
High:
>600 mg/dL
Low:
< 50 mg/dL
----------
Fibrinogen
associated with gross 
bleeding or with 
disseminated 
coagulation
Fibrin Split Product
20-40 mcg/ mL
41-50 mcg/ mL
51-60 mcg/ mL
> 60 mcg/ mL
Prothrombin Time (PT)
1.01 - 1.25 x ULN
1.26-1.5 x ULN
1.51 -3.0 x ULN
>3 x ULN
Activated Partial 
Thromboplastin (APPT)
1.01 -1.66 x ULN
1.67 - 2.33 x ULN
2.34 - 3 x ULN
> 3 x ULN
Methemoglobin
5.0 - 9.9 %
10.0 - 14.9 %
15.0 - 19.9%
> 20.0 %


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CHEMISTRIES
Grade 1
Grade 2
Grade 3
Grade 4
Hyponatremia
130-135 mEq/ L
123-129 mEq/ L
116-122 mEq/ L
< 116 mEq/ L or abnormal sodium 
with mental
status changes or seizures
Hypernatremia
146-150 mEq/ L
151-157 mEq/ L
158-165 mEq/ L
> 165 mEq/ L or abnormal sodium 
with mental
status changes or seizures
Hypokalemia
3.0 - 3.4 mEq/ L
2.5 - 2.9 mEq/ L
2.0 - 2.4 mEq/ L or 
intensive replacement 
therapy or 
hospitalization 
required
< 2.0 mEq/ L or abnormal 
potassium with
paresis, ileus or life-threatening 
arrhythmia
Hyperkalemia
5.6 - 6.0 mEq/ L
6.1 - 6.5 mEq/ L
6.6 - 7.0 mEq/l
> 7.0 mEq/ L or abnormal
potassium with life-threatening 
arrhythmia
Hypoglycemia
55-64 mg/dL
40-54 mg/dL
30-39 mg/dL
<30 mg/dL or abnormal glucose 
with mental
status changes or coma
Hyperglycemia
(nonfasting and no 
prior diabetes)
116 - 160 mg/dL 161- 250 mg/d L
251 - 500 mg/dL
> 500 mg/dL or abnormal glucose 
with ketoacidosis or seizures
Hypocalcemia
(corrected for 
albumin)
8.4 - 7.8 mg/dL
7.7 - 7.0 mg/dL
6.9 - 6.1 mg/dL
< 6.1 mg/dL or abnormal
calcium with life-threatening 
arrhythmia or tetany


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CHEMISTRIES (continued)
Grade 1
Grade 2
Grade 3
Grade 4
Hypercalcemia (correct for 
albumin)
10.6 - 11.5 mg/dL
11.6 - 12.5
mg/d L
12.6 - 13.5 mg/dL
> 13.5 mg/dL or abnormal 
calcium with life-
threatening arrhythmia
Hypomagnesemia
1.4 - 1.2 mEq/ L
1.1 - 0.9 mEq/ L
0.8 - 0.6 mEq/ L
< 0.6 mEq/ L or abnormal 
magnesium with life-
threatening arrhythmia
Hypophosphatemia
2.0 - 2.4 mg/dL
1.5 -1.9 mg/dL or
replacement Rx 
required
1.0 -1.4 mg/dL 
intensive therapy or 
hospitalization 
required
< 1.0 mg/dL or abnormal
phosphate with life-
threatening arrhythmia
Hyperbilirubinemia (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
Hyperbilirubinemia (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
BUN
1.25 - 2.5 x ULN
2.6 - 5 x ULN
5.1 - 10 x ULN
> 10 x ULN
Hyperuricemia (uric acid)
7.5 – 10.0 mg/dL
10.1 – 12.0 
mg/dL
12.1 – 15.0 mg/d L
>15.0 mg/d L
Creatinine
1.1 - 1.5 x ULN
1.6 - 3.0 x ULN
3.1 - 6 x ULN
>6 x ULN or dialysis 
required
ENZYMES
Grade 1
Grade 2
Grade 3
Grade 4
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
Alkaline Phosphatase
1.1 - <2.0 x ULN
2.0 – <3.0 x ULN
3.0 – 8.0 x ULN
> 8 x ULN
Amylase
1.1 - 1.5 x ULN
1.6 - 2.0 x ULN
2.1 - 5.0 x ULN
> 5.1 x ULN
Lipase
1.1 - 1.5 x ULN
1.6 - 2.0 x ULN
2.1 - 5.0 x ULN
> 5.1 x ULN


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URINALYSIS
Grade 1
Grade 2
Grade 3
Grade 4
Proteinuria
1+
or
200 mg - 1 gm 
loss/day
2-3+
or
1- 2 gm loss/day
4+
or
2-3.5 gm loss/day
nephrotic syndrome
or
>3.5 gm loss/day
Hematuria
microscopic only
<10 rbc/hpf
gross, no clots
>10 rbc/hpf
gross, with or without 
clots, OR RBC casts
obstructive or 
required
transfusion
CARDIOVASCULAR
Grade 1
Grade 2
Grade 3
Grade 4
Cardiac Rhythm
asymptomatic, 
transient signs, no
Rx required
recurrent/persistent; 
symptomatic Rx 
required
unstable 
dysrhythmia;
hospitalization
and treatment 
required
Hypertension
transient increase
>20 mm/ Hg; no 
treatment
recurrent, chronic 
increase
> 20mm/ Hg
/treatment required
acute treatment 
required; outpatient 
treatment or 
hospitalization
possible
end organ damage or 
hospitalization 
required
Hypotension
transient orthostatic
hypotension with 
heart rate increased 
by <20 beat/min or 
decreased by <10 
mm Hg systolic BP, 
No treatment 
required
symptoms due to 
orthostatic 
hypotension or BP 
decreased by <20 
mm Hg systolic; 
correctable with oral 
flu id treatment
requires IV fluids; no 
hospitalization 
required
mean arterial 
pressure
<60mm/ Hg or end 
organ damage or 
shock; requires 
hospitalization and 
vasopressor treatment
Pericarditis
minimal effusion
mild/ moderate 
asymptomatic 
effusion, no 
treatment
symptomatic 
effusion; pain; EKG 
changes
tamponade; 
pericardiocentesis or 
surgery required
Hemorrhage, Blood Loss
microscopic/occult
mild, no transfusion
gross blood loss;
1-2 units transfused
massive blood loss; 
>3 units transfused


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RESPIRATORY
Grade 1
Grade 2
Grade 3
Grade 4
Cough
transient- no 
treatment
persistent cough; 
treatment responsive
Paroxysmal cough; 
uncontrolled with 
treatment
--------------------
Bronchospasm, Acute
transient; no 
treatment;
70% - 80% FEV1
of peak flow
requires
treatment; normalizes 
with bronchodilator; 
FEV1 50% -
70%
(of peak flow)
no normalization 
with bronchodilator; 
FEV1 25% - 50%
of peak flow; or
retractions present
cyanosis: FEV1
<25%
of peak flow or 
intubation necessary
Dyspnea
dyspnea on exertion dyspnea with normal 
activity
dyspnea at rest
dyspnea requiring 
oxygen therapy
GASTROINTESTINAL
Grade 1
Grade 2
Grade 3
Grade 4
Nausea
mild or transient; 
maintains
reasonable intake
moderate discomfort; 
intake decreased
significantly; some 
activity limited
no significant intake; 
requires IV flu ids
hospitalization 
required;
Vomiting
1 episode in 24 hours
2-5 episodes in
24 hours
>6 episodes in 
24 hours or needing 
IV fluids
physiologic 
consequences 
requiring
hospitalization or 
requiring parenteral 
nutrition
Constipation
requiring stool
softener or dietary 
modification
requiring
laxatives
obstipation
requiring manual 
evacuation or enema
obstruction or
toxic megacolon
Diarrhea
mild or transient; 3-4 
loose
stools/day or mild
diarrhea last <1 week
moderate or 
persistent; 5-7 loose 
stools/day or diarrhea
lasting >1 week
>7 loose stools/day
or bloody diarrhea; or 
orthostatic 
hypotension or 
electrolyte imbalance 
or >2L IV fluids 
required
hypotensive shock or 
physiologic 
consequences 
requiring
hospitalization
Oral Discomfort/Dysphagia mild discomfort; no 
difficulty
swallowing
some limits on 
eating/drinking
eating/talking very 
limited; unable to 
swallow solid foods
unable to drink flu 
ids; requires IV fluids


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Status: Approved, Date: 28 December 2021
NEUROLOGICAL
Grade 1
Grade 2
Grade 3
Grade 4
Neuro-Cerebellar
slight incoordination 
dysdiadochokinesis
intention tremor, 
dysmetria,
slurred speech; 
nystagmus
locomotor ataxia
incapacitated
Psychiatric
mild anxiety or 
depression
moderate anxiety or 
depression; therapy 
required; change in 
normal routine
severe mood changes 
requiring therapy; or 
suicidal ideation; or 
aggressive ideation
acute psychosis 
requiring 
hospitalization; or 
suicidal 
gesture/attempt or 
hallucinations
Muscle Strength
subjective weakness 
no objective
symptoms/ signs
mild objective
signs/symptoms no 
decrease in function
objective weakness 
function limited
paralysis
Paresthesia (burning, 
tingling, etc.)
mild discomfort; no 
treatment required
moderate discomfort;
non-narcotic 
analgesia required
severe discomfort; or 
narcotic analgesia 
required with 
symptomatic 
improvement
incapacitating; or not 
responsive to narcotic 
analgesia
Neuro-sensory
mild impairment in 
sensation
(decreased
sensation, eg, 
vibratory, pinprick, 
hot/cold in great toes) 
in focal area or 
symmetrical
distribution; or 
change in taste, 
smell, vision and/or 
hearing
moderate
impairment (mod 
decreased sensation, 
eg, vibratory, 
pinprick, hot/cold to 
ankles) and/or joint 
position or mild
impairment that is 
not
symmetrical
severe impairment 
(decreased or loss of 
sensation to knees or 
wrists) or loss of 
sensation of at least 
mod degree in 
multiple
different body areas 
(ie, upper and lower
extremities)
sensory loss involves 
limbs and trunk; 
paralysis; or seizures


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Statistical Analysis Plan 53718678RSV2005
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Status: Approved, Date: 28 December 2021
MUSCULOSKELETAL
Grade 1
Grade 2
Grade 3
Grade 4
Arthralgia (joint pain)
mild pain not 
interfering with 
function
moderate pain, 
analgesics and/or pain 
interfering with 
function but not with 
activities of daily 
living
severe pain; pain 
and/or analgesics 
interfering with 
activities of daily 
living
disabling pain
Arthritis
mild pain with
inflammation,
erythema or joint
swelling – but not
interfering with
function
moderate pain with
inflammation,
erythema or joint 
swelling – interfering 
with function, but not 
with activities of
daily living
severe pain with
inflammation,
erythema or joint
swelling –and
interfering with
activities of daily
living
permanent and/or 
disabling joint
destruction
Myalgia
Myalgia with no 
limitation of activity
muscle
tenderness (at other 
than injection site) or 
with moderate
impairment of 
activity
severe muscle
tenderness with
marked impairment 
of activity
frank
myonecrosis
SKIN
Grade 1
Grade 2
Grade 3
Grade 4
Mucocutaneous
erythema; pruritus
diffuse, 
maculopapular rash, 
dry desquamation
vesiculation or
moist desquamation 
or ulceration
exfoliative
dermatitis, mucous 
membrane
involvement or 
erythema,
multiforme or 
suspected
Stevens-Johnson
or necrosis requiring 
surgery
Induration
<15mm
15-30 mm
>30mm
Erythema
<15mm
15-30 mm
>30mm
Edema
<15mm
15-30 mm
>30mm
Rash at Injection Site
<15mm
15-30 mm
>30mm
Pruritus
slight itching at 
injection site
moderate itching at 
injection extremity
itching over entire 
body


JNJ-53718678
Statistical Analysis Plan 53718678RSV2005
CONFIDENTIAL – FOIA Exemptions Apply in U.S.
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Status: Approved, Date: 28 December 2021
SYSTEMIC
Grade 1
Grade 2
Grade 3
Grade 4
Allergic Reaction
pruritus without rash
localized urticaria
generalized urticaria; 
angioedema
anaphylaxis
Headache
mild, no treatment 
required
transient, moderate; 
treatment required
severe; responds to 
initial narcotic 
therapy
intractable; requires 
repeated narcotic 
therapy
Fever: oral
37.7 - 38.5 C or 
100.0 - 101.5 F
38.6 - 39.5 C or 
101.6 - 102.9 F
39.6 - 40.5 C or 103 -
105 F
>40 C or
>105 F
Fatigue
normal activity 
reduced < 48 hours
normal activity 
decreased 25-
50% > 48 hours
normal activity
decreased > 50%
can’t work
unable to care for self


JNJ-53718678
Statistical Analysis Plan 53718678RSV2005
CONFIDENTIAL – FOIA Exemptions Apply in U.S.
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Status: Approved, Date: 28 December 2021
8.3.
Appendix 3 Respiratory Infection Intensity and Impact Questionnaire 
(RiiQ™)
Respiratory Infection Intensity and Impact Questionnaire (RiiQ™)a Symptom Scale
Please read each of the following questions and select the answer thinking about when you felt 
the worst in the past 24 hours.
1.
During the past 24 hours, have you had the following symptoms?
None
Mild
Moderate
Severe
a. Cough




b. Sore throat




c. Headache




d. Nasal congestion




e. Feeling feverish




f. Body aches and pains




g. Fatigue (tiredness)




h. Neck pain




i.
Interrupted sleep




j. Wheezing




k. Coughing up phlegm 
(sputum)




l.
Short of breath 




m. Loss of appetite 




                                                
a Influenza intensity and impact questionnaire (Flu-iiQ
TM) ©RH Osborne (2006). No part of the Flu-iiQ
TM may be copied or 
reproduced in any form without written permission from the authors: measuredsolutions@bigpond.com
(English – administration once daily)
Adapted with permission of RH Osborne.


JNJ-53718678
Statistical Analysis Plan 53718678RSV2005
CONFIDENTIAL – FOIA Exemptions Apply in U.S.
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Status: Approved, Date: 28 December 2021
9.
REFERENCES
Spiessens B, Debois, M. Adjusted significance levels for subgroup analyses in clinical trials. Contemp Clin Trials 
2010;31:647-656.